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Movement Disorders Clinical Practice Jun 2023Little is known about the impact of the dopamine system on development of cognitive impairment (CI) in Parkinson disease (PD).
BACKGROUND
Little is known about the impact of the dopamine system on development of cognitive impairment (CI) in Parkinson disease (PD).
OBJECTIVES
We used data from a multi-site, international, prospective cohort study to explore the impact of dopamine system-related biomarkers on CI in PD.
METHODS
PD participants were assessed annually from disease onset out to 7 years, and CI determined by applying cut-offs to four measures: (1) Montreal Cognitive Assessment; (2) detailed neuropsychological test battery; (3) Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) cognition score; and (4) site investigator diagnosis of CI (mild cognitive impairment or dementia). The dopamine system was assessed by serial Iodine-123 Ioflupane dopamine transporter (DAT) imaging, genotyping, and levodopa equivalent daily dose (LEDD) recorded at each assessment. Multivariate longitudinal analyses, with adjustment for multiple comparisons, determined the association between dopamine system-related biomarkers and CI, including persistent impairment.
RESULTS
Demographic and clinical variables associated with CI were higher age, male sex, lower education, non-White race, higher depression and anxiety scores and higher MDS-UPDRS motor score. For the dopamine system, lower baseline mean striatum dopamine transporter values ( range 0.003-0.005) and higher LEDD over time ( range <0.001-0.01) were significantly associated with increased risk for CI.
CONCLUSIONS
Our results provide preliminary evidence that alterations in the dopamine system predict development of clinically-relevant, cognitive impairment in Parkinson's disease. If replicated and determined to be causative, they demonstrate that the dopamine system is instrumental to cognitive health status throughout the disease course.
TRIAL REGISTRATION
Parkinson's Progression Markers Initiative is registered with ClinicalTrials.gov (NCT01141023).
PubMed: 37332638
DOI: 10.1002/mdc3.13751 -
Journal of Clinical Virology : the... Aug 2023SARS-CoV-2 is the causative agent of the acute respiratory disease COVID-19. In addition to the full length positive-sensed, single-stranded genomic RNA (gRNA), viral...
SARS-CoV-2 is the causative agent of the acute respiratory disease COVID-19. In addition to the full length positive-sensed, single-stranded genomic RNA (gRNA), viral subgenomic RNAs (sgRNAs) that are required for expression of the 3' region of the genome are synthesized in virus-infected cells. However, whether these sgRNA-species might be used as a measure of active virus replication and to predict infectivity is still under debate. The commonly used methods to monitor and quantitate SARS-CoV-2 infections are based on RT-qPCR analysis and the detection of gRNA. The infectivity of a sample obtained from nasopharyngeal or throat swabs is associated with the viral load and inversely correlates with Ct-values, however, a cut-off value predicting the infectivity highly depends on the performance of the assay. Furthermore, gRNA derived Ct-values result from nucleic acid detection and do not necessarily correspond to active replicating virus. We established a multiplex RT-qPCR assay on the cobas 6800 omni utility channel concomitantly detecting SARS-CoV-2 gRNA, sgRNA, and human RNaseP-mRNA used as human input control. We compared the target specific Ct-values with the viral culture frequency and performed ROC curve analysis to determine the assay sensitivity and specificity. We found no advantage in the prediction of viral culture when using sgRNA detection compared to gRNA only, since Ct-values for gRNA and sgRNA were highly correlated and gRNA offered a slightly more reliable predictive value. Single Ct-values alone only provide a very limited prediction for the presence of replication competent virus. Hence, careful consideration of the medical history including symptom onset has to be considered for risk stratification.
Topics: Humans; RNA, Viral; SARS-CoV-2; COVID-19; Subgenomic RNA; Genomics; Virus Replication
PubMed: 37327554
DOI: 10.1016/j.jcv.2023.105499 -
European Heart Journal. Cardiovascular... Nov 2023Fabry disease (FD) is a multisystemic lysosomal storage disorder caused by a defect in the alpha-galactosidase A gene that manifests as a phenocopy of hypertrophic...
Three-dimensional echocardiographic left ventricular strain analysis in Fabry disease: correlation with heart failure severity, myocardial scar, and impact on long-term prognosis.
AIMS
Fabry disease (FD) is a multisystemic lysosomal storage disorder caused by a defect in the alpha-galactosidase A gene that manifests as a phenocopy of hypertrophic cardiomyopathy. We assessed the echocardiographic 3D left ventricular (LV) strain of patients with FD in relation to heart failure severity using natriuretic peptides, the presence of a cardiovascular magnetic resonance (CMR) late gadolinium enhancement scar, and long-term prognosis.
METHODS AND RESULTS
3D echocardiography was feasible in 75/99 patients with FD [aged 47 ± 14 years, 44% males, LV ejection fraction (EF) 65 ± 6% and 51% with hypertrophy or concentric remodelling of the LV]. Long-term prognosis (death, heart failure decompensation, or cardiovascular hospitalization) was assessed over a median follow-up of 3.1 years. A stronger correlation was observed for N-terminal pro-brain natriuretic peptide levels with 3D LV global longitudinal strain (GLS, r = -0.49, P < 0.0001) than with 3D LV global circumferential strain (GCS, r = -0.38, P < 0.001) or 3D LVEF (r = -0.25, P = 0.036). Individuals with posterolateral scar on CMR had lower posterolateral 3D circumferential strain (CS; P = 0.009). 3D LV-GLS was associated with long-term prognosis [adjusted hazard ratio 0.85 (confidence interval 0.75-0.95), P = 0.004], while 3D LV-GCS and 3D LVEF were not (P = 0.284 and P = 0.324).
CONCLUSION
3D LV-GLS is associated with both heart failure severity measured by natriuretic peptide levels and long-term prognosis. Decreased posterolateral 3D CS reflects typical posterolateral scarring in FD. Where feasible, 3D-strain echocardiography can be used for a comprehensive mechanical assessment of the LV in patients with FD.
Topics: Male; Humans; Female; Cicatrix; Fabry Disease; Contrast Media; Reproducibility of Results; Gadolinium; Heart Failure; Ventricular Function, Left; Echocardiography, Three-Dimensional; Stroke Volume; Echocardiography; Prognosis; Ventricular Dysfunction, Left
PubMed: 37309820
DOI: 10.1093/ehjci/jead121 -
PLoS Pathogens Jun 2023Efficient transmission of herpesviruses is essential for dissemination in host populations; however, little is known about the viral genes that mediate transmission,...
Efficient transmission of herpesviruses is essential for dissemination in host populations; however, little is known about the viral genes that mediate transmission, mostly due to a lack of natural virus-host model systems. Marek's disease is a devastating herpesviral disease of chickens caused by Marek's disease virus (MDV) and an excellent natural model to study skin-tropic herpesviruses and transmission. Like varicella zoster virus that causes chicken pox in humans, the only site where infectious cell-free MD virions are efficiently produced is in epithelial skin cells, a requirement for host-to-host transmission. Here, we enriched for heavily infected feather follicle epithelial skin cells of live chickens to measure both viral transcription and protein expression using combined short- and long-read RNA sequencing and LC/MS-MS bottom-up proteomics. Enrichment produced a previously unseen breadth and depth of viral peptide sequencing. We confirmed protein translation for 84 viral genes at high confidence (1% FDR) and correlated relative protein abundance with RNA expression levels. Using a proteogenomic approach, we confirmed translation of most well-characterized spliced viral transcripts and identified a novel, abundant isoform of the 14 kDa transcript family via IsoSeq transcripts, short-read intron-spanning sequencing reads, and a high-quality junction-spanning peptide identification. We identified peptides representing alternative start codon usage in several genes and putative novel microORFs at the 5' ends of two core herpesviral genes, pUL47 and ICP4, along with strong evidence of independent transcription and translation of the capsid scaffold protein pUL26.5. Using a natural animal host model system to examine viral gene expression provides a robust, efficient, and meaningful way of validating results gathered from cell culture systems.
Topics: Humans; Animals; Marek Disease; Chickens; Proteogenomics; Herpesviridae; Herpesvirus 2, Gallid
PubMed: 37289833
DOI: 10.1371/journal.ppat.1011204 -
Molecular Neurodegeneration Jun 2023Apolipoprotein E (ApoE) ε4 genotype is the most prevalent risk factor for late-onset Alzheimer's Disease (AD). Although ApoE4 differs from its non-pathological ApoE3...
BACKGROUND
Apolipoprotein E (ApoE) ε4 genotype is the most prevalent risk factor for late-onset Alzheimer's Disease (AD). Although ApoE4 differs from its non-pathological ApoE3 isoform only by the C112R mutation, the molecular mechanism of its proteinopathy is unknown.
METHODS
Here, we reveal the molecular mechanism of ApoE4 aggregation using a combination of experimental and computational techniques, including X-ray crystallography, site-directed mutagenesis, hydrogen-deuterium mass spectrometry (HDX-MS), static light scattering and molecular dynamics simulations. Treatment of ApoE ε3/ε3 and ε4/ε4 cerebral organoids with tramiprosate was used to compare the effect of tramiprosate on ApoE4 aggregation at the cellular level.
RESULTS
We found that C112R substitution in ApoE4 induces long-distance (> 15 Å) conformational changes leading to the formation of a V-shaped dimeric unit that is geometrically different and more aggregation-prone than the ApoE3 structure. AD drug candidate tramiprosate and its metabolite 3-sulfopropanoic acid induce ApoE3-like conformational behavior in ApoE4 and reduce its aggregation propensity. Analysis of ApoE ε4/ε4 cerebral organoids treated with tramiprosate revealed its effect on cholesteryl esters, the storage products of excess cholesterol.
CONCLUSIONS
Our results connect the ApoE4 structure with its aggregation propensity, providing a new druggable target for neurodegeneration and ageing.
Topics: Humans; Apolipoprotein E4; Alzheimer Disease; Apolipoprotein E3; Mutation; Apolipoproteins E
PubMed: 37280636
DOI: 10.1186/s13024-023-00620-9 -
STAR Protocols Jun 2023Marek's disease virus (MDV) is a highly oncogenic alphaherpesvirus that infects immune cells and causes a deadly lymphoproliferative disease in chickens. Cytokines and...
Marek's disease virus (MDV) is a highly oncogenic alphaherpesvirus that infects immune cells and causes a deadly lymphoproliferative disease in chickens. Cytokines and monoclonal antibodies promote the survival of chicken lymphocytes in vitro. Here, we describe protocols for the isolation, maintenance, and efficient MDV infection of primary chicken lymphocytes and lymphocyte cell lines. This facilitates the investigation of key aspects of the MDV life cycle in the primary target cells of viral replication, latency, genome integration, and reactivation. For complete details on the use and execution of this protocol, please refer to Schermuly et al., Bertzbach et al. (2019), and You et al. For a comprehensive background on MDV, please see Osterrieder et al. and Bertzbach et al. (2020)..
PubMed: 37270781
DOI: 10.1016/j.xpro.2023.102343 -
BMC Immunology Jun 2023The correlation between primary immunodeficiencies (PIDs) and autoimmunity shows ethnic and geographical diversity. The aim of our study was to accumulate more data in...
BACKGROUND
The correlation between primary immunodeficiencies (PIDs) and autoimmunity shows ethnic and geographical diversity. The aim of our study was to accumulate more data in paediatric PID population.
METHODS
58 children aged 1-17 and with PID (study group) and 14 age-matched immunocompetent individuals (control group) were included in the study. Serum levels of 17 different specific IgG antibodies against autoantigens were measured by means of a quantitative enzyme immunoassay. Immunoglobulin levels were analysed in relation to a detailed medical examination.
RESULTS
Autoantibodies against one or more antigens were detected in the sera of 24.14% (n = 14) subjects in the study group. The most frequent were anti-thyroid peroxidase (anti-TPO) antibodies (n = 8; 13.8%). Anti-TPO antibody levels were elevated more often in PID patients with a positive family history of autoimmune diseases (p = 0.04). The screening for anti-deamidated gliadin peptide (DGP) and anti-tissue transglutaminase (tTG) antibodies in our series allowed identifying two previously undiagnosed cases of coeliac disease in PID patients. There was no statistically significant difference between the study and the control group in terms of the autoantibodies prevalence.
CONCLUSIONS
This study provides data on the prevalence of autoantibodies in paediatric population diagnosed with PID. Selected autoantibodies (i.e. anti-tTG, anti-DGP) might be useful for the screening of PID to avoid the delay of diagnosis of an autoimmune disease.
Topics: Child; Humans; Pilot Projects; Transglutaminases; Autoantibodies; Autoimmunity; Autoimmune Diseases; Immunoglobulin A; Gliadin
PubMed: 37270495
DOI: 10.1186/s12865-023-00543-6 -
Immunologic Research Dec 2023The effects of specific cytokines produced by T cell subsets (such as Th1, Th2, and newly discovered Th17, Treg, Tfh, or Th22) are diverse, depending on interactions...
The effects of specific cytokines produced by T cell subsets (such as Th1, Th2, and newly discovered Th17, Treg, Tfh, or Th22) are diverse, depending on interactions with other cytokines, distinct signaling pathways, phase of the disease, or etiological factor. The immunity equilibrium of the immune cells, such as the Th1/Th2, the Th17/Treg, and the Th17/Th1 balance is necessary for the maintenance of the immune homeostasis. If the balance of the T cells subsets is damaged, the autoimmune response becomes enhanced which leads to autoimmune diseases. Indeed, both the Th1/Th2 and the Th17/Treg dichotomies are involved in the pathomechanism of autoimmune diseases. The aim of the study was to determine the cytokines of Th17 lymphocytes as well as the factors modulating their activity in patients with pernicious anemia. The magnetic bead-based immunoassays used (Bio-Plex) allow simultaneous detection of multiple immune mediators from one serum sample. In our study, we showed that patients suffering from pernicious anemia develop the Th1/Th2 imbalance with a quantitative advantage of cytokines participating in Th1-related immune response, the Th17/Treg imbalance with a quantitative advantage of cytokines participating in Treg-related response, as well as the Th17/Th1 imbalance with a quantitative predominance of cytokines participating in Th1-related immune response. Our study results indicate that T lymphocytes and their specific cytokines play an role in the course of pernicious anemia. The observed changes may indicate the immune response to pernicious anemia or be an element of the pernicious anemia pathomechanism.
Topics: Humans; Cytokines; Anemia, Pernicious; T-Lymphocytes, Regulatory; Th17 Cells; Autoimmune Diseases; Th1 Cells; Th2 Cells
PubMed: 37269464
DOI: 10.1007/s12026-023-09399-9 -
Journal of Gastrointestinal Surgery :... Jul 2023Autologous fat grafting (AFG) has shown promise in the treatment of complex wounds, with trials reporting good healing rates and safety profile. We aim to investigate...
BACKGROUND
Autologous fat grafting (AFG) has shown promise in the treatment of complex wounds, with trials reporting good healing rates and safety profile. We aim to investigate the role of AFG in managing complex anorectal fistulas.
METHODS
This was a retrospective review of a prospectively maintained IRB-approved database. We examined the rates of symptom improvement, clinical closure of fistula tracts, recurrence, complications, and worsening fecal incontinence. Perianal disease activity index (PDAI) was obtained for patients undergoing combination of AFG and fistula plug treatment.
RESULTS
In total, 52 unique patients underwent 81 procedures, of which Crohn's was present in 34 (65.4%) patients. The majority of patients previously underwent more common treatments such as endorectal advancement flap or ligation of intersphincteric fistula tract. Fat-harvesting sites and processing technique were selected by the plastic surgeons based on availability of trunk fat deposits. When analyzing patients by their last procedure, 41 (80.4%) experienced symptom improvement, and 29 (64.4%) experienced clinical closure of all fistula tracts. Recurrence rate was 40.4%, and complication rate was 15.4% (7 postoperative abscesses requiring I&D and 1 bleeding episode ligated at bedside). The abdomen was the most common site of lipoaspirate harvest at 63%, but extremities were occasionally used. There were no statistically significant differences in outcomes when comparing single graft treatment to multiple treatments, Crohn's and non-Crohn's, different methods of fat preparation, and diversion.
CONCLUSION
AFG is a versatile procedure that can be done in conjunction with other therapies and does not interfere with future treatments if recurrence occurs. It is a promising and affordable method to safely address complex fistulas.
Topics: Humans; Treatment Outcome; Rectal Fistula; Surgical Flaps; Fecal Incontinence; Ligation; Crohn Disease; Inflammation; Adipose Tissue; Anal Canal; Recurrence
PubMed: 37268827
DOI: 10.1007/s11605-023-05719-4 -
Frontiers in Veterinary Science 2023To evaluate the effect of the vaccine and differentiate vaccine from virulent MDV, a new quadruplex real-time PCR assay based on TaqMan probes was developed to...
To evaluate the effect of the vaccine and differentiate vaccine from virulent MDV, a new quadruplex real-time PCR assay based on TaqMan probes was developed to differentiate and accurately quantify HVT, CVI988 and virulent MDV-1. The results showed that the limit of detection (LOD) of the new assay was 10 copies with correlation coefficients >0.994 of CVI988, HVT and virulent MDV DNA molecules without cross-reactivity with other avian disease viruses. The intra-assay and inter-assay coefficients of variation (CVs) of Ct values for the new assay were less than 3%. Analysis of replication kinetics of CVI988 and virulent MDV of collected feathers between 7 and 60 days post-infection (dpi) showed MD5 had no significant effect on the genomic load of CVI988 ( > 0.05), while vaccination with CVI988 could significantly reduce the viral load of MD5 ( < 0.05). Combined with gene PCR, this method can effectively identify virulent MDV infections in immunized chickens. These results demonstrated that this assay could distinguish between the vaccine and virulent MDV strains and had the advantages of being reliable, sensitive and specific to confirm the immunization status and monitor the circulation of virulent MDV strains.
PubMed: 37252401
DOI: 10.3389/fvets.2023.1161441