bluuebunny/crossref_metadata_2025 huggingface dataset:
Making safer preoperative arrangements for patients using vitamin K antagonists
Authors: van Fessem Joris , Willems Jessica , Kruip Marieke , Hoeks Sanne , Jan Stolker Robert
Published: January 2017

Use of vitamin K antagonists creates a risk for patient health and safety. The Dutch framework “Nationwide Standard Integrated Care of Anticoagulation” propagates a shared plan and responsibility by surgeon and anesthesiologist together in the preoperative setting. In our institution, this framework had not been implemented. Therefore, a quality-improvement project was started at the Anesthesia Department to improve perioperative safety.

After exploration of barriers, multiple interventions were carried out to encourage co-workers at the preoperative screening department to take shared responsibility: distribution of prints, adjustments in electronic patient records, introduction of a protocol and education sessions. Efficacy was measured retrospectively performing a before-after study collecting perioperative data of patients using vitamin K antagonists. The primary outcome measure was the percentage of predefined safe preoperative plans. Secondary outcome measures were (1) incidence of postoperative bleeding and thrombo-embolic events within the first 24 hours after intervention and (2) necessity to preoperative correction of anticoagulation.

Before intervention 72 (29%) safe, 93 (38%) partially unsafe and 83 (33%) unsafe arrangements were made. After the intervention these numbers were 105 (80%), 23 (17%) en 4 (3%), respectively: a significant 51% increase in safe preoperative plans (P<0.001). We observed no significant difference (P=0.369) regarding bleeding and thrombo-embolic events: pre-intervention 12 (5%) cases of postoperative bleeding were documented, vs. 6 (5%) post intervention and the number of thrombo-embolic events was 5 (2%) vs. 0. Also, no significant differences concerning preoperative correction of anticoagulation were observed: 11 (4%) vs. 8 (6%) (P=0.489).

This quality improvement project demonstrates a major improvement in safer preoperative arrangements in our institution regarding vitamin K antagonists, using the described interventions. A significant effect on bleeding or thrombo-embolic events or necessity to correction of anticoagulation could not be demonstrated.
Factors associated with relapse in adult patients discharged from the emergency department following acute asthma: a systematic review
Authors: Hill Jesse , Arrotta Nicholas , Villa-Roel Cristina , Dennett Liz , Rowe Brian H
Published: January 2017

A significant proportion of patients discharged from the emergency department (ED) with asthma exacerbations will relapse within 4 weeks. This systematic review summarises the evidence regarding relapses and factors associated with relapse in adult patients discharged from EDs after being treated for acute asthma. Following a registered protocol, comprehensive literature searches were conducted. Studies tracking outcomes for adults after ED management and discharge were included if they involved adjusted analyses. Methodological quality was assessed using the Newcastle–Ottawa Scale (NOS) and the Risk of Bias (RoB) Tool. Results were summarised using medians and IQRs or mean and SD, as appropriate. 178 articles underwent full-text review and 10 studies, of various methodologies, involving 32 923 patients were included. The majority of the studies were of high quality according to NOS and RoB Tool. Relapse proportions were 8±3%, 12±4% and 14±6% at 1, 2 and 4 weeks, respectively. Female sex was the most commonly reported and statistically significant factor associated with an increased risk of relapse within 4 weeks of ED discharge for acute asthma. Other factors significantly associated with relapse were past healthcare usage and previous inhaled corticosteroids (ICS) usage. A median of 17% of patients who are discharged from the ED will relapse within the first 4 weeks. Factors such as female sex, past healthcare usage and ICS use at presentation were commonly and significantly associated with relapse occurrence. Identifying patients with these features could provide clinicians with guidance during their ED discharge decision-making.
Non-traumatic incidental findings in patients undergoing whole-body computed tomography at initial emergency admission
Authors: Kroczek Eduard K , Wieners Gero , Steffen Ingo , Lindner Tobias , Streitparth Florian , Hamm Bernd , Maurer Martin H
Published: January 2017

Objective

To evaluate the number, localisation and importance of non-traumatic incidental findings (IFs) in patients with suspected or obvious multiple trauma undergoing whole-body CT (WBCT) in a level-1 trauma centre.

Methods

Between January 2009 and December 2013, a total of 2440 patients with trauma undergoing WBCT at admission to a level-1 trauma centre of a university hospital were retrospectively analysed, through imaging IFs unrelated to trauma with the radiological reports. All IFs were grouped into four categories according to their clinical relevance. Category 1: urgent treatment or further clarification needed; category 2: further examination and follow-up within 3–6 months required; category 3: findings with no immediate consequences for the treatment of the patient but of potential relevance in the future; category 4: harmless findings.

Results

Altogether, 5440 IFs in 2440 patients (1735 male, 705 female; mean age 45.1 years) were documented. In 204 patients (8.4%) urgent category 1 findings were reported, 766 patients (31.4%) had category 2 findings, 1236 patients (50.7%) had category 3 findings and 1173 patients (48.1%) had category 4 findings. Most IFs were detected in the abdomen/pelvis (42.5%). 602 (24.7%) of the patients had no IFs.

Conclusions

WBCT scans of unrelated trauma patients demonstrate a high rate of IF. A substantial percentage (8.4%) of patients had urgent category 1IFs and a high percentage (31.4%) had category 2 IFs requiring a follow-up. This high number of patients with polytrauma undergoing WBCT, having IFs of high relevance, poses a major challenge for the level-1 trauma centre in the acute and postacute management of these patients.
Can surf-lifeguards perform a quality cardiopulmonary resuscitation sailing on a lifeboat? A quasi-experimental study
Authors: Barcala-Furelos Roberto , Abelairas-Gomez Cristian , Palacios-Aguilar Jose , Rey Ezequiel , Costas-Veiga Javier , Lopez-Garcia Sergio , Rodriguez-Nunez Antonio
Published: January 2017

Purpose

Drowning is a high-priority public health problem around the world. The European Resuscitation Council Guidelines for Resuscitation 2015 put special emphasis on special environments like open waters. Stopping the drowning process as soon as possible and starting an early cardiopulmonary resuscitation (CPR) improve survival. Inflatable rescue boats (IRBs) are used around the world in the water rescue of drowning victims. Our objective was to test the quality of CPR performed by surf-lifeguards while sailing on an IRB.

Methods

A quasi-experimental simulation trial was conducted in Tenerife (Canary Islands—Spain) on September 2015. Ten surf-lifeguards were asked to perform a 2 min CPR on manikins in four different scenarios: (1) onshore, (2) on adrift boat, (3) on a boat sailing at 5 knots and (4) on a boat sailing at 10 knots. CPR was performed individually and was measured by means of CPRmeter (Laerdal, Norway) located on the standard manikin. Repeated measures analysis of variance was used in order to analyse the differences between scenarios.

Results

The composite of all CPR variables was over 84% in all conditions, but it was lower when CPR was performed on board: onshore (96.49±3.58%) versus adrift (91.80±3.56, p=0.04), sailing at 5 knots (88.65±5.54, p=0.03) and sailing at 10 knots (84.74±5.56, p=0.001).

Conclusion

Surf-lifeguards are able to deliver good-quality CPR even on a moving IRB, but their performance is lower than onshore. This fact should be considered in real cases to balance the risk and benefits of CPR on board.
Mandatory desexing of dogs: one step in the right direction to reduce the risk of dog bite? A systematic review
Authors: D'Onise Katina , Hazel Susan , Caraguel Charles
Published: January 2017

Introduction

Preventing dog bites is an intractable problem given the complex dog bite injury environment. Desexing of dogs has the opportunity of creating a safer injury environment, given the potential links between desexing and behaviour change in dogs.

Methods

A systematic review of the literature was conducted to examine the evidence for desexing of dogs to reduce dog bite risk within a population health paradigm. Medline and CAB Abstracts were searched for studies that reported data on the association of dog neuter status with the risk of dog bite. All definitions of dog bite were included and all empirical studies were included in the review, limited to those published in English. Quality appraisal and data extraction were based on the 2013 evidence-based practice and critical appraisal tool from the University of Auckland.

Results

Five out of six observational studies, from four study populations found evidence that intact dogs were associated with an increased risk of dog bite compared with desexed dogs. The effect sizes ranged across the studies and given the heterogeneity of the studies no single effect size on the association between desexing and dog bite risk could be estimated.

Conclusions

There is consistent evidence that desexing dogs is associated with a reduced risk of dog bite, although the studies reflect association and may not be causal. Although recent publications have suggested desexing is associated with health and behavioural costs in some breeds, population level evidence supports desexed dogs having a longer lifespan, and being less likely to wander with the added benefit of reducing unwanted litters. Thus, mandatory desexing presents a possible opportunity for prevention of dog bites expanding dog bite prevention beyond an education-only approach.
Are the poverty histories of neighbourhoods associated with psychosocial well-being among a representative sample of California mothers? An observational study
Authors: Walsemann Katrina M , Child Stephanie , Heck Katherine , Margerison-Zilko Claire , Braveman Paula , Marchi Kristen , Cubbin Catherine
Published: January 2017

Background

We examine the association between the poverty histories of neighbourhoods and three indicators of psychosocial well-being—depressive symptoms, sense of control and number of stressors—in an observational study of mothers of young children in California. We also consider if length of residence in a neighbourhood moderates the association between neighbourhood poverty history and psychosocial well-being.

Methods

Data come from the Geographic Research on Well-being (GROW) Study, a subsample of mothers who completed the population-based California Maternal and Infant Health Assessment in 2003–2007 and were reinterviewed in 2012–2013. Poverty histories of neighbourhoods were constructed using the Neighbourhood Change Database (1970–2000) and American Community Survey (2005–2009). The analytic sample included 2726 women from GROW residing in 1906 census tracts.

Results

Adjusting for individual socioeconomic and demographic characteristics, women living in neighbourhoods where poverty decreased over the 40-year period had lower odds of depressive symptoms and a greater sense of control than women living in long-term, low-poverty neighbourhoods. Women living in long-term high-poverty neighbourhoods or in neighbourhoods where poverty increased over the 40-year period reported lower sense of control than women living in long-term, low-poverty neighbourhoods and these effects were modified by length of time living in the neighbourhood. No significant effects of neighbourhood poverty histories were found for number of stressors.

Conclusions

Policies aimed at reducing neighbourhood poverty may improve mothers' psychosocial well-being.
Update on Disease-Modifying Therapies for Multiple Sclerosis
Authors: Vargas Diana L , Tyor William R
Published: January 2017

Multiple sclerosis (MS) is an autoimmune, demyelinating disease of the central nervous system (CNS). It predominantly affects young women and is one of the most common causes of disability in young adults. MS is characterized by formation of white matter lesions in the CNS as a result of inflammation, demyelination, and axonal loss. Treatment has been a focus of neurological research for over 60 years. A number of disease-modifying therapies (DMTs) have become available making MS a treatable disease. These compounds target the inflammatory response in MS. They work by decreasing the chances of relapse, decreasing the chances of new lesion formation seen on MRI of the CNS and slowing the accumulation of disability. The first drugs for MS to be available were interferon-β and glatiramer acetate. These work by modulating the inflammatory response via different mechanisms that are briefly discussed. Newer agents have since become available and have significantly changed the dynamics of MS treatment. These include fingolimod, dimethyl fumarate and teriflunomide, which are oral agents. Other second-line and third-line Food and Drug Administration (FDA) approved medications include natalizumab and alemtuzumab. Natalizumab is considered one of the most potent treatments for relapse prevention. However, the high risk of progressive multifocal leukoencephalopathy (PML), which is caused by JC virus infection in the brain, tempers the more widespread use of this agent; nevertheless, JC virus antibody tests have helped to stratify the risk of PML. Alemtuzumab, which also has a considerable side effect profile, is likewise highly efficacious. Ocrelizumab, a monoclonal antibody to CD20 on B cells, is a highly effective agent for MS that is likely to be approved soon by the FDA. MS is a major contributor to healthcare costs and it is critical that healthcare providers be aware of the availability and benefits of DMTs. It is imperative that prompt and adequate treatment be established on diagnosis. Changes in therapy should be considered when there is evidence of disease activity as well as accumulation of disability or safety or tolerability concerns.
Endovascular flow diversion for treatment of anterior communicating artery region cerebral aneurysms: a single-center cohort of 50 cases
Authors: Colby Geoffrey P , Bender Matthew T , Lin Li-Mei , Beaty Narlin , Huang Judy , Tamargo Rafael J , Coon Alexander L
Published: January 2017

Background

Flow diversion represents a novel but definitive treatment for recurrent and difficult-to-coil aneurysms of the anterior communicating artery (ACoA) region, of which reports are limited.

Objective

To determine the effectiveness of the Pipeline embolization device (PED) in treating aneurysms in the ACoA region.

Methods

We retrospectively reviewed an IRB-approved database of patients with an aneurysm at a single institution for patients with ACoA or A1–A2 aneurysms treated with PED. Data analyzed included demographics, aneurysm characteristics, procedural details, follow-up results, and outcomes.

Results

A total of 50 procedures were performed on 41 patients, including seven patients who underwent bilateral ‘H-pipe’ PED placement. The average age was 56 years and 46% of the patients were female. The average aneurysm size was 4.5 mm, and two large (>10 mm) aneurysms were treated. The vessel of origin was either the ACoA (26 aneurysms, 63%) or the A1–A2 junction (15 aneurysms, 37%). Eighteen patients (44%) had prior subarachnoid hemorrhage and 20 had previously been treated either with clipping (6 aneurysms, 15%) or coiling (14 aneurysms, 34%). Procedural success was achieved in 48/50 cases (96%) and two cases were aborted. Coils were deployed adjunctively in two cases (4%). Procedural outcomes included no deaths, one major ischemic stroke (2%), and two patients with intracranial hemorrhage (4%). Complete aneurysm occlusion was achieved in 81% of patients at 6 months and 85% of patients at last follow-up digital subtraction angiography.

Conclusions

The PED can be used safely and effectively in the treatment of aneurysms of the ACoA region. This represents a good alternative treatment option to microsurgical clipping and endovascular coiling.
Efficacy and safety of biological and targeted-synthetic DMARDs: a systematic literature review informing the 2016 update of the ASAS/EULAR recommendations for the management of axial spondyloarthritis
Authors: Sepriano Alexandre , Regel Andrea , van der Heijde Désirée , Braun Jürgen , Baraliakos Xenofon , Landewé Robert , Van den Bosch Filip , Falzon Louise , Ramiro Sofia
Published: January 2017

Objectives

To update the evidence for the efficacy and safety of (b)biological and (ts)targeted-synthetic disease-modifying anti-rheumatic drugs (DMARDs) in patients with axial spondyloarthritis (axSpA) to inform the 2016 update of the Assessment of SpondyloArthritis international Society/European League Against Rheumatism (ASAS/EULAR) recommendations for the management of axSpA.

Methods

Systematic literature review (2009–2016) for randomised controlled trials (RCT), including long-term extensions, strategy trials and observational studies (the latter was only for safety assessment and a comparator was required). Interventions were any bDMARD or tsDMARD. All relevant efficacy and safety outcomes were included.

Results

76 papers and 24 abstracts fulfilled the inclusion criteria. Large treatment effects were found both in radiographic axSpA (r-axSpA) and non-radiographic axSpA (nr-axSpA) for all tumour necrosis factor inhibitors (TNFi) (NNT to achieve ASAS40 response ranged between 2.6–5.2 for r-axSpA and 2.3–5.4 for nr-axSpA). For nr-axSpA, efficacy was superior for those who had objective signs of inflammation (positive C reactive protein or inflammation on MRI-SI). Secukinumab 150 mg has shown efficacy in two phase 3 RCTs (NNT to achieve ASAS40 response: 3.4 and 4.0). Ustekinumab and tofacitinib have shown positive results in phase 2/proof-of-concept trials; trials with apremilast, rituximab, interleukin (IL)-6 antagonists and abatacept have failed their primary end points. New (unknown) safety signals were not found in the trials but long-term observational safety data for TNFi are still scarce.

Conclusions

New evidence supports the efficacy and safety of TNFi both in r-axSpA and nr-axSpA. Secukinumab is the first drug targeting the IL-17 pathway in r-axSpA that has shown efficacy.
Efficacy and safety of non-pharmacological and non-biological pharmacological treatment: a systematic literature review informing the 2016 update of the ASAS/EULAR recommendations for the management of axial spondyloarthritis
Authors: Regel Andrea , Sepriano Alexandre , Baraliakos Xenofon , van der Heijde Désirée , Braun Jürgen , Landewé Robert , Van den Bosch Filip , Falzon Louise , Ramiro Sofia
Published: January 2017

To assess the efficacy and safety of non-biological therapies in patients with axial spondyloarthritis (axSpA) to inform the update of the Assessment of SpondyloArthritis international Society (ASAS)/European League Against Rheumatism (EULAR) recommendations for the management of axSpA. A systematic literature review (2009–2016) of all non-pharmacological treatments, non-biological drugs (except targeted synthetic disease-modifying antirheumatic drugs (DMARDs)) and surgical therapies was performed. Randomised controlled trials (RCTs) and clinical controlled trials were assessed for efficacy and safety, while observational studies with a comparator were assessed for safety. All relevant efficacy and safety outcomes were included. Study heterogeneity precluded data pooling. If possible, Cohen's effect size was calculated for non-pharmacological treatments. In total, 45 papers and 2 abstracts were included. Studies on non-pharmacological treatments were very heterogeneous but overall confirmed a benefit for regular exercises, with small improvements in disease activity, function and spinal mobility. New studies on non-steroidal anti-inflammatory drugs (NSAIDs) confirmed their efficacy and new safety signals were not found. NSAIDs used continuously compared with on-demand did not reduce the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) mean change over 2 years in patients with ankylosing spondylitis with normal C reactive protein (CRP; ≤5 mg/L) (1 ‘negative’ RCT (0.9 vs 0.8; p=0.62)), while for patients with high CRP, conflicting results were found (1 ‘positive’ RCT (0.2 vs 1.7; p=0.003), 1 ‘negative’ RCT (1.68 vs 0.96; p=0.28)). No new trials were found for conventional synthetic DMARDs (csDMARDs). Short-term high-dose systemic glucocorticoids showed limited efficacy. Regular exercises may improve several outcomes. Efficacy and safety of NSAIDs in axSpA are confirmed. Glucocorticoids are not proven to be effective in axSpA and new data on csDMARDs are lacking.
Determinants of the impact of blood pressure variability on neurological outcome after acute ischaemic stroke
Authors: de Havenon Adam , Bennett Alicia , Stoddard Gregory J , Smith Gordon , Chung Lee , O'Donnell Steve , McNally J Scott , Tirschwell David , Majersik Jennifer J
Published: January 2017

Introduction

Increased blood pressure variability (BPV) is detrimental after acute ischaemic stroke, but the interaction between BPV and neuroimaging factors that directly influence stroke outcome has not been explored.

Methods

We retrospectively reviewed inpatients from 2007 to 2014 with acute anterior circulation ischaemic stroke, CT perfusion and angiography at hospital admission, and a modified Rankin Scale (mRS) 30–365 days after stroke onset. BPV indices included SD, coefficient of variation and successive variation of the systolic blood pressure between 0 and 120 hours after admission. Ordinal logistic regression models were fitted to mRS with predictor variables of BPV indices. Models were further stratified by CT perfusion volumetric measurements, proximal vessel occlusion and collateral score.

Results

110 patients met the inclusion criteria. The likelihood of a 1-point rise in the mRS increased with every 10 mm Hg increase in BPV (OR for the 3 BPV indices ranged from 2.27 to 5.54), which was more pronounced in patients with larger ischaemic core volumes (OR 8.37 to 18.0) and larger hypoperfused volumes (OR 6.02 to 15.4). This association also held true for patients with larger mismatch volume, proximal vessel occlusion and good collateral vessels.

Conclusions

These results indicate that increased BPV is associated with worse neurological outcome after stroke, particularly in patients with a large lesion core volume, concurrent viable ischaemic penumbra, proximal vessel occlusion and good collaterals. This subset of patients, who are often not candidates for or fail acute stroke therapies such as intravenous tissue plasminogen activator or endovascular thrombectomy, may benefit from interventions aimed at reducing BPV.
Prevalence of Bartonella species infections in cats in Southern Germany
Authors: Bergmann M. , Englert T. , Stuetzer B. , Hawley J. R. , Lappin M. R. , Hartmann K.
Published: January 2017

Bartonella species are zoonotic pathogens, and infections in cats are common. However, prevalence in cats in Southern Germany is still unknown. Therefore, prevalence of Bartonella species DNA in blood of 479 Southern German cats was determined using a previously published conventional PCR targeting a fragment of the 16S‐23S rRNA intergenic spacer region. Associations between Bartonella bacteraemia, housing conditions, feline immunodeficiency virus (FIV) and feline leukaemia virus (FeLV) status, including progressive, regressive and abortive FeLV infection, were evaluated using Fisher's exact test. Prevalence of Bartonella species bacteraemia was 2.5 per cent (12/479; CI 0.01–0.04 per cent). Bartonella henselae DNA was amplified in 11 of the 12 cats. One cat was positive for Bartonella clarridgeiae DNA. Of the infected cats, 2/12 cats were ill; 6/12 cats had thrombocytopenia. There was a significantly higher risk of Bartonella species infection in young and shelter cats, but not in FIV‐infected or FeLV‐infected cats. Prevalence of Bartonella species bacteraemia is low in Southern German cats, but there is still a risk of zoonotic transmission associated with ownership of young cats. Most of the infected cats did not show clinical signs. Thrombocytopenia was common in Bartonella species‐infected cats and further studies are required to define its clinical relevance.
Basin evolution and destruction in an Early Proterozoic continental margin: the Rinkian fold–thrust belt of central West Greenland
Authors: Grocott John , McCaffrey Kenneth J. W.
Published: January 2017

In central West Greenland, early Palaeoproterozoic siliciclastic and carbonate sequences of the Karrat Group (shelf sequences of the Rae craton margin) were deposited in sedimentary basins controlled by NW- and SW-trending linked extensional fault systems. The shelf basins were later filled and overtopped by turbidite systems filling a foredeep advancing ahead of a thrust system – the Karrat Fjord thrust system – that propagated west to east. Deformation culminated in emplacement of basement-cored nappes, progressive deformation and high-grade metamorphism at
c.
1.87 Ga. Reactivation of lower plate growth faults formed dome- and basin-like folds and related thrusts that refolded the structure of the Karrat Fjord thrust system and inverted the shelf basins. The southern Karrat Fjord thrust system was reworked in a belt of intense ductile NW-directed thrusting – the Nunaarsussuaq thrust system – formed at
c.
1.84 Ga at the northern limit of the Nagssugtoqidian orogen. Kinematics of these events are at odds with the consensus view that the Rinkian fold–thrust belt is a northward extension of the Nagssugtoqidian orogen resulting from north–south convergence between the Rae and North Atlantic cratons. Application of structural restoration techniques to basin analysis of Palaeoproterozoic rocks has potential to provide new insights into Proterozoic orogenic processes worldwide.
Peroxisome proliferator-activated receptor-α expression induces alterations in cardiac myofilaments in a pressure-overload model of hypertrophy
Authors: Karam Chehade N. , Warren Chad M. , Henze Marcus , Banke Natasha H. , Lewandowski E. Douglas , Solaro R. John
Published: January 2017

Although alterations in fatty acid (FA) metabolism have been shown to have a negative impact on contractility of the hypertrophied heart, the targets of action remain elusive. In this study we compared the function of skinned fiber bundles from transgenic (Tg) mice that overexpress a relatively low level of the peroxisome proliferator-activated receptor α (PPARα), and nontransgenic (NTg) littermates. The mice (NTg-T and Tg-T) were stressed by transverse aortic constriction (TAC) and compared with shams (NTg-S and Tg-S). There was an approximate 4-fold increase in PPARα expression in Tg-S compared with NTg-S, but Tg-T hearts showed the same PPARα expression as NTg-T. Expression of PPARα did not alter the hypertrophic response to TAC but did reduce ejection fraction (EF) in Tg-T hearts compared with other groups. The rate of actomyosin ATP hydrolysis was significantly higher in Tg-S skinned fiber bundles compared with all other groups. Tg-T hearts showed an increase in phosphorylation of specific sites on cardiac myosin binding protein-C (cMyBP-C) and β-myosin heavy chain isoform. These results advance our understanding of potential signaling to the myofilaments induced by altered FA metabolism under normal and pathological states. We demonstrate that chronic and transient PPARα activation during pathological stress alters myofilament response to Ca2+through a mechanism that is possibly mediated by MyBP-C phosphorylation and myosin heavy chain isoforms.

NEW & NOTEWORTHY Data presented here demonstrate novel signaling to sarcomeric proteins by chronic alterations in fatty acid metabolism induced by PPARα. The mechanism involves modifications of key myofilament regulatory proteins modifying cross-bridge dynamics with differential effects in controls and hearts stressed by pressure overload.
Exosomes from pediatric dilated cardiomyopathy patients modulate a pathological response in cardiomyocytes
Authors: Jiang Xuan , Sucharov Juliana , Stauffer Brian L. , Miyamoto Shelley D. , Sucharov Carmen C.
Published: January 2017

Stimulation of the renin-angiotensin-aldosterone system (RAAS) and β-adrenergic receptors plays an important role in adult heart failure (HF). Despite the demonstrated benefits of RAAS inhibition and β-adrenergic receptor blockade in adult HF patients, no substantial improvement in survival rate has been observed in children with HF. This suggests that the underlying disease mechanism is uniquely regulated in pediatric HF. Here, we show that treatment of human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and neonatal rat ventricular myocytes (NRVMs) with serum from pediatric dilated cardiomyopathy (DCM) patients induces pathological changes in gene expression, which occur independently of the RAAS and adrenergic systems, suggesting that serum circulating factors play an important role in cardiac remodeling. Furthermore, exosomes purified from DCM serum induced pathological changes in gene expression in NRVMs and iPSC-CMs. Our results suggest that DCM serum exosomes mediate pathological responses in cardiomyocytes and may propagate the pediatric HF disease process, representing a potential novel therapeutic target specific to this population.

NEW & NOTEWORTHY The results of this work could alter the present paradigm of basing clinical pediatric heart failure (HF) treatment on outcomes of adult HF clinical trials. The use of serum-treated primary cardiomyocytes may define age-specific mechanisms in pediatric HF with the potential to identify unique age-appropriate and disease-specific therapy.

Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/exosomes-in-pediatric-dilated-cardiomyopathy/ .
Leonardo da Vinci: engineer, bioengineer, anatomist, and artist
Authors: West John B.
Published: January 2017

Leonardo da Vinci (1452–1519) enjoys a reputation as one of the most talented people of all time in the history of science and the arts. However, little attention has been given to his contributions to physiology. One of his main interests was engineering, and he was fascinated by structural problems and the flow patterns of liquids. He also produced a large number of ingenious designs for warfare and a variety of highly original flying machines. But of particular interest to us are his contributions to bioengineering and how he used his knowledge of basic physical principles to throw light on physiological function. For example, he produced new insights into the mechanics of breathing including the action of the ribs and diaphragm. He was the first person to understand the different roles of the internal and external intercostal muscles. He had novel ideas about the airways including the mode of airflow in them. He also worked on the cardiovascular system and had a special interest in the pulmonary circulation. But, interestingly, he was not able to completely divorce his views from those of Galen, in that although he could not see pores in the interventricular septum of the heart, one of his drawings included them. Leonardo was a talented anatomist who made many striking drawings of the human body. Finally, his reputation for many people is based on his paintings including the Mona Lisa that apparently attracts more viewers than any other painting in the world.
Genetic analysis of 10 pedigrees with inherited retinal degeneration by exome sequencing and phenotype-genotype association
Authors: Biswas Pooja , Duncan Jacque L. , Maranhao Bruno , Kozak Igor , Branham Kari , Gabriel Luis , Lin Jonathan H. , Barteselli Giulio , Navani Mili , Suk John , Parke Michelle , Schlechter Catherine , Weleber Richard G. , Heckenlively John R. , Dagnelie Gislin , Lee Pauline , Riazuddin S. Amer , Ayyagari Radha
Published: January 2017

Our purpose was to identify causative mutations and characterize the phenotype associated with the genotype in 10 unrelated families with autosomal recessive retinal degeneration. Ophthalmic evaluation and DNA isolation were carried out in 10 pedigrees with inherited retinal degenerations (IRD). Exomes of probands from eight pedigrees were captured using Nimblegen V2/V3 or Agilent V5+UTR kits, and sequencing was performed on Illumina HiSeq. The DHDDS gene was screened for mutations in the remaining two pedigrees with Ashkenazi Jewish ancestry. Exome variants were filtered to detect candidate causal variants using exomeSuite software. Segregation and ethnicity-matched control sample analysis were performed by dideoxy sequencing. Retinal histology of a patient with DHDDS mutation was studied by microscopy. Genetic analysis identified six known mutations in ABCA4 (p.Gly1961Glu, p.Ala1773Val, c.5461–10T>C), RPE65 (p.Tyr249Cys, p.Gly484Asp), PDE6B (p.Lys706Ter) and DHDDS (p.Lys42Glu) and ten novel potentially pathogenic variants in CERKL (p.Met323Val fsX20), RPE65 (p.Phe252Ser, Thr454Leu fsX31), ARL6 (p.Arg121His), USH2A (p.Gly3142Ter, p.Cys3294Trp), PDE6B (p.Gln652Ter), and DHDDS (p.Thr206Ala) genes. Among these, variants/mutations in two separate genes were observed to segregate with IRD in two pedigrees. Retinal histopathology of a patient with a DHDDS mutation showed severe degeneration of retinal layers with relative preservation of the retinal pigment epithelium. Analysis of exome variants in ten pedigrees revealed nine novel potential disease-causing variants and nine previously reported homozygous or compound heterozygous mutations in the CERKL, ABCA4, RPE65, ARL6, USH2A, PDE6B, and DHDDS genes. Mutations that could be sufficient to cause pathology were observed in more than one gene in one pedigree.
Nephron number, hypertension, and CKD: physiological and genetic insight from humans and animal models
Authors: Wang Xuexiang , Garrett Michael R.
Published: January 2017

The kidneys play a vital role in the excretion of waste products and the regulation of electrolytes, maintenance of acid–base balance, regulation of blood pressure, and production of several hormones. Any alteration in the structure of the nephron (basic functional unit of the kidney) can have a major impact on the kidney’s ability to work efficiently. Progressive decline in kidney function can lead to serious illness and ultimately death if not treated by dialysis or transplantation. While there have been numerous studies that implicate lower nephron numbers as being an important factor in influencing susceptibility to developing hypertension and chronic kidney disease, a direct association has been difficult to establish because of three main limitations: 1) the large variation in nephron number observed in the human population; 2) no established reliable noninvasive methods to determine nephron complement; and 3) to date, nephron measurements have been done after death, which doesn’t adequately account for potential loss of nephrons with age or disease. In this review, we will provide an overview of kidney structure/function, discuss the current literature for both humans and other species linking nephron deficiency and cardio-renal complications, as well as describe the major molecular signaling factors involved in nephrogenesis that modulate variation in nephron number. As more detailed knowledge about the molecular determinants of nephron development and the role of nephron endowment in the cardio-renal system is obtained, it will hopefully provide clinicians the ability to accurately identify people at risk to develop CKD/hypertension and lead to a shift in patient care from disease treatment to prevention.
Effective Combination Therapies for B-cell Lymphoma Predicted by a Virtual Disease Model
Authors: Du Wei , Goldstein Rebecca , Jiang Yanwen , Aly Omar , Cerchietti Leandro , Melnick Ari , Elemento Olivier
Published: January 2017

The complexity of cancer signaling networks limits the efficacy of most single-agent treatments and brings about challenges in identifying effective combinatorial therapies. In this study, we used chronic active B-cell receptor (BCR) signaling in diffuse large B-cell lymphoma as a model system to establish a computational framework to optimize combinatorial therapy in silico. We constructed a detailed kinetic model of the BCR signaling network, which captured the known complex cross-talk between the NFκB, ERK, and AKT pathways and multiple feedback loops. Combining this signaling model with a data-derived tumor growth model, we predicted viability responses of many single drug and drug combinations in agreement with experimental data. Under this framework, we exhaustively predicted and ranked the efficacy and synergism of all possible combinatorial inhibitions of eleven currently targetable kinases in the BCR signaling network. Ultimately, our work establishes a detailed kinetic model of the core BCR signaling network and provides the means to explore the large space of possible drug combinations. Cancer Res; 77(8); 1818–30. ©2017 AACR.
HSPA5 Regulates Ferroptotic Cell Death in Cancer Cells
Authors: Zhu Shan , Zhang Qiuhong , Sun Xiaofan , Zeh Herbert J. , Lotze Michael T. , Kang Rui , Tang Daolin
Published: January 2017

Ferroptosis is a form of regulated cell death driven by oxidative injury promoting lipid peroxidation, although detailed molecular regulators are largely unknown. Here, we show that heatshock 70-kDa protein 5 (HSPA5) negatively regulates ferroptosis in human pancreatic ductal adenocarcinoma (PDAC) cells. Mechanistically, activating transcription factor 4 (ATF4) resulted in the induction of HSPA5, which in turn bound glutathione peroxidase 4 (GPX4) and protected against GPX4 protein degradation and subsequent lipid peroxidation. Importantly, the HSPA5–GPX4 pathway mediated ferroptosis resistance, limiting the anticancer activity of gemcitabine. Genetic or pharmacologic inhibition of the HSPA5–GPX4 pathway enhanced gemcitabine sensitivity by disinhibiting ferroptosis in vitro and in both subcutaneous and orthotopic animal models of PDAC. Collectively, these findings identify a novel role of HSPA5 in ferroptosis and suggest a potential therapeutic strategy for overcoming gemcitabine resistance. Cancer Res; 77(8); 2064–77. ©2017 AACR.
CYP27A1 Loss Dysregulates Cholesterol Homeostasis in Prostate Cancer
Authors: Alfaqih Mahmoud A. , Nelson Erik R. , Liu Wen , Safi Rachid , Jasper Jeffery S. , Macias Everardo , Geradts Joseph , Thompson J. Will , Dubois Laura G. , Freeman Michael R. , Chang Ching-yi , Chi Jen-Tsan , McDonnell Donald P. , Freedland Stephen J.
Published: January 2017

In this study, we used a bioinformatic approach to identify genes whose expression is dysregulated in human prostate cancers. One of the most dramatically downregulated genes identified encodes CYP27A1, an enzyme involved in regulating cellular cholesterol homeostasis. Importantly, lower CYP27A1 transcript levels were associated with shorter disease-free survival and higher tumor grade. Loss of CYP27A1 in prostate cancer was confirmed at the protein level by immunostaining for CYP27A1 in annotated tissue microarrays. Restoration of CYP27A1 expression in cells where its gene was silenced attenuated their growth in vitro and in tumor xenografts. Studies performed in vitro revealed that treatment of prostate cancer cells with 27-hydroxycholesterol (27HC), an enzymatic product of CYP27A1, reduced cellular cholesterol content in prostate cancer cell lines by inhibiting the activation of sterol regulatory-element binding protein 2 and downregulating low-density lipoprotein receptor expression. Our findings suggest that CYP27A1 is a critical cellular cholesterol sensor in prostate cells and that dysregulation of the CYP27A1/27HC axis contributes significantly to prostate cancer pathogenesis. Cancer Res; 77(7); 1662–73. ©2017 AACR.
Cellular Model of Colon Cancer Progression Reveals Signatures of mRNAs, miRNA, lncRNAs, and Epigenetic Modifications Associated with Metastasis
Authors: Rokavec Matjaz , Horst David , Hermeking Heiko
Published: January 2017

Here, we developed and comprehensively characterized a cellular model of colon cancer progression consisting of four defined derivatives of a colon cancer cell line that resulted from consecutive epithelial–mesenchymal and mesenchymal–epithelial transitions (EMT/MET) and phenotypically recapitulate the metastatic cascade. Initial EMT was induced by prolonged exposure to IL6, a cytokine also generated by the tumor-stroma. Genome-wide characterization of transcriptional (mRNA, miRNA, and lncRNA) and epigenetic (DNA methylation, H3K4me3, H3K79me3, and H3K27me3 histone modifications) profiles of the cell derivatives, combined with correlative analyses of expression, methylation, and clinical data from the TCGA-COAD database gave insights into the molecular basis of their phenotypic changes. The signatures characterizing invasive, mesenchymal-like cell states as well as the metastases-derived epithelial-like state showed significant association with metastasis, positive nodal status, and poor survival of colon cancer patients. Global hypomethylation of gene-regulatory regions was observed during tumor progression, with the lowest degree of methylation present in cells isolated from metastases. Upregulation of an axon-guidance–related gene signature was the most significant feature of metastatic tumor cells and was also found in primary tumors from colon cancer patients with distant metastases. Furthermore, the microRNAs miR-99a, miR-100, and miR-125b showed elevated expression in mesenchymal-like cells, associated with poor survival, and promoted migration and invasion. Finally, elevated expression of H19 lncRNA due to promoter demethylation was observed in cells isolated from metastases and was associated with poor survival of colon cancer patients. In the future, our results may be further exploited for the discovery and evaluation of novel metastasis-associated mechanisms and biomarkers. Cancer Res; 77(8); 1854–67. ©2017 AACR.
Constitutive Phosphorylation of STAT3 by the CK2–BLNK–CD5 Complex
Authors: Rozovski Uri , Harris David M. , Li Ping , Liu Zhiming , Jain Preetesh , Veletic Ivo , Ferrajoli Alessandra , Burger Jan , O'Brien Susan , Bose Prithviraj , Thompson Philip , Jain Nitin , Wierda William , Keating Michael J. , Estrov Zeev
Published: January 2017

In chronic lymphocytic leukemia (CLL), STAT3 is constitutively phosphorylated on serine 727 and plays a role in the pathobiology of CLL. However, what induces constitutive phosphorylation of STAT3 is currently unknown. Mass spectrometry was used to identify casein kinase 2 (CK2), a serine/threonine kinase that coimmunoprecipitated with serine phosphorylated STAT3 (pSTAT3). Furthermore, activated CK2 incubated with recombinant STAT3 induced phosphorylation of STAT3 on serine 727. Although STAT3 and CK2 are present in normal B- and T cells, STAT3 is not constitutively phosphorylated in these cells. Further study found that CD5 and BLNK coexpressed in CLL, but not in normal B- or T cells, are required for STAT3 phosphorylation. To elucidate the relationship of CD5 and BLNK to CK2 and STAT3, STAT3 was immunoprecipitated from CLL cells, and CK2, CD5, and BLNK were detected in the immunoprecipitate. Conversely, STAT3, CD5, and BLNK were in the immunoprecipitate of CLL cells immunoprecipitated with CK2 antibodies. Furthermore, siRNA knockdown of CD5 or BLNK, or treatment with CD5-neutralizing antibodies significantly reduced the levels of serine pSTAT3 in CLL cells. Finally, confocal microscopy determined that CD5 is cell membrane bound, and fractionation studies revealed that the CK2/CD5/BLNK/STAT3 complex remains in the cytoplasm, whereas serine pSTAT3 is shuttled to the nucleus.

Implications: These data show that the cellular proteins CK2, CD5, and BLNK are required for constitutive phosphorylation of STAT3 in CLL. Whether this protein complex phosphorylates other proteins or inhibiting its activity would have clinical benefit in patients has yet to be determined. Mol Cancer Res; 15(5); 610–8. ©2017 AACR.
Impact of Ultrafiltration on Serum Sodium Homeostasis and its Clinical Implication in Patients With Acute Heart Failure, Congestion, and Worsening Renal Function
Authors: Kitai Takeshi , Grodin Justin L. , Kim Yong-Hyun , Tang W.H. Wilson
Published: January 2017

Background—

The relationship between changes in serum sodium with clinical events in acute heart failure patients using different decongestive events has not been investigated. This study aimed to describe changes in serum sodium levels during decongestion therapy in patients receiving stepped pharmacological therapy versus ultrafiltration.

Methods and Results—

We studied 188 patients who were enrolled in the CARRESS-HF trial (Cardiorenal Rescue Study in Acute Decompensated Heart Failure). Treatment-induced hyponatremia was defined as admission normonatremia (≥135 mEq/L) with a subsequent decrease (<135 mEq/L) during hospitalization. Patients treated with ultrafiltration had significantly lower sodium levels than those with conventional treatment at days 1, 4, and 7 (all
P
<0.01), whereas those at day 30 were similar between the groups. Changes in sodium levels in patients with ultrafiltration were negatively correlated to those in serum creatinine and plasma renin activity. The incidence of treatment-induced hyponatremia was significantly higher in the ultrafiltration group than those receiving conventional treatment (
P
=0.002). Although patients with discharge hyponatremia had a higher risk for composite end point of all-cause death, rehospitalization, or unscheduled hospital visit in comparison to those without (adjusted hazard ratio, 2.01; 95% confidence interval, 1.09–3.70;
P
=0.025), the risk was comparable between patients with treatment-induced hyponatremia and those who did not experience any hyponatremia (adjusted hazard ratio, 0.99; 95% confidence interval, 0.50–1.96;
P
=0.99).

Conclusions—

Fluid removal by ultrafiltration was associated with a decrease in serum sodium levels compared with diuretic treatment but returned to baseline levels at day 30. Discharge hyponatremia but not treatment-induced hyponatremia was associated with worse clinical outcomes.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00608491.
Risk Factors of Subacute Thrombosis After Intracranial Stenting for Symptomatic Intracranial Arterial Stenosis
Authors: Sun Xuan , Tong Xu , Lo Wai Ting , Mo Dapeng , Gao Feng , Ma Ning , Wang Bo , Miao Zhongrong
Published: January 2017

Background and Purpose—

We aimed to explore the risk factors of subacute thrombosis (SAT) after intracranial stenting for patients with symptomatic intracranial arterial stenosis.

Methods—

From January to December 2013, all symptomatic intracranial arterial stenosis patients who underwent intracranial stenting in Beijing Tiantan Hospital were prospectively registered into this study. Baseline clinical features and operative data were compared in patients who developed SAT with those who did not. Binary logistic regression model was used to determine the risk factors associated with SAT.

Results—

Of the 221 patients enrolled, 9 (4.1%) cases had SAT 2 to 8 days after stenting. Binary logistic analysis showed that SAT was related with tandem stenting (odds ratio [OR], 11.278; 95% confidence interval [CI], 2.422–52.519) and antiplatelet resistance (aspirin resistance: OR, 6.267; 95% CI, 1.574–24.952; clopidogrel resistance: OR, 15.526; 95% CI, 3.105–77.626; aspirin and clopidogrel resistance: OR, 12.246; 95% CI, 2.932–51.147; and aspirin or clopidogrel resistance: OR, 11.340; 95% CI, 2.282–56.344).

Conclusions—

Tandem stenting and antiplatelet resistance might contribute to the development of SAT after intracranial stenting in patients with symptomatic intracranial arterial stenosis.