scholarly journals APOE4 Copy Number-Dependent Proteomic Changes in the Cerebrospinal Fluid

2020 ◽  
pp. 1-20
Author(s):  
Miles Berger ◽  
Mary Cooter ◽  
Alexander S. Roesler ◽  
Stacey Chung ◽  
John Park ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Copy Number ◽  
Linear Models ◽  
Disease Risk ◽  
Clinical Status ◽  
Future Studies ◽  
Protein Levels ◽  
Proteomic Data ◽  
False Discovery ◽  
The One

Background: APOE4 has been hypothesized to increase Alzheimer’s disease risk by increasing neuroinflammation, though the specific neuroinflammatory pathways involved are unclear. Objective: Characterize cerebrospinal fluid (CSF) proteomic changes related to APOE4 copy number. Methods: We analyzed targeted proteomic data from ADNI CSF samples using a linear regression model adjusting for age, sex, and APOE4 copy number, and additional linear models also adjusting for AD clinical status or for CSF Aβ, tau, or p-tau levels. False discovery rate was used to correct for multiple comparisons correction. Results: Increasing APOE4 copy number was associated with a significant decrease in a CRP peptide level across all five models (q <  0.05 for each), and with significant increases in ALDOA, CH3L1 (YKL-40), and FABPH peptide levels (q <  0.05 for each) except when controlling for AD clinical status or neurodegeneration biomarkers (i.e., CSF tau or p-tau). In all models except the one controlling for CSF Aβ levels, though not statistically significant, there was a consistent inverse direction of association between APOE4 copy number and the levels of all 24 peptides from all 8 different complement proteins measured. The odds of this happening by chance for 24 unrelated peptides would be less than 1 in 16 million. Conclusion: Increasing APOE4 copy number was associated with decreased CSF CRP levels across all models, and increased CSF ALDOA, CH3L1, and FABH levels when controlling for CSF Aβ levels. Increased APOE4 copy number may also be associated with decreased CSF complement pathway protein levels, a hypothesis for investigation in future studies.

scholarly journals APOE4 Copy Number-Dependent Proteomic changes in the Cerebrospinal Fluid

2020 ◽  
Author(s):  
Miles Berger ◽  
Mary Cooter ◽  
Alexander S. Roesler ◽  
Stacey Chung ◽  
John Park ◽  
...  
Keyword(s):  
Copy Number ◽  
Disease Risk ◽  
Clinical Status ◽  
Future Studies ◽  
Complement Proteins ◽  
Protein Levels ◽  
Proteomic Data ◽  
False Discovery ◽  
Significant Expression ◽  
Lower Expression

AbstractBackgroundAPOE4 has been hypothesized to increase Alzheimer’s disease risk by increasing neuroinflammation, though the specific neuroinflammatory pathways involved are unclear.ObjectivesTo characterize CSF proteomic changes as a function of APOE4 copy number.MethodsWe analyzed targeted proteomic data obtained on ADNI CSF samples using a linear regression model adjusting for age, sex, and APOE4 copy number, and a second linear model also adjusting for AD clinical status. False Discovery Rate (FDR) was used to correct for multiple comparisons.ResultsIn the first model, increasing APOE4 copy number was associated with significant expression decreases in a CRP peptide (q=0.006), and significant expression increases in peptides from ALDOA, CH3L1 (YKL-40), and FABPH (q<0.05 for each). In the second model (controlling for age, sex, and AD clinical status), increasing APOE4 copy number was associated with significant expression decreases in a CRP peptide (q=0.009). In both models, increased APOE4 copy number was associated with trends towards lower expression of all 24 peptides from all 8 different complement proteins measured here, although none of these differences were statistically significant. The odds of this happening by chance for 24 unrelated peptides would be less than 1 in 16 million.ConclusionsIncreasing APOE4 copy number was associated with decreased CSF CRP levels and increased CSF ALDOA, CH3L1 and FABH levels; the CRP decrease remained significant after controlling for AD clinical status. Increased APOE4 copy number may also be associated with decreased CSF complement pathway protein levels, a hypothesis for investigation in future studies.

Understanding Schizophrenia: Genetic Causes and Treatment

2019 ◽  
Vol 1 (1) ◽  
pp. 6-12
Author(s):  
Fatima Javeria ◽  
Shazma Altaf ◽  
Alishah Zair ◽  
Rana Khalid Iqbal
Keyword(s):  
Copy Number ◽  
Drug Targets ◽  
Disease Risk ◽  
Mental Disease ◽  
Copy Number Variants ◽  
Aminobutyric Acid ◽  
Epigenetic Mechanisms ◽  
Gamma Aminobutyric Acid ◽  
Wide Range ◽  
Severe Mental Disease

Schizophrenia is a severe mental disease. The word schizophrenia literally means split mind. There are three major categories of symptoms which include positive, negative and cognitive symptoms. The disease is characterized by symptoms of hallucination, delusions, disorganized thinking and speech. Schizophrenia is related to many other mental and psychological problems like suicide, depression, hallucinations. Including these, it is also a problem for the patient’s family and the caregiver. There is no clear reason for the disease, but with the advances in molecular genetics; certain epigenetic mechanisms are involved in the pathophysiology of the disease. Epigenetic mechanisms that are mainly involved are the DNA methylation, copy number variants. With the advent of GWAS, a wide range of SNPs is found linked with the etiology of schizophrenia. These SNPs serve as ‘hubs’; because these all are integrating with each other in causing of schizophrenia risk. Until recently, there is no treatment available to cure the disease; but anti-psychotics can reduce the disease risk by minimizing its symptoms. Dopamine, serotonin, gamma-aminobutyric acid, are the neurotransmitters which serve as drug targets in the treatment of schizophrenia. Due to the involvement of genetic and epigenetic mechanisms, drugs available are already targeting certain genes involved in the etiology of the disease.

Economic burden of readmission due to postoperative cerebrospinal fluid leak in Chinese patients

2020 ◽  
Vol 9 (16) ◽  
pp. 1105-1115
Author(s):  
Shuqing Wu ◽  
Xin Cui ◽  
Shaoyu Zhang ◽  
Wenqi Tian ◽  
Jiazhen Liu ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Generalized Linear Models ◽  
Economic Burden ◽  
Linear Models ◽  
Chinese Patients ◽  
Cerebrospinal Fluid Leakage ◽  
Index Hospitalization ◽  
Real World Data ◽  
Factors Associated ◽  
Hospitalization Cost

Aim: This real-world data study investigated the economic burden and associated factors of readmissions for cerebrospinal fluid leakage (CSFL) post-cranial, transsphenoidal, or spinal index surgeries. Methods: Costs of CSFL readmissions and index hospitalizations during 2014–2018 were collected. Readmission cost was measured as absolute cost and as percentage of index hospitalization cost. Factors associated with readmission cost were explored using generalized linear models. Results: Readmission cost averaged US$2407–6106, 35–94% of index hospitalization cost. Pharmacy costs were the leading contributor. Generalized linear models showed transsphenoidal index surgery and surgical treatment for CSFL were associated with higher readmission costs. Conclusion: CSFL readmissions are a significant economic burden in China. Factors associated with higher readmission cost should be monitored.

scholarly journals 551. Convalescent plasma early in disease course improves survival in COVID-19

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S341-S342
Author(s):  
Varidhi Nauriyal ◽  
Anita Shallal ◽  
Amit T Vahia ◽  
Linoj Samuel ◽  
Robert Tibbetts ◽  
...  
Keyword(s):  
Scale Score ◽  
Medical Records ◽  
Clinical Status ◽  
Ordinal Scale ◽  
Optimal Timing ◽  
Care Hospital ◽  
Future Studies ◽  
Patient Gender ◽  
Significant Difference ◽  
Pcr Test

Abstract Background Convalescent plasma (CP) has been described as a potential therapy for coronavirus disease 2019 (COVID-19). Given paucity of data, we sought to describe characteristics of CP recipients in survivors and non-survivors. Methods We conducted retrospective review of electronic medical records which included any patient with a positive SARS-CoV-2 PCR test who received CP at an 890-bed quaternary care hospital in Southeast Michigan between March-May 2020. Data collected included: demographics, co-morbidities, mSOFA score on admission, laboratory values, and treatment. Outcomes assessed included inflammatory markers and clinical status based on an 8-point ordinal scalea. These values were recorded on admission, the date of CP (day 1), day 3, 7, and day 30 post-CP. Patient outcomes were stratified by ordinal scale score and compared using Mann-Whitney U tests to examine differences in clinical characteristics: scale of 1–4 (“meaningful survivor”), 5–7 (“survivor”), and 8 (“non-survivor”). Results Results of our study are summarized in Table 1 and 2. Non-survivors were older than survivors (62 vs 71 years; p=0.026). There was no statistically significant difference between patient gender, race, number of days from positive PCR test to CP, treatments, and co-morbidities. There was a trend toward higher mSOFA score on admission in non-survivors (p=0.056). A lower ordinal scale score on the date of receiving CP was significantly associated with meaningful survivorship (6 vs 7, p=0.005). Comparisons of Characteristics Based on Ordinal Scale at Day 30 Comparisons of Outcomes Based on Ordinal Scale at Day 30 Conclusion Patients who have a lower ordinal scale score on the date of CP administration are most likely to have meaningful survivorship at day 30. Future studies should evaluate optimal timing and outcomes for CP therapy in COVID-19. Disclosures All Authors: No reported disclosures

scholarly journals Alterations of mesenchymal stromal cells in cerebrospinal fluid: insights from transcriptomics and an ALS clinical trial

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ashley A. Krull ◽  
Deborah O. Setter ◽  
Tania F. Gendron ◽  
Sybil C. L. Hrstka ◽  
Michael J. Polzin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cerebrospinal Fluid ◽  
Growth Factors ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Large Scale ◽  
Therapeutic Benefit ◽  
Protein Levels ◽  
Genes Encoding ◽  
Intrathecal Space

Abstract Background Mesenchymal stromal cells (MSCs) have been studied with increasing intensity as clinicians and researchers strive to understand the ability of MSCs to modulate disease progression and promote tissue regeneration. As MSCs are used for diverse applications, it is important to appreciate how specific physiological environments may stimulate changes that alter the phenotype of the cells. One need for neuroregenerative applications is to characterize the spectrum of MSC responses to the cerebrospinal fluid (CSF) environment after their injection into the intrathecal space. Mechanistic understanding of cellular biology in response to the CSF environment may predict the ability of MSCs to promote injury repair or provide neuroprotection in neurodegenerative diseases. Methods In this study, we characterized changes in morphology, metabolism, and gene expression occurring in human adipose-derived MSCs cultured in human (hCSF) or artificial CSF (aCSF) as well as examined relevant protein levels in the CSF of subjects treated with MSCs for amyotrophic lateral sclerosis (ALS). Results Our results demonstrated that, under intrathecal-like conditions, MSCs retained their morphology, though they became quiescent. Large-scale transcriptomic analysis of MSCs revealed a distinct gene expression profile for cells cultured in aCSF. The aCSF culture environment induced expression of genes related to angiogenesis and immunomodulation. In addition, MSCs in aCSF expressed genes encoding nutritional growth factors to expression levels at or above those of control cells. Furthermore, we observed a dose-dependent increase in growth factors and immunomodulatory cytokines in CSF from subjects with ALS treated intrathecally with autologous MSCs. Conclusions Overall, our results suggest that MSCs injected into the intrathecal space in ongoing clinical trials remain viable and may provide a therapeutic benefit to patients.

scholarly journals Cerebrospinal fluid biomarkers of neuroinflammation in children with hydrocephalus and shunt malfunction

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Carolyn A. Harris ◽  
Diego M. Morales ◽  
Rooshan Arshad ◽  
James P. McAllister ◽  
David D. Limbrick
Keyword(s):  
Cerebrospinal Fluid ◽  
Inflammatory Cytokines ◽  
Protein Concentration ◽  
Shunt Revision ◽  
Csf Shunt ◽  
Shunt Failure ◽  
Revision Operation ◽  
Protein Levels ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

Abstract Background Approximately 30% of cerebrospinal fluid (CSF) shunt systems for hydrocephalus fail within the first year and 98% of all patients will have shunt failure in their lifetime. Obstruction remains the most common reason for shunt failure. Previous evidence suggests elevated pro-inflammatory cytokines in CSF are associated with worsening clinical outcomes in neuroinflammatory diseases. The aim of this study was to determine whether cytokines and matrix metalloproteinases (MMPs) contribute towards shunt failure in hydrocephalus. Methods Using multiplex ELISA, this study examined shunt failure through the CSF protein concentration profiles of select pro-inflammatory and anti-inflammatory cytokines, as well as select MMPs. Interdependencies such as the past number of previous revisions, length of time implanted, patient age, and obstruction or non-obstruction revision were examined. The pro-inflammatory cytokines were IL-1β, IL-2, IL-5, IL-6, IL-8, IL-12, IL-17, TNF-α, GM-CSF, IFN-γ. The anti-inflammatory cytokines were IL-4 and IL-10, and the MMPs were MMP-2, MMP-3, MMP-7, MMP-9. Protein concentration is reported as pg/mL for each analyte. Results Patient CSF was obtained at the time of shunt revision operation; all pediatric (< 18), totaling n = 38. IL-10, IL-6, IL-8 and MMP-7 demonstrated significantly increased concentrations in patient CSF for the non-obstructed subgroup. Etiological examination revealed IL-6 was increased in both obstructed and non-obstructed cases for PHH and congenital hydrocephalic patients, while IL-8 was higher only in PHH patients. In terms of number of past revisions, IL-10, IL-6, IL-8, MMP-7 and MMP-9 progressively increased from zero to two past revisions and then remained low for subsequent revisions. This presentation was notably absent in the obstruction subgroup. Shunts implanted for three months or less showed significantly increased concentrations of IL-6, IL-8, and MMP-7 in the obstruction subgroup. Lastly, only patients aged six months or less presented with significantly increased concentration of IL-8 and MMP-7. Conclusion Non-obstructive cases are reported here to accompany significantly higher CSF cytokine and MMP protein levels compared to obstructive cases for IL-10, IL-6, IL-8, MMP-7 and MMP-9. A closer examination of the definition of obstruction and the role neuroinflammation plays in creating shunt obstruction in hydrocephalic patients is suggested.

scholarly journals Inflammation in children with cystic fibrosis: contribution of bacterial production of long-chain fatty acids

2021 ◽  
Author(s):  
Erin Felton ◽  
Aszia Burrell ◽  
Hollis Chaney ◽  
Iman Sami ◽  
Anastassios C. Koumbourlis ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Fatty Acid ◽  
Antibiotic Treatment ◽  
Bacterial Production ◽  
Clinical Status ◽  
Achromobacter Xylosoxidans ◽  
List Type ◽  
Future Studies ◽  
Long Chain

Abstract Background Cystic fibrosis (CF) affects >70,000 people worldwide, yet the microbiologic trigger for pulmonary exacerbations (PExs) remains unknown. The objective of this study was to identify changes in bacterial metabolic pathways associated with clinical status. Methods Respiratory samples were collected at hospital admission for PEx, end of intravenous (IV) antibiotic treatment, and follow-up from 27 hospitalized children with CF. Bacterial DNA was extracted and shotgun DNA sequencing was performed. MetaPhlAn2 and HUMAnN2 were used to evaluate bacterial taxonomic and pathway relative abundance, while DESeq2 was used to evaluate differential abundance based on clinical status. Results The mean age of study participants was 10 years; 85% received combination IV antibiotic therapy (beta-lactam plus a second agent). Long-chain fatty acid (LCFA) biosynthesis pathways were upregulated in follow-up samples compared to end of treatment: gondoate (p = 0.012), oleate (p = 0.048), palmitoleate (p = 0.043), and pathways of fatty acid elongation (p = 0.012). Achromobacter xylosoxidans and Escherichia sp. were also more prevalent in follow-up compared to PEx (p < 0.001). Conclusions LCFAs may be associated with persistent infection of opportunistic pathogens. Future studies should more closely investigate the role of LCFA production by lung bacteria in the transition from baseline wellness to PEx in persons with CF. Impact Increased levels of LCFAs are found after IV antibiotic treatment in persons with CF. LCFAs have previously been associated with increased lung inflammation in asthma. This is the first report of LCFAs in the airway of persons with CF. This research provides support that bacterial production of LCFAs may be a contributor to inflammation in persons with CF. Future studies should evaluate LCFAs as predictors of future PExs.

scholarly journals Associations Between Genetically Predicted Protein Levels and COVID-19 Severity

2020 ◽  
Vol 223 (1) ◽  
pp. 19-22
Author(s):  
Jingjing Zhu ◽  
Chong Wu ◽  
Lang Wu
Keyword(s):  
False Discovery Rate ◽  
Drug Repurposing ◽  
Bonferroni Correction ◽  
Host Genetics ◽  
Protein Levels ◽  
False Discovery

Abstract It is critical to identify potential causal targets for SARS-CoV-2, which may guide drug repurposing options. We assessed the associations between genetically predicted protein levels and COVID-19 severity. Leveraging data from the COVID-19 Host Genetics Initiative comparing 6492 hospitalized COVID-19 patients and 1 012 809 controls, we identified 18 proteins with genetically predicted levels to be associated with COVID-19 severity at a false discovery rate of &lt;0.05, including 12 that showed an association even after Bonferroni correction. Of the 18 proteins, 6 showed positive associations and 12 showed inverse associations. In conclusion, we identified 18 candidate proteins for COVID-19 severity.

Dreams of Truck Drivers: A Test of the Continuity Hypothesis of Dreaming

2005 ◽  
Vol 25 (2) ◽  
pp. 179-186 ◽  
Author(s):  
Michael Schredl ◽  
Arthur Funkhouser ◽  
Nicole Arn
Keyword(s):  
Empirical Studies ◽  
Truck Drivers ◽  
The Other ◽  
Continuity Hypothesis ◽  
Future Studies ◽  
Daytime Activity ◽  
Close Relationship ◽  
The One ◽  
Dream Emotions ◽  
The Relationship

Empirical studies largely support the continuity hypothesis of dreaming. The present study investigated the frequency and emotional tone of dreams of truck drivers. On the one hand, the findings of the present study partly support the continuity regarding the time spent with driving/being in the truck and driving dreams and, on the other hand, a close relationship was found between daytime mood (feelings of stress, job satisfaction) and dream emotions, i.e., different dream characteristics were affected by different aspects of daytime activity. The results, thus, indicate that it is necessary to define very clearly how this continuity is to be conceptualized. The approach of formulating a mathematical model (cf. [1]) should be adopted in future studies in order to specify the factors and their magnitude in the relationship between waking and dreaming.

Sign in / Sign up

Export Citation Format

Share Document