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Annals of Clinical and Translational... Aug 2023Infection-triggered encephalopathy syndromes (ITES) are potentially devastating neuroinflammatory conditions. Although some ITES syndromes have recognisable MRI...
OBJECTIVE
Infection-triggered encephalopathy syndromes (ITES) are potentially devastating neuroinflammatory conditions. Although some ITES syndromes have recognisable MRI neuroimaging phenotypes, there are otherwise few biomarkers of disease. Early detection to enable immune modulatory treatments could improve outcomes.
METHODS
We measured CSF neopterin, quinolinic acid, kynurenine and kynurenine/tryptophan ratio using a liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) system. The CSF of 18 children with ITES were compared with acute encephalitis (n = 20), and three control groups, namely epilepsy (n = 20), status epilepticus (n = 18) and neurogenetic controls (n = 20).
RESULTS
The main ITES phenotypes in 18 patients were acute encephalopathy with biphasic seizures and late restricted diffusion (AESD, n = 4), febrile infection-related epilepsy syndrome (FIRES n = 4) and other ITES phenotypes. Influenza A was the most common infectious trigger (n = 5), and 50% of patients had a preceding notable neurodevelopmental or family history. CSF neopterin, quinolinic acid and kynurenine were elevated in ITES group compared to the three control groups (all p < 0.0002). The ROC (area under curve) for CSF neopterin (99.3%, CI 98.1-100) was significantly better than CSF pleocytosis (87.3% CI 76.4-98.2) (p = 0.028). Elevated CSF neopterin could discriminate ITES from other causes of seizures, status epilepticus and febrile status epilepticus (all p < 0.0002). The elevated CSF metabolites normalised during longitudinal testing in two patients with FIRES.
INTERPRETATION
CSF neopterin and quinolinic acid are neuroinflammatory and excitotoxic metabolites. This CSF metabolomic inflammatory panel can discriminate ITES from other causes of new onset seizures or status epilepticus, and rapid results (4 h) may facilitate early immune modulatory therapy.
Topics: Humans; Neopterin; Quinolinic Acid; Kynurenine; Syndrome; Neuroinflammatory Diseases; Chromatography, Liquid; Tandem Mass Spectrometry; Brain Diseases; Seizures; Status Epilepticus; Encephalitis; Biomarkers
PubMed: 37340737
DOI: 10.1002/acn3.51832 -
CNS Neuroscience & Therapeutics Apr 2024This study aimed to comprehensively explore the nutrition and gait of AD patients at different stages and the relationship between them.
AIMS
This study aimed to comprehensively explore the nutrition and gait of AD patients at different stages and the relationship between them.
METHODS
A total of 85 AD patients were consecutively enrolled in this cross-sectional study and divided into the mild cognitive impairment (MCI) due to AD (AD-MCI) and the dementia due to AD (AD-D) groups. Demographic information, nutritional status, and gait performance were compared between the two groups, and the correlation between nutritional status and gait performance was subsequently analyzed by Pearson and Spearman correlation analyses.
RESULTS
The AD-D group had lower scores on Mini-Nutritional Assessment (MNA) and MNA scales, lower levels of urea nitrogen, folic acid, and vitamin B in blood, and higher homocysteine level than those in the AD-MCI group (all p < 0.05). The AD-D group had slower step speed, shorter step length, and shorter stride length than those in the AD-MCI group (all p < 0.05). AD patients with decreased scores of MNA and MNA scales, and declined levels of urea nitrogen and vitamin B in blood had reduced gait speed and gait cadence, and prolonged step length time and stride length time, whereas homocysteine showed the almost opposite results (all p < 0.05). In the AD-MCI group, the score of scale was negatively correlated with the coefficient of variation (CV) of stride length, and the folic acid level was negatively correlated with the CV of stride length and cadence (all p < 0.05).
CONCLUSIONS
AD patients at the dementia stage had worse nutritional status and gait performance than those at the MCI stage, which was associated with worse global cognition and activities of daily living. Poorer nutritional status was associated with higher gait variability in patients at the MCI stage and with poorer gait performance in patients at the dementia stage. Early identification and intervention of patients with nutritional risk or malnutrition may improve gait performance, thus reducing the risk of falling and cognitive decline, as well as the mortality.
Topics: Humans; Alzheimer Disease; Nutritional Status; Activities of Daily Living; Cross-Sectional Studies; Cognitive Dysfunction; Gait; Folic Acid; Homocysteine; Nitrogen; Vitamins; Urea
PubMed: 37950363
DOI: 10.1111/cns.14502 -
BMC Complementary Medicine and Therapies Oct 2023Methotrexate (MTX) is a common chemotherapeutic drug that inhibits DNA synthesis and induces apoptosis. Treatment with MTX increased CD73 expression, which leads to...
BACKGROUND
Methotrexate (MTX) is a common chemotherapeutic drug that inhibits DNA synthesis and induces apoptosis. Treatment with MTX increased CD73 expression, which leads to higher levels of extracellular adenosine. Adenosine levels are also high in the tumor microenvironment through Cancer cells metabolism. That promotes the survival of cancer cells and contributes to tumor immune evasion through the Adenosine 2a Receptor. A2A receptor antagonists are an emerging class of agents that treat cancers by enhancing immunotherapy, both as monotherapy and in combination with other therapeutic agents. Caffeine is an adenosine receptor antagonist. Herein, we demonstrate the ability of a novel well prepared and characterized nano formula CAF-FA-CS-NPs (D4) for A2aR blockade when combination with MTX to improve its antitumor efficacy by enhancing the immune system and eliminating immune suppression.
METHODS
CAF-FA-CS-NPs (D4) were prepared and characterized for particle size, loading efficiency, and release profile. Molecular docking was used to validate the binding affinity of caffeine and folic acid to A2A receptor. The effects of the nano formula were evaluated on human liver cancer cells (HepG2), breast cancer cells (MCF-7), and MDA-MB-231, as well as normal human cells (WI-38). Different combination ratios of MTX and D4 were studied to identify the optimal combination for further genetic studies.
RESULTS
Molecular docking results validated that caffeine and folic acid have binding affinity to A2A receptor. The CS-NPs were successfully prepared using ionic gelation method, with caffeine and folic acid being loaded and conjugated to the nanoparticles through electrostatic interactions. The CAF loading capacity in D4 was 77.9 ± 4.37% with an encapsulation efficiency of 98.5 ± 0.37. The particle size was optimized through ratio variations. The resulting nanoparticles were fully characterized. The results showed that (D4) had antioxidant activity and cytotoxicity against different cancer cells. The combination of D4 with MTX (IC50 D4 + 0.5 IC50 MTX) resulted in the downregulation of Bcl-2, FOXP3, CD39, and CD73 gene expression levels and upregulation of Bax and A2AR gene expression levels in HepG2 cells.
CONCLUSIONS
This study suggests that CAF-FA-CS-NPs (D4) in combination with MTX may be a promising candidate for cancer immunotherapy, by inhibiting A2aR signaling and leading to improved immune activation and anti-tumor activity of MTX.
Topics: Humans; Methotrexate; Folic Acid; Chitosan; Receptor, Adenosine A2A; Caffeine; Molecular Docking Simulation; Neoplasms; Nanoparticles; Immunotherapy; Adenosine; Tumor Microenvironment
PubMed: 37891562
DOI: 10.1186/s12906-023-04212-4 -
JAMA Network Open Dec 2023Kawasaki disease is an acute systemic vasculitis that primarily affects infants and young children. No reproducible risk factors have yet been identified, but a possible...
IMPORTANCE
Kawasaki disease is an acute systemic vasculitis that primarily affects infants and young children. No reproducible risk factors have yet been identified, but a possible association between maternal folic acid supplementation and Kawasaki disease has been reported previously.
OBJECTIVE
To investigate the associations of exposure to maternal serum folic acid levels and maternal folic acid supplementation with onset of Kawasaki disease during infancy among offspring.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study used data from the Japan Environment and Children's Study, a nationwide birth cohort, which has enrolled children since 2011. This study used the data set released in October 2019, and analysis was performed in January 2023.
EXPOSURES
Maternal serum folic acid levels (≥10 ng/mL classified as exposed) during the second and third trimesters and the frequency of maternal folic acid supplementation during the first trimester and during the second and third trimesters of pregnancy (once a week or more was classified as exposed).
MAIN OUTCOMES AND MEASURES
The primary outcome was onset of Kawasaki disease in offspring up to age 12 months. Odds ratios (ORs) for each exposure were estimated, and propensity score-adjusted logistic regression was conducted on the basis of the sets of variables.
RESULTS
The study population comprised 87 702 children who were followed-up for 12 months. Of these, 336 children developed Kawasaki disease. Mothers who took folic acid supplements (31 275 mothers [35.7%]; mean [SD] age, 32 [5] years) had higher serum folic acid levels than those who did not take supplements. Higher maternal serum folic acid levels were associated with a significantly lower risk of Kawasaki disease in offspring than lower levels (folic acid ≥10 vs <10 ng/mL, 56 of 20 698 children [0.27%] vs 267 of 64 468 children [0.41%]; OR, 0.68; 95% CI, 0.50-0.92). Children whose mothers took folic acid supplementation during the first trimester had a lower prevalence of Kawasaki disease than children whose mothers did not take folic acid (131 of 39 098 children [0.34%] vs 203 of 48 053 children [0.42%]), although the difference was not statistically significant (OR, 0.83; 95% CI, 0.66-1.04). Supplementation during the second and third trimesters was associated with a significantly lower risk of Kawasaki disease compared with no supplementation (94 of 31 275 children [0.30%] vs 242 of 56 427 children [0.43%]; OR, 0.73; 95% CI, 0.57-0.94).
CONCLUSIONS AND RELEVANCE
In this cohort study, higher serum folic acid levels (≥10 ng/mL) and maternal folic acid supplementation more than once a week during the second and third trimesters were associated with reduced risk of Kawasaki disease in offspring during infancy.
Topics: Child; Infant; Female; Pregnancy; Humans; Child, Preschool; Adult; Mucocutaneous Lymph Node Syndrome; Cohort Studies; Birth Cohort; Folic Acid; Mothers
PubMed: 38153729
DOI: 10.1001/jamanetworkopen.2023.49942 -
Fertility and Sterility Sep 2023To study the effect of methotrexate on male fertility and subsequent effects on their children, for which data are scarce and contradictory.
OBJECTIVE
To study the effect of methotrexate on male fertility and subsequent effects on their children, for which data are scarce and contradictory.
DESIGN
Nationwide multiregister cohort study.
SETTING
Not applicable.
SUBJECT(S)
All children born alive in Sweden between 2006 and 2014 and their fathers. Three cohorts were defined: children to fathers with periconceptional methotrexate exposure (exposed cohort), children whose fathers stopped methotrexate intake ≥2 years before conception (previously exposed cohort), and children to fathers with no methotrexate exposure (control cohort).
EXPOSURE(S)
The father having at least one dispensed methotrexate prescription from pharmacies 0-3 months before conception, along with at least one more dispensed methotrexate prescription 0-12 months before conception (periconceptional exposure). Previously exposed cohort: the father having no dispensed methotrexate prescriptions in the 2 years before conception, but having at least two dispensed prescriptions before that.
MAIN OUTCOME MEASURES
Congenital anomalies (major and any; primary outcomes), preterm birth (PTB) and being small for gestational age (SGA; secondary outcomes), as well as need of intracytoplasmic sperm injection (ICSI) to achieve pregnancy (primary outcome in exposed cohort vs. controls, exploratory outcome in previously exposed cohort vs. controls). Outcomes were analyzed using logistic regression.
RESULTS
A total of 223 children to fathers with periconceptional methotrexate exposure were identified, along with 356 children whose fathers stopped methotrexate intake ≥2 years before conception and 809,706 not methotrexate-treated controls. In children with fathers periconceptionally exposed to methotrexate, the adjusted and unadjusted odds ratios (95% confidence intervals) for major congenital anomalies were 1.1 (0.4-2.6) and 1.1 (0.4-2.4), any congenital anomalies 1.3 (0.7-2.4) and 1.4 (0.7-2.3), PTB 1.0 (0.5-1.8) and 1.0 (0.5-1.8), SGA 1.1 (0.4-2.6) and 1.0 (0.4-2.2), and conception by use of ICSI 3.9 (2.2-7.1) and 4.6 (2.5-7.7). Use of ICSI was not increased among fathers who stopped methotrexate intake ≥2 years before conception, having adjusted and unadjusted odds ratios 0.9 (0.4-1.9) and 1.5 (0.6-2.9).
CONCLUSION
This study suggests that paternal periconceptional methotrexate use does not increase risk of congenital anomalies, PTB, or SGA in the offspring but may temporarily reduce fertility.
Topics: Pregnancy; Female; Male; Humans; Infant, Newborn; Child; Methotrexate; Cohort Studies; Sweden; Premature Birth; Semen; Fertility
PubMed: 37395690
DOI: 10.1016/j.fertnstert.2023.05.005 -
Medicine Aug 2023The study aimed to elucidate the effective chemical composition and molecular mechanism of rheumatoid arthritis (RA) treatment with Jishe Qushi capsules (JSQS) and...
The study aimed to elucidate the effective chemical composition and molecular mechanism of rheumatoid arthritis (RA) treatment with Jishe Qushi capsules (JSQS) and perform clinical validation. The effective chemical components were screened by a database. We used Cytoscape software to construct the key target-RA composite target network of JSQS. Gene Ontology biofunctional analysis and Kyoto encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed for the key targets, followed by molecular docking validation of core key targets. Ninety-nine patients chosen were divided into 49 cases in the treatment group and 50 cases in the control group according to the random number table method. The control group was treated with the combination of methotrexate (MTX) plus Glucosidorum Tripterygll Totorum. The treatment group was treated with MTX plus JSQS. The treatment effects of the 2 groups were evaluated. A total of 118 key anti-RA targets were obtained for JSQS. Quercetin in Panax notoginseng, vanillic acid, scopoletin, physcion in Gardneria angustifolia, 3,5-dimethyl-4-hydroxybenzaldehyde in Zaocys dhumnades, kaempferol in Radix Paeoniae Alba, and protocatechuic aldehyde in Cibotium barometz were the main active chemical components in the composite target network. Topology analysis yields core key targets, such as TP53, INS, IL6, VEGFA, MYC, CASP3, ESR1, EGF, CCND1, PPARG, ERBB2, NFKBIA, TLR4, RELA, and CASP8, and the results of KEGG enrichment analysis showed that JSQS mainly works through pathways in cancer, phosphatidylinositol-3-kinaseRAC-serine/threonine-protein kinase signaling, and mitogen-activated protein kinase (MAPK) signaling pathway, and aryl hydrocarbon receptor nuclear translocator signaling pathway. Molecular docking results showed that the binding fraction of PPARG, VEGFA and the effective active ingredients of ridged snake dispelling capsule was >70. In the clinical trial, morning stiffness, joint pain, and VAS scores of post-treatment in the treatment group were lower than those in the control group (P < .05). Additionally, ESR, CRP, RF, anti-CCP, TNF-α, IL-6, IL-17, and Th17/Treg were lower in the treatment group than in the control group (P < .05). JSQS exert multicomponent, multipathway, and multitarget synergistic actions in RA treatment. It can significantly improve the clinical symptoms and quality of life and delay the progression of RA disease.
Topics: Humans; Arthritis, Rheumatoid; Capsules; Methotrexate; Molecular Docking Simulation; Network Pharmacology; PPAR gamma; Quality of Life
PubMed: 37653836
DOI: 10.1097/MD.0000000000034883 -
Animals : An Open Access Journal From... Jul 2023Flesh flies (Diptera: Sarcophagidae) are regarded as significant in medical and veterinary entomology, and their development models can be utilized as considerable...
Flesh flies (Diptera: Sarcophagidae) are regarded as significant in medical and veterinary entomology, and their development models can be utilized as considerable markers to ascertain the minimum postmortem interval (PMImin). In this research, we explored the growth cycle and larval body length of Macquart 1839 (Diptera: Sarcophagidae) reared under variable temperatures ranging from 15.7 to 31.1 °C, with an average of 24.55 °C and relative humidity ranges from 31.4 to 82.8% and at six fixed temperatures of 15, 20, 25, 30, 32, and then 35 °C. Moreover, pteridine from the head was used to assess adult age grading. Our results allowed us to provide three development models: the isomorphen chart, the isomegalen chart, and the thermal summation models. The time taken for to complete its development from larviposition to adult emergence at constant temperatures of 15, 20, 25, 30, 32, and 35 °C was 1256.3 ± 124.2, 698.6 ± 15.1, 481.8 ± 35.7, 366.0 ± 13.5, and 295.8 ± 20.5 h, respectively, except 35 °C, where all pupae were unable to attain adulthood. They lasted 485.8 ± 5.4 h under variable temperatures. The minimum developmental limit () temperature and the thermal summation constant () of were 9.31 ± 0.55 °C and 7290.0 ± 388.4 degree hours, respectively. The increase in pteridine content exhibited variations across different temperatures. There was quite a considerable distinction in the pteridine contents of male and female at 15 °C ( = 0.0075) and 25 °C ( = 0.0213). At 32 °C and variable temperatures, the pteridine content between female and male was not statistically divergent. However, temperature and gender remain the main factors influencing the pteridine content in the head of We aim to provide detailed developmental data on that can be used as a valuable resource for future research and PMI estimation.
PubMed: 37570212
DOI: 10.3390/ani13152402 -
Biomedical and Environmental Sciences :... Aug 2023
Topics: Humans; Folic Acid; Folic Acid Deficiency
PubMed: 37711093
DOI: 10.3967/bes2023.108 -
Neuromuscular Disorders : NMD May 2024Azathioprine is recommended as the first-line steroid-sparing immunosuppressive agent for myasthenia gravis. Mycophenolate and methotrexate are often considered as...
Azathioprine is recommended as the first-line steroid-sparing immunosuppressive agent for myasthenia gravis. Mycophenolate and methotrexate are often considered as second-line choices despite widespread consensus on their efficacy. We aimed to gather real-world data comparing the tolerability and reasons for discontinuation for these agents, by performing a national United Kingdom survey of side effects and reasons for discontinuation of immunosuppressants in myasthenia gravis. Of 235 patients, 166 had taken azathioprine, 102 mycophenolate, and 40 methotrexate. The most common side effects for each agent were liver dysfunction for azathioprine (23 %), diarrhoea for mycophenolate (14 %), and fatigue for methotrexate (18 %). Women were generally more likely to experience side effects of immunosuppressants. Azathioprine was significantly more likely to be discontinued than mycophenolate and methotrexate due to side effects. There was no significant difference in treatment cessation due to lack of efficacy. This study highlights the significant side-effect burden of treatment for myasthenia gravis. Mechanisms to reduce azathioprine toxicity should be utilised, however mycophenolate and methotrexate appear to be good treatment choices if teratogenicity is not a concern. Women are disadvantaged due to higher frequency of side effects and considerations around pregnancy and breastfeeding. Treatments with improved tolerability are needed.
Topics: Humans; Myasthenia Gravis; Methotrexate; Female; Mycophenolic Acid; Azathioprine; Immunosuppressive Agents; Male; Middle Aged; Adult; Aged; United Kingdom
PubMed: 38626662
DOI: 10.1016/j.nmd.2024.03.010 -
Reproductive Toxicology (Elmsford, N.Y.) Sep 2023There is emerging evidence suggesting that folate status during pregnancy may play a role in fetal programming of metabolic disease. Therefore, this systematic review... (Review)
Review
There is emerging evidence suggesting that folate status during pregnancy may play a role in fetal programming of metabolic disease. Therefore, this systematic review aims to summarize and systematize the current evidence surrounding the relationship between maternal folate status during pregnancy and offspring metabolic programming, focusing on both animal and human studies. PubMed, Web of Science and Scopus databases were searched in order to identify studies conducted on pregnant women or in animals studying the association between maternal folate exposure and at least one metabolic syndrome outcome in offspring after birth (weight, blood pressure, glucose regulation parameters, triglycerides and high-density lipoprotein cholesterol (HDL-C) levels). The quality of included studies was assessed using SYRCLE Risk of Bias Tools for animal studies and NHLBI Study Quality Assessment Tools for observational studies and randomized controlled trials. Among the 10 "good" or "fair" studies that investigated excessive folate exposure during the perigestational period, 7 animal studies and 1 human study reported a positive association with development of metabolic outcomes in offspring. On the other hand, 6 of the 7 "good" or "fair" included human studies compared adequate versus low folate exposure, showing a lack of association (n = 3) or a protective effect (n = 3) regarding offspring's dysmetabolism. In conclusion, there is strong evidence from animal trials suggesting that excessive folate intake in early phases of development programs for metabolic dysfunction. While human evidence regarding excessive maternal folate exposure is currently scarce, human studies suggest that folate adequacy in pregnancy is not detrimental for metabolic function of the offspring.
Topics: Animals; Pregnancy; Humans; Female; Folic Acid; Maternal Exposure
PubMed: 37442213
DOI: 10.1016/j.reprotox.2023.108439