This article contains the clinical characteristics of the paradoxical embolized patients and the following up results. Data included are related to the article “Paradoxical embolism: Experiences from a single center”   Specifications TableValue of the data•These data provide the clinical characteristics and follow-up results of paradoxical embolism.•Most patients had one or more risk factors for thrombosis and inducing or exacerbating factor.•Long term coagulation is necessary and effective for paradoxical embolism.1The data presented include the clinical characteristics of the paradoxical embolized patients, the administrated treatment and the following up results .2Twelve patients diagnosed of paradoxical embolism in Fuwai Hospital from January 1994 to October 2015 were included. All clinical data related were collected from medical records, such as (1) demographic data; (2) case history and risk factors for thromboembolism; (3) clinical, laboratory and imaging findings of deep venous thrombosis, pulmonary embolism and systemic arterial embolic events; (4) imaging findings of an abnormal communication that allowed right to left shunt; (5) treatment and outcome; (6) follow-up data. Follow-up data were obtained from hospital records or by telephone interview with the patients or their family members. Follow-up ended on November 1st, 2015 There was no conflict of interest to declare.


Our study samples showed high levels of proinflammatory cytokine levels  in all patient groups but only high levels of α1-antichymotrypsine in VD patients compared to controls. There is no significant correlation between the laboratory and clinical variables except for a link between IL-1β and NPI scores of AD. In conclusion, this study yielded evidence of some shared mechanisms underlying AD and VD and thus motivates further studies of inflammatory markers in various types of dementia and MCI.In the past years, the possible involvement of inflammation in the pathogenesis of dementia has been the subject of several investigations. However there are restricted data about the profile of the inflammatory and soluble proteins in well evaluated Alzheimer’s disease (AD), vascular dementia (VD), mild cognitive impairment (MCI) and healthy controls. There are also no reliable data regarding the relationship between the overlapping protein levels and cognitive or functional decline. We measured levels of IL-1


The early recognition of risk factors for the occurrence of palatally displaced canines (PDC) can increase the possibility of impaction prevention.  To estimate the risk of PDC occurrence in children with dental anomalies identified early during mixed dentition. The sample comprised 730 longitudinal orthodontic records from children  with an initial mean age of 8.3 years (SD=1.36). The dental anomaly group (DA) included 263 records of patients with at least one dental anomaly identified in the initial or middle mixed dentition. The non-dental anomaly group (NDA) was composed of 467 records of patients with no dental anomalies. The occurrence of PDC in both groups was diagnosed using panoramic and periapical radiographs taken in the late mixed dentition or early permanent dentition. The prevalence of PDC in patients with and without early diagnosed dental anomalies was compared using the chi-square test (p<0.01), relative risk assessments (RR), and positive and negative predictive values (PPV and NPV). PDC frequency was 16.35% and 6.2% in DA and NDA groups, respectively. A statistically significant difference was observed between groups (p<0.01), with greater risk of PDC development in the DA group (RR=2.63). The PPV and NPV was 16% and 93%, respectively. Small maxillary lateral incisors, deciduous molar infraocclusion, and mandibular second premolar distoangulation were associated with PDC. Children with dental anomalies diagnosed during early mixed dentition have an approximately two and a half fold increased risk of developing PDC during late mixed dentition compared with children without dental anomalies. According to the guidance theory, local conditions, such as maxillary lateral incisor agenesis or microdontia, are related to canine displacement,,,,,The study by Sacerdoti and Baccetti,-,Ectopic eruption of maxillary canines has two major clinical concerns: the consequent impaction of the canine and the possibility of incisor external root resorption,,,Conversely, when there is an early orthodontic diagnosis of PDC, simpler clinical approaches such as deciduous canine extraction and rapid maxillary expansion can lead to spontaneous canine eruption in a high percentage of childrenThis retrospective longitudinal study was approved by the Research Ethical Committee of the Hospital for Rehabilitation of Craniofacial Anomalies, University of São Paulo (HRAC-USP) (379/2010). The patient records were anonymized and de-identified prior to analysis. The initial sample was composed of the orthodontic files of 810 children treated from 1980 to 2005 at the Society for the Social Promotion of Cleft Lip and Palate Patients (PROFIS). Inclusion criteria were: presence of an initial panoramic radiograph taken during the first transitional period or inter-transitional period of mixed dentition, according to the Van der LindenThe final sample was composed of 730 orthodontic records from children with an initial mean age of 8.3 years (SD=1.36), from both genders . A rough estimate of the ethnic background of the sample based on facial photograph was: White (84%), Black (12%), and Asian (4%). The experimental and control groups included 263 and 467 records, respectively, and were composed based on the analyses of the initial panoramic radiographs and dental casts to investigate the presence of the following dental anomalies: 1. Agenesis of any permanent teeth, except for third molars; 2. Microdontia of maxillary lateral incisors; 3. Infraocclusion of deciduous molars; 4. Distoangulation of mandibular second premolars; 5. Tooth transpositions.All the records were analyzed by a single calibrated examiner (ML). The examiner was precalibrated showing an agreement index ranging from 90 to 100% (Kappa test). The maxillary lateral incisor was considered as presenting microdontia when the maximum mesiodistal crown diameter was smaller than the same dimension of the opposing mandibular lateral incisor in the same patient, using the dental castsThe sample was divided into two groups. The dental anomaly group (DA) was composed of 263 patients with at least one dental anomaly identified in the initial or middle mixed dentition. Records from children without these dental anomalies in the early/middle mixed dentition (n=467) composed the non-dental anomaly group (NDA). Age and gender distribution in both groups is presented in Panoramic radiographs from late mixed dentition and/or early permanent dentition were evaluated to assess risks for the development of PDC in both groups. Considering the findings of Ericson and KurolThe frequency of PDC development was calculated in DA and NDA groups. Intergroup comparisons were performed using the Chi-square test with a significance level of 5%. In order to measure the strength of associations between occurrences of early-diagnosed dental anomalies and PDC, the relative risk (RR) at the 95% confidence interval and the positive and negative predictive values (PPV and NPV) were calculated. Additionally, the frequency of PDC development was separately calculated for each dental anomaly and compared with the control group using the Chi-square test (p<0.01) and relative risk assessment.Seventy-two individuals were affected by PDC (9.86%) with a male:female ratio of 1:3 in the combined DA and NDA groups (n=730). In this subgroup of individuals with PDC, 29.1% (n=21) showed bilateral expression, 31.9% (n=23) unilateral right expression, and 38.9% (n=28) unilateral left expression.The DA group presented PDC frequency of 16.3% compared with 6.2% of the NDA group . This diStatistically significant associations were observed between increased frequencies of PDC development and some of the dental anomalies were separately evaluated . The relThe frequency of RME performed during the mixed dentition was similar in both DA and control groups . No otheThis study evaluated longitudinal records from patients with early-diagnosed dental anomalies to estimate risks for developing PDC during the late mixed dentition.,,Previous cross-sectional studies showed an association between PDC and other dental anomalies including small maxillary lateral incisors, tooth agenesis, deciduous molar infraocclusion, and other slight tooth ectopia,,The present study is the first to evaluate a large sample with longitudinal records for dental anomalies that could be used as markers to estimate PDC risks,,Small maxillary lateral incisors and mandibular second premolar distoangulation were the main risk factors for PDC among the early-diagnosed dental anomalies . These r,,Deciduous molar infraocclusion was also confirmed to be a risk factor for PDC ; this as,,No significant differences were observed between PDC development in individuals with agenesis of maxillary lateral incisors or second premolars, and the NDA group . Peck, PA limitation of this study is the possibility of false-positive diagnosis for PDC using panoramic radiographs,Our results show that small maxillary lateral incisors, distoangulation of mandibular second premolar, and deciduous molar infraocclusion are early risk markers for PDC. Pediatric and orthodontic population with such dental anomalies diagnosed during the early mixed dentition should be carefully monitored during the critical age period for early diagnosis and intervention of maxillary canine ectopic eruption. The recognition of risk markers for the occurrence of PDC can increase the possibility of early diagnosis and intervention. Future longitudinal studies could contribute to identify other potential risk indicators for PDC including family history, female gender, hypodivergent pattern, and enamel hypoplasiaChildren with some dental anomalies diagnosed during the early mixed dentition have an approximately two and a half fold increase in risk of developing PDC during the late mixed dentition compared with children without these dental anomalies. Microdontia of maxillary lateral incisors, mandibular second premolars distoangulation, and deciduous molar infraocclusion constitute early risk markers for PDC development. When the maxillary canines are not palpable, a panoramic radiograph is highly recommended in 10-year-old children with clinically or radiographically diagnosed DA in order to investigate PDC.


Novel insights into the epigenetic control of chronic liver diseases are now emerging. Recent advances in our understanding of the critical roles of DNA methylation, histone modifications and ncRNA may now be exploited to improve management of fibrosis/cirrhosis and cancer. Furthermore, improved technologies for the detection of epigenetic markers from patients' blood and tissues will vastly improve diagnosis, treatment options and prognostic tracking. The aim of this review is to present recent findings from the field of liver epigenetics and to explore their potential for translation into therapeutics to prevent disease promoting epigenome reprogramming and reverse epigenetic changes.  If taken literally this could include all of the events involved in the regulation of gene expression. However for the purpose of this review discussion will be limited to those regulatory mechanisms that operate at the level of DNA methylation, histone modifications and the activities on non-coding regulatory RNA molecules. But in addition, readers should be aware of the critical role that transcription factors play in determining gene expression and cell phenotype. Transcription factors, which operate by recognising specific DNA motifs in the promoter/enhancer regions of genes and then modulate the activity of RNA polymerase II, are increasingly featuring as important drug targets in chronic liver disease. Typical examples being the peroxisome proliferator-activated receptors and the farnesoid X receptor for which ongoing clinical trials are determining efficacy in non-alcoholic fatty liver disease (NAFLD) and autoimmune liver disease de novo methyltransferases, establishing methylation patterns during development DNA methylation is a direct chemical modification of DNA in which methyl groups are predominantly added to cytosine residues within the context of a CpG dinucleotide DNA is packaged into chromatin of which the unit structure is the nucleosome which is comprised of two copies each of histones H2A, H2B, H3 and H4 that assemble into an octamer around which 146–147 bp of DNA is tightly wrapped. The nucleosome is a highly dynamic structure and dictates the degree to which DNA is accessible for transcription; this being determined by its degree of compaction and by post-translational modifications (PTMs) on the N-terminal tails of its constituent histones The vast majority of the human genome is transcribed, however only 2% encodes proteins. The vast majority of the transcriptome consists of non-coding RNAs (ncRNAs) that have regulatory functions and include micro RNAs (miRNA), small nucleolar RNAs (snoRNAs), small interfering RNAs (siRNAs), Piwi-interacting RNAs (piRNAs) and the long non-coding RNAs (lncRNAs). The miRNAs are an extensively studied class of single-stranded 18–22 nucleotide ncRNAs that fine-tune expression of the genome either by decreasing the stability or suppressing translation of messenger RNAs Here we will consider recent advances in the role of DNA methylation, histone modifications and ncRNAs in chronic liver diseases and in particular how new knowledge of these epigenetic mechanisms may be exploited for improving the management of the two major liver disease endpoints, fibrosis/cirrhosis and cancer.2The liver must adapt on a daily basis to a constant flux of environmental variations including circadian oscillators, nutritional/metabolic fluxes, exposure to xenobiotics, viral infections, alterations in the microbiome and the demands for epithelial repair and regeneration. Using a deep sequencing approach, Vollmers and colleagues systematically mapped the epigenetic changes occurring over 24 h in the mouse liver via its induction of hepatic reactive oxygen species (ROS) promotes H3K9 acetylation leading to increased expression of alcohol-metabolising enzymes that induce further ROS and acetylation potentially establishing feed-forward epigenetic re-landscaping HDAC3 is an important circadian regulated epigenetic writer critical for hepatic triglyceride homoeostasis and when deleted in mice results in steatosis, inflammation and fibrosis via its ability to influence DNMT activity and in addition recruits the histone acetyltransferases p300/CBP to induce IL-8 and proliferating cell nuclear antigen (PCNA) which are involved in inflammation and cell proliferation respectively Hepatitis C virus (HCV) infection promotes multiple changes in DNA methylation including at enhancer elements associated with altered expression of genes implicated in cancer and control of stem cells Hence, in summary the epigenetic landscape of the liver is acutely sensitive to environmental cues resulting in modifications that impact on its circadian controlled patterns of gene expression. In obesity and alcoholic disease the disturbance to the hepatic epigenetic landscape may promote microenvironments in which steatosis advances to inflammation, fibrosis and cancer.3Myofibroblasts are the major cellular drivers of liver fibrosis and appear during conditions of liver damage and/or infection mainly through the process of hepatic stellate cell (HSC) transdifferentiation. The conversion of quiescent HSC to their activated myofibroblast state involves vast changes in transcriptome expression that dramatically alter the phenotype and behaviour of the cell. In the past decade we have begun to shed light on the epigenetic events that reprogram the HSC transcriptome, thus revealing new regulators of fibrogenesis as well as potential biomarkers for tracking disease progression.3.1in-vivo transdifferentiation of HSC can be recapitulated in a cell culture model in which isolated HSC are maintained for several days on plastic in serum-containing media. In this widely used model, HSC transdifferentiation was accompanied by a > 20% methylation change (hypo- or hyper-methylation) in ~ 400 methylated regions including DNMT3A and DNMT3B 4) induced liver fibrosis 4 mouse fibrosis model Many of the regulatory events associated with DNA methylation in the PPARγ gene promotor has also been shown to be relevant in human disease. In a well phenotyped cohort of patients with biopsy proven NAFLD Zeybel et al. demonstrated that hypermethylation at discreet CpG dinucleotides within the human PPARγ gene promotor could be used to stratify patients with mild fibrosis (Kleiner score 0–2) from those with severe fibrosis (Kleiner score 3–4) in vivo models of chronic liver disease (bile duct ligation (BDL), CCl4 and methionine-choline deficient (MCD) diet) de novo methyltransferases DNMT3A/B expression, diminution of TET protein expression and remodeling of the HSC DNA methylome. Moreover, culture activated HSC and ex-vivo purified HSC from CCl4 injured rats also demonstrated increased DNMT3A and DNMT3B, with knock-down of the latter enzymes resulting in reduced fibrogenic features. Of note, similar fibrosis-associated epigenetic changes were observed in mechanistically distinct examples of chronic human liver disease supporting the concept that fibrosis is in part driven by alterations in the balance between the DNMTs and TETs As previously explained DNA methylation is a dynamic epigenetic marker that is regulated by DNMT and TET enzymes that stimulate CpG methylation and demethylation respectively 3.2Schistosoma mansoni and BDL induced liver fibrosis in vivo delivery of histone methyltransferase inhibitors to HSC can potently inhibit liver fibrosis 4-induced liver damage in vivoHistone acetylation is associated with active transcription and is under the control of HATs and HDACs. Niki et al. first described the anti-fibrotic effects of HDAC inhibitors showing that trichostatin A (TSA) treatment of cultured HSC suppressed fibrogenic gene expression and proliferation 3.34 exposure or BDL, this observation being confirmed in human liver with advanced fibrosis in vivo relevance in vivo and in vitro during liver fibrosis, with HOTAIR knockdown suppressing HSC activation. The authors further demonstrated that HOTAIR downregulates miR-29b expression, attenuating its control on epigenetic regulation, leading to enhanced phosphatase and tensin homolog (PTEN) methylation, which contributes to the progression of liver fibrosis A large number of miRNAs have been described that both promote  and suppress  HSC transdifferentiation 4Hepatocellular carcinoma (HCC) is the 3rd leading cause of cancer deaths worldwide and treatment options are severely limited. There is a clear need for the identification of the molecular drivers of HCC if progress is to be made in developing new medicines. Deep sequencing studies have been instrumental in identifying gene mutations and potential disease drivers in HCC. Alongside these genetic approaches is an increasing awareness of the role of epigenetic regulators in HCC which have strong potential for drug and biomarker design.4.1DNA methylation changes are common in human cancers and it was therefore unsurprising that 3700 hypomethylated promoters were identified in HCC tumour samples in vivo. Reduced SMPD3 expression was associated with early HCC recurrence following resection in vivo in a xenograft HCC HepG2 model. CDKN2A, DLEC1 and RUNX3 promoters were all confirmed to be demethylated in HCC lines following Guadecitabine treatment and correlated with inhibition of cell growth. Importantly, in contrast to decitabine, Guadecitabine was able to overcome the inhibitory effects on cell growth by macroH2A1 (variant of histone H2A), highlighting Guadecitabine as a potential HCC therapeutic, particularly in advanced disease There is vast potential for alterations in DNA methylation in HCC to be exploited for future drug and biomarker development. The de-methylating agent decitabine has been used to validate the expression of hypermethylated TSG in primary HCC and also re-expression of genes in HCC cell lines. 13 candidate TSG were identified in this study including DGK1, LDHB, NEFH, SMPD3, ACTL6B and PRPH. Functional characterisation of 2 candidates, SMPD3 and NEFH, revealed that overexpression leads to inhibition of cell proliferation, whereas by contrast knockdown increased tumour formation 4.2in vitro and in vivoHistone modifying enzymes offer much promise for HCC therapy since they are tractable targets for the design of small molecule inhibitors. The H3K27 methylase EZH2 is up-regulated in HCC tissue and is associated with cancer progression, invasion and proliferation 4.3Previous and emerging studies in HCC are now beginning to incorporate ncRNAs into our molecular understanding of HCC pathogenesis and progression As the complexity of these molecular interactions unravel, we can begin to appreciate that in most scenarios these modulators likely work together as a network of epigenetic regulators. This highlighted by a study demonstrating how HULC and MALAT1 combine in complex with TRF2 to significantly increase telomerase activity and microsatellite instability in liver cancer stem cells NCT02603224).Therapeutic targeting of ncRNA in HCC is now an imminent challenge. Emerging pre-clinical studies utilizing sophisticated drug delivery nanoparticles and animal proof of concept models such as this study successfully targeting the lncRNA TUG1 show promise for therapeutic development of antisense oligonucleotides 5The hepatic epigenome is remarkable in its capacity to adapt to dietary, metabolic, xenobiotic and microbial challenges in order to maintain cellular and functional homeostasis. However, when this capacity is breached epigenetic adaptions can become problematic and contribute to disease pathogenesis. We are now aware of how key components of the epigenetic machinery such as DNA methylation, histone PTMs and ncRNAs alter their expression or function in the context of fibrosis/cirrhosis and liver cancer. The next steps are to convert this information into bespoke medicines that either prevent disease-driving epigenome reprogramming or that reverse specific disease-promoting epigenetic changes. Furthermore there is vast potential to use the appearance of liver-derived epigenetic markers in the patient circulation for the diagnosis and prognostic tracking of chronic liver disease using no more than a few drops of blood, avoiding the need for biopsy or complex and expensive imaging modalities.


Scientific Reports6: Article number: 34474; 10.1038/srep34474 published online: 09292016; updated: 05082017.As the authors of references 25 and 26 also employed plasma-assisted molecular beam epitaxy for the synthesis of hexagonal boron nitride films, the authors would like to make the following changes to the Introduction section of their Article:23,24,25,26 and atomic layer deposition27 of hBN on metal substrates; this approach must typically be complemented by complex protocols for the removal and transfer of the grown films”.“In addition the direct growth of hBN on a two-dimensional material (HOPG) offers an alternative to chemical vapour depositionShould read:23,24, MBE25,26 and atomic layer deposition27 of hBN on metal substrates; this approach must typically be complemented by complex protocols for the removal and transfer of the grown films”.“In addition the direct growth of hBN on a two-dimensional material (HOPG) offers an alternative to chemical vapour deposition


The variables were related to brightness, color, physical aspects, soluble and total collagen as well as chemical traits. The physiological stage was defined as a classification variable in order to proceed ANOVA tests and comparison of means (P<0.05). Multivariate analysis was used to identify patterns of similarity and differentiation between samples of different physiological stages . The results revealed that meat quality varies according to different physiological stages, especially between lambs (a) and cull ewes (c). As a consequence, the physiological stage at slaughter should be taken into consideration to cote the quality of meat from indigenous sheep raised in tropical regions. The results contribute towards sensorial evaluation and the characterization of potential food products derived from indigenous sheep bred under tropical climate in developing countries.This study configures a first report regarding the variability of meat quality of locally adapted Pantaneiro sheep depending on different physiological stages and breeding systems. Pantaneiro sheep are raised in Brazil under a tropical wetland ecosystem denominated Pantanal. Twenty-nine Pantaneiro sheep from different sex and physiological stages were sorted into three groups, simulating three of the most representative ovine meat products commercialized by South American industries: a) non castrated male lambs (n = 11); b) wethers (n = 9); c) cull ewes (n = 9). Animals from each physiological stage were submitted to different breeding systems, resembling farming strategies adopted in several developing countries of South America. The effect of physiological stages on the quality of meat was accessed using 16 variables measured in the  The Midwest of Brazil presents the highest growth rates of sheep farming in the country . This reSeveral factors limit sheep breeding to play a more significant role on rural development and become a source of financial income in developing countries such as Brazil , 3. The Progress has been reported, but market and merchandising of sheep products in many developing countries still contrast with global market trends which requires urgent adjustments –13There is considerable lack of information regarding breed, geographical provenance, breeding system and traceability of age category , which may denote the quality of meat after slaughter.Food originated from indigenous breeds of sheep is an option to access and develop alternative markets –16. HoweIt is reasonable to consider that the diversification of products and market niches require efforts towards characterization , 19–21. The quality of meat has been an important subject , includiStill, in countries such as Brazil, three top products derive from sheep farming: meat from lambs (a), wethers (b) and cull ewes (c). Demands for each one of these products vary according to local market trends in different macro regions of South American countries . PhysicoConsidering some of the aspects of indigenous sheep farming, this study was designed to generate a first report on meat quality of Pantaneiro sheep, encompassing physicochemical and sensory characterization of the most common physiological stages commercialized in South American sheep industries.All protocols of experimental procedures were approved by the Animal Experimentation Ethics Committee (CEUA) of the Federal University of Grande Dourados (UFGD), The criteria to slaughter lambs (a) and wethers (b) was the body condition, which ranged from 2.5 to 3.0 . Cull ew-1 [The uncastrated lambs (a) were weaned with average weight of 19.5±4.10 kg and finished in feedlots with an 80% concentrate and 20% forage (20%) diet . The die-1 . Lambs (Cynodon spp. (Tifton85) and supplemented (1% of body weight) with the same concentrate used for lambs (water ad libitum). These animals were slaughtered at the age of 12.5±1.18 months. The cull ewes (c) were kept in extensive systems with tropical pastures of Brachiaria brizantha cv. Piatã with ad libitum mineral salt. Cull ewes (c) were slaughtered at the age of 68±13 months (The wethers (b) were kept in tropical pastures based on 3 months .All animals  were slaughtered after 16-hours of fasting (solids). Desensitization was carried out by electronarcosis (8 seconds of 220-V discharge) followed by cutting of jugular veins and carotid arteries with subsequent evisceration. Lambs (a), wethers (b) and cull ewes (c) showed initial average weight of 19.64, 19.90 and 45.04 kg, respectively. Final average weight was 35.72, 43.04 and 49.58 kg, respectively longissimus thoracis et lumborum (LM) and semimembranosus (SM) muscles were removed for meat quality analysis. All samples were analyzed with one replicate, and the final value of each variable was determined calculating a simple average for each variable.After slaughter, the carcasses were stored in a cold room at 4°C during 24 hours. Subsequently, the Evaluation of meat was performed based on color, physical characteristics, soluble and total collagen and chemical characteristics Tables The color was evaluated in lyophilized samples, submitted to acid digestion, filtration, neutralization, dilution and oxidation for colorimetric reaction. The results were based on the hydroxyproline values from absorbance readings performed in a spectrophotometer with a wavelength of 570 nm. The sample color was evaluated after 30 minutes of exposure to air to allow myoglobin reaction with oxygen . BrightnThe physical characteristics of meat were evaluated regarding water retention capacity (%) according to the method described by . The sheThe pH and temperature of the warm and the cold carcass  were monitored using a digital thermometer and pH-meter with a Testo 205/206 penetration probe. The determination of the soluble and total collagen content (%) followed the method described by  modifiedRegarding the chemical composition of meat, moisture was evaluated according to the method 950.46 . Total nlongissimusthoracis et lumborum (LM) and semimembranosus (SM) muscles. This was done using a univariate approach (PROC GLM) (p<0.05). Analyses were performed using the software SAS 9.2 . A multivariate method was used to standardize data (PROC STANDARD procedure) and to develop clustering analysis (PROC FASTCLUS procedure) assuming three clusters.The experimental design was arranged as an exploratory study. Animals were sampled from an on farm conservation flock and sorted according to pre-established physiological stages. The Shapiro-Wilk test was performed to verify the residue data normality, and the Bartlett test was performed to verify homogeneity of variances. Similar to a nested analysis approach, the effect of physiological stages (fixed effect) (lambs (a), wethers (b) and cull ewes(c)) was evaluated on the versus SM) regarding each physiological stage (The meat from lambs (a) showed different values compared with cull ewes (c) with only one exception  of the LM muscle al stage . Means bWater retention capacity, shear force and losses of weight after cooking presented similar averages (P>0.05) between physiological stages The highest concentration of total collagen was found in the meat from cull ewes. Physiological stages presented different values of total collagen All variables related to chemical composition were effected (P<0.05) by the physiological stage. The chemical analysis showed significant differences between means of lambs and cull ewes, except for the ash content of the SM muscle.The meat from wethers showed the same ether extract content than the cull ewes, regardless of the muscle type Lambs showed greater moisture content in the LM muscle Considering all 15 variables used to evaluate the quality of meat from different physiological stages, only three variables  may present similar aspects to the meat of lambs (a). The meat of some cull ewes (c) maybe similar to the meat of wethers (b). However, no cull ewes (c) presented similar meat quality compared to lambs (a) In general, the variables related to brightness (L*), the intensity of yellow (b*) and red (a*) varied according to physiological stages There is a trend to believe that many physical aspects of meat vary according to the age of animals at slaughter , 40. AgiCarcasses from older animals are associated to greater stability and texture of muscle fiber showing less soluble collagen . The samIn general, meat from different physiological stages showed appropriate quality values of collagen and pH, configuring soft meat The chemical characteristics of meat also differed between physiological stages The variation of meat quality regarding muscle types was considered to be random. However, diversifying aspects related to flavor and nutritional aspects of indigenous sheep meat was observed between different physiological stages.Fine discrimination observed with multivariate analysis Evaluation of meat from indigenous Pantaneiro sheep of different sex and physiological stages revealed suitable standards of meat quality produced in a rough and typically unique tropical ecosystem. Notable differences were observed between the quality of meat originated from lambs and cull ewes. This fine discrimination opens the door to valuable validation of how meat quality relates to sensorial aspects and consumer preferences regarding the preparation of dishes and consumption.Characterization of food products derived from locally adapted livestock in developing countries is an effort towards the development of new products with added value which may enhance merchandising, marketing strategies and consumption.S1 FileProtocols of experimental procedures were approved by commuittes(PDF)Click here for additional data file.


Data presented within this article supports the findings of the manuscript “A systematic review of fantasy driven vs contact driven internet-initiated sexual offences: Discrete or overlapping typologies?”  [1]. Inclusion and Exclusion criteria of study selection, PICO Formulation of Study Appraisal, as well as the Study Characteristics and Methodology of included studies are presented. Specifications TableValue of the data•The data allows for interpretation and assessment of studies examining the behavior of internet-initiated sexual crimes against minors, including study characteristics and methodology.•The data enables comparison of two distinct classification of internet-initiated offences commonly referred to in the literature: fantasy vs contact driven crimes.•Studies within this field primarily rely on the use of decoy victims, i.e. adults posing as children/young people who engage in proactive investigations. This data enables researchers to identify those studies that use decoy and real child victims.1The data set contains information on the Inclusion and Exclusion Criteria for Study Selection , and PIC2The process of study selection is defined in n = 5).Studies included in Broome et al.


Scientific Reports 10.1038/s41598-017-05445-3, published online 20 July 2017Correction to: This Article contains errors in the Materials and Methods section under subheading ‘Sample selection’.“All participants provided informed consent that explicitly allowed their coded genome sequencing data to be shared with other investigators”.should read:“Univ. of Pennsylvania samples were obtained from The Coriell Institute for Medical Research (CIMR). Collection of blood/tissue samples followed diagnostic consensus, using two informed consent forms: a) one with annual Univ. Miami IRB approval defining (with language appropriate for Old Order Amish) how their cells would be preserved for medical research on Major Affective Disorders; and, b) the Informed Consent Form required by the Institute for Medical Research (CIMR), later Coriell - National Institute for General Medical Sciences (NIGMS) Human Genetic Cell Repository (HGCR).The CIMR/NIGMS Informed Consent Forms makes no reference to specific diseases, types of genetic analysis that will be performed in future studies. Analysis of whole-genome re-sequencing data from consented individuals in this pedigree was also approved by the IRB of the Weill Cornell Medical College and the Perelman School of Medicine at the University of Pennsylvania. All other participants provided informed consent that explicitly allowed their coded genome sequencing data to be shared with other investigators”.


Recently, Seddik Hammad from Heidelberg University published an interesting report about a frequent misinterpretation in research on liver fibrosis : in mic4 mediated pericentral killing of CYP2E1 positive hepatocytes, which after repeated CCl4 administration leads to fibrotic bridging of pericentral areas . Hammadal., 2017).in vitro systems in toxicology aim for mimicking some of the zonated features of the liver lobule (Frey et al., 2014[Studies of hepatotoxicity often rely on the correct interpretation of histology (Schenk et al., 2017; Reif etal., 2014; Leist e


The extent to which poor academic achievement is associated with later schizophrenia is unclear. The aim of the present study was to update our prior meta-analyses which examined academic achievement in youth aged 16 years or younger who later developed schizophrenia or schizophrenia spectrum disorders (SSD) and those who did not . We also conducted a new meta-analysis on published studies that reported on general academic achievement in youth at-risk for schizophrenia/SSD aged 16 years or younger compared to typically developing youthIn addition to the five studies included in our earlier meta-analyses, a further three prospective investigations of birth or genetic high-risk cohorts were identified that reported results using objective measures of general academic achievement and of mathematics achievement for individuals who did and did not develop schizophrenia/SSD in adulthood. For our new meta-analysis we identified a total of seven studies that met the following inclusion criteria: (1) written in English; (2) objective measure of general academic achievement consisting of scores on least two core academic subjects  at age 16 years or younger; (3) results provided for youth at high risk for developing schizophrenia/SSD in adulthood by virtue of having at least one first-degree relative with the disorder or reporting psychotic like-experiences (PLEs); and (4) sufficient data to calculate effect sizes.Meta-analyses showed that by age 16 years, individuals who later developed schizophrenia/SSD presented with significantly poorer general academic achievement (d=-0.26) and mathematics achievement (d=-0.21). Findings also indicated that during adolescence, youth with a family history of schizophrenia/SSD and youth reporting PLES were characterised by significantly lower general academic achievement than healthy peers .These results show that poor academic achievement precedes illness onset, and may represent an easily identifiable non-specific marker of biological, psychological and social risk processes underpinning the development of schizophrenia/SSD.


Although some studies have suggested that transfusion recipients may have better medical outcomes if transfused with red blood cell units stored for a short time, the overall body of evidence shows mixed results. It is important to understand how using fresher stored red blood cell units for certain patient groups may affect blood availability.Based on the Stock-and-Flow simulation model of the US blood supply developed by Simonetti et al. 2014, we evaluated a newly implemented allocation method of preferentially transfusing fresher stored red blood cell units to a subset of high-risk group of critically ill patients and its potential impact on supply.Simulation results showed that, depending on the scenario, the US blood total supply might be reduced between 2-42%, when compared to the standard of care in transfusion medicine practice. Among our simulated scenarios, we observed that the number of expired red blood cell units modulated the supply levels. The age threshold of the required red blood cell units was inversely correlated with both the supply levels and the number of transfused units that failed to meet that age threshold.To our knowledge, this study represents the first attempt to develop a comprehensive framework to evaluate the impact of preferentially transfusing fresher stored red blood cells to the higher-risk critically ill patients on supply. Model results show the difficulties to identify an optimal scenario. Observational studies have estimated the effects of red blood cell (RBC) storage time on clinical outcomes among different patient groups. Some studies have shown that transfusing certain high-risk patients, such as cardiac surgery patients, with RBC units that have been stored for prolonged time may increase the risk of adverse outcomes –6. OtherResults from randomized clinical trials (RCT) have varied in their outcomes. The RECESS RCT from the National Heart, Lung, and Blood Institute  found noBased on the Stock-and-Flow simulation model of the US blood supply developed by Simonetti et al. 2014 , we explThe US blood supply model developed by Simonetti et al.  evaluateThe Collector attempted to supply the Hospital with enough young RBC units to meet the HRGs expected demand of blood for the next day. The Hospital received blood from the Collector to fulfill any need of blood demand regardless the RBCs age, while maintaining an inventory of 6 days of supply. Transfers of blood from the Collector to the Hospital occurred by using ‘standard’ phenotype compatibility rules . We defiThe daily predictions of supply and demand were derived using aggregated blood donation information from America’s Blood Centers (ABC) , and updWe used the annual average daily (AAD) age of RBCs as a summary measure for the overall evaluation of the performance of the blood system for each simulated scenario. Specifically, we used the weighted AAD age of RBCs, which represented the distribution of RBC units among different blood ages. Other measures of performance were ‘unmet RBC units by age’ and ‘percentage of unmet RBC units by age’ for HGRs and BBRs. ‘Unmet RBC units by age’ represented the amount of RBC units that failed to meet the age requirement derived from the literature –6. ‘PercWe identified three HRGs—Cardiac Surgery (CS), Trauma (TR) and Intensive Care Unit (ICU) patients , 5—from To evaluate the impact on supply of transfusing a subset of HRGs with fresher stored RBCs, we compared the baseline blood recipients to several selected scenarios  in context, we may help understanding the effect on the US blood supply if transfusing fresher storedRBC units is proven beneficial to improve recipient outcomes. However, under current assumptions, we demonstrated how the newly developed allocation method allows a relatively efficient distribution of blood while preferentially providing fresher stored RBCs to the high-risk blood recipient except for some disruptions in the US blood supply observed in certain simulated scenarios. Most importantly, implementing ‘ad-hoc’ models can help assist stakeholders and the blood community to make informed decisions that may impact the availability of blood in the US blood supply.S1 FigA flowchart of the ‘Threshold Method’ (TM) algorithm to illustrate the mechanism of allocating blood into the system 1) from the Hospital to the HRGs recipients; and 2) from the Collector Bank to the Hospital, on each day of the Monte Carlo simulation.(DOCX)Click here for additional data file.S2 Fig(DOCX)Click here for additional data file.S3 Fig(DOCX)Click here for additional data file.S4 FigThe Annual Average Daily (AAD) number of RBC units available in the system for: (A) Total Supply , average values (red), and percent reduction in total supply with respect to baseline scenario (BBR-LO) (above bars for scenarios 2 to 11); (B) Expired RBC Units,  and percentage of expired units at collector only are shown on bars; (C) Unmet RBC Units by Age by blood type at the hospital, the percentage of unmet units by age (above bars), and mean age of the transfused blood at the hospital . The scenarios are sorted in a descending order according to their total supply. Error bars represent 95% confidence intervals.”(DOCX)Click here for additional data file.S5 FigDescription of each element of the half-pie chart from inner to the outer layer as follows: 1) percentage of total RBC units transfused among elderly for the overall HRGs (blue) versus BBR (tan); 2) percentage of total RBC units transfused decomposed by HRGs ; 3) allocation method used for each recipient group ; 4) mean age of the blood transfused to each recipient group and the percentage of ‘met’ (green) and ‘unmet’ (red) RBC units by age for HRGs only (in parenthesis); and 5) mean age of the overall transfused blood given to HRGs (bold red).(DOCX)Click here for additional data file.S6 FigThe mean age of blood for the overall transfused blood at the hospital is shown above the bars.(DOCX)Click here for additional data file.S7 Fig(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.S5 Table(DOCX)Click here for additional data file.S6 TableScenario illustration, group description, and allocation method used for each scenario are also presented.(DOCX)Click here for additional data file.


G2 and the McMaster techniques for counting of gastrointestinal nematode eggs in the faeces of alpacas using two floatation solutions (saturated sodium chloride and sucrose solutions). Faecal eggs counts from both techniques were compared using the Lin’s concordance correlation coefficient and Bland and Altman statistics. Results showed moderate to good agreement between the two methods, with better agreement achieved when saturated sugar is used as a floatation fluid, particularly when faecal egg counts are less than 1000 eggs per gram of faeces. To the best of our knowledge this is the first study to assess agreement of measurements between McMaster and FECPAKG2 methods for estimating faecal eggs in South American camelids.This study aimed to compare the FECPAKThe online version of this article (10.1186/s13071-018-2861-1) contains supplementary material, which is available to authorized users. Parasitic gastroenteritis caused by gastrointestinal nematodes (GINs) is responsible for significant clinical and subclinical problems in domesticated South American camelids (SACs), alpacas and llamas, resulting in economic losses arising from lowered production of fibre, meat and/or leather , 2. AlthIn SACs, the burden of GINs can be assessed using various coprological methods originally developed for domestic ruminants , with esG2 method uses a floatation-dilution approach similar to the McMaster technique, but involves capturing digital images of samples without the use of a microscope. Digital images of samples are stored, ready for assessment by trained technicians for identification and counting nematode eggs  [G2 methods assessed using the Lin’s concordance correlation coefficient [epiR package [The arithmetic means of EPG were calculated for faecal egg counts obtained using the two methods and differences in arithmetic means were tested using the Wilcoxon signed rank test. A G + 15)] , and agrfficient . To provfficient . These l package  implemen package .G2 methods . Using sugar solution, more samples had at least more than one EPG using the McMaster technique  compared with FECPAKG2  in the proportions of positive samples tested by both methods when salt solution was used   plots showing line of perfect concordance (dotted line) and estimated concordance (solid line) between McMaster and FECPAKG2 methods using salt solution (a) and sugar solution (b). (TIF 520 kb)


Left ventricular (LV) fractal dimension (FD) on cardiac magnetic resonance (CMR) balanced steady-state free precession (SSFP) cines has already proven to be useful in making a diagnosis of non-compaction cardiomyopathy. Normal FD values for SSFP cines have been established (Captur 2015).Fast gradient echo (fGRE) sequences have different contrast between blood pool and myocardium, which affects measurement of FD. However, if FD could be measured on fGRE it would allow for retrospective analysis of scans acquired before implementation of SSFP or in patients with devices that underwent fGRE.The aim of this study was to establish a correlation between FD measured on SSFP and fGRE sequences in the same subjects.Twelve participants of Barts Cardiovascular Registry who underwent cardiac magnetic resonance (CMR) imaging with 1.5T scanners for various clinical reasons had cine short axis stack (SAX) acquired with both SSFP and fGRE sequences.We measured FD in 57 corresponding (positioned in the same LV location) SAX cine slices on SSFP and fGRE using dedicated MATLAB script and an Osirix "LVFractalAnalysisFilter" plugin written in Objective-C with equivalent architecture. The same region-based level-set segmentation and fractal procedure was implemented. Briefly: the scale parameter specifying the size of the neighbourhood (sigma) was set to 2%; size of the initial contour was set to 6 × 9 pixels; and maximum initial grid-size for fractal analysis was 45% of the original size of the region of interest estimated through the application of a scaled bounding box.We used Pearson's correlation coefficients and two-way random single measures of consistency intraclass correlation coefficients (ICC) to compare FD from SSFP and fGRE, first for values derived in MATLAB and then in Osirix.FD on fGRE was around 6.5% larger than on SSFP in MATLAB and 4.3% in Osirix (p < 0.001 and p < 0.05). There was a good agreement between the FD derived from SSFP and fGRE sequence in both MATLAB and Osirix tools .Detailed results are presented in the table and the figure.This proof-of-principle analysis shows a significant correlation between FD on SSFP and fGRE sequences. FD measured on fGRE may have utility as a research tool and further ground-truth validation of the method is encouraged.


To clarify the prognostic role of tumour protein 53 (TP53) mutations in patients with oesophageal adenocarcinoma (OAC) as there is a need for biomarkers that assist in guiding management for patients with OAC.A systematic review was conducted using MEDLINE, Embase, PubMed and Current Contents Connect to identify studies published between January 1990 and February 2015 of oesophageal cancer populations (with OAC diagnoses >50% of cases) that measured tumoural TP53 status and reported hazard ratios (HR), or adequate data for estimation of HR for survival for TP53-defined subgroups. Risk of bias for HR estimates was assessed using prespecified criteria for the appraisal of relevant domains as defined by the Cochrane Prognosis Methods Group including adherence to Grading of Recommendations, Assessment, Development and Evaluation and REporting recommendations for tumor MARKer prognostic studies guidelines, as well as assay method used (direct TP53 mutation assessment vs immunohistochemistry) and adjustment for standard prognostic factors. A pooled HR and 95% CI were calculated using a random-effects model.2=33%). A greater prognostic effect was observed in a sensitivity analysis of those studies that reported survival for OAC-only cohorts and were assessed at low risk of bias .Sixteen eligible studies (11 with OAC only and 5 mixed histology cohorts) including 888 patients were identified. TP53 mutations were associated with reduced survival (HR 1.48, 95% CI 1.16 to 1.90, IPatients with OAC and TP53 gene mutations have reduced overall survival compared with patients without these mutations, and this effect is independent of tumour stage. Oesophageal adenocarcinoma (OAC) remains one of the few GI malignancies where molecular information is not taken into account to guide patient management.Current clinicopathological staging fails to accurately identify patients with OAC with good or poor prognosis.Recent genomic findings have identified a high tumour protein 53 (TP53) mutation rate in OAC, but the prognostic impact of this remains unclear due to conflicting reports in the literature.This is the first dedicated systematic review and meta-analysis regarding the prognostic impact of TP53 mutations in patients with OAC including 16 studies with >850 patients.We identify a significant negative prognostic impact of TP53 mutations on overall survival of patients with OAC.A greater prognostic effect can be corroborated in studies that report tumour-stage adjusted survival for OAC-only cohorts and are assessed at being at low risk of bias.This study suggests that TP53 gene mutations have a clinically important negative prognostic impact on patients with OAC.In light of recent genomic findings highlighting a central role of this gene in OAC pathogenesis and drugs currently in development and testing that directly target this gene, a role for identifying TP53 mutations in OAC can be suggested.The incidence of oesophageal adenocarcinoma (OAC) has increased faster than any other cancer since the 1970s in many Western countries with highest incidence rates found in Northern and Western Europe, Northern America and Oceania,Fewer than half of the patients with a new diagnosis of OAC are eligible for curative treatment, and OAC continues to have one of the highest cancer case-fatality rates with population-based 5-year survival rates typically around 15%.The tumour-suppressor gene tumour protein 53 (TP53) , which encodes the p53 protein and is sometimes called ‘the guardian of the genome’,18Recent large-scale whole-genome and whole-exome sequencing studies have shown that both OAC and dysplastic BO harbour a very high TP53 mutation rate of up to 70%,We aimed to resolve the existing uncertainty regarding the prognostic value of TP53 for staging OAC by conducting a systematic review and meta-analysis of all published data with subgroup analysis of studies assessed as low risk of bias, and studies using direct TP53 gene mutation analysis techniques to determine TP53 mutation status, since these are the most accurate methods for determining tumoural TP53 mutations.Gastroenterology), American Society for Clinical Oncology  and American Association for Cancer Research  from 1990 to 2015.The electronic bibliographic databases MEDLINE, Embase, PubMed and Current Contents Connect were searched to identify eligible studies published between January 1990 and 8 February 2015 using MeSH terms and text words for adenocarcinoma*, o/esophagus* or o/esophageal*, TP53* or p53* or 17p13* or 17p*. In an attempt to minimize the risk of publication bias, conference abstracts and proceedings were searched through Web of Science, Embase and Scopus using the terms o/esophagus* and p53*. Further, the following major GI and oncological conferences were searched for relevant reports: Digestive Disease Week  scanned the search results (title and abstract) and retrieved full text publications using the criteria outlined below to identify eligible studies. Reference lists of relevant studies identified from the search including reviews were further screened to identify studies that may not have been identified by the strategy outlined above.Study inclusion criteria were prospective or retrospective clinical studies of OAC populations that assessed TP53 mutation status and/or p53 expression in primary tumours, and compared overall survival for TP53 mutation versus TP53 non-mutation subgroups with calculation of HR and 95% CIs, or reported adequate data for their estimation. To include all available data, we also included studies of oesophageal cancer cohorts that included patients with squamous cell carcinoma if at least ≥50% of the patient cohort had a diagnosis of OAC.Study exclusion criteria were studies of TP53 DNA germline mutations or autoantibody detection in blood; and reports available in abstract form only that did not report adequate information to determine study eligibility or to assess study methods for risk of bias.If studies did not report sufficient data to calculate HRs or in case of missing/unclear data, the corresponding author was contacted by email to request this information. If the same research unit (identified from author names and institution) published multiple reports with overlapping patient recruitment time periods, HR estimates were extracted from the most recent publication with the largest patient numbers to avoid duplication of data.Three investigators  reviewed eligible studies and extracted the following variables into a standardised data extraction form: author's name; publication year; country where study was conducted; number of patients included and general patient demographics; tumour histology (number and proportion of OAC tumours included); treatment modality ; tissue specimen type ; TP53 assay methods , immunohistochemistry (IHC), and type of antibody, dilution for IHC); criteria or cut-point used to define TP53 mutation status for the survival analysis; study prevalence of TP53 ‘mutation’ and ‘non-mutation’ subgroups; median survival of all patients and by TP53 mutation status; unadjusted and adjusted HR with 95% CI and corresponding p values where available. For consistency and to facilitate further quantitative analyses, the authors’ definitions for TP53 ‘mutations’ were used for studies performing only IHC as the respective studies did not use uniform staining classification criteria. As such, nuclear p53 protein overexpression was interpreted to represent TP53 mutations by all authors of the included studies, although loss of p53 protein expression has also been associated with tumoural TP53 gene mutations.http://www.gradeworkinggroup.org),et al's27All studies were assessed for risk of bias for the study estimate of the impact of TP53 on survival by appraising six domains  using prespecified criteria adapted from the Grading of Recommendations, Assessment, Development and Evaluation  TP53 mutation database (R17)10.1136/gutjnl-2015-310888.supp1Supplementary materialsTo estimate the effect of TP53 mutation status on OAC survival, we calculated a pooled HR and 95% CI using the generic inverse variance method. If the HR was not reported, it was estimated from the corresponding Kaplan–Meier curves using the Parmar method.2 statistic.27Because different TP53 mutation analysis methods were used across studies, we expected heterogeneity in study estimates of the TP53 mutation effect on survival, and thus we applied a random-effects model to estimate the HR.Sensitivity analysis was performed to assess the impact of tumour histology and assay type on survival by repeating the pooled HR analysis in the following subgroups: (i) OAC-only versus OAC-mixed study populations; (ii) IHC versus direct TP53 gene mutation analyses; and (iii) studies assessed as having low versus high risk of bias. Differences between subgroups were assessed with a test for interaction.34ggplot2 package.metafor and forestplot for R.38Descriptive statistics as well as quantitative analysis of the IARC TP53 mutation database to guide risk of bias assessment were performed using R statistical softwareThe search strategy yielded 323 studies, of which 16 met our eligibility criteria . Study cHalf of the studies (n=8) assessed TP53 mutation status by IHC,The clinicopathological variables and survival times reported in the included studies are summarised in HRs were reported in nine studies and extrapolated from five studies. In addition, individual patient data were available for two studies to calculate tumour stage-adjusted HR and 95% CIsFour studies2=33%, p heterogeneity=0.1). The analysis of studies including pure OAC patient cohorts showed similar results with low heterogeneity  compared with studies performing direct TP53 gene assessments (sequencing and SSCP) or LOH analyses . This difference was borderline statistically significant (p for interaction=0.05). A similar effect was seen in the subset of studies containing pure OAC cohorts . This effect size was similar in the three studies with low risk of bias that contained pure OAC cohorts  and the study appraised as being at low risk of bias  were significant sources of heterogeneity .This study indicates that mutated TP53 negatively impacts overall survival in patients with OAC, independent of tumour stage. This effect is estimated as a relative increase in hazard of death of 48%, with up to a 211% increase when studies of mixed histology cohorts or high risk of bias are excluded. This corresponds to a reduced survival time of approximately 7 months based on median survival from the included studies. This effect size is similar to the difference in median survival of stage IIIA compared with stage IIIC OAC.55To our knowledge, this is the first comprehensive systematic review and meta-analysis of the prognostic impact of TP53 mutations in patients with OAC that includes an assessment independent of tumour stage. Two previous systematic reviews and meta-analyses of various prognostic biomarkers in OAC have included an analysis of TP53 mutations.This study is timely because recent whole-genome sequencing studies have shown a high mutation rate of TP53 in OAC.58One potential explanation for earlier conflicting results for the prognostic significance of TP53 status in OAC is the use of different and potentially less accurate assay methods for TP53 mutation detection. Our study identified considerable variability in IHC methods across the included studies, such as the use of different antibodies, antibody dilutions and variable scoring systems for immunopositivity. Further, none of the included studies used loss of p53 expression as a method for interpreting the presence of TP53 gene mutations.22Recent genomic studies have found that TP53 gene mutations remain the most common genetic alteration in both OACet al,The two main limitations of this study that may affect the validity of our findings are the quality of the primary studies and data limitations to explore potential confounders. First, more than half of the studies were assessed as high risk of bias based on criteria defined by Hayden Further studies are warranted to better estimate the size of the prognostic effect independent of tumour, node, metastasis staging. Given the substantial amount of heterogeneity identified, adherence to REMARK guidelineshttp://www.clinicalTrials.gov identifier NCT00525200; http://www.p53.at) has recently completed recruitment. Moreover, multiple therapeutic options directly targeting the TP53 gene are either currently in clinical trials or are already clinically available.One approach to collect high-quality data is to include TP53 mutation analysis using targeted gene sequencing in the baseline analysis of trials of OAC therapies. If validated, TP53 analysis could be used to stratify patients in future trials. Stratifying patients based on TP53 mutation status may also have a role in clinical practice to guide treatment selection. For example, data suggest that TP53 mutation status may predict response to standard chemotherapeutic regimens such as fluorouracil or cisplatin,In summary, OAC remains one of the few GI malignancies for which molecular information is still not used to guide patient management. This study suggests that TP53 gene mutations have a clinically important negative prognostic impact on patients with OAC, which is relevant in light of recent genomic findings highlighting a central role of this gene in OAC pathogenesis and drugs currently in development and testing that directly target this gene. High-quality studies with large patient cohorts using modern sequencing technologies for TP53 mutation analysis are needed to confirm the independent prognostic effect of this frequent gene mutation.


This data aimed to audit the dental sciences related articles published in Iranian Journal of Basic Medical Sciences (IJBMS) from 2007 to 2015 over a 9 year period performed using web-based search. The data were analyzed for topic of dental sciences, type of article, international collaborations, source of funding, number of authors and authorship trends. Out of the total 18 data related to dental sciences, original articles (12), review articles (4) and short communications (2) contribute the major share. Regarding the relationship with dental sciences, the maximum number of data were related to oral pathology and microbiology (16) followed by oral medicine and radiology (7) and periodontics (7). Among the data related to dental sciences, oral cancer (3) and gingival and periodontal diseases (3) followed by dental plaque and caries (2) and orthodontic tooth movement (2) form the major attraction of the contributors. The largest numbers of data related to dental sciences were received from Mashhad University of Medical Sciences, Mashhad (4) and Tehran University of Medical Sciences,Tehran (2).The present data were compared with previous bibliometric studies done related to dental sciences  Specifications TableValue of the data.•These date describe the majority of dental sciences articles published as original articles (12),review articles (4) and short communication (2)•These data describe specialty wise majority of dental articles related to oral pathology and microbiology (16) followed by oral medicine and radiology (7),periodontics (7), community dentistry (2),orthodontics (2), prosthodontics (1) and oral and maxillofacial surgery (1).•These data describe topic wise majority of dental articles related to oral cancer (3) and gingival and periodontal diseases (3) followed by dental plaque and caries (2) and orthodontic tooth movement (2)•The data presented in this paper can be used as a guide for conducting similar studies around the globe.These data describe the dental sciences related articles published in a Basic Medical Sciences Journal from Iran.1See 2http://ijbms.mums.ac.ir/ .Bibliometric information about dental sciences articles data in a clinical medical journal from Iran and ayurveda journals from India is evident in the literature  The data published were analyzed for topic of dental sciences, type of article, international collaborations, source of funding, number of authors and authorship trends.The data regarding articles in press (articles that are not yet assigned to an issue) in IJBMS were excluded. The contents of the data were grouped into seven individual dental sciences specialities such oral pathology and microbiology, oral medicine and radiology, oral and maxillofacial surgery, periodontics, prosthodontics, orthodontics and community dentistry. The data was scrutinized for dental sciences related topic. The datas which are interdisciplinary in approach were counted under all the dental sciences specialities it belonged. The data were checked for authorship trends according to the institution of the first author.The data was analyzed using descriptive statistics.


Since 2011, the New York City (NYC) Department of Health and Mental Hygiene (DOHMH) has typically been notified of three or fewer cases of hepatitis A virus (HAV) infection each year among men who have sex with men (MSM) who reported no travel to countries where HAV is endemic. This year, DOHMH noted an increase in HAV infections among MSM with onsets in January–March 2017, and notified other public health jurisdictions via Epi-X, CDC’s communication exchange network. As a result, 51 patients with HAV infection involving MSM were linked to the increase in NYC.Confirmed cases were defined as symptomatic HAV infections with onset after December 31, 2016, in NYC residents who reported being MSM or having sexual contact with MSM, and reported no travel to areas of high or intermediate HAV endemicity. Probable cases were defined as onset of symptomatic HAV infection after December 31, 2016, in NYC residents who, irrespective of travel, reported being MSM or having sexual contact with MSM. For the period January 1–August 31, 2017, DOHMH identified 46 cases in MSM or persons with sexual contact with MSM; 36 confirmed and nine probable cases occurred in 45 MSM patients and one was in a female (confirmed case) who reported sexual contact with a bisexual male resident of a New York county outside New York City. Fifteen (33%) of the 46 patients were hospitalized, and three (7%) reported previous receipt of hepatitis A vaccine. Nineteen (41%) patients had traveled domestically during their incubation period, and eight (17%) had traveled to Western European countries where outbreaks of HAV infection among MSM are ongoing (NYC routine surveillance identified another case of HAV infection (in addition to the 46 NYC patients), in a man who was hospitalized in New York City but resided in the New York county that had been visited by the female patient. Several Colorado jurisdictions also contacted DOHMH to report increases in HAV infections among MSM. In total, 51 patients were linked to the increase in NYC, either through epidemiologic or laboratory evidence, including five non-NYC patients .Three of the 46 NYC patients and the one patient from Oregon reported sexual contact with four NYC outbreak patients . The OreSerum specimens from 25 NYC MSM patients, the NYC female patient, and the New York (non-NYC) MSM patient were sent to CDC’s Division of Viral Hepatitis Laboratory for molecular sequencing. Sequences of HAV isolated from the serum of 24 patients, including four of the eight who had traveled to Europe, matched the strains of genotype IA HAV circulating among European MSM: HAV16–090 (14 patients), VRD_521_2016 (eight), V16–25801 (two); two patients had sequences matching three Colorado MSM patients, and one had a unique sequence .Only three patients with HAV infection reported previous receipt of HAV vaccine; this ongoing investigation highlights the importance of HAV vaccination among MSM, and of determining MSM status during HAV investigations. One patient received 1 dose (as postexposure prophylaxis), but the doses for the other two patients were unknown; both reported previous receipt of HAV vaccine but did not know the number of doses. Since 1996, the Advisory Committee on Immunization Practices has recommended that all MSM receive 2 doses of HAV vaccine administered at least 6 months apart (


Nature Communications7 Article number:11362 10.1038/ncomms11362 (2016); Published 05062016; Updated 09292016.The HTML version of this Article previously published omitted Supplementary Data 8. This has now been corrected in the HTML version of the Article; the PDF was correct from the time of publication.


The A2AAR is widely expressed on cells of the immune system and numerous in vitro studies have identified its role in suppressing key stages of the inflammatory process, including leukocyte recruitment, phagocytosis, cytokine production, and immune cell proliferation. The majority of actions produced by A2AAR activation appear to be mediated by cAMP, but downstream events have not yet been well characterised. In this article, we review the current evidence for the anti-inflammatory effects of the A2AAR in different cell types and discuss possible molecular mechanisms mediating these effects, including the potential for generalised suppression of inflammatory gene expression through inhibition of the NF-κB and JAK/STAT proinflammatory signalling pathways. We also evaluate findings from in vivo studies investigating the role of the A2AAR in different tissues in animal models of inflammatory disease and briefly discuss the potential for development of selective A2AAR agonists for use in the clinic to treat specific inflammatory conditions.The production of adenosine represents a critical endogenous mechanism for regulating immune and inflammatory responses during conditions of stress, injury, or infection. Adenosine exerts predominantly protective effects through activation of four 7-transmembrane receptor subtypes termed A


Altered immune response is associated with many psychiatric disorders, but whether and how these changes confer increased risk remains unclear. In schizophrenia, robust association between illness risk and the MHC region general, and complement component 4 (C4) specifically, has been demonstrated, along with evidence from both gene enrichment and other genetic analysis highlighting the broader role of genetic variation in additional immune related networks to schizophrenia risk.In a series of recent studies from our group, we examined the effects of immune-related genetic variation, based on gene ontology, implicated in neural function both behaviourally in samples of ~1200 cases and controls, and cortically in samples of ~150 cases and controls.We found that (1) increased predicted C4A RNA expression predicted poorer performance on measures of memory recall  and a pattern of reduced cortical activity in middle temporal cortex during a measure of visual processing ; (2) variation in a curated gene set associated with both increased Schizophrenia risk and immune function  were associated with both variation in both episodic memory and general cognitive ability.Based on these findings we conclude that schizophrenia risk associated with variation within immune related genes is likely to be conferred at least partly via effects on cognition, and the molecular mechanisms involved may include effects on inflammatory response.


TNNT1) was found in the Amish populations in Pennsylvania and Ohio. This single nucleotide substitution causes a truncation of the ssTnT protein at Glu180 and the loss of the C-terminal tropomyosin (Tm)-binding site 2. As a consequence, it abolishes the myofilament integration of ssTnT and the loss of function causes an autosomal recessive nemaline myopathy (NM). More TNNT1 mutations have recently been reported in non-Amish ethnic groups with similar recessive NM phenotypes. A nonsense mutation in exon 9 truncates ssTnT at Ser108, deleting Tm-binding site 2 and a part of the middle region Tm-binding site 1. Two splicing site mutations result in truncation of ssTnT at Leu203 or deletion of the exon 14-encoded C-terminal end segment. Another splicing mutation causes an internal deletion of the 39 amino acids encoded by exon 8, partially damaging Tm-binding site 1. The three splicing mutations of TNNT1 all preserve the high affinity Tm-binding site 2 but still present recessive NM phenotypes. The molecular mechanisms for these mutations to cause myopathy provide interesting models to study and understand the structure-function relationship of TnT. This focused review summarizes the current knowledge of TnT isoform regulation, structure-function relationship of TnT and how various ssTnT mutations cause recessive NM, in order to promote in depth studies for further understanding the pathogenesis and pathophysiology of TNNT1 myopathies toward the development of effective treatments.Troponin T (TnT) is the sarcomeric thin filament anchoring subunit of the troponin complex in striated muscles. A nonsense mutation in exon 11 of the slow skeletal muscle isoform of TnT (ssTnT) gene ( A nonsense mutation in TNNT1 was first identified in the Old Order Amish  in the C-terminal end segment, partial deletion (W287ter) or error-splice out of exon 17 encoding this segment in cardiac TnT have been found to cause cardiomyopathy , slow skeletal muscle (TNNT1) and fast skeletal muscle (TNNT3) isoforms of TnT  expresses exclusively slow skeletal muscle TnT together with cardiac forms of TnI and myosin  express only cardiac TnT in the cardiac muscle. Analysis of cardiac function demonstrated that toad hearts generated lower maximum stroke volume but significantly higher resistance to the increase of afterload than that of frog hearts  contains 14 constitutively expressed exons and three alternatively spliced exons  encoding a short segment of 2 or 3 amino acids between the T1 and T2 regions of mammalian cardiac TnT  each encoding a segment of 14 amino acids also occurs in TNNT3 gene undergoes a high to low molecular weight, acidic to basic isoelectric point splice form switch during development due to alternative inclusions of N-terminal exons , but not type 2, Charcot-Marie-Tooth disease  was reported in 9 Palestinian patients from 7 unrelated families with recessively inherited NM  did not report notable clinical symptom (Johnston et al., TNNT1 myopathies may cause conditional slow TnT deficiency with symptoms such as experiencing conditional fatigue intolerance and other slow muscle-related dysfunctions.Genetically modified mice with a knockdown of the expression of slow TnT exhibited decreased muscle resistance to fatigue (Feng et al., The potential cytotoxicity of non-myofilament associated slow TnT fragments (Jeong et al., The transient expression of cardiac TnT and embryonic splice forms of fast skeletal muscle TnT in embryonic and neonatal skeletal muscle may explain the postnatal onset of ANM (Jin et al., TNNT1 myopathy patients should be able to readily rescue muscle growth and functions. The maintained slow fiber cellular environment and active regeneration also indicate that translational read-through of the nonsense stop codon in the muscles of ANM and S108ter patients may effectively restore muscle function and growth.Soleus muscle of slow TnT knockout mouse maintains a slow fiber cellular environment and exhibits signs of active regeneration (Wei et al., TNNT1 myopathies is no longer considered as a isolated disease of the Amish, and the power of genetic testing is anticipated to identify more myopathic mutations of the gene, researchers are urged to add joint effort in TnT gene expression and structural-function relationship studies, including the utilization of genetically modified mouse models of the human diseases, toward the development of effective targeted treatment of these lethal muscle diseases.Since TNNT1 myopathies demonstrate an excellent example for what we can learn from pathogenic mutations of a myofilament protein as well as how knowledges learned from protein structure-function relationship research can help us to understand the pathogenesis and pathophysiology of genetic diseases. Therefore, we hope this focused review will benefit readers with the vision beyond TNNT1 myopathy studies.In conclusion, AM: Drafting and revising the text, making figures, approval submission; JJ: Deciding the topic and contents, drafting and revising the text, making figures, approval submission.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


We present a review of the literature on Primary Progressive Aphasia (PPA) together with the analysis of neuropschychological and neuroradiologic profiles of 42 PPA patients. Mesulam originally defined PPA as a progressive degenerative disorder characterized by isolated language impairment for at least two years. The most common variants of PPA are: (1) Progressive nonfluent aphasia (PNFA), (2) semantic dementia (SD), (3) logopenic progressive aphasia (LPA). PNFA is characterized by labored speech, agrammatism in production, and/or comprehension. In some cases the syndrome begins with isolated deficits in speech. SD patients typically present with loss of word and object meaning and surface dyslexia. LPA patients have word-finding difficulties, syntactically simple but accurate language output and impaired sentence comprehension. The neuropsychological data demonstrated that SD patients show the most characteristic pattern of impairment, while PNFA and LPA overlap within many cognitive domains. The neuroimaging analysis showed left perisylvian region involvement. A comprehensive cognitive, neuroimaging and pathological approach is necessary to identify the clinical and pathogenetic features of different PPA variants.


DEAR EDITOR1Studies of quality of life measures in scar patients reveal significant interference with physical comfort as well as in social and professional life. The lay population often refers to a scar as an unsightly healed wound. Conversely, surgeons tend to think of surgical scars as an expected outcome of a violation of the dermis. Before initiating treatment, the physician must take the time to understand and diagnose each element. The extent of scar must be considered along with the patient’s intent in getting treatment.2,3This is a prospective study of 50 cases of scar revision performed in our department from 2011- 2014. Mature scars more than 2mm in diameter broad were included in the study. Patients were analysed in terms of patient satisfaction with the post-operative outcome. Patients were followed up for a minimum period of 6 months. Exclusion criteria were (i) pregnant patients, (ii) paediatric patients and (iii) patients with a follow up period of <6 months. Patients were analysed regarding their satisfaction with their post-operative outcome in the form of scar related parameters and psychological parameters. Post-operative patient satisfaction was assessed using pre and post procedure Vancouver Scar Scale scores.The largest number of cases were seen in the age group 16-30 years (78%), of which 21 patients (53.8%) were satisfied with the outcome of their corrective procedure. The preponderance in this age group could be due to the fact that young adults are highly conscious regarding their appearance . Among 2The incidence of post-operative satisfaction was slightly higher among 25 unmarried enrolled patients (60%) compared to 25 studied married patients (52%). No significant difference in post-operative satisfaction could be found in patients with decreased (n=10) or unchanged scar visibility (n=10) following operative procedure. Scars which were converted to lie parallel to Relaxed Skin Tension Lines (RSTL) were seen to have the maximum satisfaction with post-operative results (83%) compared to other patients (72%). However the small number of patients in the category (5 and 8 patients) precludes any statistically significant difference to be obtained. Eighteen patients noticed gain of function of the affected part following scar revision (n=38).All patients with gain of function in the affected part showed satisfaction with their post-operative outcome. The highest incidence of post-operative satisfaction correlates with anxiety relief following correctional procedure (84% of 13 enrolled patients). The highest post-operative satisfaction was seen to correlate with alleviation of depression following correctional procedures (89% of 19 studied patients). No significant difference was seen in post-operative satisfaction rates in patients with either increased or high self-esteem following surgical procedure. However patients with low self-esteem demonstrated lower satisfaction rates compared to their counterparts (40% vs. 56% and 60%). The highest percentage of post-operative satisfaction was seen in patients with improved social acceptance following correctional procedure (73%) when compared to others (50% and 30%). Patients with change of 4 or more between pre and post operative Vancouver Scar Scale scores were satisfied with the outcome of the revisional procedures while those with scores less than 4 were either dissatisfied or neither satisfied nor dissatisfied with the outcome. Post-operative satisfaction in an individual is multifactorial. Females appear to be marginally more satisfied as compared to males with their post operative outcomes. Patients who underwent correctional procedures for cheek scars showed maximum satisfaction post operatively probably because the cheek is an exposed area and defects if an are promptly visible. Even a small improvement in a scar in such a cosmetically important area can bring great satisfaction to the patient.4,5 Following scar revisional procedures, marked reduction in anxiety and depression as compared to pre-operative status was noticed. Also, patients with low self esteem tended to be unsatisfied with their post operative outcome. Increased social acceptance, either real or apparent, could be a major factor leading to this conclusion. Patients in whom scars came to lie parallel to or within RSTL’s post operatively, as compared to pre-operative status in which they did not, showed the maximum level of satisfaction with their corrective procedures.The authors declare no conflict of interest.


Coxiella burnetii infection(s). Use of these methods and development of criteria to define and treat such infections, especially cardiovascular infections, will improve the prognosis for patients previously thought to have chronic Q fever.Modern diagnostic methods enable clinicians to look beyond a diagnosis of chronic Q fever and discern whether patients instead have persistent focalized  We read with interest the article by Kampschreur et al. (Coxiella burnetii infection(s). The obsolete term chronic Q fever should be abandoned to prevent confusion between endocarditis, vascular infections, osteoarticular infections, lymphadenitis, genital infection, and pericarditis, which occurred in 68%, 20%, 7%, 6%, 3%, and 1%, respectively, of 494 patients with persistent focalized infection(s) who we followed during 2007–2015 at the French National Referral Center for Q Fever in Marseille, France (unpub. data).Kampschreur et al.’s use of the term chronic Q fever is misleading because it may lead to inadequate treatment of persistent focalized Another example of the deleterious effect of the Dutch Q Fever Consensus Group guidelines is the absence of screening echocardiography in the standard work-up for patients with Q fever in the Netherlands  and by avoiding drug side effects in patients with isolated elevated serologic test results. Clinicians should look beyond a diagnosis of chronic Q fever to determine whether a patient might have persistent focalized infection(s). The term fever in Q fever has evolved from a pathologic picture per se to a clinical epiphenomenon; it is now time to evolve from the concept of chronic Q fever to one of persistent focalized C. burnetii infection(s) (Accurate identification of persistent focalized


Magnetic resonance (MR) imaging has become an important diagnostic tool for the detection of impaired myocardial motion, which has been considered as a common consequence of most ischemic or non-ischemic heart diseases. Both cine DENSE and TPM have been independently adopted to delineate abnormal regional myocardial motion patterns for the estimation of the progression of cardiovascular diseases or for the evaluation of individual cardiovascular responses to treatments. However, although the similarities and differences between cine DENSE and TPM are well understood from a technical point of view, the interchangeability of those two imaging techniques in cardiovascular risk stratification is still not fully understood. The aim of the present study was to test the hypothesis that clinical metrics derived from cine DENSE and TPM are correlated for characterizing regional myocardial motion.This study complied with HIPAA regulations. Thirteen healthy volunteers and 4 asymptomatic recipients of heart transplant (HTx) were recruited following the approval of the institutional review board (IRB). For each participant, two-dimensional (2D) cine DENSE and TPM were performed at basal, midventricular and apical locations at the left ventricle (LV) with the short-axis view. DENSE-derived myocardial metrics, including peak radial strain (Err), circumferential strain (Ecc), first principal strain (E1), second principal strain (E2) and twist were measured and correlated with TPM-derived indices, including peak radial velocity (Vr), circumferential velocity (VΦ) and time to peak (TTP) in systole and diastole using Pearson correlation coefficient (r).DENSE and TPM data were successfully acquired in 17 participants and resulted in 51 data points  for comparisons. On a per-slice basis, peak Err had moderate correlations with peak Vr in systole  and in diastole . Peak E1 was moderately associated with Vr-sys  and Vr-dia . Peak twist was moderately correlated with peak VΦ in diastole . See figures DENSE and TPM can provide correlated clinical metrics for quantitatively characterizing regional myocardial motion from different technical aspects.


ER causing neuropathology and memory loss in AD. This review highlights molecular signatures of UPRER and its key molecular alliance that are affected in aging leading to the development of intriguing neuropathologies in AD. We present a summary of recent studies reporting usage of small molecules as inhibitors or activators of UPRER sensors/effectors in AD that showcase avenues for therapeutic interventions.Alzheimer’s disease (AD), a neurodegenerative disorder, is most common cause of dementia witnessed among aged people. The pathophysiology of AD develops as a consequence of neurofibrillary tangle formation which consists of hyperphosphorylated microtubule associated tau protein and senile plaques of amyloid-β (Aβ) peptide in specific brain regions that result in synaptic loss and neuronal death. The feeble buffering capacity of endoplasmic reticulum (ER) proteostasis in AD is evident through alteration in unfolded protein response (UPR), where UPR markers express invariably in AD patient’s brain samples. Aging weakens UPR Alzheimer’s disease (AD), the most common form of dementia faced by more than 40 million people worldwide, significantly affect morbidity and mortality in aged people  imposed on the neuronal cell due to misfolded protein aggregates. Also, we have discussed various therapeutic interventions targeting the molecules involved in UPR pathways aiming at averting the neuropathologies of AD.The expression pattern of neurodegenerative pathologies shows distinct molecular signatures, such as misfolded Aβ aggregation and tau protein hyperphosphorylation in the brain  microenvironment like nutrient deprivation, changes in redox potential, calcium homeostasis, hypoxia and accumulation of unfolded/misfolded protein triggers the UPRER embodies a complex network comprised of three stress-responsive transmembrane proteins, Protein Kinase RNA like ER kinase (PERK), Inositol Requiring Element 1 (IRE1) and Activating Transcription Factor 6  domain  models expressing aggregation-prone mutant tau variants, XBP-1 was identified to be playing a similar protective role  ensuing after accumulation of unfolded peptide load is well documented. The pathway focuses on invigorating folding and degradation of misfolded peptides in mitochondrial matrix through the execution of retrograde transcriptional activation , but also showed reduction in beta-amyloid aggregation in worms and transgenic mouse models of AD  revealed a deranged glucose metabolism in brain regions. Aging registers diminished brain glucose utilization that surges in AD  instates mitigating effect on hexosamine pathway (HBP), due to which O-GlcNAcylation is compromised with hyperphosphorylation on tau protein  when fed with the drug metformin showed mitigated levels of GRP78 with ensuing gain in lifespan, additionally the expression of GLUT1 and its association with the beginning of UPRER exerted neuroprotective effect , has been known to inhibit BACE1 translation through dephosphorylation of eIF2α-P  resulted in establishing long-term hippocampus memory (Martínez et al., 2+ equilibrium, thereby maintains the proper signaling in brain. The disruption in neuronal physiology is quite evident in age-related AD where ER dysfunctions are prominently expressed in the form of imbalance in proteostasis. Advancements in studies based on AD models have clearly shown how we can intervene the molecular pillars of UPRER and its associated signaling cascades to manage neurodegeneration in age-related AD. The present review is an attempt to revise functional relevance of the studies conducted in the field of management of age-related AD through therapeutic interventions on the UPRER pathway and its associate’s molecules. Studies reinforce that the strategies where intervening the molecules, which are involved in transposing effects of aging on neurodegeneration, will cause reduction in probability of AD pathology. The manifestation of ER proteostasis is a direct indication of healthy nervous system. Progression in AD witnesses glucose hypo-metabolism in brain, reduction in glucose transporters in neurons and endothelial cells of blood brain barrier in direct proportion with the amount of neurofibrillary tangles. Type 2 diabetics with higher insulin resistance are at a greater risk of AD. Recent reports elucidate that managing UPRER can exert neuroprotective effect in AD (Smith and Mallucci, mt can impede plaque formation. Aliev et al., also demonstrated link between cancer and AD where mtDNA over-proliferation and deletion induces cell cycle dysregulation prompting oncogenic pathway (Aliev et al., ER, being a central organelle in nerve cells, coordinates with the cellular homeostasis by managing translation/modification of proteins and CaER in aging-induced neuropathology in AD can be ventured upon, so that pharmacological as well as genetic tools could underscore the significance of UPRER as well as UPRmt in aged brain.We still need extensive and efficient model systems where the molecular intricacies of weakened UPRSR and RM conceived the idea. SR, ATJ, AA and RM contributed to writing of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


These models display progressive locomotor defects, disrupted organisation of the tubular ER and length-dependant defects in the axonal mitochondrial network. Here we compare our findings with those associated with more common forms HSP including: Spastin, Atlastin-1 and REEP 1 which together account for over half of all cases of autosomal dominant HSP. Furthermore, we discuss recent observations in other HSP models which are directly implicated in mitochondrial function and localization. Overall, we highlight the common features of our rare models of HSP and other models of disease which could indicate shared mechanisms underpinning neurodegeneration in these disorders.Hereditary spastic paraplegias (HSPs) are a group of inherited neurodegenerative conditions characterised by retrograde degeneration of the longest motor neurons in the corticospinal tract, resulting in muscle weakness and spasticity of the lower limbs. To date more than 70 genetic loci have been associated with HSP, however the majority of cases are caused by mutations that encode proteins responsible for generating and maintaining tubular endoplasmic reticulum (ER) structure. These ER-shaping proteins are vital for the long-term survival of axons, however the mechanisms by which mutations in these proteins give rise to HSP remain poorly understood. To begin to address this we have characterized  Hereditary spastic paraplegias (HSPs) are a group of inherited neurodegenerative disorders characterised by the retrograde degeneration of the longest motor neurons (MNs) in the corticospinal tract, leading to muscle weakness and spasticity of the lower limbs.Historically HSP was grouped into two classifications: ‘pure HSP’ exclusively exhibiting lower limb spasticity and ‘complicated HSP’ in which patients presented with additional symptoms including dementia, seizures and amyotrophy in vivo studies consistently reveal that loss of ER-shaping proteins causes profound disruption to the organisation of the ER. Expression of an SPG3A mutant form of Atlastin-1 was found to alter ER-morphology in HeLa cells from a reticular to a more tubular organisationDrosophila nervous system results in visible fragmentation of the ERER-shaping proteins comprise intramembrane hairpin-loop domains by which they localise to and insert into the ER membrane. Spastin, Atlastin-1 and REEP1 are hairpin-loop domain containing ER-shaping proteins which account for ~50% of all autosomal dominant cases of HSP (AD-HSP). Spastin gene mutations cause spastic paraplegia 4 (SPG4) subtype, which represent about 40% of AD-HSPin vivo we have recently reported on models of HSP which we have generated and characterised in the fruit fly, Drosophila melanogasterDrosophila orthologs of RTN2 and ARL6IP1 (Rtnl1 and Arl6IP1 respectively). Gene knockdown models were selected as they likely reflect the loss-of-function genetic variants expressed in SPG12 and SPG61 patients. Mutations in RTN2 include a complete gene deletion and a frameshift mutation predicted to produce a highly truncated protein, suggesting that SPG12 acts via a haploinsufficiency mechanismTo begin to understand the role of ER-shaping proteins in MNs Drosophila MNs. Specifically, mitochondria appear increasingly elongated within axon bundles and mitochondrial load within neuromuscular junction synaptic boutons is significantly reduced in loss of Arl6IP1 and loss of Rtnl1 Drosophila . Importantly, these MAMs mediate mitochondrial fission in which the ER functions to mark mitochondrial constriction sites prior to the recruitment of mitochondrial fission factors such as dynamin related protein 1 (Drp1)s of HSP . In contWhile our Rtnl1 and Arl6IP1 models of HSP represent very rare forms of disease,  family which act as microtubule motor proteins involved in the transport of membranous organelles. Mutations in KIF5A cause Charcot-Marie Tooth Disease Type 2 (CMT2) and SPG10Together these data suggest that disruption to the neuronal mitochondrial network, either directly via mitochondrial mutations or indirectly via disrupted tubular ER, underpins much of the axonal degeneration associated with HSP. Altered mitochondrial distribution could disrupt the bioenergetics of different cellular compartments, given the peculiar morphology of neurons with long axons and the requirement for energy at axonal terminals this may cause failure of normal neuronal function. This work illustrates how models of very rare forms of disease may provide novel insights into the molecular mechanisms underpinning HSP more generally and suggest novel targets for therapeutic investigation for these currently untreatable neurodegenerative disorders.