Disease-modifying Drugs Research Articles

C-type natriuretic peptide suppresses VEGFa gene expression by attenuating IL6-STAT3 signal pathway in primary synovial fibroblasts from rat knee.

C-type natriuretic peptide (CNP) can be a new disease-modifying anti-osteoarthritis drug (DMOAD) candidate because intraarticular injection of CNP attenuates both articular cartilage degradation and persistent pain in a rat knee arthritis model. This study aimed to elucidate the underlying molecular mechanisms by which CNP protects the knee joint from osteoarthritic changes. Gene expression analyses indicated that CNP did not interfere with the expression of IL1β -responsive genes in rat primary synovial fibroblasts or the monocytic cell line, RAW264.7cells. In contrast, total RNA sequence analyses indicated that CNP negatively regulated the IL6-STAT3 signaling pathway and VEGFa gene expression in rat synovial fibroblasts. As previously indicated, IL6 induced phosphorylation of 705Tyr residue of STAT3 and its nuclear translocation to activate VEGFa gene expression; however, in this study, we showed that CNP induced phosphorylation of 727Ser residue and inhibited IL6-induced nuclear translocation of STAT3. Since the IL6 pathway has been shown to accelerate articular cartilage degradation and induce knee pain, our data suggest that CNP can act as a DMOAD by negatively regulating IL6-mediated proinflammatory signals in the knee joint.

Deciphering the Role of Adrenergic Receptors in Alzheimer's Disease: Paving the Way for Innovative Therapies.

Neurodegenerative diseases are currently among the most devastating diseases with no effective disease-modifying drugs in the market, with Alzheimer's disease (AD) being the most prevalent. AD is a complex multifactorial neurodegenerative disorder characterized by progressive and severe cognitive impairment and memory loss. It is the most common cause of progressive memory loss (dementia) in the elderly, and to date, there is no effective treatment to cure or slow disease progression substantially. The role of adrenergic receptors in the pathogenesis of Alzheimer's disease and other tauopathies is poorly understood or investigated. Recently, some studies indicated a potential benefit of drugs acting on the adrenergic receptors for AD and dementias, although due to the heterogeneity of the drug classes used, the results on the whole remain inconclusive. The scope of this review article is to comprehensively review the literature on the possible role of adrenergic receptors in neurodegenerative diseases, stemming from the use of agonists and antagonists including antihypertensive and asthma drugs acting on the adrenergic receptors, but also from animal models and in vitro models where these receptors have been studied. Ultimately, we hope to obtain a better understanding of the role of these receptors, identify the gaps in knowledge, and explore the possibility of repurposing such drugs for AD, given their long history of use and safety.

Development and Validation of a Tool to Predict Onset of Mild Cognitive Impairment and Alzheimer Dementia

The ability to predict the onset of mild cognitive impairment (MCI) and Alzheimer dementia (AD) could allow older adults and clinicians to make informed decisions about dementia care. To assess whether the age at onset of MCI and AD can be predicted using a statistical modeling approach. This prognostic study used data from 2 aging and dementia cohort studies-the Australian Imaging, Biomarker and Lifestyle (AIBL) study and the Alzheimer's Disease Neuroimaging Initiative (ADNI)-for model development and validation of the Florey Dementia Index (FDI), a tool used to predict the age at onset of MCI and AD in older adults. Data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer (A4) study were used for a simulated trial. Data were collected from 1665 AIBL participants, 2029 ADNI participants, and 93 A4 participants from October 1, 2004, to March 1, 2023. The data analysis was conducted between January and August 2024. Predicted age at onset compared with clinically observed age at onset. Among the 1665 AIBL participants (741 [44.5%] female) and 2029 ADNI participants (925 [45.6%] female), the mean (SD) age at first evaluation was 71.8 (7.1) years and 74.5 (6.7) years, respectively. The FDI achieved mean absolute errors of 2.78 (95% CI, 2.63-2.93) years for predicting MCI onset and 1.48 (95% CI, 1.32-1.65) years for predicting AD onset. In the simulated trial with 93 A4 participants (48 [51.6%] female; mean [SD] age at baseline, 73.4 [5.1] years), the FDI achieved mean absolute errors of 1.57 (95% CI, 1.41-1.71) years for predicting MCI onset and 0.70 (95% CI, 0.53-0.88) years for predicting AD onset. In this prognostic study, the FDI was developed and validated to predict the onset age of MCI and AD. This tool may be useful in organizing health care for older adults with cognitive decline or dementia and in the future may help prioritize patients for the use of disease-modifying monoclonal antibody drugs.

Real-World Prevalence, Incidence and Management ofSystemic Lupus Erythematosus in Germany: ARetrospective Claims Data Analysis.

This study evaluated the prevalence and incidence of systemic lupus erythematosus (SLE) in Germany and explored real-world data on sequence of therapy (SOT; sequence of drugs as prescribed in clinical practice). This retrospective, observational, longitudinal cohort study using German claims data from the WIG2 GmbH Scientific Institute for Health Economics and Health System Research database (January 2011-December 2019), extrapolated to the statutory health insurance (SHI)-insured population, evaluated prevalence and incidence in an epidemiological analysis group and SLE treatment patterns in an incident cohort (subgroup ≥ 18years of age with incident disease and ≥ 24-month follow-up post index date). Analyses were descriptive. Based on the epidemiological analysis (N = 3017), annual SLE prevalence per 100,000 gradually increased from 40.47 in 2012 to 59.87 in 2019 in the SHI population. In contrast, annual SLE incidence was relatively stable, ranging from 8.83 in 2012 to 8.86 in 2019. In the incident cohort (n = 941), based on SOT analysis (n = 681), treatment gaps of > 60days were common: 67.1%, 51.2% and 54.9% in SOT1, SOT2 and SOT3, respectively. Corticosteroids were the most frequent monotherapy in SOT1 (31.0% vs 0% in SOT2/SOT3); 30.0-70.0% of patients received a corticosteroid combination therapy across SOTs. Over 50% of patients in each SOT received an antimalarial therapy (combination or monotherapies). The use of biologic disease-modifying drugs was low, ranging from 0.4% in SOT1 to 9.7% in SOT3. Our data demonstrate an increased prevalence of SLE with stable incidence in Germany, suggesting improved survival of affected patients. Nevertheless, suboptimal treatment patterns, including limited use of biologics, reflect a high unmet need for optimised and personalised therapies in patients with SLE.

Real-life experience with disease-modifying drugs in hereditary transthyretin amyloid polyneuropathy: A clinical and electrophysiological appraisal.

New treatments have dramatically improved the prognosis for Hereditary Transthyretin Amyloid Polyneuropathy (ATTRv-PN). However, there is a lack of routine follow-up studies outside of therapeutic trials. Our aim was to report the long-term clinical and electrophysiological evolution of a cohort of ATTRv-PN patients and to determine which biomarkers are most sensitive to change. We retrospectively collected neuropathy impairment scale (NIS), polyneuropathy disability scale (PND), overall neuropathy limitation scale (ONLS), rash built overall disability scale (RODS), electrodiagnostic data, motor unit number index (MUNIX), troponin and N-terminal pro-brain natriuretic peptide levels. Electrophysiological worsening was defined as a 20% decrease in previous values. Thirty-five patients, with a median age of 58 (interquartile ranges 42-71) years, were followed for a median of 36 (24-48) months. All patients received a transthyretin stabiliser, gene silencer or liver transplant. Overall assessment of the cohort showed clinical, biological and electrophysiological stability. However, on an individual basis, NIS worsened in 45% of patients (14/31), ONLS in 46% (13/28), PND in 28% (9/32) and RODS in 39% (11/28) at the last follow-up. Motor amplitude sum score decreased in 33% (11/33), amplitude recorded on tibialis anterior muscle in 44% (12/27), sensory amplitude sum score in 39% (11/28) and MUNIX sum score in 27% (7/26). Overall effectiveness of ATTRv-PN treatments in routine care is good. However, individual assessments show up to 40% deterioration over time. Electrophysiological measures are valuable monitoring tools but are not more sensitive to change than clinical scores. Results must be confirmed in larger cohorts.

Predicting Parkinson's Disease Using a Deep-Learning Algorithm to Analyze Prodromal Medical and Prescription Data.

Parkinson's disease (PD) is characterized by various prodromal symptoms, and these symptoms are mostly investigated retrospectively. While some symptoms such as rapid eye movement sleep behavior disorder are highly specific, others are common. This makes it challenging to predict those at risk of PD based solely on less-specific prodromal symptoms. The prediction accuracy when using only less-specific symptoms can be improved by analyzing the vast amount of information available using sophisticated deep-learning techniques. This study aimed to improve the performance of deep-learning-based screening in detecting prodromal PD using medical-claims data, including prescription information. We sampled 820 PD patients and 8,200 age- and sex-matched non-PD controls from Korean National Health Insurance cohort data. A deep-learning algorithm was developed using various combinations of diagnostic codes, medication codes, and prodromal periods. During the prodromal period from year -3 to year 0, predicting PD using only diagnostic codes yielded a high accuracy of 0.937. Adding medication codes for the same period did not increase the accuracy (0.931-0.935). For the earlier prodromal period (year -6 to year -3), the accuracy of PD prediction decreased to 0.890 when using only diagnostic codes. The inclusion of all medication-codes data increased that accuracy markedly to 0.922. A deep-learning algorithm using both prodromal diagnostic and medication codes was effective in screening PD. Developing a surveillance system with automatically collected medical-claims data for those at risk of developing PD could be cost-effective. This approach could streamline the process of developing disease-modifying drugs by focusing on the most-appropriate candidates for inclusion in accurate diagnostic tests.

Psilocybin as a Disease-Modifying Drug—a Salutogenic Approach in Psychiatry.

Treatment with so-called psychedelic drugs, including psilocybin, lysergic acid diethylamide (LSD), and others, is among the most promising recent developments in psychiatry. This review focuses on psilocybin, a substance found in all mushrooms of the genus Psilocybe, because the largest amount of available evidence relates to this drug. This review is based on pertinent publications (since 1969) that were retrieved by a selective search carried out in August 2024 in the PubMed and ScienceDirect databases employing the keywords "psilocybin" AND "long-term effects" AND "mental disorders", with an emphasis on randomized, controlled clinical trials (RCTs). The available RCTs document the efficacy of psilocybin mainly against depression, including otherwise medically refratory depression. Most of the trials revealed a strong effect, with Cohen's d ranging from 0.67 to 2.6; they used a variety of depression scales and follow-up intervals. Evidence was also found for the efficacy of psilocybin against substance use disorders (alcohol in particular) and symptoms of anxiety accompanying life-threatening somatic illnesses, such as cancer. Initial uncontrolled studies have also shown significant improvement after the administration of psilocybin for other indications. Treatment with psilocybin differs fundamentally from classic psychopharmacotherapy. Its potentially transdiagnostic, rapid, and sustainable efficacy and its positive effect on further dimensions of mental health beyond the patient's symptoms and psychopathology imply that it may have disease-modifying and salutogenic mechanisms of action. Psychotherapy accompanied by the administration of psychedelic drugs may turn out to be the first disease-modifying treatment in the history of psychiatry.

Polyneuropathy in Rheumatoid Arthritis (literature review)

Rheumatoid arthritis is the most common rheumatological disease. In addition to joint pathology, it often causes damage of other organs and tissues. This article discusses the possibility of diffuse damage of the peripheral nervous system in rheumatoid arthritis - frequency, mechanisms of damage, peculiarities of the clinical symptoms. The relevance of this problem is due to the possibility of subclinical course of polyneuropathy in rheumatoid arthritis, and, consequently, the lack of diagnosis, while one of its variants - autonomic neuropathy, is a life-threatening pathology. In the presence of pain in the clinical picture of polyneuropathy, problems arise in its interpretation (neuropathic, nociceptive - joint pain), and, therefore, errors in dose adjustment of disease-modifying drugs are possible. For neurologists the problem of polyneuropathy in rheumatoid arthritis is interesting from the point of view of diagnosing the etiology of this disease, which is always a difficult task.

Rehabilitation therapy for aquaporin-4 antibody positive neuromyelitis optica spectrum disorders

Forty-five cases with aquaporin-4 antibody-positive neuromyelitis optica spectrum disorders (NMOSD) who underwent convalescent rehabilitation were studied. After excluding three cases with recurrence during rehabilitation treatment, the Expanded Disability Status Scale of Kurtzke improved a median of 1 point. Corticosteroids were the most used disease-modifying drugs (DMDs). Three cases relapsed during rehabilitation treatment. Six cases developed febrile infections. Thirty-four cases were discharged home, but half of the cases in their 80s were transferred to a medical care hospital. In the rehabilitation treatment of NMOSD, reducing the risk of recurrence by appropriate DMDs and preventing infections are important. Information sharing using a regional collaborative medical care plan is useful.

Synthesis and Antioxidant Effects of Edaravone-Loaded MPEG-2000-DSPE Micelles in Rotenone-Induced PC12 Cell Model of Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder globally that lacks any disease-modifying drug for prevention or treatment. Oxidative stress has been identified as one of the key pathogenic drivers of Parkinson's disease (PD). Edaravone, an approved free-radical scavenger, has proven to have potential against PD by targeting multiple key pathologies, including oxidative stress, focal mitochondria, and neuroinflammation. However, its bioavailability is potentially restricted due to its poor solubility and short half-life. This study aims to develop a simple and effective drug delivery system for edaravone to enhance its solubility, stability, and bioavailability to improve its neuroprotective efficacy. An MPEG-2000-DSPE-edaravone (MDE) micelle was prepared via solvent evaporation using MPEG-2000-DSPE as a carrier to encapsulate edaravone. The morphology, particle size, zeta potential, chemical structure, and edaravone loading of MDE were evaluated. We then investigated whether such targeted edaravone delivery could provide enhanced neuroprotection. A cell model of PD was established in PC12 cells through exposure to rotenone. The effects of MDE on PC12 cells treated with or without rotenone were evaluated using a cell counting kit-8, calcein acetoxymethyl ester (AM)-propidine iodide (PI) staining, and flow cytometry. Cell migration was evaluated using a wound healing assay. Additionally, the intracellular antioxidant study was performed using an ROS-level-detecting DCFH-DA probe, and the mitochondrial membrane potentials were evaluated using a JC-1 assay. MDE with a drug-loading content of 17.6% and an encapsulation efficiency of 92.8% was successfully prepared. The resultant MDE had a mean particle size of 112.97 ± 5.54 nm with a zeta potential of -42 mV. Cytotoxicity assays confirmed that the MDE (≤200 ug/mL) exhibited promising cytocompatibility with no significant effect on cell viability, cell cycle regulation, or apoptosis levels. Likewise, compared with the free edaravone, no effect on cell migration was noted for MDE. MDE might be able to target edaravone delivery into PC12 cells, increasing the mitochondrial membrane potential and providing a significant local antioxidant effect. The results demonstrated that MPEG-2000-DSPE could be a promising material for enhancing edaravone's aqueous solubility, stability, and antioxidant effects. MDE could be a potential drug formulation for treating PD and other diseases in which oxidative stress plays a key role in pathogenesis.

Disease modifying osteoarthritis drug discovery using a temporal phenotypic reporter in 3D aggregates of primary human chondrocytes.

Our aim was to develop a novel approach to identify disease-modifying drugs for osteoarthritis (OA), focusing on stimulating type II collagen anabolism in chondrocytes. As ELISA or western blot are destructive, laborious and time consuming, primary human chondrocytes expressing Gaussia luciferase under the control of the type II collagen promoter were developed and used. We cultured them in 3D cartilage aggregates under physioxia, to temporally screen a natural product library over 3-weeks. Hit compounds were analyzed for their potential targets in silico, first by structure, then by RNA-Seq. Two hit compounds were then further analyzed using biochemical assays, dose-response curves, and histological analyses to confirm their effects on type II collagen expression and chondrogenesis. Aromoline shows promise as a potential disease modifying compound, demonstrating an increase in type II collagen expression within cartilage sourced from chondrocytes of three distinct donors. Aromoline is a bisbenzylisoquinoline alkaloid that has been studied for its antiproliferative, anti-inflammatory, and antimicrobial properties, and we are the first to explore its effects on chondrocytes and chondrogenesis. In silico analysis revealed the dopamine receptor D4 (DRD4) as a potential target, confirmed by type II collagen upregulation after aromoline treatment and with DRD4-specific agonist ABT-724. This novel approach combining in silico and in vitro methods provides a platform for drug discovery in a challenging and under-researched area. In conclusion, a novel drug (aromoline) and target receptor (DRD4) were identified as stimulating type II collagen, with the future goal of treating or preventing OA.

Conventional Synthetic Disease-modifying Drugs Remain the Mainstay of Therapy for Rheumatoid Arthritis in India.

There are limited data on the real-world utilization of disease-modifying antirheumatic drugs (DMARDs) in Indian patients with rheumatoid arthritis (RA). This was a cross-sectional study of a multicentric observational cohort of RA patients across rheumatology clinics at six centers across India. Patients who met the American College of Rheumatology (ACR) 2010 criteria for RA were included. The demographics, disease-related parameters, and current therapy in terms of DMARDs were analyzed using a structured paper or electronic case record form. This study included 4,061 patients with RA across six centers in India. A majority were female (female-to-male ratio, 6:1), and their mean [standard deviation (SD)] age at the time of enrollment was 51 (12.2) years. Rheumatoid factor and/or anti-CCP were positive in 79 and 77%, respectively. Data on DMARDs were available for 3,550 RA patients. Conventional synthetic DMARDs alone were being used in 3,289 (93%), targeted synthetic DMARDs in 203 (6%), and biological DMARDs in 67 (2%). A total of at least 18 separate types or combinations of DMARDs were being prescribed, with the most common being a combination of methotrexate and hydroxychloroquine (22%), methotrexate monotherapy (17%), and a combination of methotrexate and leflunomide (16%). Overall, the most common DMARD prescribed (as monotherapy or in combination) was methotrexate (86%), followed by hydroxychloroquine (52%) and leflunomide (37%). Cs-DMARDs remain the mainstay in the treatment of Indian patients with RA in this study, with the majority being treated with methotrexate alone or in combination with other DMARDs.

Exploring a novel outcome measure of symptom progression in knee osteoarthritis utilizing a large randomized trial.

Explore a newly defined composite measure of symptom progression for knee osteoarthritis (KOA) in a large, randomized study of a potential disease-modifying osteoarthritis drug (DMOAD). Using longitudinal KOA studies, a potential composite endpoint of time to symptom progression was defined as the first occurrence of worsening ofWestern Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain of ≥10 points with no improvement (≤9 point decrease) in WOMAC Function (0-100 scale). A post hoc analysis explored discrimination and association with structural outcomes in the sprifermin FORWARD trial through Years 3 and 5. All treatment arms of the intent-to-treat population were analyzed. Among the 549 FORWARD participants, 442 (80.5%) completed Year 3, and 378 (68.9%) completed Year 5. Sprifermin showed dose-dependent benefits in the time to symptom progression at Year 3 with hazard ratio (95% CI) for each sprifermin treatment arm vs placebo as follows: 100μg every 6 months (Q6M), 0.51 (0.28, 0.93); 100μg Q12M, 0.69 (0.40, 1.20); 30μg Q6M, 0.89 (0.53, 1.50); and 30μg Q12M, 0.80 (0.47, 1.35). Similar findings were seen through Year 5 and for a subgroup based on modern clinical trial inclusion criteria. There were increased numbers of knee replacements in symptom progressors (n=8, 5.6%) vs non-progressors (n=7, 1.7%). The symptom progression endpoint discriminated between placebo and treatment responses in a post hoc analysis of a Phase 2 investigational DMOAD KOA trial. The endpoint requires validation and further exploration in DMOAD clinical trials. NCT01919164.

Synovial Fluid White Blood Cell Count as a Potential Biomarker for the Clinical Severity of Knee Osteoarthritis: A Prospective Study

Knee osteoarthritis is categorized classically as a non-inflammatory arthropathy. However, there has been increasing evidence regarding the supplementary role of inflammation in the pathogenesis and disease progression of knee osteoarthritis. This study aims to identify a potential correlation between synovial fluid white blood cell (SF WBC) count and the severity of knee osteoarthritis clinical presentation. 200 knees (200 patients) were assessed through SF aspiration and cytology analysis for WBC count. All patients have filled out the Knee Injury and Osteoarthritis Outcome Score for clinical correlation. For the 200 knees, there was a statistically significant positive correlation between the severity of osteoarthritis clinical presentation as expressed by the Knee Injury and Osteoarthritis Outcomes Score (KOOS) and the synovial white blood cell count among the studied cases (p-value < 0.001). There was no statistically significant correlation found between the patient's age, sex, or side and KOOS or SF white cell count. The clinical severity of knee osteoarthritis is directly correlated with increased SF white cell count, and hence, SF WBCs may play a role in identifying and grading osteoarthritis clinical severity. This may raise the interest in identifying the role of using specific disease-modifying drugs that deal with the WBC function in cases of osteoarthritis along with other modalities.

Prevalence of, and Disability Due to, Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorder in Japan by the Fifth Nationwide Survey.

All 4 previous nationwide surveys of multiple sclerosis (MS) in Japan were conducted before the discovery of anti-aquaporin-4 (AQP4) antibodies; thus, neuromyelitis optica spectrum disorder (NMOSD) was included in MS, as optic-spinal MS. We aimed to clarify the epidemiologic features and trends of MS and NMOSD in Japan separately using a fifth nationwide survey. The primary survey, in which a questionnaire was sent to 3,799 selected departments (including neurology/internal medicine, pediatrics, and ophthalmology), explored the estimated number and prevalence of patients with MS or NMOSD in 2017, and the secondary survey collected detailed characteristics of the patients using a second questionnaire. The response rates for the primary and secondary surveys were 60.1% and 53.9%, respectively. The estimated total number of patients with MS or NMOSD was 24,800, 2.5-fold higher than that in the fourth survey in 2003. The crude prevalence was 19.6 per 100,000 patients (14.2 for MS and 5.4 for NMOSD), compared with 7.7 per 100,000 patients in the fourth survey. Patients with MS showed milder disability (median Expanded Disability Status Scale [EDSS] score: 2.0 [interquartile range 1.0-4.5] vs 2.5 [1.0-6.0]), decreased secondary progression (8.5% vs 15.2%), and increased usage of disease-modifying drugs (63.7% vs 37.2%) compared with those with conventional MS in the fourth survey. The proportions of oligoclonal bands and Barkhof criteria fulfillment on MRI, which are features of classical MS, increased with advancing year of birth. Patients with NMOSD also showed less disability and shorter disease duration than patients with optic-spinal MS in the fourth survey (EDSS score: 3.5 [2.0-5.5] vs 3.8 [2.0-6.0]; disease duration: 8.0 [3.9-14.8] vs 10.0 [5.0-16.0]). Among patients with NMOSD, disability was exacerbated by a history of longitudinally extensive spinal cord lesions and anti-AQP4 antibody positivity, which both decreased with advancing year of birth. The prevalences of MS (particularly with classical features) and NMOSD have been increasing in Japan, suggesting the contribution of environmental factors. However, disabilities in patients with MS and NMOSD have been mitigated. Extensive usage of various disease-modifying drugs could be a factor contributing to this disability mitigation in MS.

Direct medical costs of polyarthritis in a pediatric hospital in Mexico.

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children. The polyarticular course (polyarthritis) represents 63-66% of patients with JIA. The aim was to determine the direct medical costs (DMC) of JIA of the polyarthritis type in pediatric patients of a tertiary hospital in Mexico. An analysis of the disease costs was developed from the perspective of the Instituto de Seguridad Social del Estado de México y Municipios Maternal and Child Hospital (HMI). The time horizon was 12 years. All patients diagnosed with JIA with polyarticular course treated by the pediatric rheumatology service of the HMI from January to September 2022 and with an active clinical record were included. Different costing techniques were used. The cost components were consultations, medications, hospitalization, and office and laboratory studies. The costs are reported in USD 2021. Twenty-six records of patients with polyarticular arthritis from the HMI were analyzed, with a mean of 4,555.2 USD (standard deviation [SD] = 1,456.7) and a median of 3,828 USD (SD = 1,492) in the first 10 years of treatment. The components of DMC were medications (82.7%), office and laboratory studies (8.4%), hospitalization (8.0%), and consultations (1.8%). Biological disease-modifying drugs (bDMARDs) accounted for 95.3% of the drug component cost. The cost of bDMARDs represented the most critical cost of polyarticular JIA, reflected in the 2nd year of treatment. Including generic bDMARDs and reviewing purchase prices by health institutions in Mexico is necessary.

Pediatric onset multiple sclerosis in Kuwait

BackgroundEpidemiological data of pediatric-onset multiple sclerosis (POMS) in the Middle East is limited. ObjectiveTo determine the demographic and clinical characteristics of POMS in Kuwait. MethodsA retrospective study was conducted to assess the clinical characteristics of multiple sclerosis (MS) patients who disease onset started at age < 18 years and fulfilled the International Pediatric MS Study Group (IPMSSG) criteria for MS. ResultsOf 249 POMS who were assessed, 70.3 % were female. The mean age at onset was 15.06 +11.78 years. Brainstem / cerebellar manifestation (34.9 %) were the most frequent presentation at onset of disease, followed by spinal (29.3 %) and visual pathway (27.3 %) symptoms. At the last follow-up visits, most of the patients (83.5 %) remained in a relapsing-remitting phenotype. The annual relapse rate (ARR) was 0.18 throughout the first 2 years while on treatment. At the baseline visit, the 51.4 % of the cohort-initiated platform therapies. Breakthrough disease (36.1 %) and adverse events (9.6 %) were the most common indications to escalate or switch to other disease-modifying drugs (DMTs). ConclusionMost POMS patients continued to be in a relapsing phenotype in our longitudinal study. Disease breakthrough is common in POMS especially when using platform therapies.

From Fundamentals to Innovation in Alzheimer's Disease: Molecular Findings and Revolutionary Therapies.

Alzheimer's disease (AD) is a global health concern and the leading cause of dementia in the elderly. The prevalence of this neurodegenerative condition is projected to increase concomitantly with increased life expectancy, resulting in a significant economic burden. With very few FDA-approved disease-modifying drugs available for AD, there is an urgent need to develop new compounds capable of impeding the progression of the disease. Given the unclear etiopathogenesis of AD, this review emphasizes the underlying mechanisms of this condition. It explores not only well-studied aspects, such as the accumulation of Aβ plaques and neurofibrillary tangles, but also novel areas, including glymphatic and lymphatic pathways, microbiota and the gut-brain axis, serotoninergic and autophagy alterations, vascular dysfunction, the metal hypothesis, the olfactory pathway, and oral health. Furthermore, the potential molecular targets arising from all these mechanisms have been reviewed, along with novel promising approaches such as nanoparticle-based therapy, neural stem cell transplantation, vaccines, and CRISPR-Cas9-mediated genome editing techniques. Taking into account the overlap of these various mechanisms, individual and combination therapies emerge as the future direction in the AD strategy.

Expression of STAT- and T-cell-related genes in women with first-line treatment of relapsing-remitting multiple sclerosis.

Relapsing-remitting multiple sclerosis is associated with changes in Jak/STAT pathways in immune cells, but the influence of disease-modifying drugs on these pathways is poorly understood. The aim of this study was to evaluate the impact of first-line disease-modifying drugs used in treatment of RRMS on expression of the STAT pathway and T-cell-related genes in the blood and on serum concentrations of sgp130 and TGF-β1 in women, as well as on the level of phosphorylated STAT3 and STAT5 proteins in T cells of untreated patients and heathy controls. Expression of STAT1, STAT3, STAT5A, STAT5B, SOCS1, SOCS3, FOXP3, IKZF2, RORC and ICOS genes in the blood of untreated RRMS patients, in the blood of patients treated with interferon-β, glatiramer acetate, dimethyl fumarate or teriflunomide and in the blood of healthy controls was evaluated using droplet digital PCR. Serum concentrations of sgp130 and TGF-β1 were evaluated by ELISA. Phosphorylated STAT3 and STAT5 protein levels in T cells were evaluated by flow cytometry. STAT3 gene expression was significantly higher in untreated patients than in healthy control, but the level of phosphorylated STAT3 in T cells was significantly lower. Patients treated with interferon-β or dimethyl fumarate had significantly lower STAT3 gene expression. Patients treated with teriflunomide had higher STAT1 gene expression, than untreated patients. Patients treated with dimethyl fumarate also had significantly lower RORC gene expression than untreated patients. The study shows the impact of drugs used in first-line treatment of relapsing-remitting multiple sclerosis on expression of STAT and T-cell-related genes.

Electroacupuncture Inhibits Cartilage Degeneration in a Rat Knee Osteoarthritis (KOA) Model by Suppressing ADAMTS5 Expression.

Background Knee osteoarthritis (KOA) is characterized by cartilage degradation, osteophyte formation, and synovitis. Cartilage degradation in KOA begins with the loss of aggrecan, primarily due to A Disintegrin and Metalloproteinase with Thrombospondin Motif 5 (ADAMTS5), which is produced by chondrocytes and synovial cells and a key target for therapeutic intervention. Current treatments for KOA primarily focus on pain relief, as disease-modifying osteoarthritis drugs (DMOADs) remain unavailable. Electroacupuncture (EA), applying electrical stimulation to acupoints, has been investigated for its potential to alleviate KOA symptoms; however, the specific effects of different acupoint combinations remain unclear. This study investigates the effect of EA on pain and cartilage degeneration in a KOA rat model by examining ADAMTS5 expression in synovial tissue. Materials and methods Male Wistar rats were divided into five groups: control, sham-operated, KOA model, KOA treated with EA at ST36 (Zusanli)-LR8 (Ququan) (KOA+LR8), and KOA treated at ST36-Ex-LE2 (Heding) (KOA+Ex-LE2). The DMM (destabilization of the medial meniscus) procedure induced KOA, and EA was applied thrice weekly for four weeks. The rotarod test was used to assess motor coordination, and samples were collected for immunofluorescence, Western blot, and histological analysis. Pain was assessed via c-fos expression in the spinal cord, while Safranin O-Fast Green staining was used to evaluate cartilage degeneration via the Osteoarthritis Research Society International (OARSI) scoring system. Results The KOA group post-surgery showed reduced motor coordination, while EA at both ST36-LR8 and ST36-Ex-LE2 enhanced performance (day 28: control: 28.8 ± 0.6, sham: 28.4 ± 3.7, KOA: 19.7 ± 0.9, KOA+LR8: 24.8 ± 1.5, KOA+Ex-LE2: 26.9 ± 1.2). Expression of c-fos, elevated in the KOA group, was significantly suppressed by EA (control: 7.6 ± 0.9, sham: 13.6 ± 2.8, KOA: 24.5 ± 2.1, KOA+LR8: 12.8 ± 0.9, KOA+Ex-LE2: 17.0 ± 1.2). Histologically, KOA rats showed severe cartilage degradation and osteophyte formation, while EA at ST36-Ex-LE2 significantly reduced these changes (control: 0.2 ± 0.1, sham: 0.4 ± 0.2, KOA: 1.8 ± 0.4, KOA+LR8: 1.0 ± 0.2, KOA+Ex-LE2: 0.5 ± 0.2). The ST36-LR8 group also showed improvements, although less pronounced than the ST36-Ex-LE2 group. Western blotting revealed that DMM-induced ADAMTS5 expression was significantly inhibited by EA at ST36-Ex-LE2 but not at ST36-LR8 (control: 1.0 ± 0, sham: 1.2 ± 0.4, KOA: 3.0 ± 0.3, KOA+LR8: 2.1 ± 0.3, KOA+Ex-LE2: 1.4 ± 0.4). Conclusion EA at ST36-Ex-LE2 showed a remarkable protective effect on articular cartilage by inhibiting ADAMTS5 expression from synovium, suggesting that it can break the vicious cycle of synovitis and cartilage destruction. In contrast, EA at ST36-LR8 had a moderate effect on cartilage degeneration and ADAMTS5 expression. The difference in efficacy may be due to the anatomical differences between acupoints. ST36-Ex-LE2 coincides with an area rich in synovial fibroblasts and mast cells involved in inflammation and pain. This highlights the importance of acupoint selection to maximize the therapeutic effect of EA. The specificity of this acupoint combination provides a potential strategy for managing KOA and slowing the progression of the disease. Further studies are needed to elucidate the detailed mechanisms behind the effects of EA and explore its potential as an alternative or complementary treatment for KOA.