Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Targeting of Discoidin Domain Receptor 2 (DDR2) Prevents Myofibroblast Activation and Neovessel Formation During Pulmonary Fibrosis
Molecular Therapy 24, 1734 (October 2016). doi:10.1038/mt.2016.109
Authors: Hu Zhao, Huan Bian, Xin Bu, Shuya Zhang, Pan Zhang, Jiangtian Yu, Xiaofeng Lai, Di Li, Chuchao Zhu, Libo Yao & Jin Su
Role of HCP5-miR-139-RUNX1 Feedback Loop in Regulating Malignant Behavior of Glioma Cells
Molecular Therapy 24, 1806 (October 2016). doi:10.1038/mt.2016.103
Authors: Hao Teng, Ping Wang, Yixue Xue, Xiaobai Liu, Jun Ma, Heng Cai, Zhuo Xi, Zhen Li & Yunhui Liu
The Retinoid Agonist Tazarotene Promotes Angiogenesis and Wound Healing
Molecular Therapy 24, 1745 (October 2016). doi:10.1038/mt.2016.153
Authors: Ayman Al Haj Zen, Dorota A Nawrot, Alison Howarth, Andrea Caporali, Daniel Ebner, Aude Vernet, Jurgen E Schneider & Shoumo Bhattacharya
Exosome-mediated Delivery of Hydrophobically Modified siRNA for Huntingtin mRNA Silencing
Molecular Therapy 24, 1836 (October 2016). doi:10.1038/mt.2016.126
Authors: Marie-Cécile Didiot, Lauren M Hall, Andrew H Coles, Reka A Haraszti, Bruno MDC Godinho, Kathryn Chase, Ellen Sapp, Socheata Ly, Julia F Alterman, Matthew R Hassler, Dimas Echeverria, Lakshmi Raj, David V Morrissey, Marian DiFiglia, Neil Aronin & Anastasia Khvorova
Extracellular Antibody Drug Conjugates Exploiting the Proximity of Two Proteins
Molecular Therapy 24, 1760 (October 2016). doi:10.1038/mt.2016.119
Authors: David J Marshall, Scott S Harried, John L Murphy, Chad A Hall, Mohammed S Shekhani, Christophe Pain, Conner A Lyons, Antonella Chillemi, Fabio Malavasi, Homer L Pearce, Jon S Thorson & James R Prudent
Mesenchymal Stromal Cells Mitigate Experimental Colitis via Insulin-like Growth Factor Binding Protein 7-mediated Immunosuppression
Molecular Therapy 24, 1860 (October 2016). doi:10.1038/mt.2016.140
Authors: Yan Liao, Junxia Lei, Muyun Liu, Wanwen Lin, Dongxi Hong, Ying Tuo, Mei Hua Jiang, Huimin Xia, Maosheng Wang, Weijun Huang & Andy Peng Xiang
Integrated Safety Assessment of 2′-O-Methoxyethyl Chimeric Antisense Oligonucleotides in NonHuman Primates and Healthy Human Volunteers
Molecular Therapy 24, 1771 (October 2016). doi:10.1038/mt.2016.136
Authors: Stanley T Crooke, Brenda F Baker, T Jesse Kwoh, Wei Cheng, Dan J Schulz, Shuting Xia, Nelson Salgado, Huynh-Hoa Bui, Christopher E Hart, Sebastien A Burel, Husam S Younis, Richard S Geary, Scott P Henry & Sanjay Bhanot
Corrigendum to "Inducible HGF-secreting Human Umbilical Cord Blood-derived MSCs Produced via TALEN-mediated Genome Editing Promoted Angiogenesis"
Molecular Therapy 24, 1881 (October 2016). doi:10.1038/mt.2016.176
2016-11-07T23-22-35Z
Source: International Journal of Current Research and Review
Jobanputra G.P., Parikh U.R., Goswami H.M..
Background: Soft tissue tumors are defined as mesenchymal proliferations which occur in the extraskeletal nonepithelial tissues of the body, excluding the viscera, coverings of brain and lymphoreticular system. Soft tissue tumours are a highly heterogeneous group of tumours that are classified on a histogenetic basis according to the adult tissue they resemble Objective: To study the incidence of Soft tissue tumors at Tertiary Care Teaching Hospital and to study the morphological incidence of various Soft tissue tumors among different age groups and sex. Methods: In the Present Study, all operated cases; excised biopsies and resected specimens are taken into consideration. After processing detail microscopic examination was carried out. Results: The peak age of incidence of soft tissue tumors was between 3rd to 4th decades of age, with the male: female ratio 1.37:1. Benign tumors (89.3%) are more common than malignant tumors (10%). Most common soft tissue tumor is Lipomatous tumors. Conclusion: The study can contribute to epidemiologic knowledge of soft tissue tumors.
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2016-11-07T23-22-35Z
Source: International Journal of Current Research and Review
Neha Vijay, Ghanshyam Gupta.
Introduction: The health and growth of fetus is entirely depending upon the mental and physical health of a mother. Apart from maternal factor one more important infantile factor affects the anthropometric parameters of newborn i.e. the gender of babies. Aim: the aim of study was to know the effect of gender on anthropometric parameters of newborns of Udaipur district of Rajasthan. Method: A Cross sectional study was conducted in the Department of Anatomy, RNT Medical College and Hospitals, Udaipur, Rajasthan, India. All the anthropometric parameters of 1422 newborns were taken from; newborns delivered at Government health institutes of Udaipur district, at Pannadhay Ward of Maharana Bhopal Government Hospital of RNT Medical College and Hospitals. Results: Mean values of Birth weight, Crown Heel Length, Head Circumference, Chest Circumference, Foot Length and Skin Fold Thickness were significantly higher in male. Mean values for Abdominal Circumference, Thigh Circumference, Mid arm Circumference and Calf Circumference was also higher in male; however it was not statistically significant. Conclusion: The anthropometric parameters of newborns revealed a significant difference between male and female newborns.
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2016-11-07T23-22-35Z
Source: International Journal of Current Research and Review
Shuchita Chandorkar, Shobha Shouche, JPN Pathak.
Haemolymph of Philosamia ricini is a water reservoir which maintains homeostasis. When the insect is exposed to stresses naturally then it passes through various changes in biochemical composition. Fifth instar larvae of eri silk worm Philosamia ricini were kept under thermal stress of low and high temperature to observe the changes in carbohydrates, proteins and free amino acids. At high temperature carbohydrates showed a significant increase and a significant decrease at low temperature. Proteins and amino acids showed a significant decrease at high temperature and increase at low temperature.
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Background. Trunk function is important for standing balance, mobility, and functional outcome after stroke, but few studies have evaluated the effects of exercises aimed at improving core stability in stroke patients. Objective. To investigate the effectiveness of core stability training on trunk function, standing balance, and mobility in stroke patients. Methods. An assessor-blinded, randomized controlled trial was undertaken in a stroke rehabilitation ward, with 32 participants randomly assigned to an experimental group or a control group (n = 16 each). The experimental group received 400 minutes of core stability training in place of conventional programs within total training time, while the control group received only conventional programs. Primary outcome measures were evaluated using the Trunk Impairment Scale (TIS), which reflects trunk function. Secondary outcome measures were evaluated by pelvic tilt active range of motion in the sagittal plane, the Balance Evaluation Systems Test–brief version (Brief-BESTest), Functional Reach test, Timed Up-and-Go test (TUG), and Functional Ambulation Categories (FAC). A general linear repeated-measures model was used to analyze the results. Results. A treatment effect was found for the experimental group on the dynamic balance subscale and total score of the TIS (P = .002 and P < .001, respectively), pelvic tilt active range of motion (P < .001), Brief-BESTest (P < .001), TUG (P = .008), and FAC (P = .022). Conclusions. Core stability training has beneficial effects on trunk function, standing balance, and mobility in stroke patients. Our findings might provide support for introducing core stability training in stroke rehabilitation.
Schistosomiasis is a prevalent parasitic disease found predominantly in tropical and sub-tropical areas of the developing world, with the second highest socioeconomic and public health burden despite strenuous...
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Despite their worldwide popularity the question of using non-conventional treatments is a source of controversy among medical professionals. Although these methods may have potential benefits it presents a pro...
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Acupuncture is beneficial for controlling chemotherapy-induced nausea and vomiting (CINV). However, the effect of different acupoint combinations on controlling CINV remains unknown. This study aims to compare...
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Previous study shown that enzyme treated-rice bran effectively improved hypertension and glucose intolerance in stroke-prone spontaneously hypertensive rat (SHRSP). However, dual fermentation of rice bran's ef...
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Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) affects many adult men worldwide. The currently available therapies offer little or no proven benefit for CP/CPPS. We designed this study to assess th...
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Despite the robust regenerative capacity of skeletal muscle, there are a variety of congenital and acquired conditions in which the volume of skeletal muscle loss results in major permanent functional and cosmetic deficits. These latter injuries are referred to as volumetric muscle loss (VML) injuries or VML-like conditions, and they are characterized by the simultaneous absence of multiple tissue components (i.e., nerves, vessels, muscles, satellite cells, and matrix). There are currently no effective treatment options. Regenerative medicine/tissue engineering technologies hold great potential for repair of these otherwise irrecoverable VML injuries. In this regard, three-dimensional scaffolds have been used to deliver sustained amounts of growth factors into a variety of injury models, to modulate host cell recruitment and extracellular matrix remodeling. However, this is a nascent field of research, and more complete functional improvements require more precise control of the spatiotemporal distribution of critical growth factors over a physiologically relevant range. This is especially true for VML injuries where incorporation of a cellular component into the scaffolds might provide not only a source of new tissue formation but also additional signals for host cell migration, recruitment, and survival. To this end, we review the major features of muscle repair and regeneration for largely recoverable injuries, and then discuss recent cell- and/or growth factor-based approaches to repair the more profound and irreversible VML and VML-like injuries. The underlying supposition is that more rationale incorporation of exogenous growth factors and/or cellular components will be required to optimize the regenerative capacity of implantable therapeutics for VML repair.
Cells Tissues Organs 2015–16;202:202–213
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Effective models of mammalian tissues must allow and encourage physiologically (mimetic) correct interactions between co-cultured cell types in order to produce culture microenvironments as similar as possible to those that would normally occur in vivo. In the case of skeletal muscle, the development of such a culture model, integrating multiple relevant cell types within a biomimetic scaffold, would be of significant benefit for investigations into the development, functional performance, and pathophysiology of skeletal muscle tissue. Although some work has been published regarding the behaviour of in vitro muscle models co-cultured with organotypic slices of CNS tissue or with stem cell-derived neurospheres, little investigation has so far been made regarding the potential to maintain isolated motor neurons within a 3D biomimetic skeletal muscle culture platform. Here, we review the current state of the art for engineering neuromuscular contacts in vitro and provide original data detailing the development of a 3D collagen-based model for the co-culture of primary muscle cells and motor neurons. The devised culture system promotes increased myoblast differentiation, forming arrays of parallel, aligned myotubes on which areas of nerve-muscle contact can be detected by immunostaining for pre- and post-synaptic proteins. Quantitative RT-PCR results indicate that motor neuron presence has a positive effect on myotube maturation, suggesting neural incorporation influences muscle development and maturation in vitro. The importance of this work is discussed in relation to other published neuromuscular co-culture platforms along with possible future directions for the field.
Cells Tissues Organs 2015–16;202:143–158
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Volumetric muscle loss (VML) is a complex and heterogeneous problem due to significant traumatic or surgical loss of skeletal muscle tissue. The consequences of VML are substantial functional deficits in joint range of motion and skeletal muscle strength, resulting in life-long dysfunction and disability. Traditional physical medicine and rehabilitation paradigms do not address the magnitude of force loss due to VML and related musculoskeletal comorbidities. Recent advancements in regenerative medicine have set forth encouraging and emerging therapeutic options for VML injuries. There is significant potential that combined rehabilitative and regenerative therapies can restore limb and muscle function following VML injury in a synergistic manner. This review presents the current state of the VML field, spanning clinical and preclinical literature, with particular focus on rehabilitation and regenerative medicine in addition to their synergy. Moving forward, multidisciplinary collaboration between clinical and research fields is encouraged in order to continue to improve the treatment of VML injuries and specifically address the encompassing physiology, pathology, and specific needs of this patient population. This is a work of the US Government and is not subject to copyright protection in the USA. Foreign copyrights may apply. Published by S. Karger AG, Basel
Cells Tissues Organs 2015–16;202:237–249
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Tissue-engineered skeletal muscle has the promise to be a tool for studying physiology, screening muscle-active drugs, and clinical replacement of damaged muscle. To maximize the potential benefits of engineered muscle, it is important to understand the factors required for tissue formation and how these affect muscle function. In this review, we evaluate how biomaterials, cell source, media components, and bioreactor interventions impact muscle function and phenotype.
Cells Tissues Organs 2015–16;202:159–168
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Volumetric muscle loss (VML) results in irrecoverable loss of muscle tissue making its repair challenging. VML repair with acellular extracellular matrix (ECM) scaffolds devoid of exogenous cells has shown improved muscle function, but limited de novo muscle fiber regeneration. On the other hand, studies using minced autologous and free autologous muscle grafts have reported appreciable muscle regeneration. This raises the fundamental question whether an acellular ECM scaffold can orchestrate the spatiotemporal cellular events necessary for appreciable muscle fiber regeneration. This study compares the macrophage and angiogenic responses including the remodeling outcomes of a commercially available porcine urinary bladder matrix, MatriStem™, and autologous muscle grafts. The early heightened and protracted M1 response of the scaffold indicates that the scaffold does not recapitulate the spatiotemporal macrophage response of the autograft tissue. Additionally, the scaffold only supports limited de novo muscle fiber formation and regressing vessel density. Furthermore, scaffold remodeling is accompanied by increased presence of transforming growth factor and α-smooth muscle actin, which is consistent with remodeling of the scaffold into a fibrotic scar-like tissue. The limited muscle formation and scaffold-mediated fibrosis noted in this study corroborates the findings of recent studies that investigated acellular ECM scaffolds (devoid of myogenic cells) for VML repair. Taken together, acellular ECM scaffolds when used for VML repair will likely remodel into a fibrotic scar-like tissue and support limited de novo muscle fiber regeneration primarily in the proximity of the injured musculature. This is a work of the US Government and is not subject to copyright protection in the USA. Foreign copyrights may apply. Published by S. Karger AG, Basel
Cells Tissues Organs 2015–16;202:189–201
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Tissue-engineered skeletal muscle holds promise as a source of graft tissue for repair of volumetric muscle loss and as a model system for pharmaceutical testing. To reach this potential, engineered tissues must advance past the neonatal phenotype that characterizes the current state of the art. In this review, we describe native skeletal muscle development and identify important growth factors controlling this process. By comparing in vivo myogenesis to in vitro satellite cell cultures and tissue engineering approaches, several key similarities and differences that may potentially advance tissue-engineered skeletal muscle were identified. In particular, hepatocyte and fibroblast growth factors used to accelerate satellite cell activation and proliferation, followed by addition of insulin-like growth factor as a potent inducer of differentiation, are proven methods for increased myogenesis in engineered muscle. Additionally, we review our recent novel application of dexamethasone (DEX), a glucocorticoid that stimulates myoblast differentiation, in skeletal muscle tissue engineering. Using our established skeletal muscle unit (SMU) fabrication protocol, timing- and dose-dependent effects of DEX were measured. The supplemented SMUs demonstrated advanced sarcomeric structure and significantly increased myotube diameter and myotube fusion compared to untreated controls. Most significantly, these SMUs exhibited a fivefold rise in force production. Thus, we concluded that DEX may serve to improve myogenesis, advance muscle structure, and increase force production in engineered skeletal muscle.
Cells Tissues Organs 2015–16;202:169–179
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Although we recognize the many advantages of improved musculoskeletal health, we also note that our ability to sustain this health and to maintain quality of life in an aging population is currently deficient. However, global efforts have produced numerous advances in tissue engineering and regenerative medicine that will collectively serve to fill this deficiency in the near future. The purpose of this review is to highlight our current knowledge, to outline our recent advances, and to discuss the evolving paradigms in skeletal muscle injury and repair.
Cells Tissues Organs 2015–16;202:227–236
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Volumetric muscle loss (VML) injuries are prevalent in civilian and military trauma patients and are known to impart chronic functional deficits. The frank loss of muscle tissue that defines VML injuries is beyond the robust reparative and regenerative capacities of mammalian skeletal muscle. Given the nature of VML injuries, there is a clear need to develop therapies that promote de novo regeneration of skeletal muscle fibers, which can integrate with the remaining musculature and restore muscle strength. However, the pathophysiology of VML injuries is not completely defined, and, therefore, there may be other opportunities to improve functional outcomes other than de novo regeneration. Herein, clinical and preclinical studies of VML were reviewed to ascertain salient manifestations of VML injury that can impair limb function and muscle strength. The limited clinical data available highlighted proliferative fibrosis secondary to VML injury as a viable target to improve limb range of motion. Selected preclinical studies that used standardized neuromuscular functional assessments broadly identified that the muscle mass remaining after VML injury is performing suboptimally, and, therefore, percent VML strength deficits are significantly worse than can be explained by the initial frank loss of contractile machinery. Potential mechanisms of suboptimal strength of the remaining muscle mass suggested within the literature include intramuscular nerve damage, muscle architectural perturbations, and diminished transmission of force. Collectively, both clinical and preclinical data indicate a complex pathophysiology after VML that presents multiple therapeutic targets. This is a work of the US Government and is not subject to copyright protection in the USA. Foreign copyrights may apply. Published by S. Karger AG, Basel
Cells Tissues Organs 2015–16;202:180–188
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Skeletal muscle has an exceptional ability to regenerate and adapt following injury. Tissue engineering approaches (e.g. cell therapy, scaffolds, and pharmaceutics) aimed at enhancing or promoting muscle regeneration from severe injuries are a promising and active field of research. Computational models are beginning to advance the field by providing insight into regeneration mechanisms and therapies. In this paper, we summarize the contributions computational models have made to understanding muscle remodeling and the functional implications thereof. Next, we describe a new agent-based computational model of skeletal muscle inflammation and regeneration following acute muscle injury. Our computational model simulates the recruitment and cellular behaviors of key inflammatory cells (e.g. neutrophils and M1 and M2 macrophages) and their interactions with native muscle cells (muscle fibers, satellite stem cells, and fibroblasts) that result in the clearance of necrotic tissue and muscle fiber regeneration. We demonstrate the ability of the model to track key regeneration metrics during both unencumbered regeneration and in the case of impaired macrophage function. We also use the model to simulate regeneration enhancement when muscle is primed with inflammatory cells prior to injury, which is a putative therapeutic intervention that has not yet been investigated experimentally. Computational modeling of muscle regeneration, pursued in combination with experimental analyses, provides a quantitative framework for evaluating and predicting muscle regeneration and enables the rational design of therapeutic strategies for muscle recovery.
Cells Tissues Organs 2015–16;202:250–266
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Mental distress is a mental health problem expressed with variable levels of depressive, anxiety, panic or somatic symptoms. Owing to several factors tertiary level students are among the population with highe...
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Children with severe sepsis are known to have altered zinc homeostasis and decreased circulating zinc levels, suggesting a role for zinc supplementation to improve outcomes. We tested the hypothesis that zinc supplementation would improve survival in a juvenile model of polymicrobial sepsis. Juvenile (13–14-d-old) C57BL/6 mice were treated with 10 mg/kg of zinc via i.p. injections (or vehicle) for 3 d prior to induction of polymicrobial sepsis via i.p. cecal slurry injections. Survival after sepsis was followed for 3 d, and bacterial clearance, ex vivo phagocytosis, systemic inflammatory markers and neutrophil extracellular trap (NET) formation were quantified. We found a significant survival benefit and decreased bacterial burden among zinc supplemented mice when compared with the control group. Zinc supplementation also resulted in enhanced phagocytic activity, greater neutrophil recruitment in the peritoneal cavity and NET formation, suggesting a possible mechanism for improved bacterial clearance and survival. We also noted decreased serum cytokine levels and decreased myeloperoxidase activity in lung tissue following zinc supplementation, suggesting attenuation of the systemic inflammatory response. In conclusion, zinc supplementation improves bacterial clearance, and hence survival, in juvenile mice with polymicrobial sepsis.
Cyclooxygenase-2 (COX-2) and IL-8 are two inflammatory mediators induced by protein kinase C (PKC) via various stimuli. Both contribute significantly to cancer progression. Bufalin, a major active component of the traditional Chinese medicine Chan Su, is known to induce apoptosis in various cancer cells. This study clarifies the role and mechanism of bufalin action during PKC regulation of COX-2/IL-8 expression and investigates the associated impact on breast cancer. Using MB-231 breast cancer cells, bufalin augments PKC induction of COX-2/IL-8 at both the protein and mRNA levels, and the production of prostaglandin E2 (PGE2) and IL-8. The MAPK and NF-B pathways are involved in both the PKC-mediated and bufalin-promoted PKC regulation of COX-2/IL-8 production. Bufalin increases PKC-induced MAPKs phosphorylation and NF-B nuclear translocation. PGE2 stimulates the proliferation/migration of breast cancer cells. Furthermore, PKC-induced matrix metalloproteinase 3 expression is enhanced by bufalin. Bufalin significantly enhances breast cancer xenograft growth, which is accompanied by an elevation in COX-2/IL-8 expression. In conclusion, bufalin seems to promote the inflammatory response in vitro and in vivo, and this occurs, at least in part, by targeting the MAPK and NF-B pathways, which then enhances the growth of breast cancer cells.
Intrauterine inflammation, the major cause of early preterm birth, can have microbial and sterile aetiologies. We assessed in a Transwell model the anti-inflammatory efficacies of five drugs on human extraplacental membranes delivered after preterm spontaneous labour (30–34 wk). Drugs [TPCA1 (IKKβ inhibitor), 5 z-7-oxozeaenol (OxZ, TAK1 inhibitor), inhibitor of NF-B essential modulator binding domain (iNBD), SB239063 (p38 MAPK inhibitor) and N-acetyl cysteine (free radical scavenger free radicals)] were added after 12 h equilibration to the amniotic compartment. Concentrations of IL-6, TNF-α, MCP-1, IL-1β and PGE2 in the media, and IL6, TNFA and PTGS2 mRNA expression levels in membranes, were determined after 12 h. Data were analysed using mixed models analyses. Thirteen of the 28 membranes had histological chorioamnionitis (HCA+); five were positive for bacterial culture and six for fetal inflammatory reaction. Baseline PGE2 and cytokine production was similar between HCA– and HCA+ membranes. Anti-inflammatory effects were also similar between HCA– and HCA+ membranes. TPCA1 and OxZ were the most effective drugs; each inhibited amniotic secretion of 4/5 pro-inflammatory mediators and mRNA levels of 2/3, regardless of stimulus. We conclude that treatment with TPCA1 or OxZ, in combination with antibiotics, may minimise the adverse effects of intrauterine inflammation in pregnancy.
A novel β-lactamase CTX-M-190, derived from CTX-M-55 by a single substitution Ser133Thr, was identified in a natural Escherichia coli clinical isolate. CTX-M-190 exhibited potent hydrolytic activity against cefotaxime with kcat/Km 14.5 μM-1 s-1 and was resistant to inhibition by β-lactamase inhibitors tazobactam and sulbactam with the 50% inhibitory concentrations 77- and 55-fold higher than those of CTX-M-55, respectively. blaCTX-M-190 was located within the genetic platform, ISEcp1-blaCTX-M-orf477, which was harbored by a 70kb IncI1 plasmid.
mcr-1, the first transferable plasmid-mediated colistin resistance gene, was reported in Escherichia coli isolates from food animals, food and patients in China and now has been reported worldwide (1)....
Staphylococcus aureus is frequently isolated in the setting of infections of indwelling medical devices, which are mediated by the microbe's ability to form biofilms on a variety of surfaces. Biofilm-embedded bacteria are more resistant to antimicrobial agents than their planktonic counterparts and often cause chronic infections and sepsis, particularly in patients with prolonged hospitalizations. In this study, we demonstrate that sustained nitric oxide-releasing nanoparticles (NO-np) interfere with S. aureus adhesion and prevent biofilm formation on a rat central venous catheters (CVCs) model of infection. Confocal and scanning electron microscopy showed that NO-np treated staphylococcal biofilms displayed a considerably reduced thickness and bacterial number compared to control biofilms in vitro and in vivo, respectively. Although both phenotypes of multiple clinical strains, planktonic and biofilm-associated staphylococci, were susceptible to NO-np, bacteria within biofilms were more resistant to killing than their planktonic counterparts. Furthermore, chitosan, a biopolymer found in the exoskeleton of crustaceans and structurally integrated in the nanoparticles, seems to add considerable antimicrobial activity to the technology. Our findings suggest the promising development and translational potential of NO-np for use as a prophylactic or therapeutic against bacterial biofilms on CVCs and other medical devices.
Foreign body-associated infection is often difficult to treat, given that the associated microorganisms are in a biofilm state. Previously, we showed that low-amperage direct electrical current (DC) reduces biofilms of Propionibacterium acnes formed on implant-associated materials in vitro. Herein, low-amperage DC was compared to ceftriaxone or no treatment in a novel rat femur foreign body osteomyelitis model. A platinum implant seeded with 107 CFU/cm2 as well as 109 CFU of planktonic P. acnes were placed into the femoral medullary cavity. One week later, rats were assigned to one of three treatment groups - no treatment, ceftriaxone treatment or 200 μA DC treatment. After two weeks of treatment, there was a reduction of bacteria in bone in the ceftriaxone versus the control group (3.06 versus 6.58 log10 cfu/g of bone, respectively, p=0.0209), as well as in the 200 μA DC (0.5 log10 cfu/g of bone) versus the control group (p=0.0015). There were fewer bacteria in the DC-exposed compared to the ceftriaxone-treated animals (p=0.0330). There was a reduction of bacteria on the implanted wires between the control group (2.53 log10 cfu/cm2) and the ceftriaxone (0.1 log10 cfu/cm2) and 200 μA DC (0.1 log10 cfu/cm2) groups (p=0.0003 for both). Low-amperage DC may be useful to treat or aid in the treatment of foreign-body infections caused by P. acnes.
Under an NIH priority to identify new drugs to treat Class B parasitic agents, we performed high throughput screens, which identified Auranofin's (Ridaura™) activity against Entamoeba histolytica and Giardia intestinalis, major causes of water- and food-borne outbreaks. Auranofin, an oral, gold-containing compound FDA approved in 1985 for rheumatoid arthritis, was effective in vitro and in vivo against E. histolytica and both metronidazole-sensitive and resistant strains of Giardia. We now report the results of an NIH sponsored Phase I trial to characterize the PK and safety of auranofin in healthy volunteers using modern techniques to measure gold levels. Subjects received 6 mg po of auranofin daily, the recommended dose for rheumatoid arthritis, for 7 days and were followed for 126 days. Treatment Associate Adverse Events were reported by 47% of the subjects, but all were mild and resolved without treatment. The mean plasma gold Cmax at Day 7 was 0.312 μg/mL and t1/2 35 days, so steady state blood levels would not be reached in short term therapy. The highest concentration of gold was in feces at 7 days, 13 μM (auranofin equivalent), or more than 25X the IC50 for E. histolytica and 4X for Giardia. Modeling of higher doses (9 and 21 mg/day) was performed for systemic parasitic infections, and plasma gold levels of 0.4-1.0 mcg/mL were reached after 14 days of 21 mg/day. This Phase I trial supports the safety of auranofin and provides important PK data to support its potential use as a broad spectrum antiparasitic drug.
We reviewed 37 patients treated for bacteremia due to carbapenem-resistant Pseudomonas aeruginosa (CR-Pa). Although 65% of isolates were multiple-drug resistant, therapeutic options were available as all were susceptible to ≥1 antibiotic. Ninety-two percent of patients received active antimicrobial therapy, but only 57% received early active therapy (within 48 hours). Fourteen-day mortality was 19%. Microbiologic failure occurred in 29%. Pitt bacteremia score (P=0.046) and delayed active therapy (P=0.027) were predictive of death and microbiologic failure, respectively.
Invasive aspergillosis (IA) due to Aspergillus flavus is associated with a high mortality. Though voriconazole (VRC) is widely recommended as first-line treatment for IA, emergence of azole resistance in Aspergillus spp. is translating to treatment failure. We evaluated the efficacy of voriconazole in a non-neutropenic murine model of disseminated A. flavus infection using two voriconazole-resistant isolates (one harboring the Y319H substitution in the cyp51C-gene) and two wild-type isolates without mutations.
All isolates exhibited a dose–response relationship and voriconazole treatment improved the mouse survival in a dose-dependent manner. At 40 mg/kg, 100% efficacy was observed for 1-susceptible and 1-resistant (with mutation) isolate whereas for another susceptible and resistant isolate (without mutation) survival was 81% and 72% respectively. The Hill equation with a variable slope fitted the relationship between the AUC/MIC ratio and 14-day survival well for each strain. An F-test showed the 50% effective dose to be significantly different from each other (p=0.0023). However, contrary to expectation, there was a significant difference in exposure response relationships between strains, and it appeared that the susceptible strains required a relatively higher exposure than the resistant ones to result in the same treatment effect, the 50% effective PK/PD index (EI50) required being negatively and log-linearly related to MIC (p=0.04). We conclude that efficacy of voriconazole depended on drug exposure and the voriconazole MIC of the isolates but lower exposures are required for strains with higher MICs. These findings may have profound significance in clinical practice with respect to dosing and drug choice.
This study aims to investigate the prevalence and transmission dynamics blaNDM-1 gene in animal E coli strains. Two IncFII blaNDM-1-encodingplasmids, pHNEC46-NDM and pHNEC55-NDM, with only minor structural variation in the MDR region were found to be responsible for the transmission of blaNDM-1 in these strains. The blaNDM-1 gene can be incorporated into plasmids and stably inherited in animal-borne E. coli strains that can be maintained in animal gut microflora even without carbapenem selection pressure.
The HIV protease inhibitor lopinavir inhibits Plasmodium falciparum aspartic proteases (plasmepsins) and parasite development, and children receiving lopinavir-ritonavir experienced fewer episodes of malaria than those receiving other antiretroviral regimens. Resistance to lopinavir was selected in vitro over ~9 months, with ~4-fold decreased sensitivity. Whole genome sequencing of resistant parasites showed a mutation and increased copy number in pfmdr1, a mutation in a protein of unknown function, but no polymorphisms in plasmepsin genes.
The evidence for using combination therapy for the treatment of serious methicillin-resistant Staphylococcus aureus (MRSA) infections is growing. In this study, we investigate the synergistic effect of daptomycin combined with piperacillin+tazobactam and ampicillin+sulbactam against MRSA using time-kill experiments. Six of 8 strains demonstrated synergy between DAP and the β-lactam/β-lactamase inhibitor (BLI) combination. In 5/8 strains, the synergy occurred only in the presence of the BLI, highlighting a role for BLIs in peptide-beta-lactam synergy.
Colistin, administered as its inactive prodrug colistin methanesulfonate (CMS), is often used in multidrug-resistant Gram-negative pulmonary infections. The CMS and colistin pharmacokinetics in plasma and epithelial lining fluid (ELF) following intravenous and pulmonary dosing have not been evaluated in a large animal model with similar pulmonary architecture to humans.
Six merino sheep (34-43kg) received an intravenous or pulmonary dose of 4-8 mg/kg CMS (sodium) or 2-3 mg/kg colistin (sulfate) in a 4-way crossover study. Pulmonary dosing was achieved via jet nebulization through an endotracheal tube cuff. CMS and colistin were quantified in plasma and bronchoalveolar lavage fluid (BALF) by HPLC. ELF concentrations were calculated via the urea method. CMS and colistin were co-modelled in S-ADAPT.
Following intravenous CMS or colistin, no concentrations were quantifiable in BALF. Elimination clearance was 1.97 L/h (4% inter-individual variability) for CMS (other than conversion to colistin) and 1.08 L/h (25%) for colistin. On average 18% of a CMS dose was converted to colistin. Following pulmonary delivery, colistin was not quantifiable in plasma and CMS was detected in only one sheep. Average (SD) ELF concentrations of formed colistin were 400 (243), 384 (187) and 184 (190) mg/L at 1, 4 and 24 h after pulmonary CMS. The population pharmacokinetic model well described CMS and colistin in plasma and ELF following intravenous and pulmonary administration.
Pulmonary dosing provided high ELF and low plasma colistin concentrations, i.e. a substantial targeting advantage over intravenous administration. Predictions from the pharmacokinetic model indicate sheep are an advantageous model for translational research.
A major clinical challenge for treating infectious diseases is the duration of antimicrobial therapy required to eradicate the pathogen. We hypothesized that modulating the bacterial replication rate in the context of an antimicrobial exposure is coupled with the rate and extent of bactericidal effects. Herein we describe results from in vitro infection model (one-compartment, 24 hour; hollow-fiber, 10 day) studies designed to probe the relationship between bacterial replication rate, and the rate and extent of bactericidal effects in the context of an effective antibiotic exposure. Bacterial replication rate was modulated by varying the sodium chloride concentration (0 to 8%) in the growth media (Mueller Hinton II broth). The study drug selected was levofloxacin and the challenge isolate was Staphylococcus aureus ATCC 29213 (levofloxacin MIC, 0.125 mg/L). Within each in vitro infection model, human levofloxacin concentration-time profiles (7 hour half-life) were simulated and the challenge isolate was subjected to an effective exposure (free-drug area under the concentration-time curve to MIC (AUC:MIC ratio), 65; administered as a single dose or daily for 10 days). Over the course of each study, samples were taken from each model for bacterial density determination and drug concentration assay using LC-MS/MS. In the 24 hour one-compartment in vitro infection model studies, as the bacterial replication rate increased so too did the rate (slope, 0-4 hours) and extent (24 hour CFU/mL) of bacterial killing. In the 10 day hollow-fiber infection model studies, the time until a reduction of bacterial density to 1 X 102 CFU/mL was 10 days in the media in which the challenge isolate grew slowly and approximately 2 days in the media in which the challenge isolate grew rapidly. Together, these data provide a proof-of-concept for new adjunctive therapeutic options to antimicrobial agents alone that reduce treatment durations. Such adjunctive therapies hold the promise for marked reductions in the tonnage of antimicrobial agents administered to patient populations and selection pressure toward antimicrobial resistances.
Penicillin-binding proteins (PBPs) function as transpeptidases, carboxypeptidases or endopeptidases during peptidoglycan synthesis in bacteria. As the well-known drug targets for β-lactam antibiotics, the physiological functions of PBPs and whether they are essential for growth is of significant interest. The pathogen Pseudomonas aeruginosa (Pa) poses a particular risk to immunocompromised and cystic fibrosis patients, and is difficult to treat due to antibiotic resistance. To identify potential drug targets among the PBPs in Pa, we performed gene knockouts of all the high-molecular mass (HMM) PBPs and determined impacts on cell growth and morphology, susceptibility to β-lactams, peptidoglycan structure, virulence, and pathogenicity. Disruptions of the transpeptidase domains of most HMM PBPs, including double disruptions, had only minimal effects on cell growth. The exception was PBP3, where cell growth only occurred when the protein was conditionally expressed on an integrated plasmid. Conditional deletion of PBP3 also caused a defect in cell division and increased susceptibility to β-lactams. Knockout of PBP1a led to impaired motility, and together with its localization at the cell poles, suggests an involvement in flagellar function. Overall, these findings reveal that PBP3 represents the most promising target for drug discovery against Pa, whereas other HMM PBPs have less potential.
Estimating drug efficacy in antimalarial drug trials requires parasite genotyping to distinguish new infections from treatment failures. When using length-polymorphic molecular markers, preferential amplification of short fragments can compromise detection of co-infections, potentially leading to misclassification of treatment outcome. We quantified minority clone detectability and competition among msp1, msp2, and glurp amplicons using mixtures of P. falciparum strains and investigated the impact of template competition on genotyping outcomes in forty-four paired field samples. Substantial amplification bias was detected for all three markers with shorter fragments outperforming larger fragments. Strongest template competition was observed for marker glurp. Detection of glurp fragments in multi-clonal infections was severely compromised. Eight of forty-four sample pairs were identified as new infection by all three markers. Ten pairs were defined as new infection based on one marker alone, seven of which were defined by questionable marker glurp. The impact of size-dependent template competition on genotyping outcomes therefore calls for necessary amendments to the current WHO recommendations for PCR correction of malaria drug trial endpoints. Accuracy of genotyping outcomes could be improved by separate amplification reactions per allelic family, and basing results on markers msp1 and msp2 first, with glurp only to resolve discordant results.
Ampicillin-resistance in Enterococcus faecium is a serious concern worldwide, complicating the treatment of E. faecium infections. Penicillin-binding protein 5 (PBP5) is considered the main ampicillin resistance determinant in E. faecium. The three known E. faecium clades showed sequence variations in the pbp5 gene that are associated with their ampicillin phenotype; however, these changes alone do not explain the array of resistance levels observed among E. faecium clinical strains. We aimed to determine if the levels of PBP5 are differentially regulated between the E. faecium clades, with the hypothesis that variations in PBP5 levels could help account for the spectrum of ampicillin MICs seen in E. faecium. We studied pbp5/PBP5 mRNA and protein levels as well as the genetic environment upstream of pbp5 in 16 E. faecium strains that belong to the different E. faecium clades and cover wide range of ampicillin MICs. Our results found that pbp5/PBP5 levels are increased in subclades A1 and A2 ampicillin-resistant strains as compared to clade B and subclade A2 ampicillin-susceptible strains. Furthermore, we found evidence of major clade-associated rearrangements in the region upstream of pbp5 including large DNA fragment insertions, deletions and single nucleotides polymorphisms that may be associated with the differential regulation of PBP5 levels between the E. faecium clades. Overall, these findings highlight the contribution of the clade background to the regulation of PBP5 abundance and points to differences in the region upstream of pbp5 as likely contributors to the differential expression of ampicillin resistance.
Among various FDA approved combination antiretroviral drugs (cARVs), emtricitabine (FTC) has been a very effective nucleoside reverse transcriptase inhibitor. Thus far FTC is the only deoxycytidine nucleoside analog. However, a major drawback of FTC is its large volume distribution (averaging 1.4 L/kg) and short plasma half-life (8-10 h), necessitating a high daily dosage. Thus, we propose an innovative fabrication method of loading FTC in poly(lactic-co-glycolic acid) polymeric nanoparticles (FTC-NPs), potentially overcoming these drawbacks. Our nano-formulation demonstrated enhanced FTC loading (sized <200 nm and surface-charge of -23 mV), and no to low cytotoxicity with improved biocompatibility compared to FTC solution. An ex-vivo endosomal release assay illustrated NP entrapment prolongs FTC release over a month. Intracellular retention studies demonstrate sustained FTC retention over time with approximately 8 % (24 h) to 68 % (96 h) release with ~0.74 ìg/105 cells mean retention FTC drug concentration after 4 days of study period. In vitro HIV-1 inhibition study demonstrated FTC-NPs treatment results in IC50 value ~43 times lower in TZM-bl cells (0.00043 μg/mL) and ~3.7 times lower (0.009 μg/mL) IC50 in PBMCs, compared to FTC solution (TZM-bl cells 0.01861 and PBMCs 0.033 μg/mL). Further on primary PBMCs, FTC-NPs also illustrates a comparable HIV-1 infection blocking efficacy to FTC solution. All the above studies substantiate that FTC nano-formulation prolongs intracellular FTC concentration and inhibition of HIV infection. Therefore, FTC-NPs potentially could be a long-acting, stable formulation to ensure once biweekly dosing to prevent or treat HIV infection.
Invasive Candida albicans infections are a serious health threat for immunocompromised individuals. Fluconazole is most commonly used to treat these infections, but resistance due to the overexpression of multidrug efflux pumps is of grave concern. This study evaluated the ability of five synthetic organotellurium compounds to reverse fluconazole resistance of C. albicans clinical isolates. Compounds 1-4, at < 10 μg/ml, ameliorated fluconazole resistance of Saccharomyces cerevisiae strains overexpressing the major C. albicans multidrug efflux pumps Cdr1p and Mdr1p, whereas compound 5 only sensitized Mdr1p overexpressing strains to fluconazole. Compounds 1-4 also inhibited efflux of the fluorescent substrate rhodamine 6G and the ATPase activity of Cdr1p, whereas all five compounds 1-5 inhibited Nile red efflux by Mdr1p. Interestingly, all five compounds demonstrated synergy with fluconazole against efflux pump overexpressing fluconazole resistant C. albicans clinical isolates; isolate 95-142 overexpressing CDR1 and CDR2, isolate 96-25 overexpressing MDR1 and ERG11 and isolate 12-99 overexpressing CDR1, CDR2, MDR1 and ERG11. Overall, organotellurium compounds 1 and 2 were the most promising fluconazole-chemosensitizers of fluconazole resistant C. albicans isolates. Our data suggest that these novel organotellurium compounds inhibit pump efflux by two very important and distinct families of fungal multidrug efflux pumps, the ATP-binding cassette (ABC) transporter Cdr1p and the Major Facilitator Superfamily (MFS) transporter Mdr1p.
The absorption, distribution, metabolism, and excretion of omadacycline, a first in class aminomethylcycline antibiotic with a broad spectrum of activity against Gram-positive, Gram-negative, anaerobic, and atypical bacteria, were evaluated in rats. Tissue distribution was investigated by quantitative whole-body autoradiography in male Long Evans Hooded (LEH) rats. Following a 5 mg/kg intravenous (IV) dose, radioactivity widely and rapidly distributed into most tissues. The highest tissue-to-blood ratio was observed in bone mineral, thyroid gland, and harderian gland at 24 h post IV dose. There was no evidence of stable accumulation in uveal tract tissue suggesting no stable binding interaction with melanin. Following a 90 mg/kg oral dose in LEH rats, the highest tissue-to-blood ratios (t/b) were observed in bone mineral, harderian gland, liver, spleen, and salivary gland. Plasma protein binding was 26% in the rat and 15% - 21% in other species. Omadacycline plasma clearance was 1.2 L/h/kg and half-life was 4.6 h; steady-state volume of distribution (Vss) was 6.89 L/kg. Major circulating components in plasma were intact omadacycline and its epimer. Consistent with observations in human, approximately 80% of the dose was excreted into the feces as unchanged omadacycline after IV administration. Fecal excretion was primarily the result of biliary excretion (~40%) and direct gastrointestinal secretion (~30%). However, urinary excretion (~30%) was equally prominent after IV dosing.
Optimizing antibiotic combinations is promising to combat multidrug-resistant Pseudomonas aeruginosa. This study aimed to systematically evaluate synergistic bacterial killing and resistance prevention by carbapenem and aminoglycoside combinations, and to rationally optimize combination dosage regimens via mechanism-based modeling (MBM). We studied monotherapies and combinations of imipenem with tobramycin or amikacin against three difficult-to-treat double-resistant clinical P. aeruginosa isolates. Viable count profiles of total and resistant populations were quantified in 48h static-concentration time-kill studies (inoculum: 107.5CFU/mL). We rationally optimized combination dosage regimens via MBM and Monte Carlo simulations against isolate FADDI-PA088 (MICimipenem 16 mg/L, MICtobramycin 32 mg/L; i.e. both 98th percentiles of EUCAST). Against this isolate, imipenem (1.5xMIC) combined with 1-2 mg/L tobramycin (MIC 32 mg/L) or amikacin (MIC 4 mg/L) yielded ≥2 log10 more killing than the most active monotherapy at 48h and prevented resistance. For all three strains, synergistic killing without resistance was achieved by ≥0.88xMIC imipenem in combination with a median [range] of 0.75x [0.032-2.0] MIC tobramycin or 0.50x [0.25-0.50] MIC amikacin. The MBM indicated aminoglycosides significantly enhanced the imipenem target site concentration up to 3-fold; achieving half-maximal of this synergistic effect required an aminoglycoside concentration of 1.34 mg/L (if the aminoglycoside MIC was 4 mg/L) and 4.88 mg/L (for MICs 8-32 mg/L). An optimized combination regimen (imipenem 5g/day continuous infusion plus 7 mg/kg tobramycin 0.5 h infusion) was predicted to achieve >2.0 log10 killing and prevent regrowth at 48h in 90.3% of patients (median bacterial killing >4.0 log10) against double resistant isolate FADDI-PA088 and was therefore highly promising.
This brief presents a frequency-domain approach for the steady-state analysis of pulsewidth-modulated converters and switched circuits with nonideal switching behavior. The proposed strategy generalizes recent methodologies based on the Fourier expansion of the steady-state responses of a periodically switching circuit and on the simulation of an augmented linear-time-invariant system. This system is now also given an interpretation in terms of an equivalent circuit, which is simulated at a single frequency point to solve for all the harmonics. The method offers a modular topological approach that is combined with standard tools for circuit analysis and enables the simulation of networks with an arbitrary number of switches and driving mechanisms. Single, multiple, and possibly nonideal commutation events within the switching period are handled in the same framework, without additional complexity. The technique allows for the full frequency-domain characterization of both the functional and the noisy behavior of the circuit responses. The feasibility and strength are demonstrated via comparisons with simulations and measurements on two application examples, i. e., a full-bridge single-phase inverter and a dc-dc boost converter.
http://ift.tt/2eePdC2
In two experimental studies, the advertising effects of hard versus soft sell appeals are investigated. Both studies show that in online advertising (banner ads and viral video ads), soft sell appeals in advertisements on high involvement products generate a more positive attitude towards the ad than hard sell appeals. In print advertising however, hard sell appeals lead to a more positive Aad, due to the fact that the advertisement is perceived as less irritating and more credible. Additionally, study II revealed that using soft sell appeals in viral video ads leads to a higher intention to share, due to the generation of a positive attitude towards the ad.
http://ift.tt/2eeQ0my
Cell death is intertwined with life in development, homeostasis, pathology, and aging. Until recently, apoptosis was the best known form of programmed cell death, whereas necrosis was for a long time considered accidental owing to physicochemical injury. However, identification of crucial signaling and execution molecules, which are highly regulated, revealed that necrosis encompasses several cell death modalities that can be therapeutically targeted. The best understood form of regulated necrosis is necroptosis, which is transduced by the kinase activities of receptor interacting protein kinase-1 and receptor interacting protein kinase-3, eventually leading to the activation of mixed lineage kinase domain-like and plasma membrane permeabilization. We are only beginning to appreciate the role of necroptosis in different pathological conditions, including critical illnesses. In this review, we discuss the molecular mechanisms of necroptosis and analyze the effect of inhibiting necroptosis in experimental models of critical illnesses. In view of the identification of an increasing number of cell death modalities, we also briefly discuss the simultaneous targeting of multiple cell death modalities because, depending on the cell type and cellular conditions, various types of cell death may contribute to the pathology.
http://ift.tt/2f91rv7
Both chronic obstructive pulmonary disease (COPD) and sudden cardiac death (SCD) are major health burdens. A number of studies have addressed their interrelationship, but currently no systematic review has been published. Our objective is to give an overview of the literature of the association between COPD and SCD. A search on PubMed with both MeSH headings and free-text keywords was performed. We selected all original articles of studies in humans that assessed COPD on the one hand and SCD, electrocardiographic markers for SCD, ventricular arrhythmias, or asystole on the other. The electronic search yielded 251 articles, from which 27 full publications were selected after careful evaluation of the full-text articles. In these studies, COPD was associated with a prolonged and shortened QT interval. In patients with a myocardial infarction (MI), COPD was associated with an increased risk of ventricular arrhythmias and decreased survival. COPD was a risk factor for SCD both in cardiovascular patient groups and in community-based studies, independent from cardiovascular risk profile. Studies of the potential impact of respiratory treatment on the occurrence of SCD showed conflicting results. In conclusion, cumulating evidence associates COPD with an increased risk of SCD. Asystole and pulseless electric activity could be more common than VT/VF in deaths associated with COPD. Underlying mechanisms explaining this association require further investigation.
http://ift.tt/2fv7Lfl
Lysosomal cathepsins regulate an exquisite range of biological functions, and their deregulation is associated with inflammatory, metabolic, and degenerative diseases in humans. In this study, we identified a key cell-intrinsic role for cathepsin B as a negative feedback regulator of lysosomal biogenesis and autophagy. Mice and macrophages lacking cathepsin B activity had increased resistance to the cytosolic bacterial pathogen Francisella novicida. Genetic deletion or pharmacological inhibition of cathepsin B down-regulated mechanistic target of rapamycin activity and prevented cleavage of the lysosomal calcium channel TRP ML1. These events drove transcription of lysosomal and autophagy genes via transcription factor EB, which increased lysosomal biogenesis and activation of autophagy initiation kinase ULK1 for clearance of the bacteria. Our results identified a fundamental biological function of cathepsin B in providing a checkpoint for homeostatic maintenance of lysosome populations and basic recycling functions in the cell.
http://ift.tt/2f8XVRG
Natural killer T (NKT) cells are innate lymphocytes that differentiate into NKT1, NKT2, and NKT17 sublineages during development. However, the signaling events that control NKT sublineage specification and differentiation remain poorly understood. Here, we demonstrate that the ubiquitin-modifying enzyme TNFAIP3/A20, an upstream regulator of T cell receptor (TCR) signaling in T cells, is an essential cell-intrinsic regulator of NKT differentiation. A20 is differentially expressed during NKT cell development, regulates NKT cell maturation, and specifically controls the differentiation and survival of NKT1 and NKT2, but not NKT17, sublineages. Remaining A20-deficient NKT1 and NKT2 thymocytes are hyperactivated in vivo and secrete elevated levels of Th1 and Th2 cytokines after TCR ligation in vitro. Defective NKT development was restored by compound deficiency of MALT1, a key downstream component of TCR signaling in T cells. These findings therefore show that negative regulation of TCR signaling during NKT development controls the differentiation and survival of NKT1 and NKT2 cells.
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Background: The association of attention-deficit/hyperactivity disorder (ADHD) and tic disorder (TD) is frequent and clinically important. Very few and inconclusive attempts have been made to clarify if and how the combination of ADHD-FTD runs in families. Aim: To determine the first time in a large-scale ADHD sample whether ADHD-FTD increases the risk of ADHDH+TD in siblings and, also the first time, if this is independent of their psychopathological vulnerability in general. Methods: The study is based on the International Multicenter ADHD Genetics (IMAGE) study. The present sub-sample of 2815 individuals included ADHD-index patients with co-existing TD (ADHD-FTD, n = 262) and without TD (ADHD+TD, n = 947) as well as their 1606 full siblings (n = 358 of the ADHDH+TD index patients and n = 1248 of the ADHD-TD index patients). We assessed psychopathological symptoms in index patients and siblings by using the Strength and Difficulties Questionnaire (SDQ) and the parent and teacher Conners' long version Rating Scales (CRS). For disorder classification the Parental Account of Childhood Symptoms (PACS-Interview) was applied in n = 271 children. Odds ratio with the GENMOD procedure (PROCGENMOD) was used to test if the risk for ADHD, TD, and ADHD-FTD in siblings was associated with the related index patients' diagnoses. In order to get an estimate for specificity we compared the four groups for general psychopathological symptoms. Results: Co-existing ADHD-FTD in index patients increased the risk of both comorbid ADHD-FTD and TD in the siblings of these index patients. These effects did not extend to general psychopathology. Interpretation: Co-existence of ADHD+FTD may segregate in families. The same holds true for TD (without ADHD). Hence, the segregation of TD (included in both groups) seems to be the determining factor, independent of further behavioral problems. This close relationship between ADHD and TD supports the clinical approach to carefully assess ADHD in any case of TD.
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The joint influence of optical and (quasi-)static electric fields on the orientation of liquid crystal gives rise to peculiar effects. In this article we report on the generation of transient domains in liquid crystals, which are an order of magnitude larger than the size of the optical field profile. The formation of such a domain is due to the fact that the initially present optical field reverses the pre-tilt, and the voltage that is then applied gives rise to an amplification of the tilt angle. The resulting reorientation of the director strongly depends on the starting conditions of the preliminary present optical field. We demonstrate different switching conditions, depending on the relation between the incident angle of the beam and the pre-tilt angle. The resulting refractive index profiles give rise to lensing effects.
http://ift.tt/2eEwQVN
In this report, clinical and histological findings of a rare case of a large congenital fibropapilloma on the forehead of a warmblood foal are reported. Surgical excision was curative and no recurrence was observed after nine months. The foal did not present any other abnormalities. Morphologically, the lesion was classified as a fibro-epithelial type of skin hamartoma. The fibrous component has thus far only been reported in pigs. Although fibropapillomas are common in adult animals and are associated with papillomavirus infection, this association has not been demonstrated in foals and piglets. Additionally, there were no histopathological indications of papillomavirus infection in the present study, nor could PCR reveal the presence of papillomavirus DNA.
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Objective: We performed meta-analyses of randomized controlled trials to examine the effects of neurofeedback on attention-deficit/hyperactivity disorder (ADHD) symptoms and neuropsychological deficits in children and adolescents with ADHD. Method: We searched PubMed, Ovid, Web of Science, ERIC, and ONAHAL through August 30, 2015. Random effects models were employed. Studies were evaluated with the Cochrane Risk of Bias tool. Results: We included 13 trials (520 participants with ADHD). Significant effects were found on ADHD symptoms rated by assessors most proximal to the treatment setting, that is, the least blinded outcome measure (standardized mean difference [SMD]: ADHD total symptoms = 0.35, 95% CI = 0.11-0.59; inattention = 0.36, 95% CI = 0.09-0.63; hyperactivity/impulsivity = 0.26, 95% CI = 0.08-0.43). Effects were not significant when probably blinded ratings were the outcome or in trials with active/sham controls. Results were similar when only frequency band training trials, the most common neurofeedback approach, were analyzed separately. Effects on laboratory measures of inhibition (SMD = 0.30, 95% CI = 0.10 to 0.70) and attention (SMD = 0.13, 95% CI = -0.09 to 0.36) were not significant. Only 4 studies directly assessed whether learning occurred after neurofeedback training. The risk of bias was unclear for many Cochrane Risk of Bias domains in most studies. Conclusion: Evidence from well-controlled trials with probably blinded outcomes currently fails to support neurofeedback as an effective treatment for ADHD. Future efforts should focus on implementing standard neurofeedback protocols, ensuring learning, and optimizing clinically relevant transfer.
http://ift.tt/2fwPfl9
Data science or "data-driven research" is a research approach that uses real-life data to gain insight about the behavior of systems. It enables the analysis of small, simple as well as large and more complex systems in order to assess whether they function according to the intended design and as seen in simulation. Data science approaches have been successfully applied to analyze networked interactions in several research areas such as large-scale social networks, advanced business and healthcare processes. Wireless networks can exhibit unpredictable interactions between algorithms from multiple protocol layers, interactions between multiple devices, and hardware specific influences. These interactions can lead to a difference between real-world functioning and design time functioning. Data science methods can help to detect the actual behavior and possibly help to correct it. Data science is increasingly used in wireless research. To support data-driven research in wireless networks, this paper illustrates the step-by-step methodology that has to be applied to extract knowledge from raw data traces. To this end, the paper (i) clarifies when, why and how to use data science in wireless network research; (ii) provides a generic framework for applying data science in wireless networks; (iii) gives an overview of existing research papers that utilized data science approaches in wireless networks; (iv) illustrates the overall knowledge discovery process through an extensive example in which device types are identified based on their traffic patterns; (v) provides the reader the necessary datasets and scripts to go through the tutorial steps themselves.
http://ift.tt/2fwNuUH
REASONS FOR PERFORMING STUDY: Commercial immunoglobulin E (IgE)-based tests are available for diagnosis of food allergies and are commonly used in equine practice. However, these tests have been proven unreliable as a screening method in man and other species, but not critically evaluated in equids. Therefore, a commercially available IgE-based test for horses was evaluated. OBJECTIVES: To evaluate the consistency of the results obtained with a commercially available IgE-based test for food allergy diagnosis in ponies (Phase I) and to subject ponies to a provocation trial with the presumed allergens (Phase II). STUDY DESIGN: Allergen screening followed by experimental food provocation trials in healthy ponies. METHODS: Blood samples of 17 healthy Shetland ponies were taken at 2 different time points, sent blinded to a commercial laboratory for screening of common food allergens and the results were evaluated for consistency (Phase I). Ponies that were positive for food allergens were consecutively challenged orally with each allergen separately for 14 days (Phase II). A washout period of one week was applied in ponies with multiple positive results. Clinical parameters and serum amyloid A were monitored during the provocation trial. RESULTS: Only 7/17 ponies were negative on the IgE-based test at the 2 time points, 3 had positive results twice but only one tested positive twice for the same food allergen. No abnormalities were noted during the provocation trials. CONCLUSIONS: This study demonstrated that this IgE-based test is not a reliable screening tool for food allergy in healthy equids.
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Venipuncture is one of the most commonly done medical procedures. We report a unique case of a 23-year-old young male who presented with features suggestive of inflammatory arthritis. The symptoms, which initially started on the right side, also involved the other side after a few weeks. Although the patient's symptoms and signs were simulating inflammatory arthritis, he had atypical features like poor response to anti-inflammatory medicines and normal laboratory parameters. His musculoskeletal ultrasonography was also not suggestive of arthritis. His history was reviewed and on direct questioning he revealed a history of venipuncture for blood sample withdrawal, done from right antecubital region for routine health check on the day prior to the onset of symptoms. Complex regional pain syndrome was suspected and triple-phase radioisotope bone scan was done which was highly suggestive of this diagnosis. The patient was managed with multidimensional approach and responded very well to the treatment. Complex regional pain syndrome is usually not thought of in the initial differential diagnosis of inflammatory arthritis. In this report we highlight the need to elicit the often overlooked history of trivial trauma like venipuncture, especially in atypical cases of arthritis. Also the role of newer diagnostic modalities in such cases is emphasized.
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A novel method for geometry generation of Representative Unit Cells (RUC) of textile composites is presented. The technique retains the advantage of an analytical formulation from industrial practice however introduces variable asymmetric yarn cross-sectional shapes and paths which can be fitted to the yarn shapes and cross-sectional areas as observed from in-situ measurements. In this way interpenetrations and incorrect fibre volume fractions, which occur when using idealized constant yarn cross sections for RUC generation, are avoided. Meshing becomes easier and no fibre volume corrections are required. The new technique is validated through a comparison of 1) the novel RUC to 2) an Idealized RUC with constant yarn cross section; and 3) a model constructed from direct in-situ micro computed X-ray tomographic measurements of a carbon-epoxy weave (In-situ Model). With all three models a reasonable agreement with experimentally obtained elastic properties is found. The stress predicted by the Idealized RUC is a significantly different than predicted by the RUC generated with the new method and the In-situ Model. The latter two are in good agreement which indicates that the MESI RUC can be used for material strength prediction. The MESI RUC is also substantially less computationally intensive. Next to the construction of improved RUCs, the technique is an excellent alternative for advanced unit cell generation techniques based on production process simulations in the case that the production process is unknown or an analytic periodic geometry is required.
http://ift.tt/2fwK04R
Creating domain ontologies is usually performed by teams of knowledge engineers and domain experts, and is considered to be a time-consuming and difficult task. As a result, scientists have started to develop automatic approaches to ontology learning and population. For the proposed research, we focus on the central subtask of ontology learning, being the hypernym detection task, where the system has to detect hierarchical semantic relationships, i.e. hypernym–hyponym relationships, between domain-specific terms, resulting in a domain-specific taxonomy. We propose in this paper a hybrid approach to automatic taxonomy learning, which combines a data-driven and a knowledge-based component. The data-driven component is composed of a lexico-syntactic pattern-based module, a morpho-syntactic analyzer and a distributional model, whereas the knowledge-based component extracts structured semantic information from the Linked Open Data cloud (DBpedia) and WordNet. The proposed methodology has been applied to three different knowledge domains: viz. food , equipment and science . A thorough quantitative and qualitative evaluation has shown promising results for all considered test domains. In addition, the results show a clear contribution of all different modules to the automatic taxonomy learning task. Although there is still room for improvement for all different modules, our approach outperforms state-of-the-art systems that participated in the SemEval "Taxonomy Extraction Evaluation" task when it comes to comparing the automatically constructed taxonomy against a manually verified gold standard taxonomy. As all modules are run automatically, the system provides a flexible and domain-independent approach to automatic taxonomy learning and could be an important step in solving the knowledge acquisition bottleneck in ontology learning.
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This study presents a new field experimental approach for measuring age discrimination in hiring. In addition to the classical approach in which candidates' ages are randomly assigned within pairs of fictitious résumés that are sent to real vacancies, we randomly assign between these pairs the activities undertaken by the older candidates during their additional post-educational years. When applying this design to the case of Belgium, we find that age discrimination depends fundamentally on the older candidates' career patterns. Older age only robustly affects call-back if the older candidate was employed in an out-of-field job during his or her extra post-educational years.
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We report on efficient optical beam-steering using a hot-embossed reflective blazed grating in combination with liquid crystal. A numerical simulation of the electrical switching characteristics of the liquid crystal is performed and the results are used in an FDTD optical simulator to analyze the beam deflection. The corresponding experiment on the realized device is performed and is found to be in good agreement. Beam deflection angles of 4.4° upon perpendicular incidence are found with low applied voltages of 3.4V. By tilting the device with respect to the incoming optical beam it can be electronically switched such that the beam undergoes either total internal reflection or reflection with a tunable angle.
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This paper presents an iterative and adaptive perturbation technique for the analysis of nonuniform transmission lines. Place-dependent variations of the per-unit-length parameters are interpreted as perturbations with respect to their average values along the line. This allows casting the governing equations for the corresponding perturbations of the voltages and currents as those of a uniform transmission line with distributed sources. Therefore, standard transmission line theory is used to calculate these perturbation terms. Specifically, perturbations of increasing order are computed iteratively starting from the solution of the unperturbed line. The accuracy is adaptively adjusted by setting a threshold on the convergence of the solution. The algorithm turns out to be simple to implement and very accurate, yet faster than traditional approaches based on the discretization of the line into uniform sections. The technique is validated through the analysis of several nonuniform transmission line structures of relevance in EMC applications, namely uniformly and nonuniformly twisted wire pairs as well as a cable bundle with lacing cords.
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We respond to the letter [1] from Prof Elsner and colleagues to this journal in which comments are made regarding our recent review, "The Three Moments of Skin Cream Application: An evidence-based proposal for use of skin creams in the prevention of irritant contact dermatitis in the workplace"[2].
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Rumen bypass technologies aim at protecting nutrients, for example polyunsaturated fatty acids against degradation, in this case biohydrogenation, to ensure an unaffected passage through the rumen and enhanced intestinal absorption. Recently, a new encapsulation technology has been proposed based on the properties of the naturally occurring enzyme polyphenol oxidase (PPO). However, up till now no in vivo approval of the PPO-based bypass technology nor evidence of post-ruminal absorption is available. Proteins and PPO in this study were extracted from potato (Solanum tuberosum L.) tuber peels and used to emulsify triacylglycerols of a mixture of conjugated linoleic acid (CLA) isomers (Tonalin TG80, BASF-AG, Ludwigshafen, Germany) in water (20 mg oil per ml extract) before encapsulation was created by the cross-linking of interfacial proteins upon addition of the diphenol 4-methylcatechol (20 mM). This rumen bypass CLA emulsion or a commercially available protected CLA product (Lutrell Combi, BASF-AG, Ludwigshafen, Germany) as positive control was used to dose 7 g trans-10, cis-12 C18:2 per day to eight dairy cows during five consecutive days in a sequential set-up. Milk fat content and fatty acid composition was monitored to assess the transfer to milk of dietary CLA. Evidence for the protection in vivo against ruminal degradation, post-ruminal uptake and transfer to the milk was given as increased proportions of trans-10, cis-12 C18:2 were found in milk fat of cows compared with the periods before and after supplementation of both additives. Extra proof for the transfer to the milk was given because both supplements resulted in similar reductions in milk fat content, since trans-10, cis-12 C18:2 is known as an inhibitor of milk fat synthesis if sufficient amounts of this CLA reach the mammary gland. However, somewhat lower transfer efficiencies of trans-10, cis-12 C18:2 from the diet to the milk in the case of the rumen bypass CLA emulsions compared with the positive control and the occurrence of non-negligible levels of CLA in faecal material indicates there is still scope for further improvement of the new technology. In conclusion, the PPO based lipid protection technology could provide a worthy alternative for current rumen bypass products as the encapsulated CLA was effectively transferred to the milk.
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Infectious laryngotracheitis virus (ILTV) and infectious bronchitis virus (IBV) are two important avian respiratory viruses, which cause major economic losses in the worldwide commercial poultry. ILTV and IBV enter through respiratory and ocular routes. The ILTV and IBV invasion strategies at entry sites and subsequent pathogenesis mechanisms are poorly understood.
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Background/Purpose:
During repair of esophageal atresia with distal tracheo-esophageal fistula, air leakage through the fistula during mechanical ventilation can cause respiratory demise.
Methods:From February 2012 until November 2014, all patients with esophageal atresia and distal tracheo-esophageal fistula were subjected to preoperative tracheobronchoscopy. Relatively distal fistulas were cannulated with a Fogarty catheter and blocked by insufflation (video illustration). Relatively proximal distal fistulas were sealed by precise placement of a cuffed ventilation tube.
Results:Nine of 12 patients received Fogarty balloon placement. The fistula of the remaining 3 patients were sealed by careful tube placement. No complications related to tracheobronchoscopy or Fogarty placement were noted. All procedures were uneventful.
Conclusions:Preoperative tracheobronchoscopy to evaluate the usefulness of Fogarty balloon insertion or correct tube placement for distal tracheo-esophageal fistula is a safe and easy to perform procedure that can avoid complications in type C esophageal atresia repair.
