scholarly journals Proteomics Uncovers Immunosuppression in COVID-19 Patients with Long Disease Course

2020 ◽  
Author(s):  
Shaohua Tang ◽  
Rui Sun ◽  
Qi Xiao ◽  
Tingting Mao ◽  
Weigang Ge ◽  
...  
Keyword(s):  
Clinical Symptoms ◽  
Killer Cell ◽  
Disease Onset ◽  
Host Responses ◽  
Blood Protein ◽  
Disease Course ◽  
High Quality ◽  
Immunological Responses ◽  
Protein Levels ◽  
Independent Cohort

AbstractLittle is known regarding why a subset of COVID-19 patients exhibited prolonged positivity of SARS-CoV-2 infection. Here, we studied the sera proteomic dynamics in 37 COVID-19 patients over nine weeks, quantifying 2700 proteins with high quality. Remarkably, we found that during the first three weeks since disease onset, while clinical symptoms and outcome were indistinguishable, patients with prolonged disease course displayed characteristic immunological responses including enhanced Natural Killer cell-mediated innate immunity and regulatory T cell-mediated immunosuppression. We further showed that it is possible to predict the length of disease course using machine learning based on blood protein levels during the first three weeks. Validation in an independent cohort achieved an accuracy of 82%. In summary, this study presents a rich serum proteomic resource to understand host responses in COVID-19 patients and identifies characteristic Treg-mediated immunosuppression in patients with prolonged disease course, nominating new therapeutic target and diagnosis strategy.

FKBP51 Modulates Hippocampal Size and Function in Post-translational Regulation of Parkin

2021 ◽  
Author(s):  
Bin Qiu ◽  
Zhaohui Zhong ◽  
Shawn Righter ◽  
Yuxue Xu ◽  
Jun Wang ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Translational Regulation ◽  
Disease Onset ◽  
Fold Increase ◽  
Knock Out ◽  
Fk506 Binding Protein ◽  
Protein Levels ◽  
And Function

Abstract FK506-binding protein 51 (encoded by Fkpb51) has been associated with stress-related mental illness. To identify its function, we studied the morphological consequences of Fkbp51 deletion. Artificial Intelligence-assist morphological analysis identified that Fkbp51 knock-out (KO) mice possess more elongated CA and DG but shorter in height in coronal section when compared to WT. Primary cultured Fkbp51 KO hippocampal neurons were shown to exhibit larger dendritic outgrowth than wild-type (WT) controls, pharmacological manipulation experiments suggest that this may occur through regulation of microtubule-associated protein. Both in vitro primary culture and in vivo labeling support that FKBP51 regulates microtubule-associated protein expression. Furthermore, in the absence of differences in mRNA expression, Fkbp51 KO hippocampus exhibited decreases in βIII-tubulin, MAP2, and Tau protein levels, but a greater than 2.5-fold increase in Parkin protein. Overexpression and knock-down FKBP51 demonstrated that FKBP51 negatively regulates Parkin in a dose-dependent and ubiquitin-mediated manner. These results indicate a potential novel post-translational regulatory of Parkin by FKBP51 and significance of their interaction on disease onset.

scholarly journals Insights into Clinical, Genetic, and Pathological Aspects of Hereditary Spastic Paraplegias: A Comprehensive Overview

2021 ◽  
Vol 8 ◽  
Author(s):  
Liena E. O. Elsayed ◽  
Isra Zuhair Eltazi ◽  
Ammar E. Ahmed ◽  
Giovanni Stevanin
Keyword(s):  
Clinical Symptoms ◽  
Disease Onset ◽  
Lower Limbs ◽  
Special Focus ◽  
Clinical Genetic ◽  
Comprehensive Overview ◽  
Functional Studies ◽  
Hereditary Spastic Paraplegias ◽  
Wide Range ◽  
Complex Forms

Hereditary spastic paraplegias (HSP) are a heterogeneous group of motor neurodegenerative disorders that have the core clinical presentation of pyramidal syndrome which starts typically in the lower limbs. They can present as pure or complex forms with all classical modes of monogenic inheritance reported. To date, there are more than 100 loci/88 spastic paraplegia genes (SPG) involved in the pathogenesis of HSP. New patterns of inheritance are being increasingly identified in this era of huge advances in genetic and functional studies. A wide range of clinical symptoms and signs are now reported to complicate HSP with increasing overall complexity of the clinical presentations considered as HSP. This is especially true with the emergence of multiple HSP phenotypes that are situated in the borderline zone with other neurogenetic disorders. The genetic diagnostic approaches and the utilized techniques leave a diagnostic gap of 25% in the best studies. In this review, we summarize the known types of HSP with special focus on those in which spasticity is the principal clinical phenotype (“SPGn” designation). We discuss their modes of inheritance, clinical phenotypes, underlying genetics, and molecular pathways, providing some observations about therapeutic opportunities gained from animal models and functional studies. This review may pave the way for more analytic approaches that take into consideration the overall picture of HSP. It will shed light on subtle associations that can explain the occurrence of the disease and allow a better understanding of its observed variations. This should help in the identification of future biomarkers, predictors of disease onset and progression, and treatments for both better functional outcomes and quality of life.

scholarly journals SARS-CoV-2 infection in the Syrian hamster model causes inflammation as well as type I interferon dysregulation in both respiratory and non-respiratory tissues including the heart and kidney

2021 ◽  
Author(s):  
Magen E. Francis ◽  
Una Goncin ◽  
Andrea Kroeker ◽  
Cynthia Swan ◽  
Robyn Ralph ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Clinical Symptoms ◽  
Type I Interferons ◽  
Host Responses ◽  
Type I ◽  
Hamster Model ◽  
Organ Systems ◽  
Major Organ ◽  
Kidney Liver ◽  
Multiorgan Disease

AbstractCOVID-19 (coronavirus disease 2019) caused SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection is a disease affecting several organ systems. A model that captures all clinical symptoms of COVID-19 as well as long-haulers disease is needed. We investigated the host responses associated with infection in several major organ systems including the respiratory tract, the heart, and the kidneys after SARS-CoV-2 infection in Syrian hamsters. We found significant increases in inflammatory cytokines (IL-6, IL-1beta, and TNF) and type II interferons whereas type I interferons were inhibited. Examination of extrapulmonary tissue indicated inflammation in the kidney, liver, and heart which also lacked type I interferon upregulation. Histologically, the heart had evidence of mycarditis and microthrombi while the kidney had tubular inflammation. These results give insight into the multiorgan disease experienced by people with COVID-19 and possibly the prolonged disease in people with post-acute sequelae of SARS-CoV-2 (PASC).

scholarly journals PSEUDOMYXOMA ON APPENDICULAR MUCOCELE

2020 ◽  
Vol 8 (12) ◽  
pp. 842-846
Author(s):  
Yehouenou Tessi T. Romeo ◽  
◽  
Asaad El Bakkari ◽  
Adeyemi A. Boris ◽  
Khadija Ben El Hosni ◽  
...  
Keyword(s):  
Clinical Symptoms ◽  
Iliac Fossa ◽  
Disease Onset ◽  
Vermiform Appendix ◽  
Complete Resection ◽  
Mucocele Of The Appendix ◽  
Thin Walled ◽  
Ct Density ◽  
The Right ◽  
Underlying Pathology

Mucocele of the appendix is a descriptive term for mucinous distension of the appendiceal lumen (vermiform appendix) regardless of the underlying pathology. It refers to the progressive retrograde dilatation of the vermiform appendix with concomitant intraluminal accumulation of the mucoid substance. It is an uncommon pathology that occurs in both sexes. it especially poses the problem of differential diagnosis in particular in women because of the location of clinical symptoms in the right iliac fossa. The incidence is estimated between 0.2 % and 0.4 % of the appendectomied specimens.The estimated incidence is approximately 1/1 000 000/year. The disease onset is usually after the age of 40 years and more frequently affects females.The means of medical imaging are mainly ultrasound and scanner. On CT typical mucocele appears as a cecal-based, rounded and well-defined mass, thin-walled, with fine parietal calcifications CT density is variable, from fluid to tissue. A stercolith is sometimes visible at the base of the appendix. The wall of the mucocele may be thickened, irregular, taking the contrast there may be peri-appendicular inflammation, which may be inflammatory or tumor, without specificity.The treatment of unbroken appendicular mucocele is surgical, preferably by laparotomy than laparoscopy. The appendectomy is performed, without breaking the appendix, with complete resection of the meso-appendix, and sampling for cytology of the peritoneal fluid.

scholarly journals Mechanistic within-host models of the asexual Plasmodium falciparum infection: a review and analytical assessment

2021 ◽  
Author(s):  
Flavia Camponovo ◽  
Tamsin E Lee ◽  
Jonathan Russell ◽  
Lydia Burgert ◽  
Jaline Gerardin ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Immune Escape ◽  
Clinical Symptoms ◽  
Disease Onset ◽  
Clinical Malaria ◽  
Individual Variability ◽  
Switching Dynamics ◽  
Underlying Mechanisms ◽  
Parasite Dynamics

Background: Malaria blood-stage infection length and intensity are important drivers of disease and transmission; however, the underlying mechanisms of parasite growth and the host's immune response during infection remain largely unknown. Over the last 30 years, several mechanistic mathematical models of malaria parasite within-host dynamics have been published and used in malaria transmission models. Methods: We identified mechanistic within-host models of parasite dynamics through a review of published literature. For a subset of these, we reproduced model code and compared descriptive statistics between the models using fitted data. Through simulation and model analysis, we compare and discuss key features of the models, including assumptions on growth, immune response components, variant switching mechanisms, and inter-individual variability. Results: The assessed within-host malaria models generally replicate infection dynamics in malaria-na&iumlve individuals. However, there are substantial differences between the model dynamics after disease onset, and models do not always reproduce late infection parasitemia data used for calibration of the within host infections. Models have attempted to capture the considerable variability in parasite dynamics between individuals by including stochastic parasite multiplication rates; variant switching dynamics leading to immune escape; variable effects of the host immune responses; or via probabilistic events. For models that capture realistic length of infections, model representations of innate immunity explain early peaks in infection density that cause clinical symptoms, and model representations of antibody immune responses control the length of infection. Models differed in their assumptions concerning variant switching dynamics, reflecting uncertainty in the underlying mechanisms of variant switching revealed by recent clinical data during early infection. Overall, given the scarce availability of the biological evidence there is limited support for complex models. Conclusions: Our study suggests that much of the inter-individual variability observed in clinical malaria infections has traditionally been attributed in models to random variability, rather than mechanistic disease dynamics. Thus, we propose that newly developed models should assume simple immune dynamics that minimally capture mechanistic understandings and avoid over-parameterisation and large stochasticity which inaccurately represent unknown disease mechanisms.

scholarly journals Total Versus Free Placental Growth Factor Levels in the Pathogenesis of Preeclampsia

Hypertension ◽  
2020 ◽  
Vol 76 (3) ◽  
pp. 875-883
Author(s):  
Edouard Lecarpentier ◽  
Zsuzsanna K. Zsengellér ◽  
Saira Salahuddin ◽  
Ambart E. Covarrubias ◽  
Agnes Lo ◽  
...  
Keyword(s):  
Growth Factor ◽  
Ex Vivo ◽  
Quantitative Polymerase Chain Reaction ◽  
Placental Growth Factor ◽  
Protein Levels ◽  
Key Characteristics ◽  
Human Blood Samples ◽  
Polymerase Chain ◽  
Low Levels ◽  
Independent Cohort

Elevated circulating sFLT-1 (soluble fms-like tyrosine kinase) and low levels of its ligand, PlGF (placental growth factor), are key characteristics of preeclampsia. However, it is unclear if the low levels of plasma PlGF noted during preeclampsia are due to decreased placental production of PlGF or due to binding of PlGF by increased circulating sFLT-1. Here, we describe a biochemical procedure to dissociate PlGF-sFLT-1 complex ex vivo and when used in conjunction with an immunoassay platform, demonstrate a method to measure total and free PlGF in human blood samples. Using this method, we noted that plasma free PlGF levels were significantly lower in preeclampsia (N=22) than in nonhypertensive controls (N=24; mean, 314 versus 686 pg/mL, P <0.05), but total PlGF levels were not different (mean, 822 versus 800 pg/mL, P =0.49). In contrast, total sFLT-1 levels were significantly higher in preeclampsia than in nonhypertensive controls (mean, 16 957 versus 3029 pg/mL, P <0.01) and sFLT-1 levels correlated with bound PlGF levels (bound PlGF=total PlGF−free PlGF) in these samples ( r 2 =0.68). We confirmed these findings in an independent cohort of subjects (N=49). Furthermore, we did not detect any difference in PlGF mRNA by quantitative polymerase chain reaction or in PlGF protein expression by immunohistochemistry in preeclamptic placentas when compared with nonhypertensive controls. In contrast, sFLT-1 mRNA and protein levels were upregulated in placentas from women with preeclampsia. Taken together with prior studies, our results provide evidence that decrease in circulating PlGF noted during preeclampsia is largely mediated by excess circulating sFLT-1.

Characteristics of multiple sclerosis in aboriginals living in British Columbia, Canada

2012 ◽  
Vol 18 (9) ◽  
pp. 1239-1243 ◽  
Author(s):  
Jameelah Saeedi ◽  
Peter Rieckmann ◽  
Irene Yee ◽  
Helen Tremlett ◽  
Keyword(s):  
Multiple Sclerosis ◽  
British Columbia ◽  
Clinical Characteristics ◽  
Age At Onset ◽  
Disease Onset ◽  
Patient Characteristics ◽  
Onset Date ◽  
Disease Course ◽  
Chi Squared ◽  
Student’S T

Objectives: The objectives of this study were to identify and describe the demographic and clinical characteristics of multiple sclerosis (MS) in aboriginals in British Columbia (BC), Canada and compare these findings with non-aboriginal MS patients. Methods: This retrospective chart and database review accessed patient information from the linked BC-wide MS clinical and genetics databases. Data gathered included: demographics (age, sex and ethnicity); clinical characteristics (MS onset date, disease course and disability scores (Expanded Disability Status Scale [EDSS]). Aboriginals were identified via the database linkage augmented by physician and nurse recall. Two non-aboriginal comparator groups with definite MS were selected. Group one included all definite MS patients in the BC MS database, and group two comprised MS patients matched by sex, age at onset and initial disease course. Patient characteristics were compared using the Student’s t-test, chi-squared test, and Kaplan–Meier survival analysis was used to examine disease progression (time to sustained and confirmed EDSS 6) Results: We identified 26 aboriginals with MS, of which 19/26 (73%) were female, 23/26 (89%) had relapsing-onset MS and a mean onset age of 31.1 years. There were no significant differences between the MS aboriginals and the non-matched ( n = 5708) comparator group with respect to age, sex or disease course ( p > 0.1), However, aboriginals progressed more rapidly to EDSS 6 from disease onset ( p < 0.001) when compared with the matched and unmatched comparator groups. Conclusion: We identified a small, but important cohort of aboriginals with MS; being the largest identified to date. There was evidence of more rapid MS progression in aboriginals compared with non-aboriginals.

scholarly journals Bridging the Gap between Alzheimer’s Disease and Alzheimer’s-like Diseases in Animals

2019 ◽  
Vol 20 (7) ◽  
pp. 1664 ◽  
Author(s):  
Anita Gołaszewska ◽  
Wojciech Bik ◽  
Tomasz Motyl ◽  
Arkadiusz Orzechowski
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Clinical Symptoms ◽  
Hot Spot ◽  
Senile Plaques ◽  
Disease Onset ◽  
Suitable Model ◽  
In Vivo Models ◽  
Average Life Span

The average life span steadily grows in humans and in animals kept as pets or left in sanctuaries making the issue of elderly-associated cognitive impairment a hot-spot for scientists. Alzheimer’s disease (AD) is the most prevalent cause of progressive mental deterioration in aging humans, and there is a growing body of evidence that similar disorders (Alzheimer’s-like diseases, ALD) are observed in animals, more than ever found in senescent individuals. This review reveals up to date knowledge in pathogenesis, hallmarks, diagnostic approaches and modalities in AD faced up with ALD related to different animal species. If found at necropsy, there are striking similarities between senile plaques (SP) and neurofibrillary tangles (NFT) in human and animal brains. Also, the set of clinical symptoms in ALD resembles that observed in AD. At molecular and microscopic levels, the human and animal brain histopathology in AD and ALD shows a great resemblance. AD is fatal, and the etiology is still unknown, although the myriad of efforts and techniques were employed in order to decipher the molecular mechanisms of disease onset and its progression. Nowadays, according to an increasing number of cases reported in animals, apparently, biochemistry of AD and ALD has a lot in common. Described observations point to the importance of extensive in vivo models and extensive pre-clinical studies on aging animals as a suitable model for AD disease.

scholarly journals Validation of prediction models of severe disease course and non-achievement of remission in juvenile idiopathic arthritis: part 1—results of the Canadian model in the Nordic cohort

2019 ◽  
Vol 21 (1) ◽  
Author(s):  
Veronika Rypdal ◽  
◽  
Jaime Guzman ◽  
Andrew Henrey ◽  
Thomas Loughin ◽  
...  
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Prediction Model ◽  
Prediction Models ◽  
Severe Disease ◽  
Disease Onset ◽  
Fine Tuning ◽  
Disease Course ◽  
Internal Validation ◽  
Long Term Outcome

Abstract Background Models to predict disease course and long-term outcome based on clinical characteristics at disease onset may guide early treatment strategies in juvenile idiopathic arthritis (JIA). Before a prediction model can be recommended for use in clinical practice, it needs to be validated in a different cohort than the one used for building the model. The aim of the current study was to validate the predictive performance of the Canadian prediction model developed by Guzman et al. and the Nordic model derived from Rypdal et al. to predict severe disease course and non-achievement of remission in Nordic patients with JIA. Methods The Canadian and Nordic multivariable logistic regression models were evaluated in the Nordic JIA cohort for prediction of non-achievement of remission, and the data-driven outcome denoted severe disease course. A total of 440 patients in the Nordic cohort with a baseline visit and an 8-year visit were included. The Canadian prediction model was first externally validated exactly as published. Both the Nordic and Canadian models were subsequently evaluated with repeated fine-tuning of model coefficients in training sets and testing in disjoint validation sets. The predictive performances of the models were assessed with receiver operating characteristic curves and C-indices. A model with a C-index above 0.7 was considered useful for clinical prediction. Results The Canadian prediction model had excellent predictive ability and was comparable in performance to the Nordic model in predicting severe disease course in the Nordic JIA cohort. The Canadian model yielded a C-index of 0.85 (IQR 0.83–0.87) for prediction of severe disease course and a C-index of 0.66 (0.63–0.68) for prediction of non-achievement of remission when applied directly. The median C-indices after fine-tuning were 0.85 (0.80–0.89) and 0.69 (0.65–0.73), respectively. Internal validation of the Nordic model for prediction of severe disease course resulted in a median C-index of 0.90 (0.86–0.92). Conclusions External validation of the Canadian model and internal validation of the Nordic model with severe disease course as outcome confirm their predictive abilities. Our findings suggest that predicting long-term remission is more challenging than predicting severe disease course.

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