Disease Type Research Articles

Associations between people experiencing homelessness (PEH) and neurodegenerative disorders (NDDs): A systematic review and meta-analysis.

Homelessness represents a widespread social issue globally, yet the risk of neurodegenerative diseases (NDDs) associated with people experiencing homelessness (PEH) has not received sufficient attention. Therefore, this study aimed to explore the risk of NDDs among PEH and its variation across countries and regions through meta-analysis and systematic review. Searching from databases such as PubMed and Web of Science, relevant research articles on PEH and NDDs were identified. After multiple screening, eight articles were selected for meta-analysis. Statistical methods and models were used to evaluate the association between PEH and NDDs, stratified by disease type and country. We found that PEH had a 51% higher risk of NDDs (OR = 1.51 (95% CI: 1.21, 1.89)) compared with those with stable housing. Specifically, PEH had a significantly higher risk of developing multiple sclerosis (OR = 4.64 (95% CI: 1.96, 10.98)). Alzheimer's disease and related dementias (ADRD) (OR = 1.93 (95% CI: 1.34, 2.77)), dementia (OR = 1.69 (95% CI: 1.26, 2.27)), and cognitive impairment (OR = 1.07 (95% CI: 0.98, 1.16)) were all at higher risk. Furthermore, country and regional differences were observed, with countries such as Iran (OR = 4.64 (95% CI: 1.96, 10.98)), the Netherlands (OR = 2.14 (95% CI: 1.23, 3.73)), the United States (OR = 1.66 (95% CI: 1.25, 2.22)), and Canada (OR = 1.06 (95% CI: 1.01, 1.10)) showing a higher risk of NDDs among the PEH. The study emphasizes the significant NDD risks among PEH, providing novel perspectives on this issue and shedding light on national disparities influenced by variations in healthcare systems and social environments. This will be beneficial for academia and government to prioritize the health of PEH with NDDs, aiming to mitigate disease incidence and economic burdens while preserving social stability and upholding basic human rights.

Unraveling shared and unique genetic causal relationship between gut microbiota and four types of uterine-related diseases: Bidirectional Mendelian inheritance approaches to dissect the "Gut-Uterus Axis"

BackgroundThe gut microbiota has emerged as a pivotal factor in the etiology of uterine-related diseases. This study aims to elucidate the genetic causal link between gut microbiota composition and these conditions, focusing on the systemic impact and uterine pathology to better understand the "Gut-Uterus Axis." MethodsWe utilized pooled data from two different GWAS databases, including data from 209 gut microbiota traits and data from four uterus-related diseases. Bidirectional Mendelian Randomization (MR) approaches, incorporating Bayesian weighting and traditional inverse variance weighting (IVW) methods, were employed to explore causal relationships. The robustness of findings was ensured through sensitivity analyses, outlier testing, and MR-PRESSO analysis. ResultsSeventeen significant associations were identified between gut microbiota traits and uterine-related diseases, suggesting potential causal links. These associations were consistent across sensitivity analyses, affirming the reliability of our results. Conversely, reverse MR analyses did not reveal statistically significant associations between uterine diseases and bacterial traits, indicating a unidirectional influence of gut microbiota on uterine health. These findings highlight the complex interplay within the "Gut-Uterus Axis." ConclusionThis research establishes a causal relationship between gut microbiota and uterine diseases, advocating for targeted interventions to mitigate associated risks. It underscores the interconnectedness of gut and reproductive health, promoting a holistic approach to management and treatment within the "Gut-Uterus Axis".

Update on management of cerebral venous thrombosis.

This review intends to systematize the diagnostic and treatment approach to cerebral venous thrombosis (CVT), highlighting key studies that have been recently published. In light of the recent pandemic, new risk factors for CVT have emerged. Contrast-enhanced MRI and susceptibility-weighted imaging have been shown to offer increased sensitivity for detecting cortical vein thrombosis.Dabigatran seems to be as effective and well tolerated as warfarin for long-term anticoagulation. Partial venous recanalization often occurs in patients treated with anticoagulation only, as early as 8 days after treatment onset. For patients with CVT and impending brain herniation, two-thirds of those who undergo decompressive craniectomy survive, with one-third being functionally independent 6 months after diagnosis. CVT is an unusual type of cerebrovascular disease that mostly affects women of fertile age. Risk factors should be identified and addressed. Diagnosis relies on confirmation of venous sinus and/or vein thrombosis, usually by CT venography or MRI. Anticoagulation is the cornerstone of treatment. Despite the lack of high-quality evidence, endovascular treatment is often considered in severe cases. Special populations require tailored approaches. About 80% achieve mRS 0-1, but residual symptoms often affect quality of life and the ability to return to work.

Biallelic pathogenic variants in the LSS gene cause congenital alopecia-cataract syndrome.

Biallelic variants in the LSS gene have been reported in individuals affected by alopecia-intellectual disability syndrome 4, cataract 44, hypotrichosis 14, and palmoplantar keratoderma-congenital alopecia syndrome type 2. The present report described a Chinese girl with congenital alopecia universalis, cataract, esotropia, and nystagmus caused by compound heterozygous variants of c.1025T>G (p.Ile342Ser) and previously unreported c.1011G>A (p.Pro337=) in the LSS gene. Minigene assay confirmed the synonymous variant Pro337= at the edge of exon 9 could produce a novel splice site, leading to a 46-bp insertion of the 5' sequence of the intron 9, likely resulting in a frameshift effect. We consider that the clinical manifestations of this case represent a new type of LSS-related disease, namely congenital alopecia-cataract syndrome (CACS). Our data expand the phenotypic and genetic spectrum of LSS-related diseases.

Exploring the Effect of Active Components in Oil Tree Peony Seed Meal on Swine Disease Resistance and its Potential Mechanisms Based on Network Pharmacology and Molecular Docking.

This study aims to explore the feasibility of using network pharmacology and molecular docking technology to predict the effects of active components from oil tree peony seed meal (PSM) on swine diseases. Ten active components of PSM were screened Screening through literature search and network pharmacology standards, including Betulinic acid, Quercetin, Kaempferol, Luteolin, Isorhamnetin, Hydroxygenkwanin, Hederagenin, Benzoyl Paeoniflorin, Albiflorin, Paeoniflorin. Ten types of swine diseases were selected, including African Swine Fever, Aftosa, Swine Vesicular Disease, Transmissible Gastroenteritis, Swine Streptococcal Infection, Blue Aural Disease, Swine Infectious Atrophic Rhinitis, Swine Influenza, Swine Erysipelas, Swine Epidemic Encephalitis. The results showed that the average number of cross genes between the potential target genes of PSM active components and each swine disease target gene accounted for 7.64 % of the total number of swine disease target genes. The GO enrichment analyses showed that putative targets exist in endosomes, lysosomes, cell membranes, nerves, growth factor activity, receptor tyrosine kinase binding, enzyme binding, growth factor binding, transcription coactivator binding, oxidoreductase activity, prostaglandin E receptor activity and insulin receptor substrate binding. The KEGG enrichment analysis results showed that these putative genes were involved in various cancer progression pathways, signaling pathways, and hormone regulatory pathways. A total of 8 core targets were obtained through protein-protein interaction networks analysis, including Protein Kinase CAMP-Activated Catalytic Subunit Alpha (PRKACA), Non-Receptor Tyrosine Kinase (SRC), Mitogen-Activated Protein Kinase 1 (MAPK1), E1A Binding Protein P300 (EP300), Hypoxia Inducible Factor 1 Subunit Alpha (HIF1A), Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Beta (PIK3CB), C-X-C chemokine receptor type 4 (CXCR4) and Estrogen Receptor 2 (ESR2). The HIF-1 signaling pathway was found to be associated with all 10 selected swine diseases. The PD-L1 expression, and PD-1 checkpoint pathway in cancer, and thyroid hormone signaling pathway were not only enriches the core target with a quantity of 7, but also associated with 9 Swine diseases. In addition, the molecular docking results indicate that the core ingredients have strong affinity with hub genes. The research suggests that the active components of PSM may intervene in swine diseases through multiple components, targets, and pathways.

SLC37A4, gene responsible for glycogen storage disease type 1b, regulates gingival epithelial barrier function via JAM1 expression

Solute carrier family 37 member 4 (SLC37A4) is known to regulate glucose-6-phosphate transport from cytoplasm to the lumen of the endoplasmic reticulum, which serves to maintain glucose homeostasis. Glycogen storage disease type 1b (GSD1b) is caused by a mutation of SLC37A4, leading to a glycogenolysis defect. Although GSD1b cases are known to be complicated by periodontitis, the etiological molecular basis remains unclear. The present study investigated the effects of SLC37A4 on gingival barrier function. Examinations of immortalized human gingival epithelial (IHGE) cells showed SLC37A4 localized in the endoplasmic reticulum. SLC37A4 knockout decreased expression of JAM1, a tight junction-related protein, in IHGE cells. Using in silico analysis to investigate potential transcription factor binding sites, H6 family homeobox 3 (HMX3) was shown to be related to JAM1 expression. In HMX3-knockdown IHGE cells, JAM1 expression was markedly suppressed. Furthermore, HMX3 was scarcely detected in SLC37A4-knockout cells, while HMX3 overexpression restored JAM1 expression in those cells. Finally, using a three-dimensional multilayered gingival epithelial tissue model, knockout of SLC37A4 was also found to increase permeability to lipopolysaccharide and peptidoglycan, which was dependent on JAM1 expression. Specific downregulation of HMX3 by SLC37A4 and the consequent decrease in JAM1 expression provides findings indicating a molecular basis for the reduction in barrier function of gingival epithelial tissues in GSD1b cases.

Real-World Effectiveness and Safety of Carotegrast Methyl in Japanese Patients with Moderately Active Ulcerative Colitis

Introduction: Carotegrast methyl (CGM) is an oral, small-molecule α4-integrin antagonist, which became clinically available in Japan in May 2022. CGM is approved for remission induction treatment for moderately active ulcerative colitis (UC) with an inadequate response or intolerance to 5-aminosalicylates. Methods: We performed a single-center, retrospective, observational study of Japanese patients with moderately active UC to assess the real-world effectiveness and safety of CGM as remission induction treatment. Results: Of 14 patients, 71% (10/14) were women, and the median (range) age was 47 (20–68) years. Disease types were proctitis in 7% (1/14), left-sided colitis in 50% (7/14), and total colitis in 43% (6/14). With a median (range) treatment duration of 8 (2–26) weeks, the rate of endoscopic improvement (Mayo endoscopic subscore [MES] of 0 or 1) was 64% (9/14), and the rate of endoscopic remission (MES of 0) was 57% (8/14). After treatment with CGM, the median (range) MES decreased significantly from 3.0 (2–3) to 0.0 (0–3) (p = 0.008), the Mayo score decreased significantly from 7.0 (5–9) to 0.0 (0–9) (p = 0.006), and the clinical activity index decreased significantly from 6.0 (1–11) to 0.0 (0–9) (p = 0.015). Stool and diarrhea frequencies decreased significantly after initiating CGM, and the percentage of patients with bloody stool and abdominal pain tended to decrease. The cumulative relapse-free rate at week 26 among 9 patients who achieved endoscopic improvement with CGM was 77.8% (95% confidence interval, 36.5%–93.9%). No adverse drug reactions, including progressive multifocal leukoencephalopathy, were reported during the study period. Conclusion: This single-center, retrospective, observational study of 14 Japanese patients with UC showed that CGM was safe and effective as a remission induction treatment for moderately active UC with an inadequate response to 5-aminosalicylates in real-world settings.

Risk of Inflammatory Central Nervous System Diseases After Tumor Necrosis Factor–Inhibitor Treatment for Autoimmune Diseases

Tumor necrosis factor (TNF) inhibitors have been used extensively to treat various autoimmune diseases. However, there are ongoing debates about the risk of inflammatory central nervous system (CNS) disease events following TNF inhibitor therapy, as well as uncertainty about how this risk varies across different autoimmune diseases or TNF-blocking agents. To evaluate the risk of inflammatory CNS diseases after anti-TNF initiation and assess the difference in risk among different types of underlying autoimmune diseases or TNF inhibitors. Separate searches were conducted across PubMed, Embase, and the Cochrane Library from inception until March 1, 2024. Observational studies assessing the association between anti-TNF therapy and inflammatory CNS diseases relative to a comparator group. Study eligibility assessment and data extraction were independently conducted by 2 investigators following PRISMA guidelines. The risk ratio (RR) was used as the effect measure of the pooled analysis. The primary outcome was the risk of incident inflammatory CNS events after anti-TNF therapy for autoimmune diseases. Secondary analyses were performed based on different types of underlying autoimmune diseases and TNF inhibitors. Eighteen studies involving 1 118 428 patients with autoimmune diseases contributing more than 5 698 532 person-years of follow-up were analyzed. The incidence rates of new-onset inflammatory CNS events after initiating TNF inhibitors ranged from 2.0 to 13.4 per 10 000 person-years. Overall, exposure to TNF inhibitors was associated with a 36% increased risk of any inflammatory CNS disease compared to conventional therapies (RR, 1.36; 95% CI, 1.01-1.84; I2, 49%), mainly attributed to demyelinating diseases (RR, 1.38; 95% CI, 1.04-1.81; I2, 31%). Secondary analyses revealed a similar risk of inflammatory CNS diseases across different types of underlying autoimmune diseases (rheumatic diseases: RR, 1.36; 95% CI, 0.84-2.21; inflammatory bowel disease 1.49; 95% CI, 0.93-2.40; P for subgroup = .74) and TNF inhibitors (anti-TNF monoclonal antibodies vs etanercept: RR, 1.04; 95% CI, 0.93-1.15; I2, 0%). Compared to conventional therapies, exposure to TNF inhibitors was associated with a 36% increased risk of inflammatory CNS diseases, irrespective of background autoimmune disease or TNF inhibitor type.

FIG4-Related Parkinsonism and the Particularities of the I41T Mutation: A Review of the Literature.

Background/Objectives: The genetic underpinnings of Parkinson's disease (PD) and parkinsonism have drawn increasing attention in recent years. Mutations in the Factor-Induced Gene 4 (FIG4) have been implicated in various neurological disorders, including Charcot-Marie-Tooth disease type 4J (CMT4J), amyotrophic lateral sclerosis (ALS), and Yunis-Varón syndrome. This review aims to explore the association between FIG4 mutations and parkinsonism, with a specific focus on the rare missense mutation p.Ile41Thr (I41T). Methods: We identified 12 cases from 10 different families in which parkinsonism was reported in conjunction with CMT4J polyneuropathy. All cases involved the I41T mutation in a compound heterozygous state, combined with a FIG4 loss-of-function mutation. Data from clinical observations, neuroimaging studies, and genetic analyses were evaluated to understand the characteristics of parkinsonism in these patients. Results: In all 12 cases, parkinsonism developed either concurrently or following the onset of CMT4J neuropathy, but was never observed in isolation. Cases of both early- and late-onset parkinsonism were identified, reflecting similarities to genetic forms of parkinsonism with autosomal recessive inheritance. Imaging studies, including Dopamine transporter Single Photon Emission Computed Tomography (DaTscan) and brain magnetic resonance imaging (MRI), revealed abnormalities indicative of neurodegeneration, consistent with findings in other neurodegenerative disorders. Conclusions: The co-occurrence of parkinsonism with CMT4J in patients carrying the I41T mutation suggests an expanded spectrum of FIG4-related disorders, potentially implicating the same molecular mechanisms seen in other neurodegenerative disorders. Further research into FIG4-mediated pathways may offer valuable insights into potential therapeutic targets for disorders of both the central and peripheral nervous systems.

Use of rituximab in the of immunoinflammatory rheumatic diseases combined with Graves' disease (autoimmune polyglandular syndrome in adults): case report and literature review

Rituximab (RTM) is a chimeric (murine and human) monoclonal antibody against B-lymphocytes (CD20). RTM is widely used in hematology for lymphoproliferative diseases and in rheumatology for rheumatoid arthritis, Sjögren's disease, some types of vasculitis and systemic connective tissue diseases. The administration of RTM is associated with a depletion of B-cells mediated by the regulation of apoptosis and cytotoxic effects via complement-dependent and antibody-dependent mechanisms. Considering the pathogenesis of autoimmune damage in Graves' disease (GD), an autoimmune thyroid disease associated with thyrotoxicosis, the use of RTM could be effective in this pathology. We present three patients with a combination of diffuse toxic goiter and rheumatic pathology treated with RTM; different outcomes of GD were observed.

Comparative Analysis of Ticagrelor and Clopidogrel Effects on Medication Adherence, Adverse Events, and Laboratory Parameters in Iranian Acute Coronary Syndrome Patients Post-PCI

Background: Acute coronary syndrome (ACS) remains a critical health concern, with patient outcomes significantly influenced by the selection of antiplatelet therapy post-percutaneous coronary intervention (PCI). Existing research suggests potential benefits of ticagrelor over clopidogrel in reducing cardiovascular events. However, there is limited comparative data within the Iranian population post-angiography. Objectives: This research aimed to compare laboratory findings, adherence rates, and side effects following the administration of ticagrelor and clopidogrel in ACS patients post-PCI. Methods: A case-control study was conducted to assess the impacts of antiplatelet therapy in 200 ACS patients undergoing PCI at Masih Daneshvari Hospital, Tehran, Iran. Patients were stratified into two groups, matched by age, gender, and type of cardiac disease. One group received clopidogrel, and the other received ticagrelor. Laboratory parameters, including HDL, LDL, and CRP, were evaluated at baseline and two months after treatment initiation. Additionally, adverse effects and medication adherence were assessed to evaluate the safety and efficacy of the two antiplatelet agents. Results: The study enrolled 200 ACS patients post-PCI, with 54% male and 46% female. The age range was 38 to 84 years, with a mean age of 63.07 ± 12.54 years. Of the patients, 76% had non-ST-elevation myocardial infarction (NSTEMI), while 24% had ST-elevation myocardial infarction (STEMI). Among STEMI patients, 56.25% were treated with fibrinolytics, and 43.75% underwent primary PCI. Common adverse events included dyspnea, bleeding, and gastrointestinal symptoms. Both the ticagrelor and clopidogrel groups showed reductions in LDL levels from baseline to the two-month follow-up. Conclusions: Ticagrelor and clopidogrel were both effective in reducing LDL levels after two months of treatment. However, ticagrelor demonstrated a more pronounced decrease in CRP levels, indicating potential anti-inflammatory benefits. These findings provide insight into antiplatelet therapy's role in managing ACS patients post-PCI.

Factors Affecting Visual Acuity After Anti-Vascular Endothelial Growth Factor Therapy in Neovascular Age-Related Macular Degeneration: A Multicenter Study in Japan

Background/Objectives: Anti-vascular endothelial growth factor (VEGF) therapy is the first-line treatment for neovascular age-related macular degeneration (nvAMD). While proactive and adequate treatment generally leads to better visual outcomes, various factors, including the disease type, ocular findings, lifestyle, and systemic status, affect the visual prognosis in clinical settings. This study aimed to identify the factors that affect the visual prognosis in patients with nvAMD treated with anti-VEGF therapy. Methods: We conducted a multicenter retrospective cohort study at eight tertiary referral centers in Japan, where we reviewed the medical records of patients newly diagnosed with nvAMD between January 2014 and December 2019. These patients had started treatment with either ranibizumab (0.5 mg) or aflibercept (2.0 mg) and were followed for at least 1 year. We evaluated the impact of the disease type, systemic factors, and initial fundus findings on the best-corrected visual acuity (BCVA) at 1 year. Results: This study included 182 patients (129 men, 53 women), with a mean age of 75.0 ± 8.6 years. The disease types were categorized as typical AMD (53%), polypoidal choroidal vasculopathy (PCV) (43%), and retinal angiomatous proliferation (RAP) (4%). Univariate analysis identified age, the baseline logarithm of the minimum angle of resolution BCVA, intraretinal fluid (IRF), pigment epithelial detachment (PED), and subretinal hyperreflective material (SHRM). Multivariate analysis identified the following significant risk factors associated with vision worsening: age, smoking history, diabetes, and the presence of IRF and PED. Conclusions: The presence of IRF, PED, and SHRM at the start of treatment and a history of smoking and diabetes may be associated with a poor visual prognosis in patients with nvAMD.

Exploration of the shared gene signatures and molecular mechanisms between Alzheimer’s disease and intracranial aneurysm

Although Alzheimer’s disease (AD) and intracranial aneurysm (IA) were two different types of diseases that occurred in the brain, ruptured IA (RIA) survivors may experience varying degrees of cognitive dysfunction. Neither AD nor IA is easily recognizable by an early onset so that the incidence of adverse clinical outcomes would be on the rise. Therefore, we focused on the exploration of the shared genes and molecular mechanisms between AD and IA, which would be significant for the efficiency of co-screening and co-diagnosis. Two GEO datasets were selected for the weighted gene co-expression network analysis (WGCNA) and differentially expressed gene screening, obtaining 78 overlapped genes. Next, 9 hub genes were identified by the protein-protein interaction network, including PIK3CA, GAB1, IGF1R, PLCB1, PGR, PDGFRB, PLCE1, FGFR3, and SYNJ1. The interactions among the hub genes, miRNA, and TFs were also explored. Meanwhile, we performed GO and KEGG pathway enrichment analyses for the results of WGCNA and hub genes, which showed that the Ras signaling and Rap1 signaling were the main shared pathogenesis. In conclusion, the present bioinformatics analysis revealed that AD and IA had the shared genes and molecular mechanisms, and these outcomes were associated with inflammation and calcium homeostasis, which could provide research clues for further studies.

Optimizing the Use of Personal Values to Promote Medication Adherence: A Randomized Controlled Trial Comparing Affective and Behavioral Responses to Theory-Driven Domain Congruent Versus Incongruent Values Approaches.

Self-affirmation theory (SAT) and acceptance and commitment therapy (ACT) embody competing approaches to leveraging personal values to motivate behavior change but are rarely compared in the domain of health behavior. This study compares these theory-driven values-based interventions for promoting medication adherence. To compare affective and behavioral responses to competing values-based medication adherence interventions. In this three-armed randomized trial, participants with cancer (n = 95) or diabetes (n = 97) recruited online using Prolific and prescribed daily oral medication for that disease completed a one-session online writing intervention leveraging (1) a domain incongruent (DI) value, where the value was not connected to medication adherence; (2) a domain congruent (DC) value, where the value was connected to adherence; or (3) a control condition, focused on medication adherence procedures. There were no main effects of conditions on reported medication adherence at the 1-month follow-up. During the intervention, positive affect was higher in the values conditions than control (p < .001), and trended higher in DI versus DC (p = .054). Negative affect did not vary between the values and control groups (p = .093) but was lower in DI versus DC (p = .006). Improvements in positive affect over the course of the intervention were associated with increased adherence behavior for individuals who started with low levels of positive affect (p = .003). Disease type did not moderate findings. Consistent with SAT, focusing on DI values led to more positive and less negative affect than connecting values directly to behavior in a threatening domain such as chronic illness. For some participants, increases in positive affect predicted greater adherence.

Development and validation of a machine learning-based nomogram for prediction of unplanned reoperation post-spinal surgery within 30 days

Unplanned reoperation post-spinal surgery (URPS) leads to prolonged hospital stays, higher costs, decreased patient satisfaction, and adversely affects postoperative rehabilitation. This study aimed to develop and validate prediction models (nomograms) for early URPS risk factors using machine learning (ML) methods, aiding spine surgeons in designing prevention strategies, promoting early recovery, reducing complications and improving patient satisfaction. Medical records of 639 patients who underwent reoperation post-spinal surgery (RPS) from the First Affiliated Hospital of Air Force Medical University (2018 - 2022) were collected, including baseline indicators, perioperative indicators, and laboratory indicators. After applying inclusion and exclusion criteria, 122 URPS and 155 non-URPS patients were identified and randomly divided into training (82 URPS, 111 non-URPS) and validation (40 URPS, 44 non-URPS) cohorts. Three ML methods (LASSO regression, Random Forest, and SVM-RFE) were used to select feature variables, and their intersection was used to develop the prediction model, tested on the validation cohort. Six factors-implant, postoperative suction drainage (PSD), gelatin sponge (GS), anticoagulants (ATG), antibiotics (ATB), and disease type (DT)-were identified to construct a nomogram diagnostic model. The area under the curve (AUC) of this nomogram was 0.829 (95% CI 0.771-0.886) in the training cohort and 0.854 (95% CI 0.775-0.933) in the validation cohort. Calibration curves demonstrated satisfactory agreement between predictions and actual probabilities. The decision curve indicated clinical usefulness with a threshold between 1% and 90%. The established model can effectively predict URPS in patients and can assist spine surgeons in devising personalized and rational clinical prevention strategies.

Palliative rehabilitation and quality of life: systematic review and meta-analysis

ImportanceInternational guidelines recommend the integration of multidisciplinary rehabilitation into palliative care services but its impact on quality of life across disease types is not well understood.ObjectiveTo determine the effect of...

Sensory-Motor Neuropathy in Mfn2 T105M Knock-in Mice and Its Reversal by a Novel Piperine-Derived Mitofusin Activator.

Mitochondrial dysfunction is a hallmark of many genetic neurodegenerative diseases, but therapeutic options to reverse mitochondrial dysfunction are limited. While recent studies support the possibility of improving mitochondrial fusion/fission dynamics and motility to correct mitochondrial dysfunction and resulting neurodegeneration in Charcot-Marie-Tooth disease (CMT) and other neuropathies, the clinical utility of reported compounds and relevance of preclinical models are uncertain. Here, we describe motor and sensory neuron dysfunction characteristic of clinical CMT type 2 A in a CRISPR/Casp-engineered Mfn2 Thr105Met (T105M) mutant knock-in mouse. We further demonstrate that daily oral treatment with a novel mitofusin activator derived from the natural product piperine can reverse these neurologic phenotypes. Piperine derivative 8015 promoted mitochondrial fusion and motility in Mfn2-deficient cells in a mitofusin-dependent manner and reversed mitochondrial dysfunction in cultured fibroblasts and reprogrammed motor neurons from a human CMT2A patient carrying the MFN2 T105M mutation. Like previous mitofusin activators, 8015 exhibited stereospecific functionality, but the more active stereoisomer, 8015-P2, is unique in that it has subnanomolar potency and undergoes entero-hepatic recirculation which extends its in vivo half-life. Daily administration of 8015-P2 to Mfn2 T105M knock-in mice for 6 weeks normalized neuromuscular and sensory dysfunction and corrected histological/ultrastructural neurodegeneration and neurogenic myoatrophy. These studies describe a more clinically relevant mouse model of CMT2A and an improved mitofusin activator derived from piperine. We posit that 8015-P2 and other piperine derivatives may benefit CMT2A or other neurodegenerative conditions wherein mitochondrial dysdynamism plays a contributory role. SIGNIFICANCE STATEMENT: Mitochondrial dysfunction is widespread and broadly contributory in neurodegeneration, but difficult to target therapeutically. Here, we describe 8015-P2, a new small molecule mitofusin activator with ∼10-fold greater potency and improved in vivo pharmacokinetics versus comparators, and demonstrate its rapid reversal of sensory and motor neuron dysfunction in an Mfn2 T105M knock-in mouse model of Charcot-Marie-Tooth disease type 2 A. These findings further support the therapeutic approach of targeting mitochondrial dysdynamism in neurodegeneration.

The Emerging Role of Immunoglobulins and Complement in the Stimulation of Neuronal Activity and Repair: Not as Simple as We Thought

Neurologic disorders such as traumatic brain injury, multiple sclerosis, Alzheimer’s disease, and drug-resistant epilepsy have a high socioeconomic impact around the world. Current therapies for these disorders are often not effective. This creates a demand for the development of new therapeutic approaches to treat these disorders. Recent data suggest that autoreactive naturally occurring immunoglobulins produced by subsets of B cells, called B1 B cells, combined with complement, are actively involved in the processes of restoration of neuronal functions during pathological conditions and remyelination. The focus of this review is to discuss the possibility of creating specific therapeutic antibodies that can activate and fix complement to enhance neuronal survival and promote central nervous system repair after injuries associated with many types of neurodegenerative diseases.

Rice Leaf Diseases Classification Using Deep Learning Algorithms for Smartphone Application Development: An Empirical Study

Rice is the most widely consumed grain across the world. The rice plants often suffer from diseases. Early detection of such diseases and adopting remedial measures can help the farmers to avoid major losses and can produce best-quality crops in large quantities. However, the conventional rice leaf disease detection techniques are often not accurate, time-consuming and sometimes require laboratory testing. In this context, automatic rice leaf disease detection techniques are presented based on the various deep learning classifiers (namely MobileNetV2, ResNet50, VGG16 and Le-Net5) and an Android application is also developed in order to instantly determine the possible rice diseases from the uploaded rice leaf images captured by the smartphone. The developed models are tested using the publicly available benchmark rice leaf dataset containing three types of rice leaf diseases, namely bacterial leaf blight, leaf smut and brown spot. Experimental results show that MobileNetV2 model performed better compared to other models in terms of classification accuracy, recall and [Formula: see text]-score. The results of statistical significance test also confirmed the superiority of the MobileNetV2 model over other compared deep learning models.

Incretin Mimetics as Potential Disease Modifying Treatment for Alzheimer's Disease.

Alzheimer's disease is a devastating neurodegenerative condition that exerts a significant global burden. Despite recent efforts, disease modifying therapies remain extremely limited, with a tremendous proportion of patients having to rely on symptomatic treatment only. Epidemiological and pathological overlaps exist between Alzheimer's disease and diabetes mellitus type 2, with people with diabetes mellitus type 2 at a significantly increased risk of developing Alzheimer's disease in the future. Incretin mimetics, also known as GLP-1/GIP receptor agonists, are useful tools licensed for the treatment of diabetes mellitus type 2 which have recently been the subject of news coverage for their off-label use as weight loss medications. Emerging evidence highlights the possible neuroprotective function of incretin mimetics in models of Alzheimer's disease as well as in clinical studies. This review details the pre-clinical and clinical studies that have explored the effectiveness of incretin mimetics to alleviate Alzheimer's disease associated pathology and cognitive impairment, while also highlighting the progress made to examine the effectiveness of these molecules in Parkinson's disease. Should clinical trials prove effective, incretin mimetics may be able to be repurposed and become useful novel tools as disease-modifying treatments for Alzheimer's disease and other neurodegenerative diseases.