Etanercept monotherapy has been studied and approved for treatment of polyarticular juvenile idiopathic arthritis (JIA). The following study evaluates the safety and efficacy of combination therapy ...of etanercept and methotrexate compared to etanercept monotherapy in JIA.
We perfomed an open, non-randomised study on patients who had previously failed to respond to at least one disease-modifying antirheumatic drug (DMARD). A total of 722 patients with JIA in whom at least 1 item of follow-up data was recorded were identified; of these, 118 patients treated with further slow acting drugs were excluded. In all, 504 patients were treated with a combination of etanercept and methotrexate. A total of 100 patients treated with etanercept only were in the control group. Efficacy was calculated using the American College of Rheumatology paediatric scores for 30, 50 and 70% improvement (PedACR30/50/70). Adverse events (AEs) and serious adverse events (SAEs) were reported.
After 12 months 55 patients in the monotherapy group and 376 patients in the etanercept and methotrexate group were available for comparison. For the intention to treat analysis, 65 patients discontinuing treatment prematurely were included. All activity parameters decreased significantly in both treatment groups. After 12 months 81%/74%/62% of patients of the etanercept and methotrexate group and 70%/63%/45% of patients of the etanercept monotherapy group achieved PedACR30/50/70 scores, respectively (p<0.05 for PedACR30, p<0.01 for PedACR70). The likelihood of achieving a PedACR70 increased with combination therapy with an odds ratio of 2.1 (95% CI 1.2 to 3.5). In total, 25 infectious and 23 non-infectious SAEs including 3 malignancies occurred in the etanercept and methotrexate group, and 1 infectious and 3 non-infectious SAEs occurred in the single etanercept group.
The patients' disease activity improved during etanercept monotherapy and etanercept and methotrexate combination therapy. Tolerability in both treatment groups was comparable.
Multidistrict litigation (“MDL”) is an immensely powerful tool. In an MDL, cases that share a common question of fact are consolidated in a single district for pretrial proceedings. MDLs abide by the ...general principle that governs all transfers within the federal system: because transfer is no more than a “housekeeping measure,” an action retains the choice-of-law rules of the state in which it was filed. If a case filed in California is transferred to an MDL pending in Iowa, the transferee court in Iowa applies California’s choice-of-law rules. As a result, the cases maintain their identities through the retention of their individual home state’s choice-of-law rules. It is thus a critical feature of MDLs—which have far fewer procedural protections than class actions—that transfer to an MDL does not change the applicable law for any individual action. In non-aggregate litigation, this general transfer rule no longer applies, however, when a case is transferred pursuant to a forum-selection clause. Under the Supreme Court’s 2013 decision in Atlantic Marine Construction Co. v. U.S. District Court, the transferee court applies its own choice-of-law rules instead. Thus, if a case filed in California is transferred to Iowa in accordance with a forum-selection clause, the transferee court in Iowa applies Iowa’s choice-of-law rules. Although Atlantic Marine involved a non-aggregate proceeding, courts have begun to consider whether this principle should control choice of law in complex litigation governed by a forum-selection clause. This Note argues that it should not. To begin, extending Atlantic Marine to the MDL context might allow the fact of consolidation to change the outcome in a case. Doing so would also expand due process concerns already inherent in aggregate proceedings, and MDL is not an appropriate forum in which to allow parties discretion to craft their own rules of dispute resolution. Accordingly, to preserve the integrity of the MDL process, MDL courts should consistently apply the choice-of-law rules of the transferor court, even when an action is governed by a valid forum-selection clause.
Meibomian gland loss in ocular GvHD was described as a mechanism contributing to dry eye and severe damage to the ocular surface. Infrared images of upper eyelid meibomian glands from 86 ocular GvHD ...patients, from 10 patients after allogeneic stem cell transplantation (aSCT) without ocular GvHD, from 32 patients prior to aSCT and from 30 healthy controls were analyzed retrospectively and evaluated using two grading schemes. The upper meibomian gland area (uMGA) was calculated and set in relation to the total tarsal area of the lid. Results demonstrate that meibomian gland loss is significantly increased in patients with ocular GvHD as well as in patients prior to aSCT in comparison with controls (P between 0.05 and <0.001). Patients after aSCT without ocular GvHD had no significant difference in uMGA in comparison with controls. This study suggests that meibomian gland loss in GvHD patients is likely to be a multifactorial process that also occurs prior to aSCT, possibly due to underlying diseases and/or secondary to chemotherapy or irradiation. In addition, the question has to be addressed whether meibomian gland loss could serve as a predictor for the development of ocular GvHD. Overall, infrared meibography should be included in routine examination of patients undergoing aSCT and during follow-up.
The COVID-19 pandemic has serious social, economic and health consequences. Particularly in these times, it is important to maintain individual health. Therefore, it is important to take part in ...routine health checkups. Consequently, our objective was to describe the frequency and to identify the determinants of postponed routine health checkups.
Cross-sectional data from the nationally representative online-survey “COVID-19 Snapshot Monitoring in Germany (COSMO)” was used (wave 17; July 2020).
In sum, 974 individuals were included in our analytical sample (average age was 45.9 years, SD: 16.5, 18–74 years). Postponed routine health checkups (yes or no) since March 2020 due to the COVID-19 pandemic were assessed.
More than 16% of the individuals reported postponed routine health checkups in the past few months due to the COVID-19 pandemic. Particularly, individuals aged 30–49 years had postponed health checkups (21%). The probability of postponed health checkups was positively associated with the presence of chronic diseases (odds ratio OR: 1.68, 95% confidence interval CI: 1.15–2.47), higher affect regarding COVID-19 (OR: 1.44, 95%-CI: 1.16–1.78), and higher presumed severity of COVID-19 (OR: 1.17, 95%-CI: 1.01–1.35), whereas the outcome measure was not associated with socioeconomic factors. Data showed that a sizeable part (about one of six individuals) of the population reported postponed routine health checkups due to the COVID-19 pandemic between March and July 2020.
Postponed checkups should not be neglected during the COVID-19 pandemic. Individuals at risk for postponed health checkups should be appropriately addressed.
Ultraviolet light B (UVB)-irradiation is linked to various ocular pathologies such as limbal stem cell defects in pterygium. Despite the large circumstantial evidence linking UVB irradiation and ...limbal epithelial stem cell damage, the precise molecular responses of limbal stem cells to UVB irradiation are unclear. Here the effect of UVB irradiation on the putative stem cell phenotype, limbal niche cells and the subsequent effects on corneal (lymph)angiogenic privilege were investigated. Primary human limbal epithelial stem cells and fibroblasts were irradiated with 0.02J/cm2 of UVB, a low dose corresponding to 3min of solar irradiation. UVB irradiation caused significant reduction of limbal epithelial and limbal fibroblast proliferation for 24h, but apoptosis of limbal epithelial stem cells only. Moreover, UVB induced stem-like character loss of limbal epithelial cells, as their colony forming efficiency and putative stem cell marker expression significantly decreased. Interestingly, limbal epithelial cells co-cultured with UVB-irradiated limbal fibroblasts also exhibited loss of stem cell character and decrease of colony forming efficiency. Conditioned media from limbal epithelial cells inhibited lymphatic endothelial cell proliferation and tube network complexity; however this effect diminished following UVB irradiation. In contrast, pro-inflammatory and macrophage-recruiting cytokines such as TNFα, IFNγ and MCP1 were significantly upregulated following cell irradiation of limbal fibroblasts. These data demonstrate the key role of the limbal stem cell niche in response to UVB and subsequent (lymph)angiogenic and inflammatory events. These data suggest that the known pro(lymph)angiogenic effect of UVB irradiation in pterygium is not linked to a direct up-regulation of pro-angiogenic cytokines, but rather to indirect macrophage-recruiting cytokines being upregulated after UVB irradiation.
•UVB caused limbal epithelial cell differentiation.•Limbal epithelial cells co-cultured with irradiated fibroblasts cells also became differentiated.•Limbal fibroblast conditioned medium stimulated lymphatic endothelial activity. This was reversed by UVB•Proangiogenic proteins are downregulated in limbal fibroblasts following UVB•UVB causes an increase in the levels of immune cell recruiting pro-inflammatory proteins
Proteolysis of cellular substrates by caspases (cysteine-dependent aspartate-specific proteases) is one of the hallmarks of apoptotic cell death. Although the activation of apoptotic caspases is ...considered a 'late-stage' event in apoptosis signaling, past the commitment stage, one caspase family member, caspase-2, splits the cell death community into half - those searching for evidence of an apical initiator function of this molecule and those considering it as an amplifier of the apoptotic caspase cascade, at best, if relevant for apoptosis at all. This review screens past and present biochemical as well as genetic evidence for caspase-2 function in cell death signaling and beyond.
Corneal (lymph) angiogenesis is a predominant risk-factor for immune rejection after transplantation. Techniques to regress pre-existing pathological corneal lymphatic vessels prior to ...transplantation are missing so far. Therefore we analysed the possibility to regress corneal lymphatic vessels by photodynamic therapy (PDT), after intrastromal verteporfin injection.
Combined hemangiogenesis and lymphangiogenesis was induced in female BALB/c mice using the murine model of suture-induced inflammatory neovascularisation. Thereafter, the treatment group received an intrastromal injection of verteporfin (controls: phosphate buffered saline (PBS)) followed by PDT. Corneas were excised at different time points (1 day, 5 days and 10 days) after PDT and corneal whole mounts were stained with CD31 and LYVE-1 to quantify hemangiogenesis and lymphangiogenesis.
Whereas blood vessels showed no significant reduction after PDT, lymphatic vessels could significantly be reduced with PDT after intrastromal verteporfin injection: 1 day after PDT, lymphatic vessels were reduced by 62% (p=0.20). After 5 days and 10 days, lymphatic vessels were reduced by 51% and 48% (p<0.001), respectively.
This study for the first time shows that PDT after corneal intrastromal verteporfin injection can selectively regress lymphatic vessels. This may become a new 'preconditioning strategy' to reduce pre-existing corneal lymphatic vessels prior to transplantation and thereby reduce allograft rejection in high-risk patients.
P53-induced protein with a death domain (PIDD) has been described as primary p53 target gene, induced upon DNA damage. More than 10 years after its discovery, its physiological role in the DNA damage ...response remains enigmatic, as it seems to be able to execute life-death decisions in vitro, yet genetic ablation in mice failed to reveal an obvious phenotype. Nonetheless, evidence is accumulating that it contributes to the fine-tuning of the DNA-damage response by orchestrating critical processes such as caspase activation or nuclear factor κB translocation and can also exert additional nuclear functions, for example, the modulation of translesion synthesis. In this review, we aim to integrate these observations and propose possible unexplored functions of PIDD.
Essentials
The role of protein C (PC) activation in experimental autoimmune encephalitis (EAE) is unknown.
PC activation is required for mitochondrial function in the central nervous system.
Impaired ...PC activation aggravates EAE, which can be compensated for by soluble thrombomodulin.
Protection of myelin by activated PC or solulin is partially independent of immune‐modulation.
Summary
Background
Studies with human samples and in rodents established a function of coagulation proteases in neuro‐inflammatory demyelinating diseases (e.g. in multiple sclerosis MS and experimental autoimmune encephalitis EAE). Surprisingly, approaches to increase activated protein C (aPC) plasma levels as well as antibody‐mediated inhibition of PC/aPC ameliorated EAE in mice. Hence, the role of aPC generation in demyelinating diseases and potential mechanisms involved remain controversial. Furthermore, it is not known whether loss of aPC has pathological consequences at baseline (e.g. in the absence of disease).
Objective
To explore the role of thrombomodulin (TM)‐dependent aPC generation at baseline and in immunological and non‐immunological demyelinating disease models.
Methods
Myelination and reactive oxygen species (ROS) generation were evaluated in mice with genetically reduced TM‐mediated protein C activation (TMPro/Pro) and in wild‐type (WT) mice under control conditions or following induction of EAE. Non‐immunological demyelination was analyzed in the cuprizone‐diet model.
Results
Impaired TM‐dependent aPC generation already disturbs myelination and mitochondrial function at baseline. This basal phenotype is linked with increased mitochondrial ROS and aggravates EAE. Reducing mitochondrial ROS (p66Shc deficiency), restoring aPC plasma levels or injecting soluble TM (solulin) ameliorates EAE in TMPro/Pro mice. Soluble TM additionally conveyed protection in WT‐EAE mice. Furthermore, soluble TM dampened demyelination in the cuprizone‐diet model, demonstrating that its myelin‐protective effect is partially independent of an immune‐driven process.
Conclusion
These results uncover a novel physiological function of TM‐dependent aPC generation within the CNS. Loss of TM‐dependent aPC generation causes a neurological defect in healthy mice and aggravates EAE, which can be therapeutically corrected.
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