Gadolinium decreases inflammation related to myocardial ischemia and reperfusion injury

<p>Abstract</p> <p>Background</p> <p>The lanthanide cation, gadolinium (GdCl₃) protects the myocardium against infarction following ischemia and reperfusion. Neutrophils and macrophages are the main leukocytes responsible for infarct expansion after reperfusion. GdCl₃interferes with macrophage and neutrophil function in the liver by decreasing macrophage secretion of inflammatory cytokines and neutrophil infiltration. We hypothesized that GdCl₃protects against ischemia and reperfusion injury by decreasing inflammation. We determined the impact of GdCl₃treatment for reperfusion injury on 1) circulating monoctye and neutrophil counts, 2) secretion of inflammatory cytokines, and 3) influx of monocytes and neutrophils into the myocardium.</p> <p>Methods</p> <p>Rats (n = 3-6/gp) were treated with saline or GdCl₃(20 μmol/kg) 15 min prior to a 30 min period of regional ischemia and 120 min reperfusion. Sham rats were not subject to ischemia. Blood was collected either after 30 min ischemia or 120 min reperfusion and hearts were harvested at 120 min reperfusion for tissue analysis. Blood was analyzed for leukocytes counts and cytokines. Tissue was analyzed for cytokines and markers of neutrophil and monocyte infiltration by measuring myeloperoxidase (MPO) and α-naphthyl acetate esterase (ANAE).</p> <p>Results</p> <p>GdCl₃did not affect the number of circulating neutrophils prior to ischemia. Two hours reperfusion resulted in a 2- and 3- fold increase in circulating monocytes and neutrophils, respectively. GdCl₃decreased the number of circulating monocytes and neutrophils during reperfusion to levels below those present prior to ischemia. Furthermore, after 120 min of reperfusion, GdCl₃decreased ANAE and MPO activity in the myocardium by 1.9-fold and 6.5-fold respectively. GdCl₃decreased MPO activity to levels below those measured in the Sham group. Serum levels of the major neutrophil chemoattractant cytokine, IL-8 were increased from pre-ischemic levels during ischemia and reperfusion in both control and GdCl₃treated rats. Likewise, IL-8 levels increased throughout the 3 hour time period in the Sham group. There was no difference in IL-8 detected in the myocardium after 120 min reperfusion between groups. In contrast, after 120 min reperfusion GdCl₃decreased the myocardial tissue levels of macrophage secreted cytokines, GM-CSF and IL-1.</p> <p>Conclusion</p> <p>GdCl₃treatment prior to ischemia and reperfusion injury decreased circulating monocytes and neutrophils, macrophage secreted cytokines, and leukocyte infiltration into injured myocardium. These results suggest GdCl₃decreased monoctye and neutrophil migration and activation and may be a novel treatment for inflammation during ischemia and reperfusion.</p

Urban Sanitation: New Terminology for Globally Relevant Solutions?

Progress toward Sustainable Development Goals for global access to safe sanitation is lagging significantly. In this Feature, we propose that misleading terminology leads to errors of categorization and hinders progress toward sanitation service provision in urban areas. Binary classifications such as “offsite/onsite” and “sewered/nonsewered” do not capture the need for “transport to treatment” or the complexity of urban sanitation and should be discarded. “Fecal sludge management” is used only in the development context of low- or middle-income countries, implying separate solutions for “poor” or “southern” contexts, which is unhelpful. Terminology alone does not solve problems, but rather than using outdated or “special” terminology, we argue that a robust terminology that is globally relevant across low-, middle-, and upper-income contexts is required to overcome increasingly unhelpful assumptions and stereotypes. The use of accurate, technically robust vocabulary and definitions can improve decisions about management and selection of treatment, promote a circular economy, provide a basis for evidence-based science and technology research, and lead to critical shifts and transformations to set policy goals around truly safely managed sanitation. In this Feature, the three current modes of sanitation are defined, examples of misconceptions based on existing terminology are presented, and a new terminology for collection and conveyance is proposed: (I) fully road transported, (II) source-separated mixed transport, (III) mixed transport, and (IV) fully pipe transported

Systemic AAV8-Mediated Gene Therapy Drives Whole-Body Correction of Myotubular Myopathy in Dogs

X-linked myotubular myopathy (XLMTM) results from MTM1 gene mutations and myotubularin deficiency. Most XLMTM patients develop severe muscle weakness leading to respiratory failure and death, typically within 2 years of age. Our objective was to evaluate the efficacy and safety of systemic gene therapy&nbsp;in the p.N155K canine model of XLMTM by performing a dose escalation study. A recombinant adeno-associated virus serotype 8 (rAAV8) vector expressing canine myotubularin (cMTM1) under the muscle-specific desmin promoter (rAAV8-cMTM1) was administered by simple peripheral venous infusion in XLMTM dogs at 10&nbsp;weeks of age, when signs&nbsp;of the disease are already present. A comprehensive analysis of survival, limb strength, gait, respiratory function, neurological assessment, histology, vector biodistribution, transgene expression, and immune response was performed over a 9-month study period. Results indicate that systemic gene therapy was well tolerated, prolonged lifespan, and corrected the skeletal musculature throughout the body in a dose-dependent manner, defining an efficacious dose in this large-animal model of the disease. These results support the development of gene therapy clinical trials for XLMTM

Evaluating the Clinical Validity of Gene-Disease Associations: An Evidence-Based Framework Developed by the Clinical Genome Resource

Supplemental Data Supplemental Data include 65 figures and can be found with this article online at http://dx.doi.org/10.1016/j.ajhg.2017.04.015. Supplemental Data Document S1. Figures S1–S65 Download Document S2. Article plus Supplemental Data Download Web Resources ClinGen, https://www.clinicalgenome.org/ ClinGen Gene Curation, https://www.clinicalgenome.org/working-groups/gene-curation/ ClinGen Gene Curation SOP, https://www.clinicalgenome.org/working-groups/gene-curation/projects-initiatives/gene-disease-clinical-validity-sop/ ClinGen Knowledge Base, https://search.clinicalgenome.org/kb/agents/sign_up OMIM, http://www.omim.org/ Orphanet, http://www.orpha.net/consor/cgi-bin/index.php With advances in genomic sequencing technology, the number of reported gene-disease relationships has rapidly expanded. However, the evidence supporting these claims varies widely, confounding accurate evaluation of genomic variation in a clinical setting. Despite the critical need to differentiate clinically valid relationships from less well-substantiated relationships, standard guidelines for such evaluation do not currently exist. The NIH-funded Clinical Genome Resource (ClinGen) has developed a framework to define and evaluate the clinical validity of gene-disease pairs across a variety of Mendelian disorders. In this manuscript we describe a proposed framework to evaluate relevant genetic and experimental evidence supporting or contradicting a gene-disease relationship and the subsequent validation of this framework using a set of representative gene-disease pairs. The framework provides a semiquantitative measurement for the strength of evidence of a gene-disease relationship that correlates to a qualitative classification: “Definitive,” “Strong,” “Moderate,” “Limited,” “No Reported Evidence,” or “Conflicting Evidence.” Within the ClinGen structure, classifications derived with this framework are reviewed and confirmed or adjusted based on clinical expertise of appropriate disease experts. Detailed guidance for utilizing this framework and access to the curation interface is available on our website. This evidence-based, systematic method to assess the strength of gene-disease relationships will facilitate more knowledgeable utilization of genomic variants in clinical and research settings

Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine

Business model innovations for scaling-up FSM [Faecal Sludge Management] businesses in low- and middle-income countries [Abstract only]

The majority of urban populations in low- and middle-income countries rely on onsite sanitation systems, which produce large amounts of faecal sludge. Collecting and treating faecal sludge could provide a viable business opportunity for private firms or public organizations. Despite the increasing efforts to create sustainable and economically viable businesses in the context of faecal sludge management (FSM), most businesses are still in the mode of securing their existence and maintaining their survival. Success is limited, and businesses have not been able to scale-up. Scaling-up entails reaching a critical mass and being able to cover a certain geographical service area. Scaling-up implies that the business provides reliable emptying services, which are affordable for poor people. An example of scaling-up is that businesses not only provide emptying services, but also faecal sludge treatment and resource recovery. IWMI and Sandec/Eawag are exploring the role of business model innovations in the scaling-up process of faecal sludge management. Our preliminary results suggest two distinct paths on how business model innovations can drive the scaling-up processes: (i) organic business growth; and (ii) replication of micro-enterprises. The first path represents a typical ‘organic’ business growth path. An ‘organic’ business growth means that the FSM enterprise attempts to make a stepwise extension of the business. Critical innovations in the business model refer to the tariff system, business planning and execution, and the market development for value added end-products. As an example, we will present Manila Water in the Philippines, and their success in scaling up FSM. The second path refers to a replication of micro-enterprises. Micro-enterprises are small firms, that specialize in FSM. They are operated with few employees (e.g. entrepreneur, helper, driver). Microenterprises compete with each other, which, in turn, helps lead to affordable prices. To remain profitable, the micro-enterprises have to drive business model innovations. Compared to path one, the business model innovations are not driven by a single organization, but rather through collective actions among the micro-enterprises. Path two illustrates “coopetition”. Coopetition means microenterprises compete to find customers, but cooperate in technology innovation to drive down costs, and innovate treatment technologies and resource recovery. As an example, we will present honeysucker businesses in Bangalore, India. The paper contributes to a better understanding of business challenges in the scaling-up process of FSM. It provides guidance for increasing geographical coverage, enhancing usage of emptying services, and increasing affordability of sanitation services at the household level

Business model innovations for scaling-up FSM [Faecal Sludge Management] businesses in low- and middle-income countries [Abstract only].

Paper presented at the Second International Faecal Sludge Management Conference, Durban, South Africa, 29 October - 1 November 2012The majority of urban populations in low- and middle-income countries rely on onsite sanitation systems, which produce large amounts of faecal sludge. Collecting and treating faecal sludge could provide a viable business opportunity for private firms or public organizations. Despite the increasing efforts to create sustainable and economically viable businesses in the context of faecal sludge management (FSM), most businesses are still in the mode of securing their existence and maintaining their survival. Success is limited, and businesses have not been able to scale-up. Scaling-up entails reaching a critical mass and being able to cover a certain geographical service area. Scaling-up implies that the business provides reliable emptying services, which are affordable for poor people. An example of scaling-up is that businesses not only provide emptying services, but also faecal sludge treatment and resource recovery. IWMI and Sandec/Eawag are exploring the role of business model innovations in the scaling-up process of faecal sludge management. Our preliminary results suggest two distinct paths on how business model innovations can drive the scaling-up processes: (i) organic business growth; and (ii) replication of micro-enterprises. The first path represents a typical 'organic' business growth path. An 'organic' business growth means that the FSM enterprise attempts to make a stepwise extension of the business. Critical innovations in the business model refer to the tariff system, business planning and execution, and the market development for value added end-products. As an example, we will present Manila Water in the Philippines, and their success in scaling up FSM. The second path refers to a replication of micro-enterprises. Micro-enterprises are small firms, that specialize in FSM. They are operated with few employees (e.g. entrepreneur, helper, driver). Microenterprises compete with each other, which, in turn, helps lead to affordable prices. To remain profitable, the micro-enterprises have to drive business model innovations. Compared to path one, the business model innovations are not driven by a single organization, but rather through collective actions among the micro-enterprises. Path two illustrates "coopetition". Coopetition means microenterprises compete to find customers, but cooperate in technology innovation to drive down costs, and innovate treatment technologies and resource recovery. As an example, we will present honeysucker businesses in Bangalore, India. The paper contributes to a better understanding of business challenges in the scaling-up process of FSM. It provides guidance for increasing geographical coverage, enhancing usage of emptying services, and increasing affordability of sanitation services at the household level