Unveiling the age-related dynamics in Sjögren's syndrome: Insights from heart rate variability and autonomic function.

BACKGROUND: Sjögren's Syndrome (SS), mainly affecting women in their midlife, is characterized by persistent inflammation in glands producing tears and saliva, often leading to significant complications. This study investigates the differences in autonomic system functioning between individuals with SS and healthy controls. METHODS: From April 2019 to December 2022, 329 diagnosed primary SS (pSS) patients and 30 healthy controls were enrolled at Taipei Veterans General Hospital, Taipei, Taiwan. The study assessed autonomic nervous system functioning using various HRV metrics. Participants were divided based on age and AECG criteria, including salivary gland biopsy and autoantibody status. RESULTS: Significant differences in Heart Rate Variability (HRV) were observed between pSS patients and healthy controls. The total power index was notably lower in pSS patients (4.98 ± 1.29) than in controls (5.54 ± 1.21, p = .022). Additionally, Vagal (VAG) activity was significantly reduced in the pSS group (4.95 ± 1.33) compared to the healthy control group (5.47 ± 1.19, p = .041). Age-stratified analysis highlighted that the ≤50 years pSS group had a higher heart rate (77.74 ± 10.42) compared to the >50 years group (73.86 ± 10.35, p = .005). This group also showed a higher total power index (5.78 ± 1.30) versus the >50 years group (4.68 ± 1.19, p < .001), and significantly lower VAG activity (4.70 ± 1.26, p = .007) compared to healthy controls. Furthermore, the Standard Deviation of Normal-to-Normal Intervals (SDNN) was greater in the ≤50 years SS group (44.45 ± 37.12) than in the >50 years group (33.51 ± 26.18, p = .007). In pSS patients, those positive for both salivary gland biopsy and autoantibodies demonstrated a lower Total Power (4.25 ± 1.32) and R-wave validity (93.50 ± 4.79, p < .05) than other groups, suggesting more severe autonomic imbalance. The R-R interval variation (RRIV) was also significantly higher in this dual-positive group (696.10 ± 975.41, p < .05). Additionally, the ESSPRI for dryness was markedly higher in the dual-positive group (8.10 ± 1.45, p < .05), indicating more severe symptoms. These findings reveal significant variations in autonomic function in SS patients, especially in those with dual-positive biopsy and autoantibody status. CONCLUSION: This study demonstrates significant autonomic dysfunction in pSS patients compared to healthy controls, particularly in those positive for both salivary gland biopsy and autoantibodies. The age-stratified analysis further emphasizes the impact of aging on autonomic system functioning in pSS, suggesting a need for age-specific management approaches in pSS patient care.

Incidence of nerve injury following acupuncture treatments in Taiwan.

OBJECTIVE: Acupuncture, a widely employed traditional therapeutic modality known for its efficacy in pain alleviation and diverse condition management, may inadvertently result in mechanical nerve injury due to its invasive nature. This research aimed to ascertain the incidence of nerve injuries post-acupuncture, identify associated risk factors, and map the distribution of nerve injury sites. METHODS: A case-control study nested in the National Health Insurance Research Database (NHIRD) 2000-2018 two million cohort was conducted. Patients previously diagnosed with nerve injury, surgery, or degeneration before acupuncture were excluded. Cases were defined as patients receiving acupuncture and seeking medical attention for nerve injury (ICD9-CM code 950-957) within 14 days post-procedure, while control groups comprised patients undergoing acupuncture without subsequent adverse events. Invasive treatments prior to adverse events and adverse events occurring more than 14 days post-acupuncture were excluded. To ensure case-control comparability, factors such as age, gender, socioeconomic status, and medical facility environment were controlled using propensity score matching. RESULTS: The study encompassed 14,507,847 acupuncture treatments administered to 886,753 patients, with 8361 instances of post-acupuncture nerve injury identified, representing an incidence rate of approximately 5.76 per 10,000 procedures. Age emerged as a significant risk factor, with the adjusted odds ratios escalating with age. Several comorbidities including diabetes, hypothyroidism, liver cirrhosis, chronic kidney disease, herpes zoster, hepatitis virus, rheumatoid arthritis, systemic lupus erythematosus, dementia, and cerebrovascular accidents were associated with an elevated risk of nerve injury post-acupuncture. CONCLUSION: This study underscores the importance of meticulous patient profiling and cautious therapeutic approach in acupuncture, considering the evident influence of various demographic, systemic, and treatment-related factors on the incidence of nerve injuries.

Polypyrimidine tract-binding protein induces p19(Ink4d) expression and inhibits the proliferation of H1299 cells.

The expression of polypyrimidine tract-binding protein (PTB) is up-regulated in many types of cancer. Here, we studied the role of PTB in the growth of non small cell lung cancer cells. Data showed that PTB overexpression inhibited the growth of H1299 cells at least by inhibiting DNA synthesis. Quantitative real-time PCR and Western blot analyses showed that PTB overexpression in H1299 cells specifically induced the expression of p19(Ink4d), an inhibitor of cyclin-dependent kinase 4. Repression of p19(Ink4d) expression partially rescued PTB-caused proliferation inhibition. PTB overexpression also inhibited the growth and induced the expression of p19(Ink4d) mRNA in A549 cells. However, Western blot analyses failed to detect the presence of p19(Ink4d) protein in A549 cells. To address how PTB induced p19(Ink4d) in H1299 cells, we showed that PTB might up-regulate the activity of p19(Ink4d) gene (CDKN2D) promoter. Besides, PTB lacking the RNA recognition motif 3 (RRM3) was less effective in growth inhibition and p19(Ink4d) induction, suggesting that RNA-binding activity of PTB plays an important role in p19(Ink4d) induction. However, immunoprecipitation of ribonuclearprotein complexes plus quantitative real-time PCR analyses showed that PTB might not bind p19(Ink4d) mRNA, suggesting that PTB overexpression might trigger the other RNA-binding protein(s) to bind p19(Ink4d) mRNA. Subsequently, RNA electrophoretic mobility-shift assays revealed a 300-base segment (designated as B2) within the 3'UTR of p19(Ink4d) mRNA, with which the cytoplasmic lysates of PTB-overexpressing cells formed more prominent complexes than did control cell lysates. Insertion of B2 into a reporter construct increased the expression of the chimeric luciferase transcripts in transfected PTB-overexpressing cells but not in control cells; conversely, overexpression of B2-containing reporter construct in PTB-overexpressing cells abolished the induction of p19(Ink4d) mRNA. In sum, we have shown that PTB plays as a negative regulator in H1299 cell proliferation at least by inducing p19(Ink4d) expression at transcriptional and post-transcriptional levels.

Gene expression profiling suggests a pathological role of human bone marrow-derived mesenchymal stem cells in aging-related skeletal diseases.

Aging is associated with bone loss and degenerative joint diseases, in which the aging of bone marrow-derived mesenchymal stem cell (bmMSC)[1] may play an important role. In this study, we analyzed the gene expression profiles of bmMSC from 14 donors between 36 and 74 years old, and obtained age-associated genes (in the background of osteoarthritis) and osteoarthritis-associated genes (in the background of old age). Pathway analysis of these genes suggests that alterations in glycobiology might play an important role in the aging of human bmMSC. On the other hand, antigen presentation and signaling of immune cells were the top pathways enriched by osteoarthritis-associated genes, suggesting that alteration in immunology of bmMSC might be involved in the pathogenesis of osteoarthritis. Most intriguingly, we found significant age-associated differential expression of HEXA, HEXB, CTSK, SULF1, ADAMTS5, SPP1, COL8A2, GPNMB, TNFAIP6, and RPL29; those genes have been implicated in the bone loss and the pathology of osteoporosis and osteoarthritis in aging. Collectively, our results suggest a pathological role of bmMSC in aging-related skeletal diseases, and suggest the possibility that alteration in the immunology of bmMSC might also play an important role in the etiology of adult-onset osteoarthritis.

A region within the 5'-untranslated region of hypoxia-inducible factor-1alpha mRNA mediates its turnover in lung adenocarcinoma cells.

Previously, we showed that CL1-5 cells express more hypoxia-inducible factor-1alpha (HIF-1alpha) than the parental CL1 cells, which bestows CL1-5 cells a stronger invasive activity. Here, we investigated the mechanisms underlying the differential expression of HIF-1alpha mRNA in CL1 and CL1-5 cells. Data showed that the transcription rate of HIF-1alpha gene in CL1 cells was slightly higher than that of CL1-5 cells, suggesting that the expression of HIF-1alpha mRNA in CL1 cells was repressed by post-transcriptional mechanisms. RNA electrophoretic mobility shift assays revealed a 61-base segment (designated as D5) within the 5'-untranslated repeat of HIF-1alpha mRNA, with which the CL1 cell lysates formed more prominent complexes (including complex I) than did CL1-5 cell lysates. Insertion of D5 into a reporter construct reduced the half-life of the chimeric transcripts in transfected CL1 but not CL1-5 cells; conversely, overexpression of D5-containing reporter construct in CL1 cells increased HIF-1alpha mRNA. We also identified the polypyrimidine tract-binding protein (PTB) as a required component of complex I. Deletion of the RNA recognition motif 1 (RRM1) or RRM3 of PTB abolished the formation of complex I. Our data showed that CL1 cells expressed more PTB than CL1-5 cells. Inhibition of PTB expression in CL1 cells decreased the formation of complex I, whereas overexpression of PTB in CL1-5 cells increased the levels of complex I, decreased the stability of HIF-1alpha and D5-containing chimeric mRNAs, and decreased cell invasiveness. In sum, we have identified in lung adenocarcinoma cells a mechanism that regulates HIF-1alpha expression by modulating HIF-1alpha mRNA stability.

Hypoxia-inducible factor-1alpha regulates matrix metalloproteinase-1 activity in human bone marrow-derived mesenchymal stem cells.

We examined the mRNA levels of hypoxia-inducible factor-1alpha (HIF-1alpha) in bone marrow mesenchymal stem cells (bmMSCs) of eight osteoarthritis patients. BmMSC-1, expressing higher HIF-1alpha mRNA and protein than bmMSC-5, elicited higher matrix metalloproteinase-1 (MMP1) activity and stronger invasive capacity. In vitro invasion assays and quantitative PCR analyses showed that targeted inhibition of HIF-1alpha in bmMSC-1 decreased its invasion and expressions of MMP1 and MMP3, whereas overexpression of HIF-1alpha in bmMSC-5 increased its invasion and expressions of MMP1 and MMP3. Therefore, HIF-1alpha can regulate MMP1 and MMP3 expressions in human bmMSCs, which might suggest a pathophysiological role of bmMSC expressing high HIF-1alpha in bone diseases.

Hypoxia-inducible factor 1alpha regulates lung adenocarcinoma cell invasion.

We studied the role of hypoxia-inducible factor-1alpha (HIF-1alpha) in human lung adenocarcinoma cell invasion using a metastatic cell model composed of low invasive CL1 and highly invasive CL1-5 cells. We showed that HIF-1alpha was expressed in CL1-5 but not in CL1 cells under normoxic condition, and that inhibition of HIF-1alpha expression by a small interfering RNA decreased invasiveness of CL1-5 cells. Complementary, overexpression of HIF-1alpha increased the invasiveness of CL1 and gastric cancer SC-M1 cells. Subsequently, we showed that urokinase-type plasminogen activator receptor (uPAR), and matrix metalloproteinases (MMPs) 1 and 2 were critical in HIF-1alpha-induced invasion. Mechanistic studies revealed that HIF-1alpha overexpression could increase the expression of uPAR and MMP1, but not MMP2. However, ELISA assays on the conditioned media generated from control CL1 and CL1 cells overexpressing HIF-1alpha showed that overexpression of HIF-1alpha increased the levels of endogenous free active MMP2 and total free MMP2, and the former was blocked by inhibition of MMP1 expression. We conclude that (i) HIF-1alpha overexpression enhances lung cancer cell invasion at least through up-regulating the expression and activities of uPAR, MMP1, and MMP2; and (ii) induction of MMP1 participates in cell invasion and also plays an important role in HIF-1alpha-induced activation of MMP2.