Increase In Tissue Resistance Research Articles

Identification of the serum metabolomic profile for acute ischemic preconditioning in athletes.

In recent years, ischemic preconditioning (IPC) has emerged as an effective strategy to increase tissue resistance against long-term ischemic damage and has been increasingly integrated into exercise regimens. However, further research is needed to explore the impact of IPC-mediated metabolic alterations from an exercise standpoint to conduct a comprehensive exploration of metabolic alterations and their exercise-related mechanisms during acute IPC. Nontarget metabolomics was performed on blood samples obtained from 8 male athletes both before and after IPC. The studies included the identification of differentially abundant metabolites, analysis of receiver operating characteristic (ROC) curves, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis for differentially abundant metabolites, and metabolite set enrichment analysis (MSEA). Nineteen differentially abundant metabolites were identified, with increasing levels of five metabolites, such as O-desmethyltramadol and D-gluconate, whereas 14 metabolites, including 9-hydroxy-10e, 12z-octadecadienoic acid (9-HODE), tetradione, 2-hexenal, (2,4-dichlorophenoxy)acetic acid (2,4-D), and phosphatidylserine (PS), decreased. ROC curve analysis revealed an AUC of 0.9375 for D-gluconate. Both KEGG enrichment analysis and MSEA revealed enrichment in the pentose phosphate pathway (PPP). This study revealed that PPP, D-gluconate, O-desmethyltramadol, and D-2-aminobutyric acid could be upregulated within 5 min after acute IPC, whereas 2,4-D, PS, 9-HODE, 2-hexenal, and tetradinone could be downregulated. These identified metabolites show promise for improving physical functional status and could be harnessed to enhance athletic performance.

Reverberating Action Potentials and the Emergence of Short Circuit Propagation in Gliosis

This study explores the intriguing phenomenon of action potentials reverberating and propagating in high-resistance tissues, such as gliosis, leading to the emergence of short circuits within the brain. Gliosis, characterized by increased tissue resistance, presents a unique environment for electrical signals. My research investigates the possible mechanisms behind these reverberations and their role in the creation of self-empowering short circuits that can potentially affect the entire brain's functionality. Understanding these processes may have significant implications for the treatment and management of neurological disorders associated with gliosis and abnormal electrical activity in the brain.

ИСПОЛЬЗОВАНИЕ ПРЕПАРАТОВ ГИАЛУРОНОВОЙ КИСЛОТЫ ДЛЯ СТИМУЛЯЦИИ РЕГЕНЕРАЦИИ ПРИ РАЗВИТИИ ТРОФИЧЕСКИХ НАРУШЕНИЙ У ПАЦИЕНТОВ С ХРОНИЧЕСКИМИ ОБЛИТЕРИРУЮЩИМИ ЗАБОЛЕВАНИЯМИ АРТЕРИЙ НИЖНИХ КОНЕЧНОСТЕЙ

Trophic ulcers as a result of chronic vascular diseases of the lower extremities are an urgent and complex task of surgical treatment. Local treatment of the ulcer is an important role after revascularization. Hyaluronic acid (HA) preparations are among the most promising in this regard. HA provides increased tissue resistance to ischemia, suppression of the inflammatory response, stimulation and acceleration of tissue regeneration. HA ensures the formation of a temporary matrix in a fresh wound, facilitates the diffusion of nutrients and cleans the wound from products of cellular metabolism. Secondly, it takes an active part in the proliferation and migration of keratinocytes, which make up the bulk of the epidermis. Due to the insignificant use of HA in local therapy of trophic disorders of chronic vascular diseases of the lower extremities, it is interesting to further study the effect as part of complex and pathogenetically oriented treatment in patients of this group.

Assessment of Antihypoxic Activity of S-analoges of Dihydropyrimidin-2-ones and Their Condensed Derivatives

Introduction. Antioxydant activity, membrane stabilizing and cytoprotective effect of dihydropyrimidin analoges are widely described in various literary sources. One of the importantant mechanisms of action of antioxidants is their antihypoxic activity. It is the ability to increase tissue resistance to hypoxia. The search for drugs to increase the body's resistance under hypoxic conditions is an actual task in experimental and clinical pharmacology.Aim. Study of the antihypoxic activity of new S-analogs of dihydropyrimidin-2-ones and their condensed derivatives in various models of hypoxia.Materials and methods. 13 compounds S-analogs of dihydropyrimidin-2-ones and their condensed derivatives are objects of research. Their structure has been confirmed by spectroscopy methods. The antihypoxic activity was carried out by recommended methods for preclinical study of new pharmacological substances.Results and discussion. This paper presents the results of testing the obtained compounds of different structures on three models of hypoxia. The activity of a number of condensed tricyclic derivatives of dihydropyrimidine-2-thiones was studied in more detail using a model of acute normobaric hypoxia with hypercapnia.Conclusion. The compounds did not demonstrate high antihypoxic activity; some «structure-property» patterns were revealed.

Hyperprolactinemia and insulin resistance.

Hyperprolactinaemia is the most common dysfunction of the hypothalamic-pituitary axis and occurs more commonly in women. The prevalence of hyperprolactinaemia ranges from 0.4% in the general adult population to as high as 9-17% in women with reproductive diseases. It is accompanied by the phenomenon of insulin resistance (IR), which is also a significant clinical problem nowadays. The prevalence of IR is increasing, particularly in developing countries and in younger populations, with estimates of prevalence ranging from 20 to 40% in different populations. The aim of our review is to summarize recent data on the possible association between IR and hyperprolactinaemia. This review is based on an electronic search of the literature in the PubMed database published from 2000 to 2022 using combinations of the following keywords: IR, hyperprolactinemia or IR and hyperprolactinemia. The references included in previously published review articles were also checked, and any relevant papers were also included. Numerous scientific studies have shown a relationship between IR and hyperprolactinaemia. Increased plasma prolactin (PRL) levels are often associated with an increase in tissue resistance to insulin. There are many scientific theories explaining the probable mechanisms of this phenomenon. One is the finding that glucose and PRL act synergistically in inducing the transcription of insulin genes. It is also suggested that PRL may act as a regulator of insulin sensitivity and metabolic homeostasis in adipose tissue. The topic of the mutual correlation of hyperprolactinaemia and IR is important, and it certainly requires further research and observation.

Bile acid-based advanced drug delivery systems, bilosomes and micelles as novel carriers for therapeutics.

Diabetes mellitus affects almost half a billion patients worldwide and results from either destruction of β-cells responsible for insulin secretion or increased tissue resistance to insulin stimulation and the reduction of glycemic control. Novel drug delivery systems can improve treatment efficacy in diabetic patients. The low aqueous solubility of most oral antidiabetic drugs decreases drug bioavailability; therefore, there is a demand for the use of novel methods to overcome this issue. The application of bile acids mixed micelles and bilosomes can provide an enhancement in drug efficacy. Bile acids are amphiphilic steroidal molecules that contain a saturated tetracyclic hydrocarbon cyclopentanoperhydrophenanthrene ring, and consist of three 6-membered rings and a 5-membered ring, a short aliphatic side chain, and a tough steroid nucleus. This review offers a comprehensive and informative data focusing on the great potential of bile acid, their salts, and their derivatives for the development of new antidiabetic drug delivery system.

Second Attempt of Guided Tissue Regeneration on a Previous Successfully Grafted Site with Periodontal Breakdown-A 5-Year Follow-up.

Guided tissue regeneration (GTR) has been proven to promote attachment and regeneration of periodontal tissue. However, there is a 20 to 40% incidence of attachment loss on regenerated attachments reported in the literature. To my knowledge, this is the first case report on a second attempt in GTR on a previous successful grafted site with clinical attachment loss. A healthy 17-year-old Chinese male patient had GTR performed with xenograft particles and bovine resorbable membrane on his root-canal treated, fused upper right lateral incisor and upper right canine (#12-#13) in 2007. Probing depth on the mid-palatal region of #12-#13 was reduced to 4 mm and maintained for the next 4 years. But in the fifth year, probing depth increased to 11 mm with no endodontic symptoms, and a second attempt of GTR using the same materials was carried out. The probing depth at the surgical site was reduced to 4 mm and successfully maintained for another 5 years. Irregular maintenance and the presence of plaque retentive factor could have caused the clinical attachment loss on #12-#13. This case shows it is possible to attempt GTR on a previous successfully grafted site. GTR did not increase tissue resistance against periodontal breakdown. Hence, proper maintenance planning for GTR sites is important to prevent periodontal breakdown.

Metabolic therapy in cardiology from the perspective of evidence-based medicine

Over the past few decades, various applications of the metabolic drugs have been extensively tested. Most of them affect oxygen-dependent processes, improving cellular metabolism and increasing tissue resistance to hypoxia and ischemia. The most promising candidates include components of the respiratory chain, purine nucleosides, and creatine phosphate which affect glucose oxidation and fatty acid metabolism in the Krebs cycle. This review critically evaluates the most popular drugs of this group (adenosine triphosphate, adenosine-5-monophosphate, creatine phosphate, coenzyme Q10, cytochrome C, adenosine, glucose-insulin-potassium solution, L-carnitine, mildronate, and trimetazidine), which are widely represented on the pharmaceutical market. Of all metabolic drugs, only trimetazidine was included in the European and Russian recommendations for the second-line treatment of stable angina. In most clinical studies, the therapeutic efficacy of metabolic drugs has been evaluated using the surrogate endpoints. Despite being actively advertised and widely used in the clinical practice, metabolic drugs currently do not have a convincing evidence base for affecting prognosis (mortality and/or major adverse cardiovascular events). Further studies in large-scale randomised trials are needed to confirm the beneficial effects of the metabolic drugs in cardiovascular medicine.

Lrp1 Regulation of Pulmonary Function. Follow-Up of Human GWAS in Mice.

Human genome-wide association studies (GWASs) have identified more than 270 loci associated with pulmonary function; however, follow-up studies to determine causal genes at these loci are few. SNPs in low-density lipoprotein receptor-related protein 1 (LRP1) are associated with human pulmonary function in GWASs. Using murine models, we investigated the effect of genetic disruption of the Lrp1 gene in smooth muscle cells on pulmonary function in naive animals and after exposure to bacterial LPS or house dust mite extract. Disruption of Lrp1 in smooth muscle cells leads to an increase in tissue resistance, elastance, and tissue elastance at baseline. Furthermore, disruption of Lrp1 in smooth muscle increases airway responsiveness as measured by increased total lung resistance and airway resistance after methacholine. Immune cell counts in BAL fluid were increased in animals with Lrp1 disruption. The difference in airway responsiveness by genotype observed in naive animals was not observed after LPS or house dust mite extract exposure. To further explore the mechanisms contributing to changes in pulmonary function, we identified several ligands dysregulated with Lrp1 disruption in smooth muscle cells. These data suggest that dysregulation of LRP1 in smooth muscle cells affects baseline pulmonary function and airway responsiveness and helps establish LRP1 as the causal gene at this GWAS locus.

TLR5 agonist entolimod reduces the adverse toxicity of TNF while preserving its antitumor effects.

Tumor necrosis factor alpha (TNF) is capable of inducing regression of solid tumors. However, TNF released in response to Toll-like receptor 4 (TLR4) activation by bacterial lipopolysaccharide (LPS) is the key mediator of cytokine storm and septic shock that can cause severe tissue damage limiting anticancer applications of this cytokine. In our previous studies, we demonstrated that activation of another Toll-like receptor, TLR5, could protect from tissue damage caused by a variety of stresses including radiation, chemotherapy, Fas-activating antibody and ischemia-reperfusion. In this study, we tested whether entolimod could counteract TNF-induced toxicity in mouse models. We found that entolimod pretreatment effectively protects livers and lungs from LPS- and TNF-induced toxicity and prevents mortality caused by combining either of these agents with the sensitizer, D-galactosamine. While LPS and TNF induced significant activation of apoptotic caspase 3/7, lipid tissue peroxidation and serum ALT accumulation in mice without entolimod treatment, these indicators of toxicity were reduced by entolimod pretreatment to the levels of untreated control mice. Entolimod was effective when injected 0.5-48 hours prior to, but not when injected simultaneously or after LPS or TNF. Using chimeric mice with hematopoiesis differing in its TLR5 status from the rest of tissues, we showed that this protective activity was dependent on TLR5 expression by non-hematopoietic cells. Gene expression analysis identified multiple genes upregulated by entolimod in the liver and cultured hepatocytes as possible mediators of its protective activity. Entolimod did not interfere with the antitumor activity of TNF in mouse hepatocellular and colorectal tumor models. These results support further development of TLR5 agonists to increase tissue resistance to cytotoxic cytokines, reduce the risk of septic shock and enable safe systemic application of TNF as an anticancer therapy.

MiR-21-KO Alleviates Alveolar Structural Remodeling and Inflammatory Signaling in Acute Lung Injury.

Acute lung injury (ALI) is characterized by enhanced permeability of the air–blood barrier, pulmonary edema, and hypoxemia. MicroRNA-21 (miR-21) was shown to be involved in pulmonary remodeling and the pathology of ALI, and we hypothesized that miR-21 knock-out (KO) reduces injury and remodeling in ALI. ALI was induced in miR-21 KO and C57BL/6N (wildtype, WT) mice by an intranasal administration of 75 µg lipopolysaccharide (LPS) in saline (n = 10 per group). The control mice received saline alone (n = 7 per group). After 24 h, lung function was measured. The lungs were then excised for proteomics, cytokine, and stereological analysis to address inflammatory signaling and structural damage. LPS exposure induced ALI in both strains, however, only WT mice showed increased tissue resistance and septal thickening upon LPS treatment. Septal alterations due to LPS exposure in WT mice consisted of an increase in extracellular matrix (ECM), including collagen fibrils, elastic fibers, and amorphous ECM. Proteomics analysis revealed that the inflammatory response was dampened in miR-21 KO mice with reduced platelet and neutrophil activation compared with WT mice. The WT mice showed more functional and structural changes and inflammatory signaling in ALI than miR-21 KO mice, confirming the hypothesis that miR-21 KO reduces the development of pathological changes in ALI.

Relationship of Circulating Tumor Necrosis Factor Alpha (TNF-α) and Insulin Secretion and Resistance in Euglycaemic Dogs

Background: Insulin resistance is a state that is characterized with reduced sensitivity of peripheral tissues to insulin. It can be related with increased level of tumor necrosis factor alpha (TNF-α) in dogs. Insulin resistance can be evaluated by homeostasis model assessment (HOMA-IR, HOMA-β). The aim of this study was to determine correlation of circulating TNF-α level with insulin production and insulin resistance indexes in euglycaemic dogs. Materials, Methods & Results: Seventydogs of normal body score were included in this study. After blood sampling levels of glucose, insulin and TNF-α were determined and indexes HOMA-IR and HOMA-β were calculated. Three groups in accordance to TNF-α levels were formed: the first-TNF-α 0-2.0 pg/mL, the second-TNF-α below median (2.1-17.0 pg/mL) and the third-TNF-α above median (17.1-51.8 pg/mL). Differences in insulin and glucose levels, HOMA-IR and HOMA-β were determined in all three groups. ANOVA and posthock LSD analyses were used. Correlation between HOMA-IR and HOMA-β was determined. Linear regression between HOMA-β/HOMA-IR ratio and glucose concentration was calculated. SPSS statistical program was used (IBM). Highest insulin level was detected in the second group and the lowest was detected in the third group. The lowest glucose level was detected in the first group. The highest value of HOMA-β index was noted in the first group and it decreases with TNF-α increase. The highest HOMA-IR value was detected in the second group and the lowest was in the third group. Positive correlation was noted between HOMA-IR and HOMA-β. Significant linear correlation was noted between glucose levels in function of HOMA-β/HOMA-IR (R2= 0.51-0.78, P = 0.0007). The first group showed the minor change of glucose level (b= 0.29 mmol/L). In the third group the greatest change of glucose level in function of HOMA-β/HOMA-IR was noted (b= 0.52 mmol/L). In the third group the highest increase of glucose level followed by decrease in HOMA-β/HOMA-IR ratio was noted. Discussion: Increase of TNF-α followed by increase of insulin was noted in the second group. That indicates reduced insulin action and compensatory increase in his concentrations in order to achieve the same effect. TNF-α induces reduction in expression of glucose transporter 4 that is insulin-regulating hormone. Serine phosphorylation of insulin receptor substrate-1 that is induced by TNF-α causes inhibition of insulin receptors. These actions cause insulin resistance and compensatory increase in insulin secretion. Increased tissue resistance is reflected in increased HOMA-IR index which is directly associated with insulin and glucose level. Increase of insulin value and HOMA-IR index were noted in second group. This indicates the influence of TNF-α on insulin resistance. The lowest insulin level was noted in the third group of dogs. Decrease in production and secretion leads to reduction in circulating insulin and can be evaluated by HOMA-β index. The highest value of this index was noted in first group and decreases with TNF-α increase. This can be related with apoptotic effect that TNF-α has on beta- pancreatic cells. Increase of HOMA-β index causes increase of HOMA-IR. This is indication of increased peripheral resistance. Compensatory mechanism for that state is increased insulin secretion. Glucose level will increase more during increase of HOMA-IR and decrease of HOMA-β. This indicates that TNF-α regulates glucose level directly and explains differences in glucose concentrations in dogs with different concentrations of TNF-α showed. Values of insulin resistance indexes, glucose and insulin were affected by circulating concentration of TNF-α. The most unfavorable change in glucose concentration based on insulin production and tissue resistance was founded in dogs with the highest circulating TNF-α concentration in blood.

Pharmacology for preconditioning in clinical studies

The main purpose of this study was to review and introduce the physical and pharmacological stimuli and their potential effects with respect to the pharmacological impacts of preconditioning (PC) in cardiovascular and ischemia clinical studies. In this review, data were retrieved from the Information Sciences Institute, PubMed, Scientific Information Database, and Scopus databases, with a further emphasis on the articles published in the last 10 years. Key words used for this purpose included ischemia, reperfusion, heart, infarction, and preconditioning. The eligible and relevant clinical trials on pharmacological stimuli were included in this review. The relevant articles, all have been published from 1983-2016. Today, many studies are being performed to implement and apply PC in clinical human cases, in order to minimize the ischemia reperfusion (IR)-induced complication in certain conditions such as myocardial infarction and heart surgery. The Drugs used in the studies are mostly common agents such as nitroglycerin, oxygen, adenosine, etc., and are among commonly used drugs in cardiovascular diseases, which often increase tissue resistance, and conveniently used in the patient's bedside and are accepted by the patients. Using a physical or pharmacological stimulus before prolonged ischemia increases tissue resistance by activating intracellular mechanisms, thereby reducing the IR-induced, cardiac damage and erythema. © RJPT All right reserved.

Voluntary running protects against neuromuscular dysfunction following hindlimb ischemia-reperfusion in mice.

Ischemia-reperfusion (IR) due to temporary restriction of blood flow causes tissue/organ damages under various disease conditions, including stroke, myocardial infarction, trauma, and orthopedic surgery. In the limbs, IR injury to motor nerves and muscle fibers causes reduced mobility and quality of life. Endurance exercise training has been shown to increase tissue resistance to numerous pathological insults. To elucidate the impact of endurance exercise training on IR injury in skeletal muscle, sedentary and exercise-trained mice (5 wk of voluntary running) were subjected to ischemia by unilateral application of a rubber band tourniquet above the femur for 1 h, followed by reperfusion. IR caused significant muscle injury and denervation at neuromuscular junction (NMJ) as early as 3 h after tourniquet release as well as depressed muscle strength and neuromuscular transmission in sedentary mice. Despite similar degrees of muscle atrophy and oxidative stress, exercise-trained mice had significantly reduced muscle injury and denervation at NMJ with improved regeneration and functional recovery following IR. Together, these data suggest that endurance exercise training preserves motor nerve and myofiber structure and function from IR injury and promote functional regeneration. NEW & NOTEWORTHY This work provides the first evidence that preemptive voluntary wheel running reduces neuromuscular dysfunction following ischemia-reperfusion injury in skeletal muscle. These findings may alter clinical practices in which a tourniquet is used to modulate blood flow.

Morphological and ultrastructural changes in the placenta of the diabetic pregnant Egyptian women

Diabetes mellitus (DM) is a chronic metabolic disease in which the body fails to produce enough insulin or increased tissue resistance to insulin. The diabetes may have profound effects on placental development and function. This study was designed to detect the placental changes in pregnancy associated with DM comparing these changes with normal placenta. The study was carried out on sixty full-term placentae; divided into three equal groups; control group (group I): placentae of normal pregnancy, uncontrolled diabetes (group II): placentae from pregnant women whose blood glucose is poorly controlled during pregnancy. Controlled diabetes (group III): includes placentae from diabetic women whose blood glucose is controlled during pregnancy. The placentae from group II tend to be heavier and exhibited immaturity of villi, villous edema, fibrosis, excessive syncytial knots formation and infarctions. In addition to, fibrinoid necrosis, increased thickness of vasculosyncytial membrane, syncytial basement membrane, microvillous abnormalities and vascular endothelial changes were demonstrated. The syncytial multivesicular knots were present in placentae of group II. The nuclei within these syncytial knots display condensed chromatin, either dispersed throughout the nucleus or in the form of dense peripheral clumps with and numerous cytoplasmic vacuoles. The syncytial basement membrane showed focal areas of increase in its thickness and irregularity. Villous cytotrophoblasts showed increased number and activity in the form of numerous secretory granules, abundant dilated RER, larger distorted mitochondria. Villous vessels showed various degrees of abnormalities in the form of endothelial cell enlargement, folding, thickening and protrusion of their luminal surfaces into vascular lumen making it narrower in caliber. In placentae of group III, most of these abnormalities decreased. In most of placentae of group III, the VSM appeared nearly normal in thickness and showed nearly normal composition of one layer of syncytiotrophoblastic cells, one layer of smooth, regular capillary endothelium and the space between them. Mild microvillous abnormalities were noted in few placentae as they appeared short and blunted with mild decrease in their number per micron. The electron picture of syncytial knots appeared nearly normal containing aggregations of small, condensed hyperchromatic nuclei, minimal vacuoles could be seen in the cytoplasm of syncytial knots. Syncytial basement membrane appeared regular and nearly normal in its thickness and composition coming in direct contact with fetal blood capillaries but mild abnormalities were noted in the basement membrane in few placentae as increased its thickness and deposition of fibers or fibrinoid. Regarding cytotrophoblasts in the terminal villi of placentae with controlled diabetes, these cells appeared nearly normal. They were scattered beneath the syncytium and were active containing mitochondria, rough endoplasmic reticulum, free ribosomes and a large nucleus with fine dispersed chromatin. The vascular ultrastructural pattern in terminal villi of placentae of this group showed no significant abnormalities and was normally distributed in the villous tree. The luminal surface of the vascular endothelium appeared regular smooth in the majority of placentae of this group. The endothelial cells appeared connected to each other with tight junctions. It could be concluded that whether if long-term diabetes is controlled or not, placentae of diabetic mother showed a variety of significant histological structural changes seen more frequently than in the placentae of pregnant women without diabetes.

Sex-Related Differences in Pulmonary Function following 6 Months of Cigarette Exposure: Implications for Sexual Dimorphism in Mild COPD.

Female smokers have increased risk of chronic obstructive pulmonary disease (COPD) compared with male smokers who have a similar history of cigarette smoke exposure. We have shown previously that chronic smoke exposure for 6 months leads to increased airway wall remodeling in female C57BL/6 mice compared with male C57BL/6 mice. These differences, however, were not evident in female ovariectomized mice exposed to cigarette smoke. Herein, we report on the pulmonary function test results from the flexiVent system, which was used to determine the potential functional consequences of the histologic changes observed in these mice. We found that tissue damping (G) was increased in female compared to male or ovariectomized female mice after smoke exposure. At low oscillating frequencies, complex input resistance (Zrs) and impedance (Xrs) of the respiratory system was increased and decreased, respectively, in female but not in male or ovariectomized female mice after smoke exposure. Quasistatic pressure-volume curves revealed a reduction in inspiratory capacity in female mice but not in male or ovariectomized female mice after smoke exposure. The remaining lung function measurements including quasistatic compliance were similar amongst all groups. This is the first study characterizing a sexual dimorphism in respiratory functional properties in a mouse model of COPD. These findings demonstrate that increased airway remodeling in female mice following chronic smoke exposure is associated with increased tissue resistance in the peripheral airways. These data may explain the importance of female sex hormones and the increased risk of airway disease in female smokers.

SU‐G‐TeP3‐09: Proton Minibeam Radiation Therapy Increases Normal Tissue Resistance

Purpose:The dose tolerances of normal tissues continue being the main limitation in radiotherapy. To overcome it, we recently proposed a novel concept: proton minibeam radiation therapy (pMBRT) [1]. It allies the physical advantages of protons with the normal tissue preservation observed when irradiated with submillimetric spatially fractionated beams (minibeam radiation therapy) [2]. The dose distributions are such that the tumor receives a homogeneous dose distribution, while normal tissues benefit from the spatial fractionation of the dose. The objective of our work was to implement this promising technique at a clinical center (Proton therapy center in Orsay) in order to evaluate the potential gain in tissue sparing.Methods:Dose distributions were measured by means of gafchromic films and a PTW microdiamond detector (60019). Once the dosimetry was established, the whole brain of 7 weeks old male Fischer 344 rats was irradiated. Half of the animals received conventional seamless proton irradiation (25 Gy in one fraction). The other rats were irradiated with pMBRT (58 Gy peak dose in one fraction). The average dose deposited in the same targeted volume was in both cases 25 Gy.Results:The first complete set of dosimetric data in such small proton field sizes was obtained [3]. Rats treated with conventional proton irradiation exhibited severe moist desquamation and permanent epilation afterwards. The minibeam group, on the other hand, exhibited no skin damage and no clinical symptoms. MRI imaging and histological analysis are planned at 6 months after irradiation.Conclusion:Our preliminary results indicate that pMBRT leads to an increase in tissue resistance. This can open the door to an efficient treatment of very radioresistant tumours. [1] Prezado et al. Med. Phys. 40, 031712, 1–8 (2013).[2] Prezado et al., Rad. Research. 184, 314‐21 (2015). [3] Peucelle et al., Med. Phys. 42 7108‐13 (2015).

Investigation of the metabolic consequences of impregnating spinach leaves with trehalose and applying a pulsed electric field

The impregnation of leafy vegetables with cryoprotectants using a combination of vacuum impregnation (VI) and pulsed electric fields (PEF) has been proposed by our research group as a method of improving their freezing tolerance and consequently their general quality after thawing. In this study, we have investigated the metabolic consequences of the combination of these unit operations on spinach. The vacuum impregnated spinach leaves showed a drastic decrease in the porosity of the extracellular space. However, at maximum weight gain, randomly located air pockets remained, which may account for oxygen-consuming pathways in the cells being active after VI. The metabolic activity of the impregnated leaves showed a drastic increase that was further enhanced by the application of PEF to the impregnated tissue. Impregnating the leaves with trehalose by VI led to a significant accumulation of trehalose-6-phosphate (T6P), however, this was not further enhanced by PEF. It is suggested that the accumulation of T6P in the leaves may increase metabolic activity, and increase tissue resistance to abiotic stress.

Chronic heart failure modifies respiratory mechanics in rats: a randomized controlled trial.

ABSTRACTObjectiveTo analyze respiratory mechanics and hemodynamic alterations in an experimental model of chronic heart failure (CHF) following myocardial infarction.MethodTwenty-seven male adult Wistar rats were randomized to CHF group (n=12) or Sham group (n=15). Ten weeks after coronary ligation or sham surgery, the animals were anesthetized and submitted to respiratory mechanics and hemodynamic measurements. Pulmonary edema as well as cardiac remodeling were measured.ResultsThe CHF rats showed pulmonary edema 26% higher than the Sham group. The respiratory system compliance (Crs) and the total lung capacity (TLC) were lower (40% and 27%, respectively) in the CHF rats when compared to the Sham group (P<0.01). There was also an increase in tissue resistance (Gti) and elastance (Hti) (28% and 45%, respectively) in the CHF group. Moreover, left ventricular end-diastolic pressure was higher (32 mmHg vs 4 mmHg, P<0.01), while the left ventricular systolic pressure was lower (118 mmHg vs 130 mmHg, P=0.02) in the CHF group when compared to the control. Pearson’s correlation coefficient showed a negative association between pulmonary edema and Crs (r=–0.70, P=0.0001) and between pulmonary edema and TLC (r=–0.67, P=0.0034). Pulmonary edema correlated positively with Gti (r=0.68, P=0.001) and Hti (r=0.68, P=0.001). Finally, there was a strong positive relationship between pulmonary edema and heart weight (r=0.80, P=0.001).ConclusionRats with CHF present important changes in hemodynamic and respiratory mechanics, which may be associated with alterations in cardiopulmonary interactions.

Guanylyl cyclase activation reverses resistive breathing-induced lung injury and inflammation.

Inspiratory resistive breathing (RB), encountered in obstructive lung diseases, induces lung injury. The soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) pathway is down-regulated in chronic and acute animal models of RB, such as asthma, chronic obstructive pulmonary disease, and in endotoxin-induced acute lung injury. Our objectives were to: (1) characterize the effects of increased concurrent inspiratory and expiratory resistance in mice via tracheal banding; and (2) investigate the contribution of the sGC/cGMP pathway in RB-induced lung injury. Anesthetized C57BL/6 mice underwent RB achieved by restricting tracheal surface area to 50% (tracheal banding). RB for 24 hours resulted in increased bronchoalveolar lavage fluid cellularity and protein content, marked leukocyte infiltration in the lungs, and perturbed respiratory mechanics (increased tissue resistance and elasticity, shifted static pressure-volume curve right and downwards, decreased static compliance), consistent with the presence of acute lung injury. RB down-regulated sGC expression in the lung. All manifestations of lung injury caused by RB were exacerbated by the administration of the sGC inhibitor, 1H-[1,2,4]oxodiazolo[4,3-]quinoxalin-l-one, or when RB was performed using sGCα1 knockout mice. Conversely, restoration of sGC signaling by prior administration of the sGC activator BAY 58-2667 (Bayer, Leverkusen, Germany) prevented RB-induced lung injury. Strikingly, direct pharmacological activation of sGC with BAY 58-2667 24 hours after RB reversed, within 6 hours, the established lung injury. These findings raise the possibility that pharmacological targeting of the sGC-cGMP axis could be used to ameliorate lung dysfunction in obstructive lung diseases.