Nanoparticle system for the local delivery of disease modifying osteoarthritic drugs

Purpose: The purpose of this study is to develop the nanoparticles that i) can be injected intra-articularly ii) target to cartilage due to an opposite charge difference with the extracellular cartilaginous matrix and iii) due to their small size can penetrate into the cartilage. In this way retention time in the joint can be prolonged. By releasing disease modifying OA drugs (DMOAD) in the vicinity of chondrocytes such materials may be beneficial for restoring cartilage tissue homeostasis. Here we demonstrate the generation of drug-containing nanoparticles for intra-articular joint therapy. Methods: We have prepared nanoparticles of biodegradable poly ethylene glycol- poly lactic acid PEG-PLA co-block polymers. The hydrophilic PEG and hydrophobic PLA ends of this polymer make it possible to generate micelles that contain drugs. The polymers are functionalized with UV-sensitive acrylate groups that can be stabilized by UV-crosslinking. These drug containing nanoparticles will be used for intra-articular joint injection and release of DMOADs. We have also established co-culture systems in vitro using MSCs and chondrocytes where the effect of these molecules and nanocarriers can be tested. Results: Micelle type nanoparticles using PEG-PLA co-block polymers were prepared. The obtained dexamethasone loaded nanoparticles had diameters of 20-80 nm. These nanoparticles are photo-crosslinked at their hydrophobic cores which provides stability to the structure and resulted in a slight decrease in average particle size . Dexamethasone was successfully encapsulated in these nanoparticles. The current release profiles show initial burst release in the first 8 hours followed by a sustained release over at least 3 days. Conclusions: We have generated nanoparticles that can serve as a carrier system to deliver clinically relevant disease modifying osteoarthritic drugs in a more effective way after intra-articular injection. We are currently investigating the retention of nanoparticles in the joint and are developing strategies to target these particles to cartilag

Tocilizumab as an Effective Treatment Option in Children with Refractory Intermediate and Panuveitis

Purpose: To describe the results of tocilizumab treatment in children with refractory non-anterior uveitis.Methods: A case series of seven children with refractory non-anterior uveitis (onset ≤16 years) with leakage on fluorescein angiogram (FA) were treated with tocilizumab intravenously every 4 weeks (eight mg/kg). Minimum follow-up was 6 months. Reported outcomes are changes in BCVA, central macular thickness (CMT) on OCT image, FA scores, dose of systemic steroids, complications and side effects.Results: In all patients, there was an improvement of macular edema and capillary leakage on FA. The median FA score decreased from 14 (10-18) at baseline to 8 (2-9) after 6 months of treatment (p = .018). The CMT decreased from 321 (314-384) to 295 (255-312) (p = .043). BCVA improved in five eyes and worsened in one eye due to cataract. No systemic or ocular complications were reported.Conclusion: Tocilizumab is an effective therapeutic option for reducing disease activity in children with refractory non-anterior uveitis

Hysterectomy Does Not Cause Constipation

PURPOSE: This study was designed to evaluate the risk on development and persistence of constipation after hysterectomy. METHODS: We conducted a prospective, observational, multicenter study with three-year follow-up in 13 teaching and nonteaching hospitals in the Netherlands. A total of 413 females who underwent hysterectomy for benign disease other than symptomatic uterine prolapse were included. All patients underwent vaginal hysterectomy, subtotal abdominal hysterectomy, or total abdominal hysterectomy. A validated disease-specific quality-of-life questionnaire was completed before and three years after surgery to assess the presence of constipation. RESULTS: Of the 413 included patients, 344 (83 percent) responded at three-year follow-up. Constipation had developed in 7 of 309 patients (2 percent) without constipation before surgery and persisted in 16 of 35 patients (46 percent) with constipation before surgery. Preservation of the cervix seemed to be associated with an increased risk of the development of constipation (relative risk, 6.6; 95 percent confidence interval, 1.3-33.3; P=0.02). Statistically significant risk factors for the persistence of constipation could not be identified. CONCLUSIONS: Hysterectomy does not seem to cause constipation. In nearly half of the patients reporting constipation before hysterectomy, this symptom will disappear

Next-Generation HLA Sequence Analysis Uncovers Shared Risk Alleles Between Clinically Distinct Forms of Childhood Uveitis

PURPOSE. Classical alleles of the human leukocyte antigen (HLA) complex have been linked to specific entities of pediatric noninfectious uveitis, yet genetic predisposition encoded by the HLA super-locus across the patient population remains understudied. METHODS. We performed next-generation full-length sequencing of HLA-A, HLA-B, HLA-C, HLA-DPB1, HLA-DQB1, and HLA-DRB1 in 280 cases. Dense genotype data from 499 Dutch controls from Genome of the Netherlands were imputed using an HLA-specific reference panel (n = 5225 samples from European ancestry). Cases and controls were compared using logistic regression models adjusting for sex. RESULTS. In total, 179 common and rare alleles were detected. Considering all cases and controls, HLA-DQB1*04:02 and HLA-DRB1*08:01 were identified as the principal HLA association, which was mainly driven by 92 cases with juvenile idiopathic arthritis-associated uveitis (JIA-U). The HLA-DQB1*04:02-HLA-DRB1*08:01 haplotype was also the primary association for the phenotypically similar idiopathic chronic anterior uveitis without arthritis (CAU). Also, HLA-DQB1*05:03 was an independent risk allele for CAU, but not in JIA-U. Analysis of 185 cases with other forms of uveitis revealed HLA-wide associations (P < 2.79 × 10 −4) for HLA-DRB1*01:02, HLA-DRB1*04:03, and HLA-DQB1*05:03, which could be primarily attributed to cases with panuveitis. Finally, amino acid substitution modeling revealed that aspartic acid at position 57 that distinguishes the risk allele HLA-DQB1*05:03 (for CAU and panuveitis) from nonrisk alleles, significantly increased the binding capacity of naturally presented ligands to HLA-DQ. CONCLUSIONS. These results uncovered novel shared HLA associations among clinically distinct phenotypes of pediatric uveitis and highlight genetic predisposition affecting the antigen presentation pathway

Systematic monitoring of needs for care and global outcomes in patients with severe mental illness

<p>Abstract</p> <p>Background</p> <p>It was hypothesised that the introduction of tools that allow clinicians to assess patients' needs and to negotiate treatment (Cumulative Needs for Care Monitor; CNCM), would be associated with global outcome improvements in patients diagnosed with severe mental illness.</p> <p>Methods</p> <p>The CNCM was introduced in one region in South Limburg (the Netherlands) in 1998 (REGION-1998) and in the rest of South Limburg in 2004 (REGION-2004). By comparing these two regions, changes after the introduction of the CNCM could be assessed (between-region comparison). In addition, a pre-post within-patient comparison was conducted in both regions.</p> <p>Results</p> <p>The within-patient comparison revealed that global outcomes of psychopathology and impairment improved in the first 3-5 years after the introduction of the CNCM. The between-region comparison revealed an improvement in global psychopathology but not in global impairment in REGION-2004 after 2004, while there was no such improvement in REGION-1998.</p> <p>Conclusion</p> <p>Systematic clinical monitoring of individual severe mental illness patients, in combination with provision of feedback, is associated with global improvement in psychopathology. More research is needed to determine the degree to which this association reflects a causal effect.</p

Whole Transcriptome Analysis Reveals Heterogeneity in B Cell Memory Populations in Patients With Juvenile Idiopathic Arthritis-Associated Uveitis

Purpose: Patients with juvenile idiopathic arthritis (JIA) are prone to developing chronic anterior uveitis (JIA-U+). Although several risk factors for JIA-U+ have been identified, the underlying etiology is poorly understood. Histopathological studies demonstrate B cell infiltrates in eye tissues of patients with JIA-U+. Methods: We performed transcriptome profiling of peripheral blood CD19-positive B cells taken from 14 cases with JIA-U+, 13 JIA cases without uveitis (JIA-U−), and five healthy controls. Deconvolution-based estimation was used to determine the immune cell fractions for each sample. Results: Deconvolution results revealed that naive B cells made up on average 71% of the CD19-positive cell fractions analyzed. Differential expression analysis identified 614 differentially expressed genes (DEGs) between the groups at nominal significance and six genes at a false discovery rate of 5% (FDR < 0.05). Head-to-head comparison of all JIA-U− versus JIA-U+ revealed no DEGs in the CD19+ B cell pool (FDR < 0.05). However, principal component analysis based on a panel of key genes for B cell subsets revealed that JIA-U+ cases bifurcate into distinct clusters, characterized by markedly disparate expression for genes associated with specific memory B cell populations. CIBERSORT analysis of the overall transcriptome of the new uveitis cluster identified an increased proportion of memory B cells. Conclusion: These data show that JIA-U− and JIA-U+ have a globally similar transcriptome considering the global peripheral CD19-positive B cell pool. However, heterogeneity in B cell memory genes among cases with uveitis suggests a role for specific memory B cell subsets in the etiology of JIA-U+

A Network of Serum Proteins Predict the Need for Systemic Immunomodulatory Therapy at Diagnosis in Noninfectious Uveitis

Purpose: Early identification of patients with noninfectious uveitis requiring steroid-sparing immunomodulatory therapy (IMT) is currently lacking in objective molecular biomarkers. We evaluated the proteomic signature of patients at the onset of disease and associated proteomic clusters with the need for IMT during the course of the disease. Design: Multicenter cohort study. Participants: Two hundred thirty treatment-free patients with active noninfectious uveitis. Methods: We used aptamer-based proteomics (n = 1305 proteins) and a bioinformatic pipeline as a molecular stratification tool to define the serum protein network of a Dutch discovery cohort (n = 78) of patients and healthy control participants and independently validated our results in another Dutch cohort (n = 111) and a United States cohort (n = 67). Multivariate Cox analysis was used to assess the relationship between the protein network and IMT use. Main Outcome Measures: Serum protein levels and use of IMT. Results: Network-based analyses revealed a tightly coexpressed serum cluster (n = 85 proteins) whose concentration was consistently low in healthy control participants (n = 26), but varied among patients with noninfectious uveitis (n = 52). Patients with high levels of the serum cluster at disease onset showed a significantly increased need for IMT during follow-up, independent of anatomic location of uveitis (hazard ratio, 3.42; 95% confidence interval, 1.22-9.5; P = 0.019). The enrichment of neutrophil-associated proteins in the protein cluster led to our finding that the neutrophil count could serve as a clinical proxy for this proteomic signature (correlation: r = 0.57, P = 0.006). In an independent Dutch cohort (n = 111), we confirmed that patients with relatively high neutrophil count at diagnosis (> 5.2 × 10 9/L) had a significantly increased chance of requiring IMT during follow-up (hazard ratio, 3.2; 95% confidence interval, 1.5-6.8; P = 0.002). We validated these findings in a third cohort of 67 United States patients. Conclusions: A serum protein signature correlating with neutrophil levels was highly predictive for IMT use in noninfectious uveitis. We developed a routinely available tool that may serve as a novel objective biomarker to aid in clinical decision-making for noninfectious uveitis