Silencing EIF3A ameliorates pulmonary arterial hypertension through HDAC1 and PTEN/PI3K/AKT pathway in vitro and in vivo.

Pulmonary vascular remodeling caused by the excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs) is the hallmark feature of pulmonary arterial hypertension (PAH). Eukaryotic initiation factor 3 subunit A (EIF3A) exhibited proliferative activity in multiple cell types. The present study investigated the role of EIF3A in the progression of PAH. A monocrotaline (MCT)-induced PAH rat model was constructed, and adeno-associated virus type 1 (AAV1) carrying EIF3A shRNA was intratracheally delivered to PAH rats to block EIF3A expression. PASMCs were isolated from rats and treated with PDGF-BB to simulate PASMC proliferation, and shRNA for EIF3 was conducted to investigate the mechanism behind the role of EIF3A in PASMC function in vitro. EIF3A expression was upregulated in pulmonary arteries, and EIF3A inhibition effectively improved pulmonary hypertension and right ventricular hypertrophy and suppressed MCT-induced vascular remodeling in vivo. In addition, we found that genetic knockdown of EIF3A reduced PDGF-triggered proliferation and arrested cell cycle, accompanied by downregulated proliferation-related protein expression in PASMCs. Mechanistically, the histone deacetylase 1 (HDAC1)-mediated PTEN/PI3K/AKT pathway was recognized as a primary mechanism in PAH progression. Silencing EIF3A decreased HDAC1 expression, and further inhibited the excessive proliferation of PASMCs by increasing the phosphatase and tension homolog (PTEN) expression and suppressing the AKT phosphorylation. Notably, HDAC1 expression reversed the effect of silencing EIF3A on PAH and PTEN/PI3K/AKT pathway. Collectively, silencing EIF3A improved PAH by decreasing PASMC proliferation through the HDAC1-mediated PTEN/PI3K/AKT pathway. These findings suggest that targeting EIF3A may represent a potential approach for the treatment of PAH.

Correction to: Mindray 3-directional NMT Module (a new generation "Tri-axial" neuromuscular monitor) versus the Relaxometer mechanomyograph and versus the TOF-Watch SX acceleromyograph.

In the original publication of the article, the article note "Ashraf A. Dahaba and Zhao Yang Xiao equally contributed to the study and are both first authors." was published incorrectly. The correct statement should read as "Ashraf A. Dahaba and Zhao Yang Xiao equally contributed to the study and are both first authors and are both co-corresponding authors."

Mindray 3-directional NMT Module (a new generation "Tri-axial" neuromuscular monitor) versus the Relaxometer mechanomyograph and versus the TOF-Watch SX acceleromyograph.

Recently introduced Mindray "3-directional" neuromuscular transmission transducer (NMT, Shenzhen, China) acceleromyograph) claim to monitor thumb movement in 3 different directions. We compared NMT with the gold standard Relaxometer® mechanomyograph (MMG, Groningen University, Netherlands) in Study-1 and with TOF-Watch SX™ (WTCH) acceleromyograph from which it was developed in Study-2. We used first twitch (T1%) and train-of-four (TOF) ratio rocuronium 0.6 mg kg-1 neuromuscular block to evaluate NMT diagnostic accuracy in indicating 3 clinically relevant time points namely; MMG T1 5% (95% twitch depression) for tracheal intubation, MMG T1 25% for repeat neuromuscular blocking agents (NMBAs) administration, and MMG 0.9 TOF ratio full neuromuscular block recovery. We compared onset time (time from beginning of rocuronium administration until maximal depression), Dur25 (time until T1 25% recovery) and Dur0.9 (time until 0.9 TOF ratio recovery). In Study-1, NMT showed low sensitivity in indicating MMG time for tracheal intubation, repeat NMBAs administration and full neuromuscular block recovery (6.25%, 38.9% and 38.9% respectively). NMT onset time, Dur25 and Dur0.9 (2:51 ± 00:57, 36:50 ± 24:25, 70:08 ± 25:27 min:s) were significantly longer than MMG (1:56 ± 00:46, 30:26 ± 20:24, 62:03 ± 20:01). In Study-2, NMT onset time, Dur25 and Dur0.9 (02:37 ± 00:53, 35:38 ± 11:54, 53:40 ± 13:49) were not significantly different than WTCH (02:23 ± 00:45, 33:27 ± 12:51, 53:57 ± 12:47). NMT could not efficaciously detect MMG time for tracheal intubation; NMBAs repeat dose administration or full neuromuscular block recovery. Data from NMT cannot be used interchangeably with MMG. Our study revealed that NMT Tri-axial acceleromyography seems to offer no advantage over the MMG gold standard or the classic Mono-axial TOF-Watch SX monitor.

Changes in plasma orexin-A levels in sevoflurane-remifentanil anesthesia in young and elderly patients undergoing elective lumbar surgery.

BACKGROUND: Delayed emergence from general anesthesia frequently occurs in elderly patients, but the reason is not clear. Orexin has been shown to be involved in arousal from general anesthesia. In this study, we examined plasma orexin-A levels in both elderly and young patients during the anesthesia arousal cycle. METHODS: We recruited 41 patients scheduled for elective lumbar surgery and eventually evaluated 34 patients. Patients were divided into a young group (age 30-55, N = 16) and an elderly group (age 65-77, N = 18). Anesthesia with sevoflurane-remifentanil was titrated to maintain the Bispectral Index between 45 and 65. The times from stopping anesthesia to eyes opening and extubation were recorded. Arterial blood was collected, and plasma orexin-A was determined by radioimmunoassay at the following 4 time points: preanesthesia (T0), 1 hour after anesthesia induction (T1), emergence (5 minutes after tracheal extubation) (T2), and 30 minutes after tracheal extubation (T3). RESULTS: The times from stopping anesthesia to eyes opening and tracheal extubation were both significantly longer in the elderly group than in the young group (P = 0.004, P = 0.01, respectively). Basal (T0) orexin-A levels were higher in the elderly group than in the young group (T0, 26.13 ± 1.25 vs 17.9 ± 1.30 pg/mL, P < 0.0001). Plasma orexin-A levels did not change during induction of anesthesia in either group but significantly increased at T2 (vs T0, P <0.0001) in both elderly (35.0 ± 1.7 pg/mL) and young (29.2 ± 1.9 pg/mL) groups. Orexin-A levels were significantly higher in the elderly than in the young group at T1, T2, and T3. CONCLUSION: Plasma orexin-A levels are not responsible for the delayed emergence from general anesthesia in elderly patients.

Gut microbiota-derived metabolite trimethylamine N-oxide aggravates cognitive dysfunction induced by femoral fracture operation in mice.

An increasing number of elderly individuals are experiencing postoperative cognitive dysfunction (POCD) problems after undergoing hip replacement surgery, with gut microbiota metabolites playing a role in its pathogenesis. Among these, the specific effects of trimethylamine N-oxide (TMAO) on POCD are still unclear. This study aimed to explore the role of TMAO on cognitive dysfunction and underlying mechanisms in mice. The POCD model was created through femoral fracture surgery in elderly mice, followed by cognitive function assessments using the Morris Water Maze and Novel Object Recognition tests. The gut microbiota depletion and fecal microbiota transplantation were performed to examine the relationship between TMAO levels and cognitive outcomes. The effects of TMAO treatment on cognitive dysfunction, microglial activation, and inflammatory cytokine levels in the brain were also evaluated, with additional assessment of the role of microglial ablation in reducing TMAO-induced cognitive impairment. Elevated TMAO levels were found to be associated with cognitive decline in mice following femoral fracture surgery, with gut microbiota depletion mitigating both TMAO elevation and cognitive dysfunction. In contrast, fecal microbiota transplantation from postoperative mice resulted in accelerated cognitive dysfunction and TMAO accumulation in germ-free mice. Furthermore, TMAO treatment worsened cognitive deficits, neuroinflammation, and promoted microglial activation, which were reversed through the ablation of microglia. TMAO exacerbates cognitive dysfunction and neuroinflammation in POCD mice, with microglial activation playing a crucial role in this process. Our findings may provide new therapeutic strategies for managing TMAO-related POCD and improving the quality of life for elderly patients.

A multicenter survey of perioperative anxiety in China: Pre- and postoperative associations.

OBJECTIVES: To describe patient characteristics associated with preoperative anxiety and subsequently assess the relationship between preoperative anxiety and postoperative anxiety, pain, sleep quality, nausea and vomiting. METHODS: The study collected data from patients undergoing elective operation from 12 hospitals in China. The State-Trait Anxiety Inventory (STAI) and the Athens Insomnia Scale (AIS) were used to assess anxiety and sleep quality before surgery. Evaluations of anxiety, pain, sleep quality, nausea and vomiting were quantified using the Visual Analogue Scale on postoperative days 1 and 2. RESULTS: Data from 997 patients were analyzed. Preoperatively, 258 (25.9%) patients had high anxiety (STAI-State>44). Multivariate analyses showed a significant relationship between high anxiety and female gender (OR: 1.66, 95% CI: 1.08-2.57, p = 0.02), highly invasive surgery (OR: 2.29, 95% CI: 1.29-4.06, p = 0.005), higher trait anxiety (OR: 1.24, 95% CI: 1.20-1.28, p < 0.001) and insomnia (AIS ≥ 6, OR: 1.79, 95% CI: 1.17-2.76, p = 0.008). Preoperative anxiety demonstrated a negative correlation with postoperative anxiety following highly invasive surgery; this became a positive relationship following less invasive surgery. Preoperative anxiety was also positively related to postoperative pain and poor sleep quality. The correlation between preoperative anxiety and postoperative nausea and vomiting was not statistically significant. CONCLUSION: Female gender, highly invasive surgery, higher trait anxiety and insomnia are independent risk factors for high preoperative anxiety. Surgical invasiveness influences association between pre- and postoperative anxiety. Higher preoperative anxiety is related to poorer sleep quality and more severe pain postoperatively.

[Effects of Ginkgo biloba extract against excitotoxicity induced by NMDA receptors and mechanism thereof].

OBJECTIVE: To observe the effects of Ginkgo biloba extract (GBE) on N-methyl-D-aspartate (NMDA) excitotoxicity and focal cerebral ischemia, and further explore the neuroprotective mechanisms of GBE. METHODS: Neonatal SD rat hippocampus was taken out to make into cell suspension. immunohistochemistry with neuron nucleoprotein monoclonal antibody (NeuN) was used to calculate the percentage of NeuN positive cells. Twelve days after incubation the suspension of neurons were randomly divided into 4 groups: normal control group (exposed to normal saline for 15 min and then to DMEM without NMDA and glycine for 24 h), NMDA group (exposed to culture fluid with NMDA of the terminal concentration of 100 micromol/L and glycine of the terminal concentration of 10 micromol/L for 15 min and then to DMEM without NMDA and glycine for 24 h), MK-801 group (exposed to MK-801, an NMDAR antagonist, for 2 min, to culture fluid with NMDA for 15 min, and then to DMEM without NMDA and glycine for 24 h), and GBE pretreatment group (exposed to GBE of the terminal concentration of 150 microg/ml for 3 d, culture fluid with NMDS for 15 min, and then to DMEM without NMDA and glycine foe 24 h). Trypan blue staining was used to calculate the survival rate of the neurons. The lactic dehydrogenase (LDH) level in the supernatant of cultured cell suspension was detected. Whole-cell patch clamp recording was carried out to evaluate the modulatory effects of GBE on NMDA-activated currents in the rat hippocampal neurons. 108 SD rats were randomly divided into 5 groups: sham operation group (n = 12), standard middle cerebral artery occlusion (MCAO) group (n = 24, undergoing MCAO and then reperfusion), MK-801 acute administration group (n = 24, undergoing MCAO and immediate peritoneal administration of MK-801 1 mg/kg), GBE acute administration group (n = 24, undergoing peritoneal injection of GBE 100 mg/kg immediately after the MCAO), and GBE pretreatment group (n = 24, undergoing peritoneal administration of GBE every day for 7 days before the MCAO). The 4 groups were re-divided into 4 subgroups with 3 approximately 4 rats: 0.5 h ischemia, and 3 h, 1 d, and 7 d ischemia-reperfusion (IR) subgroups. The neurological symptoms were evaluated by Longa's scoring after the rats became conscious. The rats were killed at different time-points, their brains were taken out to undergo 2, 3, 5-triphenyl-tetrazolium chloride staining, the areas of cerebral infarction were calculated, and immunohistochemistry was used to evaluate the contents of NeuN and microtubule-associated protein (MAP-2). RESULTS: The cell viability of the GBE group was 85% +/- 5%, significantly higher than that of the NMDA group (39.8% +/- 2.1%, P < 0.01), and significantly lower than that of the MK-801 group (93.8% +/- 2.7%, P < 0.05). The LDH efflux of the GBE group was 87 U/L +/- 8 U/L, significantly lower than that of the NMDA group (138 U/L +/- 12 U/L, P < 0.01) and significantly higher than that of the MK-801 group (47 U/L +/- 7 U/L, P < 0.05). The inward current (I(NMDA)) of the NMDA group was significantly activated, The inhibitory rate of the NMDA-activated I(NMDA) of the GBE group was 40% +/- 17%, significantly lower than that of the MK-801 group (78% +/- 18%, P < 0.05); After washing out with standard extracellular solution, the I(NMDA) could recover to 91% +/- 8% in the GBE group, but not in the MK-801 group (P < 0.05), which indicated that GBE had lower affinity to NMDA receptor than MK-801. The Longa's scores of the 3 h and 24 h IR subgroups of the GBS pretreatment group were all significantly lower than those of the corresponding subgroups of the standard MCAO and GBE acute administration groups. The symptoms of the MK-801 were the most severe. Cerebral infarction began to appear in the 1-day subgroups. The cerebral infarction areas of the 1 d subgroups of the GBF pretreatment and MK-801 groups were 11.5% +/- 1.3% and 6.5% +/- 0.9% respectively, both significantly smaller than those of the MCAO and GBE acute administration groups (24.5% +/- % and 22.9% +/- 1.3% respectively, both P < 0.01), however, there was no significant difference in the cerebral infarction area between the GBE acute administration and MCAO group. It was true too for the cerebral infarction areas of the 7 d subgroups. Except in the control group, loss of NeuN positive neuron was seen in all groups, especially the MCAO and GBE acute administration groups. Except in the control group, the MAP-2 positive neurons were decreased in all groups, especially the MCAO and GBE acute administration groups, and 1 day and 7 days after the IR MAP-2 positive neurons were almost unseen in the MCAO and GBE acute administration groups, however, could be seen in small amounts in the GBE and MK-801 groups (all P < 0.01). CONCLUSION: GBE pretreatment protects the neurons from excitotoxicity induced by over-activated NMDA receptor and focal cerebral ischemia, which can be explained by the mild blocking effect of GBE on NMDA receptor with low affinity, comparing with MK-801, and GBE is expected to interfere in excitotoxicity in clinic without neurotoxic behaviors.

Xylometazoline hydrochloride nasal spray combined with laser artificial nasolacrimal duct implantation for nasolacrimal duct obstruction / 国际眼科杂志(Guoji Yanke Zazhi)

@#AIM: To study the role of xylometazoline hydrochloride nasal spray in combination therapy of nasolacrimal duct obstruction and to investigate the effect of nasal inflammation on nasolacrimal duct obstruction. <p>METHODS: Totally 279 patients with nasolacrimal duct obstruction were collected, who received lacrimal passage irrigation, CT angiography for lacrimal passage and nasal endoscope before treated by lacrimal laser forming and artificial nasolacrimal duct implantation combined with xylometazoline hydrochloride nasal spray. In group A, 137 patients were treated with antibiotic eye drop and non-steroidal anti-inflammatory drugs after operations. In group B, 142 patients were treated with xylometazoline hydrochloride nasal spray besides the same treatment for group A. <p>RESULTS:In the 279 patients 217(77.8%), in which 105 cases(76.6%)were in group A and 112 cases(78.9%)were in group B, were suffered with nasal inflammation, including nasal mucosal hyperemia, inferior turbinate hypertrophy, middle turbinate hypertrophy. At 3mo after the ducts were drawn, efficacy of group B was 95.8%, which was significant better than that of group A(86.1%, <i>P</i><0.05).<p>CONCLUSION: Nasal inflammation was an important factor in the incidence of nasolacrimal duct obstruction, which shoud pay more attention in the process of diagnosis and treatment. Combination therapy could improve the cure rate of nasolacrimal duct obstruction.

Analysis on pathogenic bacteria and drug sensitivity of canalicular inflammation / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To analyze the pathogenic bacteria and drug sensitivity in cases of canalicular inflammation. ●METHODS: Lacrimal sac secretion from 57 cases ( 57 eyes) with canalicular inflammation. used to do bacterial cultures and drug sensitivity tests. Grind open the sulfur particles from canaliculus for bacterial smear. ●RESULTS:After squeeze canalicular, there are 56 sulfur granules from 57 patients. All of the Sulfur particles smears were found in actinomycetes. A total of 55 from 57 cases of lacrimal secretions for bacterial culture were positive, and 63 strains were cultured. The main pathogen are Staphylococcus epidermidis, Streptococcus viridans and pneumococcus. Drug susceptibility test results showed that:rifampicin, cefoxitin, chloramphenicol, and mezlocillin are sensitivity. ●CONCLUSION:Actinomycetes were the main pathogens to canalicular inflammation, and most of the presence of co- infection with other bacteria. Rifampin, cefoxitin, chloramphenicol, and mezlocillin are sensitivity canalicular inflammation.