bluuebunny/crossref_metadata_2025 huggingface dataset:
Timed motor function tests capacity in healthy children
Authors: Pereira Aline Chacon , Ribeiro Márcia Gonçalves , Araújo Alexandra Prufer de Queiroz Campos
Published: November 2015

Objective

Motor function tests are used clinically and in research in children, particularly in those with neuromuscular disorders. Timed function tests are recommended in the follow-up of patients with neuromuscular disorders. This study was designed to know how healthy children perform on simple timed motor function tests.

Material and methods

In a cross-sectional observational study, 345 children aged 2–12 years, followed at the Federal University of Rio de Janeiro's Institute of Paediatric, were evaluated. To be eligible they had to have acquired independent walking before the age of 14 months, be able to cope and willing to participate in the study. Anthropometric and vital signs were verified, as well as contact with smokers. The following timed motor function tests were measured: time to rise from the floor (TRF), time to walk 10 meters (10MWT) and time to run 10 meters (10MRT).

Results

Improvement in time to perform those motor functions was found to occur in healthy preschool children. Stabilisation of mean times for those motor functions was seen thereafter: TRF of 1.2 s, 10MWT of 10 s and 10MRT of 5 s.

Conclusions

Walking and rising speed improve with age in preschoolers, as expected, and is shown to occur up to a plateau level. Our findings for the 10MWT, 10MRT and TRF are in line with those published in 2008 for the 6 minute walk test (6MWT). The motor functions used in the present study require less time and space than the ones in the 6MWT. They should be considered more universally applicable. Those tests could be used in childcare clinics as a screening for motor disorders such as the neuromuscular diseases.

Trial registration number

1.098.302.
Sudden cardiac arrest during emergency caesarean delivery in a 31-year-old woman, due to accelerated structural valve degeneration of an aortic valve bioprosthesis
Authors: O'Sullivan Crochan John , Bühlmann Lerjen Eva , Pellegrini Daniela , Eberli Franz Robert
Published: November 2015

The choice of prosthetic valve to implant in women of childbearing age requiring a valve replacement is challenging. Mechanical valves mandate the use of oral anticoagulation (OAC) for the prevention of thromboembolic complications, but the use of OAC during pregnancy can lead to maternal and fetal complications, in particular, warfarin embryopathy. Conversely, the use of bioprosthetic valves during pregnancy eliminates the need for OAC, but can instead be associated with accelerated structural valve degeneration. We present the case of a 31-year-old woman with a bioprosthetic valve in the aortic position, who developed undetected accelerated structural valve degeneration 5.5 years following implantation of a Mitroflow bioprosthetic aortic valve, and who suffered a catastrophic complication during emergency caesarean delivery as a result.
Clinical implication of blood glucose monitoring in general dental offices: the Ehime Dental Diabetes Study
Authors: Harase Tadahiro , Nishida Wataru , Hamakawa Tomohiro , Hino Satoshi , Shigematsu Kenji , Kobayashi Satoru , Sako Hirofumi , Ito Shirou , Murakami Hajime , Nishida Kei , Inoue Hiroshi , Fujisawa Masahito , Yoshizu Hiroshi , Kawamura Ryoichi , Takata Yasunori , Onuma Hiroshi , Shimizu Keita , Hamakawa Hiroyuki , Osawa Haruhiko
Published: November 2015

Objective

We examined whether general dentists can contribute to the detection of patients with undiagnosed diabetes and prediabetes by monitoring blood glucose in dental clinics.

Research design and methods

A total of 716 patients who visited clinics for dental treatment were enrolled and classified into 3 groups (mild, moderate, and severe) according to Kornman's criteria for periodontitis. The correlations between the casual blood glucose level, presence or absence of the history of diabetes, and/or severity of periodontitis were evaluated.

Results

68 patients (9.5%) had hyperglycemia (blood glucose ≥200 mg/dL). Of these patients, 20 (29.4%) did not have a history of diabetes. Blood glucose tended to be higher with greater periodontitis severity. Of the 3 groups, the severe periodontitis group had the highest proportion of patients with hyperglycemia (p<0.0001).

Conclusions

Patients with dental problems could be screened for diabetes, especially undiagnosed diabetes. General dentists could function as practitioners to screen for diabetes.

Trial registration number

UMIN-CTR 000014877.
Potential economic consequences of a cardioprotective agent for patients with myocardial infarction: modelling study
Authors: Verhoef Talitha I , Morris Stephen , Mathur Anthony , Singer Mervyn
Published: November 2015

Objective

To investigate the cost-effectiveness of a hypothetical cardioprotective agent used to reduce infarct size in patients undergoing percutaneous coronary intervention (PCI) after anterior ST-elevation myocardial infarction.

Methods

Design: A cost-utility analysis using a Markov model.Setting: The National Health Service in the UK.Patients: Patients undergoing PCI after anterior ST-elevation myocardial infarction.Interventions: A cardioprotective agent given at the time of reperfusion compared to no cardioprotection. We assumed the cardioprotective agent (given at the time of reperfusion) would reduce the risk and severity of heart failure (HF) after PCI and the risk of mortality after PCI (with a relative risk ranging from 0.6 to 1). The costs of the cardioprotective agent were assumed to be in the range £1000–4000.Main outcome measures: The incremental costs per quality-adjusted life-year (QALY) gained, using 95% CIs from 1000 simulations.

Results

Incremental costs ranged from £933 to £3820 and incremental QALYs from 0.04 to 0.38. The incremental cost-effectiveness ratio (ICER) ranged from £3311 to £63 480 per QALY gained. The results were highly dependent on the costs of a cardioprotective agent, patient age, and the relative risk of HF after PCI. The ICER was below the willingness-to-pay threshold of £20 000 per QALY gained in 71% of the simulations.

Conclusions

A cardioprotective agent that can reduce the risk of HF and mortality after PCI has a high chance of being cost-effective. This chance depends on the price of the agent, the age of the patient and the relative risk of HF after PCI.
Perspectives on financial incentives to health service providers for increasing breast feeding and smoking quit rates during pregnancy: a mixed methods study
Authors: Hoddinott Pat , Thomson Gill , Morgan Heather , Crossland Nicola , MacLennan Graeme , Dykes Fiona , Stewart Fiona , Bauld Linda , Campbell Marion K
Published: November 2015

Objective

To explore the acceptability, mechanisms and consequences of provider incentives for smoking cessation and breast feeding as part of the Benefits of Incentives for Breastfeeding and Smoking cessation in pregnancy (BIBS) study.

Design

Cross-sectional survey and qualitative interviews.

Setting

Scotland and North West England.

Participants

Early years professionals: 497 survey respondents included 156 doctors; 197 health visitors/maternity staff; 144 other health staff. Qualitative interviews or focus groups were conducted with 68 pregnant/postnatal women/family members; 32 service providers; 22 experts/decision-makers; 63 conference attendees.

Methods

Early years professionals were surveyed via email about the acceptability of payments to local health services for reaching smoking cessation in pregnancy and breastfeeding targets. Agreement was measured on a 5-point scale using multivariable ordered logit models. A framework approach was used to analyse free-text survey responses and qualitative data.

Results

Health professional net agreement for provider incentives for smoking cessation targets was 52.9% (263/497); net disagreement was 28.6% (142/497). Health visitors/maternity staff were more likely than doctors to agree: OR 2.35 (95% CI 1.51 to 3.64; p<0.001). Net agreement for provider incentives for breastfeeding targets was 44.1% (219/497) and net disagreement was 38.6% (192/497). Agreement was more likely for women (compared with men): OR 1.81 (1.09 to 3.00; p=0.023) and health visitors/maternity staff (compared with doctors): OR 2.54 (95% CI 1.65 to 3.91; p<0.001). Key emergent themes were ‘moral tensions around acceptability’, ‘need for incentives’, ‘goals’, ‘collective or divisive action’ and ‘monitoring and proof’. While provider incentives can focus action and resources, tensions around the impact on relationships raised concerns. Pressure, burden of proof, gaming, box-ticking bureaucracies and health inequalities were counterbalances to potential benefits.

Conclusions

Provider incentives are favoured by non-medical staff. Solutions which increase trust and collaboration towards shared goals, without negatively impacting on relationships or increasing bureaucracy are required.
Factors contributing to the rapid rise of caesarean section: a prospective study of primiparous Chinese women in Shanghai
Authors: Ji Honglei , Jiang Hong , Yang Limin , Qian Xu , Tang Shenglan
Published: November 2015

Objective

To identify factors contributing to the rapid rise of caesarean section in Shanghai through the prospective observation of changes in the preferred mode of delivery in pregnancy among primiparous Chinese women.

Design

Prospective study.

Setting

Two general hospitals in Shanghai.

Participants

A cohort of 832 low-risk primiparous women participated in the investigation from 2010–2012 three consecutive times, from their second to third trimester and, finally, 1–2 days post partum.

Methods

Participants were interviewed, using standard questionnaires, for information on demographic characteristics, maternal childbirth self-efficacy, their preference of delivery mode before childbirth and on the people most influential to them when making decisions on delivery mode. Caesarean section indications in the medical records were extracted by the investigators and assessed against clinical guidelines. Caesarean sections were categorised into three groups: guideline-defined indications, doctor-defined indications and maternal request.

Main outcome measures

Preferred mode of delivery; indications for caesarean section; actual mode of delivery; determinants of caesarean section.

Results

Of 832 pregnant women enrolled, 13.2% preferred caesarean section in the second trimester. This figure rose to 17.0% in the third trimester among 599 followed women. Of 523 women completing all three interviews, 58.1% underwent caesarean section. However, 34.9% of women undergoing caesarean section did not have any indications listed in the clinical guidelines nor based on maternal request. Multinomial regression analysis showed that doctors’ influence was one of the significant risk factors of undergoing caesarean section, with doctor-defined indications. Participants with low maternal childbirth self-efficacy were more likely to request caesarean sections themselves.

Conclusions

When deciding to deliver via caesarean section without justified clinical indications in the guideline, Chinese doctors played an important role in decision-making. Among primiparous Chinese women, decisions to use caesarean sections were often made during the third trimester or during the process of labour.
Informed shared decision-making programme on the prevention of myocardial infarction in type 2 diabetes: a randomised controlled trial
Authors: Buhse Susanne , Mühlhauser Ingrid , Heller Tabitha , Kuniss Nadine , Müller Ulrich Alfons , Kasper Jürgen , Lehmann Thomas , Lenz Matthias
Published: November 2015

Objective

To evaluate an informed shared decision-making programme (ISDM-P) for people with type 2 diabetes under high fidelity conditions.

Design

Randomised, single-blinded trial with sham control intervention and follow-up of 6 months.

Setting

Single-centre diabetes clinic providing care according to the national disease management programme in Germany.

Participants

154 people with type 2 diabetes without diagnosis of ischaemic heart disease or stroke.

Interventions

The ISDM-P is executed by diabetes educators. Core component is a patient decision aid on the prevention of myocardial infarction supplemented by a 90 min group teaching session. The structurally equivalent control intervention addresses stress issues.

Main outcome measures

Primary outcome was risk comprehension, including realistic expectations about benefits and harms of interventions. It was assessed by a 12-item questionnaire after the teaching session when patients set and prioritise their treatment goals. Key secondary outcome was adherence to treatment goals, operationalised as achievement of individual goals and medication uptake. ISDM-P teaching sessions were video-taped to monitor intervention fidelity.

Results

72 of 77 ISDM-P and 71 of 77 control patients completed the questionnaire (score 0–12). ISDM-P patients achieved higher levels of risk comprehension, mean score 8.25 vs 2.62, difference 5.63 (95% CI 4.82 to 6.44), and realistic expectations (score 0–6), 4.51 vs 0.85, 3.67 (3.23 to 4.11). More ISDM-P patients wished to take statins, 59.2% vs 30.4%, 28.7% (12.9% to 44.5%); more prioritised blood pressure control, 51.4% vs 25.7%, and fewer intensive glucose control, 33.3% vs 60%, p=0.002. More ISDM-P patients achieved their glycated haemoglobin goals, 95.8% vs 85.7%, 10.1% (0.6% to 19.5%). Achievement of prioritised goals and medication uptake were comparable between groups.

Conclusions

The ISDM-P on preventive measures in type 2 diabetes was effective under high fidelity conditions. Involvement of diabetes educators may facilitate implementation of the informed shared decision-making.

Trial registration number

ISRCTN84636255.
The NeuroAiD Safe Treatment (NeST) Registry: a protocol
Authors: Venketasubramanian Narayanaswamy , Kumar Ramesh , Soertidewi Lyna , Abu Bakar Azizi , Laik Carine , Gan Robert
Published: November 2015

Introduction

NeuroAiD (MLC601, MLC901), a combination of natural products, has been shown to be safe and to aid neurological recovery after brain injuries. The NeuroAiD Safe Treatment (NeST) Registry aims to assess its use and safety in the real-world setting.

Methods and analysis

The NeST Registry is designed as a product registry that would provide information on the use and safety of NeuroAiD in clinical practice. An online NeST Registry was set up to allow easy entry and retrieval of essential information including demographics, medical conditions, clinical assessments of neurological, functional and cognitive state, compliance, concomitant medications, and side effects, if any, among patients on NeuroAiD. Patients who are taking or have been prescribed NeuroAiD may be included. Participation is voluntary. Data collected are similar to information obtained during standard care and are prospectively entered by the participating physicians at baseline (before initialisation of NeuroAiD) and during subsequent visits. The primary outcome assessed is safety (ie, non-serious and serious adverse event), while compliance and neurological status over time are secondary outcomes. The in-person follow-up assessments are timed with clinical appointments. Anonymised data will be extracted and collectively analysed. Initial target sample size for the registry is 2000. Analysis will be performed after every 500 participants entered with completed follow-up information.

Ethics and dissemination

Doctors who prescribe NeuroAiD will be introduced to the registry by local partners. The central coordinator of the registry will discuss the protocol and requirements for implementation with doctors who show interest. Currently, the registry has been approved by the Ethics Committees of Universiti Kebangsaan Malaysia (Malaysia) and National Brain Center (Indonesia). In addition, for other countries, Ethics Committee approval will be obtained in accordance with local requirements.

Trial registration number

NCT02536079.
Implementing an institution-wide quality improvement policy to ensure appropriate use of continuous cardiac monitoring: a mixed-methods retrospective data analysis and direct observation study
Authors: Rayo Michael F , Mansfield Jerry , Eiferman Daniel , Mignery Traci , White Susan , Moffatt-Bruce Susan D
Published: November 2015

Background

Hospitals have been slow to adopt guidelines from the American Heart Association (AHA) limiting the use of continuous cardiac monitoring for fear of missing important patient cardiac events. A new continuous cardiac monitoring policy was implemented at a tertiary-care hospital seeking to monitor only those patients who were clinically indicated and decrease the number of false alarms in order to improve overall alarm response.

Methods

Leadership support was secured, a cross-functional alarm management task force was created, and a system-wide policy was developed based on current AHA guidelines. Process measures, including cardiac monitoring rate, monitored transport rate, emergency department (ED) boarding rate and the percentage of false, unnecessary and true alarms, were measured to determine the policy's impact on patient care. Outcome measures, including length of stay and mortality rate, were measured to determine the impact on patient outcomes.

Results

Cardiac monitoring rate decreased 53.2% (0.535 to 0.251 per patient day, p<0.001), monitored transport rate decreased 15.5% (0.216 to 0.182 per patient day, p<0.001), ED patient boarding rate decreased 36.6% (5.5% to 3.5% of ED patients, p<0.001) and the percentage of false alarms decreased (18.8% to 9.6%, p<0.001). Neither the length of stay nor mortality changed significantly after the policy was implemented.

Conclusions

The observed improvements in process measures coupled with no adverse effects to patient outcomes suggest that the overall system became more resilient to current and emerging demands. This study indicates that when collaboration across a diverse team is coupled with strong leadership support, policies and procedures such as this one can improve clinical practice and patient care.
Efficacy of psychotropic drugs in functional dyspepsia: systematic review and meta-analysis
Authors: Ford Alexander C , Luthra Pavit , Tack Jan , Boeckxstaens Guy E , Moayyedi Paul , Talley Nicholas J
Published: November 2015

Objective

Functional dyspepsia (FD) is a chronic gastroduodenal disorder. Individuals with FD demonstrate visceral hypersensitivity, abnormal central pain processing, and low mood, but it is unclear whether psychotropic drugs are an effective treatment for the condition. We performed a systematic review and meta-analysis of randomised controlled trials (RCTs).

Design

MEDLINE, EMBASE, EMBASE Classic, PsychINFO and the Cochrane Controlled Trials Register were searched (up to June 2015) for RCTs recruiting adults with FD comparing psychotropic drugs with placebo. We contacted authors directly to maximise trial eligibility and minimise risk of bias for studies. Dichotomous symptom data were pooled to obtain relative risk (RR) of remaining symptomatic after therapy, with 95% CIs.

Results

The search identified 2795 citations; 13 RCTs (1241 patients) were eligible. Ten trials were at low risk of bias. The RR of FD symptoms not improving with psychotropic drugs versus placebo was 0.78 (95% CI 0.68 to 0.91) (number needed to treat=6; 95% CI 4 to 16). However, benefit was limited to antipsychotics and tricyclic antidepressants. When only studies that excluded individuals with coexistent mood disorder were considered, there was no benefit. Total numbers of adverse events and adverse events leading to withdrawal were significantly more common, with a number needed to harm of 21 for both.

Conclusions

Psychotropic drugs may be an effective treatment for FD, but the effect appears to be limited to antipsychotics and tricyclic antidepressants with fewer trials for other agents, meaning that firm conclusions for efficacy cannot be made. More data from high quality RCTs are required to support their use in the treatment of FD.
Effective components of nurse-coordinated care to prevent recurrent coronary events: a systematic review and meta-analysis
Authors: Snaterse Marjolein , Dobber Jos , Jepma Patricia , Peters Ron J G , ter Riet Gerben , Boekholdt S Matthijs , Buurman Bianca M , Scholte op Reimer Wilma J M
Published: November 2015

Current guidelines on secondary prevention of cardiovascular disease recommend nurse-coordinated care (NCC) as an effective intervention. However, NCC programmes differ widely and the efficacy of NCC components has not been studied. To investigate the efficacy of NCC and its components in secondary prevention of coronary heart disease by means of a systematic review and meta-analysis of randomised controlled trials. 18 randomised trials (11 195 patients in total) using 15 components of NCC met the predefined inclusion criteria. These components were placed into three main intervention strategies: (1) risk factor management (13 studies); (2) multidisciplinary consultation (11 studies) and (3) shared decision making (10 studies). Six trials combined NCC components from all three strategies. In total, 30 outcomes were observed. We summarised observed outcomes in four outcome categories: (1) risk factor levels (16 studies); (2) clinical events (7 studies); (3) patient-perceived health (7 studies) and (4) guideline adherence (3 studies). Compared with usual care, NCC lowered systolic blood pressure (weighted mean difference (WMD) 2.96 mm Hg; 95% CI 1.53 to 4.40 mm Hg) and low-density lipoprotein cholesterol (WMD 0.23 mmol/L; 95% CI 0.10 to 0.36 mmol/L). NCC also improved smoking cessation rates by 25% (risk ratio 1.25; 95% CI 1.08 to 1.43). NCC demonstrated to have an effect on a small number of outcomes. NCC that incorporated blood pressure monitoring, cholesterol control and smoking cessation has an impact on the improvement of secondary prevention. Additionally, NCC is a heterogeneous concept. A shared definition of NCC may facilitate better comparisons of NCC content and outcomes.
The job of ‘ethics committees’
Authors: Moore Andrew , Donnelly Andrew
Published: November 2015

What should authorities establish as the job of ethics committees and review boards? Two answers are: (1) review of proposals for consistency with the duly established and applicable code and (2) review of proposals for ethical acceptability. The present paper argues that these two jobs come apart in principle and in practice. On grounds of practicality, publicity and separation of powers, it argues that the relevant authorities do better to establish code-consistency review and not ethics-consistency review. It also rebuts bad code and independence arguments for the opposite view. It then argues that authorities at present variously specify both code-consistency and ethics-consistency jobs, but most are also unclear on this issue. The paper then argues that they should reform the job of review boards and ethics committees, by clearly establishing code-consistency review and disestablishing ethics-consistency review, and through related reform of the basic orientation, focus, name, and expertise profile of these bodies and their actions.
Emergent mechanical thrombectomy for acute stroke using the Mindframe Capture LP system: initial single-center experience
Authors: Cerejo Russell , John Seby , Bauer Andrew , Hussain Muhammad S , Bain Mark , Rasmussen Peter , Hui Ferdinand , Masaryk Thomas , Toth Gabor
Published: November 2015

Background

Mechanical thrombectomy using stentrievers is the standard of care for emergent large vessel occlusion stroke. Data on the use of stentrievers in smaller caliber vessels are sparse.

Objective

To present our initial experience with the Mindframe Capture LP device, which was designed for mechanical thrombectomy in small cerebral arteries.

Methods

A retrospective chart review was conducted of patients who underwent Mindframe device assisted emergent thrombectomy. Clinical, imaging, procedural and early follow-up data were obtained.

Results

Nine patients met inclusion criteria (5 men, median age 62 years). Median National Institute of Health Stroke Scale (NIHSS) score was 18 (IQR 9–22), and 6 patients received intravenous tissue plasminogen activator. Six patients had M2 segment occlusions, and 2 patients had distal M1 segment occlusions of the middle cerebral artery. One had distal basilar artery occlusion. Median vessel diameter at the thrombus was 1.7 mm (IQR 1.5–2.5). In all 9 patients the Mindframe device was used together with manual aspiration, with median groin puncture to recanalization time of 35 min (IQR 27–54), and median procedural time of 67 min (IQR 51–91). Final Thrombolysis in Cerebral Infarction score was 3 and 2b in 4 patients each (89% total), and 2a in 1 patient. No patient had any postprocedural complications or symptomatic intracerebral hemorrhage. Median postprocedure and discharge NIHSS were 4 and 1, respectively.

Conclusions

Our data suggest that the Mindframe device is safe and effective for rapid treatment of acute strokes involving small caliber intracranial vessels. Further study in a larger cohort is warranted.
Aneurysms in the target vessels of stroke patients subjected to mechanical thrombectomy: prevalence and impact on treatment
Authors: Zibold Felix , Kleine Justus F , Zimmer Claus , Poppert Holger , Boeckh-Behrens Tobias
Published: November 2015

Background and purpose

Coincidental aneurysms in the target vessels of stroke patients with large vessel occlusions (LVO) may pose risks during endovascular mechanical thrombectomy (MTE), but there are almost no data on this subject. Motivated by an incident of rupture of a hidden aneurysm induced by withdrawal of a stent retriever during a MTE procedure, this study examines the prevalence of aneurysms, associated complications, and implications for treatment strategies in patients with LVO stroke.

Methods

A single-center retrospective analysis of angiographic and CT/MRI images and case records of 300 consecutive patients with LVO stroke treated with MTE was performed.

Results

Aneurysms related to target vessels were detected in 11/300 patients, in 10/11 in the anterior circulation. In 9/11 patients the aneurysms were unknown prior to the stroke. The observed prevalence was >2-fold higher than expected for a healthy reference population. There was one complication (aneurysm rupture), as described above. In two subsequent patients with known aneurysms, MTE was conducted mainly with aspiration techniques which failed, contributing to a low recanalization rate in patients with aneurysm (45%).

Conclusions

The prevalence of aneurysms is relatively high in patients with LVO stroke, particularly in older, female, hypertensive patients, presumably reflecting overlapping risk factors. MTE should not be withheld from patients with LVO stroke with aneurysms, but particularly cautious approaches may be warranted. Further research in larger samples is required to obtain precise data on the prevalence and associated complication rates in MTE procedures. This is necessary to estimate the true risk and to tailor endovascular strategies in these patients.
Scanning electron microscopy and energy‐dispersive x‐ray spectroscopy (SEM‐EDX) confirms shooting of a hen harrier (Circus cyaneus)
Authors: Hopkins Timothy Charles , Peniche Gabriela , Murphy Stephen , Carter Ian , Shorrock Guy , Kearns Stuart , Blunn Gordon , Goodship Allen , Sainsbury Anthony W
Published: November 2015

The hen harrier (Circus cyaneus) remains severely restricted as a breeding species in England despite sufficient habitat for over 300 breeding pairs. Human persecution is the main limiting factor and in the UK, there have been 45 confirmed incidents of shooting of hen harriers since records began (Royal Society for the Protection of Birds unpublished data). The authors report the pathological examination of a hen harrier, the detection of suspected ballistic fragments by radiograph and explain how scanning electron microscopy and energy‐dispersive x‐ray spectroscopy (SEM‐EDX) was used to confirm (i) the composition of one ballistic remnant and (ii) that the remnant had been projected into and had damaged the bone. The authors report the use of post‐analysis software to discriminate apparent anomalies produced by the proprietary SEM‐EDX software package and discuss broader uses of SEM‐EDX for wildlife crime investigation.
Cardiac remodeling in the mouse model of Marfan syndrome develops into two distinctive phenotypes
Authors: Tae Hyun-Jin , Petrashevskaya Natalia , Marshall Shannon , Krawczyk Melissa , Talan Mark
Published: November 2015

Marfan syndrome (MFS) is a systemic disorder of connective tissue caused by mutations in fibrillin-1. Cardiac dysfunction in MFS has not been characterized halting the development of therapies of cardiac complication in MFS. We aimed to study the age-dependent cardiac remodeling in the mouse model of MFS FbnC1039G+/− mouse [Marfan heterozygous (HT) mouse] and its association with valvular regurgitation. Marfan HT mice of 2–4 mo demonstrated a mild hypertrophic cardiac remodeling with predominant decline of diastolic function and increased transforming growth factor-β canonical (p-SMAD2/3) and noncanonical (p-ERK1/2 and p-p38 MAPK) signaling and upregulation of hypertrophic markers natriuretic peptides atrium natriuretic peptide and brain natriuretic peptide. Among older HT mice (6–14 mo), cardiac remodeling was associated with two distinct phenotypes, manifesting either dilated or constricted left ventricular chamber. Dilatation of left ventricular chamber was accompanied by biochemical evidence of greater mechanical stress, including elevated ERK1/2 and p38 MAPK phosphorylation and higher brain natriuretic peptide expression. The aortic valve regurgitation was registered in 20% of the constricted group and 60% of the dilated group, whereas mitral insufficiency was observed in 40% of the constricted group and 100% of the dilated group. Cardiac dysfunction was not associated with the increase of interstitial fibrosis and nonmyocyte proliferation. In the mouse model fibrillin-1, haploinsufficiency results in the early onset of nonfibrotic hypertrophic cardiac remodeling and dysfunction, independently from valvular abnormalities. MFS heart is vulnerable to stress-induced cardiac dilatation in the face of valvular regurgitation, and stress-activated MAPK signals represent a potential target for cardiac management in MFS.
Endothelial PPAR-γ provides vascular protection from IL-1β-induced oxidative stress
Authors: Mukohda Masashi , Stump Madeliene , Ketsawatsomkron Pimonrat , Hu Chunyan , Quelle Frederick W. , Sigmund Curt D.
Published: November 2015

Loss of peroxisome proliferator-activated receptor (PPAR)-γ function in the vascular endothelium enhances atherosclerosis and NF-κB target gene expression in high-fat diet-fed apolipoprotein E-deficient mice. The mechanisms by which endothelial PPAR-γ regulates inflammatory responses and protects against atherosclerosis remain unclear. To assess functional interactions between PPAR-γ and inflammation, we used a model of IL-1β-induced aortic dysfunction in transgenic mice with endothelium-specific overexpression of either wild-type (E-WT) or dominant negative PPAR-γ (E-V290M). IL-1β dose dependently decreased IκB-α, increased phospho-p65, and increased luciferase activity in the aorta of NF-κB-LUC transgenic mice. IL-1β also dose dependently reduced endothelial-dependent relaxation by ACh. The loss of ACh responsiveness was partially improved by pretreatment of the vessels with the PPAR-γ agonist rosiglitazone or in E-WT. Conversely, IL-1β-induced endothelial dysfunction was worsened in the aorta from E-V290M mice. Although IL-1β increased the expression of NF-κB target genes, NF-κB p65 inhibitor did not alleviate endothelial dysfunction induced by IL-1β. Tempol, a SOD mimetic, partially restored ACh responsiveness in the IL-1β-treated aorta. Notably, tempol only modestly improved protection in the E-WT aorta but had an increased protective effect in the E-V290M aorta compared with the aorta from nontransgenic mice, suggesting that PPAR-γ-mediated protection involves antioxidant effects. IL-1β increased ROS and decreased the phospho-endothelial nitric oxide synthase (Ser1177)-to-endothelial nitric oxide synthase ratio in the nontransgenic aorta. These effects were completely abolished in the aorta with endothelial overexpression of WT PPAR-γ but were worsened in the aorta with E-V290M even in the absence of IL-1β. We conclude that PPAR-γ protects against IL-1β-mediated endothelial dysfunction through a reduction of oxidative stress responses but not by blunting IL-1β-mediated NF-κB activity.
Immunotargeting of Antigen xCT Attenuates Stem-like Cell Behavior and Metastatic Progression in Breast Cancer
Authors: Lanzardo Stefania , Conti Laura , Rooke Ronald , Ruiu Roberto , Accart Nathalie , Bolli Elisabetta , Arigoni Maddalena , Macagno Marco , Barrera Giuseppina , Pizzimenti Stefania , Aurisicchio Luigi , Calogero Raffaele Adolfo , Cavallo Federica
Published: November 2015

Resistance to therapy and lack of curative treatments for metastatic breast cancer suggest that current therapies may be missing the subpopulation of chemoresistant and radioresistant cancer stem cells (CSC). The ultimate success of any treatment may well rest on CSC eradication, but specific anti-CSC therapies are still limited. A comparison of the transcriptional profiles of murine Her2+ breast tumor TUBO cells and their derived CSC-enriched tumorspheres has identified xCT, the functional subunit of the cystine/glutamate antiporter system xc−, as a surface protein that is upregulated specifically in tumorspheres. We validated this finding by cytofluorimetric analysis and immunofluorescence in TUBO-derived tumorspheres and in a panel of mouse and human triple negative breast cancer cell-derived tumorspheres. We further show that downregulation of xCT impaired tumorsphere generation and altered CSC intracellular redox balance in vitro, suggesting that xCT plays a functional role in CSC biology. DNA vaccination based immunotargeting of xCT in mice challenged with syngeneic tumorsphere-derived cells delayed established subcutaneous tumor growth and strongly impaired pulmonary metastasis formation by generating anti-xCT antibodies able to alter CSC self-renewal and redox balance. Finally, anti-xCT vaccination increased CSC chemosensitivity to doxorubicin in vivo, indicating that xCT immunotargeting may be an effective adjuvant to chemotherapy. Cancer Res; 76(1); 62–72. ©2015 AACR.
PIK3CAH1047R Accelerates and Enhances KRASG12D-Driven Lung Tumorigenesis
Authors: Green Shon , Trejo Christy L. , McMahon Martin
Published: November 2015

KRAS-activating mutations drive human non–small cell lung cancer and initiate lung tumorigenesis in genetically engineered mouse (GEM) models. However, in a GEM model of KRASG12D-induced lung cancer, tumors arise stochastically following a latency period, suggesting that additional events are required to promote early-stage tumorigenic expansion of KRASG12D-mutated cells. PI3Kα (PIK3CA) is a direct effector of KRAS, but additional activation of PI3′-lipid signaling may be required to potentiate KRAS-driven lung tumorigenesis. Using GEM models, we tested whether PI3′-lipid signaling was limiting for the promotion of KRASG12D-driven lung tumors by inducing the expression of KRASG12D in the absence and presence of the activating PIK3CAH1047R mutation. PIK3CAH1047R expression alone failed to promote tumor formation, but dramatically enhanced tumorigenesis initiated by KRASG12D. We further observed that oncogenic cooperation between KRASG12D and PIK3CAH1047R was accompanied by PI3Kα-mediated regulation of c-MYC, GSK3β, p27KIP1, survivin, and components of the RB pathway, resulting in accelerated cell division of human or mouse lung cancer–derived cell lines. These data suggest that, although KRASG12D may activate PI3Kα by direct biochemical mechanisms, PI3′-lipid signaling remains rate-limiting for the cell-cycle progression and expansion of early-stage KRASG12D-initiated lung cells. Therefore, we provide a potential mechanistic rationale for the selection of KRAS and PIK3CA coactivating mutations in a number of human malignancies, with implications for the clinical deployment of PI3′ kinase–targeted therapies. Cancer Res; 75(24); 5378–91. ©2015 AACR.
The Inescapable Influence of Noncoding RNAs in Cancer
Authors: Adams Brian D. , Anastasiadou Eleni , Esteller Manel , He Lin , Slack Frank J.
Published: November 2015

This report summarizes information presented at the 2015 Keystone Symposium on “MicroRNAs and Noncoding RNAs in Cancer.” Nearly two decades after the discovery of the first miRNA, the role of noncoding RNAs in developmental processes and the mechanisms behind their dysregulation in cancer has been steadily elucidated. Excitingly, miRNAs have begun making their way into the clinic to combat diseases such as hepatitis C and various forms of cancer. Therefore, at this Keystone meeting, novel findings were presented that enhance our view on how small and long noncoding RNAs control developmental timing and oncogenic processes. Recurring themes included (i) how miRNAs can be differentially processed, degraded, and regulated by ribonucleoprotein complexes, (ii) how particular miRNA genetic networks that control developmental process, when disrupted, can result in cancer disease, (iii) the technologies available to therapeutically deliver RNA to combat diseases such as cancer, and (iv) the elucidation of the mechanism of actions for long noncoding RNAs, currently a poorly understood class of noncoding RNA. During the meeting, there was an emphasis on presenting unpublished findings, and the breadth of topics covered reflected how inescapable the influence of noncoding RNAs is in development and cancer. Cancer Res; 75(24); 5206–10. ©2015 AACR.
Prognostic Value of Flow‐Mediated Vasodilation in Brachial Artery and Fingertip Artery for Cardiovascular Events: A Systematic Review and Meta‐Analysis
Authors: Matsuzawa Yasushi , Kwon Taek‐Geun , Lennon Ryan J. , Lerman Lilach O. , Lerman Amir
Published: November 2015

Background

Endothelial dysfunction plays a pivotal role in cardiovascular disease progression, and is associated with adverse events. The purpose of this systematic review and meta‐analysis was to investigate the prognostic magnitude of noninvasive peripheral endothelial function tests, brachial artery flow‐mediated dilation (FMD), and reactive hyperemia–‐peripheral arterial tonometry (RH‐PAT) for future cardiovascular events.

Methods and Results

Databases of MEDLINE, EMBASE, and the Cochrane Library were systematically searched. Clinical studies reporting the predictive value of FMD or RH‐PAT for cardiovascular events were identified. Two authors selected studies and extracted data independently. Pooled effects were calculated as risk ratio (RR) for continuous value of FMD and natural logarithm of RH‐PAT index (Ln_RHI) using random‐effects models. Thirty‐five FMD studies of 17 280 participants and 6 RH‐PAT studies of 1602 participants were included in the meta‐analysis. Both endothelial function tests significantly predicted cardiovascular events (adjusted relative risk [95% CI]: 1% increase in FMD 0.88 [0.84–0.91],
P
<0.001, 0.1 increase in Ln_RHI 0.79 [0.71–0.87],
P
<0.001). There was significant heterogeneity in the magnitude of the association across studies. The magnitude of the prognostic value in cardiovascular disease subjects was comparable between these 2 methods; a 1 SD worsening in endothelial function was associated with doubled cardiovascular risk.

Conclusions

Noninvasive peripheral endothelial function tests, FMD and RH‐PAT, significantly predicted cardiovascular events, with similar prognostic magnitude. Further research is required to determine whether the prognostic values of these 2 methods are independent of each other and whether an endothelial function–guided strategy can provide benefit in improving cardiovascular outcomes.
Impact of Obstructive Sleep Apnea Syndrome on Endothelial Function, Arterial Stiffening, and Serum Inflammatory Markers: An Updated Meta‐analysis and Metaregression of 18 Studies
Authors: Wang Jiayang , Yu Wenyuan , Gao Mingxin , Zhang Fan , Gu Chengxiong , Yu Yang , Wei Yongxiang
Published: November 2015

Background

Obstructive sleep apnea syndrome (
OSAS
) has been indicated to contribute to the development of cardiovascular disease; however, the underlying mechanism remains unclear. This study aimed to test the hypothesis that
OSAS
may be associated with cardiovascular disease by elevating serum levels of inflammatory markers and causing arterial stiffening and endothelial dysfunction.

Methods and Results

Related scientific reports published from January 1, 2006, to June 30, 2015, were searched in the following electronic literature databases: PubMed, Excerpta Medica Database,
ISI
Web of Science, Directory of Open Access Journals, and the Cochrane Library. The association of
OSAS
with serum levels of inflammatory markers, endothelial dysfunction, and arterial stiffening were investigated. Overall, 18 eligible articles containing 736 patients with
OSAS
and 424 healthy persons were included in this meta‐analysis. Flow‐mediated dilation in patients with moderate–severe
OSAS
was significantly lower than that in controls (standardized mean difference −1.02, 95%
CI
−1.31 to −0.73,
P
<0.0001). Carotid‐femoral pulse wave velocity (standardized mean difference 0.45, 95%
CI
0.21–0.69,
P
<0.0001), augmentation index (standardized mean difference 0.57, 95%
CI
0.25–0.90,
P
<0.0001), and serum levels of high‐sensitivity C‐reactive protein and C‐reactive protein (standardized mean difference 0.58, 95%
CI
0.42–0.73,
P
<0.0001) were significantly higher in patients with
OSAS
than in controls.

Conclusion

OSAS
, particularly moderate–severe
OSAS
, appeared to reduce endothelial function, increase arterial stiffness, and cause chronic inflammation, leading to the development of cardiovascular disease.
Identification of a Novel Heart–Liver Axis: Matrix Metalloproteinase‐2 Negatively Regulates Cardiac Secreted Phospholipase A
2
to Modulate Lipid Metabolism and Inflammation in the Liver
Authors: Hernandez‐Anzaldo Samuel , Berry Evan , Brglez Vesna , Leung Dickson , Yun Tae Jin , Lee Jun Seong , Filep Janos G. , Kassiri Zamaneh , Cheong Cheolho , Lambeau Gérard , Lehner Richard , Fernandez‐Patron Carlos
Published: November 2015

Background

Endocrine functions of the heart have been well established. We investigated the hypothesis that cardiac secretion of a unique phospholipase A
2
recently identified by our laboratory (cardiac secreted phospholipase A
2
[
sPLA
2
]) establishes a heart–liver endocrine axis that is negatively regulated by matrix metalloproteinase‐2 (MMP‐2).

Methods and Results

In
Mmp2
−/−
mice, cardiac (but not hepatic)
sPLA
2
was elevated, leading to hepatic inflammation, immune cell infiltration, dysregulation of the sterol regulatory element binding protein‐2 and liver X receptor‐α pathways, abnormal transcriptional responses to dietary cholesterol, and elevated triglycerides in very low‐density lipoprotein and in the liver. Expression of monocyte chemoattractant protein‐3, a known MMP‐2 substrate, was elevated at both
mRNA
and protein levels in the heart. Functional studies including in vivo antibody neutralization identified cardiac monocyte chemoattractant protein 3 as a possible agonist of cardiac
sPLA
2
secretion. Conversely, systemic
sPLA
2
inhibition almost fully normalized the cardiohepatic phenotype without affecting monocyte chemoattractant protein‐3. Finally, wild‐type mice that received h
igh‐performance liquid chromatography
–isolated cardiac
sPLA
2
from
Mmp2

−/−

donors developed a cardiohepatic gene expression profile similar to that of
Mmp2

−/−

mice.

Conclusions

These findings identified the novel MMP‐2/cardiac
sPLA
2
pathway that endows the heart with important endocrine functions, including regulation of inflammation and lipid metabolism in the liver. Our findings could also help explain how

MMP
2

deficiency leads to cardiac problems, inflammation, and metabolic dysregulation in patients.
Role of Titin Missense Variants in Dilated Cardiomyopathy
Authors: Begay Rene L. , Graw Sharon , Sinagra Gianfranco , Merlo Marco , Slavov Dobromir , Gowan Katherine , Jones Kenneth L. , Barbati Giulia , Spezzacatene Anita , Brun Francesca , Di Lenarda Andrea , Smith John E. , Granzier Henk L. , Mestroni Luisa , Taylor Matthew ,   the Familial Cardiomyopathy Registry
Published: November 2015

Background

The titin gene (

TTN

) encodes the largest human protein, which plays a central role in sarcomere organization and passive myocyte stiffness.

TTN

truncating mutations cause dilated cardiomyopathy (
DCM
); however, the role of

TTN

missense variants in
DCM
has been difficult to elucidate because of the presence of background

TTN

variation.

Methods and Results

A cohort of 147
DCM
index subjects underwent
DNA
sequencing for 313

TTN

exons covering the N2B and N2
BA
cardiac isoforms of

TTN

. Of the 348 missense variants, we identified 44 “severe” rare variants by using a bioinformatic filtering process in 37 probands. Of these, 5 probands were double heterozygotes (additional variant in another
DCM
gene) and 7 were compound heterozygotes (2

TTN

“severe” variants). Segregation analysis allowed the classification of the “severe” variants into 5 “likely” (cosegregating), 5 “unlikely” (noncosegregating), and 34 “possibly” (where family structure precluded segregation analysis) disease‐causing variants. Patients with
DCM
carrying “likely” or “possibly” pathogenic

TTN

“severe” variants did not show a different outcome compared with “unlikely” and noncarriers of a “severe”

TTN

variant. However, the “likely” and “possibly” disease‐causing variants were overrepresented in the C‐zone of the A‐band region of the sarcomere.

Conclusions

TTN

missense variants are common and present a challenge for bioinformatic classification, especially when informative families are not available. Although
DCM
patients carrying bioinformatically “severe”

TTN

variants do not appear to have a worse clinical course than noncarriers, the nonrandom distribution of “likely” and “possibly” disease‐causing variants suggests a potential biological role for some

TTN

missense variants.
Is Dental Utilization Associated with Oral Health Literacy?
Authors: Burgette J.M. , Lee J.Y. , Baker A.D. , Vann W.F.
Published: November 2015

The objectives of this study were to examine the pattern of association between dental utilization and oral health literacy (OHL). As part of the Carolina Oral Health Literacy Project, clients in the Women, Infants, and Children’s Special Supplemental Nutrition Program completed a structured 30-min in-person interview conducted by 2 trained interviewers at 9 sites in 7 counties in North Carolina. Data were collected on clients’ OHL, sociodemographics, dental utilization, self-efficacy, and dental knowledge. The outcome, OHL, was measured with a dental word recognition test (30-item Rapid Estimate of Adult Literacy in Dentistry). Descriptive and multiple linear regression methods were used to examine the distribution of OHL and its association with covariates. After adjusting for age, education, race, marital status, self-efficacy, and dental knowledge, multiple linear regression showed that dental utilization was not a significant predictor of OHL ( P > 0.05). Under the conditions of this study, dental utilization was not a significant predictor of OHL.