bluuebunny/crossref_metadata_2025 huggingface dataset:
Telomeric dysfunction triggers an unstable growth arrest leading to irreparable genomic lesions and entry into cellular senescence
Authors: Ghadaouia Sabrina , Olivier Marc Alexandre , Martinez Aurélie , Malaquin Nicolas , Cardin Guillaume B , Rodier Francis
Published: October 2018

Replicative senescence is the permanent growth arrest caused by gradual telomere attrition occurring at each round of genome replication. Critically shortened telomeres lose their protective shelterin complex and t-loop structure revealing uncapped chromosome ends that are recognized as DNA double-strand breaks causing a p53-dependent DNA damage response (DDR) towards proliferation arrest. Because telomeres are heterogeneous in length within a single cell, the number of short telomeres necessary for senescence onset remains ill defined. Using controlled Tin2-mediated shelterin inactivation, we show that telomere uncapping is not sufficient to trigger senescence. While uncapping generates expected telomeric DNA damage detection, the associated weak DDR allows a rapid bypass of the primary growth arrest and re-entry into the cell cycle despite dysfunctional telomeres. During the ensuing mitosis, fused telomeres lead to additional DNA breaks and to genomic instability including chromosomes bridges or micronuclei, which sustain a secondary entry into stable growth arrest. The loss of p53 prevented both primary and secondary growth arrest, leading to amplified genomic instablility. Our results support a new multistep model for entry into telomere-mediated replicative senescence in normal cells, which is not directly induced by telomere uncapping, but rather by an amplification of DNA lesions caused by telomere fusions that leads to permanent irreparable genome damage.
Periplasmic protein EipA determines envelope stress resistance and virulence inBrucella abortus
Authors: Herrou Julien , Willett Jonathan W. , Fiebig Aretha , Varesio Lydia M. , Czyż Daniel M. , Cheng Jason X. , Ultee Eveline , Briegel Ariane , Bigelow Lance , Babnigg Gyorgy , Kim Youngchang , Crosson Sean
Published: October 2018

Molecular components of theBrucella abortuscell envelope play a major role in its ability to infect, colonize and survive inside mammalian host cells. In this study, we have defined a role for a conserved gene of unknown function inB. abortusenvelope stress resistance and infection. Expression of this gene, which we nameeipA,is directly activated by the essential cell cycle regulator, CtrA.eipAencodes a soluble periplasmic protein that adopts an unusual eight-stranded β-barrel fold. Deletion ofeipAattenuates replication and survival in macrophage and mouse infection models, and results in sensitivity to treatments that compromise the integrity of the cell envelope. Transposon disruption of genes required for LPS O-polysaccharide biosynthesis is synthetically lethal witheipAdeletion. This genetic connection between O-polysaccharide andeipAis corroborated by our discovery thateipAis essential inBrucella ovis, a naturally rough species that harbors mutations in several genes required for O-polysaccharide production. Conditional depletion ofeipAexpression inB. ovisresults in a cell chaining phenotype, providing evidence thateipAdirectly or indirectly influences cell division inBrucella. We conclude that EipA is a molecular determinant ofBrucellavirulence that functions to maintain cell envelope integrity and influences cell division.
Automatic navigation system for the mouse brain
Authors: Tappan Susan J. , Eastwood Brian S. , O’Connor Nathan , Wang Quanxin , Ng Lydia , Feng David , Hooks Bryan M. , Gerfen Charles R. , Hof Patrick R. , Schmitz Christoph , Glaser Jack R.
Published: October 2018

Identification and delineation of brain regions in histologic mouse brain sections is especially pivotal for many neurogenomics, transcriptomics, proteomics and connectomics studies, yet this process is prone to observer error and bias. Here we present a novel brain navigation system, named NeuroInfo, whose general principle is similar to that of a global positioning system (GPS) in a car. NeuroInfo automatically navigates an investigator through the complex microscopic anatomy of histologic sections of mouse brains (thereafter: “experimental mouse brain sections”). This is achieved by automatically registering a digital image of an experimental mouse brain section with a three-dimensional (3D) digital mouse brain atlas that is essentially based on the third version of the Allen Mouse Brain Common Coordinate Framework (CCF v3), retrieving graphical region delineations and annotations from the 3D digital mouse brain atlas, and superimposing this information onto the digital image of the experimental mouse brain section on a computer screen. By doing so, NeuroInfo helps in solving the long-standing problem faced by researchers investigating experimental mouse brain sections under a light microscope—that of correctly identifying the distinct brain regions contained within the experimental mouse brain sections. Specifically, NeuroInfo provides an intuitive, readily-available computer microscopy tool to enhance researchers’ ability to correctly identify specific brain regions in experimental mouse brain sections. Extensive validation studies of NeuroInfo demonstrated that this novel technology performs remarkably well in accurately delineating regions that are large and/or located in the dorsal parts of mouse brains, independent on whether the sections were imaged with fluorescence or brightfield microscopy. This novel navigation system provides a highly efficient way for registering a digital image of an experimental mouse brain section with the 3D digital mouse brain atlas in a minute and accurate delineation of the image in real-time.
Assembly of Yeast Spindle Pole Body and its Components Revealed by Electron Cryo-Tomography
Authors: Li Sam , Fernandez Jose-Jesus
Published: October 2018

Spindle pole body (SPB) is the microtubule organizing center (MTOC) in yeast. It plays essential roles during many cellular processes, ranging from mitosis to karyogamy. Here, we used electron cryo-tomography (cryo-ET) and image processing to study SPB and its component purified from the budding yeast. The 3D images and models of SPB at various cell cycle stages were reconstructed by cryo-ET and were analyzed. The results reveal SPB as a cylindrical shaped structure composed of multiple layers. The central layers are arranged with a degree of crystalline order. By using subtomogram averaging methods, we studied the purified “sheet” from over-expressed Spc42p. Our analysis of the SPBs and its components provides new insights into the assembly of this organelle and its cellular function as an MTOC.
Genes with high network connectivity are enriched for disease heritability
Authors: Kim Samuel S. , Dai Chengzhen , Hormozdiari Farhad , van de Geijn Bryce , Gazal Steven , Park Yongjin , O’Connor Luke , Amariuta Tiffany , Loh Po-Ru , Finucane Hilary , Raychaudhuri Soumya , Price Alkes L.
Published: October 2018

Recent studies have highlighted the role of gene networks in disease biology. To formally assess this, we constructed a broad set of pathway, network, and pathway+network annotations and applied stratified LD score regression to 42 independent diseases and complex traits (average N=323K) to identify enriched annotations. First, we constructed annotations from 18,119 biological pathways, including 100kb windows around each gene. We identified 156 pathway-trait pairs whose disease enrichment was statistically significant (FDR < 5%) after conditioning on all genes and on annotations from the baseline-LD model, a stringent step that greatly reduced the number of pathways detected; most of the significant pathway-trait pairs were previously unreported. Next, for each of four published gene networks, we constructed probabilistic annotations based on network connectivity using closeness centrality, a measure of how close a gene is to other genes in the network. For each gene network, the network connectivity annotation was strongly significantly enriched. Surprisingly, the enrichments were fully explained by excess overlap between network annotations and regulatory annotations from the baseline-LD model, validating the informativeness of the baseline-LD model and emphasizing the importance of accounting for regulatory annotations in gene network analyses. Finally, for each of the 156 enriched pathway-trait pairs, for each of the four gene networks, we constructed pathway+network annotations by annotating genes with high network connectivity to the input pathway. For each gene network, these pathway+network annotations were strongly significantly enriched for the corresponding traits. Once again, the enrichments were largely explained by the baseline-LD model. In conclusion, gene network connectivity is highly informative for disease architectures, but the information in gene networks may be subsumed by regulatory annotations, such that accounting for known annotations is critical to robust inference of biological mechanisms.
Electron Cryo-Tomography Provides Insight into Procentriole Architecture and Assembly Mechanism
Authors: Li Sam , Fernandez Jose-Jesus , Marshall Wallace F. , Agard David A.
Published: October 2018

Centriole is an essential structure with multiple functions in cellular processes. Centriole biogenesis and homeostasis is tightly regulated. Using electron cryo-tomography (cryoET) we present the structure of procentrioles fromChlamydomonas reinhardtii. We identified a set of non-tubulin components attached to the triplet microtubule (MT), many are at the junctions of tubules likely to reinforce the triplet. We describe structure of the A-C linker that bridges neighboring triplets. We find that POC1 is an integral component of the A-C linker. Its conserved WD40 β-propeller domain provides sites for attachment to other A-C linker components. The twist of A-C linker results in an iris diaphragm-like motion of the triplets in the longitudinal direction of procentriole. Finally, we identified two assembly intermediates at the growing ends of procentriole allowing us to propose a model for the procentriole assembly. Our results provide a comprehensive structural framework for understanding the molecular mechanisms underpinning procentriole biogenesis and assembly.
Potentially repurposable drugs for schizophrenia identified from its interactome
Authors: Karunakaran Kalyani B. , Chaparala Srilakshmi , Ganapathiraju Madhavi K.
Published: October 2018

From the schizophrenia drug-target interactome,1we studied the drugs that targeted multiple proteins in the interactome, or those that target proteins with many targets, or those that target novel (computationally predicted) interactors of schizophrenia associated proteins. In schizophrenia, gene expression has been described as a measurable aspect of the disease reflecting the action of risk genes. We studied each of the selected drugs using the NextBio software suite, and shortlisted those that had a negative correlation with gene expression of schizophrenia. This analysis resulted in 12 drugs whose differential gene expression (drug versus normal) had an anti-correlation with differential expression for schizophrenia (disorder versus normal). Some of these drugs were already being tested for their clinical activity in schizophrenia and other neuropsychiatric disorders. Several proteins in the protein interactome of the targets of several of these drugs were associated with various neuropsychiatric disorders. The network of genes which were differentially expressed on drug treatment, and had an anti-correlation with gene expression in schizophrenia, were significantly enriched in pathways relevant to schizophrenia etiology and GWAS genes associated with traits or diseases that had pathophysiological overlap with schizophrenia. Drugs that are structurally similar to the shortlisted drugs, or targeted the same genes as these drugs, have also demonstrated clinical activity in schizophrenia and other related disorders. This integrated computational analysis may help translate insights from the schizophrenia drug-protein interactome to clinical research - an important step, especially in the field of psychiatric drug development, facing a high failure rate.
Retracted: Nifedipine alone or combined with sildenafil citrate for management of threatened preterm labour: a randomised trial
Authors: Maher MA , Sayyed TM , El‐khadry SW
Published: October 2018

Objective

To study the tocolytic action of nifedipine combined with sildenafil citrate (SC) and if the combination is superior to nifedipine alone in inhibiting threatened preterm labour (PTL).

Design

Prospective randomised study.

Setting

An Egyptian university hospital.

Population

Women with threatened PTL who received either nifedipine with SC or nifedipine alone.

Methods

Patients were randomly allocated to receive either (1) nifedipine 20 mg orally (stat dose), followed by 10 mg orally every 6–8 hours at the same time as vaginal administration of SC (25 mg at 8‐hourly intervals) or (2) nifedipine alone. Medications were continued for 48–72 hours.

Main outcome measures

The percentage of women who remained undelivered during hospitalisation.

Results

From January 2015 to November 2016, 239 women were randomised. The baseline characteristics of participants were similar. Nifedipine combined with SC was associated with more women remaining undelivered (81.8 versus 68.6%; P = 0.018) during hospitalisation. Regarding secondary outcomes, the addition of SC was also associated with fewer deliveries within 7 days of admission (9.1 versus 20.3%; P = 0.014), prolonged latency (29 versus 7 days; P = 0.002), fewer admissions to neonatal intensive care units (31.4 versus 44.1%; P = 0.043), fewer very preterm deliveries (from 28 to <32 weeks, 20.7 versus 38.1%; P = 0.043), and increased neonatal birthweight (1900 versus 1500 g; P = 0.018).

Conclusions

Vaginal SC combined with nifedipine is an effective option for tocolytic therapy during threatened PTL.

Tweetable abstract

Vaginal SC enhances the tocolytic effect of nifedipine.
Environmental impact assessments can misrepresent species distributions: a case study of koalas in Queensland, Australia
Authors: Cristescu R. H. , Scales K. L. , Schultz A. J. , Miller R. L. , Schoeman D. S. , Dique D. , Frère C. H.
Published: October 2018

Vegetation clearing has been implicated as a major contributor to biodiversity loss. It therefore stands to reason that developers should face a regulatory requirement to assess potential impacts and to avoid, mitigate and compensate for loss of vegetation wherever proposed infrastructure developments impact on vegetation considered to be habitat for threatened species. Environmental Impact Assessments (EIA) rely on accurate information to describe the distributions of threatened species within the footprint of proposed infrastructure developments, which is critical to ensuring appropriate mitigation of potentially deleterious impacts on these populations. EIA survey guidelines seek to determine species’ presence accurately, while acknowledging the limits imposed by time and budget constraints. As such, the EIA guidelines may recommend: (1) stratifying the landscape based on previous knowledge of habitat variables relevant to a species; and (2) targeting survey effort to strata with high probability of occupancy. Here, we use koala Phascolarctos cinereus surveys as a case study to explore the extent to which application of EIA guidelines result in accurate occupancy estimates. We compared the presence/absence distribution across one landscape survey and three EIA surveys, and found that koala occupancy was not well predicted by koala habitat criteria widely used to inform sampling design. In the context of EIA, we provide an example of how targeting survey effort to strata with high probability of occupancy risks misrepresenting true occurrence patterns. A general issue with survey designs that rely on previous knowledge is that they self‐reinforce erroneous assumptions. Our findings stand as a warning that EIA might neither quantify the impact of proposed infrastructure developments adequately, nor inform the ensuing mitigation measures. Threatened species’ protection in the face of infrastructure development will require new approaches to EIAs to ensure that providers are enabled to undertake comprehensive environmental surveys capable of detecting priority species.
Comparison of nicotine exposure during pregnancy when smoking and abstinent with nicotine replacement therapy: systematic review and meta‐analysis
Authors: Hickson Charlotte , Lewis Sarah , Campbell Katarzyna Anna , Cooper Sue , Berlin Ivan , Claire Ravinder , Oncken Cheryl , Coleman‐Haynes Tom , Coleman Tim
Published: October 2018

Background and aims

Smoking during pregnancy is strongly associated with negative pregnancy and perinatal outcomes. Some guidelines recommend nicotine replacement therapy (NRT) for smoking cessation during pregnancy, but adherence with NRT is generally poor and could be partially explained by nicotine‐related safety concerns. We compared pregnant women's cotinine and nicotine exposures from smoking with those when they were abstinent from smoking and using NRT.

Design

Systematic review with meta‐analysis and narrative reporting. Twelve studies were included: in most, only one type of NRT was used. Seven were quality‐assessed and judge of variable quality.

Setting

Studies from any setting that reported nicotine or cotinine levels when smoking and later when abstinent and using NRT.

Participants

Pregnant women who smoked and became abstinent but used NRT either in a cessation study or in a study investigating other impacts of NRT.

Measurements

We quality‐assessed longitudinal cohort studies using a modified version of the Newcastle–Ottawa scale. For meta‐analysis, we used mean within‐person differences in cotinine or nicotine levels when smoking and at later follow‐up when abstinent and using NRT. Where such data were not available, we calculated differences in group mean levels and reported these narratively, indicating where data were not completely longitudinal.

Findings

Of the 12 included studies, four cotinine‐measuring studies (n = 83) were combined in a random effects meta‐analysis; the pooled estimate for the mean difference (95% confidence intervals) in cotinine levels between when women were smoking and abstinent but using NRT was 75.3 (57.1 to 93.4) ng/ml (I2 = 42.1%, P = 0.11). Of eight narratively‐described studies, six reported lower cotinine and/or nicotine levels when abstinent and using NRT; two had mixed findings, with higher levels when abstinent but using NRT reported from at least one assay time‐point.

Conclusions

Pregnant women who use nicotine replacement therapy instead of smoking reduce their nicotine exposure.
Implications of deranged activated partial thromboplastin time for anaesthesia and surgery
Authors: Loizou E. , Mayhew D. J. , Martlew V. , Murthy B. V. S.
Published: October 2018

Bleeding during and after surgery ranges from trivial to fatal. Bleeding is in part determined by the patient's coagulation status. The UK National Institute for Health and Care Excellence recommends a pre‐operative clotting test for patients with a history of abnormal bleeding. Anaesthetists are familiar with the prothrombin time assay, used to monitor warfarin effect, but anaesthetists may be less familiar with the activated partial thromboplastin time (APTT), which tests the function of the ‘intrinsic’ clotting pathway. The activated partial thromboplastin time may be prolonged due to contamination, anticoagulant therapy, clotting factor deficiencies, lupus anticoagulant or acquired inhibitors of specific clotting factors. A prolonged activated partial thromboplastin time should lead to: further testing to exclude heparin contamination or therapy, mixing studies to identify factor deficiencies and if necessary dynamic studies, such as the dilute Russell's viper venom time and the Actin FS‐activated partial thromboplastin time, to identify direct factor inhibitors. These tests identify abnormalities and their implications for bleeding, helping anaesthetists and haematologists to manage haemostasis for individual patients.
Body temperature, cutaneous heat loss and skin blood flow during epidural anaesthesia for emergency caesarean section
Authors: Mullington C. J. , Low D. A. , Strutton P. H. , Malhotra S.
Published: October 2018

It is not clear how converting epidural analgesia for labour to epidural anaesthesia for emergency caesarean section affects either cutaneous vasomotor tone or mean body temperature. We hypothesised that topping up a labour epidural blocks active cutaneous vasodilation (cutaneous heat loss and skin blood flow decrease), and that as a result mean body temperature increases. Twenty women in established labour had body temperature, cutaneous heat loss and skin blood flow recorded before and after epidural top‐up for emergency caesarean section. Changes over time were analysed with repeated measures ANOVA. Mean (SD) mean body temperature was 36.8 (0.5)°C at epidural top‐up and 36.9 (0.6)°C at delivery. Between epidural top‐up and delivery, the mean (SD) rate of increase in mean body temperature was 0.5 (0.5) °C.h−1. Following epidural top‐up, chest (p < 0.001) and forearm (p = 0.004) heat loss decreased, but head (p = 0.05), thigh (p = 0.79) and calf (p = 1.00) heat loss did not change. The mean (SD) decrease in heat loss was 15 (19) % (p < 0.001). Neither arm (p = 0.06) nor thigh (p = 0.10) skin blood flow changed following epidural top‐up. Despite the lack of change in skin blood flow, the most plausible explanation for the reduction in heat loss and the increase in mean body temperature is blockade of active cutaneous vasodilation. It is possible that a similar mechanism is responsible for the hyperthermia associated with labour epidural analgesia.
Activin A target genes are differentially expressed between normal and neoplastic adult human testes: clues to gonocyte fate choice
Authors: Szarek M. , Bergmann M. , Konrad L. , Schuppe H.‐C. , Kliesch S. , Hedger M. P. , Loveland K. L.
Published: October 2018

Background

Human testicular germ cell tumours (TGCT) arise from germ cell neoplasia in situ (GCNIS) cells that originate from foetal germ cell precursors. Activin A is central to normal foetal testis development, and its dysregulation may contribute to TGCT aetiology.

Objective

(i) To test whether the expression profiles of activin A targets in normal and neoplastic human testes indicates functional links with TGCT progression. (ii) To investigate whether activin A levels influence MMP activity in a neoplastic germ cell line.

Materials and Methods

(1) Bouin's fixed, paraffin‐embedded human testes were utilized for PCR‐based transcript analysis and immunohistochemistry. Samples (n = 5 per group) contained the following: (i) normal spermatogenesis, (ii) GCNIS or (iii) seminoma. CXCL12, CCL17, MMP2 and MMP9 were investigated. (2) The human seminoma‐derived TCam‐2 cell line was exposed to activin A (24 h), and target transcripts were measured by qRT‐PCR (n = 4). ELISA (n = 4) and gelatin zymography (n = 3) showed changes in protein level and enzyme activity, respectively.

Results

(i) Cytoplasmic CXCL12 was detected in Sertoli and other somatic cells, including those surrounding seminoma cells. Anti‐CCL17 labelled only the cytoplasm of Sertoli cells surrounding GCNIS, while anti‐MMP2 and anti‐MMP9 labelled germline and epithelial‐like cells in normal and neoplastic testes. (ii) Exposing TCam‐2 cells to activin A (50 ng/mL) elevated MMP2 and MMP9 transcripts (fourfold and 30‐fold), while only MMP2 protein levels were significantly higher after activin A (5 ng/mL and 50 ng/mL) exposure. Importantly, gelatin zymography revealed activin A increased production of activated MMP2.

Discussion

Detection of CCL17 only in GCNIS tumours may reflect a change in Sertoli cell phenotype to a less mature state. Stimulation of MMP2 activity by activin A in TCam‐2 cells suggests activin influences TGCT by modulating the tumour niche.

Conclusion

This knowledge provides a basis for understanding how physiological changes that influence activin/TGF‐β superfamily signalling may alter germ cell fate.
Heterogeneity in arterial hypertension and ocular perfusion pressure definitions: Towards a consensus on blood pressure‐related parameters for glaucoma studies
Authors: Barbosa‐Breda João , Abegão‐Pinto Luis , Van Keer Karel , Jesus Danilo A. , Lemmens Sophie , Vandewalle Evelien , Rocha‐Sousa Amândio , Stalmans Ingeborg
Published: October 2018

Purpose

Glaucoma studies have long taken into account the blood pressure (BP) status of patients. This study summarizes and evaluates the impact of the different criteria that have been used for BP‐related variables in glaucoma research.

Methods

Studies included in two meta‐analyses that reviewed the role of BP in glaucoma were analyzed. Additional studies published after the search periods of the meta‐analyses were also included. Criteria for the definition of arterial hypertension and other BP‐related variables, such as mean arterial pressure (MAP) and mean ocular perfusion pressure (MOPP), were retrieved.

Results

Sixty‐four studies were evaluated. One‐third used 140 mmHg as a systolic BP cut‐off to define hypertension, 20% used 160 mmHg and the remaining half used various other criteria. Less than 20% of studies reported MAP and/or MOPP. While eight of the ten studies reporting MAP used a correct formula that only happened for five of the eleven studies reporting MOPP. Using as an example average blood pressure values, incorrectly used formulas could have led to an overestimation of more than 100% of the expected values.

Conclusion

Considerable heterogeneity exists in BP‐related variables in glaucoma research and different definitions can lead to large disparities. Glaucoma research would benefit from a consensus regarding blood pressure parameters.
Acceleration of cancer science with genome editing and related technologies
Authors: Sakuma Tetsushi , Yamamoto Takashi
Published: October 2018

Genome editing includes various edits of the genome, such as short insertions and deletions, substitutions, and chromosomal rearrangements including inversions, duplications, and translocations. These variations are based on single or multiple DNA double‐strand break (DSB)‐triggered in cellulo repair machineries. In addition to these “conventional” genome editing strategies, tools enabling customized, site‐specific recognition of particular nucleic acid sequences have been coming into wider use; for example, single base editing without DSB introduction, epigenome editing with recruitment of epigenetic modifiers, transcriptome engineering using RNA editing systems, and in vitro detection of specific DNA and RNA sequences. In this review, we provide a quick overview of the current state of genome editing and related technologies that multilaterally contribute to cancer science.
Role of triggering receptor expressed on myeloid cells 2 in neuroinflammation and neurodegeneration of the central nervous system
Authors: Takahashi Kazuya
Published: October 2018

Triggering receptor expressed on myeloid cells 2 (TREM2) is a member of the TREM family of innate immune receptors. It is expressed on the cell membrane of myeloid lineage cells including osteoclasts and microglia. Since it was reported that rare TREM2 variants, such as R47H and R62H, increase the risk of late‐onset Alzheimer's disease, it has been pointed out that many TREM2 variants relate to other neurodegenerative diseases, including amyotrophic lateral sclerosis, Parkinson's disease and frontotemporal dementia. Although there are still conflicting reports as to whether TREM2 promotes or suppresses neurodegenerative or neuroinflammatory diseases, TREM2 has recently been considered to play a key role in the concept of disease‐associated microglia. In disease‐associated microglia induction, TREM2 might have a role as a microglia‐specific checkpoint.
Clinical study of dentocraniofacial characteristics in patients with Williams syndrome
Authors: Matsuno Sahori , Tsuji Michiko , Hikita Rina , Matsumoto Tsutomu , Baba Yoshiyuki , Moriyama Keiji
Published: October 2018

Williams syndrome (WS) is a rare congenital anomaly that is characterized by distinctive facial features, congenital heart disease, and behavioral characteristics that include mental retardation. However, only a few reports have documented the dentocraniofacial morphological characteristics of WS in Japanese individuals. The aim of this study was to analyze the dentocraniofacial morphology and growth patterns in a group of nine Japanese subjects (two males and seven females; mean age at admission, 10.1 years) with WS. The analytical methods included an initial medical questionnaire, lateral cephalography, panoramic radiography, dental casts, and oral examinations. The dental findings showed congenitally missing teeth, microdontia, and peg‐shaped teeth. Regarding cranial morphology, microcephaly occurred at high frequencies, and a short posterior cranial base and thick calvarial bones, including frontal, parietal, and occipital bones, were seen in patients with WS. An analysis of maxillofacial morphology showed the large gonial angles and lingual inclination of the lower incisors in patients with WS. In addition, the chin button was deficient and in three of four growing subjects the maxillofacial growth pattern demonstrated a downward and backward tendency. The results of this study provide important information that will improve our understanding of the characteristics of patients with WS.
Early development of visual attention in infants in rural Malawi
Authors: Pyykkö Juha , Forssman Linda , Maleta Kenneth , Ashorn Per , Ashorn Ulla , Leppänen Jukka M.
Published: October 2018

Eye tracking research has shown that infants develop a repertoire of attentional capacities during the first year. The majority of studies examining the early development of attention comes from Western, high‐resource countries. We examined visual attention in a heterogeneous sample of infants in rural Malawi (N = 312–376, depending on analysis). Infants were assessed with eye‐tracking‐based tests that targeted visual orienting, anticipatory looking, and attention to faces at 7 and 9 months. Consistent with prior research, infants exhibited active visual search for salient visual targets, anticipatory saccades to predictable events, and a robust attentional bias for happy and fearful faces. Individual variations in these processes had low to moderate odd‐even split‐half and test‐retest reliability. There were no consistent associations between attention measures and gestational age, nutritional status, or characteristics of the rearing environment (i.e., maternal cognition, psychosocial well‐being, socioeconomic status, and care practices). The results replicate infants’ early attentional biases in a large, unique sample, and suggest that some of these biases (e.g., bias for faces) are pronounced in low‐resource settings. The results provided no evidence that the initial manifestation of infants’ attentional capacities is associated with risk factors that are common in low‐resource environments.
Average e′ velocity on transthoracic echocardiogram is a novel predictor of left atrial appendage sludge or thrombus in patients with atrial fibrillation
Authors: Garshick Michael S. , Mulliken Jennifer , Schoenfeld Matthew , Riedy Katherine , Guo Yu , Zhong Judy , Dodson John A. , Saric Muhamed , Skolnick Adam H.
Published: October 2018

Background

Studies have demonstrated the value of transthoracic echocardiogram (TTE) diastolic parameters in predicting left atrial appendage (LAA) thrombus; however, these studies have been small. We aim to clarify the relationship between TTE diastolic parameters, in particular average e′, and LAA thrombus or sludge.

Methods

A case‐control review was conducted of subjects with non‐valvular atrial fibrillation (n = 2263) who had undergone TEE (transesophageal echocardiogram) and had a TTE within 1 year of TEE. Cases of LAA sludge or thrombus were matched to controls by age, sex, left ventricular ejection fraction (LVEF), and anticoagulation status.

Results

Forty‐three subjects (mean age 73 ± 12, 65% male, LVEF 47%, 44% on anticoagulation) with LAA sludge or thrombus were identified. Compared to matched controls, average TTE e′ (7.3 ± 2.1 cm/s vs 8.7 ± 2.1 cm/s, P < 0.001) and the E:e′ ratio (15 ± 7 cm/s vs 12 ± 5 cm/s; P = 0.005) were significant predictors of LAA sludge or thrombus. Average TTE e′ value of >11 cm/s had 100% sensitivity for ruling out LAA sludge or thrombus.

Conclusion

In individuals with atrial fibrillation, average e′ >11 cm/s on TTE is a promising independent predictor of the absence of LAA sludge or thrombus on TEE.
Right atrial to left atrial volume index ratio is associated with increased mortality in patients with pulmonary hypertension
Authors: Mysore Manu M. , Bilchick Kenneth C. , Ababio Priscilla , Ruth Benjamin K. , Harding William C. , Breathett Khadijah , Chadwell Kimberley , Patterson Brandy , Mwansa Hunter , Jeukeng Christiana M. , Kwon Younghoon , Kennedy Jamie L. W. , Mihalek Andrew D. , Mazimba Sula
Published: October 2018

Background

Pulmonary hypertension (PH) is characterized by increased pulmonary vascular resistance leading to right heart failure. Elevated right atrial (RA) pressure reflects right ventricular (RV) pressure overload and is an established risk factor for mortality in PH. We hypothesized that PH patients with an increased ratio of RA to LA volume index (RAVI/LAVI), would have increased mortality.

Methods

We evaluated the association of RAVI/LAVI with mortality in 124 patients seen at a single academic center's PH clinic after adjusting for the REVEAL risk score, an established risk score in PH. LA and RA volume indices were measured in the four‐and two‐chamber views by two independent researchers. Multivariable logistic regression was used to model the independent association of RAVI/LAVI with survival.

Results

Among 124 patients (mean age 62 ± 12.7 years, 68.6% female), each unit increase in RAVI/LAVI was associated with a nearly twofold increase in mortality (OR: 1.91, 95% CI: 1.20–3.04). In a multivariable logistic regression, each unit increase in RAVI/LAVI was associated with a nearly twofold increase in mortality (OR: 1.73, 95% CI: 1.003–2.998). Furthermore, RAVI/LAVI in the highest quartile (>1.42) was significantly associated with elevated right atrial pressure (RAP) to pulmonary artery wedge pressure ratio (RAP/PAWP) (0.76 ± 0.41, P = 0.02) compared with the lowest quartile (<0.77), suggesting an interaction between invasive hemodynamic data, atrial structural changes, and mortality in PH.

Conclusions

Increased RAVI/LAVI in PH is associated with decreased survival and accounts for atrial structural remodeling related to invasive hemodynamics. These findings support further study of this index in predicting outcomes in PH.
Multimodal imaging evaluation of a primary cardiac lymphoma in an immunocompetent patient
Authors: Wang Shuyuan , Li Meng , Zhang Li , Xie Mingxing
Published: October 2018

Primary cardiac lymphoma (PCL) is a rare extranodal lymphoma that involves only the heart and/or pericardium. It is fatal in the absence of a prompt diagnosis and adequate therapy. Here, we report an immunocompetent 55‐year‐old Chinese man with palpitations and occasional chest distress for 1 month. Multimodal imaging work‐up showed a tumor infiltrated into the myocardium, which greatly contribute to a timely pathology diagnosis of PCL.
Left ventricular endocardial longitudinal dysfunction persists after acute myocarditis with preserved ejection fraction
Authors: Di Bella Gianluca , Carerj Scipione , Recupero Antonino , Donato Rocco , Pugliatti Pietro , Falanga Gabriella , Pedri Stefano , Vizzari Giampiero , Campisi Mariapaola , Zito Concetta , de Gregorio Cesare
Published: October 2018

Background

The aim of present study was to assess left ventricular (LV) myocardial deformation and changes over time in patients with acute myocarditis (AM) with preserved ejection fraction detected by late gadolinium enhancement (LGE) magnetic resonance imaging.

Methods

Thirty‐five male patients with AM diagnoses and preserved systolic function based on cardiac magnetic resonance imaging (MRI) were prospectively enrolled. On admission, echocardiography with measurements of global and segmental longitudinal (LS) strains was performed both at the endocardial (ENDO) and epicardial (EPI) levels. Findings were compared to 25 control subjects. Twenty‐six patients were also monitored over a 22‐month follow‐up (FU group).

Results

On admission, global ENDO‐LS was poorer in magnitude in AM (−19.2 ± 3.1) than in controls (−24.0 ± 1.05) (P < 0.0001), whereas EPI‐LS was not different (−20.6 ± 3.4 vs −19.7 ± 6 P = NS). A functional increase in magnitude in both ENDO‐LS (−20.8 ± 5.4, P = NS) and EPI‐LS (−22.6 ± 4.6, P = 0.02) was found in FU vs AM patients.

Conclusions

The present study demonstrates a steady ENDO‐LS impairment in infarct‐like AM during a 2‐year follow‐up period, despite a preserved LV ejection fraction.
The effect of pegylated granulocyte colony‐stimulating factor on collateral function and myocardial ischaemia in chronic coronary artery disease: A randomized controlled trial
Authors: Traupe Tobias , Stoller Michael , Gloekler Steffen , Meier Pascal , Seiler Christian
Published: October 2018

Objective

To test the effect of long‐term pegfilgrastim on collateral function and myocardial ischaemia in patients with chronic stable coronary artery disease (CAD).

Methods

This was a prospective clinical trial with randomized 2:1 allocation to pegfilgrastim or placebo for 6 months. The primary study endpoint was collateral flow index (CFI) as obtained during a 1‐minute ostial coronary artery balloon occlusion. CFI is the ratio of mean coronary occlusive divided by mean aortic pressure both subtracted by central venous pressure (mm Hg/mm Hg). Secondary endpoints were signs of myocardial ischaemia determined during the same coronary occlusion, that is quantitative intracoronary (i.c.) ECG ST‐segment shift (mV) and the occurrence of angina pectoris. Endpoints were obtained at baseline before and at follow‐up after three subcutaneous study drug injections.

Results

Collateral flow index in the pegfilgrastim group changed from 0.096 ± 0.076 at baseline to 0.126 ± 0.070 at follow‐up (P = 0.0039), while in the placebo group CFI changed from 0.157 ± 0.146 to 0.122 ± 0.043, respectively (P = 0.29); the CFI increment at follow‐up was +0.030 ± 0.075 in the pegfilgrastim group and −0.034 ± 0.148 in the placebo group (P = 0.0172). In the pegfilgrastim group, i.c. ECG ST‐segment shift changed from +1.23 ± 1.01 mV at baseline to +0.93 ± 0.97 mV at follow‐up (P = 0.0049), and in the placebo group, it changed from +0.98 ± 1.02 mV to +1.43 ± 1.09 mV, respectively (P = 0.05). At follow‐up, the fraction of patients free from angina pectoris during coronary occlusion had increased in the pegfilgrastim but not in the placebo group.

Conclusion

Pegfilgrastim given over the course of 6 months improves collateral function in chronic stable CAD, which is reflected by reduced myocardial ischaemia during a controlled coronary occlusion.
INFORMING RETIREMENT SAVINGS DECISIONS: A FIELD EXPERIMENT ON SUPPLEMENTAL PLANS
Authors: Clark Robert L. , Hammond Robert G. , Morrill Melinda S. , Khalaf Christelle
Published: October 2018

Although supplemental saving plans can be an important part of an individual's financial security in retirement, contribution rates remain low, particularly among those with lower salaries and less education. We report findings from an intervention that provided information on key aspects of the employer‐provided supplemental saving plans to older public employees in North Carolina. Among workers participating in a supplemental plan, individuals who received an informational flyer increased their contributions in the months following the intervention relative to the control group. In contrast, individuals who were not enrolled in a retirement saving plan were not moved to begin contributing to a supplemental plan. The results suggest that informational interventions can induce workers who are already engaged in the saving process to reassess their level of retirement preparedness. (JEL C93, D14, D9)
Analysis of fungal endophytes in Scottish Sitka spruce plantations shows extensive infections, novel host partners and gives insights into origins
Authors: Anderson Stewart Carly R. , Doilom Mingkwan , Taylor Joanne E.
Published: October 2018

This preliminary study identified the fungal endophytes of Sitka spruce (Picea sitchensis)in four Scottish plantations, analysed their recruitment possibilities and community structure across the sites, and identified the possible origins of the endophytes in this non‐native host. Although Sitka spruce is native to north‐western North America, it comprises a huge portion of Scottish forestry and is an economically vital timber tree. Needles from two age classes were collected and cultured for emerging endophyte isolates. Using a combination of morphological features and genetic sequencing of the nuclear ribosomalITSregions of representative morphological types, 57 morphotypes were recorded which represented at least 15 different species, including a hypothesized sister species to the pathogen ofPseudotsuga menziesiiin North America and Europe,Nothophaeocryptopus gaeumannii(previouslyP. gaeumannii) that was present at all sites tested. Diversity, recruitment, site, needle age and needle part effects are discussed. The phylogeny ofNothophaeocryptopusbased on analysis of combinedITSand Tub2 sequence data is given in order to assess the relationship of the unknown endophyte to the Douglas fir pathogenN. gaeumannii.
Neurological effects of glucocerebrosidase gene mutations
Authors: Mullin S. , Hughes D. , Mehta A. , Schapira A. H. V.
Published: October 2018

The association between Gaucher disease (GD) and Parkinson disease (PD) has been described for almost two decades. In the biallelic state (homozygous or compound heterozygous) mutations in the glucocerebrosidase gene (GBA) may cause GD, in which glucosylceramide, the sphingolipid substrate of the glucocerebrosidase enzyme (GCase), accumulates in visceral organs leading to a number of clinical phenotypes. In the biallelic or heterozygous state, GBA mutations increase the risk for PD. Mutations of the GBA allele are the most significant genetic risk factor for idiopathic PD, found in 5%–20% of idiopathic PD cases depending on ethnicity. The neurological consequences of GBA mutations are reviewed and the proposition that GBA mutations result in a disparate but connected range of clinically and pathologically related neurological features is discussed. The literature relating to the clinical, biochemical and genetic basis of GBA PD, type 1 GD and neuronopathic GD is considered highlighting commonalities and distinctions between them. The evidence for a unifying disease mechanism is considered.
Obinutuzumab, a new anti‐CD20 antibody, and chlorambucil are active and effective in anti‐myelin‐associated glycoprotein antibody polyneuropathy
Authors: Briani C. , Visentin A. , Salvalaggio A. , Cacciavillani M. , Trentin L.
Published: October 2018

Background and purpose

Rituximab, a chimeric anti‐CD20 monoclonal antibody, has been used in polyneuropathy associated with anti‐myelin‐associated glycoprotein (anti‐MAG) antibody polyneuropathy with controversial results. Herein, two patients with anti‐MAG antibody neuropathy and concurrent chronic lymphocytic leukemia (CLL) are reported, who dramatically responded to obinutuzumab, a novel glycoengineered humanized anti‐CD20 monoclonal antibody.

Methods

Patient 1 was an 82‐year‐old man with severe demyelinating sensory‐motor neuropathy. He was wheelchair‐bound, with loss of sensation up to the knees. He had a CLL, immunoglobulin M (IgM) lambda monoclonal gammopathy, with anti‐MAG antibodies >70 000 Bühlmann titer units (BTU). Patient 2 was an 84‐year‐old woman with demyelinating neuropathy, paresthesias and gait instability. She had CLL and IgM kappa paraprotein with anti‐MAG antibodies >70 000 BTU. Both patients were treated with obinutuzumab intravenously at 100 mg on day +1, 900 mg +2, then at 1000 mg on days 8 and 15 of cycle 1 and day 1 of cycles 2–6; chlorambucil was given orally at 0.5 mg/kg on days 1 and 15 of cycles 1–6.

Results

Patient 1 at cycle 6 was able to stand, gait was possible with monolateral support, hypoesthesia and strength improved. M‐protein and IgM level decreased. In patient 2, already after three cycles, the monoclonal component disappeared and there was dramatic improvement of symptoms and gait normalization. At the end of therapy anti‐MAG antibody titer decreased to 5462 BTU. Neurophysiology also improved.

Conclusions

In our patients, obinutuzumab was effective as a first‐line treatment of anti‐MAG antibody polyneuropathy. CLL might have had a role in the response to therapy, but the associations might be considered in future trials.
Antitumor activity of sulforaphane in mice model of skin cancer via blocking sulfatase‐2
Authors: Alyoussef Abdullah , Taha Medhat
Published: October 2018

Although there are many treatment options for skin cancer, the chemotherapeutic agents for skin cancer are linked with many adverse effects as well as the development of multidrug resistance. Sulforaphane is an isothiocyanate, which is found in cruciferous vegetables. Consumption of sulforaphane‐rich diet has been linked to inhibition of UV‐exposed skin carcinogenesis. Therefore, the goal of this study was to determine the ability of sulforaphane to reduce skin cancer in mice through inhibition of sulfatase‐2 enzyme. Epicutaneous application of 7,12‐dimethylbenz (a) anthracene was performed on the shaved dorsal skin of mice followed by croton oil. Sulforaphane (9 μmol/mouse/day) was administered to mice orally. Skin was removed from the dorsal area for assessment of sulfatase‐2, glypican‐3, heparan sulphate proteoglycans (HSPGs), nuclear factor (NF)κB, nuclear factor E2‐related factor 2 (Nrf2), tumor necrosis factor (TNF)‐α, IL‐1β and caspase‐3. In addition, skin sections were stained with haematoxylin/eosin, Mallory and cytokeratin immunostaining. We found that, sulforaphane blocked sulfatase‐2 activity, leading to significant elevation in HSPGs as well as significant reduction in glypican‐3. In addition, sulforaphane significantly activated Nrf2 and reduced both the gene and protein expression of NFκB, TNF‐α, IL‐1β and caspase‐3. In parallel, stained sections obtained from skin cancer mice treated with sulforaphane showed significant reduction in hyperkeratosis, acanthosis and epithelial dysplasia. The collective results indicate that sulforaphane suppresses skin cancer via blocking sulfatase‐2 with subsequent elevation in HSPGs and reduction in glypican‐3. Moreover, sulforaphane attenuated skin cancer‐induced activation of inflammatory and apoptotic pathways.
The preparation and characterization of porous alumina ceramics using an eco‐friendly pore‐forming agent
Authors: Alzukaimi Julian , Jabrah Rafi
Published: October 2018

This work presents the preparation of porous alumina ceramics through the sacrificial phase method, using an eco‐friendly material, namely waste coffee grounds, as a pore‐forming agent. The effects of coffee grounds content in the green ceramic bodies on the linear and volumetric shrinkage, as well as the total and open porosity of the sintered product, were evaluated. The influence of the resulting porosity on mechanical properties of the prepared porous alumina was determined using Brazilian disk compression test for the determination of the indirect tensile strength of the prepared samples. Microstructure and pores morphology were characterized by scanning electron microscopy. Porosities in the range 35‐54 vol% were achieved, by varying the coffee grounds content from 0 to 50 wt% in the green bodies. The indirect tensile strength of the final obtained porous alumina ceramic decreased accordingly from 57.4 MPa to 17.7 MPa.