Combination of computed tomography measurements and flexible video bronchoscope guidance for accurate placement of the right-sided double-lumen tube: a randomised controlled trial.

OBJECTIVE: To compare the modified strategy for the right-sided double-lumen tube (R-DLT) placement using a combination of CT measurements and flexible video bronchoscopy guidance with traditional bronchoscopy technique. TRIAL DESIGN, SETTING AND PARTICIPANTS: Double-blind, parallel randomised control trial at a tertiary care medical centre in China. 100 patients undergoing video-assisted thoracoscopic surgery and requiring R-DLT were randomly allocated to the control group and the intervention group. INTERVENTION: The control group used the traditional bronchoscopy-guided technique. In the intervention group, the length and anteroposterior diameter of the right main bronchus (RMB) were measured on CT images to select the side and size of the Rüsch tube, and then a black depth marker was placed on the tube according to the difference between the length of the RMB and the bronchial cuff. Under the guidance of bronchoscopy, the depth marker should be placed parallel to the tracheal carina and a characteristic white line on the tube should be parallel to the midline of the tracheal carina. MAIN OUTCOMES: The primary endpoint was the positioning of right upper lobe (RUL) ventilatory slot and RUL bronchial orifice. The secondary endpoints included intubation data and perioperative adverse events. RESULTS: Compared with the control group, our modified strategy significantly increased the optimal and acceptable position rate (76% vs 98%, respectively; p<0.039), decreased the replacement rate (80% vs 94%; p=0.042), shortened the intubation time (101.4±7.3 s vs 75.2±8.1 s; p=0.019) and reduced the incidence of transient hypoxaemia (25% vs 6%; p=0.022), subglottic resistance (20% vs 6%; p=0.037), tracheobronchial injury (35% vs 13%; p=0.037) and postoperative RUL collapse (15% vs 2%; p=0.059). CONCLUSION: This study demonstrates the superiority of our strategy and provides a new viable method for R-DLT placement. TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Registry (ChiCTR1900021676).

Blockage of Galectin-Receptor Interactions Attenuates Mouse Hepatic Pathology Induced by Toxoplasma gondii Infection.

Toxoplasma gondii (T. gondii), one of the most important Apicomplexan protozoa, causes toxoplasmosis in human throughout the world. Galectin (Gal)-9 triggers a series of immune events via binding to its receptors, including T cell immunoglobulin and mucin-containing molecule 3, CD137, CD44, and protein disulfide isomerase. To examine the regulatory role of galectin-receptor interactions in anti-toxoplasmic activities, C57BL/6 mice were infected with T. gondii RH strain and intraperitoneally injected with alpha (α)-lactose to block the interactions of galectins and their receptors. Heatmaps showed upregulated values for Gal-9 and CD137 in the livers of T. gondii-infected mice and T. gondii-infected mice treated with α-lactose. Compared with T. gondii-infected mice, T. gondii-infected mice treated with α-lactose showed significantly increased survival rate, decreased tissue parasite burden, attenuated liver histopathology, increased mRNA expression levels of CD137, IFNγ, IL-4, and IL-10 in the liver, and increased Gal-9 mRNA expression level in the spleen. Correlation analysis showed that significant positive correlations existed between the mRNA expression levels of Gal-9 and CD137, Gal-9 and IFNγ, as well as between CD137 and IFNγ in the liver and spleen of T. gondii-infected mice; between CD137 and IFNγ in the liver of T. gondii-infected mice treated with α-lactose. In addition, blockage of galectin-receptor interactions showed enhanced M2 macrophage polarization in the liver of T. gondii-infected mice. Our data indicate that Gal-9-CD137 interaction may play an important role in T. gondii proliferation and liver inflammation in mice during acute T. gondii infection, through regulating T cell and macrophage immune responses.

Effect of Intravenous Lidocaine on Serum Interleukin-17 After Video-Assisted Thoracic Surgery for Non-Small-Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Trial.

PURPOSE: Surgical stress promotes tumor metastasis. Interleukin (IL)-17 plays a pivotal role in cancer progression, and high IL-17 expression predicts poor prognosis of non-small-cell lung cancer (NSCLC). Lidocaine may exert tumor-inhibiting effects. We hypothesize that intravenous lidocaine attenuates surgical stress and reduces serum IL-17 levels during video-assisted thoracic surgery (VATS) for NSCLC. METHODS: This randomized, double-blind, placebo-controlled trial included 60 early-stage NSCLC patients undergoing VATS, into a lidocaine group (n = 30; intravenous lidocaine bolus 1.0 mg/kg, and 1.0 mg/kg/h until the end of surgery) or a normal saline control group (n = 30). The primary outcome was serum IL-17 level at 24 hours postoperatively. The secondary outcomes included serum IL-17 level at the time of post-anesthesia care unit (PACU) discharge, serum cortisol level at PACU discharge and postoperative 24 hours, pain scores (0-10) from PACU discharge to 48 hours postoperatively, incidences of postoperative nausea and vomiting, dizziness, and arrhythmia during 0-48 hours postoperatively, and 30-day mortality. Long-term outcomes included chemotherapy, cancer recurrence, and mortality. RESULTS: The lidocaine group had lower serum IL-17 at 24 hours postoperatively compared with the control group (23.0 ± 5.8 pg/mL vs 27.3 ± 8.2 pg/mL, difference [95% CI] = -4.3 [-8.4 to -0.2] pg/mL; P = 0.038). The lidocaine group also had reduced serum IL-17 (difference [95% CI] = -4.6 [-8.7 to -0.5] pg/mL), serum cortisol (difference [95% CI] = -37 [-73 to -2] ng/mL), and pain scores (difference [95% CI] = -0.7 [-1.3 to -0.1] points) at PACU discharge. During a median follow-up of 10 (IQR, 9-13) months, 2 patients in the lidocaine group and 6 patients in the control group received chemotherapy, one patient in the control group had cancer recurrence, and no death event occurred. CONCLUSION: Intravenous lidocaine was associated with reduced serum IL-17 and cortisol following VATS procedures in early-stage NSCLC patients. TRIAL REGISTRATION: ChiCTR2000030629.

Suppression of WNK1-SPAK/OSR1 Attenuates Bone Cancer Pain by Regulating NKCC1 and KCC2.

Our preliminary experiment indicated the activation of with-nolysine kinases 1 (WNK1) in bone cancer pain (BCP) rats. This study aimed to investigate the underlying mechanisms via which WNK1 contributed to BCP. A rat model of BCP was induced by Walker-256 tumor cell implantation. WNK1 expression and distribution in the lumbar spinal cord dorsal horn and dorsal root ganglion were examined. SPS1-related proline/alanine-rich kinase (SPAK), oxidative stress-responsive kinase 1 (OSR1), sodium-potassium-chloride cotransporter 1 (NKCC1), and potassium-chloride cotransporter 2 (KCC2) expression were assessed. Pain behaviors including mechanical allodynia and movement-evoked pain were measured. BCP rats exhibited significant mechanical allodynia, with increased WNK1 expression in the dorsal horn and dorsal root ganglion neurons, elevated SPAK/OSR1 and NKCC1 expression in the dorsal root ganglion, and decreased KCC2 expression in the dorsal horn. WNK1 knock-down by small interfering alleviated mechanical allodynia and movement-evoked pain, inhibited WNK1-SPAK/OSR1-NKCC1 activities, and restored KCC2 expression. In addition, closantel (a WNK1-SPAK/OSR1 inhibitor) improved pain behaviors, downregulated SPAK/OSR1 and NKCC1 expression, and upregulated KCC2 expression in BCP rats. Activation of WNK1-SPAK/OSR1 signaling contributed to BCP in rats by modulating NKCC1 and KCC2 expression. Therefore, suppression of WNK1-SPAK/OSR1 may serve as a potential target for BCP therapy. PERSPECTIVE: Our findings demonstrated that the WNK1-SPAK/OSR1 signaling contributed to BCP in rats via regulating NKCC1 and KCC2. Suppressing this pathway reduced pain behaviors. Based on these findings, the WNK1-SPAK/OSR1 signaling may be a potential target for BCP therapy.

A Human Proteome Array Approach to Identifying Key Host Proteins Targeted by Toxoplasma Kinase ROP18.

Toxoplasma kinase ROP18 is a key molecule responsible for the virulence of Toxoplasma gondii; however, the mechanisms by which ROP18 exerts parasite virulence via interaction with host proteins remain limited to a small number of identified substrates. To identify a broader array of ROP18 substrates, we successfully purified bioactive mature ROP18 and used it to probe a human proteome array. Sixty eight new putative host targets were identified. Functional annotation analysis suggested that these proteins have a variety of functions, including metabolic process, kinase activity and phosphorylation, cell growth, apoptosis and cell death, and immunity, indicating a pleiotropic role of ROP18 kinase. Among these proteins, four candidates, p53, p38, UBE2N, and Smad1, were further validated. We demonstrated that ROP18 targets p53, p38, UBE2N, and Smad1 for degradation. Importantly, we demonstrated that ROP18 phosphorylates Smad1 Ser-187 to trigger its proteasome-dependent degradation. Further functional characterization of the substrates of ROP18 may enhance understanding of the pathogenesis of Toxoplasma infection and provide new therapeutic targets. Similar strategies could be used to identify novel host targets for other microbial kinases functioning at the pathogen-host interface.

A modified procedure for lumbar intrathecal catheterization in rats.

OBJECTIVES: Intrathecal catheterization and drug delivery in rats has always been a very important method for neuroscience and pain research. Although the technique has been continually improved since the first report, the experience gained over the years suggested that some defects remained unsolved. On the basis of modification of the standard epidural needle, lumbar needle, and intrathecal tube, we aimed to develop a simple and practical technique for intrathecal catheterization, which was similar to the 'needle-through-needle technique' used in combined spinal-epidural (CSE) anesthesia. METHODS: For comparison, rats received intrathecal catheterization via either laminectomy at L3-4 (control group) or our modified method (modification group). The operation time, success rate, and the incidence of postoperative complication were recorded. Thermal paw withdrawal latency, mechanical paw withdrawal threshold, Rota-rod, and body weight were measured on pre-operative day 1 and postoperative day 1-3, 5, 7, 14, 21, respectively. RESULTS: Compared with control group, our modified method was more practical to grasp and could bring about higher success rate, firmer catheters immobility, less weight loss, and minimal mortality. There was no difference between the two groups in spinal cord injury, hematoma, location of lumbar enlargement, and lateral location of the catheters tip. The procedure itself did not interfere with behavioral tests and motor coordination. CONCLUSION: We suggest that the modified method of intrathecal catheterization is well suitable for long-term behavior and pharmacology research on spinal cord.