In vitro and in vivo delivery of a sustained release nanocarrier-based formulation of an MRTF/SRF inhibitor in conjunctival fibrosis

BACKGROUND: Sustained drug delivery is a large unmet clinical need in glaucoma. Here, we incorporated a Myocardin-Related Transcription Factor/Serum Response Factor inhibitor, CCG-222740, into slow release large unilamellar vesicles derived from the liposomes DOTMA (1,2-di-O-octadecenyl-3-trimethylammonium propane) and DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine), and tested their effects in vitro and in vivo. RESULTS: The vesicles were spherical particles of around 130 nm and were strongly cationic. A large amount of inhibitor could be incorporated into the vesicles. We showed that the nanocarrier CCG-222740 formulation gradually released the inhibitor over 14 days using high performance liquid chromatography. Nanocarrier CCG-222740 significantly decreased ACTA2 gene expression and was not cytotoxic in human conjunctival fibroblasts. In vivo, nanocarrier CCG-222740 doubled the bleb survival from 11.0 ± 0.6 days to 22.0 ± 1.3 days (p = 0.001), decreased conjunctival scarring and did not have any local or systemic adverse effects in a rabbit model of glaucoma filtration surgery. CONCLUSIONS: Our study demonstrates proof-of-concept that a nanocarrier-based formulation efficiently achieves a sustained release of a Myocardin-Related Transcription Factor/Serum Response Factor inhibitor and prevents conjunctival fibrosis in an established rabbit model of glaucoma filtration surgery

Thermal Properties of Graphene, Carbon Nanotubes and Nanostructured Carbon Materials

Recent years witnessed a rapid growth of interest of scientific and engineering communities to thermal properties of materials. Carbon allotropes and derivatives occupy a unique place in terms of their ability to conduct heat. The room-temperature thermal conductivity of carbon materials span an extraordinary large range - of over five orders of magnitude - from the lowest in amorphous carbons to the highest in graphene and carbon nanotubes. I review thermal and thermoelectric properties of carbon materials focusing on recent results for graphene, carbon nanotubes and nanostructured carbon materials with different degrees of disorder. A special attention is given to the unusual size dependence of heat conduction in two-dimensional crystals and, specifically, in graphene. I also describe prospects of applications of graphene and carbon materials for thermal management of electronics.Comment: Review Paper; 37 manuscript pages; 4 figures and 2 boxe

Primary aneurysmal bone cyst of coronoid process

BACKGROUND: Aneurysmal bone cysts are relatively uncommon in the facial skeleton. These usually affect the mandible but origin from the coronoid process is even rarer. To the best of our knowledge, this is the first reported case of a coronoid process aneurysmal bone cyst presenting as temporal fossa swelling. CASE PRESENTATION: A 17 year old boy presented with a progressively increasing swelling in the left temporal region developed over the previous 8 months. An expansile lytic cystic lesion originating from the coronoid process of the left mandible and extending into the infratemporal and temporal fossa regions was found on CT scan. It was removed by a superior approach to the infratemporal fossa. CONCLUSION: Aneurysmal bone cyst of the coronoid process can attain enormous dimensions until the temporal region is also involved. A superior approach to the infratemporal fossa is a reasonable approach for such cases, providing wide exposure and access to all parts of the lesion and ensuring better control and complete excision

Evidence Based Development of a Novel Lateral Fibula Plate (VariAx Fibula) Using a Real CT Bone Data Based Optimization Process During Device Development

Development of novel implants in orthopaedic trauma surgery is based on limited datasets of cadaver trials or artificial bone models. A method has been developed whereby implants can be constructed in an evidence based method founded on a large anatomic database consisting of more than 2.000 datasets of bones extracted from CT scans. The aim of this study was the development and clinical application of an anatomically pre-contoured plate for the treatment of distal fibular fractures based on the anatomical database

Imaging of Nitric Oxide in Nitrergic Neuromuscular Neurotransmission in the Gut

Background: Numerous functional studies have shown that nitrergic neurotransmission plays a central role in peristalsis and sphincter relaxation throughout the gut and impaired nitrergic neurotransmission has been implicated in clinical disorders of all parts of the gut. However, the role of nitric oxide (NO) as a neurotransmitter continues to be controversial because: 1) the cellular site of production during neurotransmission is not well established; 2) NO may interacts with other inhibitory neurotransmitter candidates, making it difficult to understand its precise role. Methodology/Principal Findings: Imaging NO can help resolve many of the controversies regarding the role of NO in nitrergic neurotransmission. Imaging of NO and its cellular site of production is now possible. NO forms quantifiable fluorescent compound with diaminofluorescein (DAF) and allows imaging of NO with good specificity and sensitivity in living cells. In this report we describe visualization and regulation of NO and calcium ($Ca^{2+}$) in the myenteric nerve varicosities during neurotransmission using multiphoton microscopy. Our results in mice gastric muscle strips provide visual proof that NO is produced de novo in the nitrergic nerve varicosities upon nonadrenergic noncholinergic (NANC) nerve stimulation. These studies show that NO is a neurotransmitter rather than a mediator. Changes in NO production in response to various pharmacological treatments correlated well with changes in slow inhibitory junction potential of smooth muscles. Conclusions/Significance: Dual imaging and electrophysiologic studies provide visual proof that during nitrergic neurotransmission NO is produced in the nerve terminals. Such studies may help define whether NO production or its signaling pathway is responsible for impaired nitrergic neurotransmission in pathological states

The Potential of Medical Abortion to Reduce Maternal Mortality in Africa: What Benefits for Tanzania and Ethiopia?

BACKGROUND: Unsafe abortion is estimated to account for 13% of maternal mortality globally. Medical abortion is a safe alternative. METHODS: By estimating mortality risks for unsafe and medical abortion and childbirth for Tanzania and Ethiopia, we modelled changes in maternal mortality that are achievable if unsafe abortion were replaced by medical abortion. We selected Ethiopia and Tanzania because of their high maternal mortality ratios (MMRatios) and contrasting situations regarding health care provision and abortion legislation. We focused on misoprostol-only regimens due to the drug's low cost and accessibility. We included the impact of medical abortion on women who would otherwise choose unsafe abortion and on women with unwanted/mistimed pregnancies who would otherwise carry to term. RESULTS: Thousands of lives could be saved each year in each country by implementing medical abortion using misoprostol (2122 in Tanzania and 2551 in Ethiopia assuming coverage equals family planning services levels: 56% for Tanzania, 31% for Ethiopia). Changes in MMRatios would be less pronounced because the intervention would also affect national birth rates. CONCLUSIONS: This is the first analysis of impact of medical abortion provision which takes into account additional potential users other than those currently using unsafe abortion. Thousands of women's lives could be saved, but this may not be reflected in as substantial changes in MMRatios because of medical abortion's demographic impact. Therefore policy makers must be aware of the inability of some traditional measures of maternal mortality to detect the real benefits offered by such an intervention

Genome-wide haplotype-based association analysis of major depressive disorder in Generation Scotland and UK Biobank

Generation Scotland received core funding from the Chief Scientist Office of the Scottish Government Health Directorate CZD/16/6 and the Scottish Funding Council HR03006. Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” (STRADL) Reference 104036/Z/14/Z. YZ acknowledges support from China Scholarship Council. IJD is supported by the Centre for Cognitive Ageing and Cognitive Epidemiology which is funded by the Medical Research Council and the Biotechnology and Biological Sciences Research Council (MR/K026992/1). AMMcI and T-KC acknowledges support from the Dr Mortimer and Theresa Sackler Foundation. We are grateful to all the families who took part, the general practitioners and the Scottish School of Primary Care for their help in recruiting them, and the whole Generation Scotland team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, healthcare assistants and nurses. Ethics approval for the study was given by the NHS Tayside committee on research ethics (reference 05/S1401/8)Peer reviewedPublisher PD

Congenital anomalies of the male urethra

The spectrum of congenital anomalies of the male urethra is presented. The embryologic basis of each anomaly, when known, is discussed. Clinical and imaging features of each entity are presented

Lipopolysaccharide and Tumor Necrosis Factor Regulate Parkin Expression via Nuclear Factor-Kappa B

Inflammation and oxidative stress have been implicated in the pathophysiology of Parkinson's disease (PD) and inhibition of microglial activation attenuates degeneration of dopaminergic (DA) neurons in animal models of PD. Loss-of-function mutations in the parkin gene, which encodes an E3 ubiquitin ligase, cause autosomal recessive parkinsonism. While most studies on Parkin have focused on its function in neurons, here we demonstrate that Parkin mRNA and protein is detectable in brain-resident microglia and peripheral macrophages. Using pharmacologic and genetic approaches, we found that Parkin levels are regulated by inflammatory signaling. Specifically, exposure to LPS or Tumor Necrosis Factor (TNF) induced a transient and dose-dependent decrease in Parkin mRNA and protein in microglia, macrophages and neuronal cells blockable by inhibitors of Nuclear Factor-Kappa B (NF-κB) signaling and not observed in MyD88-null cells. Moreover, using luciferase reporter assays, we identified an NF-κB response element in the mouse parkin promoter responsible for mediating the transcriptional repression, which was abrogated when the consensus sequence was mutated. Functionally, activated macrophages from Parkin-null mice displayed increased levels of TNF, IL-1β, and iNOS mRNA compared to wild type macrophages but no difference in levels of Nrf2, HO-1, or NQO1. One implication of our findings is that chronic inflammatory conditions may reduce Parkin levels and phenocopy parkin loss-of-function mutations, thereby increasing the vulnerability for degeneration of the nigrostriatal pathway and development of PD

Pre-hospital ECG for acute coronary syndrome in urban India: A cost-effectiveness analysis

<p>Abstract</p> <p>Background</p> <p>Patients with acute coronary syndrome (ACS) in India have increased pre-hospital delay and low rates of thrombolytic reperfusion. Use of ECG could reduce pre-hospital delay among patients who first present to a general practitioner (GP). We assessed whether performing ECG on patients with acute chest pain would improve long-term outcomes and be cost-effective.</p> <p>Methods</p> <p>We created a Markov model of urban Indian patients presenting to a GP with acute chest pain to compare a GP's performing an ECG versus not performing one. Variables describing the accuracy of a GP's referral decision in chest pain and ACS, ACS treatment patterns, the effectiveness of thrombolytic reperfusion, and costs were derived from Indian data where available and other developed world studies. The model was used to estimate the incremental cost-effectiveness ratio (ICER) of the intervention in 2007 US dollars per quality adjusted life years (QALY) gained.</p> <p>Results</p> <p>Under baseline assumptions, the ECG strategy cost an additional $12.65 per QALY gained compared to no ECG. Sensitivity analyses around the cost of the ECG, cost of thrombolytic, and referral accuracy of the GP yielded ICERs for the ECG strategy ranging between cost-saving and$1124/QALY. All results indicated the intervention is cost-effective under current World Health Organization recommendations.</p> <p>Conclusions</p> <p>While direct presentation to the hospital with acute chest pain is preferable, in urban Indian patients presenting first to a GP, an ECG performed by the GP is a cost-effective strategy to reduce disability and mortality. This strategy should be clinically studied and considered until improved emergency transport services are available.</p