bluuebunny/crossref_metadata_2025 huggingface dataset:
Automatic identification of type 2 diabetes, hypertension, ischaemic heart disease, heart failure and their levels of severity from Italian General Practitioners' electronic medical records: a validation study
Authors: Gini Rosa , Schuemie Martijn J , Mazzaglia Giampiero , Lapi Francesco , Francesconi Paolo , Pasqua Alessandro , Bianchini Elisa , Montalbano Carmelo , Roberto Giuseppe , Barletta Valentina , Cricelli Iacopo , Cricelli Claudio , Dal Co Giulia , Bellentani Mariadonata , Sturkenboom Miriam , Klazinga Niek
Published: December 2016

Objectives

The Italian project MATRICE aimed to assess how well cases of type 2 diabetes (T2DM), hypertension, ischaemic heart disease (IHD) and heart failure (HF) and their levels of severity can be automatically extracted from the Health Search/CSD Longitudinal Patient Database (HSD). From the medical records of the general practitioners (GP) who volunteered to participate, cases were extracted by algorithms based on diagnosis codes, keywords, drug prescriptions and results of diagnostic tests. A random sample of identified cases was validated by interviewing their GPs.

Setting

HSD is a database of primary care medical records. A panel of 12 GPs participated in this validation study.

Participants

300 patients were sampled for each disease, except for HF, where 243 patients were assessed.

Outcome measures

The positive predictive value (PPV) was assessed for the presence/absence of each condition against the GP's response to the questionnaire, and Cohen's κ was calculated for agreement on the severity level.

Results

The PPV was 100% (99% to 100%) for T2DM and hypertension, 98% (96% to 100%) for IHD and 55% (49% to 61%) for HF. Cohen's kappa for agreement on the severity level was 0.70 for T2DM and 0.69 for hypertension and IHD.

Conclusions

This study shows that individuals with T2DM, hypertension or IHD can be validly identified in HSD by automated identification algorithms. Automatic queries for levels of severity of the same diseases compare well with the corresponding clinical definitions, but some misclassification occurs. For HF, further research is needed to refine the current algorithm.
Provider and service-user perspectives of volunteer health-worker service provision in Ayeyarwady Region, Myanmar: a qualitative study
Authors: Watt Nicola , Yupar Aye , Sender Paul , Campbell Fiona , Legido-Quigley Helena , Howard Natasha
Published: December 2016

Objectives

To explore perspectives and reported experiences of service users, community providers and policymakers related to volunteer health-worker services provision in a rural area of Myanmar.

Methods

A qualitative interview study was conducted in rural communities with 54 service users and 17 community providers in Ayeyarwady Region, Myanmar, and with 14 national managers and policymakers in Yangon Myanmar. Topics included reasons for seeking health services, views and experiences, and comparison with experiences of other services. Data were analysed thematically using deductive and inductive coding.

Results

Accessibility and affordability were important to all participants. Service users described the particular relevance of trust, familiarity and acceptability in choosing a provider. Perceived quality and effectiveness were necessary for trust to develop. Perceived value of volunteers was a cross-cutting dimension, which was interpreted differently by different participants.

Conclusions

Results suggest that volunteers are appropriate and valued, and support ‘availability’, ‘accessibility’ and ‘acceptability’ as dimensions of health services access in this setting. However, social complexities should be considered to ensure effective service delivery. Further research into trust-building, developing quality perceptions and resulting service-user choices would be useful to inform effective policy and planning.
Our current approach to root cause analysis: is it contributing to our failure to improve patient safety?
Authors: Kellogg Kathryn M , Hettinger Zach , Shah Manish , Wears Robert L , Sellers Craig R , Squires Melissa , Fairbanks Rollin J
Published: December 2016

Background

Despite over a decade of efforts to reduce the adverse event rate in healthcare, the rate has remained relatively unchanged. Root cause analysis (RCA) is a process used by hospitals in an attempt to reduce adverse event rates; however, the outputs of this process have not been well studied in healthcare. This study aimed to examine the types of solutions proposed in RCAs over an 8-year period at a major academic medical institution.

Methods

All state-reportable adverse events were gathered, and those for which an RCA was performed were analysed. A consensus rating process was used to determine a severity rating for each case. A qualitative approach was used to categorise the types of solutions proposed by the RCA team in each case and descriptive statistics were calculated.

Results

302 RCAs were reviewed. The most common event types involved a procedure complication, followed by cardiopulmonary arrest, neurological deficit and retained foreign body. In 106 RCAs, solutions were proposed. A large proportion (38.7%) of RCAs with solutions proposed involved a patient death. Of the 731 proposed solutions, the most common solution types were training (20%), process change (19.6%) and policy reinforcement (15.2%). We found that multiple event types were repeated in the study period, despite repeated RCAs.

Conclusions

This study found that the most commonly proposed solutions were weaker actions, which were less likely to decrease event recurrence. These findings support recent attempts to improve the RCA process and to develop guidance for the creation of effective and sustainable solutions to be used by RCA teams.
The impact of child restraint legislation on the incidence of severe paediatric injury in Chile
Authors: Nazif-Muñoz J Ignacio , Gariépy Geneviève , Falconer James , Gong Annie , Macpherson Alison
Published: December 2016

Background

The objective of this study is to determine the association between Chile's 2005 child restraint legislation (CRL) and the incidence of severe paediatric motor vehicle-related injury.

Methods

We analysed motor vehicle injury data from Chile's Road Safety Commission from 2000 to 2012 to determine the association between Chile's 2005 CRL and severe paediatric injury. Using Poisson time-series models we assessed the effect of the law on two outcome variables: (1) severely injured children per vehicle fleet; and (2) severely injured children per population.

Results

Chile's 2005 CRL is significantly associated with a 24% reduction in severely injured children per vehicle, and 19% reduction in severely injured children per population in the 1st year of its enactment. In 2007 this law is also significantly associated with a 17% decrease in severely injured children per vehicle, and with an 11% decrease in severely injured children per population. However, this legislation had a short-term effect since no reductions in severely injured children per vehicle were observed after 2009 and no reductions for severely injured children per population were registered after 2008.

Conclusions

This is the first study to examine the association between CRL and severe paediatric injury in a Latin-American country. This study suggests that Chile's CRL was only effective in the short term. To support this type of reforms in the long term, other measures such as police enforcement, public information campaigns and involvement of public health professionals in educating parents about the benefits of using child restraints should be considered.
Intra-abdominalCandidaspp infection in acute abdomen in a quality assurance (QA)-certified academic setting
Authors: Rodolico Vito , Di Carlo Paola , Gulotta Gaspare , D'Arpa Francesco , Salamone Giuseppe , Cocorullo Gianfranco , Agrusa Antonino , Giammanco Anna , Sergi Consolato
Published: December 2016

Aims

To evaluate the contribution of light microscopy to detectingCandidaspp infection in patients with complicated intra-abdominal infections (IAIs) admitted for acute abdomen to a quality assurance (QA)-certified surgical emergency ward.

Methods

We conducted a retrospective study (2008–2012) of 809 abdominal intraoperative or biopsy tissue specimens obtained from patients admitted with acute abdomen and microbiological samples positive forCandidaspp. Demographic data, mortality, comorbidities, specimen type, microscopy results, special histological staining performed, antimicrobial therapy were collected and analysed. Any comments at the multidisciplinary team meeting was recorded in minutes of and approved.

Results

Sixty-six patients with complicated IAIs due toCandidaspp were identified (39 male, 27 female, mean±SD age 75±20 years).Candida albicanswas isolated in 35 cases andCandida non-albicansspp in 31 cases.Candidaspp were isolated from blood in 50% of all selected microbiological specimens. Patients were stratified according toCandidaspp(albicansvsnon-albicans), underlying cancer disease and no previous antimicrobial administration, and a positive correlation withC. albicansisolation was found (p=0.009 and p=0.048, respectively). Out of 41 cases with microscopic evaluation, we identified yeast forms, pseudohyphae or both, indicative ofCandidaspp, in 23. Identification ofCandidaspp in histological specimens was higher inC. albicanscases than inC. non-albicanscases (73% vs 37.5%). Microscopy allowed prompt treatment of all patients.

Conclusions

Light microscopy still has great diagnostic significance, being a solid QA step. It provides rapid information and clues in patients who may harbour impaired defence mechanisms, concurrent chronic conditions and/or cancer.
Is being in paid work beyond state pension age beneficial for health? Evidence from England using a life-course approach
Authors: Di Gessa Giorgio , Corna Laurie M , Platts Loretta G , Worts Diana , McDonough Peggy , Sacker Amanda , Price Debora , Glaser Karen
Published: December 2016

Background

Given the current policy emphasis in many Western societies on extending working lives, we investigated the health effects of being in paid work beyond state pension age (SPA). Until now, work has largely focused on the health of those who exit the labour force early.

Methods

Our data come from waves 2–4 of the English Longitudinal Study of Ageing, including the life history interview at wave 3. Using logistic and linear regression models, we assessed the longitudinal associations between being in paid work beyond SPA and 3 measures of health (depression, a latent measure of somatic health and sleep disturbance) among men aged 65–74 and women aged 60–69. Our analyses controlled for baseline health and socioeconomic characteristics, as well as for work histories and health in adulthood and childhood.

Results

Approximately a quarter of women and 15% of men were in paid work beyond SPA. Descriptive bivariate analyses suggested that men and women in paid work were more likely to report better health at follow-up. However, once baseline socioeconomic characteristics as well as adulthood and baseline health and labour market histories were accounted for, the health benefits of working beyond SPA were no longer significant.

Conclusions

Potential health benefits of working beyond SPA need to be considered in the light of the fact that those who report good health and are more socioeconomically advantaged are more likely to be working beyond SPA to begin with.
Management of Alcohol Misuse in Patients with Liver Diseases
Authors: Peng Jennifer L , Patel Milan Prakash , McGee Breann , Liang Tiebing , Chandler Kristina , Tayarachakul Sucharat , O'Connor Sean , Liangpunsakul Suthat
Published: December 2016

Excessive alcohol use not only causes alcoholic liver disease (ALD) but also increases the risk of liver-related mortality in patients who already have other chronic liver diseases. Screening for alcohol misuse or alcohol use disorder (AUD) among patients with underlying liver disease is essential. This clinical review covers what is known about ALD, the impact of alcohol in patients with underlying liver diseases, current management of alcohol misuse and AUD, and the management of alcohol misuse and AUD specifically in patients with liver diseases. Several treatment options for alcohol misuse and AUD exist such as psychosocial intervention and behavioral and pharmacological therapies. The strategies used in the treatment of alcohol misuse and AUD are still applicable in those who consume alcohol and have underlying liver disease. However, certain medications still need to be carefully used due to potentially worsening already compromised liver function. Screening of ongoing alcohol use in subjects with liver disease is important, and prompt intervention is needed to prevent the associated morbidity and mortality from the detrimental effects of continued alcohol use on underlying liver disease. Considering alcoholism is a complex disease, probably a multidisciplinary approach combining psychotherapy and comprehensive medical care will be the most effective. Future research could focus on identifying additional treatment options for addressing the psychotherapy component since the self-determination and will to quit drinking alcohol can play such a crucial role in promoting abstinence.
A comparative study of cognitive behavioural therapy and shared reading for chronic pain
Authors: Billington Josie , Farrington Grace , Lampropoulou Sofia , Lingwood Jamie , Jones Andrew , Ledson James , McDonnell Kate , Duirs Nicky , Humphreys Anne-Louise
Published: December 2016

The case for psychosocial interventions in relation to chronic pain, one of the most common health issues in contemporary healthcare, is well-established as a means of managing the emotional and psychological difficulties experienced by sufferers. Using mixed methods, this study compared a standard therapy for chronic pain, cognitive behavioural therapy (CBT), with a specific literature-based intervention, shared reading (SR) developed by national charity, The Reader. A 5-week CBT group and a 22-week SR group for patients with chronic pain ran in parallel, with CBT group members joining the SR group after the completion of CBT. In addition to self-report measures of positive and negative affect before and after each experience of the intervention, the 10 participants kept twice-daily (12-hourly) pain and emotion diaries. Qualitative data were gathered via literary-linguistic analysis of audio/video-recordings and transcriptions of the CBT and SR sessions and video-assisted individual qualitative interviews with participants. Qualitative evidence indicates SR's potential as an alternative or long-term follow-up or adjunct to CBT in bringing into conscious awareness areas of emotional pain otherwise passively suffered by patients with chronic pain. In addition, quantitative analysis, albeit of limited pilot data, indicated possible improvements in mood/pain for up to 2 days following SR. Both findings lay the basis for future research involving a larger sample size.
FromFace/Offto the face race: the case of Isabelle Dinoire and the future of the face transplant
Authors: Bound Alberti Fay
Published: December 2016

Isabelle Dinoire, the world's first face transplant recipient has died, 11 years after the procedure that brought her unwanted fame and media attention. While medical debates centre mainly on ethical and medical concerns like immunosuppressant use, the psychological hazards of face transplants are still being overlooked. Using medical and media reports and examining the gendering of clinical and patient narratives, this article argues we need to look again at face transplants and their motivation for individuals as well as society.
Constructing diagnostic likelihood: clinical decisions using subjective versus statistical probability
Authors: Kinnear John , Jackson Ruth
Published: December 2016

Background

Although physicians are highly trained in the application of evidence-based medicine, and are assumed to make rational decisions, there is evidence that their decision making is prone to biases. One of the biases that has been shown to affect accuracy of judgements is that of representativeness and base-rate neglect, where the saliency of a person’s features leads to overestimation of their likelihood of belonging to a group. This results in the substitution of ‘subjective’ probability for statistical probability.

Methods

This study examines clinicians’ propensity to make estimations of subjective probability when presented with clinical information that is considered typical of a medical condition. The strength of the representativeness bias is tested by presenting choices in textual and graphic form. Understanding of statistical probability is also tested by omitting all clinical information.

Results

For the questions that included clinical information, 46.7% and 45.5% of clinicians made judgements of statistical probability, respectively. Where the question omitted clinical information, 79.9% of clinicians made a judgement consistent with statistical probability. There was a statistically significant difference in responses to the questions with and without representativeness information (χ2 (1, n=254)=54.45, p<0.0001).

Conclusions

Physicians are strongly influenced by a representativeness bias, leading to base-rate neglect, even though they understand the application of statistical probability. One of the causes for this representativeness bias may be the way clinical medicine is taught where stereotypic presentations are emphasised in diagnostic decision making.
Age-adjusted D-dimer excludes pulmonary embolism and reduces unnecessary radiation exposure in older adults: retrospective study
Authors: Nobes Jennifer , Messow Claudia-Martina , Khan Mohammed , Hrobar Petr , Isles Chris
Published: December 2016

Background

Patients in whom a diagnosis of pulmonary embolism (PE) is suspected and whose D-dimers are elevated frequently require CT pulmonary angiogram (CTPA) for diagnosis. Because D-dimer rises with age, an age-adjusted D-dimer threshold may prevent unnecessary radiation exposure from CTPA in older patients.

Objective

To determine the efficacy and safety of implementing an age-adjusted D-dimer threshold to exclude PE.

Design, settings and patients

Retrospective comparison of conventional and age-adjusted D-dimer thresholds in 1000 consecutive patients who had both D-dimer and CTPA.

Main outcome measures

Conventional and age-adjusted D-dimer thresholds for excluding PE were <250 ng/mL and 5× age for patients older than 50 years, respectively. We defined patients as unlikely to have PE using the revised Geneva score (RGS) and two different categories of clinical risk: RGS ≤5 and RGS ≤10.

Results

We diagnosed PE by CTPA in 244 (24.4%) patients. 3/86 patients (3.5%) whose D-dimer was below the conventional threshold of 250 ng/mL had PE (RGS 3, 9 and 14), all of which were judged to be light clot load (group 1). 3/108 patients (2.8%) whose D-dimer lay between 250 ng/mL and the age-adjusted threshold had PE (RGS 6, 8 and 9), all of which were again judged to be light clot load (group 2). 62/108 group 2 patients with RGS ≤5 were considered unlikely to have PE as were 102/108 using the RGS clinical risk category ≤10. None of the 62 patients with RGS ≤5 had PE while 3/102 patients with RGS ≤10 had PE. 236/806 patients (29.3%) whose D-dimer was above the age-adjusted threshold had PE (group 3).

Conclusions

In a consecutive series of 1000 patients, an RGS ≤5 and an age-adjusted D-dimer would have led to 62 fewer CTPA at a cost of no missed PEs.
Identifying flares in rheumatoid arthritis: reliability and construct validation of the OMERACT RA Flare Core Domain Set
Authors: Bykerk Vivian P , Bingham Clifton O , Choy Ernest H , Lin Daming , Alten Rieke , Christensen Robin , Furst Daniel E , Hewlett Sarah , Leong Amye , March Lyn , Woodworth Thasia , Boire Gilles , Haraoui Boulos , Hitchon Carol , Jamal Shahin , Keystone Edward C , Pope Janet , Tin Diane , Thorne J Carter , Bartlett Susan J
Published: December 2016

Objective

To evaluate the reliability of concurrent flare identification using 3 methods (patient, rheumatologist and Disease Activity Score (DAS)28 criteria), and construct validity of candidate items representing the Outcome Measures in Rheumatology Clinical Trials (OMERACT) RA Flare Core Domain Set.

Methods

Candidate flare questions and legacy measures were administered at consecutive visits to Canadian Early Arthritis Cohort (CATCH) patients between November 2011 and November 2014. The American College of Rheumatology (ACR) core set indicators were recorded. Concordance to identify flares was assessed using the agreement coefficient. Construct validity of flare questions was examined: convergent (Spearman's r); discriminant (mean differences between flaring/non-flaring patients); and consequential (proportions with prior treatment reductions and intended therapeutic change postflare).

Results

The 849 patients were 75% female, 81% white, 42% were in remission/low disease activity (R/LDA), and 16–32% were flaring at the second visit. Agreement of flare status was low–strong (κ's 0.17–0.88) and inversely related to RA disease activity level. Flare domains correlated highly (r's≥0.70) with each other, patient global (r's≥0.66) and corresponding measures (r's 0.49–0.92); and moderately highly with MD and patient-reported joint counts (r's 0.29–0.62). When MD/patients agreed the patient was flaring, mean flare domain between-group differences were 2.1–3.0; 36% had treatment reductions prior to flare, with escalation planned in 61%.

Conclusions

Flares are common in rheumatoid arthritis (RA) and are often preceded by treatment reductions. Patient/MD/DAS agreement of flare status is highest in patients worsening from R/LDA. OMERACT RA flare questions can discriminate between patients with/without flare and have strong evidence of construct and consequential validity. Ongoing work will identify optimal scoring and cut points to identify RA flares.
Effects of a structured exercise programme in sedentary dogs with chronic diarrhoea
Authors: Huang H.‐P. , Lien Y.‐H.
Published: December 2016

The aim of this investigation was to evaluate the effects of a structured exercise programme in sedentary dogs with chronic diarrhoea. Twenty‐two dogs were enrolled in the study. All dogs received oral prednisolone (1 mg/kg/day for 14 days, followed by a tapering dosage) for 10 weeks. After four weeks of prednisolone treatment, dogs were assigned to either the exercise or control group (n=11 each). Owners of dogs in the exercise group were instructed to guide their dogs in structured exercise training (low‐intensity to moderate‐intensity aerobic and resistance exercise three to five days per week). After 10 weeks of prednisolone treatment with concomitant 6 weeks of complementary exercise, the Canine Inflammatory Bowel Disease Activity Index (CIBDAI) score had decreased significantly in the exercise group (from 8.8±1.5 at the start of the exercise programme to 2.4±1.5; P<0.001); no such change was observed in the control group (from 9.2±0.9 to 9.2±1.1). CIBDAI scores differed significantly between the groups at the end of the 10‐week study period (P<0.001). The exercise programme affected all six CIBDAI parameters significantly; bodyweight (P<0.001, adjusted r2=0.722) was most affected. A structured exercise programme may have positive effects on clinical symptoms in sedentary dogs with chronic diarrhoea.
Compression and shear strength characteristics of compacted loess at high suctions
Authors: Ng Charles Wang Wai , Sadeghi Hamed , Jafarzadeh Fardin
Published: December 2016

Compression and shear behavior of a loosely compacted loess is investigated via two series of saturated and unsaturated direct shear tests. The vapor transfer mechanism is used to modify a shear box device for control of suction at high range. In spite of significant volumetric strain upon wetting (up to 14%), suction-induced volumetric shrinkage is less than 2% for all suction levels considered because of the as-compacted moisture content at the dry side of the optimum value. During shearing, all unsaturated tests dried to high suctions indicate a strain-softening mode of failure associated with noticeable dilation. There is a continuous increase in peak strength with suction but at a reduced rate, which cannot be captured by the improved Bishop’s effective stress model, as it underestimates the contribution of high suctions by approaching zero degree of saturation. Unsaturated tests at high suctions also show an increased rate of dilation with suction for both values of net stress, which cannot be predicted well by the classical stress–dilatancy models. It is shown that for suction values beyond 8 MPa, dilation angle increases by 2° and 6° per 100 MPa increase of suction under net stress of 50 and 200 kPa, respectively.
Metadata provide insights on patterns of epiparasitism in mistletoes (Santalales), an overlooked topic in forest biology
Authors: Wilson Carol A. , Calvin Clyde L.
Published: December 2016

Mistletoes are aerial-branch parasites belonging to one of five families in the Santalales. Usually, mistletoe hosts are autotrophic, but if the hosts themselves are parasitic, the plant parasitizing the host is an epiparasite. Three categories of epiparasites are recognized, chance-, obligate-, and auto-epiparasites. Loranthaceae and Viscaceae comprise about 97% of mistletoe species and also the largest number of epiparasites. We report frequencies and biogeographical distributions of epiparasite – parasite host combinations for Loranthaceae and Viscaceae, and we summarize epiparasitism in other mistletoe families. Parasitic hosts are primarily recruited from Loranthaceae, whereas most epiparasites are members of Viscaceae. Twenty-seven species are considered likely to be obligate epiparasites. Data suggest species abundance influences whether mistletoes serve as host to other mistletoes. We found no reports of epiparasitism in Misodendraceae and only a few reports for Santalaceae, although Santalaceae are often root-parasitic hosts. In Phacellaria (Amphorogynaceae) all species are obligate epiparasites, mainly on Loranthaceae. Epiparasitism occurs worldwide and is most common in the tropics and subtropics. The greatest number of reports is from Oceania, the smallest from Africa. Epiparasitism in mistletoes has received little research attention, yet our research shows that this life form contributes to species and structural diversity in forest ecosystems across the globe.
Run-of-River hydropower and salmonids: potential effects and perspective on future research
Authors: Gibeau P. , Connors B.M. , Palen W.J.
Published: December 2016

The spatial footprint of individual run-of-river (RoR) hydropower facilities is smaller than reservoir-storage hydroelectric projects and their impacts to aquatic ecosystems are often assumed to be negligible. However, these effects are poorly understood, especially for salmonids whose freshwater habitat often overlaps with RoR hydropower potential. Flow regulation for RoR hydropower is unique in how it influences the seasonality and magnitude of flow diversion and because low-head dams can be overtopped at high flows. Based on a review of the primary literature, we identified three pathways of effects by which RoR hydropower may influence salmonids: reduction of flow, presence of low-head dams impounding rivers, and anthropogenic flow fluctuations. We synthesized empirical evidence of effects of RoR hydropower on river ecosystems from 31 papers, of which only 10 explicitly considered salmonids. We identified key research gaps including impacts of extended low-flow periods, anthropogenic flow fluctuations, and cumulative effects of multiple RoR projects. Filling these gaps is necessary to help manage and conserve salmonid populations in the face of the growing global demand for small-scale hydropower.
Wavelengths, transition probabilities, and oscillator strengths for M-shell transitions in tungsten ions with partially filled 3p subshell
Authors: Xu Min , Yan Anying , Wu Shuang , Hu Feng , Li Xiangfu
Published: December 2016

Wavelengths, transition probabilities, and oscillator strengths have been calculated for M-shell electric dipole (E1) transitions in Al-like W61+ through Cl-like W57+, with partially filled 3p subshell. The fully relativistic multiconfiguration Dirac–Fock (MCDF) method, taking quantum electrodynamical effect and Breit correction into account, was used in the calculations. Calculated energy levels of M-shell excited states in Al-like through Cl-like W ions from the method were compared with some available theoretical and experimental results, and good agreement with them was achieved.
Hepato- and neuro-protective influences of biopropolis on thioacetamide-induced acute hepatic encephalopathy in rats
Authors: Mostafa Rasha E. , Salama Abeer A.A. , Abdel-Rahman Rehab F. , Ogaly Hanan A.
Published: December 2016

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that ultimately occurs as a complication of acute or chronic liver failure; accompanied by hyperammonemia. This study aimed to evaluate the potential of biopropolis as a hepato- and neuro-protective agent using thioacetamide (TAA)-induced acute HE in rats as a model. Sixty Wistar rats were divided into 5 groups: Group 1 (normal control) received only saline and paraffin oil. Group 2 (hepatotoxic control) received TAA (300 mg/kg, once). Groups 3, 4, and 5 received TAA followed by vitamin E (100 mg/kg) and biopropolis (100 and 200 mg/kg), respectively, daily for 30 days. Evidences of HE were clearly detected in TAA-hepatotoxic group including significant elevation in the serum level of ammonia, liver functions, increased oxidative stress in liver and brain, apoptotic DNA fragmentation and overexpression of iNOS gene in brain tissue. The findings for groups administered biopropolis, highlighted its efficacy as a hepato- and neuro-protectant through improving the liver functions, oxidative status and DNA fragmentation as well as suppressing the brain expression of iNOS gene. In conclusion, biopropolis, at a dose of 200 mg/kg per day protected against TAA-induced HE through its antioxidant and antiapoptotic influence; therefore, it can be used as a protective natural product.
Analysis of the histone cluster in Senegalese sole (Solea senegalensis): evidence for a divergent evolution of two canonical histone clusters
Authors: Merlo Manuel Alejandro , Iziga Roger , Portela-Bens Silvia , Cross Ismael , Kosyakova Nadezda , Liehr Thomas , Manchado Manuel , Rebordinos Laureana
Published: December 2016

The Senegalese sole (Solea senegalensis) is commercially very important and a priority species for aquaculture product diversification. The main histone cluster was identified within two BAC clones. However, two replacement histones (H1.0 and H3.3) were found in another BAC clone. Different types of canonical histones H2A and H2B were found within the same species for the first time. Phylogenetic analysis demonstrated that the different types of H1, H2A, and H2B histones were all more similar to each other than to canonical histones from other species. The canonical histone H3 of S. senegalensis differs from subtypes H3.1 and H3.2 in humans at the site of residue 96, where a serine is found instead of an alanine. This same polymorphism has been found only in Danio rerio. The karyotype of S. senegalensis comprises 21 pairs of chromosomes, distributed in 3 metacentric pairs, 2 submetacentric pairs, 4 subtelocentric pairs, and 12 acrocentric pairs. The two BAC clones that contain the clusters of canonical histones were both mapped on the largest metacentric pair, and mFISH analysis confirmed the co-location with the dmrt1 gene in that pair. Three chromosome markers have been identified which, in addition to those previously described, account for 18 chromosome pairs in S. senegalensis.
Microsatellite markers reveal low frequency of natural hybridization between the white-footed mouse (Peromyscus leucopus) and deer mouse (Peromyscus maniculatus) in southern Quebec, Canada
Authors: Leo Sarah S.T. , Millien Virginie
Published: December 2016

In some parts of southern Quebec, two closely related rodent species — the white-footed mouse (Peromyscus leucopus) and the deer mouse (Peromyscus maniculatus) — have recently come in contact because of climate-driven changes in the distribution of the former. Both species share similar morphology, ecology, and life history traits, which suggests that natural hybridization may be possible. Hybridization among these two species can have important implications on the ecological roles these rodents play in disease transmission, yet few researchers have attempted to examine this phenomenon and results from previous hybridization experiments have remained inconclusive and conflicting. In this study, we attempt to investigate the occurrence of hybridization among white-footed mice and deer mice in southern Quebec by genotyping wild caught specimens with selectively neutral, polymorphic microsatellite markers. Our analyses suggest that hybridization may be occurring at extremely low frequency between both species in our study area. The presence of such hybridization events, even at low frequencies, may have implications on disease transmission risk in the region and further detailed studies are necessary.
Chronic exposure to water-pipe smoke induces cardiovascular dysfunction in mice
Authors: Nemmar Abderrahim , Al-Salam Suhail , Yuvaraju Priya , Beegam Sumaya , Yasin Javed , Ali Badreldin H.
Published: December 2016

Water-pipe tobacco smoking is becoming prevalent in all over the world including Western countries. There are limited data on the cardiovascular effects of water-pipe smoke (WPS), in particular following chronic exposure. Here, we assessed the chronic cardiovascular effects of nose-only WPS exposure in C57BL/6 mice. The duration of the session was 30 minutes/day, 5 days/week for 6 consecutive months. Control mice were exposed to air. WPS significantly increased systolic blood pressure. The relative heart weight and plasma concentrations of troponin-I and B-type natriuretic peptide were increased in mice exposed to WPS. Arterial blood gas analysis showed that WPS caused a significant decrease in [Formula: see text] and an increase in [Formula: see text]. WPS significantly shortened the thrombotic occlusion time in pial arterioles and venules and increased the number of circulating platelet. Cardiac lipid peroxidation, measured as thiobarbituric acid-reactive substances, was significantly increased, while superoxide dismutase activity, total nitric oxide activity, and glutathione concentration were reduced by WPS exposure. Likewise, immunohistochemical analysis of the heart revealed an increase in the expression of inducible nitric oxide synthase and cytochrome c by cardiomyocytes of WPS-exposed mice. Moreover, hearts of WPS-exposed mice showed the presence of focal interstitial fibrosis. WPS exposure significantly increased heart DNA damage assessed by Comet assay. We conclude that chronic nose-only exposure to WPS impairs cardiovascular homeostasis. Our findings provide evidence that long-term exposure to WPS is harmful to the cardiovascular system and supports interventions to control the spread of WPS, particularly amid youths.

NEW & NOTEWORTHY No data are available on the chronic cardiovascular effects of water-pipe smoke (WPS). Our findings provide experimental evidence that chronic exposure to WPS increased blood pressure, relative heart weight, troponin I, and B-type natriuretic peptide in plasma and induced hypoxemia, hypercapnia, and thrombosis. Moreover, WPS caused cardiac oxidative stress, DNA damage, and fibrosis.
Cartilage rings contribute to the proper embryonic tracheal epithelial differentiation, metabolism, and expression of inflammatory genes
Authors: Turcatel Gianluca , Millette Katelyn , Thornton Matthew , Leguizamon Stephanie , Grubbs Brendan , Shi Wei , Warburton David
Published: December 2016

The signaling cross talk between the tracheal mesenchyme and epithelium has not been researched extensively, leaving a substantial gap of knowledge in the mechanisms dictating embryonic development of the proximal airways by the adjacent mesenchyme. Recently, we reported that embryos lacking mesenchymal expression of Sox9 did not develop tracheal cartilage rings and showed aberrant differentiation of the tracheal epithelium. Here, we propose that tracheal cartilage provides local inductive signals responsible for the proper differentiation, metabolism, and inflammatory status regulation of the tracheal epithelium. The tracheal epithelium of mesenchyme-specific Sox9Δ/Δmutant embryos showed altered mRNA expression of various epithelial markers such as Pb1fa1, surfactant protein B ( Sftpb), secretoglobulin, family 1A, member 1 ( Scgb1a1), and trefoil factor 1 ( Tff1). In vitro tracheal epithelial cell cultures confirmed that tracheal chondrocytes secrete factors that inhibit club cell differentiation. Whole gene expression profiling and ingenuity pathway analysis showed that the tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and transforming growth factor-β (TGF-β) signaling pathways were significantly altered in the Sox9 mutant trachea. TNF-α and IFN-γ interfered with the differentiation of tracheal epithelial progenitor cells into mature epithelial cell types in vitro. Mesenchymal knockout of Tgf-β1 in vivo resulted in altered differentiation of the tracheal epithelium. Finally, mitochondrial enzymes involved in fat and glycogen metabolism, cytochrome c oxidase subunit VIIIb ( Cox8b) and cytochrome c oxidase subunit VIIa polypeptide 1 ( Cox7a1), were strongly upregulated in the Sox9 mutant trachea, resulting in increases in the number and size of glycogen storage vacuoles. Our results support a role for tracheal cartilage in modulation of the differentiation and metabolism and the expression of inflammatory-related genes in the tracheal epithelium by feeding into the TNF-α, IFN-γ, and TGF-β signaling pathways.
Differentially expressed genes and gene networks involved in pig ovarian follicular atresia
Authors: Terenina Elena , Fabre Stephane , Bonnet Agnès , Monniaux Danielle , Robert-Granié Christèle , SanCristobal Magali , Sarry Julien , Vignoles Florence , Gondret Florence , Monget Philippe , Tosser-Klopp Gwenola
Published: December 2016

Ovarian folliculogenesis corresponds to the development of follicles leading to either ovulation or degeneration, this latter process being called atresia. Even if atresia involves apoptosis, its mechanism is not well understood. The objective of this study was to analyze global gene expression in pig granulosa cells of ovarian follicles during atresia. The transcriptome analysis was performed on a 9,216 cDNA microarray to identify gene networks and candidate genes involved in pig ovarian follicular atresia. We found 1,684 significantly regulated genes to be differentially regulated between small healthy follicles and small atretic follicles. Among them, 287 genes had a fold-change higher than two between the two follicle groups. Eleven genes ( DKK3, GADD45A, CAMTA2, CCDC80, DAPK2, ECSIT, MSMB, NUPR1, RUNX2, SAMD4A, and ZNF628) having a fold-change higher than five between groups could likely serve as markers of follicular atresia. Moreover, automatic confrontation of deregulated genes with literature data highlighted 93 genes as regulatory candidates of pig granulosa cell atresia. Among these genes known to be inhibitors of apoptosis, stimulators of apoptosis, or tumor suppressors INHBB, HNF4, CLU, different interleukins ( IL5, IL24), TNF-associated receptor ( TNFR1), and cytochrome-c oxidase ( COX) were suggested as playing an important role in porcine atresia. The present study also enlists key upstream regulators in follicle atresia based on our results and on a literature review. The novel gene candidates and gene networks identified in the current study lead to a better understanding of the molecular regulation of ovarian follicular atresia.
mda-7/IL-24 Mediates Cancer Cell–Specific Death via Regulation of miR-221 and the Beclin-1 Axis
Authors: Pradhan Anjan K. , Talukdar Sarmistha , Bhoopathi Praveen , Shen Xue-Ning , Emdad Luni , Das Swadesh K. , Sarkar Devanand , Fisher Paul B.
Published: December 2016

Melanoma differentiation-associated gene-7/IL-24 (mda-7/IL-24) displays broad-spectrum anticancer activity in vitro, in vivo in preclinical animal models, and in a phase I/II clinical trial in patients with advanced cancers without harming normal cells or tissues. Here we demonstrate that mda-7/IL-24 regulates a specific subset of miRNAs, including cancer-associated miR-221. Either ectopic expression of mda-7/IL-24 or treatment with recombinant His-MDA-7 protein resulted in downregulation of miR-221 and upregulation of p27 and PUMA in a panel of cancer cells, culminating in cell death. Mda-7/IL-24–induced cancer cell death was dependent on reactive oxygen species induction and was rescued by overexpression of miR-221. Beclin-1 was identified as a new transcriptional target of miR-221, and mda-7/IL-24 regulated autophagy through a miR-221/beclin-1 feedback loop. In a human breast cancer xenograft model, miR-221–overexpressing MDA-MB-231 clones were more aggressive and resistant to mda-7/IL-24–mediated cell death than parental clones. This is the first demonstration that mda-7/IL-24 directly regulates miRNA expression in cancer cells and highlights the novelty of the mda-7/IL-24–miR-221–beclin-1 loop in mediating cancer cell–specific death. Cancer Res; 77(4); 949–59. ©2016 AACR.
Exploring the Benefit/Risk Associated with Antiangiogenic Agents for the Treatment of Non–Small Cell Lung Cancer Patients
Authors: Kurzrock Razelle , Stewart David J.
Published: December 2016

Following the approval of bevacizumab, an antibody targeting VEGF-A, for advanced non-squamous non–small cell lung cancer (NSCLC) in 2006, intensive efforts were put into the clinical development of antiangiogenic agents for NSCLC. Currently, the other antiangiogenic agents approved for NSCLC are ramucirumab, a VEGF receptor-2 (VEGFR-2)–targeting antibody indicated for both squamous and non-squamous NSCLC in the United States, and nintedanib, an anti–VEGFR-1/2/3, platelet-derived growth factor receptor-α/β, fibroblast growth factor receptor-1/2/3 angiokinase inhibitor indicated for adenocarcinoma of the lung in the European Union. Many other antiangiogenic agents are being evaluated in phase III trials for NSCLC, including aflibercept, sunitinib, sorafenib, cediranib, and vandetanib. Although many of the same signaling pathways are targeted by these novel agents, mixed efficacy results have been observed in these trials. Moreover, safety issues have raised concerns about using antiangiogenic agents in this patient population, and fatal bleeding events have been reported. Importantly, although no biomarker has yet been validated for antiangiogenic agents in NSCLC, biomarkers that show potential include circulating levels of short VEGF-A isoforms, expression of neuropilin-1 and VEGFR-1 in tumors and plasma, genetic variants in VEGF-A and VEGFR, and tumor protein p53 mutations (with the latter having been shown to correlate with increased levels of VEGF-A transcripts). This review provides an overview of the clinical benefit and risk associated with the use of antiangiogenic agents for NSCLC, and summarizes the research to date on the identification of predictive biomarkers for antiangiogenic therapies. Clin Cancer Res; 23(5); 1137–48. ©2016 AACR.
Increased Vascular Permeability Measured With an Albumin-Binding Magnetic Resonance Contrast Agent Is a Surrogate Marker of Rupture-Prone Atherosclerotic Plaque
Authors: Phinikaridou Alkystis , Andia Marcelo E. , Lavin Begoña , Smith Alberto , Saha Prakash , Botnar René M.
Published: December 2016

Background—

Compromised structural integrity of the endothelium and higher microvessel density increase vascular permeability. We investigated whether vascular permeability measured in vivo by magnetic resonance imaging using the albumin-binding contrast agent, gadofosveset, is a surrogate marker of rupture-prone atherosclerotic plaque in a rabbit model.

Methods and Results—

New Zealand white rabbits (n=10) were rendered atherosclerotic by cholesterol-diet and endothelial denudation. Plaque rupture was triggered with Russell’s viper venom and histamine. Animals were imaged pre-triggering, at 3 and 12 weeks, to quantify plaque area, vascular permeability, vasodilation, and stiffness and post-triggering to identify thrombus. Plaques identified on the pretrigger scans were classified as stable or rupture-prone based on the absence or presence of thrombus on the corresponding post-trigger magnetic resonance imaging, respectively. All rabbits had developed atherosclerosis, and 60% had ruptured plaques. Rupture-prone plaques had higher vessel wall relaxation rate (R
1
; 2.30±0.5 versus 1.86±0.3 s
−1
;
P
<0.001), measured 30 minutes after gadofosveset administration, and higher R
1
/plaque area ratio (0.70±0.06 versus 0.47±0.02,
P
= 0.01) compared with stable plaque at 12 weeks. Rupture-prone plaques had higher percent change in R
1
between the 3 and 12 weeks compared with stable plaque (50.80±7.2% versus 14.22±2.2%;
P
<0.001). Immunohistochemistry revealed increased vessel wall albumin and microvessel density in diseased aortas and especially in ruptured plaque. Electron microscopy showed lack of structural integrity in both luminal and microvascular endothelium in diseased vessels. Functionally, the intrinsic vasodilation of the vessel wall decreased at 12 weeks compared with 3 weeks (18.60±1.0% versus 23.43±0.8%;
P
<0.001) and in rupture-prone compared with stable lesions (16.40±2.0% versus 21.63±1.2%;
P
<0.001). Arterial stiffness increased at 12 weeks compared with 3 weeks (5.00±0.1 versus 2.53±0.2 m/s;
P
<0.001) both in animals with stable and rupture-prone lesions.

Conclusions—

T1 mapping using an albumin-binding contrast agent (gadofosveset) could quantify the changes in vascular permeability associated with atherosclerosis progression and rupture-prone plaques.
Magnetic Resonance–Augmented Cardiopulmonary Exercise Testing
Authors: Barber Nathaniel J. , Ako Emmanuel O. , Kowalik Gregorz T. , Cheang Mun H. , Pandya Bejal , Steeden Jennifer A. , Moledina Shahin , Muthurangu Vivek
Published: December 2016

Background—

Conventional cardiopulmonary exercise testing can objectively measure exercise intolerance but cannot provide comprehensive evaluation of physiology. This requires additional assessment of cardiac output and arteriovenous oxygen content difference. We developed magnetic resonance (MR)–augmented cardiopulmonary exercise testing to achieve this goal and assessed children with right heart disease.

Methods and Results—

Healthy controls (n=10) and children with pulmonary arterial hypertension (PAH; n=10) and repaired tetralogy of Fallot (n=10) underwent MR-augmented cardiopulmonary exercise testing. All exercises were performed on an MR-compatible ergometer, and oxygen uptake was continuously acquired using a modified metabolic cart. Simultaneous cardiac output was measured using a real-time MR flow sequence and combined with oxygen uptake to calculate arteriovenous oxygen content difference. Peak oxygen uptake was significantly lower in the PAH group (12.6±1.31 mL/kg per minute;
P
=0.01) and trended toward lower in the tetralogy of Fallot group (13.5±1.29 mL/kg per minute;
P
=0.06) compared with controls (16.7±1.37 mL/kg per minute). Although tetralogy of Fallot patients had the largest increase in cardiac output, they had lower resting (3±1.2 L/min per m
2
) and peak (5.3±1.2 L/min per m
2
) values compared with controls (resting 4.3±1.2 L/min per m
2
and peak 6.6±1.2 L/min per m
2
) and PAH patients (resting 4.5±1.1 L/min per m
2
and peak 5.9±1.1 L/min per m
2
). Both the PAH and tetralogy of Fallot patients had blunted exercise–induced increases in arteriovenous oxygen content difference. However, only the PAH patients had significantly reduced peak values (6.9±1.3 mlO2/100 mL) compared with controls (8.4±1.4 mlO2/100 mL;
P
=0.005).

Conclusions—

MR-augmented cardiopulmonary exercise testing is feasible in both healthy children and children with cardiac disease. Using this novel technique, we have demonstrated abnormal exercise patterns in oxygen uptake, cardiac output, and arteriovenous oxygen content difference.