tbuckley/cabot-search huggingface dataset:
Interventional studies for preventing surgical site infections in sub-Saharan Africa – A systematic review
Authors: Alexander M. Aiken, David M. Karuri, Anthony K. Wanyoro, Jana Macleod
Journal: International Journal of Surgery (2012)

There is a great need for safe surgical services in sub-Saharan Africa, but a major difficulty of performing surgery in this region is the high risk of post-operative surgical site infection (SSI). We aimed to systematically review which interventions had been tested in sub-Saharan Africa to reduce the risk of SSI and to synthesize their findings. We searched Medline, Embase and Global Health databases for studies published between 1995 and 2010 without language restrictions and extracted data from full-text articles. We identified 24 relevant articles originating from nine countries in sub-Saharan Africa. The methodological quality of these publications was diverse, with inconsistency in definitions used for SSI, period and method of post-operative follow-up and classification of wound contamination. Although it was difficult to synthesise information between studies, there was consistent evidence that use of single-dose pre-operative antibiotic prophylaxis could reduce, sometimes dramatically, the risk of SSI. Several studies indicated that alcohol-based handrubs could provide a low-cost alternative to traditional surgical hand-washing methods. Other studies investigated the use of drains and variants of surgical technique. There were no African studies found relating to several other promising SSI prevention strategies, including use of checklists and SSI surveillance. There is extremely limited research from sub-Saharan Africa on interventions to curb the occurrence of SSI. Although some of the existing studies are weak, several high-quality studies have been published in recent years. Standard methodological approaches to this subject are needed.
Constitutive activation of SHP2 in mice cooperates with ICSBP deficiency to accelerate progression to acute myeloid leukemia
Authors: Iwona Konieczna, Elizabeth Horvath, Hao Wang, Stephan Lindsey, Gurveen Saberwal, Ling Bei, Weiqi Huang, Leonidas Platanias, Elizabeth A. Eklund
Journal: Journal of Clinical Investigation (2008)

Myeloproliferative disorders (MPDs) are characterized by cytokine hypersensitivity and apoptosis resistance. Development of a block in myeloid differentiation is associated with progression of MPD to acute myeloid leukemia (AML) and portends poor prognosis. Identifying molecular markers of this transition may suggest targets for therapeutic intervention. Interferon consensus sequence binding protein (ICSBP, also known as IRF8) is an interferon-regulatory transcription factor that functions as a leukemia tumor suppressor. In mice, ICSBP deficiency induces an MPD that progresses to AML over time, suggesting that ICSBP deficiency is sufficient for myeloproliferation, but additional genetic lesions are necessary for AML. Since activity of ICSBP is influenced by tyrosine phosphorylation state, we hypothesized that mutations in molecular pathways that regulate this process might synergize with ICSBP deficiency for progression to AML. Consistent with this, we found that constitutive activation of SHP2 protein tyrosine phosphatase synergized with ICSBP haploinsufficiency to facilitate cytokine-induced myeloproliferation, apoptosis resistance, and rapid progression to AML in a murine bone marrow transplantation model. Constitutive SHP2 activation cooperated with ICSBP deficiency to increase the number of progenitors in the bone marrow and myeloid blasts in circulation, indicating a block in differentiation. Since SHP2 activation and ICSBP deficiency may coexist in human myeloid malignancies, our studies have identified a molecular mechanism potentially involved in disease progression in such diseases.
Protection of ischemic/reperfused canine myocardium by CL18/6, a monoclonal antibody to adhesion molecule ICAM-1
Authors: J.C. Hartman, D. C. Anderson, A. L. Wiltse, C. L. Lane, C. L. Rosenbloom, A. M. Manning, W. R. Humphrey, T. M. Wall, R. J. Shebuski
Journal: Cardiovascular Research (1995)

A blocking monoclonal antibody to intercellular adhesion molecule-1 (ICAM-1), CL18/6, previously has been demonstrated to inhibit neutrophil attachment to isolated vascular endothelium and cardiomyocytes. Due to the well known participation of ICAM-1 in the inflammatory responses associated with myocardial ischemia/reperfusion injury, we investigated if CL18/6 could attenuate myocardial ischemia/reperfusion injury in vivo.Saline (3-5 ml, i.v., n = 6), non-blocking control MAb CL18/1D8 or CL18/6 (both 0.5 mg kg-1, i.v., n = 4) were administered prior to coronary occlusion (1 h) and subsequent reperfusion (5 h) produced by inflation of a coronary balloon angioplasty catheter in isoflurane-anesthetized, closed-chest dogs. Heart rate and arterial pressure were measured, and regional myocardial blood flow (rMBF), and myeloperoxidase activity (MPO) to index local neutrophil sequestration, were determined. Myocardial infarct size (IS) was evaluated using the tetrazolium staining technique and expressed as a percent of area at risk (AR).Changes in heart rate and arterial pressure were insignificant throughout the experiment. rMBF (mean +/- s.e.m.) in the ischemic subendocardium for each treatment group was: Saline (0.07 +/- 0.02 ml min-1 g-1); CL18/1D8 (0.04 +/- 0.02); CL18/6 (0.06 +/- 0.02). IS/AR% was: saline (37 +/- 3%); CL18/1D8 (39 +/- 9%); CL18/6 (15 +/- 4%*); * = significantly different from CL18/1D8 and saline, P < 0.05. MPO assayed from AR immediately adjacent to the infarct was significantly reduced below infarct MPO only in the CL18/6 treated group-36%).The results indicate that CL18/6 antagonism of ICAM-1 provided cardioprotection associated with reduced neutrophil activity in vulnerable myocardium, and suggest that ICAM-1 mediated neutrophil sequestration in endangered cardiac tissue is an important mechanism of myocardial ischemia/reperfusion injury.
Protein kinase D1 (PKD1) activation mediates a compensatory protective response during early stages of oxidative stress-induced neuronal degeneration
Authors: Arunkumar Asaithambi, Arthi Kanthasamy, Hariharan Saminathan, Vellareddy Anantharam, Anumantha G Kanthasamy
Journal: Molecular Neurodegeneration (2011)

Oxidative stress is a key pathophysiological mechanism contributing to degenerative processes in many neurodegenerative diseases and therefore, unraveling molecular mechanisms underlying various stages of oxidative neuronal damage is critical to better understanding the diseases and developing new treatment modalities. We previously showed that protein kinase C delta (PKCδ) proteolytic activation during the late stages of oxidative stress is a key proapoptotic signaling mechanism that contributes to oxidative damage in Parkinson's disease (PD) models. The time course studies revealed that PKCδ activation precedes apoptotic cell death and that cells resisted early insults of oxidative damage, suggesting that some intrinsic compensatory response protects neurons from early oxidative insult. Therefore, the purpose of the present study was to characterize protective signaling pathways in dopaminergic neurons during early stages of oxidative stress.Herein, we identify that protein kinase D1 (PKD1) functions as a key anti-apoptotic kinase to protect neuronal cells against early stages of oxidative stress. Exposure of dopaminergic neuronal cells to H2O2 or 6-OHDA induced PKD1 activation loop (PKD1S744/748) phosphorylation long before induction of neuronal cell death. Blockade of PKCδ cleavage, PKCδ knockdown or overexpression of a cleavage-resistant PKCδ mutant effectively attenuated PKD1 activation, indicating that PKCδ proteolytic activation regulates PKD1 phosphorylation. Furthermore, the PKCδ catalytic fragment, but not the regulatory fragment, increased PKD1 activation, confirming PKCδ activity modulates PKD1 activation. We also identified that phosphorylation of S916 at the C-terminal is a preceding event required for PKD1 activation loop phosphorylation. Importantly, negative modulation of PKD1 by the RNAi knockdown or overexpression of PKD1S916A phospho-defective mutants augmented oxidative stress-induced apoptosis, while positive modulation of PKD1 by the overexpression of full length PKD1 or constitutively active PKD1 plasmids attenuated oxidative stress-induced apoptosis, suggesting an anti-apoptotic role for PKD1 during oxidative neuronal injury.Collectively, our results demonstrate that PKCδ-dependent activation of PKD1 represents a novel intrinsic protective response in counteracting early stage oxidative damage in neuronal cells. Our results suggest that positive modulation of the PKD1-mediated compensatory protective mechanism against oxidative damage in dopaminergic neurons may provide novel neuroprotective strategies for treatment of PD.
Enterocyte proliferation and intracellular bacteria in animals.
Authors: S McOrist, C J Gebhart, G H Lawson
Journal: Gut (1994)

Considerable proliferation of enterocytes, forming adenomatous growths within the intestinal mucosa, is a consistent feature of a number of enteric conditions in animals, now referred to under the general heading of pro- liferative enteropathy.These were originally described in pigs as adenomas of the ileum and colon1 and this condition was found to have a worldwide occurrence.2Similar conditions were subsequently described in a number of other animal species, again under the general heading of proliferative enteropathy or enteritis.The degree, however, of mucosal proliferation, corresponding to a description of hyperplasia, through adenoma to a more carcinomatous form, varies between species.Occasional reports of the condition in the fox,3 horse,4 and guinea pig5 describe a hyperplastic condition of the mucosa whereas hamsters6 7 develop adenomatous lesions similar to the pig, and the rat8 and ferret9 can develop an apparently carcinomatous condition with true metastases to local lymph nodes.Study of the disease was revolutionised in 1974 by the discovery that these lesions in pigs had the con- sistent presence of intracellular bacteria lying free in the cytoplasm of proliferating entero- cytes.'0These bacteria were not detected in normal animals or in unaffected portions of the intestine.The disease is infectious and is trans- mitted by oral exposure of animals to diseased mucosa.
Combined pulmonary fibrosis and emphysema syndrome associated with familial SFTPC mutation
Authors: V. Cottin, P. Reix, C. Khouatra, F. Thivolet-Bejui, D. Feldmann, J.-F. Cordier
Journal: Thorax (2011)

The syndrome of combined pulmonary fibrosis and emphysema (CPFE) in adults has not been previously associated with mutations of the surfactant protein-C ( SFTPC ) gene.

A 32-year-old woman, never smoker, presented with dyspnoea and dry cough, 3 days after a caesarean delivery. Physical examination revealed finger clubbing and bilateral basal crackles. There was no manifestation indicative of connective tissue disease. High-resolution computed tomography (HRCT) of the chest showed conspicuous centrilobular emphysema in the upper zones of the lungs, and diffuse, infiltrative lung disease in the lower zones (figure 1). Emphysema was apparent even in areas devoid of infiltrative changes. The bronchoalveolar lavage differential cell count was 57% neutrophils, 40% macrophages and 3% lymphocytes. Pulmonary function test …
The pan erbB inhibitor PD168393 enhances lysosomal dysfunction-induced apoptotic death in malignant peripheral nerve sheath tumor cells
Authors: L. Kohli, N. Kaza, N. J. Lavalley, K. L. Turner, S. Byer, S. L. Carroll, K. A. Roth
Journal: Neuro-Oncology (2012)

Malignant peripheral nerve sheath tumors (MPNSTs) are rapidly progressive Schwann cell neoplasms. The erbB family of membrane tyrosine kinases has been implicated in MPNST mitogenesis and invasion and, thus, is a potential therapeutic target. However, tyrosine kinase inhibitors (TKIs) used alone have limited tumoricidal activity. Manipulating the autophagy lysosomal pathway in cells treated with cytostatic agents can promote apoptotic cell death in some cases. The goal of this study was to establish a mechanistic basis for formulating drug combinations to effectively trigger death in MPNST cells. We assessed the effects of the pan erbB inhibitor PD168393 on MPNST cell survival, caspase activation, and autophagy. PD168393 induced a cytostatic but not a cytotoxic response in MPNST cells that was accompanied by suppression of Akt and mTOR activation and increased autophagic activity. The effects of autophagy modulation on MPNST survival were then assessed following the induction of chloroquine (CQ)–induced lysosomal stress. In CQ-treated cells, suppression of autophagy was accompanied by increased caspase activation. In contrast, increased autophagy induction by inhibition of mTOR did not trigger cytotoxicity, possibly because of Akt activation. We thus hypothesized that dual targeting of mTOR and Akt by PD168393 would significantly increase cytotoxicity in cells exposed to lysosomal stress. We found that PD168393 and CQ in combination significantly increased cytotoxicity. We conclude that combinatorial therapies with erbB inhibitors and agents inducing lysosomal dysfunction may be an effective means of treating MPNSTs.
Brain–gut interactions in the regulation of satiety: new insights from functional brain imaging
Authors: Qasim Aziz
Journal: Gut (2012)

Since the US army surgeon, William Beaumont, first described the effects of emotion on the gastric function of Alexis St Martin, a Canadian voyager who developed a gastrocutaneous fistula after a gunshot wound,1 considerable progress has been made in our understanding of the human brain–gut axis. Animal studies show that this axis, which comprises neural, hormonal and immune pathways, modulates all aspects of gut function and, perhaps most importantly, also modulates feeding behaviour. Our understanding of the human brain–gut axis has been greatly facilitated by functional brain imaging techniques, which have been used extensively to study visceral pain in health and disease. This work has led to important insights into the visceral pain neuromatrix, and its modulation by psychological and pharmacological factors.2 With advanced brain imaging methods, it has now become possible to study brain–gut communication that occurs through gut peptide hormones, affording an opportunity to understand the central mechanisms of satiety in health and conditions such as obesity and anorexia.

Eating behaviour is not just dictated by metabolic requirements but also by hedonic, psychological, social and environmental influences. Indeed, extremes of eating behaviours leading to obesity and anorexia in the Western world have occurred in the setting of abundance but also a more demanding and stressful environment. While animal studies have improved our basic understanding of the homoeostatic mechanisms of energy balance, translation to humans is limited by the inability to investigate the influence of hedonic and psychological influences on eating behaviour. This limitation is now being overcome through exciting recent brain imaging studies in humans, which are demonstrating a network of brain areas that are activated in response to nutrient ingestion, food cues and orexigenic and anorexigenic gut peptides. …
Mammalian RNase H2 removes ribonucleotides from DNA to maintain genome integrity
Authors: Bjoern Hiller, Martin Achleitner, Silke Glage, Ronald Naumann, Rayk Behrendt, Axel Roers
Journal: The Journal of Experimental Medicine (2012)

Ribonucleases H (RNases H) are endonucleases which cleave the RNA moiety of RNA/DNA hybrids. Their function in mammalian cells is incompletely understood. RNase H2 mutations cause Aicardi-Goutières syndrome, an inflammatory condition clinically overlapping with lupus erythematosus. We show that RNase H2 is essential in mouse embryonic development. RNase H2–deficient cells proliferated slower than control cells and accumulated in G2/M phase due to chronic activation of a DNA damage response associated with an increased frequency of single-strand breaks, increased histone H2AX phosphorylation, and induction of p53 target genes, most prominently the cyclin-dependent kinase inhibitor 1 encoding cell cycle inhibitor p21. RNase H2–deficient cells featured an increased genomic ribonucleotide load, suggesting that unrepaired ribonucleotides trigger the DNA damage response in these cells. Collectively, we show that RNase H2 is essential to remove ribonucleotides from the mammalian genome to prevent DNA damage.
S73 Circulating Regulators of Acute Muscle Wasting in the Critically Ill: GDF-15 a Potential Novel Driver of Acute Muscle Wasting
Authors: Saa Bloch, Jy Lee, SJ Wort, MI Polkey, PR Kemp, Mjd Griffiths
Journal: Thorax (2012)

<h3>Introduction</h3> Acute muscle wasting in the critically ill manifesting as intensive care unit acquired paresis (ICUAP) is common, and causes significant morbidity and mortality. The pathological mechanisms underlying ICUAP are poorly understood and, other than rehabilitation, no therapeutic interventions exist. It was hypothesised that known or potential circulating modulators of muscle mass: insulin-like growth factor-1 (IGF-1), myostatin and growth and differentiation factor-15 (GDF-15) would have distinct dynamic profiles in patients who develop acute muscle wasting in a novel human model of ICUAP. <h3>Methods</h3> In a prospective observational study of 42 patients undergoing elective high-risk cardiothoracic surgery (at the Royal Brompton Hospital, London, UK) those who developed muscle wasting were identified by ultrasound. Circulating IGF-1, myostatin and GDF-15 were assayed pre-operatively and over the first week post-operatively. The ability of GDF-15 to cause muscle wasting in vitro was determined in cultured C2C12 myotubes. <h3>Main results</h3> 23 of 42 patients (55%) developed quadriceps atrophy. Plasma concentrations of IGF-1 and unexpectedly myostatin, known mediators of muscle hypertrophy and atrophy respectively, both decreased from baseline in the first post operative days. By contrast, plasma GDF-15 concentrations increased in all patients. This increase in GDF-15 was higher (535%±308% versus 495%±247%) and sustained at day 7 in those who developed muscle wasting (day 7 compared with baseline, p&lt;0.01), but recovered in the non-wasting group (p&gt;0.05). Furthermore IGF-1 also did not recover in those who developed muscle wasting (day 7 compared with baseline, p&lt;0.01) but did in the non-wasting group (p&gt;0.05). Myostatin recovered to baseline in both groups. Finally, we demonstrated that GDF-15 caused atrophy of myotubes in vitro (average control myotube diameter was 26.3±9.0 µm versus 22.3±7.5 µm for GDF-15 treated myotubes, equating to 15% myotube atrophy, p= 0.011). <h3>Conclusion</h3> This data supports the hypothesis that acute muscle loss occurs as a result of an imbalance between drivers of muscle atrophy and hypertrophy. GDF-15 is a potential novel mediator of muscle atrophy in ICUAP, which may become a therapeutic target in patients with ICUAP and other forms of acute muscle wasting.
Comprehensive transcriptome analysis of mouse embryonic stem cell adipogenesis unravels new processes of adipocyte development
Authors: Nathalie Billon, Raivo Kolde, Jüri Reimand, Miguel C Monteiro, Meelis Kull, Hedi Peterson, Konstantin Tretyakov, Priit Adler, Brigitte Wdziekonski, Jaak Vilo, Christian Dani
Journal: Genome biology (2010)

Abstract Background The current epidemic of obesity has caused a surge of interest in the study of adipose tissue formation. While major progress has been made in defining the molecular networks that control adipocyte terminal differentiation, the early steps of adipocyte development and the embryonic origin of this lineage remain largely unknown. Results Here we performed genome-wide analysis of gene expression during adipogenesis of mouse embryonic stem cells (ESCs). We then pursued comprehensive bioinformatic analyses, including de novo functional annotation and curation of the generated data within the context of biological pathways, to uncover novel biological functions associated with the early steps of adipocyte development. By combining in-depth gene regulation studies and in silico analysis of transcription factor binding site enrichment, we also provide insights into the transcriptional networks that might govern these early steps. Conclusions This study supports several biological findings: firstly, adipocyte development in mouse ESCs is coupled to blood vessel morphogenesis and neural development, just as it is during mouse development. Secondly, the early steps of adipocyte formation involve major changes in signaling and transcriptional networks. A large proportion of the transcription factors that we uncovered in mouse ESCs are also expressed in the mouse embryonic mesenchyme and in adipose tissues, demonstrating the power of our approach to probe for genes associated with early developmental processes on a genome-wide scale. Finally, we reveal a plethora of novel candidate genes for adipocyte development and present a unique resource that can be further explored in functional assays.
NOD2 regulates hematopoietic cell function during graft-versus-host disease
Authors: Olaf Penack, Odette M. Smith, Amy Cunningham-Bussel, Xin Liu, Uttam Rao, Nury Yim, Il-Kang Na, Amanda M. Holland, Arnab Ghosh, Sydney X. Lu, Robert R. Jenq, Chen Liu, George F. Murphy, Katharina Brandl, Marcel R.M. van den Brink
Journal: The Journal of Experimental Medicine (2009)

Nucleotide-binding oligomerization domain 2 (NOD2) polymorphisms are independent risk factors for Crohn's disease and graft-versus-host disease (GVHD). In Crohn's disease, the proinflammatory state resulting from NOD2 mutations have been associated with a loss of antibacterial function of enterocytes such as paneth cells. NOD2 has not been studied in experimental allogeneic bone marrow transplantation (allo-BMT). Using chimeric recipients with NOD2(-/-) hematopoietic cells, we demonstrate that NOD2 deficiency in host hematopoietic cells exacerbates GVHD. We found that proliferation and activation of donor T cells was enhanced in NOD-deficient allo-BMT recipients, suggesting that NOD2 plays a role in the regulation of host antigen-presenting cells (APCs). Next, we used bone marrow chimeras in an experimental colitis model and observed again that NOD2 deficiency in the hematopoietic cells results in increased intestinal inflammation. We conclude that NOD2 regulates the development of GVHD through its inhibitory effect on host APC function.