Case report: Immunoglobulin A deficiency in patients with juvenile rheumatoid arthritis treated with aspirin

In three patients with juvenile rheumatoid arthritis, serum IgA concentrations were within the normal limit at the onset of disease and before aspirin administration. After aspirin administration, their serum IgA levels gradually decreased. After discontinuation of aspirin, their serum IgA levels gradually increased. These results suggest that IgA deficiency may be due to aspirin administration in such patients. The IgA production in vitro of peripheral blood mononuclear cells from a patient taken 3 months of discontinuation of aspirin was markedly inhibited by preincubation with aspirin. Since the patients' serum IgG and IgM levels hardly changed the heavy chain class switching may be influenced by aspirin through some undefined mechanisms.Abbreviations CH heavy chain constant region - ³H-TdR ³H-thymidine - Hepes N-2-hydroxyethyl-piperazine-N-2-ethanesulfonic acid - JRA juvenile rheumatoid arthritis - MEM minimum essential medium - PBMCs peripheral blood mononuclear cells - PBS phosphate buffered saline - PFCs plaque forming cells - PWM pokeweed mitogen - SI stimulation index     

Effect of APOE and a polygenic risk score on incident dementia and cognitive decline in a healthy older population

Few studies have measured the effect of genetic factors on dementia and cognitive decline in healthy older individuals followed prospectively. We studied cumulative incidence of dementia and cognitive decline, stratified by APOE genotypes and polygenic risk score (PRS) tertiles, in 12,978 participants of the ASPirin in Reducing Events in the Elderly (ASPREE) trial. At enrolment, participants had no history of diagnosed dementia, cardiovascular disease, physical disability or cognitive impairment. Dementia (adjudicated trial endpoint) and cognitive decline, defined as a >1.5 standard deviation decline in test score for either global cognition, episodic memory, language/executive function or psychomotor speed, versus baseline scores. Cumulative incidence for all‐cause dementia and cognitive decline was calculated with mortality as a competing event, stratified by APOE genotypes and tertiles of a PRS based on 23 common non‐APOE variants. During a median 4.5 years of follow‐up, 324 participants developed dementia, 503 died. Cumulative incidence of dementia to age 85 years was 7.4% in all participants, 12.6% in APOE ε3/ε4 and 26.6% in ε4/ε4. APOE ε4 heterozygosity/homozygosity was associated with a 2.5/6.3‐fold increased dementia risk and 1.4/1.8‐fold cognitive decline risk, versus ε3/ε3 (p < 0.001 for both). High PRS tertile was associated with a 1.4‐fold dementia risk versus low (CI 1.04–1.76, p = 0.02), but was not associated with cognitive decline (CI 0.96–1.22, p = 0.18). Incidence of dementia among healthy older individuals is low across all genotypes; however, APOE ε4 and high PRS increase relative risk. APOE ε4 is associated with cognitive decline, but PRS is not.     

Low-dose aspirin use and survival in breast cancer patients: A nationwide cohort study

BackgroundPreclinical evidence from breast cancer cell lines and animal models suggest that aspirin could have anti-cancer properties. In a large breast cancer patient cohort, we investigated whether post-diagnostic low-dose aspirin use was associated with a reduction in the risk of breast cancer-specific mortality.MethodsWe identified 15,140 newly diagnosed breast cancer patients within the Scottish Cancer Registry. Linkages to the Scottish Prescribing Information System provided data on dispensed medications and breast cancer-specific deaths were identified from National Records of Scotland Death Records. Time-dependent Cox regression models were used to calculate hazard ratios (HR) and 95% CIs for breast cancer-specific and all-cause mortality by post-diagnostic low-dose aspirin use. HRs were adjusted for a range of potential confounders including age at diagnosis, year of diagnosis, cancer stage, grade, cancer treatments received, comorbidities, socioeconomic status and use of statins. Secondary analysis investigated the association between pre-diagnostic low-dose aspirin use and breast cancer-specific and all-cause mortality.ResultsPost-diagnostic users of low-dose aspirin appeared to have increased breast cancer-specific mortality compared with non-users (HR 1.44, 95% CI 1.26, 1.65) but this association was entirely attenuated after adjustment for potential confounders (adjusted HR 0.92, 95% CI 0.75, 1.14). Findings were similar in analysis by increasing duration of use and in analysis of pre-diagnostic low-dose aspirin use.ConclusionIn this large nationwide study of breast cancer patients, we found little evidence of an association between post-diagnostic low-dose aspirin use and cancer-specific mortality.     

An ovary‐specific mucin is associated with choriogenesis mediated by prostaglandin signaling in Spodoptera exigua

Polytrophic ovarioles of Spodoptera exigua, a lepidopteran insect, begins with the development of oocytes and differentiation of nurse cells followed by vitellogenesis and choriogenesis. Compared with previtellogenic and vitellogenic developments, choriogenesis has not been clearly understood yet in endocrine control. This study investigated the expression and function of a mucin‐like structural protein of S. exigua called Se‐Mucin1 in choriogenesis. It was highly expressed in ovarioles containing chorionated oocytes. The expression level of Se‐Mucin1 was increased during adult stage as early as 18 h after adult emergence, reaching the maximal level at 24 h and later. Interestingly, DNA amount of Se‐Mucin1 was increased by almost four folds during early adult stage while other genes (hexokinase and glyceraldehyde‐3‐phosphate dehydrogenase) not directly associated with chorion formation did not show genomic DNA increase, suggesting specific gene amplification of Se‐Mucin1. RNA interference (RNAi) suppressed Se‐Mucin1 expression by injecting 1 μg of double‐strand RNA to teneral females (<5 h after emergence), which exhibited significantly impaired fecundity and egg hatching rate. Eggs laid by RNAi‐treated females were malformed in eggshell structures with loss of mesh‐like fibers. Treatment with aspirin, a prostaglandin (PG) biosynthesis inhibitor, suppressed the induction of Se‐Mucin1 expression during early adult stage and impaired egg development. An addition of PGE₂ significantly rescued such impairment in Se‐Mucin1 expression and subsequent egg development. These results suggest that PGs mediate choriogenesis of S. exigua by activating the expression of chorion‐associated genes including Se‐Mucin1.     

Bioactive lipid mediators in plasma are predictors of preeclampsia irrespective of aspirin therapy

There are few early biomarkers to identify pregnancies at risk of preeclampsia (PE) and abnormal placental function. In this cross-sectional study, we utilized targeted ultra-performance liquid chromatography-ESI MS/MS and a linear regression model to identify specific bioactive lipids that serve as early predictors of PE. Plasma samples were collected from 57 pregnant women prior to 24-weeks of gestation with outcomes of either PE (n = 26) or uncomplicated term pregnancies (n = 31), and the profiles of eicosanoids and sphingolipids were evaluated. Significant differences were revealed in the eicosanoid, (±)11,12 DHET, as well as multiple classes of sphingolipids; ceramides, ceramide-1-phosphate, sphingomyelin, and monohexosylceramides; all of which were associated with the subsequent development of PE regardless of aspirin therapy. Profiles of these bioactive lipids were found to vary based on self-designated race. Additional analyses demonstrated that PE patients can be stratified based on the lipid profile as to PE with a preterm birth linked to significant differences in the levels of 12-HETE, 15-HETE, and resolvin D1. Furthermore, subjects referred to a high-risk OB/GYN clinic had higher levels of 20-HETE, arachidonic acid, and Resolvin D1 versus subjects recruited from a routine, general OB/GYN clinic. Overall, this study shows that quantitative changes in plasma bioactive lipids detected by ultra-performance liquid chromatography-ESI-MS/MS can serve as an early predictor of PE and stratify pregnant people for PE type and risk.     

Nonsteroidal anti-inflammatory drugs as antipyretics and modulators of a molecular clock(s) in the appendix of Sauromatum venosum inflorescence

• The appendix of the Sauromatum senosum inflorescence is a striking example of thermogenesis in plants. On the day of opening, the Sauromatum appendix becomes hot, reaching up to 32 °C. Aspirin, salicylic acid and 2,6-dihydroxybenzoic acid, a subclass of NSAIDs, induce a temperature rise from three mitochondrial sources: alternative oxidase, F₁F_O-ATP synthase and adenine nucleotide translocator. This temperature rise is synchronized and compounded under various light/dark regimes. We studied the effect of different subgroups of NSAIDs on the temperature rise.
• Tissue slices of appendix of Sauromatum and Arum italicum inflorescences at a pre-mature stage were treated with the three inducers in combination with one NSAID under constant light or darkness and under different photoperiods.
• Temperature rise generated by the three heat sources in the presence of inducers and different non-selective NSAIDs were not compounded and occurred at three different times. Under constant light, DuP-697, ibuprofen, flurbiprofen, acetaminophen and diclofenac suppressed the temperature rise induced by the three salicylates. Desynchronization and delayed temperature rise were detected with 6/42-h light/ dark and 15/33-h light/dark regimes in the presence of celecoxib and ibuprofen. With a 24/24-h light/dark regime, temperature rise was suppressed in the presence of ibuprofen. There were differences in response to individual NSAIDs between appendix tissue of A. italicum and S. venosum.
• Mitochondrial energy balance is affected by NSAIDs. There is an interaction between light/dark regime and temperature rise and a relationship between timing mechanism and temperature rise.