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1.  Effect of Canagliflozin on Renal Threshold for Glucose, Glycemia, and Body Weight in Normal and Diabetic Animal Models 
PLoS ONE  2012;7(2):e30555.
Canagliflozin is a sodium glucose co-transporter (SGLT) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus (T2DM).
14C-alpha-methylglucoside uptake in Chinese hamster ovary-K cells expressing human, rat, or mouse SGLT2 or SGLT1; 3H-2-deoxy-d-glucose uptake in L6 myoblasts; and 2-electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed. Graded glucose infusions were performed to determine rate of urinary glucose excretion (UGE) at different blood glucose (BG) concentrations and the renal threshold for glucose excretion (RTG) in vehicle or canagliflozin-treated Zucker diabetic fatty (ZDF) rats. This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity.
Treatment with canagliflozin 1 mg/kg lowered RTG from 415±12 mg/dl to 94±10 mg/dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RTG. Canagliflozin dose-dependently decreased BG concentrations in db/db mice treated acutely. In ZDF rats treated for 4 weeks, canagliflozin decreased glycated hemoglobin (HbA1c) and improved measures of insulin secretion. In obese animal models, canagliflozin increased UGE and decreased BG, body weight gain, epididymal fat, liver weight, and the respiratory exchange ratio.
Canagliflozin lowered RTG and increased UGE, improved glycemic control and beta-cell function in rodent models of T2DM, and reduced body weight gain in rodent models of obesity.
PMCID: PMC3280264  PMID: 22355316
2.  Cutaneous angiosarcoma of the eyelids 
PMCID: PMC1771628  PMID: 12642333
angiosarcoma; eyelids
4.  Urinary retention secondary to mephedrone 
BMJ Case Reports  2013;2013:bcr2013008816.
We discuss a case of a 25-year-old man who presented to the acute medical take with a mixed overdose of mephedrone and paracetamol. Sixteen hours after ingestion, he reported that he was unable to micturate. A bladder scan confirmed that he was in urinary retention and he was catheterised. We discuss the increasingly popular recreational drug mephedrone including its more common side effects.
PMCID: PMC3603932  PMID: 23436895
5.  Lower gastrointestinal adverse effects of NSAIDS: an extreme example of a common problem 
BMJ Case Reports  2013;2013:bcr2012008274.
Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed throughout the world. Their adverse effects on the upper gastrointestinal (GI) tract are well documented and well known among clinicians and often mitigated against by coprescribing proton pump inhibitors. This case exemplifies the lesser-known lower GI adverse effects of NSAIDS. A 55-year-old patient took a large mixed overdose including more than 11 g of diclofenac. He went onto require subtotal colectomy following widespread perforations of an ulcerated large bowel as a direct result of exposure to a high-dose of NSAIDs. However, the upper GI tract remained relatively unaffected in comparison. This case highlights important lessons from recent literature identifying an increasing incidence of lower GI complications of NSAIDS, the limited protective effect of PPIs on the lower GI tract and the need for clinicians to now consider the integrity of the whole GI tract when prescribing NSAIDS.
PMCID: PMC3604199  PMID: 23429022
6.  Psycho-social factors related to willingness to use pre-exposure prophylaxis for HIV prevention among Black men who have sex with men attending a community event 
Sexual health  2014;11(3):244-251.
In the US, Black men who have sex with men (BMSM) are disproportionately affected by HIV/AIDS. Pre-exposure prophylaxis (PrEP) holds tremendous promise for curbing the HIV/AIDS epidemic among these men. However, many psycho-social components must be addressed in order to effectively implement this prevention tool among BMSM.
We assessed PrEP knowledge and use, health care access experiences, race-based medical mistrust, sexual partners and behaviors, and drug and alcohol use among 699 men attending a community event in the southeastern US. We used generalized linear modeling to assess factors associated with their willingness to use PrEP.
Three hundred ninety-eight men reported being BMSM and HIV negative status. Among these men, 60% reported being willing to use PrEP. Lack of being comfortable with talking to a health care provider about having sex with men, not having discussed having sex with a man with a health care provider, race-based medical mistrust, and alcohol consumption and substance use were all identified as barriers to willingness to use PrEP. Sexual risk taking, including number of sex partners and STI diagnosis, was not associated with willingness to use PrEP.
Findings from the current paper demonstrate the importance of acknowledging the role of various psycho-social factors in the uptake of PrEP. It is imperative that we prioritize research into better understanding these barriers as the failure to do so will impede the tremendous potential of this prevention technology.
PMCID: PMC4331017  PMID: 25001553
PrEP; BMSM; medical mistrust; substance use
7.  Vagus Nerve Stimulation Therapy Randomized to Different Amounts of Electrical Charge for Treatment-Resistant Depression: Acute and Chronic Effects 
Brain stimulation  2012;6(4):631-640.
Major depressive disorder is a prevalent, disabling, and often chronic or recurrent psychiatric condition. About 35% of patients fail to respond to conventional treatment approaches and are considered to have treatment-resistant depression (TRD).
We compared the safety and effectiveness of different stimulation levels of adjunctive vagus nerve stimulation (VNS) therapy for the treatment of TRD.
In a multicenter, double blind study, 331 patients with TRD were randomized to one of three dose groups: LOW (0.25 mA current, 130 μs pulse width), MEDIUM (0.5–1.0 mA, 250 μs), or HIGH (1.25–1.5 mA, 250 μs). A highly treatment-resistant population (>97% had failed to respond to ≥6 previous treatments) was enrolled. Response and adverse effects were assessed for 22 weeks (end of acute phase), after which output current could be increased, if clinically warranted. Assessments then continued until Week 50 (end of long-term phase).
VNS therapy was well tolerated. During the acute phase, all groups showed statistically significant improvement on the primary efficacy endpoint (change in Inventory of Depressive Symptomatology-Clinician Administered Version [IDS-C]), but not for any between-treatment group comparisons. In the long-term phase, mean change in IDS-C scores showed continued improvement. Post-hoc analyses demonstrated a statistically significant correlation between total charge delivered per day and decreasing depressive symptoms; and analysis of acute phase responders demonstrated significantly greater durability of response at MEDIUM and HIGH doses than at the LOW dose.
TRD patients who received adjunctive VNS showed significant improvement at study endpoint compared with baseline, and the effect was durable over 1 year. Higher electrical dose parameters were associated with response durability.
PMCID: PMC4321876  PMID: 23122916
Dose response; Treatment durability; Treatment-resistant depression; VNS efficacy; Vagus nerve stimulation
8.  Immune response to immunodominant Mycobacterium tuberculosis antigen ESAT-6 derived peptide is HLA-haplotype dependent 
The antigenic proteins of Mycobacterium tuberculosis (Mtb) have been defined. We used synthetic peptides of secreted antigens, early secreted antigenic target 6 (ESAT-6) and cultural filtrate protein-10 (CFP-10), of Mtb and characterized the immune response in context of HLA genes. Humanized mice lacking endogenous class II molecules but expressing various human DR and DQ HLA transgenes singly or as a haplotype were used to study the HLA-mediated immune response to peptides. Our observations showed that the overall response to the promiscuous ESAT-6 31-45 peptide may be dependent on the HLA haplotype rather than a single DR or DQ molecule. Further, our data showed that HLA transgenes generated a highly variable TH response to this promiscuous peptide. This provides an explanation for the variability of the bacillus Calmette-Guerin (BCG) vaccine. Our data highlights the use of HLA transgenic mice for determining the pathogenicity or therapeutic nature of a peptide in the context of HLA alleles.
PMCID: PMC4316384  PMID: 25664343
HLA; humanized mice ESAT-6; CFP-10; Tuberculosis
9.  Clinical validation of controlled grass pollen challenge in the Environmental Exposure Unit (EEU) 
The Environmental Exposure Unit (EEU), a controlled allergen exposure model of allergic rhinitis (AR), has traditionally utilized ragweed pollen. We sought to clinically validate the use of grass pollen in the EEU.
Healthy volunteers with a history of AR symptoms during grass pollen season and supportive skin test responses attended the EEU for 3 hrs of rye grass pollen exposure (Lolium Perenne). Non-atopic controls were also recruited. Participants assessed individual rhinoconjunctivitis symptoms to generate Total Nasal Symptom Score (TNSS; max 12) and Total Symptom Score (TSS; max 24) and recorded Peak Nasal Inspiratory Flow (PNIF) q30min while in the EEU. Participants returned the following day for an additional 3 hrs of pollen exposure. Two separate groups allowed for the exploration of lower vs. higher pollen concentrations and subsequent effects on symptoms.
78 participants were screened, of whom 39 were eligible and attended the 2x3h EEU visits, plus 8 non-atopic controls. Mean TSS, TNSS and PNIF values amongst participants in the higher pollen concentration group (target 3500 grains/m3) after the first 3 hr exposure were 18.9, 9.7 and 68 L/min, respectively. In comparison, mean TSS, TNSS and PNIF values in the lower pollen concentration (2500 grains/m3) group were only 13.3, 7.6, and 82 L/min, respectively. The subsequent day of pollen exposure did not appreciably alter the maximal TSS/TNSSs, but rather resulted in a more rapid onset of symptomatology, with higher mean scores at the 30 min, 60 min and 90 min timepoints. The non-atopic controls remained asymptomatic.
This study provides clinical validation of the ability to generate allergic rhinoconjunctivitis symptoms amongst grass-allergic individuals in the EEU.
PMCID: PMC4316395  PMID: 25653682
Allergic rhinitis; Environmental exposure unit; Grass pollen; Controlled allergen challenge
10.  Remarkable diversity of intron-1 of the para voltage-gated sodium channel gene in an Anopheles gambiae/Anopheles coluzzii hybrid zone 
Malaria Journal  2015;14:9.
Genomic differentiation between Anopheles gambiae and Anopheles coluzzii - the major malaria vectors in sub-Saharan Africa - is localized into large “islands” toward the centromeres of chromosome-X and the two autosomes. Linkage disequilibrium between these genomic islands was first detected between species-specific polymorphisms within ribosomal DNA genes (IGS-rDNA) on the X-chromosome and a single variant at position 702 of intron 1 (Int-1702) of the para Voltage-Gated Sodium Channel (VGSC) gene on chromosome arm 2 L. Intron-1 sequence data from West and Central Africa revealed two clearly distinct and species-specific haplogroups, each characterized by very low polymorphism, which has been attributed to a selective sweep. The aim of this study was to analyse Int-1 sequence diversity in A. gambiae and A. coluzzii populations from the Far-West of their range, in order to assess whether this selective-sweep signature could persist in a zone of high interspecific hybridization.
A 531 bp region of VGSC Int-1 was sequenced in 21 A. coluzzii, 31 A. gambiae, and 12 hybrids from The Gambia and Guinea Bissau, located within the Far-West geographical region, and in 53 A. gambiae s.l. samples from the rest of the range.
Far-West samples exhibit dramatic Int-1 polymorphism, far higher within each country than observed throughout the rest of the species range. Moreover, patterning of haplotypes within A. coluzzii confirms previous evidence of a macro-geographic subdivision into a West and a Central African genetic cluster, and reveals a possible genetic distinction of A. coluzzii populations from the Far-West.
The results suggest a relaxation of selective pressures acting across the VGSC gene region in the hybrid zone. Genetic differentiation in the Far-West could be attributable to a founder effect within A. coluzzii, with subsequent extensive gene flow with secondarily-colonizing A. gambiae, potentially yielding a novel insight on the dynamic processes impacting genetic divergence of these key malaria vectors.
Electronic supplementary material
The online version of this article (doi:10.1186/s12936-014-0522-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4308935  PMID: 25604888
Mosquito; Malaria; Hybridization
11.  S-nitrosothiol signaling regulates hepatogenesis and improves outcome following toxic liver injury 
Cell reports  2014;6(1):56-69.
Toxic liver injury is a leading cause of liver failure and death, due to the organ’s inability to regenerate amidst massive cell death, and few therapeutic options exist. The mechanisms coordinating damage protection and repair are poorly understood. Here, we show that S-nitrosothiols regulate liver growth during development and after injury in vivo: in zebrafish, NO enhanced liver formation independent of cGMP-mediated vasoactive effects. Following acetaminophen (APAP) exposure, inhibition of the enzymatic regulator, S-nitrosoglutathione reductase (GSNOR), minimized toxic liver damage, increased cell proliferation, and improved survival through sustained activation of the cytoprotective Nrf2 pathway. Preclinical studies of APAP injury in GSNOR-deficient mice confirmed conservation of hepatoprotective properties of S-nitrosothiol signaling across vertebrates; a GSNOR-specific inhibitor improved liver histology and acted together with the approved therapy N-acetylcysteine, to expand the therapeutic time window and improve outcome. These studies demonstrate that GSNOR inhibitors will be beneficial therapeutic candidates to treat liver injury.
PMCID: PMC4008725  PMID: 24388745
12.  Chemical Pyrophosphorylation of Functionally Diverse Peptides 
A highly selective and convenient method for the synthesis of pyrophosphopeptides in solution is reported. The remarkable compatibility with functional groups (alcohol, thiol, amine, carboxylic acid) in the peptide substrates suggests that the intrinsic nucleophilicity of the phosphoserine residue is much higher than previously appreciated. Because the methodology operates in polar solvents, including water, a broad range of pyrophosphopeptides can be accessed. We envision these peptides will find widespread applications in the development of mass spectrometry and antibody-based detection methods for pyrophosphoproteins.
PMCID: PMC3992712  PMID: 24350643
13.  Association Between Stillbirth and Illicit Drug Use and Smoking During Pregnancy 
Obstetrics and gynecology  2014;123(1):113-125.
To compare illicit drug and smoking use in pregnancies with and without stillbirth.
The Stillbirth Collaborative Research Network conducted a case-control study from March 2006 to September 2008, covering more than 90% of deliveries to residents of five a priori defined geographically diverse regions. The study attempted to include all stillbirths and representative liveborn controls. Umbilical cord samples from cases and controls were collected and frozen for subsequent batch analysis. Maternal serum was collected at delivery and batch analyzed for cotinine.
For 663 stillbirth deliveries, 418 (63%) had cord homogenate and 579 (87%) had maternal cotinine assays performed. For 1,932 live birth deliveries, 1,050 (54%) had cord homogenate toxicology and 1,545 (80%) had maternal cotinine assays performed. A positive cord homogenate test for any illicit drug was associated with stillbirth (OR 1.94; 95% CI 1.16, 3.27). The most common individual drug was cannabis (OR 2.34; 95% CI 1.13, 4.81), although the effect was partially confounded by smoking. Both maternal self-reported smoking history and maternal serum cotinine levels were associated in a dose-response relationship with stillbirth. Positive serum cotinine < 3 ng/ml and no reported history of smoking (proxy for passive smoke exposure) also was associated with stillbirth (OR 2.06; 95% CI 1.24, 3.41).
Cannabis, smoking, illicit drug use, and apparent exposure to second-hand smoke, separately or in combination, during pregnancy were associated with an increased risk of stillbirth. As cannabis use may be increasing with increased legalization, the relevance of these findings may increase as well.
PMCID: PMC3931517  PMID: 24463671
Melanoma represents a significant malignancy in humans and dogs. Different from genetically engineered models, sporadic canine melanocytic neoplasms share several characteristics with human disease that could make dogs a more relevant pre-clinical model. Canine melanomas rarely arise in sun-exposed sites. Most occur in the oral cavity, with a subset having intraepithelial malignant melanocytes mimicking the in situ component of human mucosal melanoma. The spectrum of canine melanocytic neoplasia includes benign lesions with some analogy to nevi, as well as invasive primary melanoma, and widespread metastasis. Growing evidence of distinct subtypes in humans, differing in somatic and predisposing germ-line genetic alterations, cell of origin, epidemiology, relationship to ultraviolet radiation and progression from benign to malignant tumors, may also exist in dogs. Canine and human mucosal melanomas appear to harbor BRAF, NRAS and c-kit mutations uncommonly, compared to human cutaneous melanomas, although both species share AKT and MAPK signaling activation. We conclude that there is significant overlap in the clinical and histopathological features of canine and human mucosal melanomas. This represents opportunity to explore canine oral cavity melanoma as a pre-clinical model.
PMCID: PMC4066658  PMID: 24128326
melanoma; animal model; comparative study; clinical trial design; image analysis; digital telepathology; signal transduction
15.  Breast cancer susceptibility risk associations and heterogeneity by E-cadherin tumor tissue expression 
E-cadherin is involved in cell-cell adhesion and epithelial-to-mesenchymal transitions (EMT). In cancers, loss or inactivation of E-cadherin is associated with epithelial cell proliferation and invasion. Here, we sought to determine if risk associations for 18 breast cancer susceptibility single nucleotide polymorphisms (SNPs) differed by E-cadherin tumor tissue expression in the Polish Breast Cancer Study (PBCS), using data on 1,347 invasive breast cancer cases and 2,366 controls. E-cadherin expression (low/high) was assessed using immunohistochemical staining of tumor tissue microarrays. Replication data on 2,006 cases and 6,714 controls from the Study of Epidemiology and Risk Factors in Cancer Heredity (SEARCH) was used to follow-up promising findings from PBCS. In PBCS, we found the rs11249433 SNP at the 1p11.2 locus to be more strongly associated with risk of E-cadherin low tumors (OR = 1.30, 95% CI 1.08 – 1.56) than with E-cadherin high tumors (OR = 1.06, 95% CI 0.95 – 1.18; case-only p-heterogeneity (p-het) = 0.05). Findings in PBCS for rs11249433 were replicated in SEARCH. Combined analyses of the two datasets for SNP rs11249433 revealed significant heterogeneity by E-cadherin expression (combined case-only p-het = 0.004). Further, among carriers of rs11249433, the highest risk was seen for E-cadherin low tumors that were ER-positive and of lobular histology. Our results in two independent data sets suggest that rs11249433, which is located between the NOTCH2 and FCGR1B genes within the 1p11.2 locus, is more strongly associated with risk of breast tumors with low or absent E-cadherin expression, and suggest that evaluation of E-cadherin tumor tissue expression may be useful in clarifying breast cancer risk factor associations.
PMCID: PMC4159747  PMID: 24292867
16.  Ethical Issues in Using Twitter for Public Health Surveillance and Research: Developing a Taxonomy of Ethical Concepts From the Research Literature 
The rise of social media and microblogging platforms in recent years, in conjunction with the development of techniques for the processing and analysis of “big data”, has provided significant opportunities for public health surveillance using user-generated content. However, relatively little attention has been focused on developing ethically appropriate approaches to working with these new data sources.
Based on a review of the literature, this study seeks to develop a taxonomy of public health surveillance-related ethical concepts that emerge when using Twitter data, with a view to: (1) explicitly identifying a set of potential ethical issues and concerns that may arise when researchers work with Twitter data, and (2) providing a starting point for the formation of a set of best practices for public health surveillance through the development of an empirically derived taxonomy of ethical concepts.
We searched Medline, Compendex, PsycINFO, and the Philosopher’s Index using a set of keywords selected to identify Twitter-related research papers that reference ethical concepts. Our initial set of queries identified 342 references across the four bibliographic databases. We screened titles and abstracts of these references using our inclusion/exclusion criteria, eliminating duplicates and unavailable papers, until 49 references remained. We then read the full text of these 49 articles and discarded 36, resulting in a final inclusion set of 13 articles. Ethical concepts were then identified in each of these 13 articles. Finally, based on a close reading of the text, a taxonomy of ethical concepts was constructed based on ethical concepts discovered in the papers.
From these 13 articles, we iteratively generated a taxonomy of ethical concepts consisting of 10 top level categories: privacy, informed consent, ethical theory, institutional review board (IRB)/regulation, traditional research vs Twitter research, geographical information, researcher lurking, economic value of personal information, medical exceptionalism, and benefit of identifying socially harmful medical conditions.
In summary, based on a review of the literature, we present a provisional taxonomy of public health surveillance-related ethical concepts that emerge when using Twitter data.
PMCID: PMC4285736  PMID: 25533619
social media; twitter messaging; ethics
18.  A national survey of the diagnosis and management of suspected ventilator-associated pneumonia 
BMJ Open Respiratory Research  2014;1(1):e000066.
Ventilator-associated pneumonia (VAP) affects up to 20% of patients admitted to intensive care units (ICU). It is associated with increased morbidity, mortality and healthcare costs. Despite published guidelines, variability in diagnosis and management exists, the extent of which remains unclear. We sought to characterise consultant opinions surrounding diagnostic and management practice for VAP in the UK.
An online survey was sent to all consultant members of the UK Intensive Care Society (n=∼1500). Data were collected regarding respondents’ individual practice in the investigation and management of suspected VAP including use of diagnostic criteria, microbiological sampling, chest X-ray (CXR), bronchoscopy and antibiotic treatments.
339 (23%) responses were received from a broadly representative spectrum of ICU consultants. All respondents indicated that microbiological confirmation should be sought, the majority (57.8%) stating they would take an endotracheal aspirate prior to starting empirical antibiotics. Microbiology reporting services were described as qualitative only by 29.7%. Only 17% of respondents had access to routine reporting of CXRs by a radiologist. Little consensus exists regarding technique for bronchoalveolar lavage (BAL) with the reported volume of saline used ranging from 5 to 500 mL. 24.5% of consultants felt inadequately trained in bronchoscopy.
There is wide variability in the approach to diagnosis and management of VAP among UK consultants. Such variability challenges the reliability of the diagnosis of VAP and its reported incidence as a performance indicator in healthcare systems. The data presented suggest increased radiological and microbiological support, and standardisation of BAL technique, might improve this situation.
PMCID: PMC4275666  PMID: 25553248
Respiratory Infection; Pneumonia; Assisted Ventilation
20.  A familial risk enriched cohort as a platform for testing early interventions to prevent severe mental illness 
BMC Psychiatry  2014;14(1):344.
Severe mental illness (SMI), including schizophrenia, bipolar disorder and severe depression, is responsible for a substantial proportion of disability in the population. This article describes the aims and design of a research study that takes a novel approach to targeted prevention of SMI. It is based on the rationale that early developmental antecedents to SMI are likely to be more malleable than fully developed mood or psychotic disorders and that low-risk interventions targeting antecedents may reduce the risk of SMI.
Families Overcoming Risks and Building Opportunities for Well-being (FORBOW) is an accelerated cohort study that includes a large proportion of offspring of parents with SMI and embeds intervention trials in a cohort multiple randomized controlled trial (cmRCT) design. Antecedents are conditions of the individual that are distressing but not severely impairing, predict SMI with moderate-to-large effect sizes and precede the onset of SMI by at least several years. FORBOW focuses on the following antecedents: affective lability, anxiety, psychotic-like experiences, basic symptoms, sleep problems, somatic symptoms, cannabis use and cognitive delay. Enrolment of offspring over a broad age range (0 to 21 years) will allow researchers to draw conclusions on a longer developmental period from a study of shorter duration. Annual assessments cover a full range of psychopathology, cognitive abilities, eligibility criteria for interventions and outcomes. Pre-emptive early interventions (PEI) will include skill training for parents of younger children and courses in emotional well-being skills based on cognitive behavioural therapy for older children and youth. A sample enriched for familial risk of SMI will enhance statistical power for testing the efficacy of PEI.
FORBOW offers a platform for efficient and unbiased testing of interventions selected according to best available evidence. Since few differences exist between familial and ’sporadic’ SMI, the same interventions are likely to be effective in the general population. Comparison of short-term efficacy of PEI on antecedents and the long term efficacy for preventing the onset of SMI will provide an experimental test of the etiological role of antecedents in the development of SMI.
PMCID: PMC4267051  PMID: 25439055
Severe mental illness; Schizophrenia; Bipolar disorder; Major depressive disorder; Cohort study; High-risk offspring; Targeted prevention; Early interventions
21.  Atg16l1 is Required for Autophagy in Intestinal Epithelial Cells and Protection of Mice from Salmonella Infection 
Gastroenterology  2013;145(6):10.1053/j.gastro.2013.08.035.
Background & Aims
Intestinal epithelial cells aid in mucosal defense by providing a physical barrier against entry of pathogenic bacteria and secreting anti-microbial peptides (AMPs). Autophagy is an important component of immune homeostasis. However, little is known about its role in specific cell types during bacterial infection in vivo. We investigated the role of autophagy in the response of intestinal epithelial and antigen-presenting cells to Salmonella infection in mice.
We generated mice deficient in Atg16l1 in epithelial cells (Atg16l1f/f x Villin-cre) or CD11c+ cells (Atg16l1f/f x CD11c-cre); these mice were used to assess cell type-specific, anti-bacterial autophagy. All responses were compared to Atg16l1f/f mice (controls). Mice were infected with Salmonella enterica serovar Typhimurium; cecum and small intestine tissues were collected for immunofluorescence, histology, and quantitative reverse transcription PCR analyses of cytokines and AMPs. Modulators of autophagy were screened to evaluate their effects on anti-bacterial responses in human epithelial cells.
Autophagy was induced in small intestine and cecum following infection with S Typhimurium, and required Atg16l1. S Typhimurium colocalized with microtubule-associated protein 1 light chain 3 beta (Map1lc3b or LC3) in the intestinal epithelium of control mice but not in Atg16l1f/f x Villin-cre mice. Atg16l1f/f x Villin-cre mice also had fewer Paneth cells and abnormal granule morphology, leading to reduced expression of AMP. Consistent with these defective immune responses, Atg16l1f/f x Villin-cre mice had increased inflammation and systemic translocation of bacteria compared with control mice. In contrast, we observed few differences between Atg16l1f/f x CD11c-cre and control mice. Trifluoperazine promoted autophagy and bacterial clearance in HeLa cells; these effects were reduced upon knockdown of ATG16L1.
Atg16l1 regulates autophagy in intestinal epithelial cells and is required for bacterial clearance. It is also required to prevent systemic infection of mice with enteric bacteria.
PMCID: PMC3840157  PMID: 23973919
mouse model; autophagy; intestinal barrier; mucosa
22.  Implementation of Geriatric Acute Care Best Practices:Initial Results of The NICHE SITE Self -Evaluation 
Nursing & health sciences  2013;15(4):518-524.
Nurses Improving Care of Healthsystem Elders (NICHE) provides hospitals with tools and resources to implement a geriatric initiative to improve health outcomes and experiences for older adults and their families. Beginning in 2011, members have engaged in a process of program self-evaluation, designed to evaluate internal progress toward developing, sustaining and disseminating NICHE. This manuscript describes the NICHE Site Self -evaluation and reports the inaugural self-evaluation data in 180 North American hospitals. NICHE members evaluate their program utilizing the following dimensions of a geriatric acute care program: guiding principles, organizational structures, leadership, geriatric staff competence, interdisciplinary resources and processes, patient- and family-centered approaches, environment of care, and quality metrics. The majority of NICHE sites were at the progressive implementation level (n= 100, 55.6%), having implemented interdisciplinary geriatric education and the geriatric resource nurse (GRN) model on at least one unit; 29% have implemented the GRN model on multiple units, including specialty areas. Bed size, teaching status, and Magnet® status were not associated with level of implementation, suggesting that NICHE implementation can be successful in a variety of settings and communities.
PMCID: PMC3949432  PMID: 23656606
acute care; models; older adults; program evaluation
24.  Delayed Administration of Bone Marrow Mesenchymal Stem Cell Conditioned Medium Significantly Improves Outcome After Retinal Ischemia in Rats 
Delayed treatment after ischemia is often unsatisfactory. We hypothesized that injection of bone marrow stem cell (BMSC) conditioned medium after ischemia could rescue ischemic retina, and in this study we characterized the functional and histological outcomes and mechanisms of this neuroprotection.
Retinal ischemia was produced in adult Wistar rats by increasing intraocular pressure for 55 minutes. Conditioned medium (CM) from rat BMSCs or unconditioned medium (uCM) was injected into the vitreous 24 hours after the end of ischemia. Recovery was assessed 7 days after ischemia using electroretinography, at which time we euthanized the animals and then prepared 4-μm-thick paraffin-embedded retinal sections. TUNEL and Western blot were used to identify apoptotic cells and apoptosis-related gene expression 24 hours after injections; that is, 48 hours after ischemia. Protein content in CM versus uCM was studied using tandem mass spectrometry, and bioinformatics methods were used to model protein interactions.
Intravitreal injection of CM 24 hours after ischemia significantly improved retinal function and attenuated cell loss in the retinal ganglion cell layer. CM attenuated postischemic apoptosis and apoptosis-related gene expression. By spectral counting, 19 proteins that met stringent identification criteria were increased in the CM compared to uCM; the majority were extracellular matrix proteins that mapped into an interactional network together with other proteins involved in cell growth and adhesion.
By restoring retinal function, attenuating apoptosis, and preventing retinal cell loss after ischemia, CM is a robust means of delayed postischemic intervention. We identified some potential candidate proteins for this effect.
Injection of bone marrow stem cell conditioned medium 24 hours after retinal ischemia significantly attenuated ischemic injury.
PMCID: PMC4062399  PMID: 24699381
retina; ischemia; stem cells; conditioned medium
25.  DNMT3A: the DioNysian MonsTer of acute myeloid leukaemia 
In the mythology of Ancient Greece, there was often a creative tension between the opposing forces of the gods Apollo and Dionysius, the two sons of Zeus. The Apollonian force was considered to be rational and lifegiving, whilst Dionysian forces were chaotic and elemental. Acute myeloid leukaemia is characterised by the clash of these forces: the chaotic proliferation of immature myeloid cells in the bone marrow overcomes the normal, orderly production of healthy blood cells. DNMT3A mutations occur early in the leukaemogenic process and may even act as “founder” mutations – the first step in a pathway towards malignant transformation. As such, these mutations may represent a Dionysian agent of disorder, inciting the chaotic myeloid proliferation and arrest of differentiation which are hallmarks of AML. This review will focus on the role of DNMT3A mutations in leukaemia pathogenesis, their influence on prognosis, and the potential for therapeutic targeting.
PMCID: PMC4250269  PMID: 25469209
DNMT3A; AML; acute myeloid leukaemia; prognosis

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