Discovery of small-molecule protein stabilizers toward exogenous alpha-l-iduronidase to reduce the accumulated heparan sulfate in mucopolysaccharidosis type I cells.

Synthesis of a series of l-iduronic acid (IdoA)- and imino-IdoA-typed C-glycosides for modulating α-l-iduronidase (IDUA) activity is described. In an enzyme inhibition study, IdoA-typed C-glycosides were more potent than imino-IdoA analogs, with the most potent IdoA-typed C-glycoside 27c showing an IC50 value of 1 µM. On the other hand, co-treatment of 12 with rh-α-IDUA in mucopolysaccharidosis type I (MPS I) fibroblasts exhibited a nearly 3-fold increase of the IDUA activity, resulting in a clear reduction of the accumulated heparan sulfate (HS) compared to the exogenous enzyme treatment alone. This is the first report of small molecules facilitating IDUA stabilization, enhancing enzyme activity, and reducing accumulated HS in MPS I cell-based assays, which reveals that small molecules as rh-α-IDUA stabilizers to improve enzyme replacement therapy (ERT) efficacy toward MPS I is feasible and promising.

Idiopathic Multicentric Castleman Disease with Strikingly Elevated IgG4 Concentration in the Serum and Abundant IgG4-Positive Cells in the Tissue: A Case Report.

Idiopathic multicentric Castleman disease (iMCD) can be challenging to distinguish clinically and histopathologically from Immunoglobulin G4-related disease (IgG4RD). A 73-year-old man was referred to a rheumatologist for suspected autoimmune-related polyclonal hypergammaglobulinemia. The patient had a history of multiple lymphadenopathies in the neck for over 20 years. Laboratory data showed elevated serum immunoglobulin G4 (IgG4) levels, hypergammaglobulinemia, high C-reactive protein (CRP) levels, marked anemia, and positivity for several autoantibodies. Additionally, imaging studies revealed multiple enlarged lymph nodes and multifocal, ill-defined, small patchy opacities over the lung. Biopsies of the neck lymph node and right lung revealed typical features of multicentric Castleman disease (MCD). Immunohistochemical staining was negative for human herpesvirus-8 (HHV-8) in both lymph nodes and the right lung, sub-classified as iMCD, whereas the IgG4/IgG ratio was >40%, which raised the suspicion of IgG4RD. However, serological cytokine analysis demonstrated an increased interleukin-6 (IL-6) level, alongside systemic inflammatory and histopathological features, distinguishing MCD from IgG4RD in this patient. The patient was treated with short-term glucocorticoids and regular infusion of an anti-IL-6 receptor monoclonal antibody (tocilizumab), with satisfactory clinical and radiographic responses. Notably, differentiating MCD from IgG4RD is crucial for optimal treatment. Clinical and pathological features may assist in distinguishing between these two diseases.

High-Intensity Post-Stroke Rehabilitation Is Associated with Lower Risk of Pressure Ulcer Development in Patients with Stroke: Real-World Evidence from a Nationwide, Population-Based Cohort Study.

Background and Objectives: Multiple factors are associated with pressure ulcer (PU) development, including limited mobility following stroke. We performed a nationwide cohort study to investigate the impact of rehabilitation intensity on the incidence of post-stroke PU. Materials and Methods: Data of patients diagnosed with stroke between 2000 and 2012 were collected from the 2000 Longitudinal Health Insurance Database (Taiwan). Based on the number of rehabilitation sessions attended within 90 days of discharge, the rehabilitation intensity was classified as low, medium, or high. After adjusting for sociodemographic factors and comorbidities, the Cox proportional hazards model evaluated the risk of PU development during the 12-year follow-up period. Kaplan−Meier curves were used to estimate the cumulative incidence of PUs. Results: Our study included 18,971 patients who had their first episode of stroke. Of these, 9829 (51.8%) underwent rehabilitation therapy after discharge. Female patients and patients with a National Institutes of Health Stroke Scale (NIHSS) score >13 points, who commenced high-intensity post-stroke rehabilitation after discharge had a significantly lower risk of PU development than those who underwent low-intensity post-stroke rehabilitation after discharge. Cumulative survival analysis showed a significantly lower cumulative incidence of PU during the 12-year follow-up period in the high-intensity rehabilitation group. Conclusion: Compared with low-intensity post-stroke rehabilitation, high-intensity post-stroke rehabilitation after discharge from hospital is associated with a lower risk of post-stroke PU development, especially in female stroke patients and patients with a NIHSS score >13 points. High-intensity rehabilitation is also associated with a significantly lower cumulative incidence of PU events during the 12-year follow-up period.