Iron Dyshomeostasis and Ferroptosis: A New Alzheimer\u27s Disease Hypothesis?

Iron plays a crucial role in many physiological processes of the human body, but iron is continuously deposited in the brain as we age. Early studies found iron overload is directly proportional to cognitive decline in Alzheimer\u27s disease (AD). Amyloid precursor protein (APP) and tau protein, both of which are related to the AD pathogenesis, are associated with brain iron metabolism. A variety of iron metabolism-related proteins have been found to be abnormally expressed in the brains of AD patients and mouse models, resulting in iron deposition and promoting AD progression. Amyloid β (Aβ) and hyperphosphorylated tau, two pathological hallmarks of AD, can also promote iron deposition in the brain, forming a vicious cycle of AD development-iron deposition. Iron deposition and the subsequent ferroptosis has been found to be a potential mechanism underlying neuronal loss in many neurodegenerative diseases. Iron chelators, antioxidants and hepcidin were found useful for treating AD, which represents an important direction for AD treatment research and drug development in the future. The review explored the deep connection between iron dysregulation and AD pathogenesis, discussed the potential of new hypothesis related to iron dyshomeostasis and ferroptosis, and summarized the therapeutics capable of targeting iron, with the expectation to draw more attention of iron dysregulation and corresponding drug development

Ischemic stroke risk in East Asian patients with CHA2DS2-VASc score of 1: systematic review and meta-analysis

Background: The use of anticoagulation for stroke prevention in patients with atrial fibrillation (AF) and CHA2DS2-VASc score of 1 has been debated, partially due to limited data on ischemic stroke risk and specific clinical trials in these patients. East Asian patients have a different stroke risk profile compared to non-East Asians. We performed a systematic review and meta-analysis of ischemic stroke risk in AF patients with a CHA2DS2-VASc score of 1 in East Asian countries. Methods: A comprehensive literature search for studies evaluating ischemic stroke risk related with AF with CHA2DS2-VASc score of 1 was conducted by two reviewers. We used a fixed-effect model first, then a random-effect model if heterogeneity was assessed with I2. Results: After pooling 6 studies, the annual rate of ischemic stroke in East Asian patients with AF and a CHA2DS2-VASc score of 1 was 1.66% (95% CI: 0.71%-2.61%, I2 = 98.4%). There was a wide range in reported pooled rates between countries, from 0.59% to 3.13%. Significant difference existed not only in the community-based studies (Chinese: 2.10% vs. Japanese: 0.60%), but also from the hospital-based studies (Chinese: 3.55% vs. Japanese: 0.42%). Confining the analysis to those on no antithrombotic treatment had limited effect on the summary estimate (eg. Chinese: 4.28% vs. Japanese: 0.6%). In Chinese studies, ischemic stroke rate was lower in females than males (female: 1.40% vs. male: 1.79%). However, the low event rate in Japanese studies may reflect unrecorded anticoagulation status at follow-up. Conclusions: Some regional differences between East Asian countries were observed for ischemic stroke risk in patients with a CHA2DS2-VASc score of 1. This may reflect methodological differences in studies and unrecorded anticoagulation use at followup, but further prospective studies are required to ascertain ischemic stroke risks, as well as the differences and reasons for this between East Asians and non-East Asians

Additional file 1 of Acute pancreatitis in pregnancy: a 10-year, multi-center, retrospective study in Beijing

Additional file 1: Data 1. The basic information of fetus of APIP patients

Additional file 1 of The hepato-ovarian axis: genetic evidence for a causal association between non-alcoholic fatty liver disease and polycystic ovary syndrome

Additional file 1: Table S1. Key characteristics of participating studies. Table S2. GWAS significant SNPs used as genetic instruments for fasting insulin and fasting glucose. Table S3. GWAS significant SNPs used as genetic instruments for serum SHBG levels and bioavailable testosterone levels in women. Table S4. Direct causal effects of NAFLD, fasting insulin, fasting glucose, serum SHBG levels, and serum bioavailable testosterone levels on PCOS risk via multivariable MR analysis. Table S5. Direct causal effects of NAFLD, fasting insulin, fasting glucose, and serum SHBG levels on serum bioavailable testosterone levels via multivariable MR analysis. Table S6. Direct causal effects of NAFLD, fasting insulin, and fasting glucose on serum SHBG levels via multivariable MR analysis. Table S7. Obesity-related genome-wide significant genetic variants. Table S8. Directional pleiotropy test using MR-Egger intercepts. Table S9. Horizontal pleiotropy test using MR-PRESSO. Table S10. Linkage disequilibrium score regression results on genetic correlations between NAFLD, fasting insulin, fasting glucose, SHBG, BT, and PCOS. Table S11. Indirect causal effects between NAFLD and PCOS via fasting insulin, serum SHBG levels, and serum bioavailable testosterone levels through step-wise MR analysis

Treatment of difficult-to-treat depression – clinical guideline for selected interventions

Difficult-to-treat-depression (DTD) is a clinical challenge. The interventions that are well-established for DTD are not suitable or effective for all the patients. Therefore, more treatment options are highly warranted. We formulated an evidence-based guideline concerning six interventions not well-established for DTD in Denmark. Selected review questions were formulated according to the PICO principle with specific definitions of the patient population (P), the intervention (I), the comparison (C), and the outcomes of interest (O), and systematic literature searches were performed stepwise for each review question to identify relevant systematic reviews/meta-analyses, and randomized controlled trials. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to assess the methodological quality of the included studies. Clinical recommendations were formulated based on the evidence, the risk-benefit ratio, and perceived patient preferences. We found sufficient evidence for a weak recommendation of repetitive transcranial magnetic stimulation (rTMS) and cognitive behavioural analysis system of psychotherapy (CBASP). The use of bright light therapy in DTD was not sufficiently supported by the evidence, but should be considered as good clinical practice. The interventions should be considered in addition to ongoing antidepressant treatment. We did not find sufficient evidence to recommend intravenous ketamine/esketamine, rumination-focused psychotherapy, or cognitive remediation to patients with DTD. The evidence supported two of the six reviewed interventions, however it was generally weak which emphasizes the need for more good quality studies. This guideline does not cover all treatment options and should be regarded as a supplement to relevant DTD-guidelines

Data from: SYNGAP1 encephalopathy: a distinctive generalized developmental and epileptic encephalopathy

Objective. To delineate the epileptology, a key part of the SYNGAP1 phenotypic spectrum, in a large patient cohort. Methods. Patients were recruited via investigators' practices or social media. We included patients with (likely) pathogenic SYNGAP1 variants or chromosome 6p21.32 microdeletions incorporating SYNGAP1. We analysed patients' phenotypes using a standardized epilepsy questionnaire, medical records, EEG, MRI and seizure videos. Results. We included 57 patients (53% male, median age 8 years) with SYNGAP1 mutations (n=53) or microdeletions (n=4). 56/57 patients had epilepsy: generalized in 55, with focal seizures in seven and infantile spasms in one. Median seizure onset age was 2 years. A novel type of drop attack was identified comprising eyelid myoclonia evolving to a myoclonic-atonic (n=5) or atonic (n=8) seizure. Seizure types included eyelid myoclonia with absences (65%), myoclonic seizures (34%), atypical (20%) and typical (18%) absences and atonic seizures (14%), triggered by eating in 25%. Developmental delay preceded seizure onset in 54/56 (96%) patients of whom early developmental history was available. Developmental plateauing or regression occurred with seizures in 56 in the context of developmental and epileptic encephalopathies (DEEs). 55/57 patients had intellectual disability, which was moderate to severe in 50. Other common features included behavioural problems (73%), high pain threshold (72%), eating problems including oral aversion (68%), hypotonia (67%), sleeping problems (62%), autism spectrum disorder (54%) and ataxia or gait abnormalities (51%). Conclusions. SYNGAP1 mutations cause a generalized DEE with a distinctive syndrome combining epilepsy with eyelid myoclonia and myoclonic-atonic seizures, and predilection to seizures triggered by eating