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bioRxiv2015

Rising out of the ashes: additive genetic variation for susceptibility to Hymenoscyphus fraxineus in Fraxinus excelsior

Ash dieback due to Hymenoscyphus fraxineus is threatening the Fraxinus excelsior species in most of its natural range in Europe and it is becoming obvious that other species in the Fraxinus genus are susceptible to the disease. The fungal pathogen apparently originates from Asia where it may act as an endophyte of local species like F. mandshurica. Previous studies reported significant levels of genetic variability for susceptibility in F. excelsior either in field or inoculation experiments. The present study was based on a field experiment planted in 1995, fifteen years before onset of the disease. Crown and collar status were monitored on 788 trees from 23 open-pollinated progenies originating from 3 French provenances. Susceptibility was modelled using a Bayesian approach where spatio-temporal effects were explicitly taken into account, thus providing accurate narrow-sense heritability estimates (h2). While moderate narrow-sense heritability estimates for Crown Dieback (CD, h2 = 0.42 in this study) have already been reported in the literature, this study is first to show that Collar Lesions are also heritable (h2 = 0.49 for prevalence and h2 = 0.42 for severity) and that there is significant genetic correlation between the severities of both traits (rspearman=0.40). Unexpectedly, their spatio-temporal dynamics followed almost opposite patterns. While no significant Provenance effect were detected for any trait, significant Family effects were found for both CD and CL. Moreover, the analysis strategy implemented here allowed to compute Individual Breeding Values (IBV) and to show that there is more genetic variability within families than between families. In agreement with previous reports, early flushing correlates with better crown status. Consequences of these results in terms of management and breeding are discussed.

Pathology↗

bioRxiv2016

A novel mutation in the nucleoporin NUP35 causes murine degenerative colonic smooth muscle myopathy

Chronic Intestinal Pseudo-Obstruction (CIPO) is a rare, but life-threatening, disease characterized by severe intestinal dysmotility. Histopathological studies of CIPO patients have identified several different mechanisms that appear to be responsible for the dysmotility, including defects in neurons, smooth muscle or interstitial cells of Cajal. Currently there are few mouse models of the various forms of CIPO. We generated a mouse with a point mutation in the RNA Recognition Motif of the Nup35 gene, which encodes a component of the nuclear pore complex. Nup35 mutants developed a severe megacolon and exhibited reduced lifespan. Histopathological examination revealed a degenerative myopathy that developed after birth and specifically affected smooth muscle in the colon; smooth muscle in the small bowel and the bladder were not affected. Furthermore, no defects were found in enteric neurons or interstitial cells of Cajal. Nup35 mice are likely to be a valuable model for the sub-type of CIPO characterized by degenerative myopathy. Our study also raises the possibility that Nup35 polymorphisms could contribute to some cases of CIPO.\n\nSignificance StatementChronic Intestinal Pseudo-Obstruction (CIPO) is a disabling bowel disorder in which the symptoms resemble those caused by mechanical obstruction, but no physical obstruction is present. Some patients with CIPO have defects in intestinal neurons while in other CIPO patients the muscle cells in the bowel wall appear to degenerate, but the underlying cause of these defects is unknown in most CIPO patients. We generated a mouse that has a mutation in Nup35, which encodes a component of the pores found within the membrane of the cell nucleus. The mutant mice developed intestinal obstruction, which we showed was due to degeneration of the muscle cells in the colon. This mouse is likely to provide new insights into some forms of CIPO.

Pathology↗

bioRxiv2016

On Post-Acquisition Motion Compensation for Prostate Perfusion Analysis

Dynamic Contrast enhance magnetic resonance imaging has been established as an accurate method to detect and localize prostate cancer. Time series of three-dimensional datasets of the prostate are acquired and used to obtain per-voxel signal-intensity vs. time curves. These are then used to differentiate cancerous from non-cancerous tissue. However, rectal peristalsis and patient movement may result in spatial-mismatching of the serial datasets and therefore, incorrect enhancement curves. In this work, we discuss and test four methods based on image registration to compensate for these movements. These methods include a serial approach that uses the registration of consecutive images and the accumulation of the obtained transformations, an all-to one registration approach, an approach that first aligns a sub-set of images that are already closely aligned, and then uses synthetic references to register the remaining images, and an approach that uses independent component analysis (ICA) to create synthetic references and register the images to these. We conclude that the method based on ICA does not provide a viable approach for motion compensation in prostate perfusion imaging, and that the serial approach fails when motion artifacts are present in the series. The other two approaches provide qualitatively pleasing results.

Pathology↗

bioRxiv2016

A rhesus macaque model of Asia lineage Zika virus infection

Infection with Asian lineage Zika virus has been associated with Guillain-Barre syndrome and fetal abnormalities 1-4, but the mechanisms and risk factors for these outcomes remain unknown. Here we show that rhesus macaques are susceptible to infection by an Asian-lineage virus closely related to strains currently circulating in the Americas. Following subcutaneous inoculation, Zika virus RNA was detected in plasma one day post-infection (dpi) in all animals (N = 8, including 2 animals infected during the first trimester of pregnancy). Plasma viral loads peaked above 1 x 105 viral RNA copies/mL in seven of eight animals. Viral RNA was also present in saliva, urine, and cerebrospinal fluid (CSF), consistent with case reports from infected humans. Viral RNA was cleared from plasma and urine by 21 dpi in non-pregnant animals. In contrast, both pregnant animals remained viremic longer, up to 57 days. In all animals, infection was associated with transient increases in proliferating natural killer cells, CD8+ T cells, CD4+ T cells, and plasmablasts. Neutralizing antibodies were detected in all animals by 21 dpi. Rechallenge of three non-pregnant animals with the Asian-lineage Zika virus 10 weeks after the initial challenge resulted in no detectable virus replication, suggesting that primary Zika virus infection elicits protective immunity against homologous virus strains. These data establish that Asian-lineage Zika virus infection of rhesus macaques provides a relevant animal model for studying pathogenesis in pregnant and non-pregnant individuals and evaluating potential interventions against human infection, including during pregnancy.

Pathology↗

bioRxiv2016

Statistical Analysis of Zika Virus Correlation to Microcephaly

A Statistical Analysis was performed to probe the correlation between the Zika Virus (ZIKV) and its possibility to induce Microcephaly in infants. It was found that without considering a false positive on tests for ZIKV on mothers there seems to be a statistical significance on ZIKV to cause Microcephaly in infants with a probability of [Formula]. It was also shown that without knowing the confidence of the false positive tests of ZIKV it is not possible to statistically assert that this significance is true. It is proposed that to be able to discard the hypothesis of ZIKV not to cause the disease it is necessary to have a 30% of confidence in the ZIKV test.

Pathology↗

bioRxiv2016

PODOCYTURIA mRNAs: EARLIER AND SUPERIOR PREDICTORS OF CARDIOVASCULAR OUTCOMES

Increased filtration of albumin, a result of injury to glomerular endothelial and epithelial cells (podocytes), leads to increased albumin excretion rate (AER) which defines \"moderate albuminuria\", a predictor of cardiovascular events (CVD). Since filtered albumin is modified by renal proximal tubule albumin retrieval, we hypothesized that urinary podocyte shedding (podocyturia), as a biomarker of ongoing glomerular microvascular injury, may be a more relevant and earlier predictor of CVD than moderate albuminuria.\n\nType II diabetic subjects (mean age: 46/60 men/women) with normal AER [<2.26 mg/mmole (20 g/mg) creatinine] and free of overt cardiovascular disease (CVD) were studied. AER and podocyte-specific proteins (podocin and nephrin) mRNAs were measured at baseline (Visit 1), 3-4 years later (Visit 2) and at 7 years (Visit 3). Development of CVD (acute coronary syndrome, stroke, and/or peripheral vascular disease) was collected as outcome. Seven-year Kaplan-Meier time-to-event (log rank) data were compared among baseline biomarker tercile groups (low, intermediate, high).\n\nAll three biomarkers increased significantly between visits. Visit 1AER terciles exhibited similar time to CVD (p=0.127), in contrast with step-wise and substantial increases in CVD events predicted by Visit 1 podocin and nephrin terciles. Considered as continuous factors, the covariate-adjusted hazard ratios (95% confidence intervals) [HR] were highest for podocin mRNA [HR=15.9 (6.1-41.8); p<0.001], intermediate for nephrin mRNA [HR=7.61 (3.75-15.5); p<0*001] and lowest for AER [HR=1.17 (1.01-1.36); p=0*041].\n\nCompared to moderate albuminuria, podocyturia predicts more accurately and at a significantly earlier time point the presence of silent systemic vascular injury ultimately manifesting as overt cardiovascular events.

Pathology↗

bioRxiv2016

Substoichiometric molecular control and amplification of the initiation and nature of amyloid fibril formation: lessons from and for blood clotting. BioRXiv preprint.

The chief and largely terminal element of normal blood clotting is considered to involve the polymerisation of the mainly -helical fibrinogen to fibrin, with a binding mechanism involving knobs and holes but with otherwise littl change in protein secondary structure. We recognise, however, that extremely unusual mutations, or mechanical stressing, can cause fibrinogen to adopt a conformation containing extensive {beta}-sheets. Similarly, prions can change morphology from a largely alpha-helical to a largely {beta}-sheet conformation, and the latter catalyses both the transition and the self-organising polymerisation of the {beta}-sheet structures. Many other proteins can do this, where it is known as amyloidogenesis. When fibrin is formed in samples from patients harbouring different diseases it can have widely varying diameters and morphologies. We here develop the idea, and summarise the evidence, that in many cases the anomalous fibrin fibre formation seen in such diseases actually amounts to amyloidogenesis. In particular, fibrin can interact withthe amyloid-{beta} (A{beta}) protein that is misfolded in Alzheimer's disease. Seeing these unusual fibrin morphologies as true amyloids explains a great deal about fibrin(ogen) biology that was previously opaque, and provides novel strategies for treating such coagulopathies. The literature on blood clotting can usefully both inform and be informed by that on prions and on the many other widely recognised ({beta})-amyloid proteins.\n\n\"Novel but physiologically important factors that affect fibrinolysis have seldom been discovered and characterized in recent years\" [1]

Pathology↗

bioRxiv2016

Sacral agenesis: A whole exome sequencing and copy number study

BackgroundCaudal regression syndrome (CRS) or sacral agenesis is a rare congenital disorder characterized by a constellation of congenital caudal anomalies affecting the caudal spine and spinal cord, the hindgut, the urogenital system, and the lower limbs. CRS is a complex condition, attributed to an abnormal development of the caudal mesoderm, likely caused by the effect of interacting genetic and environmental factors. A well-known risk factor is maternal type 1 diabetes.\n\nResultsIn this pilot study, exome sequencing and copy number variation (CNV) analyses of 4 CRS trios implicate a number of candidate genes, including MORN1, ZNF330, CLTCL1 and PDZD2. De novo mutations were found in SPTBN5, MORN1 and ZNF330 and inherited predicted damaging mutations in PDZD2 (homozygous) and CLTCL1 (compound heterozygous) as well as in CRS-related genes PTEN (heterozygous) and VANGL1 (heterozygous). In addition, a compound heterozygous mutation in GLTSCR2, a direct regulator of PTEN was identified.\n\nTwo CNV deletions, one de novo (chr3q13.13) and one homozygous (chr8p23.2), were detected in one of our CRS patients. These deletions overlapped with CNVs previously reported in patients with similar phenotype.\n\nConclusionDespite the genetic diversity and the complexity of the phenotype, this pilot study identified genetic features common across CRS patients.

Pathology↗

bioRxiv2016

GPR4 Deficiency Alleviates Intestinal Inflammation in a Mouse Model of Inflammatory Bowel Disease

GPR4 is a proton-sensing G protein-coupled receptor that can be activated by extracellular acidosis. It has recently been demonstrated that activation of GPR4 by acidosis increases the expression of numerous inflammatory and stress response genes in vascular endothelial cells (ECs) and also augments EC-leukocyte adhesion. Inhibition of GPR4 by siRNA or small molecule inhibitors reduces endothelial cell inflammation. As acidotic tissue microenvironments exist in many types of inflammatory disorders, including inflammatory bowel disease (IBD), we examined the role of GPR4 in IBD using a dextran sulfate sodium (DSS)-induced colitis mouse model. We observed that GPR4 mRNA expression was increased in mouse and human IBD tissues when compared to control intestinal tissues. To determine the function of GPR4 in IBD, wild-type and GPR4-deficient mice were treated with 3% DSS for 7 days to induce acute colitis. Our results showed that the severity of colitis was decreased in GPR4-deficient DSS-treated mice in comparison to wild-type DSS-treated mice. Clinical parameters, macroscopic disease indicators, and histopathological features were less severe in the DSS-treated GPR4-deficient mice than the DSS-treated wild-type mice. Inflammatory gene expression, leukocyte infiltration, and isolated lymphoid follicle (ILF) formation were reduced in intestinal tissues of DSS-treated GPR4-null mice. Collectively, our results suggest GPR4 provides a pro-inflammatory role in IBD as the absence of GPR4 ameliorates intestinal inflammation in the acute DSS-induced IBD mouse model.

Pathology↗

bioRxiv2016

H&E-stained Whole Slide Deep Learning Predicts SPOP Mutation State in Prostate Cancer

A quantitative model to genetically interpret the histology in whole microscopy slide images is desirable to guide downstream immuno-histochemistry, genomics, and precision medicine. We constructed a statistical model that predicts whether or not SPOP is mutated in prostate cancer, given only the digital whole slide after standard hematoxylin and eosin [H&E] staining. Using a TCGA cohort of 177 prostate cancer patients where 20 had mutant SPOP, we trained multiple ensembles of residual networks, accurately distinguishing SPOP mutant from SPOP non-mutant patients (test AUROC=0.74, p=0.0007 Fishers Exact Test). We further validated our full metaensemble classifier on an independent test cohort from MSK-IMPACT of 152 patients where 19 had mutant SPOP. Mutants and non-mutants were accurately distinguished despite TCGA slides being frozen sections and MSK-IMPACT slides being formalin-fixed paraffin-embedded sections (AUROC=0.86, p=0.0038). Moreover, we scanned an additional 36 MSK-IMPACT patients having mutant SPOP, trained on this expanded MSK-IMPACT cohort (test AUROC=0.75, p=0.0002), tested on the TCGA cohort (AUROC=0.64, p=0.0306), and again accurately distinguished mutants from non-mutants using the same pipeline. Importantly, our method demonstrates tractable deep learning in this \"small data\" setting of 20-55 positive examples and quantifies each predictions uncertainty with confidence intervals. To our knowledge, this is the first statistical model to predict a genetic mutation in cancer directly from the patients digitized H&E-stained whole microscopy slide. Moreover, this is the first time quantitative features learned from patient genetics and histology have been used for content-based image retrieval, finding similar patients for a given patient where the histology appears to share the same genetic driver of disease i.e. SPOP mutation (p=0.0241 Kosts Method), and finding similar patients for a given patient that does not have have that driver mutation (p=0.0170 Kosts Method).\n\nSignificance StatementThis is the first pipeline predicting gene mutation probability in cancer from digitized H&E-stained microscopy slides. To predict whether or not the speckle-type POZ protein [SPOP] gene is mutated in prostate cancer, the pipeline (i) identifies diagnostically salient slide regions, (ii) identifies the salient region having the dominant tumor, and (iii) trains ensembles of binary classifiers that together predict a confidence interval of mutation probability. Through deep learning on small datasets, this enables automated histologic diagnoses based on probabilities of underlying molecular aberrations and finds histologically similar patients by learned genetic-histologic relationships.\n\nConception, Writing: AJS, TJF. Algorithms, Learning, CBIR: AJS. Analysis: AJS, MAR, TJF. Supervision: MAR, TJF.

Pathology↗

bioRxiv2017

Highly efficient maternal-fetal Zika virus transmission in pregnant rhesus macaques

Infection with Zika virus (ZIKV) is associated with human congenital fetal anomalies. To model fetal outcomes in nonhuman primates, we administered Asian-lineage ZIKV subcutaneously to four pregnant rhesus macaques. While non-pregnant animals clear viremia within 10-12 days, maternal viremia was prolonged in 3 of 4 pregnancies. Fetal head growth velocity in the last month of gestation determined by ultrasound assessment of head circumference was decreased in comparison with biparietal diameter and femur length within each fetus, both within normal range. ZIKV RNA was detected in tissues from all four fetuses at term cesarean section. In all pregnancies, neutrophilic infiltration was present at the maternal-fetal interface (decidua, placenta, fetal membranes), in various fetal tissues, and in fetal retina, choroid, and optic nerve (first trimester infection only). Consistent vertical transmission in this primate model may provide a platform to assess risk factors and test therapeutic interventions for interruption of fetal infection.

pathology↗

bioRxiv2017

Accumulation of Minor Alleles of Common SNPs in Schizophrenia

Schizophrenia is a common neuropsychiatric disorder with a lifetime risk of 1%. A number of large scale genome wide association studies have identified numerous individual risk single nucleotide polymorphisms (SNPs) whose precise roles in schizophrenia remain unknown. Accumulation of many of these risk alleles has been found to be a more important risk factor. Consistently, recent studies showed a role for enrichment of minor alleles (MAs) in complex diseases. Here we studied the role of MAs in general in schizophrenia using public datasets. Relative to matched controls, schizophrenia cases showed higher minor allele content (MAC), especially for the sporadic cases. By linkage analysis, we identified 82 419 SNPs that could be used to predict 2.2% schizophrenia cases with 100% certainty. Pathway enrichment analysis of these SNPs identified 17 pathways, 15 of which are known to be linked with Schizophrenia with the remaining 2 associated with other mental disorders. These results suggest a role for a collective effect of MAs in schizophrenia and provide a method to genetically screen for schizophrenia.\n\nAbbreviations

pathology↗

bioRxiv2017

A review of diagnostic approaches to medullary thyroid carcinoma

Medullary thyroid carcinoma (MTC), occurring sporadically or as an autosomal dominant trait, accounts for 5-10% of all thyroid gland neoplasms. While the sporadic variant originates from somatic rearranged-during-transfection (RET) mutations, the inherited variant is preceded by germ-line mutations of the RET proto-oncogene. Analysis of the transformations of this certain gene is the cornerstone of diagnostic and prognostic approaches in MTC. Additionally, a panel of histopathological evaluations, biochemical markers, and imaging procedures play a pivotal role in the management of MTC. The survival rate of MTC is relatively low compared to differentiated thyroid neoplasia and is highly influenced by the stage of tumors. Improvement in MTC surveillance significantly depends on early diagnosis as well as implementation of proper screening modalities in hereditary subtypes. The present review addresses medullary thyroid carcinoma, and in particular, the current diagnostic approaches to this challenging malignancy.

pathology↗

bioRxiv2017

Comparative Transcriptome Profiling Conferring Of Resistance To Fusarium Oxysporum Infection Between Resistant And Susceptible Tomato

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

pathology↗

bioRxiv2017

Obesity/Type II Diabetes Alters Macrophage Polarization Resulting in a Fibrotic Tendon Healing Response

Type II Diabetes (T2DM) dramatically impairs the tendon healing response, resulting in decreased collagen organization and mechanics relative to non-diabetic tendons. Despite this burden, there remains a paucity of information regarding the mechanisms that govern impaired healing of diabetic tendons.\n\nMice were placed on either a high fat diet (T2DM) or low fat diet (lean) and underwent flexor tendon transection and repair surgery. Healing was assessed via mechanical testing, histology and changes in gene expression associated with collagen synthesis, matrix remodeling, and macrophage polarization. Obese/diabetic tendons healed with increased scar formation and impaired mechanical properties. Consistent with this, prolonged and excess expression of extracellular matrix (ECM) components were observed in obese/T2DM tendons. Macrophages are involved in both inflammatory and matrix deposition processes during healing. Obese/T2DM tendons healed with increased expression of markers of pro-inflammatory M1 macrophages, and elevated and prolonged expression of M2 macrophages markers that are involved in ECM deposition. Here we demonstrate that tendons from obese/diabetic mice heal with increased scar formation and increased M2 polarization, identifying excess M2 macrophage activity and matrix synthesis as a potential mechanism of the fibrotic healing phenotype observed in T2DM tendons, and as such a potential target to improve tendon healing in T2DM.

pathology↗

bioRxiv2017

Glioma Grade Map: A Machine-Learning Based Imaging Biomarker For Tumor Characterization

PurposeTo use T1-, T2-weighted and diffusion tensor MR images to portray glioma grade by employing a voxel-wise supervised machine learning approach, and to assess the feasibility of this tool in preoperative tumor characterization.\n\nMaterials and MethodsConventional MRI, DTI datasets and histopathological evaluations of 40 patients with WHO grade II-IV gliomas were retrospectively analyzed. Databases were construed incorporating preoperative images, tumor delineation and grades. This data was used to train a multilayer perceptron based artificial neural network that performed voxel-by-voxel correlation of tumor grade and the feature vector. Results were mapped to grayscale images, whereas grade map was defined as a composite image that depicts grade assignments for intra-tumoral regions. The voxel-wise probability for high grade tumor classification was calculated for the entire tumor volumes, defined as the grade index.\n\nResultsThe color hue on glioma grade maps allowed the discrimination of low and high grade cases. This method revealed connection between the heterogeneous appearance of tumors and the histopathological findings. Classification by the grade index had 92.31% specificity, 85.71% sensitivity.\n\nConclusionGlioma grade maps are advantageous in the visualization of the heterogeneous nature of intra-tumoral diffusion and relaxivity and can further enhance the characterization of tumors by providing a preoperative modality that expands information available for clinicians.\n\nABBREVIATIONS

pathology↗

bioRxiv2017

DeepDeath: Learning To Predict The Underlying Cause Of Death With Big Data

Multiple cause-of-death data provides a valuable source of information that can be used to enhance health standards by predicting health related trajectories in societies with large populations. These data are often available in large quantities across U.S. states and require Big Data techniques to uncover complex hidden patterns. We design two different classes of models suitable for large-scale analysis of mortality data, a Hadoop-based ensemble of random forests trained over N-grams, and the DeepDeath, a deep classifier based on the recurrent neural network (RNN). We apply both classes to the mortality data provided by the National Center for Health Statistics and show that while both perform significantly better than the random classifier, the deep model that utilizes long short-term memory networks (LSTMs), surpasses the N-gram based models and is capable of learning the temporal aspect of the data without a need for building ad-hoc, expert-driven features.

pathology↗

bioRxiv2017

Chondroitin Sulfate Flourishes Gut Sulfatase-Secreting Bacteria To Damage Mucus Layers, Leak Bacterial Debris, And Trigger Inflammatory Lesions In Mice

BackgroundAn interaction of the food types with the gut microbiota changes is deeply implicated in human health and disease. To verify whether animal-based diets would lead to gut dysbiosis, systemic inflammation and inflammatory pathogenesis, we fed mice with chondroitin sulfate (CS), a sulfate-containing O-glycan naturally occurring in livestock and poultry products, and monitored the dynamic changes of microbial flores, inflammatory signatures, and pathogenic hallmarks.\n\nResultsA metagenomic gut microbiota analysis revealed the overgrowth of sulfatase-secreting bacteria and sulfate-reducing bacteria in the gastrointestinal tracts of mice upon daily CS feeding. Sulfatase-secreting bacteria compromise gut integrity through prompting mucin degradation and mucus lesions, which were evident from the upregulation of secretary leukocyte protease inhibitor (SLPI) and mucin 1/4 (MUC-1/4). A synchronous elevation of lipopolysaccharide (LPS) and tumor necrosis factor (TNF-) levels in the serum as well as cerebral, hepatic, cardiac and muscular tissues suggests bacterial endotoxinemia, chronic low-grade inflammation and mitochondrial dysfunction, eventually leading to the onset of global inflammatory pathogenesis towards arthritis, dementia, tumor, and fatty liver.\n\nConclusionsCS triggers the early-phase and multi-systemic pathogenesis like arthritis, dementia, tumor, and fatty liver by enhancing gut opportunistic infection and evoking low-grade inflammation in mice. A plausible reason for the inconsistency of CS in treatment of osteoarthritis (OA) was also discussed.

pathology↗