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JAMA Neurology Jan 2024Nonmotor symptoms of Parkinson disease (PD) often predate the movement disorder by decades. Currently, there is no blood biomarker to define this prodromal phase.
IMPORTANCE
Nonmotor symptoms of Parkinson disease (PD) often predate the movement disorder by decades. Currently, there is no blood biomarker to define this prodromal phase.
OBJECTIVE
To investigate whether α-synuclein in neuronally derived serum-extracellular vesicles identifies individuals at risk of developing PD and related dementia.
DESIGN, SETTING, AND PARTICIPANTS
This retrospective, cross-sectional multicenter study of serum samples included the Oxford Discovery, Marburg, Cologne, and Parkinson's Progression Markers Initiative cohorts. Participants were recruited from July 2013 through August 2023 and samples were analyzed from April 2022 through September 2023. The derivation group (n = 170) included participants with isolated rapid eye movement sleep behavior disorder (iRBD) and controls. Two validation groups were used: the first (n = 122) included participants with iRBD and controls and the second (n = 263) included nonmanifest GBA1N409S gene carriers, participants with iRBD or hyposmia, and available dopamine transporter single-photon emission computed tomography, healthy controls, and patients with sporadic PD. Overall the study included 199 participants with iRBD, 20 hyposmic participants with available dopamine transporter single-photon emission computed tomography, 146 nonmanifest GBA1N409S gene carriers, 21 GBA1N409S gene carrier patients with PD, 50 patients with sporadic PD, and 140 healthy controls. In the derivation group and validation group 1, participants with polysomnographically confirmed iRBD were included. In the validation group 2, at-risk participants with available Movement Disorder Society prodromal markers and serum samples were included. Among 580 potential participants, 4 were excluded due to alternative diagnoses.
EXPOSURES
Clinical assessments, imaging, and serum collection.
MAIN OUTCOME AND MEASURES
L1CAM-positive extracellular vesicles (L1EV) were immunocaptured from serum. α-Synuclein and syntenin-1 were measured by electrochemiluminescence. Area under the receiver operating characteristic (ROC) curve (AUC) with 95% CIs evaluated biomarker performance. Probable prodromal PD was determined using the updated Movement Disorder Society research criteria. Multiple linear regression models assessed the association between L1EV α-synuclein and prodromal markers.
RESULTS
Among 576 participants included, the mean (SD) age was 64.30 (8.27) years, 394 were male (68.4%), and 182 were female (31.6%). A derived threshold of serum L1EV α-synuclein distinguished participants with iRBD from controls (AUC = 0.91; 95% CI, 0.86-0.96) and those with more than 80% probability of having prodromal PD from participants with less than 5% probability (AUC = 0.80; 95% CI, 0.71-0.89). Subgroup analyses revealed that specific combinations of prodromal markers were associated with increased L1EV α-synuclein levels. Across all cohorts, L1EV α-synuclein differentiated participants with more than 80% probability of having prodromal PD from current and historic healthy control populations (AUC = 0.90; 95% CI, 0.87-0.93), irrespective of initial diagnosis. L1EV α-synuclein was increased in at-risk participants with a positive cerebrospinal fluid seed amplification assay and was above the identified threshold in 80% of cases (n = 40) that phenoconverted to PD or related dementia.
CONCLUSIONS AND RELEVANCE
L1EV α-synuclein in combination with prodromal markers should be considered in the stratification of those at high risk of developing PD and related Lewy body diseases.
Topics: Female; Humans; Male; Middle Aged; alpha-Synuclein; Biomarkers; Cross-Sectional Studies; Dopamine Plasma Membrane Transport Proteins; Extracellular Vesicles; Lewy Body Disease; Parkinson Disease; REM Sleep Behavior Disorder; Retrospective Studies
PubMed: 38048087
DOI: 10.1001/jamaneurol.2023.4398 -
JCI Insight Feb 2024Intrahepatic macrophages in nonalcoholic steatohepatitis (NASH) are heterogenous and include proinflammatory recruited monocyte-derived macrophages. The receptor for...
Intrahepatic macrophages in nonalcoholic steatohepatitis (NASH) are heterogenous and include proinflammatory recruited monocyte-derived macrophages. The receptor for advanced glycation endproducts (RAGE) is expressed on macrophages and can be activated by damage associated molecular patterns (DAMPs) upregulated in NASH, yet the role of macrophage-specific RAGE signaling in NASH is unclear. Therefore, we hypothesized that RAGE-expressing macrophages are proinflammatory and mediate liver inflammation in NASH. Compared with healthy controls, RAGE expression was increased in liver biopsies from patients with NASH. In a high-fat, -fructose, and -cholesterol-induced (FFC)-induced murine model of NASH, RAGE expression was increased, specifically on recruited macrophages. FFC mice that received a pharmacological inhibitor of RAGE (TTP488), and myeloid-specific RAGE KO mice (RAGE-MKO) had attenuated liver injury associated with a reduced accumulation of RAGE+ recruited macrophages. Transcriptomics analysis suggested that pathways of macrophage and T cell activation were upregulated by FFC diet, inhibited by TTP488 treatment, and reduced in RAGE-MKO mice. Correspondingly, the secretome of ligand-stimulated BM-derived macrophages from RAGE-MKO mice had an attenuated capacity to activate CD8+ T cells. Our data implicate RAGE as what we propose to be a novel and potentially targetable mediator of the proinflammatory signaling of recruited macrophages in NASH.
Topics: Animals; Humans; Mice; Hepatitis; Macrophages; Non-alcoholic Fatty Liver Disease; Receptor for Advanced Glycation End Products
PubMed: 38175729
DOI: 10.1172/jci.insight.169138 -
Endokrynologia Polska 2021The phenomenon of autoimmunity develops as a result of the triggering factor released by damaged cells. This leads to an infiltration of CD4+ cells involved in... (Review)
Review
The phenomenon of autoimmunity develops as a result of the triggering factor released by damaged cells. This leads to an infiltration of CD4+ cells involved in stimulating the effector cells cytotoxicity and stimulating the humoral response. One of the most common autoimmune disorders are autoimmune thyroid diseases, including Hashimoto's thyroiditis and Graves's diseases. Helper T lymphocytes, which are divided into Th1, Th2, Tregs, and the relatively new groups Th17, Th22, and Th9, are involved in the pathogenesis of AITD. CD4+ cell subtypes mature and differentiate by specific transcription factors and in a specific interleukin environment. Not only are Th1 and Th2 cells involved in the development of AITD, but also Th17, Th22, and Th9 lymphocytes and their correlation to Tregs lymphocytes. The plasticity of the CD4+ cells is very important, affecting the balance between these cells, as well the factors modulating their phenotypic variability. Patients with AITD have an increased percentage of Th17, Th22, and Th9 cells as well as defective function of Tregs lymphocytes. The balance between Th17 cells (and also other cytotoxic T cells) and Treg cells is also very important. Understanding the role of CD4 cells in the pathogenesis of AITD may be important not only for the development of the knowledge, but also for determining therapeutic targets.
Topics: Autoimmune Diseases; CD4-Positive T-Lymphocytes; Graves Disease; Hashimoto Disease; Humans; T-Lymphocytes, Helper-Inducer
PubMed: 34647609
DOI: 10.5603/EP.a2021.0076 -
Reviews in Endocrine & Metabolic... Jun 2022Pasireotide, a novel multireceptor-targeted somatostatin receptor ligand (SRL) is characterized by a higher affinity to somatostatin receptor type 5 than type 2, unlike... (Review)
Review
Pasireotide, a novel multireceptor-targeted somatostatin receptor ligand (SRL) is characterized by a higher affinity to somatostatin receptor type 5 than type 2, unlike first-generation SRLs. Because of the broader binding profile, pasireotide has been suggested to have a greater clinical efficacy in acromegaly than first-generation SRLs and to be efficacious in Cushing's disease. The consequence of this binding profile is the increased blood glucose level in some patients. This results from the inhibition of both insulin secretion and the incretin effect and only a modest suppression of glucagon. A monthly intramuscular formulation of long-acting release pasireotide has been approved for both acromegaly and Cushing's disease treatment. This review presents data on the efficacy and safety of pasireotide treatment mostly in patients with acromegaly and Cushing's disease. Moreover, other possible therapeutic applications of pasireotide are mentioned.
Topics: Acromegaly; Humans; Ligands; Pituitary ACTH Hypersecretion; Receptors, Somatostatin; Somatostatin
PubMed: 35067849
DOI: 10.1007/s11154-022-09710-3 -
Poultry Science Feb 2024The concept of backyard poultry historically encompassed "food-producing animals." Nevertheless, a recent shift in livestock production paradigms within developed... (Review)
Review
The concept of backyard poultry historically encompassed "food-producing animals." Nevertheless, a recent shift in livestock production paradigms within developed countries is evident, as backyard poultry owners now raise their birds for purposes beyond self-consumption, raising animals in a familiar way, and fostering emotional bonds with them. Because backyard animals are frequently privately owned, and the resulting products are typically not marketed, very little information is available about the demographic profile of backyard owners and information on flocks' characteristics, husbandry, and welfare. Thus, this review aims to clarify the characteristics of backyard poultry, highlighting the prevalent infectious diseases and the zoonotic risk to which farmers are exposed. According to the FAO, there are different types of poultry production systems: intensive, sub-intensive, and extensive. The system conditions, requirements, and the resulting performance differ extensively due to the type of breed, feeding practices, prevalence of disease, prevention and control of diseases, flock management, and the interactions among all these factors. The presence and transmission of infectious diseases in avian species is a problem that affects both the animals themselves and public health. Bacterial (Escherichia coli, Salmonella, Campylobacter, and Mycoplasma), parasitic (helminths, louses, and mites), and viral (Avian influenza, Newcastle, Marek, Infectious Bronchitis, Gumboro, Infectious Laringotracheitis, and Fowlpox) are the most important pathogens involved in backyard poultry health. In addition, Avian influenza, Salmonella, Campylobacter, and E. coli, could be a risk for backyard farmers and/or backyard-derived products consumers. Thus, proper biosecurity implementation measures are mandatory to control them. While the principles and practices of on-farm biosecurity may be well-versed among commercial farmers, hobbyists, and backyard farmers might not be familiar with the necessary steps to protect their flocks from infectious diseases and curb their transmission. This sector represents the fourth category of poultry farming, characterized by the lowest biosecurity standards. Consequently, it is imperative to address the legal status of backyard poultry, educate owners about biosecurity measures, and promote proper veterinary care and disease control.
Topics: Animals; Poultry; Influenza in Birds; Chickens; Escherichia coli; Communicable Diseases; Poultry Diseases; Animal Husbandry
PubMed: 38056053
DOI: 10.1016/j.psj.2023.103284 -
Scientific Reports Feb 2023Purinergic receptors (PRs) have been reported as potential therapeutic targets for many viral infections including herpesviruses, which urges the investigation into...
Purinergic receptors (PRs) have been reported as potential therapeutic targets for many viral infections including herpesviruses, which urges the investigation into their role in Marek's disease (MD), a herpesvirus induced cancer in chickens that is an important pathogen for the poultry industry. MD is caused by MD virus (MDV) that has a similar viral life cycle as human varicella zoster virus in that it is shed from infected epithelial skin cells and enters the host through the respiratory route. In this report, PR responses during natural MDV infection and disease progression was examined in MD-resistant white Leghorns (WL) and MD-susceptible Pure Columbian (PC) chickens during natural infection. Whole lung lavage cells (WLLC) and liver tissue samples were collected from chickens infected but showing no clinical signs of MD (Infected) or presenting with clinical disease (Diseased). RNA was extracted followed by RT-qPCR analysis with gene specific primers against members of the P1, P2X, and P2Y PR families. Differential expression (p < 0.05) was observed in breed and disease conditions. Some PRs showed tissue specific expression (P1A1, P2X1, and P2X6 in WLLC) whereas others responded to MDV infection only in MD-susceptible (PC) chickens (P1A2A, P2X1, P2X5, P2X7). P2Y PRs had differential expression in both chicken lines in response to MDV infection and MD progression. This study is the first to our knowledge to examine PR responses during MDV infection and disease progression. These results suggest PR signaling may an important area of research for MDV replication and MD.
Topics: Animals; Humans; Chickens; Marek Disease; Herpesviridae; Herpesvirus 2, Gallid; Disease Susceptibility; Disease Progression
PubMed: 36739336
DOI: 10.1038/s41598-023-29210-x -
Frontiers in Immunology 2021Delayed wound healing can cause significant issues for immobile and ageing individuals as well as those living with co-morbid conditions such as diabetes, cardiovascular... (Review)
Review
Delayed wound healing can cause significant issues for immobile and ageing individuals as well as those living with co-morbid conditions such as diabetes, cardiovascular disease, and cancer. These delays increase a patient's risk for infection and, in severe cases, can result in the formation of chronic, non-healing ulcers (e.g., diabetic foot ulcers, surgical site infections, pressure ulcers and venous leg ulcers). Chronic wounds are very difficult and expensive to treat and there is an urgent need to develop more effective therapeutics that restore healing processes. Sustained innate immune activation and inflammation are common features observed across most chronic wound types. However, the factors driving this activation remain incompletely understood. Emerging evidence suggests that the composition and structure of the wound microbiome may play a central role in driving this dysregulated activation but the cellular and molecular mechanisms underlying these processes require further investigation. In this review, we will discuss the current literature on: 1) how bacterial populations and biofilms contribute to chronic wound formation, 2) the role of bacteria and biofilms in driving dysfunctional innate immune responses in chronic wounds, and 3) therapeutics currently available (or underdevelopment) that target bacteria-innate immune interactions to improve healing. We will also discuss potential issues in studying the complexity of immune-biofilm interactions in chronic wounds and explore future areas of investigation for the field.
Topics: Animals; Bacteria; Biofilms; Chronic Disease; Diabetic Foot; Humans; Immunity, Innate; Microbiota; Models, Immunological; Wound Healing
PubMed: 33897696
DOI: 10.3389/fimmu.2021.648554 -
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 -
Viruses Nov 2019Marek's disease virus (MDV) is an alphaherpesvirus that causes Marek's disease, a malignant lymphoproliferative disease of domestic chickens. While MDV vaccines protect...
Marek's disease virus (MDV) is an alphaherpesvirus that causes Marek's disease, a malignant lymphoproliferative disease of domestic chickens. While MDV vaccines protect animals from clinical disease, they do not provide sterilizing immunity and allow field strains to circulate and evolve in vaccinated flocks. Therefore, there is a need for improved vaccines and for a better understanding of innate and adaptive immune responses against MDV infections. Interferons (IFNs) play important roles in the innate immune defenses against viruses and induce upregulation of a cellular antiviral state. In this report, we quantified the potent antiviral effect of IFNα and IFNγ against MDV infections in vitro. Moreover, we demonstrate that both cytokines can delay Marek's disease onset and progression in vivo. Additionally, blocking of endogenous IFNα using a specific monoclonal antibody, in turn, accelerated disease. In summary, our data reveal the effects of IFNα and IFNγ on MDV infection and improve our understanding of innate immune responses against this oncogenic virus.
Topics: Animals; Antibodies, Monoclonal; Chickens; Disease Progression; Herpesvirus 2, Gallid; Immunity, Innate; Interferon-alpha; Interferon-gamma; Marek Disease; Marek Disease Vaccines; Poultry Diseases
PubMed: 31795203
DOI: 10.3390/v11121103 -
Neurology Aug 2022Parkinson disease (PD) is a chronic progressive neurodegenerative disease with increasing worldwide prevalence. Despite many trials of neuroprotective therapies in...
Parkinson disease (PD) is a chronic progressive neurodegenerative disease with increasing worldwide prevalence. Despite many trials of neuroprotective therapies in manifest PD, no disease-modifying therapy has been established. Over the past several decades, a series of breakthroughs have identified discrete populations at substantially increased risk of developing PD. Based on this knowledge, now is the time to design and implement PD prevention trials. This endeavor builds on experience gained from early prevention trials in Alzheimer disease and Huntington disease. This article first reviews prevention trial precedents in these other neurodegenerative diseases before focusing on the critical design elements for PD prevention trials, including whom to enroll for these trials, what therapeutics to test, and how to measure outcomes in prevention trials. Our perspective reflects progress and remaining challenges that motivated a 2021 conference, "Planning for Prevention of Parkinson: A Trial Design Symposium and Workshop."
Topics: Alzheimer Disease; Humans; Huntington Disease; Neurodegenerative Diseases; Parkinson Disease; Research Design
PubMed: 36219787
DOI: 10.1212/WNL.0000000000200789