bluuebunny/crossref_metadata_2025 huggingface dataset:
The Role of Histopathology and Immunohistochemistry in the Diagnosis of Cutaneous Leishmaniasis Without “Discernible” Leishman–Donovan Bodies
Authors: Dias-Polak David , Geffen Yuval , Ben-Izhak Ofer , Bergman Reuven
Published: March 2017

Background:

Histopathology plays an important role in the diagnosis of cutaneous leishmaniasis (CL) but Leishman–Donovan (LD) bodies may not always be discernible. Recently, anti–CD1a antibody (Ab), clone MTB1, was found to decorate LD bodies immunohistochemically.

Objective:

Can histopathology without discernible LD bodies be used to diagnose CL, and can immunohistochemistry using anti–CD1a Ab, clone MTB1, detect LD bodies in these cases.

Methods:

Suspected CL lesions were studied histopathologically and immunohistochemically, and the patients' clinical files were reviewed.

Results:

Of the 196 patients with suspected CL, direct smear demonstrated LD bodies in 50 (25.5%). Of the remaining 146 patients, 118 underwent biopsy. In 56 (47.5%) patients, the hematoxylin-eosin–stained sections revealed LD bodies. In 47 (39.8%) patients, LD bodies were not discerned but the histopathology demonstrated histiocytic infiltrates with varying numbers of plasma cells along with other inflammatory cells, and negative Ziehl–Neelsen and periodic acid–Schiff stains. This pattern was termed “histopathology consistent with leishmaniasis.” The history, clinical findings, and response to anti–leishmania therapy supported the diagnosis of CL in all of them, and immunostains for CD1a, clone MTB1, detected LD bodies in 11 (23.4%) of these 47 patients.

Conclusions:

“Histopathology consistent with CL” along with appropriate clinical findings supports the diagnosis of CL in an endemic area, and immunostains with CD1a Ab, clone MTB1, may help in the minority of the cases.
LARGE SILICONE DROPLETS AFTER INTRAVITREAL BEVACIZUMAB (AVASTIN)
Authors: Avery Robert L. , Castellarin Alessandro A. , Dhoot Dilsher S. , Pieramici Dante J. , Nasir Ma'an A. , Steinle Nathan C. , Avery Logan P. , Gordon Gabriel M.
Published: March 2017

Purpose:

Despite its off-label status, intravitreal bevacizumab is the most commonly used intraocular anti–vascular endothelial growth factor agent. Regulation of compounding pharmacies has recently increased to make compounded pharmaceuticals safer. Despite these changes, a marked increase in symptomatic, large silicone oil droplets following intravitreal bevacizumab injections was noticed.

Methods:

Retrospective chart review was performed. Within a single private practice, patients who were noted to have large or symptomatic silicone oil bubbles after an intravitreal injection were reviewed.

Results:

A recent, dramatic increase in the incidence of large or symptomatic silicone oil droplets was noted, with 23 cases noted in the past 5 months, compared with 1 in the previous decade. Patients frequently noted a circular floater consisting of a dark ring surrounding a bright central area immediately following an injection of intravitreal bevacizumab. All bevacizumab injections were from single-piece insulin syringes. B-scan ultrasonography produced a very characteristic reverberation pattern. No inflammation or visual acuity loss was noted because of the droplets; however, some patients were annoyed enough to consider vitrectomy.

Conclusion:

Patients should be carefully evaluated for this possibility, and the characteristic symptom of a round floater consisting of a dark ring surrounding a bright center, and the prominent reverberation pattern on B-scan ultrasonography may help increase detection. Changes in consent forms and discussion of this possibility are indicated while investigation into the cause of this increased incidence continues, especially if one is administering bevacizumab via the one-piece insulin syringes commonly used by compound pharmacies.
Coronary Artery Disease Complexity on the Outcomes of a Staged Approach of Pci Followed by Minimally Invasive Valve Surgery
Authors: Pineda Andrés M. , Gowani Saqib A. , Mihos Christos G. , Chandra Ramesh , Santana Orlando , Lamelas Joseph , Beohar Nirat
Published: March 2017

Objective

A staged approach of percutaneous coronary intervention (PCI) followed by minimally invasive valve surgery (MIVS) is an alternative to the combined coronary artery bypass graft and valve surgery for patients with concomitant coronary artery (CAD) and valvular heart disease. We sought to evaluate the impact of the complexity of CAD, as assessed by the Syntax score, on the outcomes of the staged approach.

Methods

We retrospectively evaluated 138 patients who underwent PCI and MIVS at our institution between January 2009 and June 2013. The baseline Syntax score was calculated, and the patients were divided into two groups: low risk (Syntax scores, 0–22) or intermediate-high risk (>22).

Results

There were 125 patients with low (mean ± standard deviation, 8 ± 5) and 13 with intermediate-high (mean ± standard deviation, 26 ± 4) Syntax scores. Baseline, PCI, and operative characteristics were similar between the groups, except for an observed higher incidence of peripheral arterial disease, multivessel coronary disease, mitral valve replacement, and a higher predicted The Society of Thoracic Surgeons mortality risk score in the intermediate-high Syntax group. The short-term postoperative complications, 30-day mortality, and 3-year survival (84% vs 77%) were similar between the groups. Patients in the intermediate-high-risk group had a higher incidence of repeat target vessel revascularization during follow-up (0.8% vs 16.7%).

Conclusions

A staged approach of PCI followed by MIVS is a safe and feasible alternative for patients with valvular heart disease and concomitant CAD. However, it may confer an increased incidence of repeat target vessel revascularization in patients with intermediate- to high-complexity CAD.
Endoscopic Fundoplication
Authors: Ebright Michael I. , Sridhar Praveen , Litle Virginia R. , Narsule Chaitan K. , Daly Benedict D. , Fernando Hiran C.
Published: March 2017

Objective

Transoral incisionless fundoplication (TIF) is a completely endoscopic approach to treat gastroesophageal reflux disease (GERD). We previously reported our initial results demonstrating safety and early effectiveness. We now present an updated experience describing outcomes with longer follow-up.

Methods

For a three-year period, TIF procedures were performed on 80 patients. Preoperative workup routinely consisted of contrast esophagram and manometry. PH testing was reserved for patients with either atypical symptoms or typical symptoms unresponsive to protonpump inhibitors (PPIs). Heartburn severity was longitudinally assessed using the GERD health-related quality of life index. Safety analysis was performed on all 80 patients, and an effectiveness analysis was performed on patients with at least 6-month follow-up.

Results

Mean procedure time was 75 minutes. There were seven (8.75%) grade 2 complications and one (1.25%) grade 3 complication (aspiration pneumonia). The median length of stay was 1 day (mean, 1.4). Forty-one patients had a minimum of 6-month of follow-up (mean, 24 months; range, 6–68 months). The mean satisfaction scores at follow-up improved significantly from baseline ( P < 0.001). Sixty-three percent of patients had completely stopped or reduced their PPI dose. Results were not impacted by impaired motility; however, the presence of a small hiatal hernia or a Hill grade 2/4 valve was associated with reduced GERD health-related quality of life scores postoperatively.

Conclusions

At a mean follow-up of 24 months, TIF is effective. Although symptoms and satisfaction improved significantly, many patients continued to take PPIs. Future studies should focus on longer-term durability and comparisons with laparoscopic techniques.
Eosinophilic Esophagitis and Esophageal Granular Cell Tumor
Authors: Riffle Mary Ellen , Polydorides Alexandros D. , Niakan Jessica , Chehade Mirna
Published: March 2017

Esophageal granular cell tumors (GCTs) are rare. Eosinophilic esophagitis (EoE) is an immune-mediated disease characterized by esophageal eosinophilia despite proton pump inhibitor (PPI) therapy. Given that GCTs occur at sites of scarring and inflammation, we sought to determine the prevalence of EoE in patients with esophageal GCTs. Our center’s pathology database was searched for GCT specimens from 1995 to 2014. Slides were blindly rereviewed. GCTs were scored for atypical cytological features. Presence and number of eosinophils in the tumor and the surrounding esophageal epithelium and any EoE features were recorded. Medical records were reviewed. From >30,000 esophageal cases, 23 esophageal GCTs were identified, with 18 available for review (16 adult, 2 pediatric). Median patient age was 38.7 years. Four adults had esophageal intraepithelial eosinophilia (peak 38 to 68 eosinophils/high power field [HPF]); 2 confirmed to have EoE, 1 with PPI-responsive esophageal eosinophilia, and 1 had not received PPI therapy. Both pediatric cases had confirmed EoE (peak 24 and 34 eosinophils/HPF). In total, 12/18 GCTs had intratumoral eosinophilia (peak 1 to 16 eosinophils/HPF). All 6 cases with esophageal eosinophilia had intratumoral eosinophilia. Two GCTs displayed atypical cytologic features. Esophageal eosinophilia was present in 25% of adult and 100% of pediatric GCTs, the majority confirmed to have EoE. Overall, 67% of cases had intratumoral eosinophilia and 2 had atypical features. On the basis of these findings, we propose evaluating surrounding tissue for eosinophilia when esophageal GCT is diagnosed, and adding GCT as a potential complication of untreated EoE. Research for an immunologic link between EoE and esophageal GCTs is needed.
Use of Imaging in Children With Witnessed Physical Abuse
Authors: Melville John D. , Hertz Stephanie K. , Steiner R. Daryl , Lindberg Daniel M.
Published: March 2017

Objective

Physicians are occasionally asked to evaluate children who are reported to have been victims of witnessed abuse, but who have no injuries noted on examination. The rate of injury in these patients is presently unknown. This is important because abuse allegations are brought for both altruistic and other reasons. This study compares the use of skeletal survey and neuroimaging in well-appearing and clearly injured children reported to be victims of witnessed child abuse.

Methods

Retrospectively planned secondary analysis of the Examination of Siblings to Recognize Abuse cohort of children referred to a child abuse pediatrician with concerns for physical abuse. Children were selected who presented to a medical provider with a history of witnessed child abuse including shaking. Rates of radiographically evident injuries are noted among children with and without injuries noted on physical examination.

Results

Among 2890 children evaluated by a child abuse pediatrician, 90 children (3.1%) presented with a history of witnessed abuse. Among these, 51 children (57%) had injuries noted on physical examination; 9 (29%) of 31 skeletal surveys and 9 (35%) of 26 neuroimaging studies revealed injuries. Of 39 children (43%) with witnessed abuse and normal examination, 3 (10%) of 30 skeletal surveys and 2 (8%) of 25 neuroimaging studies revealed an injury.

Conclusions

A significant minority of children evaluated for allegations of witnessed abuse will have occult injuries identified radiographically. Absence of injury on examination should not deter physicians from obtaining otherwise indicated skeletal surveys and neuroimaging in children reported to have experienced witnessed abuse.
Psychotherapy Research and the NIMH: An Either/Or or Both/And Research Agenda?
Authors: PLAKUN ERIC M.
Published: March 2017

There is a need for psychotherapy research to determine the effective, nonspecific or shared elements of psychotherapy regardless of therapy school. In an apparent “either/or” rather than “both/and” choice, the National Institute of Mental Health (NIMH) has committed its research resources to study of neural mechanisms and biomarkers, while greatly reducing funding for research into clinical methods, including psychotherapy. This column explores the potential effect of this decision on patient care and reviews questions raised by some about whether the underlying “big idea” behind the NIMH research approach is supported by the results of several decades of brain and genomics research. Patients are left to hope for clinically meaningful research findings concerning brain or gene mechanisms of mental disorders, as if they are just around the corner, when the actual benefit of such research likely remains decades away.
Potential Mechanisms of Hematological Adverse Drug Reactions in Patients Receiving Clozapine in Combination With Proton Pump Inhibitors
Authors: WICIŃSKI MICHAŁ , WĘCLEWICZ MATEUSZ M. , MIĘTKIEWICZ MATEUSZ , MALINOWSKI BARTOSZ , GRZEŚK ELŻBIETA , KLONOWSKA JOANNA
Published: March 2017

Clozapine is a second-generation antipsychotic which has proven efficacy in treating the symptoms of schizophrenia. Although clozapine therapy is associated with a number of adverse drug reactions, it is frequently used. One of the most common adverse drug reactions is gastroesophageal reflux disease which is an indication for treatment with proton pump inhibitors (PPIs). Coadministration of clozapine and PPIs increases the risk of hematological adverse drug reactions, including neutropenia and agranulocytosis. The mechanism in idiosyncratic agranulocytosis is not dose related and involves either a direct toxic or an immune-allergic effect. It is suspected that the clozapine metabolites nitrenium ion and N-desmethylclozapine may cause apoptosis or impair growth of granulocytes. Formation of N-desmethylclozapine is correlated with activity of the cytochrome P450 enzymes 1A2 and 3A4 (CYP1A2 and CYP3A4). Nitrenium ion is produced by the flavin-containing monooxygenase system of leukocytes. A drug interaction between clozapine and a PPI is a consequence of the induction of common metabolic pathways either by the PPI or clozapine. Findings to date suggest that indirect induction of flavin-containing monooxygenase by omeprazole through the aryl hydrocarbon receptor increases the expression of the enzyme mRNA and in the long term may cause the increase in activity. Moreover, induction of CYP1A2, especially by omeprazole and lansoprazole, may increase the serum concentration of N-desmethylclozapine, which can accumulate in lymphocytes and may achieve toxic levels. Another hypothesis that may explain hematological adverse drug reactions is competitive inhibition of CYP2C19, which may contribute to increased serum concentrations of toxic metabolites.
Social Disequilibrium and the Risk of HIV Acquisition: A Multilevel Study in Rural KwaZulu-Natal Province, South Africa
Authors: Tomita Andrew , Vandormael Alain M. , Bärnighausen Till , de Oliveira Tulio , Tanser Frank
Published: March 2017

Background:

Few population-based multilevel studies have quantified the risks that social context poses in rural communities with high HIV incidence across South Africa. We investigated the individual, social, and community challenges to HIV acquisition risk in areas with high and low incidence of HIV infection (hotspots/coldspots).

Methods:

The cohort (N = 17,376) included all HIV-negative adults enrolled in a population-based HIV surveillance study from 2004 to 2015 in a rural South African community with large labor migrancy. Multilevel survival models were fitted to examine the social determinants (ie, neighborhood migration intensity), community traits (ie, HIV prevalence), and individual determinants of HIV acquisition risk in identified hotspots/coldspots.

Results:

The HIV acquisition risk (adjusted hazard ratio [aHR] = 1.05, 95% confidence interval [CI]: 1.01 to 1.09) was greater in hotspots with higher neighborhood migration intensity among men. In women, higher neighborhood migration intensity (aHR = 1.02, 95% CI: 1.01 to 1.02) was associated with a greater HIV acquisition risk, irrespective of whether they lived in hotspot/coldspot communities. HIV acquisition risk was greater in communities with a higher prevalence of HIV in both men (aHR = 1.07, 95% CI: 1.03 to 1.12) and women (aHR = 1.03, 95% CI: 1.01 to 1.05), irrespective of hotspot/coldspot locations.

Conclusion:

HIV acquisition risk was strongly influenced by gender (ie, young women), behavior (ie, sexual debut, contraception, circumcision), and social determinants. Certain challenges (ie, community disease prevalence) for HIV acquisition risk impacted both sexes, regardless of residence in hotspot/coldspot communities, whereas social determinants (ie, neighborhood migration intensity) were pronounced in hotspots among men. Future intervention scale-up requires addressing the social context that contributes to HIV acquisition risk in rural areas with high migration.
Evaluation of Reproducibility of Diffusion Tensor Imaging in the Brachial Plexus at 3.0 T
Authors: Ho Michael J. , Manoliu Andrei , Kuhn Felix Pierre , Stieltjes Bram , Klarhöfer Markus , Feiweier Thorsten , Marcon Magda , Andreisek Gustav
Published: March 2017

Objective

The aim of this study was to evaluate the reproducibility of 3 T magnetic resonance imaging diffusion tensor imaging (DTI) of the brachial plexus in healthy subjects.

Methods

Ten healthy volunteers were included, and morphological and DTI sequences of the nerve roots of the brachial plexus from C5 to T1 of both sides were repeatedly acquired on a 3 T magnetic resonance system (MAGNETOM Skyra; Siemens Healthcare, Erlangen, Germany). A prototype diffusion-weighted single-shot echo-planar imaging sequence-enabling slice-specific shim adjustments was performed with b-values of 0 and 800 s/mm2 in 30 gradient directions, resulting in an acquisition time of about 6 minutes each in axial orientation. Between scans, subjects were moved and repositioned in the scanner, coils were reinserted, and new localizers were acquired. Image analysis was performed using MITK Diffusion software toolkit. Two independent readers performed diffusion data postprocessing, and regions of interest (ROIs) were set on the proximal postganglionic trunk at each spinal level, bilaterally to obtain values for fractional anisotropy (FA) and mean diffusivity (MD). Interreader and intrareader agreement as well as test-retest reproducibility of DTI metrics were assessed.

Results

Intraclass correlation coefficients (ICCs) for interreader and intrareader agreement did not differ significantly between measurements for FA and MD. In particular, ICCs for interreader agreement of FA ranged from 0.741 to 0.961 and that of MD ranged from 0.802 to 0.998, and ICCs for intrareader agreement of FA ranged from 0.759 to 0.949 and that of MD ranged from 0.796 to 0.998. The test-retest reproducibility of DTI metrics showed an overall moderate to strong correlation (r > 0.707), with few minor exceptions, for both FA and MD values.

Conclusions

Diffusion tensor imaging metrics in the brachial plexus are reproducible. Future applications of DTI for a possible clinical use should be further investigated.
Carpal Tunnel Syndrome Grading Using High-Resolution Ultrasonography
Authors: El Habashy Hala R. , El Hadidy Reem A. , Ahmed Sandra M. , El Sayed Basma B. , Ahmed Aya S.
Published: March 2017

Purpose:

Carpal tunnel syndrome (CTS) is a common entrapment neuropathy of the wrist. The diagnosis of CTS has been a concern for physicians for a long time. The aim of this study is to evaluate the use of the median nerve (MN) cross-sectional area (CSA) in the wrist compared with the CSA in the forearm to grade the severity of CTS in Egyptian patients.

Methods:

The CSAs of the MN in the wrist and forearm were measured in 72 wrists that were diagnosed with CTS via nerve conduction studies and 80 healthy wrists. The CTS group was subdivided into three subgroups (mild, moderate, and severe CTS). The ratio of the CSA of the MN in the wrist to that in the forearm was used to calculate cutoff values for CTS grading.

Results:

There were positive correlations between the CSAs of the MN in the wrist and MN conduction latency. At a wrist–forearm ratio of 1.7, the high-resolution ultrasonography showed 96.1% accuracy in the detection of CTS.

Conclusions:

High-resolution ultrasonography can be used in CTS grading.
Mechanistic movement models to understand epidemic spread
Authors: Fofana Abdou Moutalab , Hurford Amy
Published: March 2017

An overlooked aspect of disease ecology is considering how and why animals come into contact with one and other resulting in disease transmission. Mathematical models of disease spread frequently assume mass-action transmission, justified by stating that susceptible and infectious hosts mix readily, and foregoing any detailed description of host movement. Numerous recent studies have recorded, analysed and modelled animal movement. These movement models describe how animals move with respect to resources, conspecifics and previous movement directions and have been used to understand the conditions for the occurrence and the spread of infectious diseases when hosts perform a type of movement. Here, we summarize the effect of the different types of movement on the threshold conditions for disease spread. We identify gaps in the literature and suggest several promising directions for future research. The mechanistic inclusion of movement in epidemic models may be beneficial for the following two reasons. Firstly, the estimation of the transmission coefficient in an epidemic model is possible because animal movement data can be used to estimate the rate of contacts between conspecifics. Secondly, unsuccessful transmission events, where a susceptible host contacts an infectious host but does not become infected can be quantified. Following an outbreak, this enables disease ecologists to identify ‘near misses’ and to explore possible alternative epidemic outcomes given shifts in ecological or immunological parameters.

This article is part of the themed issue ‘Opening the black box: re-examining the ecology and evolution of parasite transmission’.
Global change, parasite transmission and disease control: lessons from ecology
Authors: Cable Joanne , Barber Iain , Boag Brian , Ellison Amy R. , Morgan Eric R. , Murray Kris , Pascoe Emily L. , Sait Steven M. , Wilson Anthony J. , Booth Mark
Published: March 2017

Parasitic infections are ubiquitous in wildlife, livestock and human populations, and healthy ecosystems are often parasite rich. Yet, their negative impacts can be extreme. Understanding how both anticipated and cryptic changes in a system might affect parasite transmission at an individual, local and global level is critical for sustainable control in humans and livestock. Here we highlight and synthesize evidence regarding potential effects of ‘system changes’ (both climatic and anthropogenic) on parasite transmission from wild host–parasite systems. Such information could inform more efficient and sustainable parasite control programmes in domestic animals or humans. Many examples from diverse terrestrial and aquatic natural systems show how abiotic and biotic factors affected by system changes can interact additively, multiplicatively or antagonistically to influence parasite transmission, including through altered habitat structure, biodiversity, host demographics and evolution. Despite this, few studies of managed systems explicitly consider these higher-order interactions, or the subsequent effects of parasite evolution, which can conceal or exaggerate measured impacts of control actions. We call for a more integrated approach to investigating transmission dynamics, which recognizes these complexities and makes use of new technologies for data capture and monitoring, and to support robust predictions of altered parasite dynamics in a rapidly changing world.

This article is part of the themed issue ‘Opening the black box: re-examining the ecology and evolution of parasite transmission’.
Who acquires infection from whom and how? Disentangling multi-host and multi-mode transmission dynamics in the ‘elimination’ era
Authors: Webster Joanne P. , Borlase Anna , Rudge James W.
Published: March 2017

Multi-host infectious agents challenge our abilities to understand, predict and manage disease dynamics. Within this, many infectious agents are also able to use, simultaneously or sequentially, multiple modes of transmission. Furthermore, the relative importance of different host species and modes can itself be dynamic, with potential for switches and shifts in host range and/or transmission mode in response to changing selective pressures, such as those imposed by disease control interventions. The epidemiology of such multi-host, multi-mode infectious agents thereby can involve a multi-faceted community of definitive and intermediate/secondary hosts or vectors, often together with infectious stages in the environment, all of which may represent potential targets, as well as specific challenges, particularly where disease elimination is proposed. Here, we explore, focusing on examples from both human and animal pathogen systems, why and how we should aim to disentangle and quantify the relative importance of multi-host multi-mode infectious agent transmission dynamics under contrasting conditions, and ultimately, how this can be used to help achieve efficient and effective disease control.

This article is part of the themed issue ‘Opening the black box: re-examining the ecology and evolution of parasite transmission’.
Distinct blood DNA methylation profiles in subtypes of orofacial cleft
Authors: Sharp Gemma C , Ho Karen , Davies Amy , Stergiakouli Evie , Humphries Kerry , McArdie Wendy , Sandy Jonathan , Davey Smith George , Lewis Sarah , Relton Caroline L
Published: March 2017

Background

There is evidence that different subtypes of orofacial cleft have distinct aetiologies, although the precise molecular mechanisms underlying these are unknown. Given the key role of epigenetic processes such as DNA methylation in embryonic development, it is likely that aberrant DNA methylation may also play a part in the development of orofacial clefts.

Methods

In this study, we explored whether blood samples from children with different cleft subtypes showed distinct DNA methylation profiles.

In whole blood samples from 150 children from the Cleft Collective cohort study, we measured DNA methylation at over 450,000 sites on the genome. We then carried out epigenome-wide association studies (EWAS) to test the association between methylation at each site and cleft subtype (cleft lip only CLO n=50; cleft palate only CPO n=50; cleft lip and palate CLP n=50).

Results

We found four genomic regions differentially methylated in CLO compared to CLP, 17 in CPO compared to CLP and 294 in CPO compared to CLO. These regions included several mapping to genes that have previously been implicated in the development of orofacial clefts (for example,TBX1, COL11A2, HOXA2, PDGFRA) and over 250 novel associations.

Conclusion

Our finding of distinct methylation profiles in different cleft subtypes might reflect differences in their aetiologies, with DNA methylation either playing a causal role in development of OFC subtypes or reflecting causal genetic or environmental factors.
3D Mapping Reveals Network-specific Amyloid Progression and Subcortical Susceptibility
Authors: Canter RG , Choi H , Wang J , Watson LA , Yao CG , Abdurrob F , Bousleiman SM , Delalle I , Chung K , Tsai L-H
Published: March 2017

Alzheimer’s disease is a progressive, neurodegenerative condition for which there is no cure. Prominent hypotheses posit that accumulation of beta-amyloid (Aβ) peptides drives the neurodegeneration that underlies memory loss, however the spatial origins of the lesions remain elusive. Using SWITCH, we created a spatiotemporal map of Aβ deposition in a mouse model of amyloidosis. We report that structures connected by the fornix show primary susceptibility to Aβ accumulation and demonstrate that aggregates develop in increasingly complex networks with age. Notably, the densest early Aβ aggregates occur in the mammillary body coincident with electrophysiological alterations. In later stages, the fornix itself also develops overt Aβ burden. Finally, we confirm Aβ in the mammillary body of postmortem patient specimens. Together, our data suggest that subcortical memory structures are particularly vulnerable to Aβ deposition and that functional alterations within and physical propagation from these regions may underlie the affliction of increasingly complex networks.

Author Contributions

RGC, KC, L-HT, ID conceived of the work and planned the experiments.

RGC, HC, JW, LAW, CGY, FA, SMB performed experiments and analyzed data.

HC built the custom microscope.

RGC, L-HT, KC, ID wrote the manuscript.
Compositionally distinct nuclear pore complexes of functionally distinct dimorphic nuclei in ciliateTetrahymena
Authors: Iwamoto Masaaki , Osakada Hiroko , Mori Chie , Fukuda Yasuhiro , Nagao Koji , Obuse Chikashi , Hiraoka Yasushi , Haraguchi Tokuko
Published: March 2017

SUMMARY STATEMENT

Our study demonstrates compositional and structural differences of the nuclear pore complex between the functionally differentiated macronucleus and micronucleus within a single cytoplasm of ciliated protozoa.

The nuclear pore complex (NPC), a gateway for nucleocytoplasmic trafficking, is composed of about 30 different proteins called nucleoporins. It remains unknown whether the NPCs within a species are homogeneous or vary depending on the cell type, or physiological condition. Here, we present evidence for compositionally distinct NPCs that form within a single cell in a binucleated ciliate. InTetrahymena thermophila,each cell contains both a transcriptionally-active macronucleus (MAC) and a germline micronucleus (MIC). By combiningin silicoanalysis, mass spectrometry analysis for immuno-isolated proteins, and subcellular localization analysis of GFP fused proteins, we identified numerous novel components of MAC and MIC NPCs. Core members of the Nup107-160 scaffold complex were enriched in MIC NPCs. Strikingly, two paralogs of Nup214 and of Nup153 localized exclusively to either MAC or MIC NPCs. Furthermore, the transmembrane components Pom121 and Pom82 localize exclusively to MAC and MIC NPCs, respectively. Our results argue that functional nuclear dimorphism in ciliates is likely to depend on compositional and structural specificity of NPCs.
Genetic regulatory effects modified by immune activation contribute to autoimmune disease associations
Authors: Kim-Hellmuth Sarah , Bechheim Matthias , Pütz Benno , Mohammadi Pejman , Nédélec Yohann , Giangreco Nicholas , Becker Jessica , Kaiser Vera , Fricker Nadine , Beier Esther , Boor Peter , Castel Stephane , Nöthen Markus M. , Barreiro Luis B. , Pickrell Joseph K. , Müller-Myhsok Bertram , Lappalainen Tuuli , Schumacher Johannes , Hornung Veit
Published: March 2017

The immune system plays a major role in human health and disease, and understanding genetic causes of interindividual variability of immune responses is vital. We isolated monocytes from 134 genotyped individuals, stimulated the cells with three defined microbe-associated molecular patterns (LPS, MDP, and ppp-dsRNA), and profiled the transcriptome at three time points. After mapping expression quantitative trait loci (eQTL), we identified 417 response eQTLs (reQTLs) with differing effect between the conditions. We characterized the dynamics of genetic regulation on early and late immune response, and observed an enrichment of reQTLs in distalcis-regulatory elements. Response eQTLs are also enriched for recent positive selection with an evolutionary trend towards enhanced immune response. Finally, we uncover novel reQTL effects in multiple GWAS loci, and show a stronger enrichment of response than constant eQTLs in GWAS signals of several autoimmune diseases. This demonstrates the importance of infectious stimuli modifying genetic predisposition to disease.
Calcium oscillations in wounded fibroblast monolayers are spatially regulated through substrate mechanics
Authors: Lembong Josephine , Sabass Benedikt , Stone Howard A.
Published: March 2017

The maintenance of tissue integrity is essential for the life of multicellular organisms. Healing of a skin wound is a paradigm for how various cell types localize and repair tissue perturbations in an orchestrated fashion. To investigate biophysical mechanisms associated with wound localization, we focus on a model system consisting of a fibroblast monolayer on an elastic substrate. We find that the creation of an edge in the monolayer causes cytosolic calcium oscillations throughout the monolayer. The oscillation frequency increases with cell density, which shows that wound-induced calcium oscillations occur collectively. Inhibition of myosin II reduces the number of oscillating cells, demonstrating a coupling between actomyosin activity and calcium response. The spatial distribution of oscillating cells depends on the stiffness of the substrate. For soft substrates with a Young’s modulusE~ 360 Pa, oscillations occur on average within 0.2 mm distance from the wound edge. Increasing substrate stiffness leads to an average localization of oscillations away from the edge (up to ~0.6 mm). In addition, we use traction force microscopy to determine stresses between cells and substrate. We find that an increase of substrate rigidity leads to a higher traction magnitude. ForE< ~2 kPa, the traction magnitude is strongly concentrated at the monolayer edge, while forE> ~8 kPa, traction magnitude is on average almost uniform beneath the monolayer. Thus, the spatial occurrence of calcium oscillations correlates with the cell-substrate traction. Overall, the experiments with fibroblasts demonstrate a collective, chemomechanical localization mechanism at the edge of a wound with a potential physiological role.
Scalable Multi-Sample Single-Cell Data Analysis by Partition-Assisted Clustering and Multiple Alignments of Networks
Authors: Li Ye Henry , Li Dangna , Samusik Nikolay , Wang Xiaowei , Guan Leying , Nolan Garry P. , Wong Wing Hung
Published: March 2017

Mass cytometry (CyTOF) has greatly expanded the capability of cytometry. It is now easy to generate multiple CyTOF samples in a single study, with each sample containing single-cell measurement on 50 markers for more than hundreds of thousands of cells. Current methods do not adequately address the issues concerning combining multiple samples for subpopulation discovery, and these issues can be quickly and dramatically amplified with increasing number of samples. To overcome this limitation, we developed Partition-Assisted Clustering and Multiple Alignments of Networks (PAC-MAN) for the fast automatic identification of cell populations in CyTOF data closely matching that of expert manual-discovery, and for alignments between subpopulations across samples to define dataset-level cellular states. PAC-MAN is computationally efficient, allowing the management of very large CyTOF datasets, which are increasingly common in clinical studies and cancer studies that monitor various tissue samples for each subject.

Author Summary

Recently, the cytometry field has experienced rapid advancement in the development of mass cytometry (CyTOF). CyTOF enables a significant increase in the ability to monitor 50 or more cellular markers for millions of cells at the single-cell level. Initial studies with CyTOF focused on few samples, in which expert manual discovery of cell types were acceptable. As the technology matures, it is now feasible to collect more samples, which enables systematic studies of cell types across multiple samples. However, the statistical and computational issues surrounding multi-sample analysis have not been previously examined in detail. Furthermore, it was not clear how the data analysis could be scaled for hundreds of samples, such as those in clinical studies. In this work, we present a scalable analysis pipeline that is grounded in strong statistical foundation. Partition-Assisted Clustering (PAC) offers fast and accurate clustering and Multiple Alignments of Networks (MAN) utilizes network structures learned from each homogeneous cluster to organize the data into data-set level clusters. PAC-MAN thus enables the analysis of a large CyTOF dataset that was previously too large to be analyzed systematically; this pipeline can be extended to the analysis of similarly large or larger datasets.
Comparative transcriptome profiling conferring of resistance toFusarium oxysporuminfection between resistant and susceptible tomato
Authors: Zhao Min , Ji Hui-Min , Gao Yin , Cao Xin-Xin , Mao Hui-Yin , Liu Peng , Ouyang Shou-Qiang
Published: March 2017

ABASTRCAT

Tomato Fusarium wilt caused byFusarium oxysporumf. sp.lycopersici(FOL) is a destructive disease of tomato worldwide which causes severe yield loss of the crops. As exploring gene expression and function approaches constitute an initial point for investigating pathogen-host interaction, we performed a transcriptional analysis to unravel regulated genes in tomato infected by FOL. Differentially expressed genes (DEG) upon inoculation with FOL were presented at twenty-four hours post-inoculation including four treatments: Moneymaker_H2O, Moneymaker_FOL, Motelle_H2O and Motelle_FOL. A total of more than 182.6 million high quality clean reads from the four libraries were obtained. A large overlap was found in DEGs between susceptible tomato cultivar Moneymaker and resistant tomato cultivar Motelle. All Gene Ontology terms were mainly classified into catalytic activity, metabolic process and binding. However, Gene Ontology enrichment analysis evidenced specific categories in infected Motelle. Statistics of pathway enrichment of DEGs resulted that the taurine and hypotaurine metabolism, the stibenoid, diarylheptanoid and gingerol biosynthesis, the starch and sucrose metabolism were the top three pathway affected in both groups. Interestingly, plant-pathogen pathway was greatly regulated in Motelle treated with FOL. Combining with qRT-PCR facilitated the identification of regulated pathogenicity associated genes upon infected resistant or susceptible tomato. Our data showed that a coordinated machinery played a critical role in prompting the response, which could help in generating models of mediated resistance responses with assessment of genomic gene expression patterns.
Neuron density fundamentally relates to architecture and connectivity of the primate cerebral cortex
Authors: Beul Sarah F. , Hilgetag Claus C.
Published: March 2017

Studies of structural brain connectivity have revealed many intriguing features of complex cortical networks. To advance integrative theories of cortical organization, an understanding is required of how connectivity interrelates with other aspects of brain structure. Recent studies have suggested that interareal connectivity may be related to a variety of macroscopic as well as microscopic architectonic features of cortical areas. However, it is unclear how these features are inter-dependent and which of them most strongly and fundamentally relate to structural corticocortical connectivity. Here, we systematically investigated the relation of a range of microscopic and macroscopic architectonic features of cortical organization, namely layer III pyramidal cell soma size, dendritic synapse count, dendritic synapse density and dendritic tree size as well as area neuron density, to multiple properties of cortical connectivity, using a comprehensive, up-to-date structural connectome of the primate brain. Importantly, relationships were investigated by multi-variate analyses to account for the interrelations of features. Of all considered factors, the classical architectonic parameter of neuron density most strongly and consistently related to essential features of cortical connectivity (existence and laminar patterns of projections, area degree), and in conjoint analyses largely abolished effects of cellular morphological features. These results reveal neuron density as a central architectonic indicator of the primate cerebral cortex that is closely related to essential aspects of brain connectivity and is also highly indicative of further features of the architectonic organization of cortical areas such as the considered cellular morphological measures. Our findings integrate several aspects of cortical micro-and macroscopic organization, with implications for cortical development and function.
Transcriptional interference by RNA polymerase III affects expression of the Polr3e gene
Authors: Yeganeh Meghdad , Praz Viviane , Cousin Pascal , Hernandez Nouria
Published: March 2017

Overlapping gene arrangements can potentially contribute to gene expression regulation. A mammalian interspersed repeat (MIR) nested in antisense orientation within the first intron of the Polr3e gene, encoding an RNA polymerase III (Pol III) subunit, is conserved in mammals and highly occupied by Pol III. Using a fluorescence assay, CRISPR/Cas9-mediated deletion of the MIR in mouse embryonic stem cells, and chromatin immunoprecipitation assays, we show that the MIR affects Polr3e expression through transcriptional interference. Our study reveals a mechanism by which a Pol II gene can be regulated at the transcription elongation level by transcription of an embedded antisense Pol III gene.
The evaluation of QM/MM-driven molecular docking combined with MM/GBSA calculations as a halogen-bond scoring strategy
Authors: Kurczab Rafał
Published: March 2017

The combination of quantum mechanics/molecular mechanics-driven (QM/MM) molecular docking with binding free-energy calculations was successfully used to reproduce the X-ray geometries of protein–ligand complexes with halogen bonding. The procedure involves quantum-polarized ligand docking (QPLD) to obtain the QM-derived ligand atomic charges in the protein environment at the B3PW91/cc-pVTZ level and the MM/GBSA (generalized-Born/surface area) algorithm to calculate the binding free energies of resultant complexes. The performance was validated using a set of 106 X-ray complexes and compared with the Glide and AutoDock VinaXB scoring functions in terms of RMSD and the reconstruction of halogen-bond geometry (distance and σ-hole angle). The results revealed that docking and scoring using the QPLD–GBSA procedure outperformed the remaining scoring functions in the majority of instances. Additionally, a comparison of the orientation of the top ranked binding poses calculated using the fixed atomic charges of ligands obtained from force-field parameterization and by QM calculations in the protein environment provides strong evidence that the use of QM-derived charges is significant.
3-(4-Chlorobutyl)-3H-indole-5-carbonitrile
Authors: Manikandan Devakumar , Gomathi Sundaramoorthy , Nirmalram Jeyaraman Selvaraj , Tagore Sadasivam Sharmila , Sethuraman Velusamy , Agim Joseph , Butcher Ray
Published: March 2017

In the title compound, C13H12ClN2, the indole moiety and the chloroalkyl substituent are nearly coplanar, making a dihedral angle of 1.27 (10)°. In the crystal, a supramolecular sheet parallel to the ab plane is generated via weak C—H...Cl hydrogen bonds, aromatic π–π stacking [centroid–centroid distances of 3.5563 (13) and 3.6792 (13) Å] and C—H...π interactions.
Self-adaptive NGSA algorithm and optimal design of inductors for magneto-fluid hyperthermia
Authors: Di Barba Paolo , Dughiero Fabrizio , Forzan Michele , Sieni Elisabetta
Published: March 2017

Purpose

This paper aims to present the optimal design of an inductor used to heat a magnetic nanoparticle fluid injected in a cell culture inside a Petri dish.

Design/methodology/approach

The inductor design is driven by means of a multi-objective optimization algorithm that generalizes the migration-non-dominated sorting genetic algorithm (NSGA); it is called self-adapting migration-NSGA.

Findings

The optimized device is able to synthesize a uniform magnetic field in a nanoparticle fluid, substantially helping its heating capability. The ultimate scope is to assist the cancer therapy based on magnetic fluid hyperthermia (MFH).

Originality/value

The optimal design of an inductor for MFH applications has been carried out by applying an improved version of migration-based NSGA-II algorithm including automatic stop and a self-adapting concept. The modified optimization algorithm is suitable to find better optimal solutions with respect to a standard version of NSGA-II.
Numerical modeling of hybrid laser welding taking into account phase change of material
Authors: Doležel Ivo , Kotlan Václav , Hamar Roman , Pánek David
Published: March 2017

Purpose

This paper aims to present a three-dimensional (3D) model of hybrid laser welding of a steel plate. Before welding, the plate is pre- and/or post-heated by induction to avoid mechanical stresses in material due to high gradients of temperature. Welding itself is realized by laser beam without welding rod. The model takes into account existence of both solid and liquid phases in the weld.

Design/methodology/approach

Presented is the complete mathematical model of the above heat treatment process, taking into account all relevant nonlinearities (saturation curve of the processed steel material and temperature dependences of its physical parameters). Its numerical solution is realized by the finite element method. Some important results are compared with experimental data.

Findings

In comparison with the former model developed by the authors that did not take into account the phase change, the results are more realistic and exhibit a better accordance with measurements. On the other hand, they strongly depend on sufficiently accurate knowledge of material parameters in both solid and liquid levels (that represent the input data).

Research limitations/implications

The quality of calculated results strongly depends on the material properties and their temperature dependencies. In case of alloys (whose chemical composition may vary in some range), such data are often unavailable and must be estimated on the basis of experiments. Another quantity that has to be calibrated is the time dependence of power delivered by the laser beam, which is due to the production of a plasma cloud above the exposed spot.

Practical implications

The presented model and methodology of its solution may represent a basis for design of the complete technology of laser welding with induction pre-heating and/or post-heating.

Originality/value

Fully 3D model of hybrid laser welding (supplemented with pre- and/or post-heating by magnetic induction) taking into account both solid and liquid phases of welded metal and influence of the plasma cloud is presented.
Influence of the magnetic permeability on modeling of induction surface hardening
Authors: Barglik Jerzy , Smalcerz Albert
Published: March 2017

Purpose

Modeling of induction surface hardening strongly depends on accuracy of material properties data and their temperature characteristics. However, it is especially complicated in case of the magnetic permeability dependent not only on temperature but also on the magnetic strength. This paper aims to estimate the influence of the magnetic permeability on modeling of coupled physical fields describing the process. Investigations are provided for the gear wheels made of the steel C45E.

Design/methodology/approach

Computation of coupled electromagnetic temperature and hardness fields is based on FEM methods. The Flux 3D software is applied for the numerical simulation of coupled electromagnetic and temperature fields. The QT Steel software is applied for a determination of the hardness and microstructure distributions.

Findings

Obtained results may be used as a kind of background for the design of induction surface hardening systems.

Research limitations/implications

The presented calculation model provided quite a good accuracy of hardness distribution validated by the experiments. Next work in the field should be aimed at taking into account a dependence of the magnetic permeability on the field current frequency.

Originality/value

Mathematical model of induction surface hardening with taking into account time dependence on the magnetic permeability on temperature and magnetic strength is elaborated. Experimental validation of hardness distribution is provided. A quite reasonable convergence between simulations and measurements was achieved.