-
Italian Journal of Pediatrics Oct 2021Recurrent respiratory infections (RRIs) are a common clinical condition in children, in fact about 25% of children under 1 year and 6% of children during the first...
Recurrent respiratory infections (RRIs) are a common clinical condition in children, in fact about 25% of children under 1 year and 6% of children during the first 6 years of life have RRIs. In most cases, infections occur with mild clinical manifestations and the frequency of episodes tends to decrease over time with a complete resolution by 12 years of age. However, RRIs significantly reduce child and family quality of life and lead to significant medical and social costs.Despite the importance of this condition, there is currently no agreed definition of the term RRIs in the literature, especially concerning the frequency and type of infectious episodes to be considered. The aim of this consensus document is to propose an updated definition and provide recommendations with the intent of guiding the physician in the complex process of diagnosis, management and prevention of RRIs.
Topics: Adenoidectomy; Adjuvants, Immunologic; Administration, Intranasal; Algorithms; Antibiotic Prophylaxis; Antioxidants; Child; Complementary Therapies; Humans; Hyaluronic Acid; Influenza Vaccines; Pneumococcal Vaccines; Prebiotics; Probiotics; Pyrrolidonecarboxylic Acid; Recurrence; Respiratory Tract Infections; Resveratrol; Thiazolidines; Tonsillectomy; Vitamins
PubMed: 34696778
DOI: 10.1186/s13052-021-01150-0 -
Nutrients Aug 2020Magnesium deficiency may occur for several reasons, such as inadequate intake or increased gastrointestinal or renal loss. A large body of literature suggests a... (Review)
Review
Magnesium deficiency may occur for several reasons, such as inadequate intake or increased gastrointestinal or renal loss. A large body of literature suggests a relationship between magnesium deficiency and mild and moderate tension-type headaches and migraines. A number of double-blind randomized placebo-controlled trials have shown that magnesium is efficacious in relieving headaches and have led to the recommendation of oral magnesium for headache relief in several national and international guidelines. Among several magnesium salts available to treat magnesium deficiency, magnesium pidolate may have high bioavailability and good penetration at the intracellular level. Here, we discuss the cellular and molecular effects of magnesium deficiency in the brain and the clinical evidence supporting the use of magnesium for the treatment of headaches and migraines.
Topics: Administration, Oral; Biological Availability; Dietary Supplements; Headache; Humans; Magnesium; Magnesium Deficiency; Migraine Disorders; Pyrrolidonecarboxylic Acid; Randomized Controlled Trials as Topic
PubMed: 32878232
DOI: 10.3390/nu12092660 -
JAMA Neurology Oct 2022β-amyloid plaques and neurofibrillary tau deposits biologically define Alzheimer disease. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
β-amyloid plaques and neurofibrillary tau deposits biologically define Alzheimer disease.
OBJECTIVE
To perform post hoc analyses of amyloid reduction after donanemab treatment and assess its association with tau pathology and clinical measures.
DESIGN, SETTING, AND PARTICIPANTS
The Study of LY3002813 in Participants With Early Symptomatic Alzheimer's Disease (TRAILBLAZER-ALZ) was a phase 2, placebo-controlled, randomized clinical trial conducted from December 18, 2017, to December 4, 2020, with a double-blind period of up to 76 weeks and a 48-week follow-up period. The study was conducted at 56 centers in the US and Canada. Enrolled were participants from 60 to 85 years of age with gradual and progressive change in memory function for 6 months or more, early symptomatic Alzheimer disease, elevated amyloid, and intermediate tau levels.
INTERVENTIONS
Donanemab (an antibody specific for the N-terminal pyroglutamate β-amyloid epitope) dosing was every 4 weeks: 700 mg for the first 3 doses, then 1400 mg for up to 72 weeks. Blinded dose-reduction evaluations occurred at 24 and 52 weeks based on amyloid clearance.
MAIN OUTCOMES AND MEASURES
Change in amyloid, tau, and clinical decline after donanemab treatment.
RESULTS
The primary study randomized 272 participants (mean [SD] age, 75.2 [5.5] years; 145 female participants [53.3%]). The trial excluded 1683 of 1955 individuals screened. The rate of donanemab-induced amyloid reduction at 24 weeks was moderately correlated with the amount of baseline amyloid (Spearman correlation coefficient r, -0.54; 95% CI, -0.66 to -0.39; P < .001). Modeling provides a hypothesis that amyloid would not reaccumulate to the 24.1-centiloid threshold for 3.9 years (95% prediction interval, 1.9-8.3 years) after discontinuing donanemab treatment. Donanemab slowed tau accumulation in a region-dependent manner as measured using neocortical and regional standardized uptake value ratios with cerebellar gray reference region. A disease-progression model found a significant association between percentage amyloid reduction and change on the integrated Alzheimer Disease Rating Scale only in apolipoprotein E (APOE) ε4 carriers (95% CI, 24%-59%; P < .001).
CONCLUSIONS AND RELEVANCE
Results of post hoc analyses for donanemab-treated participants suggest that baseline amyloid levels were directly associated with the magnitude of amyloid reduction and inversely associated with the probability of achieving complete amyloid clearance. The donanemab-induced slowing of tau was more pronounced in those with complete amyloid clearance and in brain regions identified later in the pathologic sequence. Data from other trials will be important to confirm aforementioned observations, particularly treatment response by APOE ε4 status.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03367403.
Topics: Aged; Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Amyloidosis; Apolipoprotein E4; Epitopes; Female; Humans; Infant; Plaque, Amyloid; Positron-Emission Tomography; Pyrrolidonecarboxylic Acid; tau Proteins
PubMed: 36094645
DOI: 10.1001/jamaneurol.2022.2793 -
Nature Medicine Apr 2019Cancer cells can evade immune surveillance through the expression of inhibitory ligands that bind their cognate receptors on immune effector cells. Expression of...
Cancer cells can evade immune surveillance through the expression of inhibitory ligands that bind their cognate receptors on immune effector cells. Expression of programmed death ligand 1 in tumor microenvironments is a major immune checkpoint for tumor-specific T cell responses as it binds to programmed cell death protein-1 on activated and dysfunctional T cells. The activity of myeloid cells such as macrophages and neutrophils is likewise regulated by a balance between stimulatory and inhibitory signals. In particular, cell surface expression of the CD47 protein creates a 'don't eat me' signal on tumor cells by binding to SIRPα expressed on myeloid cells. Using a haploid genetic screen, we here identify glutaminyl-peptide cyclotransferase-like protein (QPCTL) as a major component of the CD47-SIRPα checkpoint. Biochemical analysis demonstrates that QPCTL is critical for pyroglutamate formation on CD47 at the SIRPα binding site shortly after biosynthesis. Genetic and pharmacological interference with QPCTL activity enhances antibody-dependent cellular phagocytosis and cellular cytotoxicity of tumor cells. Furthermore, interference with QPCTL expression leads to a major increase in neutrophil-mediated killing of tumor cells in vivo. These data identify QPCTL as a novel target to interfere with the CD47 pathway and thereby augment antibody therapy of cancer.
Topics: Aminoacyltransferases; Animals; Antigens, Differentiation; CD47 Antigen; Cell Line, Tumor; Cell Membrane; Humans; Immunotherapy; Mice, Transgenic; Neoplasms; Opsonin Proteins; Pyrrolidonecarboxylic Acid; Receptors, Immunologic
PubMed: 30833751
DOI: 10.1038/s41591-019-0356-z -
Minerva Pediatrica Oct 2020The rising incidence of allergic disease requires more specific, effective and safe therapeutic strategies. In this regard, several kinds of biologically active... (Review)
Review
The rising incidence of allergic disease requires more specific, effective and safe therapeutic strategies. In this regard, several kinds of biologically active substances, commonly known as immunostimulants, have been introduced for the prevention and treatment of allergic diseases in pediatric population. Among the heterogeneous group of biologically active molecules to date available, pidotimod (Axil, Valeas S.p.A, Milan) is proved to be able to ameliorate both innate and adaptive immunity and enhances the immune system properties often impaired in patients with allergic disorders.
Topics: Adaptive Immunity; Adjuvants, Immunologic; Adolescent; Asthma; Child; Child, Preschool; Chronic Urticaria; Dermatitis, Atopic; Desensitization, Immunologic; Food Hypersensitivity; Humans; Hypersensitivity; Immunity, Innate; Immunologic Factors; Pyrrolidonecarboxylic Acid; Rhinitis, Allergic; Thiazolidines
PubMed: 32731733
DOI: 10.23736/S0026-4946.20.05967-8 -
International Journal of Molecular... Jul 2014The single-mutation of genes associated with Alzheimer's disease (AD) increases the production of Aβ peptides. An elevated concentration of Aβ peptides is prone to... (Review)
Review
The single-mutation of genes associated with Alzheimer's disease (AD) increases the production of Aβ peptides. An elevated concentration of Aβ peptides is prone to aggregation into oligomers and further deposition as plaque. Aβ plaques and neurofibrillary tangles are two hallmarks of AD. In this review, we provide a broad overview of the diverses sources that could lead to AD, which include genetic origins, Aβ peptides and tau protein. We shall discuss on tau protein and tau accumulation, which result in neurofibrillary tangles. We detail the mechanisms of Aβ aggregation, fibril formation and its polymorphism. We then show the possible links between Aβ and tau pathology. Furthermore, we summarize the structural data of Aβ and its precursor protein obtained via Nuclear Magnetic Resonance (NMR) or X-ray crystallography. At the end, we go through the C-terminal and N-terminal truncated Aβ variants. We wish to draw reader's attention to two predominant and toxic Aβ species, namely Aβ4-42 and pyroglutamate amyloid-beta peptides, which have been neglected for more than a decade and may be crucial in Aβ pathogenesis due to their dominant presence in the AD brain.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Cholinesterase Inhibitors; Humans; Nootropic Agents; Protein Isoforms; Pyrrolidonecarboxylic Acid; tau Proteins
PubMed: 25032844
DOI: 10.3390/ijms150712631 -
Critical Care (London, England) May 2019
Topics: Aged; Cerebrovascular Circulation; Critical Illness; Female; Glutathione; Homeostasis; Humans; Male; Middle Aged; Oxidative Stress; Prospective Studies; Pyrrolidonecarboxylic Acid; Shock, Septic; Spain
PubMed: 31064383
DOI: 10.1186/s13054-019-2454-1 -
Frontiers in Cellular and Infection... 2023Disordered gut microbiota (GM) structure and function may contribute to osteoporosis (OP). This study explores how traditional Chinese medicine (TCM) intervention... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Disordered gut microbiota (GM) structure and function may contribute to osteoporosis (OP). This study explores how traditional Chinese medicine (TCM) intervention affects the structure and function of the GM in patients with OP.
METHOD
In a 3-month clinical study, 43 patients were randomly divided into two groups receiving conventional treatment and combined TCM (Yigu decoction, YGD) treatment. The correlation between the intestinal flora and its metabolites was analyzed using 16S rDNA and untargeted metabolomics and the combination of the two.
RESULTS
After three months of treatment, patients in the treatment group had better bone mineral density (BMD) than those in the control group ( < 0.05). Patients in the treatment group had obvious abundance changes in GM microbes, such as Bacteroides, Escherichia-Shigella, Faecalibacterium, Megamonas, Blautia, Klebsiella, Romboutsia, Akkermansia, and Prevotella_9. The functional changes observed in the GM mainly involved changes in metabolic function, genetic information processing and cellular processes. The metabolites for which major changes were observed were capsazepine, Phe-Tyr, dichlorprop, D-pyroglutamic acid and tamsulosin. These metabolites may act through metabolic pathways, the citrate cycle (TCA cycle) and beta alanine metabolism. Combined analysis showed that the main acting metabolites were dichlorprop, capsazepine, D-pyroglutamic acid and tamsulosin.
CONCLUSION
This study showed that TCM influenced the structure and function of the GM in patients with OP, which may be one mechanism by which TCM promotes the rehabilitation of patients with OP through the GM.
Topics: Humans; Gastrointestinal Microbiome; Pyrrolidonecarboxylic Acid; Tamsulosin; RNA, Ribosomal, 16S
PubMed: 37475958
DOI: 10.3389/fcimb.2023.1091083 -
Acta Neuropathologica Communications Apr 2022Amyloid plaques contain many proteins in addition to beta amyloid (Aβ). Previous studies examining plaque-associated proteins have shown these additional proteins are...
Amyloid plaques contain many proteins in addition to beta amyloid (Aβ). Previous studies examining plaque-associated proteins have shown these additional proteins are important; they provide insight into the factors that drive amyloid plaque development and are potential biomarkers or therapeutic targets for Alzheimer's disease (AD). The aim of this study was to comprehensively identify proteins that are enriched in amyloid plaques using unbiased proteomics in two subtypes of early onset AD: sporadic early onset AD (EOAD) and Down Syndrome (DS) with AD. We focused our study on early onset AD as the drivers of the more aggressive pathology development in these cases is unknown and it is unclear whether amyloid-plaque enriched proteins differ between subtypes of early onset AD. Amyloid plaques and neighbouring non-plaque tissue were microdissected from human brain sections using laser capture microdissection and label-free LC-MS was used to quantify the proteins present. 48 proteins were consistently enriched in amyloid plaques in EOAD and DS. Many of these proteins were more significantly enriched in amyloid plaques than Aβ. The most enriched proteins in amyloid plaques in both EOAD and DS were: COL25A1, SMOC1, MDK, NTN1, OLFML3 and HTRA1. Endosomal/lysosomal proteins were particularly highly enriched in amyloid plaques. Fluorescent immunohistochemistry was used to validate the enrichment of four proteins in amyloid plaques (moesin, ezrin, ARL8B and SMOC1) and to compare the amount of total Aβ, Aβ40, Aβ42, phosphorylated Aβ, pyroglutamate Aβ species and oligomeric species in EOAD and DS. These studies showed that phosphorylated Aβ, pyroglutamate Aβ species and SMOC1 were significantly higher in DS plaques, while oligomers were significantly higher in EOAD. Overall, we observed that amyloid plaques in EOAD and DS largely contained the same proteins, however the amount of enrichment of some proteins was different in EOAD and DS. Our study highlights the significant enrichment of many proteins in amyloid plaques, many of which may be potential therapeutic targets and/or biomarkers for AD.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Brain; Down Syndrome; Glycoproteins; High-Temperature Requirement A Serine Peptidase 1; Humans; Intercellular Signaling Peptides and Proteins; Plaque, Amyloid; Proteome; Pyrrolidonecarboxylic Acid
PubMed: 35418158
DOI: 10.1186/s40478-022-01356-1 -
IUBMB Life Jul 2018Glutathione was discovered in 1888, over 125 years ago. Since then, our understanding of various functions and metabolism of this important molecule has grown over these... (Review)
Review
Glutathione was discovered in 1888, over 125 years ago. Since then, our understanding of various functions and metabolism of this important molecule has grown over these years. But it is only now, in the last decade, that a somewhat complete picture of its metabolism has emerged. Glutathione metabolism has till now been largely depicted and understood by the γ-glutamyl cycle that was proposed in 1970. However, new findings and knowledge particularly on the transport and degradation of glutathione have revealed that many aspects of the γ-glutamyl cycle are incorrect. Despite this, an integrated critical analysis of the cycle has never been undertaken and this has led to the cycle and its errors perpetuating in the literature. This review takes a careful look at the γ-glutamyl cycle and its shortcomings and presents a "glutathione cycle" that captures the current understanding of glutathione metabolism. © 2018 IUBMB Life, 70(7):585-592, 2018.
Topics: Amino Acids; Animals; Bacteria; Biological Transport; Fungi; Glutamic Acid; Glutathione; Humans; Mammals; Metabolic Networks and Pathways; Plants; Pyrrolidonecarboxylic Acid; Yeasts; gamma-Glutamyltransferase
PubMed: 29667297
DOI: 10.1002/iub.1756