bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome‐wide differential expression reveals candidate genes involved in the pathogenesis of lupus and lupus nephritis
Authors: AlFadhli Suad , Ghanem Aqeel A. M. , Nizam Rasheeba
Published: September 2015

Background

Systemic lupus erythematosus (lupus) is an autoimmune disease characterized by multiorgan pathology, accelerated apoptosis and hyper‐autoantibody production against self‐components. The root cause of lupus remains unknown, although multiple susceptibility factors have been reported in different ethnic group.

Objective

We aimed to explore the genome‐wide differential expression spectrum of lupus and its severe form lupus nephritis (LN) in Arab females.

Methods

A total of 98 subjects: 40 lupus, 18 LN and 40 age/gender/ethnically matched healthy controls (HC) were recruited. Carefully chosen subjects (n = 11) were employed for whole human‐genome expression profiling using high‐density Human Exon 1.0.ST arrays (Affymetrix) and statistical analysis was carried out using appropriate software. Validation cohorts (n = 98) were investigated to quantify the expression of the nine selected candidate genes relative to GAPDH as endogenous control.

Results

Genome‐wide differential analysis revealed seven candidate genes in lupus and 36 in LN, when individually compared to HC (anova Welch t‐test, P ≤ 0.005, Tukey's honestly post hoc analysis). Analysis of differentially expressed genes with a fold change of 2, revealed 16 Gene Ontology terms satisfying a P ≤ 0.05. We further detected five distinct inflammatory and metabolic pathways such as TWEAK, osteopontin, endochondral ossification, fluropyrimidine activity and urea cycle and metabolism of amino groups that significantly contribute to the pathogenesis of lupus (P < 0.05). Validation of selected candidate genes (IRF9, ABCA1, APOBEC3, CEACAM3, OSCAR, TNFA1P6, MMP9, SLC4A1) revealed significant differences in expression, indicating their promissory role in the pathogenesis of lupus.

Conclusion

Our study provides central gene regulators of therapeutic potential, indicating the future prospects of the study.
Atypical central retinal artery occlusion: an uncommon cause of retinopathy and visual loss in dermatomyositis
Authors: Sharma Mukta , Prashar Aditi , Tuli Rajiv , Sharma Rattan K. , Mahajan Vikram K.
Published: September 2015

Several ophthalmic manifestations in patients with dermatomyositis have been described but involvement of the retina is rare. A 39‐year‐old man diagnosed with dermatomysitis had developed sudden painless visual loss in the left eye. He was non‐diabetic and non‐hypertensive. He was on treatment with systemic prednisolone (50 mg/day) and methotrexate (7.5 mg/day) for dermatomyositis. His visual acuity was finger counting at 2 feet in the left eye and 6/6 in the right eye. Left fundus showed slight blurring of the optic disc margins, large peripapillary flame‐shaped haemorrhages and extensive area of opacification suggestive of central retinal artery occlusion (CRAO) with sparing of the area supplied by the cilioretinal artery. The exact pathomechanism of CRAO in dermatomyositis remains poorly elucidated. The infarctive events following endothelial damage and platelet thrombi occurring in arterioles and capillaries of retina, optic disc and choriocapillaries causing ischemia/infarction have been suggested as possible reasons. However, central artery occlusion from high intraocular pressure from marked (heliotrope) orbital edema appears more plausible in our case. The degree of retinal damage is variable when CRAO lasts between 105 and 240 min and irreversible profound visual loss may occur from its occlusion lasting for more than 240 min. A prompt ophthalmological opinion/management is recommended to limit its progression.
Hypovitaminosis D in a Young Lebanese Population: Effect of GC Gene Polymorphisms on Vitamin D and Vitamin D Binding Protein Levels
Authors: Medlej‐Hashim Myrna , Jounblat Rania , Hamade Aline , Ibrahim Jose Noel , Rizk Francine , Azzi Georges , Abdallah Marwa , Nakib Layane , Lahoud May , Nabout Rita
Published: September 2015

Bioactive vitamin D is a steroid hormone transported in blood via the vitamin D binding protein (DBP). Our study aimed to investigate the vitamin D status in a young Lebanese population and study the association of hypovitaminosis with levels of DBP. Polymorphisms in the GC gene that encodes DBP were also screened.

Blood samples were collected from 179 university students. Vitamin D status and DBP levels were assayed by enzyme‐linked immunosorbent assay (ELISA). DNA was extracted from 128 participants, and genotyping of the two GC gene SNPs, rs7041, and rs4588, was carried out by restriction fragment length polymorphism.

Forty‐seven percent of participants had hypovitaminosis D (<20 ng/ml). A significant positive correlation was observed between vitamin D status and DBP. Genotyping data showed that participants carrying the rs7041 GG and rs4588 AA genotypes had higher concentrations of DBP than those carrying other genotypes. Four allelic versions of the GC gene were observed, one of which, GC*3, was encountered for the first time in this study, and was found to be associated with both normal vitamin D and high DBP levels. Modifying genes such as GC could therefore affect DBP levels, and contribute, along with environmental factors, to the hypovitaminosis D observed in sunny countries.
Cities, villages, and suburbs: What sets them apart when it comes to giving blood?
Authors: Carrier Élianne , Cloutier Marie‐Soleil , Charbonneau Johanne
Published: September 2015

Key Messages

Blood donation in rural areas is highly affected by local culture.

Accessibility to blood drives greatly affects blood donation, regardless of place of residence.

Donors from suburban environments put their family and children at the centre of their motivation for giving blood.
The geography of skier adaptation to adverse conditions in the Ontario ski market
Authors: Rutty Michelle , Scott Daniel , Johnson Peter , Jover Eric , Pons Marc , Steiger Robert
Published: September 2015

Key Messages

Spatial patterns of skiers may vary as a result of snow conditions.

This study examined where and how far skiers in Ontario (Canada) are willing to travel in response to local lack of snow.

Majority of respondents (59–60%) would travel to five key resorts in Ontario; an additional 11–15% of respondents opted to travel to Quebec or the state of New York.
Targeted complement inhibition and microvasculature in transplants: a therapeutic perspective
Authors: Khan M A , Hsu J L , Assiri A M , Broering D C
Published: September 2015

Active complement mediators play a key role in graft-versus-host diseases, but little attention has been given to the angiogenic balance and complement modulation during allograft acceptance. The complement cascade releases the powerful proinflammatory mediators C3a and C5a anaphylatoxins, C3b, C5b opsonins and terminal membrane attack complex into tissues, which are deleterious if unchecked. Blocking complement mediators has been considered to be a promising approach in the modern drug discovery plan, and a significant number of therapeutic alternatives have been developed to dampen complement activation and protect host cells. Numerous immune cells, especially macrophages, develop both anaphylatoxin and opsonin receptors on their cell surface and their binding affects the macrophage phenotype and their angiogenic properties. This review discusses the mechanism that complement contributes to angiogenic injury, and the development of future therapeutic targets by antagonizing activated complement mediators to preserve microvasculature in rejecting the transplanted organ.
Lower serum osteocalcin concentrations are associated with brain microstructural changes and worse cognitive performance
Authors: Puig Josep , Blasco Gerard , Daunis‐i‐Estadella Josep , Moreno María , Molina Xavier , Alberich‐Bayarri Angel , Xifra Gemma , Pedraza Salvador , Ricart Wifredo , Fernández‐Aranda Fernando , Fernández‐Real José Manuel
Published: September 2015

Objective

Rodent models have found that osteocalcin crosses the blood–brain barrier and regulates behaviour. No data are available on osteocalcin's effects on brain microstructure and cognitive performance in humans. We evaluated the association between serum osteocalcin concentrations and (i) brain microstructural changes on magnetic resonance imaging (MRI) and (ii) neuropsychological performance.

Design, Patients and Measurements

We studied 24 consecutive obese subjects (13 women; age, 49·8 ± 8·1 years; body mass index [BMI], 43·9 ± 4·54 kg/m2) and 20 healthy volunteers (10 women; age, 48·8 ± 9·5 years; BMI, 24·3 ± 3·54 kg/m2) in a cross‐sectional study within the multicentre FLORINASH Project. FLAIR signal intensity and DTI‐metrics (primary (λ1), secondary (λ2) and tertiary (λ3) eigenvalues; fractional anisotropy (FA); and mean diffusivity) in the caudate, hypothalamus, thalamus and putamen, and in subcortical white matter were assessed. Cognitive performance evaluated by neuropsychological test battery.

Results

Lower osteocalcin concentrations were associated with BMI, higher λ1, λ2 and λ3 values at the caudate and lower FLAIR signal intensity at the caudate and putamen. Obese patients with lower osteocalcin concentrations had higher FA at putamen and thalamus. Lower osteocalcin concentrations were associated with higher Iowa Gambling Task (IGT) scores. FLAIR signal intensity at the caudate <601·832 yielded 85·7% sensitivity, 64·3% specificity, 70·6% negative predictive value and 81·8% positive predictive value for IGT score. Lower osteocalcin was an independent predictor of worse cognitive performance on multivariate analysis (F = 3·551, P = 0·01343; R2 = 0·103). Bayesian information criterion demonstrated that osteocalcin had the predominant role in predicting IGT score.

Conclusions

Lower serum osteocalcin concentrations are associated with brain microstructural changes and worse cognitive performance.
Fetal phenotypes in otopalatodigital spectrum disorders
Authors: Naudion S. , Moutton S. , Coupry I. , Sole G. , Deforges J. , Guerineau E. , Hubert C. , Deves S. , Pilliod J. , Rooryck C. , Abel C. , Le Breton F. , Collardeau‐Frachon S. , Cordier M.P. , Delezoide A.L. , Goldenberg A. , Loget P. , Melki J. , Odent S. , Patrier S. , Verloes A. , Viot G. , Blesson S. , Bessières B. , Lacombe D. , Arveiler B. , Goizet C. , Fergelot P.
Published: September 2015

Otopalatodigital spectrum disorders (OPDSD) include OPD syndromes types 1 and type 2 (OPD1, OPD2), Melnick–Needles syndrome (MNS), and frontometaphyseal dysplasia (FMD). These conditions are clinically characterized by variable skeletal dysplasia associated in males, with extra‐skeletal features including brain malformations, cleft palate, cardiac anomalies, omphalocele and obstructive uropathy. Mutations in the FLNA gene have been reported in most FMD and OPD2 cases and in all instances of typical OPD1 and MNS. Here, we report a series of 10 fetuses and a neonatally deceased newborn displaying a multiple congenital anomalies syndrome suggestive of OPDSD and in whom we performed FLNA analysis. We found a global mutation rate of 44%. This series allows expanding the clinical and FLNA mutational spectrum in OPDSD. However, we emphasize difficulties to correctly discriminate OPDSD based on clinical criteria in fetuses due to the major overlap between these conditions. Molecular analyses may help pathologists to refine clinical diagnosis according to the type and the location of FLNA mutations. Discriminating the type of OPDSD is of importance in order to improve the genetic counseling to provide to families.
Computerized respiratory sounds: a comparison between patients with stable and exacerbated COPD
Authors: Jácome Cristina , Oliveira Ana , Marques Alda
Published: September 2015

Introduction

Diagnosis of acute exacerbations of chronic obstructive pulmonary disease (AECOPD) is often challenging as it relies on patients’ clinical presentation. Computerized respiratory sounds (CRS), namely crackles and wheezes, may have the potential to contribute for the objective diagnosis/monitoring of an AECOPD.

Objectives: This study explored if CRS differ during stable and exacerbation periods in patients with COPD.

Methods

13 patients with stable COPD and 14 with AECOPD were enrolled. CRS were recorded simultaneously at trachea, anterior, lateral and posterior chest locations using seven stethoscopes. Airflow (0.4–0.6l/s) was recorded with a pneumotachograph. Breathing phases were detected using airflow signals; crackles and wheezes with validated algorithms.

Results

At trachea, anterior and lateral chest, no significant differences were found between the two groups in the number of inspiratory/expiratory crackles or inspiratory wheeze occupation rate. At posterior chest, the number of crackles (median 2.97–3.17 vs. 0.83–1.2, P < 0.001) and wheeze occupation rate (median 3.28%–3.8% vs. 1.12%–1.77%, P = 0.014–0.016) during both inspiration and expiration were significantly higher in patients with AECOPD than in stable patients. During expiration, wheeze occupation rate was also significantly higher in patients with AECOPD at trachea (median 3.12% vs. 0.79%, P < 0.001) and anterior chest (median 3.55% vs. 1.28%, P < 0.001).

Conclusion

Crackles and wheezes are more frequent in patients with AECOPD than in stable patients, particularly at posterior chest. These findings suggest that these CRS can contribute to the objective diagnosis/monitoring of AECOPD, which is especially valuable considering that they can be obtained by integrating computerized techniques with pulmonary auscultation, a noninvasive method that is a component of patients’ physical examination.
Prediction of long‐term survival by using the Glasgow Prognostic Score in patients with hepatocellular carcinoma after liver transplantation
Authors: Abe Tomoyuki , Tashiro Hirotaka , Hattori Minoru , Kuroda Shintaro , Tahara Hiroyuki , Ohira Masahiro , Kobayashi Tsuyoshi , Ide Kentaro , Ishiyama Kohei , Ohdan Hideki
Published: September 2015

Aim

This study aimed to validate the prognostic value of the Glasgow Prognostic Score (GPS) in patients who underwent living donor liver transplantation (LDLT) for hepatocellular carcinoma (HCC).

Methods

Data were retrospectively collected for HCC patients who underwent LDLT. Univariate and multivariate analyses were performed to identify variables associated with overall and recurrence‐free survival. Patients were separated into two groups based on the GPS. The predictive ability of the GPS was compared with other variable scores (modified GPS and hepatic GPS) to identify the most accurate test for this population.

Results

Univariate analysis identified a GPS of 1 or 2 (P = 0.018), multiple tumors (P = 0.032) and HCC beyond the Milan criteria (P = 0.015) as factors significantly associated with poor overall survival. Hepatitis B negative status (P = 0.034), a GPS of 1 or 2 (P = 0.030), α‐fetoprotein of 20.0 ng/mL or more (P = 0.042) and HCC beyond the Milan criteria (P = 0.002) were identified as factors significantly associated with poor recurrence‐free survival. Multivariate analysis indicated that HCC beyond the Milan criteria and a GPS of 1 or 2 were independent risk factors for long‐term outcomes. Among the scoring systems evaluated in this study, the GPS was the best predictive system in our population. Moreover, a new scoring system that combined the GPS and the Milan criteria showed the highest prognostic values.

Conclusion

Novel prediction scores combining the GPS and the Milan criteria provide a precise, objective, and quick approach for selecting appropriate HCC patients for LDLT.
Temperature Dependence of Efficiency in GaInN/GaN Light‐Emitting Diodes with a GaInN Underlayer
Authors: Kim Kyurin , Meyaard David S. , Lin Guan‐Bo , Schubert E. Fred , Kim Jong Kyu , Cho Jaehee
Published: September 2015

The temperature dependence of the efficiency (i.e., temperature‐mediated efficiency droop) in blue light‐emitting diodes (LEDs) is investigated. A GaInN/GaN LED with a GaInN underlayer having an indium mole fraction of 8% shows less temperature dependence of efficiency, compared to the LED without an underlayer. Better carrier confinement in the active region of the LED with a GaInN underlayer is proposed to reduce carrier leakage from the active region at high temperature. The results indicate that the insertion of an underlayer leads to an improvement of the LED's radiative efficiency and its high‐temperature‐tolerant performance.
Underestimation of plasma level of factor V coagulant activity and fibrinogen concentration together with prolonged prothrombin time, activated partial thromboplastin time and thrombin time can result from pre‐analytical very low calcium level in citrated sample tube
Authors: d'Audigier C. , Delassasseigne C. , Robert A. , Eschwège V.
Published: September 2015

Introduction

Pre‐analytical phase is a critical step in the haemostasis laboratory cycle. Numerous variations affect tests results, and it is crucial to detect them in order to reject improper specimens before reporting test results. Comparing to prior results or requesting, a repeat sample can help in pre‐analytical irregularity assessment.

Methods

Each time a sample addressed to our laboratory displayed aberrant results or discordant with a prior report, another specimen was asked and both were analysed through calcium (Ca) level, prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen concentration, factor II, factor VII+X and factor V coagulant activity measurements. Among these, all the primary citrated samples from inpatients without anticoagulant treatment, displaying very low calcium level (‘Ca 0’ samples), were selected for this 2 years study.

Results

A total of 17 samples could be identified. Ca level in their paired repeat samples was always >1.00 mmol/L. Coagulation testing for ‘Ca 0’ samples showed a significant prolongation of PT, APTT, TT and a significant decrease for fibrinogen concentration and factor V coagulant activity.

Conclusion

We identified factor V coagulant activity, as the parameter with the most important variation in case of very low calcium level in presumed citrated sample tubes probably contaminated with EDTA.
Increasing prevalence of childhood overweight and obesity in a coastal province in China
Authors: Zhang Y. , Zhao J. , Chu Z. , Zhou J.
Published: September 2015

Background

The increasing prevalence of childhood obesity constitutes a serious public health problem in both developed and developing countries.

Objectives

The present study examined the prevalent trends in overweight and obesity among children and adolescents in Shandong, China spanning 29 years (1985–2014).

Methods

Data for this study were obtained from four cross‐sectional surveys of schoolchildren carried out in 1985, 1995, 2005 and 2014 in Shandong Province, China. A total of 39 943 students aged 7–18 years were included in this study (14 458 in 1985, 7 198 in 1995, 8 568 in 2005 and 9 719 in 2014).

Results

Using IOTF criteria, the prevalence of overweight and obesity increased from 1.73% and 0.05% for boys, 1.67% and 0.04% for girls in 1985 to 20.83% and 10.39% for boys, 15.81% and 4.35% for girls in 2014; Using World Health Organization criteria, the prevalence of overweight and obesity increased from 2.76% and 0.45% for boys, 2.46% and 0.11% for girls in 1985 to 20.30% and 18.16% for boys, 18.89% and 6.58% for girls in 2014, respectively.

Conclusion

Childhood overweight and obesity has entered the extensively epidemic stage in this region at present. Comprehensive strategies of intervention should include periodical monitoring, education on pattern of nutrition, oxygen‐consuming physical exercises and healthy dietary behaviour.
Age at spermarche: 15‐year trend and its association with body mass index in Chinese school‐aged boys
Authors: Song Y. , Ma J. , Wang H.‐J. , Wang Z. , Lau P. W. C. , Agardh A.
Published: September 2015

Background

Little is known about the secular trends in age at spermarche among boys, and the association between body mass index (BMI) and male puberty is controversial.

Objective

This study aimed to estimate the trend in age at spermarche in China and explore the association of spermarche with BMI.

Methods

We used four cross‐sectional Chinese National Surveys on Students' Constitution and Health (CNSSCH; 1995, 2000, 2005 and 2010). Median age at spermarche was determined using probit analysis. Logistic regression was used to assess the association of spermarche with BMI.

Results

Age at spermarche among Chinese boys dropped from 14.57 to 14.03 years from 1995 to 2010 with a decrease of 4.3 months per decade. Boys with BMI‐for‐age z‐score lower than −2 had the latest age at spermarche. A higher BMI or BMI‐for‐age z‐score was associated with an increased likelihood of having reached spermarche, and this association was consistently observed at all survey points.

Conclusion

This study provides important evidence of a secular trend of earlier age at spermarche over the past 15 years in China, and this decrease was accompanied by a simultaneous increase in BMI. Strategies and interventions focusing on thinness may promote both their nutritional status and puberty development among Chinese boys.
Inhibition of interleukin‐1β‐mediated interleukin‐1 receptor‐associated kinase 4 phosphorylation by zinc leads to repression of memory T helper type 17 response in humans
Authors: Lee Hyunju , Kim Bonah , Choi Yeon Ho , Hwang Yuri , Kim Dong Hyun , Cho Sunjung , Hong Sung Jun , Lee Won‐Woo
Published: September 2015

Zinc is an essential trace element that plays pivotal roles in multiple facets of the immune system. Besides its catalytic and structural roles, zinc also functions as an intracellular signalling molecule, and changes in zinc levels can cause both direct and indirect modulation of immune responses. Further, cytoplasmic levels of bioavailable zinc in immune cells are largely influenced by many extracellular stimuli. Here we provide evidence that zinc represses memory T helper type 17 responses in humans by inhibiting interleukin‐1β (IL‐1β)‐mediated signal. In vitro zinc treatment of CD4+ T cells in the presence of activated monocytes inhibited interferon‐γ‐producing cells and IL‐17‐producing cells, but not IL‐4‐producing cells. Of note, production of IL‐17+ cells from memory CD4+ T cells, which is significantly up‐regulated by lipopolysaccharide‐stimulated monocytes, was preferentially repressed by zinc. Increased cytoplasmic zinc in T cells suppressed IL‐1β signalling through repression of phosphorylation of IL‐1 receptor‐associated kinase 4 (IRAK4), so leading to an inhibitory effect on T helper type 17 responses facilitated by monocyte‐derived IL‐1β in humans. These findings suggest that extracellular zinc bioavailability may affect memory CD4+ T‐cell responses by modulating the zinc‐mediated signalling pathway.
Accessible Conceptions of Statistical Inference: Pulling Ourselves Up by the Bootstraps
Authors: Wild Chris J. , Pfannkuch Maxine , Regan Matt , Parsonage Ross
Published: September 2015

With the rapid, ongoing expansions in the world of data, we need to devise ways of getting more students much further, much faster. One of the choke points affecting both accessibility to a broad spectrum of students and faster progress is classical statistical inference based on normal theory. In this paper, bootstrap‐based confidence intervals and randomisation tests conveyed through dynamic visualisation are developed as a means of reducing cognitive demands and increasing the speed with which application areas can be opened up. We also discuss conceptual pathways and the design of software developed to enable this approach.
Plasma MMP and TIMP evaluation in patients with deep venous thrombosis: could they have a predictive role in the development of post‐thrombotic syndrome?
Authors: de Franciscis Stefano , Gallelli Luca , Amato Bruno , Butrico Lucia , Rossi Alessio , Buffone Gianluca , Caliò Francesco G , De Caridi Giovanni , Grande Raffaele , Serra Raffaele
Published: September 2015

Post‐thrombotic syndrome (PTS) is a condition that can develop in about half of the patients with deep vein thrombosis (DVT) of lower limbs.

In the present study, we evaluated the expression of inflammatory biomarkers in the early phases of DVT and their correlation with the onset of PTS.

Patients were enrolled after the first episode of DVT and were followed up for 1, 4, 8, 12 and 18 months. At each visit, blood sample was collected to evaluate plasma levels of matrix metalloproteinase (MMP)‐1,‐2,‐3,‐7,‐8 and ‐9 MMP inhibitors, TIMP‐1,‐2, neutrophil gelatinase‐associated lipocalin (NGAL) and cytokines TNF‐α and IL‐6.

Analysis included 201 patients [86 males (42·79%) and 115 females (57·21%); average age 56 ± 7 years].

Of the 201 patients, 47 (23·38%; 21 males, 26 females) developed PTS during the follow‐up period.

The control group was made up of 60 individuals without DVT (22 males and 38 females).

High plasma levels of MMPs, NGAL and cytokines were recorded during the acute phase after DVT. Moreover, patients with PTS showed higher levels of MMP‐1 and MMP‐8 with respect to patients without PTS.

There is a close relationship between DVT, the individual risk of PTS and specific biomarkers such as MMPs and other related molecules, which may help guide prevention and therapy based on the patient's individual risk profile, and has to be studied in future.
Breeding implications resulting from classification of patellae luxation in dogs
Authors: van Grevenhof E.M. , Hazewinkel H.A.W. , Heuven H.C.M.
Published: September 2015

Patellar luxation (PL) is one of the major hereditary orthopaedic abnormalities observed in a variety of dog breeds. When the patellae move sideways out of the trochlear groove, this is called PL. The PL score varies between dogs from normal to very severe. Reducing the prevalence of PL by breeding could prevent surgery, thereby improve welfare. Orthopaedic specialists differentiate between normal and loose patellae, where the patellae can be moved to the edge of the trochlear groove, considering scoring loose patellae as normal in the future. Loose patellae are considered acceptable for breeding so far by the breeding organization. The aim of this study was to analyse the genetic background of PL to decide on the importance of loose patellae when breeding for healthy dogs. Data are available from two dog breeds, that is Flat‐coated Retrievers (n = 3808) and Kooiker dogs (n = 794), with a total of 4602 dogs. Results show that loose patellae indicate that dogs are genetically more susceptible to develop PL because family members of the dogs with loose patellae showed more severe PL. In addition, the estimated breeding values for dogs with loose patellae indicate that breeding values of dogs with loose patellae were worse than breeding values obtained for dogs with a normal score. Given these results, it is advised to orthopaedic specialists to continue to score loose patellae as a separate class and to dog breeders to minimize the use of dogs in breeding with a genetically higher susceptibility for PL.
Evolutionary history of the subnival flora of the Himalaya‐Hengduan Mountains: first insights from comparative phylogeography of four perennial herbs
Authors: Luo Dong , Yue Ji‐Pei , Sun Wen‐Guang , Xu Bo , Li Zhi‐Min , Comes Hans Peter , Sun Hang
Published: September 2015

Aim

The Himalaya‐Hengduan Mountain (HHM) biodiversity hotspot including the ‘sky islands’ of Southwest China harbour exceptional plant diversity and endemicity at subnival summits (most of them exceeding 4300 m a.s.l.). This study is the first using a comparative phylogeographical framework to gain insights into the temporal origin of this highly fragmented subnival flora, and the historical factors shaping its genetic architecture as exemplified by four perennial herbs.

Location

Himalaya‐Hengduan Mountains, China.

Methods

Based on nuclear and/or chloroplast (cp) DNA sequences for each of the four studied species, we performed AMOVA and mismatch distributional analyses to assess molecular structure, diversity and demographic history in relation to current and last glacial distributions using ecological niche modelling (ENM). Time‐calibrated phylogenetic reconstructions of cpDNA data were used to infer species‐specific stem and crown ages.

Results

Our time estimates suggest that these species originated during the Late Pliocene or early‐to‐mid Pleistocene, whereas their onset of diversification generally falls into the mid‐Pleistocene. All four species exhibited island‐like population genetic structures, with all of them showing signatures of recent population growth and/or spatial expansion based on cpDNA. By contrast, ENM indicated that species broad‐scale distributions remained fairly stable over the last glacial/post‐glacial cycle.

Main conclusions

The temporal origin of the four subnival HHM species is likely associated with tectonic changes in the region, while their near‐simultaneous onset of diversification during the ‘Naynayxungla Glaciation’ (0.72–0.50 Ma) could reflect initial population divergence through climate‐induced habitat fragmentation. Despite a rather stable distributional history, geographical population isolation and localized range expansion/contractions likely resulted in significant genetic structure and differentiation over the last glacial/post‐glacial cycle. Overall, the present results are strongly indicative of shared evolutionary histories and phylogeographical structures among subnival plants from the ‘sky island system’ of the HHM region.
High phylogeographical complexity within Mediterranean islands: insights from the Corsican fire salamander
Authors: Salvi Daniele , Bisconti Roberta , Canestrelli Daniele
Published: September 2015

Aim

Mediterranean islands have been the subject of intense phylogeographical investigation. While most studies have focused on the processes of colonization and dispersal between landmasses, the phylogeographical structures within islands have received less attention. Here, we investigate the Pleistocene evolutionary history of the fire salamander Salamandra corsica. Our main aim is to shed more light on the importance of intra‐island micro‐evolutionary processes in structuring the patterns of biodiversity on Mediterranean islands.

Location

Corsica Island.

Methods

We sampled 165 individuals across the entire range of S. corsica, and we sequenced two mitochondrial (cytb and cox1) and one nuclear (ßfib) gene fragments. We used Bayesian phylogeographical and historical demographic analyses based on DNA sequence data, together with species distribution modelling (SDM) under the present and past bioclimatic envelopes.

Results

Bayesian phylogeographical analyses indicated that S. corsica (re)colonized its northern range during the Last Interglacial period from an ancestral area located in central‐southern Corsica. According to these analyses and the SDM, S. corsica was already established throughout the island during the last glacial phase, although likely with a fragmented distribution. Historical demographic analyses suggested a post‐glacial demographic expansion, probably associated with the climate‐driven spatial and temporal dynamics of forested habitats.

Main conclusions

Despite its restricted and insular distribution, S. corsica showed past demographic and range dynamics that are comparable to those of wide‐ranging species on the continent. These dynamics are not consistent with temporal, spatial, and demographic patterns previously seen for other Corsican endemics. Such patterns of complex Pleistocene evolutionary histories and extensive phylogeographical discordance are also emerging from other insular systems. We conclude that island endemics should not be considered, a priori, as single populations and conservation units, and that the use of co‐occurrence patterns of island populations as inferential tools in historical biogeography should also be carefully reconsidered.
Systemic effects of treatment with mTOR inhibitors in tuberous sclerosis complex: a comprehensive review
Authors: Sadowski K. , Kotulska K. , Schwartz R. A. , Jóźwiak S.
Published: September 2015

Tuberous sclerosis complex (TSC) is a genetic multisystem disorder associated with constitutive overactivation of the mammalian target of rapamycin (mTOR) pathway and characterized by development of benign tumours in various organs. mTOR inhibitors have proven to be effective in the targeted therapy of certain TSC‐associated pathologies such as subependymal giant cell astrocytomas (SEGAs) and renal angiomyolipomas (AMLs). Accumulating experimental and clinical data suggest that mTOR inhibitors might have a systemic, disease‐modifying influence on affected individuals. This systematic review provides an analysis of available clinical data concerning systemic effect of mTOR inhibitors and the influence of mTOR inhibition on different manifestations of TSC in individual patients.
Exposure to moxifloxacin and cytomegalovirus replication is associated with skin squamous cell carcinoma development in lung transplant recipients
Authors: Gerber S.R. , Seifert B. , Inci I. , Serra A.L. , Kohler M. , Benden C. , Hofbauer G.F.L. , Schuurmans M.M.
Published: September 2015

Background

Lung transplant recipients (LTR) are at increased risk for squamous cell carcinoma of the skin (SCC), but risk factors (RF) are incompletely understood.

Objective

To assess associations between exposure to certain medications and viral infections, and subsequent SCC development.

Methods

Retrospective study examining incidence and potential RF for SCC in LTR transplanted from 1992 to 2010 followed up at one centre. Cumulative incidence and Cox proportional hazards regression models were used to evaluate RF in the first year post‐transplant for SCC formation during the follow‐up.

Results

In 205 analysed LTR, 46 patients were diagnosed with SCC during a median follow‐up of 4.9 years. The cumulative incidences of first SCC were 16.7% and 34.1%, for 5 and 10 years post‐transplantation respectively. Multivariable analysis identified CMV replication (HR 7.69, 95% CI 2.93–20.2, P < 0.001) and moxifloxacin exposure (HR 2.35, 95% CI 1.15–4.81, P = 0.020) during the first year post‐transplantation as independent RF for SCC development during follow‐up.

Conclusion

In our cohort, moxifloxacin use and CMV replication during the first year post‐transplantation were associated with increased risk for SCC. These two factors could be indicators of over‐immunosuppression. Their role in SCC development requires investigations in larger cohorts and prospective studies.
Host specialization involving attraction, avoidance and performance, in two phytophagous moth species
Authors: Orsucci M. , Audiot P. , Pommier A. , Raynaud C. , Ramora B. , Zanetto A. , Bourguet D. , Streiff R.
Published: September 2015

Host specialization plays a key role in the extreme diversification of phytophagous insects. Whereas proximate mechanisms of specialization have been studied extensively, their consequences for species divergence remain unclear. Preference for, and performance on hosts are thought to be a major source of divergence in phytophagous insects. We assessed these major components of specialization in two moth species, the European corn borer (ECB) and the Adzuki bean borer (ABB), by testing their oviposition behaviour in different conditions (choice or no‐choice set‐ups) and their performances, by reciprocal transplant at the larval stage on the usual host and an alternative host plant. We demonstrated that both ABB and ECB have a strong preference for their host plants for oviposition, but that relative larval performances on the usual host and an alternative host differed according to the experiment and the trait considered (weight or survival). Finally, we show for the first time that the preference for maize in ECB conceals a strong avoidance of mugwort. The differences in performance, attraction and avoidance between ECB and ABB are discussed in the light of the underlying mechanisms and divergence process.
Risk of developing advanced colorectal neoplasia after removing high‐risk adenoma detected at index colonoscopy in young patients: A KASID study
Authors: Park Soo‐Kyung , Kim Nam Hee , Jung Yoon Suk , Kim Won Hee , Eun Chang Soo , Ko Bong Min , Seo Geom Seog , Cha Jae Myung , Park Jae Jun , Kim Kyeong Ok , Moon Chang Mo , Jung Yoonho , Kim Eun Soo , Jeon Seong Ran , Lee Chang Kyun , Park Dong Il ,   Intestinal cancer study group of the Korean Association for the Study of Intestinal Diseases (KASID)
Published: September 2015

Background and Aim:

Advanced adenoma (> 10 mm in diameter, villous structure, or high‐grade dysplasia) in young patients may have different characteristics and prognosis compared with those in older patients. We aimed to compare the incidence of colorectal neoplasms in young patients with older patients after removing high‐risk adenoma (advance adenoma or ≥ 3 adenomas).

Methods:

A retrospective, multicenter study was conducted at 13 university hospitals in Korea. The 1479 patients who removed high‐risk adenoma at index colonoscopy and followed by surveillance colonoscopy ≥ 2.5 years after were included. The cumulative incidence of overall and advanced colorectal neoplasms was compared according to the age groups (group 1: < 50 years, group 2: 50–70 years, and group 3: ≥ 70 years).

Results:

The prevalence of advance adenoma detected at index colonoscopy was significantly higher in group 1 than in groups 2 and 3 (85.4%, 78.1%, and 77.2%, respectively; P = 0.035). The 5 years cumulative incidence of overall and advanced colorectal neoplasms were 61.9%, 67.9%, and 74.7% (P < 0.001), and 11.7%, 17.9%, and 27.1% (P = 0.001) in groups 1, 2, and 3, respectively. In multivariate analysis, age > 70 years was a significant risk factor for developing overall (hazard ratio [HR] 1.41, 95% confidence interval [CI] 1.12–1.82, P = 0.004) and advanced colorectal neoplasms (HR = 2.56, 95% CI 1.43–4.59, P = 0.002).

Conclusion:

The cumulative incidence of overall and advanced colorectal neoplasms was significantly higher in older patients than in young patient groups. Age was a significant risk factor for developing colorectal neoplasms after removing high‐risk adenoma.
Crohn's disease prognosis and early immunomodulator therapy: Results from the CONNECT study
Authors: Kim Bun , Cheon Jae Hee , Moon Hyun Jin , Park Yi Rang , Ye Byong Duk , Yang Suk‐Kyun , Seo Geom Seog , Jang Byung Ik , Kim You Sun , Kim Joo Sung , Han Dong Soo , Kim Young‐Ho , Kim Won Ho
Published: September 2015

Background:

It is unknown whether the treatment initiating time of immunomodulators such as thiopurines affects the course of Crohn's disease (CD). We evaluated the efficacy of early immunomodulator therapy (EIT) on the prognosis of patients with CD.

Methods:

We retrospectively analyzed 1157 patients with CD who were enrolled in the CrOhn's disease cliNical NEtwork and CohorT study and received immunomodulator therapy. The patients were divided into an EIT group and a conventional therapy group based on whether immunomodulators were initiated within six months after being diagnosed with CD. We compared the rates of intestinal surgery, bowel complications, and hospitalization because of CD between the groups.

Results:

Patient age at diagnosis and sex were not significantly different between the two groups. The mean duration of follow‐up was 105.8 ± 51.5 months. A Kaplan–Meier analysis identified that the EIT group was superior to the conventional therapy group in terms of delaying surgery (P = 0.017). In multivariate analysis, EIT was an independent predicting factor associated with delaying the onset of complications (P = 0.050). Patients were divided into two groups based on the year of CD diagnosis: from 1982 to 1999 (A) and from 2000 to 2008 (B). In group A, the time from diagnosis to the start of immunomodulatory therapy was longer (P < 0.001), and the time to first intestinal surgery was shorter than group B (P = 0.002).

Conclusions:

The early use of immunomodulators was associated with a good prognosis as defined by a need for surgery and the occurrence of complications in CD in our multicenter study.
Metabotropic GABAB receptors mediate GABA inhibition of acetylcholine release in the rat neuromuscular junction
Authors: Malomouzh Artem I. , Petrov Konstantin A. , Nurullin Leniz F. , Nikolsky Evgeny E.
Published: September 2015

Gamma‐aminobutyric acid (GABA) is an amino acid which acts as a neurotransmitter in the central nervous system. Here, we studied the effects of GABA on non‐quantal, spontaneous, and evoked quantal acetylcholine (ACh) release from motor nerve endings. We found that while the application of 10 μM of GABA had no effect on spontaneous quantal ACh release, as detected by the frequency of miniature endplate potentials, GABA reduced the non‐quantal ACh release by 57%, as determined by the H‐effect value. Finally, the evoked quantal ACh release, estimated by calculating the quantal content of full‐sized endplate potentials (EPPs), was reduced by 34%. GABA's inhibitory effect remained unchanged after pre‐incubation with picrotoxin, an ionotropic GABAA receptor blocker, but was attenuated following application of the GABAB receptor blocker CGP 55845, which itself had no effect on ACh release. An inhibitor of phospholipase C, U73122, completely prevented the GABA‐induced decrease in ACh release. Immunofluorescence demonstrated the presence of both subunits of the GABAB receptor (GABABR1 and GABABR2) in the neuromuscular junction. These findings suggest that metabotropic GABAB receptors are expressed in the mammalian neuromuscular synapse and their activation results in a phospholipase C‐mediated reduction in the intensity of non‐quantal and evoked quantal ACh release.

image

We investigated the effect of gamma‐aminobutyric acid (GABA) on neuromuscular transmission. GABA reduced the non‐quantal and evoked quantal release of acetylcholine. These effects are mediated by GABAB receptors and are implemented via phospholipase C (PLC) activation. Our findings suggest that in the mammalian neuromuscular synapse, metabotropic GABAB receptors are expressed and their activation results in a reduction in the intensity of acetylcholine release.
Gene expression profiling of the inner ear
Authors: Schimmang Thomas , Maconochie Mark
Published: September 2015

The identification of transcriptional differences has served as an important starting point in understanding the molecular mechanisms behind biological processes and systems. The developmental biology of the inner ear, the biology of hearing and of course the pathology of deafness are all processes that warrant a molecular description if we are to improve human health. To this end, technological innovation has meant that larger scale analysis of gene transcription has been possible for a number of years now, extending our molecular analysis of genes to beyond those that are currently in vogue for a given system. In this review, some of the contributions gene profiling has made to understanding developmental, pathological and physiological processes in the inner ear are highlighted.
Monitoring a ‘metabolic shift’ after surgical resection of oral squamous cell carcinomas by serum lactate dehydrogenase
Authors: Grimm M. , Krimmel M. , Hoefert S. , Kraut W. , Calgéer B. , Biegner T. , Teriete P. , Munz A. , Reinert S.
Published: September 2015

Objectives

Monitoring surgical removal of oral squamous cell carcinomas (OSCC) is being routinely performed through clinical and imaging follow‐up. We analyzed the potential use of serum lactate, lactate dehydrogenase (LDH), and LDH isoenzymes (LDH 1‐5) as biomarkers in blood for the monitoring of surgical removal of OSCC.

Materials and Methods

Serum lactate, LDH, and LDH isoenzymes (LDH 1‐5) have been prospectively assessed in healthy individuals (n = 19), patients with OSCC (n = 34: primary OSCC, n = 32 and recurrent OSCC, n = 2) before surgery and after curative tumor resection (n = 26). LDHA and LDHB expressions were analyzed by immunohistochemistry (IHC) in the same OSCC tumor specimen.

Results

Positive LDHA tumor tissue expression measured by IHC (n = 34/34, 100%) was significantly associated with increased serum LDH‐5 (n = 24/34, 71%, P = 0.0258) but weak significantly associated with increased total serum LDH (n = 23/34, 68%, P = 0.0592). Positive LDHB tumor tissue expression measured by IHC (n = 25/34, 74%) was significantly associated with increased total serum LDH (P = 0.0172). After surgery, serum LDH and LDH‐5 isoenzyme significantly decreased and LDH‐1 significantly increased in the aftercare. A significantly inverse correlation of LDHA with LDHB IHC scores was found (P < 0.0001).

Conclusions

The association of LDHA and LDHB measured by IHC with serum LDH indicates that analyzing this enzyme could serve as a favorable ‘liquid biopsy’ (non‐invasive diagnostic tool) for OSCC.
Peginterferon add‐on results in more HBsAg decline compared to monotherapy in HBeAg‐positive chronic hepatitis B patients
Authors: Brouwer W. P. , Sonneveld M. J. , Xie Q. , Guo S. , Zhang N. , Zeuzem S. , Tabak F. , Zhang Q. , Simon K. , Akarca U. S. , Streinu‐Cercel A. , Hansen B. E. , Janssen H. L. A.
Published: September 2015

It is unknown whether peginterferon (PEG‐IFN) add‐on to entecavir (ETV) leads to more HBsAg decline compared to PEG‐IFN monotherapy or combination therapy, and whether ETV therapy may prevent HBsAg increase after PEG‐IFN cessation. We performed a post hoc analysis of 396 HBeAg‐positive patients treated for 72 weeks with ETV + 24 weeks PEG‐IFN add‐on from week 24 to 48 (add‐on, n = 85), 72 weeks with ETV monotherapy (n = 90), 52 weeks with PEG‐IFN monotherapy (n = 111) and 52 weeks PEG‐IFN + lamivudine (combination, n = 110) within 2 randomized trials. HBsAg decline was assessed at the end of PEG‐IFN (EOP) and 6 months after PEG‐IFN (EOF) discontinuation. Differences in baseline characteristics were accounted for using inversed probability of treatment weights. At EOP, a HBsAg reduction of ≥1log10 IU/mL was more frequently achieved for patients in the add‐on or combination therapy arms (both 36%), compared to PEG‐IFN mono (20%) or ETV (8%) (add‐on vs PEG‐IFN mono P = 0.050). At EOF, the HBsAg reduction ≥1log10 IU/mL was only sustained in patients treated with ETV consolidation (add‐on vs combination and PEG‐IFN mono: 40% vs 23% and 18%, P = 0.029 and P = 0.003, respectively). For add‐on, combination, PEG‐IFN mono and ETV, the mean HBsAg‐level change at EOF was −0.84, −0.81, −0.68 and −0.33 log10 IU/mL, respectively (P > 0.05 for PEG‐IFN arms). HBeAg loss at EOF was 36%, 31%, 33% and 20%, respectively (P > 0.05). PEG‐IFN add‐on for 24 weeks results in more on‐treatment HBsAg decline than does 52 weeks of PEG‐IFN monotherapy. ETV therapy may maintain the HBsAg reduction achieved with PEG‐IFN.