Naphtho[2,1-b]furan, dodecahydro-3a,6,6,9a-tetramethyl-, (3aR,5aS,9aS,9bR)- was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, photoirritation/photoallergenicity, skin sensitization, and environmental safety. Data show that naphtho[2,1-b]furan, dodecahydro-3a,6,6,9a-tetramethyl-, (3aR,5aS,9aS,9bR)- is not genotoxic, provide a calculated Margin of Exposure (MOE) > 100 for the repeated dose toxicity and reproductive toxicity endpoints, and show that there are no safety concerns for naphtho[2,1-b]furan, dodecahydro-3a,6,6,9a-tetramethyl-, (3aR,5aS,9aS,9bR)- for skin sensitization under the current declared levels of use. The photoirritation/photoallergenicity endpoints were evaluated based on data and ultraviolet/visible (UV/Vis) spectra; naphtho[2,1-b]furan, dodecahydro-3a,6,6,9a-tetramethyl-, (3aR,5aS,9aS,9bR)- is not photoirritating/photoallergenic. The local respiratory toxicity endpoint was evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class III material, and the exposure to naphtho[2,1-b]furan, dodecahydro-3a,6,6,9a-tetramethyl-, (3aR,5aS,9aS,9bR)- is below the TTC (0.47 mg/day). The environmental endpoints were evaluated; naphtho[2,1-b]furan, dodecahydro-3a,6,6,9a-tetramethyl-, (3aR,5aS,9aS,9bR)- was found not to be Persistent, Bioaccumulative, and Toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use (VoU) in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.
Background Chronic nonbacterial osteomyelitis (CNO), sometimes also referred to as chronic recurrent multifocal osteomyelitis (CRMO), is a rare autoinflammatory bone disease primarily affecting children and adolescents. In the absence of diagnostic criteria and biomarkers, CNO remains a diagnosis of exclusion, and treatment is largely empiric. Objective This initiative of the German Society of Pediatric and Adolescent Rheumatology (GKJR) aimed to develop evidence-, practice-, and consensus-based recommendations for the diagnosis and management of CNO, incorporating current knowledge on pathophysiology, therapeutic strategies and disease monitoring. Methods Based on a systematic literature review and a subsequent Delphi survey, preliminary statements were developed. This was followed by expert group voting exercises (nominal group exercise) to agree final statements and recommendations. Results Statements and recommendations were developed for the diagnosis, treatment and disease monitoring of CNO in a multidisciplinary expert group, involving patients/families. Where available, diagnostic workup should include whole-body skeletal imaging (usually MRI). Treatment options include first-line (NSAIDs, short-term corticosteroids) and second-line (conventional and/or biologic DMARDs, bisphosphonates) agents. In patients with vertebral involvement, rapid treatment with bisphosphonates and/or TNF inhibitors is recommended. As CNO is a chronic disease, long-term monitoring is recommended, including follow-up after treatment discontinuation. Conclusion Although evidence levels are low to moderate, consensus statements and recommendations provide structured guidance for clinicians diagnosing and treating CNO. They provide a framework for harmonized care aiming at improved long-term outcomes.
Neuroinflammation is deeply intertwined with dopaminergic (DA) neurodegeneration in Parkinson’s disease (PD). We tested whether delphinidin, an anthocyanidin with reported inflammasome/NF-κB modulatory activity, alters neuroinflammation and nigrostriatal integrity in a progressive AAV1/2-A53T α-synuclein (hαSYN) mouse model. Once-daily intraperitoneal delphinidin for nine weeks modestly ameliorated asymmetric forepaw use, attenuated the hαSYN-induced loss of striatal TH⁺ terminal density, and was associated with modest alterations in dopamine turnover, yet did not prevent the loss of DA neurons in the substantia nigra (SN). On the immunological level, delphinidin attenuated the innate immune response by reducing the number and activity of CD11b+ microglia in both the SN and striatum. In contrast, CD4+-mediated adaptive inflammation remained unchanged, while the number of CD8+ T cells increased in the SN. Notably, approximately 48% of CD8+ T cells in the SN of these mice were identified as CD8+CD122+ regulatory T cells, known for their anti-inflammatory properties. In conclusion, delphinidin was associated with a partial attenuation of neuroinflammatory changes and a context-dependent shift towards a more anti-inflammatory CD8⁺CD122+ T cell phenotype in the SN. However, these changes did not translate into protection of SN DA somata, revealing a dissociation between striatal terminal preservation and nigral cell body survival, and underscoring the limitations of targeting innate immunity alone under the current dosing paradigm.
BackgroundThere is mounting evidence that conventional replacement strategies with calcium and vitamin D are insufficient to fully prevent complications of chronic hypoparathyroidism (HypoPT) in all patients.MethodsTo investigate the disease burden of chronic HypoPT, we performed a survey in 205 HypoPT patients (159 females; median age 55 years; median disease duration 16 years). Patients received a disease-specific questionnaire asking for subjective health status, comorbidities, disease-related emergencies and interference of HypoPT with daily and work life. Patients were further assessed by the SF-36 questionnaire. Data was compared to sex- and age-matched subjects from the Study of Health in Pomerania SHIP-START, the German Health Interview and Examination Survey for Adults (DEGS1) and to 214 patients with adrenal insufficiency.ResultsClinical symptoms associated with HypoPT during the past 12 months were reported by 92% of patients, requiring medical intervention in 32%. Since primary diagnosis of HypoPT, 36% of patients had presented at least once at an emergency department due to severe hypocalcemia (14.7 events per 100 patient years). Trigger factors for hypocalcemic symptoms were reported by 76% of patients (e.g. physical activity, infections, hot weather). In comparison to population-based controls, patients with HypoPT showed a higher prevalence of renal insufficiency (11% vs. 2%, p<0.001) and more frequently received antihypertensive (44% vs. 34%; p=0.003) and antiepileptic drugs (5% vs. 2%, p=0.01). Lifetime prevalence of both depression (22% vs. 15%, p=0.003) and anxiety (21% vs. 6%, p<0.001) were increased in HypoPT. SF-36 values indicated significantly reduced subjective health status in HypoPT patients compared to controls as well as patients with adrenal insufficiency.ConclusionDespite established treatment, chronic HypoPT is associated with a variety of symptoms with a significant impact on daily life and work life.Trial registrationhttps://ClinicalTrials.gov/NCT03437174.
OBJECTIVES:No app-based nonpharmacological intervention has yet demonstrated to meaningfully improve disease activity, functional status, and disease-specific quality of life in axial spondyloarthritis (axSpA). We evaluated Axia, a CE-marked smartphone application designed for axSpA, that combines personalised exercise therapy, patient education, and disease management, supported by gamification for long-term adherence. METHODS:To evaluate its clinical efficacy, a 12-week monocentric randomised controlled interventional trial was conducted involving 200 patients with axSpA with stable pharmacotherapy. Patients were randomised (1:1) to either using Axia (intervention group [IG]) or standard of care (control group [CG]). RESULTS:A total of 186 participants (mean age 50.61 years, 66% females, 56% with radiographic axSpA, mean Bath Ankylosing Spondylitis Disease Activity Index [BASDAI] 5.17, and 58% received biologicals or Janus kinase inhibitors) completed the study (95 in the IG and 91 in the CG). Compared to CG, participants in the IG demonstrated significant improvements in BASDAI (analysis of covariance [ANCOVA]-estimated group difference: -1.508, P < .001), Bath Ankylosing Spondylitis Functional Index (-1.139; P < .001), and Ankylosing Spondylitis Quality of Life questionnaire (-2.297; P < .001), all exceeding minimal clinically important difference thresholds. A significantly higher proportion of patients in the IG achieved an Assessment of Spondyloarthritis International Society (ASAS)20 response compared to the CG (51% vs 9%; P < .001), and the ASAS40 response rate was also higher (23% vs 3%; P < .001). No concerning safety signals were observed. CONCLUSIONS:These findings support the potential of Axia as a safe and effective nonpharmacological intervention to further improve the state of care of patients with axSpA in addition to conventional anti-inflammatory pharmacotherapy.
