Association between systemic sclerosis and risk of cerebrovascular and cardiovascular disease: a meta-analysis.

We aimed to evaluate the association between systemic sclerosis (SSc) and major cerebrovascular/cardiovascular risks through a systematic approach. Databases were systematically searched from their inception to October 10, 2023 for studies comparing cerebrovascular/cardiovascular event rates between patients with SSc and controls. The primary outcome was the stroke risk in patients with SSc. Secondary outcomes included risk of myocardial infarction (MI), cardiovascular disease (CVD), peripheral vascular disease (PVD), and venous thromboembolism (VTE). Seventeen studies with 6,642,297 participants were included. SSc was associated with a significantly increased risk of stroke (HR, 1.64; 95% confidence interval [CI], 1.35-2.01), CVD (HR, 2.12; 95% CI, 1.36-3.3), MI (HR, 2.15; 95% CI, 1.23-3.77), VTE (HR, 2.75; 95% CI, 1.77-4.28), and PVD (HR, 5.23; 95% CI, 4.25-6.45). Subgroup analysis revealed a significantly increased stroke risk in the non-Asian group (HR, 1.55; 95% CI, 1.26-1.9), while the Asian group displayed a higher but not statistically significant risk (HR, 1.86; 95% CI, 0.97-3.55). The study found that SSc is associated with a significantly increased risk of cerebrovascular/cardiovascular events. These findings highlight the importance of vasculopathy in SSc and suggest the need for enhanced clinical monitoring and preventive measures in this high-risk population.

Immune pathway activation in neurons triggers neural damage after stroke.

Ischemic brain injury is a severe medical condition with high incidences in elderly people without effective treatment for the resulting neural damages. Using a unilateral mouse stroke model, we analyze single-cell transcriptomes of ipsilateral and contralateral cortical penumbra regions to objectively reveal molecular events with single-cell resolution at 4 h and 1, 3, and 7 days post-injury. Here, we report that neurons are among the first cells that sense the lack of blood supplies by elevated expression of CCAAT/enhancer-binding protein ß (C/EBPß). To our surprise, the canonical inflammatory cytokine gene targets for C/EBPß, including interleukin-1ß (IL-1ß) and tumor necrosis factor α (TNF-α), are subsequently induced also in neuronal cells. Neuronal-specific silencing of C/EBPß or IL-1ß and TNF-α substantially alleviates downstream inflammatory injury responses and is profoundly neural protective. Taken together, our findings reveal a neuronal inflammatory mechanism underlying early pathological triggers of ischemic brain injury.

Sodium arsenite and dimethylarsenic acid induces apoptosis in OC3 oral cavity cancer cells.

Although arsenic is an environmental toxicant, arsenic trioxide (ATO) is used to treat acute promyelocytic leukemia (APL) with anticancer effects. Studies have demonstrated oral cancer is in the top 10 cancers in Taiwan. High rate of oral cancers is linked to various behaviors, such as excessive alcohol consumption and tobacco use. Similarly, betel chewing is a strong risk factor in oral cancer. In the present study, oral squamous carcinoma OC3 cells were investigated with the treatments of sodium arsenite (NaAsO2) and dimethylarsenic acid (DMA), respectively, to examine if arsenic compounds have anti­cancer efforts. It was found that 1 µM NaAsO2 and 1 mM DMA for 24 h induced rounded contours with membrane blebbing phenomena in OC3 cells, revealing cell apoptotic characteristics. In addition, NaAsO2 (10­100 µM) and DMA (1­100 mM) significantly decreased OC3 cell survival. In cell cycle regulation detected by flow cytometry, NaAsO2 and DMA significantly augmented percentage of subG1 and G2/M phases in OC3 cells, respectively. Annexin V/PI double staining assay was further used to confirm NaAsO2 and DMA did induce OC3 cell apoptosis. In mechanism investigation, western blotting assay was applied and the results showed that NaAsO2 and DMA significantly induced phosphorylation of JNK, ERK1/2 and p38 and then the cleavages of caspase­8, ­9, ­3 and poly ADP­ribose polymerase (PARP) in OC3 cells, dynamically. In conclusion, NaAsO2 and DMA activated MAPK pathways and then apoptotic pathways to induce OC3 oral cancer cell apoptosis.

General anesthesia but not conscious sedation improves functional outcome in patients receiving endovascular thrombectomy for acute ischemic stroke: A meta-analysis of randomized clinical trials and trial sequence analysis.

Background: This study aimed at comparing the difference in prognostic outcomes between patients receiving general anesthesia (GA) and conscious sedation (CS) for endovascular thrombectomy after acute ischemic stroke. Methods: Databases from Medline, Embase, Google scholar, and Cochrane library were searched for randomized controlled studies (RCTs) comparing patients undergoing GA and CS for endovascular thrombectomy following anterior circulation ischemic stroke. The primary outcome was frequency of 90-day good functional outcome [defined as modified Rankin Scale score of ≤ 2], while secondary outcomes included successful recanalization rate (SRR) [i.e., modified thrombolysis in cerebral infarction = 2b or 3], mortality risk, symptomatic intracranial hemorrhage (ICH), procedure-related complications, hypotension, pneumonia, neurological outcome at post-procedure 24-48 h, and puncture-to-recanalization time. Results: Six RCTs including 883 patients published between 2016 and 2022 were included. Merged results revealed a higher SRR [risk ratio (RR) = 1.11, 95% CI: 1.03-1.2, p = 0.007; I 2 = 29%] and favorable neurological outcomes at 3-months (RR = 1.2, 95% CI: 1.01-1.41, p = 0.04; I 2 = 8%) in the GA group compared to CS group, without difference in the risk of mortality (RR = 0.88), symptomatic ICH (RR = 0.91), procedure-related complications (RR = 1.05), and pneumonia (RR = 1.9) as well as post-procedure neurological outcome (MD = -0.21) and successful recanalization time (MD = 3.33 min). However, GA was associated with a higher risk of hypotension compared with that of CS. Conclusion: Patients with acute anterior circulation ischemic stroke receiving GA were associated with a higher successful recanalization rate as well as a better 3-month neurological outcome compared to the use of CS. Further investigations are warranted to verify our findings. Systematic review registration: www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022342483, identifier: CRD42022342483.

Association between trace elements and preeclampsia: A retrospective cohort study.

BACKGROUND: Preeclampsia is the main cause of maternal and perinatal death. Multiple studies suggest that trace elements were associated with preeclampsia, but the results varied, and less known about early or mid-term pregnancy of trace elements and preeclampsia. We aim to explore the association between mid-term pregnancy trace elements levels and preeclampsia. METHODS: The retrospective cohort study was consecutively conducted in Foshan Fosun Chancheng Hospital, Guangdong Province, China, from August 1, 2019, to November 30, 2019. Trace elements are derived from the laboratory data system, measured in maternal whole blood during 12-27 (+6) weeks of pregnancy by flame atomic absorption spectrometer method. Preeclampsia diagnosis and covariance were ascertained from the electronic medical records system. We used multivariable logical regression to estimate odds ratios (OR) and 95% CIs. RESULTS: A total of 2186 participants were included in this study, and 59 (2.70%) women developed preeclampsia. After multivariable adjustment, the OR of Mg levels for preeclampsia was 0.35 (95%CI:0.06,2.20). The fifth quintiles of Mg were associated with 0.29 (95% CI：0.10,0.85) times lower risk of preeclampsia compared with the first quintile, with a dose-response trend (P for trend = 0.056). Per 1 µmol/L increment in Cu was associated with 11% lower risk of preeclampsia (OR=0.89; 95% CI, 0.78,1.02). Compared with the first quintile, the second, third，fourth，fifth quintile of Cu was associated with a odd ratio of 0.12 (95% CI:0.03,0.43),0.67 (95% CI:0.30,1.48),0.33 (95% CI:0.15,0.76) and 0.26 (95% CI:0.10,0.66),respectively. Null associations were observed for Zn, Fe, Ca. CONCLUSIONS: Higher blood Mg and Cu levels in mid-term pregnancy were associated with lower preeclampsia risk.

Arsenic compounds induce apoptosis by activating the MAPK and caspase pathways in FaDu oral squamous carcinoma cells.

For a number of years, oral cancer has remained in the top ten most common types of cancer, with an incidence rate that is steadily increasing. In total, ~75% oral cancer cases are associated with lifestyle factors, including uncontrolled alcohol consumption, betel and tobacco chewing, and the excessive use of tobacco. Notably, betel chewing is highly associated with oral cancer in Southeast Asia. Arsenic is a key environmental toxicant; however, arsenic trioxide has been used as a medicine for the treatment of acute promyelocytic leukemia, highlighting its anticancer properties. The present study aimed to investigate the role of arsenic compounds in the treatment of cancer, using FaDu oral squamous carcinoma cells treated with sodium arsenite (NaAsO2) and dimethyl arsenic acid (DMA). The results demonstrated that FaDu cells exhibited membrane blebbing phenomena and high levels of apoptosis following treatment with 10 µM NaAsO2 and 1 mM DMA for 24 h. The results of cell viability assay demonstrated that the rate of FaDu cell survival was markedly reduced as the concentration of arsenic compounds increased from 10 to 100 µM NaAsO2, and 1 to 100 mM DMA. Moreover, flow cytometry was carried out to further examine the effects of arsenic compounds on FaDu cell cycle regulation; the results revealed that treatment with NaAsO2 and DMA led to a significant increase in the percentage of FaDu cells in the sub­G1 and G2/M phases of the cell cycle. An Annexin V/PI double staining assay was subsequently performed to verify the levels of FaDu cell apoptosis following treatment with arsenic compounds. Furthermore, the results of the western blot analyses revealed that the expression levels of caspase­8, ­9 and ­3, and poly ADP­ribose polymerase, as well the levels of phosphorylated JNK and ERK1/2 were increased following treatment with NaAsO2 and DMA in the FaDu cells. On the whole, the results of the present study revealed that treatment with NaAsO2 and DMA promoted the apoptosis of FaDu oral cancer cells, by activating MAPK pathways, as well as the extrinsic and intrinsic apoptotic pathways.

Cordycepin Induces Apoptosis through JNK-Mediated Caspase Activation in Human OEC-M1 Oral Cancer Cells.

Cordycepin, a bioactive compound extracted from Cordyceps sinensis, can induce apoptosis in human OEC-M1 oral cancer cells. However, the exact mechanism is still unclear. The present study aimed to investigate the underlying mechanism of cordycepin-induced apoptosis in OEC-M1 cells. Following treatment with cordycepin, apoptosis was examined and quantified using a DNA laddering assay and a cytokeratin 18 fragment enzyme-linked immunosorbent assay, respectively. Expressions of mitogen-activated protein kinases (MAPKs) and apoptosis-related proteins were detected by the western blot analysis. Our results show that a pan-caspase inhibitor, Z-VAD-FMK, could significantly inhibit cordycepin-induced apoptosis in OEC-M1 cells. In addition, treatment with cordycepin not only activated caspase-8, caspase-9, and caspase-3 but also induced Bid and poly ADP-ribose polymerase cleavages. Furthermore, cordycepin also induced the activation of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase, and p38 MAPKs. Among MAPKs, activation of JNK solely contributed to cordycepin-induced apoptosis with the activation of caspase-8, caspase-9, and caspase-3 and cleavage of PARP. Taken together, the present study demonstrated that cordycepin activated JNK and caspase pathways to induce apoptosis in OEC-M1 cells.

Strategy of harvesting extended thoracodorsal artery perforator flaps for resurfacing the large soft-tissue defects of extremities.

BACKGROUND: The authors presented their strategy to harvest extended thoracodorsal artery (TDA) perforator flaps for resurfacing the large soft-tissue defects of extremities. MATERIALS AND METHODS: Thirty-three free extended TDA perforator flaps were harvested in 33 patients. The mean flap size was 145.2 cm2. The maximal flap length and the width were 30 cm and 10 cm, respectively. The color Doppler sonography (CDS) was used for preoperative assessment of perforators. Indocyanine green angiography (ICGA) was used for intraoperative assessment of flap viability in three patients. RESULTS: The vascular thrombosis, donor-site scar widening, and delayed recipient-site wound healing were not significantly related to the patient and flap characteristics. Flap tip or partial necrosis was significantly related to age and peripheral vascular disease. True positive rate, false negative rate, and positive predictive value of CDS for perforator identification were not different significantly between attending surgeon and residents. In the distance discrepancy of CDS, significant difference was found based on the classifications of perforator size, perforator type, and sonographic operator. The ICGA identified a hypoperfused distal area in a 30 cm long flap. CONCLUSION: The CDS locates the TDA perforators more precisely when scanned by experienced hands, in larger size or septocutaneous perforators. Using reliable and more perforators, applying muscle-sparing technique, considering suprafascial course of perforator and proper flap orientation are helpful in harvesting extended TDA perforator flaps. ICGA is an option for assessing flap viability, especially in elders and patients with peripheral vascular diseases.

FGF9/FGFR1 promotes cell proliferation, epithelial-mesenchymal transition, M2 macrophage infiltration and liver metastasis of lung cancer.

Fibroblast growth factors 9 (FGF9) modulates cell proliferation, differentiation and motility for development and repair in normal cells. Abnormal activation of FGF9 signaling is associated with tumor progression in many cancers. Also, FGF9 may be an unfavorable prognostic indicator for non-small cell lung cancer patients. However, the effects and mechanisms of FGF9 in lung cancer remain elusive. In this study, we investigated the FGF9-induced effects and signal activation profiles in mouse Lewis lung carcinoma (LLC) in vitro and in vivo. Our results demonstrated that FGF9 significantly induced cell proliferation and epithelial-to-mesenchymal transition (EMT) phenomena (migration and invasion) in LLC cells. Mechanism-wise, FGF9 interacted with FGFR1 and activated FAK, AKT, and ERK/MAPK signal pathways, induced the expression of EMT key proteins (N-cadherin, vimentin, snail, MMP2, MMP3 and MMP13), and reduced the expression of E-cadherin. Moreover, in the allograft mouse model, intratumor injection of FGF9 to LLC-tumor bearing C57BL/6 mice enhanced LLC tumor growth which were the results of increased Ki67 expression and decreased cleaved caspase-3 expression compared to control groups. Furthermore, we have a novel finding that FGF9 promoted liver metastasis of subcutaneous inoculated LLC tumor with angiogenesis, EMT and M2-macrophage infiltration in the tumor microenvironment. In conclusion, FGF9 activated FAK, AKT, and ERK signaling through FGFR1 with induction of EMT to stimulate LLC tumorigenesis and hepatic metastasis. This novel FGF9/LLC allograft animal model may therefore be useful to study the mechanism of liver metastasis which is the worst prognostic factor for lung cancer patients with distant organ metastasis.

Inflammasomes and Fibrosis.

Fibrosis is the final common pathway of inflammatory diseases in various organs. The inflammasomes play an important role in the progression of fibrosis as innate immune receptors. There are four main members of the inflammasomes, such as NOD-like receptor protein 1 (NLRP1), NOD-like receptor protein 3 (NLRP3), NOD-like receptor C4 (NLRC4), and absent in melanoma 2 (AIM2), among which NLRP3 inflammasome is the most studied. NLRP3 inflammasome is typically composed of NLRP3, ASC and pro-caspase-1. The activation of inflammasome involves both "classical" and "non-classical" pathways and the former pathway is better understood. The "classical" activation pathway of inflammasome is that the backbone protein is activated by endogenous/exogenous stimulation, leading to inflammasome assembly. After the formation of "classic" inflammasome, pro-caspase-1 could self-activate. Caspase-1 cleaves cytokine precursors into mature cytokines, which are secreted extracellularly. At present, the "non-classical" activation pathway of inflammasome has not formed a unified model for activation process. This article reviews the role of NLRP1, NLRP3, NLRC4, AIM2 inflammasome, Caspase-1, IL-1ß, IL-18 and IL-33 in the fibrogenesis.

Association of blood lead levels with preeclampsia: A cohort study in China.

BACKGROUND: Preeclampsia is the main cause of maternal and perinatal death, especially in developing countries. Multiple studies suggest that blood lead levels in pregnancy are a risk factor for preeclampsia, even with low levels of blood lead. But less knows the dose-effect relationship of preeclampsia in low blood lead levels. OBJECTIVES: This study aims to assess the association between blood lead levels and preeclampsia and to explore its dose-effect relationship between low blood lead levels and preeclampsia. METHODS: The retrospective cohort study was consecutively conducted in a comprehensive tertiary hospital in Foshan city of Guangdong Province, China, from August 1, 2019, to November 30, 2019. Blood lead levels were measured in maternal whole blood in 12-27 (+6) weeks of pregnancy, using atomic absorption spectrometer. Preeclampsia diagnosis was ascertained from the electronic medical records system. The risk of preeclampsia was estimated by multivariable logical regression analysis, and a two-stage linear regression model was established to find out the dose-effect. RESULTS: A total of 2174 people were included in this study, and 59 (2.7%) women developed preeclampsia. The dose-effect analysis revealed a non-linear association between blood lead levels and the risk of preeclampsia, with a cut-off point at 4.2 µg/dl. When blood lead levels were over 4.2 µg/dl, the risk of preeclampsia increased significantly with an increase in blood lead levels (OR = 2.05, 95%CI: 1.50, 2.81). In the multivariate regression models, per 1 µg/dl increment in blood lead levels was associated with 43% higher risk of developing preeclampsia (OR = 1.43,95%CI:1.17,1.74). Moreover, the association between blood lead levels and preeclampsia was stable in different subgroups. CONCLUSIONS: Low levels of lead exposure had a dose-effect relationship of preeclampsia, with a cut-off point at 4.2 µg/dl. Blood lead levels had a non-linear association with preeclampsia. When the blood lead levels were higher than 4.2 µg/dl, the risk of preeclampsia increases by 105% for every 1 µg/dl increase in blood lead levels.

High-energy x-ray radiation effects on the exfoliated quasi-two-dimensional ß-Ga2O3 nanoflake field-effect transistors.

The effects of x-ray irradiation on the mechanically exfoliated quasi-two-dimensional (quasi-2D) ß-Ga2O3 nanoflake field-effect transistors (FETs) under the condition of biasing voltage were systematically investigated for the first time. It has been revealed that the device experienced two stages during irradiation. At low ionizing doses (<240 krad), the device performance is mainly influenced by the photo-effect and the subsequent persistent photocurrent (PPC) effect as a result of the pre-existing electron traps (e-trap) in the oxides far away from the SiO2/ß-Ga2O3 interface. At larger doses (>240 krad), the device characteristics are dominated by the radiation-induced structural or compositional deterioration. The newly-generated e-traps are found located at the SiO2/ß-Ga2O3 interface. This study shed light on the future radiation-tolerant device fabrication process development, paving a way towards the feasibility and practicability of ß-Ga2O3-based devices in extreme-environment applications.

Parathyroid hormone-related protein induces fibronectin up-regulation in rat mesangial cells through reactive oxygen species/Src/EGFR signaling.

Parathyroid hormone-related protein (PTHrP) is known to be up-regulated in both glomeruli and tubules in patients with diabetic kidney disease (DKD), but its role remains unclear. Previous studies show that PTHrP-induced hypertrophic response in mesangial cells (MCs) and epithelial-mesenchymal transition (EMT) in tubuloepithelial cells can be mediated by TGF-ß1. In the present study, although long-term PHTrP (1-34) treatment increased the mRNA and protein level of TGF-ß1 in primary rat MCs, fibronectin up-regulation occurred earlier, suggesting that fibronectin induction is independent of TGF-ß1/Smad signaling. We thus evaluated the involvement of epidermal growth factor receptor (EGFR) signaling and found that nicotinamide adenine dinucleotide phosphate oxidase-derived reactive oxygen species mediates PTHrP (1-34)-induced Src kinase activation. Src phosphorylates EGFR at tyrosine 845 and then transactive EGFR. Subsequent PI3K activation mediates Akt and ERK1/2 activation. Akt and ERK1/2 discretely lead to excessive protein synthesis of fibronectin. Our study thus demonstrates the new role of PTHrP in fibronectin up-regulation for the first time in glomerular MCs. These data also provided new insights to guide development of therapy for glomerular sclerosis.

Soluble Epoxide Hydrolase Inhibitor and 14,15-Epoxyeicosatrienoic Acid-Facilitated Long-Term Potentiation through cAMP and CaMKII in the Hippocampus.

Epoxyeicosatrienoic acids (EETs) are derived from arachidonic acid and metabolized by soluble epoxide hydrolase (sEH). The role of EETs in synaptic function in the central nervous system is still largely unknown. We found that pharmacological inhibition of sEH to stabilize endogenous EETs and exogenous 14,15-EET significantly increased the field excitatory postsynaptic potential (fEPSP) response in the CA1 area of the hippocampus, while additionally enhancing high-frequency stimulation- (HFS-) induced long-term potentiation (LTP) and forskolin- (FSK-) induced LTP. sEH inhibitor (sEHI) N-[1-(oxopropyl)-4-piperidinyl]-N'-[4-(trifluoromethoxy) phenyl)-urea (TPPU) and exogenous 14,15-EET increased HFS-LTP, which could be blocked by an N-methyl-D-aspartate (NMDA) receptor subunit NR2B antagonist. TPPU- or 14,15-EET-facilitated FSK-mediated LTP can be potentiated by an A1 adenosine receptor antagonist and a phosphodiesterase inhibitor, but is prevented by a cAMP-dependent protein kinase (PKA) inhibitor. sEHI and 14,15-EET upregulated the activation of extracellular signal-regulated kinases (ERKs) and Ca2+/calmodulin- (CaM-) dependent protein kinase II (CaMKII). Phosphorylation of synaptic receptors NR2B and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluR1 was increased by TPPU and 14,15-EET administration. These results indicated that EETs increased NMDAR- and FSK-mediated synaptic potentiation via the AC-cAMP-PKA signaling cascade and upregulated the ERKs and CaMKII, resulting in increased phosphorylation of NR2B and GluR1 in the hippocampus.

Dual roles of parathyroid hormone related protein in TGF-ß1 signaling and fibronectin up-regulation in mesangial cells.

Little is known about the cross-talk between parathyroid hormone (PTH) related protein (PTHrP) and TGF-ß1 in mesangial cells (MCs). Our results showed that PTHrP treatment (≤3 h) induced internalization of PTH1R (PTH/PTHrP receptor)-TßRII (TGF-ß type 2 receptor) complex and suppressed TGF-ß1-mediated Smad2/3 activation and fibronectin (FN) up-regulation. However, prolonged PTHrP treatment (12-48 h) failed to induce PTH1R-TßRII association and internalization. Total protein levels of PTH1R and TßRII were unaffected by PTHrP treatment. These results suggest that internalization of PTH1R and TßRII after short PTHrP treatment might not lead to their proteolytic destruction, allowing the receptors to be recycled back to the plasma membrane during prolonged PTHrP exposure. Receptor re-expression at the cell surface allows PTHrP to switch from its initial inhibitory effect to promote induction of FN. Our study thus demonstrates the dual roles of PTHrP on TGF-ß1 signaling and FN up-regulation for the first time in glomerular MCs. These data also provided new insights to guide development of therapy for diabetic kidney disease (DKD).

Parathyroid hormone-related peptide (1-34) reduces alveolar bone loss in type 1 diabetic rats.

OBJECTIVE: To investigate the role of parathyroid hormone related protein (PTHrP) in diabetic periodontitis. METHODS: After injected with 55mg/kg streptozotocin, diabetic rats were treated subcutaneously with low-dose (40µg/kg, once daily for 5days per week), middle-dose (80µg/kg) or high-dose (160µg/kg) PTHrP(1-34) peptide. Treatment continued for 12 weeks. Changes in periodontal tissues were confirmed by micro-computerized tomography assay and H&E analysis. We used tartrate resistant acid phosphatase (TRAP) staining to identify osteoclast cells. The expression of TNF-α, IL-1ß and IL-6 was assessed by immunohistochemistry and Western blot. RESULTS: Tooth-supporting structure loss was observed in periodontal tissues of diabetic rats. PTHrP (1-34) attenuated alveolar bone loss, especially in the middle-dose and high-dose group. Whereas TNF-α, IL-1ß and IL-6 protein levels were increased in the diabetic gingival tissues, PTHrP (1-34) treatment inhibited the increase of IL-1ß and IL-6, but had no effect on TNF-α. CONCLUSION: Type 1 diabetes increased the susceptibility to periodontal disease. Intermittent administration of PTHrP (1-34) exhibited an inhibitory effect on alveolar bone resorption and the gingival inflammation in periodontal tissues of diabetic rats.

Incidence, risk factors, and phenomenological characteristics of postoperative delirium in patients receiving intravenous patient-controlled analgesia: a prospective cohort study.

BACKGROUND: Intravenous patient-controlled analgesia (IVPCA) is a common method of relieving pain which is a risk factor of postoperative delirium (POD). However, research concerning POD in IVPCA patients is limited. OBJECTIVE: We aimed to determine the incidence, risk factors, and phenomenological characteristics of POD in patients receiving IVPCA. METHODS: A prospective, cohort study was conducted in post-general anesthesia IVPCA patients aged ≥60 years. POD was measured by the Nursing Delirium Screening Scale (NuDESC; 0-10). Delirium, pain severity at rest and/or on movement, and side effects of IVPCA during 3 postoperative days were examined twice-daily by the acute pain service team. Pain severity is measured by an 11-point verbal numerical rating scale (11-point VNRS) (0-10). An 11-point VNRS >3 was considered inadequate pain relief. If POD (detected by NuDESC ≥1) is suspected, consulting a neurologist or a psychiatrist to confirm suspected POD is required. RESULTS: In total, 1,608 patients were included. The incidence rate of POD was 2.2%. Age ≥70 years and American Society of Anesthesiologists physical status >III were the risk factors of POD in IVPCA patients. Approximately three-quarters of all POD cases occurred within the first 2 postoperative days. For pain at rest, patients with inadequate pain relief had significantly greater rates of POD than patients with adequate pain relief (day 1, 8.4% vs 1.5%, P<0.001; day 2, 9.6% vs 2.0%, P=0.028; day 3, 4.1% vs 2.1%, P=0.412). However, the incidence of POD was not associated with movement-evoked pain relief. Most (79.9%) POD cases in IVPCA patients showed either one or two symptoms. The symptoms of POD were ranked from high to low as disorientation (65.7%), illusions/hallucinations (37.1%), inappropriate communication (31.4%), inappropriate behavior (25.7%), and psychomotor retardation (14.2%). CONCLUSION: The incidence rate of POD in IVPCA patients was low. Further research is warranted concerning POD and IVPCA pain management.

Soluble epoxide hydrolase inhibitor enhances synaptic neurotransmission and plasticity in mouse prefrontal cortex.

BACKGROUND: The soluble epoxide hydrolase (sEH) is an important enzyme chiefly involved in the metabolism of fatty acid signaling molecules termed epoxyeicosatrienoic acids (EETs). sEH inhibition (sEHI) has proven to be protective against experimental cerebral ischemia, and it is emerging as a therapeutic target for prevention and treatment of ischemic stroke. However, the role of sEH on synaptic function in the central nervous system is still largely unknown. This study aimed to test whether sEH C-terminal epoxide hydrolase inhibitor, 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA) affects basal synaptic transmission and synaptic plasticity in the prefrontal cortex area (PFC). Whole cell and extracellular recording examined the miniature excitatory postsynaptic currents (mEPSCs) and field excitatory postsynaptic potentials (fEPSPs); Western Blotting determined the protein levels of glutamate receptors and ERK phosphorylation in acute medial PFC slices. RESULTS: Application of the sEH C-terminal epoxide hydrolase inhibitor, AUDA significantly increased the amplitude of mEPSCs and fEPSPs in prefrontal cortex neurons, while additionally enhancing long term potentiation (LTP). Western Blotting demonstrated that AUDA treatment increased the expression of the N-methyl-D-aspartate receptor (NMDA) subunits NR1, NR2A, NR2B; the α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits GluR1, GluR2, and ERK phosphorylation. CONCLUSIONS: Inhibition of sEH induced an enhancement of PFC neuronal synaptic neurotransmission. This enhancement of synaptic neurotransmission is associated with an enhanced postsynaptic glutamatergic receptor and postsynaptic glutamatergic receptor mediated synaptic LTP. LTP is enhanced via ERK phosphorylation resulting from the delivery of glutamate receptors into the PFC by post-synapse by treatment with AUDA. These findings provide a possible link between synaptic function and memory processes.

Risk of Shingles in Adults with Primary Sjogren's Syndrome and Treatments: A Nationwide Population-Based Cohort Study.

BACKGROUND: Primary Sjögren's syndrome (pSS) is associated with immunological dysfunctions--a well-known risk factor of shingles. This study aimed to examine the incidence and risk of shingles in adults with pSS and pharmacological treatments. METHODS: This retrospective population-based cohort study was conducted using National Health Insurance claims data. Using propensity scores, 4,287 pSS adult patients and 25,722-matched cohorts by age, gender, selected comorbidities and Charlson comorbidity index scores were identified. Kaplan-Meier analysis and Cox regression were conducted to compare the differences in developing shingles. In pSS, oral and eye dryness are treated with substitute agents. Extraglandular features are often treated with pharmacological drugs including steroids and immunosuppressants. pSS patients were grouped as follows: no pharmacological drugs, steroids alone; immunosuppressants alone; combined therapies. RESULTS: During the follow-up, 463 adults with pSS (10.80%) and 1,345 control cohorts (5.23%) developed shingles. The cumulative incidence of shingles in pSS patients (18.74/1,000 patient-years) was significantly higher than controls (8.55/1,000 patient-years). The adjusted hazard ratio (HR) of shingles was 1.69 (95% confidence interval (CI) 1.50-1.90). In age-subgroup analyses, incidences of shingles in pSS increased with age and peaked in pSS patients aged ≧60; however, adjusted HRs decreased with age. Compared to control cohorts with no drugs, adjusted HRs for shingles in pSS patients were ranked from high to low as: combined therapies (4.14; 95% CI 3.14-5.45) > immunosuppressants alone (3.24; 95% CI 2.36-4.45) > steroids alone (2.54; 95% CI 2.16-2.97) > no pharmacological drugs (2.06; 95% CI 1.76-2.41). Rates of shingles-associated hospitalization and postherpetic neuralgia were 5.62% and 24.41%, both of which were significantly higher than those (2.60%; 13.01%) in the control cohorts. CONCLUSIONS: Adults with pSS were at greater risk for shingles than control cohorts. Drug exposures significantly increased the risk of shingles in pSS.

Blocking VEGF/Caveolin-1 signaling contributes to renal protection of fasudil in streptozotocin-induced diabetic rats.

AIM: RhoA/ROCK signaling plays an important role in diabetic nephropathy, and ROCK inhibitor fasudil exerts nephroprotection in experimental diabetic nephropathy. In this study we investigated the molecular mechanisms underlying the protective actions of fasudil in a rat model of diabetic nephropathy. METHODS: Streptozotocin (STZ)-induced diabetic rats, to which fasudil or a positive control drug enalapril were orally administered for 8 months. Metabolic parameters and blood pressure were assessed during the treatments. After the rats were euthanized, kidney samples were collected for histological and molecular biological studies. VEGF, VEGFR1, VEGFR2 and fibronectin expression, and Src and caveolin-1 phosphorylation in the kidneys were assessed using RT-PCR, Western blot and immunohistochemistry assays. The association between VEGFR2 and caveolin-1 was analyzed with immunoprecipitation. RESULTS: Chronic administration of fasudil (30 and 100 mg·kg(-1)·d(-1)) or enalapril (10 mg/kg, bid) significantly attenuated the glomerular sclerosis and albuminuria in the diabetic rats. Furthermore, fasudil treatment prevented the upregulation of VEGF, VEGFR1, VEGFR2 and fibronectin, and the increased association between VEGFR2 and caveolin-1 in the renal cortices, and partially blocked Src activation and caveolin-1 phosphorylation on tyrosine 14 in the kidneys, whereas enalapril treatment had no effects on the VEGFR2/Src/caveolin-1 signaling pathway. CONCLUSION: Fasudil exerts protective actions in STZ-induced diabetic nephropathy by blocking the VEGFR2/Src/caveolin-1 signaling pathway and fibronectin upregulation. Thus, VEGFR2 may be a potential therapeutic target for the treatment of diabetic nephropathy.