bluuebunny/crossref_metadata_2025 huggingface dataset:
Nebulette is a powerful cytolinker organizing desmin and actin in mouse hearts
Authors: Hernandez Daniel A. , Bennett Christina M. , Dunina-Barkovskaya Lyubov , Wedig Tatjana , Capetanaki Yassemi , Herrmann Harald , Conover Gloria M.
Published: October 2016

In the hearts of patients bearing nebulette mutations, a severe general disorganization in cardiomyocytes of the extrasarcomeric desmin intermediate filament system is frequently observed. However, the molecular and functional relationship between the desmin cytoskeleton and nebulette-containing sarcomeres is still unclear. Here we report a high-affinity in vitro interaction between nebulette and desmin filaments. A major interaction site has been mapped to the desmin α-helical rod domain, indicating that the filament core is directly involved in the binding of nebulette. The disease-mutant desmin variants E245D and T453I exhibited increased binding affinity for nebulette, delayed filament assembly kinetics, and caused significant weakening of networks. In isolated chick cardiomyocytes and sections from canine heart, we revealed by ground-state depletion and confocal microscopies that module 5 of nebulette extends outward from Z-disk–associated desmin filaments toward the center of the sarcomere. Accordingly, in the myocardium of Des−/−mice, elevated levels of cardiac actin correlated with alterations in the distribution of nebulette. Our data suggest that a well-organized desmin network is required to accommodate an optimal conformation of nebulette on sarcomeres to bind and recruit cardiac α-actin. Hence we propose that nebulette acts in synergy with nebulin to reinforce and temporally fine-tune striated muscle relaxation–contraction cycles.
Identification of novel nesprin-1 binding partners and cytoplasmic matrin-3 in processing bodies
Authors: Rajgor Dipen , Hanley Jonathan G. , Shanahan Catherine M.
Published: October 2016

Nesprins are highly conserved spectrin repeat–containing scaffold proteins predominantly known to function at the nuclear envelope (NE). However, nesprin isoforms are emerging with localizations and scaffolding functions at sites away from the NE, suggesting their functions are more diverse than originally thought. In this study, we combined nesprin-1 coimmunoprecipitations with mass spectrometry to identify novel nesprin-1 binding partners for isoforms that localize to subcellular compartments beyond the NE. We show that one of these interactors, matrin-3 (matr3), localizes to mRNA processing bodies (PBs), where we have previously shown a nesprin-1 isoform to localize. Furthermore, we show that Matr3 is part of PB mRNP complexes, is a regulator of miRNA-mediated gene silencing, and possibly shuttles to stress granules in stressed cells. More importantly, we identify a new C-terminally truncated Matr3 isoform that is likely to be involved in these functions and PB localization. This study highlights several novel nesprin-1 binding partners and a new function and localization for Matr3 in cytoplasmic RNA granules.
Stronger net posterior cortical forces and asymmetric microtubule arrays produce simultaneous centration and rotation of the pronuclear complex in the earlyCaenorhabditis elegansembryo
Authors: Coffman Valerie C. , McDermott Matthew B. A. , Shtylla Blerta , Dawes Adriana T.
Published: October 2016

Positioning of microtubule-organizing centers (MTOCs) incorporates biochemical and mechanical cues for proper alignment of the mitotic spindle and cell division site. Current experimental and theoretical studies in the early Caenorhabditis elegans embryo assume remarkable changes in the origin and polarity of forces acting on the MTOCs. These changes must occur over a few minutes, between initial centration and rotation of the pronuclear complex and entry into mitosis, and the models do not replicate in vivo timing of centration and rotation. Here we propose a model that incorporates asymmetry in the microtubule arrays generated by each MTOC, which we demonstrate with in vivo measurements, and a similar asymmetric force profile to that required for posterior-directed spindle displacement during mitosis. We find that these asymmetries are capable of and important for recapitulating the simultaneous centration and rotation of the pronuclear complex observed in vivo. The combination of theoretical and experimental evidence provided here offers a unified framework for the spatial organization and forces needed for pronuclear centration, rotation, and spindle displacement in the early C. elegans embryo.
MIToS.jl: mutual information tools for protein sequence analysis in the Julia language
Authors: Zea Diego J , Anfossi Diego , Nielsen Morten , Marino-Buslje Cristina
Published: October 2016

Motivation

MIToS is an environment for mutual information analysis and a framework for protein multiple sequence alignments (MSAs) and protein structures (PDB) management in Julia language. It integrates sequence and structural information through SIFTS, making Pfam MSAs analysis straightforward. MIToS streamlines the implementation of any measure calculated from residue contingency tables and its optimization and testing in terms of protein contact prediction. As an example, we implemented and tested a BLOSUM62-based pseudo-count strategy in mutual information analysis.

Availability and Implementation

The software is totally implemented in Julia and supported for Linux, OS X and Windows. It’s freely available on GitHub under MIT license: http://mitos.leloir.org.ar.

Supplementary information

Supplementary data are available at Bioinformatics online.
Aseptically Processed Placental Membrane Improves Healing of Diabetic Foot Ulcerations: Prospective, Randomized Clinical Trial
Authors: DiDomenico Lawrence A. , Orgill Dennis P. , Galiano Robert D. , Serena Thomas E. , Carter Marissa J. , Kaufman Jarrod P. , Young Nathan J. , Zelen Charles M.
Published: October 2016

Background:

Allogeneic grafts derived from amnion/chorion are known to be efficacious in healing chronic diabetic foot ulcerations (DFUs). The goal of this study was to compare aseptically processed dehydrated human amnion and chorion allograft (dHACA) versus standard of care (SOC) in facilitating wound closure in nonhealing DFUs.

Methods:

Patients with DFUs treated with SOC (off-loading, appropriate debridement, and moist wound care) after a 2-week screening period were randomized to either SOC or wound-size-specific dHACA (AmnioBand, Musculoskeletal Transplant Foundation, Edison, N.J.) applied weekly for up to 12 weeks plus SOC. Primary endpoint was the percentage of wounds healed at 6 weeks between groups.

Results:

At 6 weeks, 70% (14/20) of the dHACA-treated DFUs healed compared with 15% (3/20) treated with SOC alone. Furthermore, at 12 weeks, 85% (17/20) of the DFUs in the dHACA group healed compared with 25% (5/20) in the SOC group, with a corresponding mean time to heal of 36 and 70 days, respectively. At 12 weeks, the mean number of grafts used per healed wound for the dHACA group was 3.8 (median 3.0), and mean cost of the tissue to heal a DFU was $1400. The mean wastage at 12 weeks was 40%. One adverse event and 1 serious adverse event occurred in the dHACA group; neither was graft related. Three adverse events and 1 serious adverse event occurred in the SOC group.

Conclusion:

Aseptically processed dHACA heals diabetic foot wounds significantly faster than SOC at 6 and 12 weeks with minimal graft wastage.
Cochleariform Process Abutment on TBCT in Early Congenital Cholesteatoma
Authors: Lee Chang Ho , Kim So Young , Kim Hyoung-Mi , Kim Young Ju , Kim Ji Yoon , Kim Mi Kyung
Published: October 2016

Objectives:

To study the influence of the cochleariform process abutment (CPA) of early congenital cholesteatomas (CC) (ECCs) on surgical outcomes.

Study Design:

Retrospective case review.

Setting:

University hospital otology referral clinic.

Patients:

Two hundred consecutive pediatric ECC patients.

Interventions:

The patients were classified into three groups based on the temporal bone computed tomography (TBCT) findings of ECC: A) the absence of CPA, B) the presence of CPA, and C) the presence of CPA and extension posterior to the malleus handle.

Main Outcome Measures:

Residual CC according to each of the TBCT and surgical stages during 34.9 ± 20.1 months of follow-up.

Results:

Group A was significantly associated with effortless delivery without matrix tearing (77%) even with simple myringotomy. Only 17% of group B experienced this outcome, and troublesome matrix tearing occurred in significantly more patients (p < 0.0001). Residual CCs were present in 17.5% of group B if matrix tears occurred, which was comparable to group C (22.0%) and significantly greater than group A (4.4%, p = 0.03). Normal hearing was preserved in 97.5% of the ECC patients both when the ECCs did not recur and when they recurred without CPA. However, residual ECCs with positive CPAs in five children (2.5%) required ossicle removal, and subsequent hearing loss.

Conclusions:

CPA is directly related to intraoperative matrix tear or increased recidivism, that CPA should be the landmark to distinguish stage II ECC from stage I. Surgeons should evaluate CPA on preoperative TBCTs of ECC patients, and restrict myringotomy approach to CPA negative ECC.
Usefulness of the Saccharin Test for Assessment of Eustachian Tube Function in Patients With Chronic Otitis Media With Perforation
Authors: Ikehata Miki , Ohta Shigeto , Mishiro Yasuo , Katsura Hirokazu , Miuchi Shinya , Tsuzuki Kenzo , Sakagami Masafumi
Published: October 2016

Objective:

The eustachian tube (ET) has two important functions, ventilation and clearance of the middle ear. We evaluated the ET ventilator function by the sonotubometry and the inflation-deflation test that are widely used today, and the ET clearance function by the saccharin test. Results of both tests were compared with surgical outcomes, and assessed which test was more closely related to the surgical outcomes.

Study Design:

Prospective case series.

Setting:

A single university hospital.

Patients and Intervention:

One hundred four ears of 95 patients with chronic otitis media with perforation underwent type I tympanoplasty.

Main Outcomes and Measures:

Based on sonotubometry and the inflation–deflation test, the patients were divided into normal, stenosis, and patulous types. Based on the saccharin test, they were divided into a normal function group and a partial/gross dysfunction group. Surgical outcomes about the hearing results and the condition of the eardrum were assessed 1 year postoperatively. Preoperative evaluation of ET function was compared with the surgical outcome.

Results:

Sonotubometry and inflation-deflation tests showed there was no significant difference among the groups about the hearing improvement and the surgical success rate. The saccharin test showed that the rate of the hearing improvement was significantly lower in the gross dysfunction group and that the success rate of Type I tympanoplasty was significantly higher in the normal group than in the dysfunction group.

Conclusion:

There is a relationship between the saccharin test results and surgical outcomes.
Can Probiotics Reduce Diarrhea and Infant Mortality in Africa?
Authors: Del Piano Mario , Coggiola Francesco , Pane Marco , Amoruso Angela , Nicola Stefania , Mogna Luca
Published: October 2016

Background:

Diarrhea accounts for 9% of the mortality among children under 5 years of age worldwide, and it is significantly associated with malnutrition. Each year, diarrhea kills around 760,000 children under 5 years of age and most of these are in sub-Saharan Africa.

In Uganda, the infant mortality rate of 58 per 1000 is unacceptably high, and the major contributors include malnutrition, diarrhea, pneumonia, malaria, prematurity, sepsis, and newborn illnesses.

There is an urgent need for intervention to prevent and control diarrheal diseases.

Study Design:

Our open-label, randomized controlled study has the primary endpoint of reducing diarrhea and infectious diseases (number of episodes/severity) and the secondary endpoint of decreasing infant mortality. The trial is currently conducted in Luzira, a suburb of Kampala, the capital of Uganda, and in Gulu and Lira, in the north of Uganda.

The study is projected to enroll 4000 babies (control=2000 and treatment=2000) who will be followed till 1 year of life. As controls, 2000 babies of the same community are planned to be considered.

The probiotic product selected for the trial is composed of 3 designated microorganisms, namely Bifidobacterium breve BR03 (DSM 16604), B. breve B632 (DSM 24706), and Lactobacillus delbrueckii subsp. delbrueckii LDD01 (DSM 22106). The concentration of the 3 bacteria is 108 viable cells/strain/daily dose (5 drops).

Perspectives:

For a total sample of 4000 babies, the study has an 80% power at a 5% significance level.
The Possible Innovative Use of Bifidobacterium longum W11 in Association With Rifaximin
Authors: Graziano Teresa , Amoruso Angela , Nicola Stefania , Deidda Francesca , Allesina Serena , Pane Marco , Piffanelli Pietro , Strozzi Francesco , Mogna Luca , Del Piano Mario
Published: October 2016

Goals:

The aim of the study was to unequivocally demonstrate the nontransmissibility of the genes mediating the resistance of the strain Bifidobacterium longum W11 (LMG P-21586) to rifaximin.

Background:

Most antibiotic treatments can induce unfavorable side effects such as antibiotic-associated diarrhea, which is largely attributable to the disruption of the intestinal microbiota. The parallel intake of probiotic bacteria might reduce these events, even if with generally very poor results. In this regard, the use of antibiotic-resistant beneficial bacteria could represent a worthy strategy.

Study:

Rifaximin was tested in parallel with rifampicin, rifapentine, and rifabutin, all rifamycin derivates, using 5 different concentrations. Susceptibility tests were performed by the disc diffusion method of Kirby-Bauer, and inhibition zones were measured after incubation at 37°C. B. longum BL03 was used as comparison. The B. longum W11 genome was sequenced on Illumina MiSeq with a 250 PE reads module. After mapping the reads with the reference bacterial genome, the alignment data were processed using FreeBayes software.

Results:

B. longum BL03 was inhibited by all antibiotics even at the lowest concentration. In contrast, the W11 strain was inhibited by rifampicin, rifabutin, and rifaximin only at the highest concentration (512 μg/mL). The genomic analysis showed a mutation into the chromosomal DNA. No transposable elements were found, and the genetic locus was not flanked by close mobile genetic elements.

Conclusions:

B. longum W11 could be used in combined therapy with rifaximin, thus opening new focused frontiers in the probiotic era while preserving the necessary safety of use for consumers.
Probiotics and Diverticular Disease
Authors: Lahner Edith , Annibale Bruno
Published: October 2016

Diverticular disease (DD) is a common gastrointestinal condition. Clinical spectrum ranges from asymptomatic diverticulosis to symptomatic uncomplicated or complicated DD. Symptoms related to uncomplicated DD are not specific and may be indistinguishable from those of irritable bowel syndrome. Low-grade inflammation, altered intestinal microbiota, visceral hypersensitivity, and abnormal colonic motility have been identified as factors potentially contributing to symptoms. Probiotics may modify the gut microbial balance leading to health benefits. Probiotics, due to their anti-inflammatory effects and ability to maintain an adequate bacterial colonization in the colon, are promising treatment options for DD. This review focuses on the available evidence on the efficacy of prebiotics in uncomplicated DD.
Gut Microbiota and Risk of Developing Celiac Disease
Authors: Cenit Maria C. , Codoñer-Franch Pilar , Sanz Yolanda
Published: October 2016

Gut microbiota shapes the development of the mucosal immune system and may provide protection against immune-mediated diseases. Celiac disease (CD) is a chronic inflammatory condition triggered by dietary gluten proteins, recently associated with gut microbiota alterations in cross-sectional studies comparing patients and controls. Whether or not these differences are causally related to the disease has yet to be elucidated, but evaluation of specific bacteria isolated from CD patients in experimental models suggests that they can promote an adverse response to dietary gluten, whereas other commensal bacteria can be protective. Genetic and environmental factors associated with increased CD risk have also been linked to shifts in the gut microbiota composition in infants early in life. Epigenetic mechanisms also seem to play an important role in modulating gut microbiota composition and function and, theoretically, could also influence CD risk. Here, we review the current knowledge on how host genetics, environmental factors, and epigenetic modifications could modulate gut microbiota functionality and how this may influence CD risk. Greater understanding of the role of this triad in CD onset and pathogenesis will be valuable in designing proof-of concept interventions in the gut ecosystem, with a view to improving CD management.
In Vitro Activity of Lactobacillus fermentum LF5 Against Different Candida Species and Gardnerella vaginalis
Authors: Deidda Francesca , Amoruso Angela , Allesina Serena , Pane Marco , Graziano Teresa , Del Piano Mario , Mogna Luca
Published: October 2016

Goals:

This study was undertaken to demonstrate the ability of Lactobacillus fermentum LF5 (DSM 32277) to inhibit in vitro different Candida species and Gardnerella vaginalis to weigh its potential effectiveness even in mixed vaginal infections.

Background:

A wide female population is suffering from various vulvovaginal infections. These diseases are often associated with a decrease in the concentration of Lactobacilli in the vagina. Mixed vaginal infections represent >20% of women with vulvovaginal infection.

Study:

LF5 strain was cocultured in De Man, Rogosa and Sharpe with Candida according to a 1:100 ratio in favor of the yeast. Each culture was sampled after 24 hours of incubation for the selective enumeration of the yeasts performed on yeast extract glucose chloramphenicol agar medium.

The growth of Gardnerella alone (positive control) and in the presence of different concentrations of neutralized supernatants of L. fermentum LF5 ranging from 5% to 20% was quantified by means of optical density at 600 nm (OD600).

Results:

L. fermentum LF5 demonstrated the ability to inhibit significantly the growth of the 5 species of Candida by at least 4 logarithms.

Furthermore, L. fermentum LF5 showed a significant activity after both 24 and 48 hours (46% and 82% with 20% of neutralized supernatant, respectively). A significant dose-dependent growth inhibition was recorded in particular after 48 hours of incubation, even achieving a 80% inhibition of G. vaginalis growth.

Conclusions:

The biotherapeutic LF5 could be the only documented strain effective in mixed forms. For this purpose, a human clinical trial is in progress.
The Role of Oligosaccharides in Host-Microbial Interactions for Human Health
Authors: Ross Sarah A. , Lane Jonathan A. , Marotta Mariarosaria , Kavanaugh Devon , Ryan Joseph Thomas , Joshi Lokesh , Hickey Rita M.
Published: October 2016

Milk oligosaccharides have many associated bioactivities which can contribute to human health and offer protective properties to the host. Such bioactivities include anti-infective properties whereby oligosaccharides interact with bacterial cells and prevent adhesion to the host and subsequent colonization. Milk oligosaccharides have also been shown to alter the glycosylation of intestinal cells, leading to a reduction in pathogenic colonization. In addition, these sugars promote adhesion of commensal bacterial strains to host cells as well as possessing the ability to alter mucin expression in intestinal cells and improve barrier function. The ability of milk oligosaccharides to alter the transcriptome of both commensal bacterial strains and intestinal epithelial cells has also been revealed, indicating the potential of many cell types to detect the presence of milk oligosaccharides and respond accordingly at the genetic level. Interestingly, domestic animal milk may provide a bioactive source of oligosaccharides for formula supplementation with the aim of emulating the gold standard that is human milk. Overall, this review highlights the ability of milk oligosaccharides to promote health in a variety of ways, for example, through direct bacterial interactions, immunomodulatory activities, promotion of gut barrier function, and induction of protective transcriptional responses.
Could the 3D Printing Technology be a Useful Strategy to Obtain Customized Nutrition?
Authors: Severini Carla , Derossi Antonio
Published: October 2016

Within the concept of personalized nutrition we want to introduce the terms of “customized food formula” which refers to the preparation (at home) or the production (at industrial level) of new food formulations having nutrients and functional compounds necessary to prevent diseases or to reduce the risk for each subject (or subjects category) who exhibit a susceptibility to diseases. Three-dimensional (3D) printing is a group of technologies of growing interest able to produce, slice by slice, materials with any desired shape, dimension, and structure properties. The application of 3D printing in food science, as called “3D food printing,” is a pioneering technology that could allow to build personalized foods by depositing nutrients and functional compounds or soft-materials obtained by their mixture. Also by 3D food printing it is expected to obtain personalized food formula having desired shape, dimension, and microstructure. This would be useful for people having swallowing problems. In this paper we analyzed the first examples of 3D food printing available in literature as well as we reported our results focused on the production of 3D printed wheat-based snacks enriched with insect powder (Tenebrio molitor) with the aim to improve the quality and the content of proteins.
Gut Microbiota and Obesity
Authors: Valsecchi Chiara , Carlotta Tagliacarne Sara , Castellazzi Annamaria
Published: October 2016

Intestinal microbiota is composed by symbiotic innocuous bacteria and potential pathogens also called pathobionts. The human gut normally hosts roughly 1014 bacterial organisms of up to 1000 different species. The genome size of this microbial organ, collectively named microbiome, exceeds the size of the human nuclear genome by 2 orders of magnitude.
Bipolar Disorder With Psychotic Features and Ocular Toxoplasmosis
Authors: Del Grande Claudia , Contini Carlo , Schiavi Elisa , Rutigliano Grazia , Maritati Martina , Seraceni Silva , Pinto Barbara , Dell’Osso Liliana , Bruschi Fabrizio
Published: October 2016

Recent evidence suggests the involvement of Toxoplasma gondii infection in the emergence of psychotic and affective disorders. In this report, we describe the case of a young Brazilian woman affected by recurrent ocular toxoplasmosis and presenting with a manic episode with psychotic features in the context of a diagnosis of Bipolar Disorder (BD), type I. We observed a relationship between ocular manifestations and the clinical course of bipolar illness, confirmed by molecular analyses (nested-PCR), as well as by the high level of T. gondii specific IgG. This case report is the first showing the presence of circulating parasite DNA at the time of occurrence of psychiatric symptoms, thus providing further support for a possible role of the parasite in the pathogenesis of some cases of BD.
Assessing Binary Diagnoses of Bio-behavioral Disorders
Authors: Cicchetti Domenic V. , Klin Ami , Volkmar Fred R.
Published: October 2016

Cohen's (Educ Psychol Meth. 1960;23:37–40) kappa statistic has been criticized recently for providing low chance-corrected coefficients (<0.40) despite high levels of examiner agreement (e.g., ≥85%). The AC1 statistic (Series. 2002;2:1–9; BMC Med Res Methodol. 2013;13:61), the alpha statistic (J Clin Epidemiol. 1996;49:775–782), the B statistic (BMC Med Res Methodol. 2013;13:97), and the delta statistic (Commun Statist Theory Meth. 2008;37:760–772) were developed to “correct” this “problem.” Each of these statistics produces inaccurate results because they either derive from levels of chance agreement that are incorrect (Gwet's AC1 statistic) or fail to correct for chance levels of agreement (the alpha, B, and delta approaches). Implications for diagnoses of psychiatric disorders are critically discussed. The importance of kappa is demonstrated in a number of clinical scenarios.
Simulated Keratometry Repeatability in Subjects with and without Down Syndrome
Authors: Ravikumar Ayeswarya , Marsack Jason D. , Benoit Julia S. , Anderson Heather A.
Published: October 2016

Purpose

To assess the repeatability of simulated keratometry measures obtained with Zeiss Atlas topography for subjects with and without Down syndrome (DS).

Methods

Corneal topography was attempted on 140 subjects with DS and 138 controls (aged 7–59 years). Subjects who had at least three measures in each eye were included in analysis (DS: n = 140 eyes (70 subjects) and controls: n = 264 eyes (132 subjects)). For each measurement, the steep corneal power (K), corneal astigmatism, flat K orientation, power vector representation of astigmatism (J0, J45), and astigmatic dioptric difference were determined for each measurement (collectively termed keratometry values here).For flat K orientation comparisons, only eyes with >0.50 DC of astigmatism were included (DS: n = 131 eyes (68 subjects) and control: n = 217 eyes (119 subjects)). Repeatability was assessed using (1) group mean variability (average standard deviation (SD) across subjects), (2) coefficient of repeatability (COR), (3) coefficient of variation (COV), and (4) intraclass correlation coefficient (ICC).

Results

The keratometry values showed good repeatability as evidenced by low group mean variability for DS versus control eyes (≤0.26D vs. ≤0.09D for all dioptric values; 4.51° vs. 3.16° for flat K orientation); however, the group mean variability was significantly higher in DS eyes than control eyes for all parameters (p ≤ 0.03). On average, group mean variability was 2.5 times greater in the DS eyes compared to control eyes across the keratometry values. Other metrics of repeatability also indicated good repeatability for both populations for each keratometry value, although repeatability was always better in the control eyes.

Conclusions

DS eyes showed more variability (on average: 2.5×) compared to controls for all keratometry values. Although differences were statistically significant, on average 91% of DS eyes had variability ≤0.50D for steep K and astigmatism, and 75% of DS eyes had variability ≤5 degrees for flat K orientation.
Modeling Corneal Oxygen with Scleral Gas Permeable Lens Wear
Authors: Compañ Vicente , Aguilella-Arzo Marcel , Edrington Timothy B. , Weissman Barry A.
Published: October 2016

Purpose

The main goal of this current work is to use an updated calculation paradigm, and updated boundary conditions, to provide theoretical guidelines to assist the clinician whose goal is to improve his or her scleral gas permeable (GP) contact lens wearing patients’ anterior corneal oxygen supply.

Methods

Our model uses a variable value of corneal oxygen consumption developed through Monod equations that disallows negative oxygen tensions within the stroma to predict oxygen tension at the anterior corneal surface of scleral GP contact lens wearing eyes, and to describe oxygen tension and flux profiles, for various boundary conditions, through the lens, tears, and cornea. We use several updated tissue and boundary parameters in our model. Tear exchange with GP scleral lenses is considered nonexistent in this model.

Results

The majority of current scleral GP contact lenses should produce some levels of corneal hypoxia under open eye conditions. Only lenses producing the thinnest of tear vaults should result in anterior corneal surface oxygen tensions greater than a presumed critical oxygen tension of 100 mmHg. We also find that corneal oxygen tension and flux are each more sensitive to modification in tear vault than to changes in lens oxygen permeability, within the ranges of current clinical manipulation.

Conclusions

Our study suggests that clinicians would be prudent to prescribe scleral GP lenses manufactured from higher oxygen permeability materials and especially to fit without excessive corneal clearance.
“Simple Mucinous Cyst” of the Pancreas
Authors: Krasinskas Alyssa M. , Oakley Gerard J. , Bagci Pelin , Jang Kee-Taek , Kuan Shih-Fan , Reid Michelle D. , Erbarut Ipek , Adsay Volkan
Published: October 2016

Pancreatic cysts >1 cm lined by nonpapillary mucinous epithelium without ovarian-type stroma pose diagnostic challenges. The term “simple mucinous cyst” was recently proposed for this entity. Our goal was to determine the clinicopathologic characteristics of these cysts, as they have not been previously described. Of the 39 patients with pancreatic resections included in this study, the mean age was 65 years and the female-to-male ratio was 4:1. The characteristics of the cysts are as follows: 82% had elevated cyst fluid carcinoembryonic antigen levels, 67% were unilocular, 69% occurred in the body/tail, 92% did not communicate with pancreatic ducts, the mean size was 2.4 cm (range, 1.0 to 5.5 cm), the cyst contents tended to be serous (48%) or viscous (28%), all had a smooth lining (only 1 had focal excrescences) composed of bland columnar mucinous epithelium (low-grade dysplasia) in 92% with focal high-grade dysplasia in 8%, and 65% had degenerative changes (granulation-like tissue, hemorrhage, and myxoid stroma). The cyst lining was CK7+ and 97% had a MUC5AC+ and/or MUC6+ gastric phenotype; overt intestinal features were absent. In total, 55% of cysts tested (fluid and/or resections) harbored KRAS mutations. The term “simple mucinous cyst” is useful to apply to >1 cm mucinous cysts that do not have characteristic features of intraductal papillary mucinous neoplasms or mucinous cystic neoplasms. KRAS mutations can be detected in these typically bland cysts, and in rare instances, focal high-grade dysplasia may be present. Hence, these cysts should be viewed as neoplastic and treated similarly to other mucinous pancreatic cysts.
Plasma microRNAs Are Potential Biomarkers of Acute Rejection After Hindlimb Transplantation in Rats
Authors: Oda Hiroki , Ikeguchi Ryosuke , Yurie Hirofumi , Kaizawa Yukitoshi , Ohta Souichi , Yamamoto Koji , Aoyama Tomoki , Matsuda Shuichi
Published: October 2016

Background

The development of effective immunosuppressive regimens has resulted in many cases of successful hand transplantation. Visual skin inspection and histological evaluation are used to assess the rejection of hand transplants, but these methods are largely subjective. In this study, we aimed to determine the potential of microRNAs (miRNAs) as biomarkers for acute rejection in vascularized composite allotransplants.

Methods

In allograft group, 7 male Brown-Norway rats (RT1n) were used as donors and 13 male Lewis rats (RT1l) were used as recipients. In control group, 8 Lewis rats were used as donors and recipients. The hindlimbs of donor rats were transplanted orthotopically to recipient rats. Skin changes were noted daily. Skin biopsies were obtained from 5 recipients and evaluated histologically. Plasma samples were obtained from the other 8 recipients before transplant and 7, 10, and 14 days posttransplant and used to measure miRNA expression.

Results

Skin changes occurred at a mean of 11.0 days posttransplant. Rejection in most skin biopsies taken 7 and 10 days posttransplant was histologically classified as grade 0, whereas that in most biopsies taken 14 days posttransplant was classified as grade 3. We found that expression of miRNA-146a and miRNA-155 was significantly upregulated at 10 and 14 days posttransplant compared with that at 7 days posttransplant. In control group, there were no significant changes in plasma miRNAs expressions.

Conclusions

The upregulation of plasma miRNA-146a and miRNA-155 was detected before the histological evaluation methods could diagnose complete rejection in the rat hindlimb transplantation model. Plasma miRNA-146a and miRNA-155 may be potential biomarkers of acute rejection after vascularized composite allotransplantation.
Liberation From Renal Replacement Therapy After Cadaveric Liver Transplantation
Authors: Hilmi Ibtesam A. , Al-Khafaji Ali , Damian Daniela , Rosario-Rivera Bedda L. , Abdullah Ali , Kellum John A.
Published: October 2016

Background

Renal failure requiring renal replacement therapy (RRT) is common in patients with end-stage liver disease (ESLD) and is associated with worse outcomes following liver transplantation (LT). We investigated the factors associated with liberation from posttransplant RRT and studied the impact of RRT on patient and graft outcomes.

Methods

A 5-year retrospective study of ESLD patients who received pretransplant RRT was conducted. Variables associated with liberation from RRT at 30 days and at 1-year posttransplant were analyzed. We used propensity matching to compare patient and graft outcomes in the study cohort to those of a control group who underwent LT but not pretransplant RRT.

Results

Sixty-four patients were included in the study. Twenty-four (38%) were liberated from RRT at 30 days posttransplant. Duration of pretransplant RRT (odds ratio [OR], 0.94; 95% confidence interval [CI], 0.89-0.98) and severe postreperfusion syndrome (OR, 0.26; 95% CI, 0.08-0.87) were significantly associated with continued RRT at 1-month posttransplant. At one year, 34 (53%) patients were liberated from RRT. Age was significantly associated with lack of liberation from RRT (OR, 0.933; 95% CI, 0.875-0.995). Compared with propensity matched controls, patients who received RRT pretransplant had worse graft and patient survival at 1 year (52% vs 82%; P = 0.01, and 53% vs 83%; P = 0.003, respectively).

Conclusions

In ESLD patients who received pretransplant RRT, one third were liberated from RRT at 1 month, and half at 1 year. Longer duration of pretransplant RRT, postreperfusion syndrome, and older age were associated with lower likelihood of liberation from RRT. Patients who required pretransplant RRT had worse graft and patient survivals compared to matched patients who did not require RRT. Patients who were liberated from RRT post-LT had similar outcomes to patients who never required pre-LT RRT.
iCARE: R package to build, validate and apply absolute risk models
Authors: Choudhury Parichoy Pal , Maas Paige , Wilcox Amber , Wheeler William , Brook Mark , Check David , Garcia-Closas Montserrat , Chatterjee Nilanjan
Published: October 2016

This report describes a R package, called the Individualized Coherent Absolute Risk Estimation (iCARE) tool, that allows researchers to build and evaluate models for absolute risk and apply them to estimate an individual’s risk of developing disease during a specified time interval based on a set of user defined input parameters. An attractive feature of the software is that it gives users flexibility to update models rapidly based on new knowledge on risk factors and tailor models to different populations by specifying three input arguments: (1) a model for relative risk, (2) an age-specific disease incidence rate, (3) the distribution of risk factors for the population of interest. The tool can handle missing information on risk factors for individuals for whom risks are to be predicted using a coherent approach where all estimates are derived from a single model after appropriate model averaging. The software allows single nucleotide polymorphisms (SNPs) to be incorporated into the model using published odds ratios and allele frequencies. The validation component of the software implements the methods for evaluation of model calibration, discrimination and risk-stratification based on independent validation datasets. We provide an illustration of the utility ofiCAREfor building, validating and applying absolute risk models using breast cancer as an example.
Giardia colonizes and encysts in high density foci in the murine small intestine
Authors: Barash NR , Nosala C , Pham JK , Mclnally SG , Gourguechon S , McCarthy-Sinclair B , Dawson SC
Published: October 2016

Giardiais a highly prevalent, yet understudied protistan parasite causing diarrheal disease worldwide. Hosts ingestGiardiacysts from contaminated sources. In the gastrointestinal tract, cysts excyst to become motile trophozoites, colonizing and attaching to the gut epithelium. Trophozoites later differentiate into infectious cysts that are excreted and contaminate the environment. Due to the limited accessibility of the gut, the temporospatial dynamics of giardiasis in the host is largely inferred from laboratory culture and thus may not mirrorGiardiaphysiology in the host. Here we have developed bioluminescent imaging (BLI) to directly interrogate and quantify thein vivotemporospatial dynamics of giardiasis, thereby providing an improved murine model to evaluate anti-Giardiadrugs. Using BLI, we determined that parasites primarily colonize the proximal small intestine non-uniformly in high-density foci. By imaging encystation-specific bioreporters, we show that encystation initiates shortly after inoculation and continues throughout the entire duration of infection. Encystation also initiates in high-density foci in the proximal small intestine, and high-density laboratory cultures of parasites are also stimulated to encyst. This work overturns the assumption that parasites encyst later during infection as they are dislodged and travel through the colon. We suggest that these high-density regions of parasite colonization likely result in localized pathology to the epithelium, and encystation occurs when trophozoites reach a threshold density due to local nutrient depletion. This more accurate visualization of giardiasis redefines the dynamics ofin vivo Giardialife cycle, paving the way for future mechanistic studies of density-dependent parasitic processes in the host.

Significance

Giardiais a single-celled parasite causing both acute and chronic diarrheal disease in over one billion people worldwide. Due to limited access to the site of infection in the gastrointestinal tract, our understanding of the dynamics ofGiardiainfections in the host has remained limited, and largely inferred from laboratory culture. To better understand giardiasis in the host, we developed imaging methods to quantifyGiardiaexpressing bioluminescent physiological reporters in live mice. We discovered that parasites primarily colonize and encyst in the proximal small intestine in discrete, high-density foci. Furthermore, this work provides evidence of a parasite density-based threshold for the differentiation ofGiardiainto cysts in the host. These findings overturn existing paradigms of giardiasis infection dynamics in the host.
An Oscillatory Network Model of Head Direction, Spatially Periodic Cells and Place Cells Using Locomotor Inputs
Authors: Soman Karthik , Muralidharan Vignesh , Chakravarthy V. Srinivasa
Published: October 2016

We propose a computational modeling approach that explains the formation of a range of spatial cells like head direction cells, grid cells, border cells and place cells which are believed to play a pivotal role in the spatial navigation of an animal. Most existing models insert special symmetry conditions in the models in order to obtain such symmetries in the outcome; our models do not require such symmetry assumptions. Our modeling approach is embodied in two models: a simple one (Model #1) and a more detailed version (Model #2). In Model #1, velocity input is presented to a layer of Head Direction cells, with no special topology requirements, the outputs of which are presented to a layer of Path Integration neurons. A variety of spatially periodic responses resembling grid cells, are obtained using the Principal Components of Path Integration layer. In Model #2, the input consists of the locomotor rhythms from the four legs of a virtual animal. These rhythms are integrated into the phases of a layer of oscillatory neurons, whose outputs drive a layer of Head Direction cells. The Head Direction cells in turn drive a layer of Path Integration neurons, which in turn project to two successive layers of Lateral Anti Hebbian Networks (LAHN). Cells in the first LAHN resemble grid cells (with both hexagonal and square gridness), and border cells. Cells in the second LAHN exhibit place cell behaviour and a new cell type known as corner cell. Both grid cells and place cells exhibit phase precession in 1D and 2D spaces. The models outline the neural hierarchy necessary to obtain the complete range of spatial cell responses found in the hippocampal system.
Association of polygenic risk for major psychiatric illness with subcortical volumes and white matter integrity in UK Biobank
Authors: Reus LM , Shen X , Gibson J , Wigmore E , Ligthart L , Adams MJ , Davies G , Cox SR , Hagenaars SP , Bastin ME , Deary IJ , Whalley HC , McIntosh AM
Published: October 2016

Major depressive disorder (MDD), schizophrenia (SCZ) and bipolar disorder (BP) are common, disabling and heritable psychiatric diseases with a complex overlapping polygenic architecture. Individuals with these disorders, as well as their unaffected relatives, show widespread structural differences in corticostriatal and limbic networks. Structural variation in many of these brain regions is also heritable and polygenic but whether their genetic architecture overlaps with major psychiatric disorders is unknown. We sought to address this issue by examining the impact of polygenic risk of MDD, SCZ, and BP on subcortical brain volumes and white matter (WM) microstructure in a large single sample of neuroimaging data; the UK Biobank Imaging study. The first release of UK Biobank imaging data compromised participants with overlapping genetic data and subcortical volumes (N = 978) and WM measures (N = 816). Our, findings however, indicated no statistically significant associations between either subcortical volumes or WM microstructure, and polygenic risk for MDD, SCZ or BP. In the current study, we found little or no evidence for genetic overlap between major psychiatric disorders and structural brain measures. These findings suggest that subcortical brain volumes and WM microstructure may not be closely linked to the genetic mechanisms of major psychiatric disorders.
A shared representation of order between encoding and recognition in visual short-term memory
Authors: Kalm Kristjan , Norris Dennis
Published: October 2016

Most complex tasks require people to bind individual stimuli into a sequence in short term memory (STM). For this purpose information about the order of the individual stimuli in the sequence needs to be in active and accessible form in STM over a period of few seconds. Here we investigated how the temporal order information is shared between the presentation and response phases of an STM task. We trained a classification algorithm on the fMRI activity patterns from the presentation phase of the STM task to predict the order of the items during the subsequent recognition phase. While voxels in a number of brain regions represented positional information during either presentation and recognition phases, only voxels in the lateral prefrontal cortex (PFC) and the anterior temporal lobe (ATL) represented position consistently across task phases. A shared positional code in the ATL might reflect verbal recoding of visual sequences to facilitate the maintenance of order information over several seconds.
Genetic, transcriptome, proteomic and epidemiological evidence for blood brain barrier disruption and polymicrobial brain invasion as determinant factors in Alzheimer’s disease
Authors: Carter C.J.
Published: October 2016

Multiple pathogens have been detected in Alzheimer’s disease (AD) brains. A bioinformatics approach was used to assess relationships between pathogens and AD genes (GWAS), the AD hippocampal transcriptome and plaque or tangle proteins. Host/pathogen interactomes (C.albicans,C.Neoformans, Bornavirus,B.Burgdorferri, cytomegalovirus, Ebola virus, HSV-1, HERV-W, HIV-1, Epstein-Barr, hepatitis C, influenza,C.Pneumoniae,P.Gingivalis,H.Pylori,T.Gondii,T.Cruzi) significantly overlap with misregulated AD hippocampal genes, with plaque and tangle proteins and, except Bornavirus, Ebola and HERV-W, with AD genes. Upregulated AD hippocampal genes match those upregulated by multiple bacteria, viruses, fungi or protozoa in immunocompetent blood cells. AD genes are enriched in bone marrow and immune locations and in GWAS datasets reflecting pathogen diversity, suggesting selection for pathogen resistance. The age of AD patients implies resistance to infections afflicting the younger. APOE4 protects against malaria and hepatitis C, and immune/inflammatory gain of function applies to APOE4, CR1, TREM2 and presenilin variants. 30/78 AD genes are expressed in the blood brain barrier (BBB), which is disrupted by AD risk factors (ageing, alcohol, aluminium, concussion, cerebral hypoperfusion, diabetes, homocysteine, hypercholesterolaemia, hypertension, obesity, pesticides, pollution, physical inactivity, sleep disruption and smoking). The BBB and AD benefit from statins, NSAIDs, oestrogen, melatonin and the Mediterranean diet. Polymicrobial involvement is supported by the upregulation of pathogen sensors/defenders (bacterial, fungal, viral) in the AD brain, blood or CSF. Cerebral pathogen invasion permitted by BBB inadequacy, activating a hyper-efficient immune/inflammatory system, betaamyloid and other antimicrobial defence may be responsible for AD which may respond to antibiotic, antifungal or antiviral therapy.
A risk stratification approach for improved interpretation of diagnostic accuracy statistics
Authors: Katki Hormuzd A. , Schiffman Mark
Published: October 2016

Diagnostic accuracy statistics, including predictive values, risk-differences, Youden’s index and Area Under the Curve (AUC), assess the promise of novel biomarkers proposed as diagnostic tests. We reinterpret these statistics in light of risk-stratification (how well a biomarker separates those at higher risk from those at lower risk) to better understand their implications for public-health programs. We introduce an intuitively simple statistic, Mean Risk Stratification (MRS): the average change in risk (pre-test vs. post-test) revealed for tested individuals. High MRS implies better risk separation achieved by testing. MRS demonstrates that conventional predictive values can mislead because they do not account for disease prevalence or test-positivity rates. Little risk-stratification is possible for rare diseases, demonstrating a “high-bar” to justify population-based screening. Importantly, we demonstrate that the risk-difference, Youden’s index, and AUC measure only multiplicative relative gains in risk-stratification: AUC=0.6 achieves only 20% of maximum risk-stratification (AUC=0.9 achieves 80%). However, large relative gains in risk-stratification might not imply large absolute gains if disease is rare or if the test is rarely positive. We illustrate MRS by our experience comparing the performance of cervical cancer screening tests in China vs. the USA. The test with the worst AUC=0.72 in China (visual inspection with ascetic acid) provides twice the risk-stratification of the test with best AUC=0.83 in the USA (human papillomavirus and Pap cotesting) because China has three times more cervical precancer/cancer. MRS could be routinely calculated to better understand the clinical/public-health implications of standard diagnostic accuracy statistics.