CT-guided transthoracic pulmonary artery catheterization: an experimental study in a porcine model.

OBJECTIVES: We investigated the safety and feasibility of CT-guided transthoracic pulmonary artery catheterization (TPAC) in a porcine model. METHODS: Procedures were conducted on ten mature Bama miniature pigs. After anesthesia, chest CT was performed in the left lateral decubitus position to determine the puncture route. Under the guidance of multiple CT scans, the introducer sheath was inserted from the right chest wall of the pig into the right pulmonary artery using the Seldinger technique. Then, a catheter connected with a transducer was inserted into the sheath to measure the pulmonary artery pressure. Finally, an active approximator was used to close the puncture site on the pulmonary artery. The pigs were followed up for 8 weeks to evaluate the operation-related complications and survival. RESULTS: Ten of 11 CT-guided TPAC procedures were successfully performed on ten pigs, rendering a technical success rate of 90.9%. One pig had hemoptysis while the needle was being inserted during the first operation, and a second procedure was successfully conducted 17 days later. Other complications, including pulmonary bleeding along the needle track (3 of 11; 27.3%), unclosed pulmonary artery puncture sites (3 of 10; 30%), pneumothorax (1 of 11; 9.1%), and hemopericardium (1 of 11; 9.1%), spontaneously resolved without complication-specific treatment. The mean pulmonary arterial pressure was 32 ± 17.6 mmHg. All animals survived the procedure and reached the end of the follow-up period. CONCLUSIONS: CT-guided TPAC is feasible and safe in a porcine model, serving as a potential alternative pathway for pulmonary artery intervention. KEY POINTS: • TPAC is feasible and safe in a porcine model, serving as a potential alternative pathway for pulmonary artery intervention. • This novel approach allows for faster access to the pulmonary artery, and it might be easier to operate the tip of the catheter to super-select the intent branch of the pulmonary artery. • TPAC can be an alternative pulmonary artery intervention pathway in patients with mechanical right-heart valves, great-vessel transposition, and other obstacles.

Clinical characteristics and postoperative outcomes of systemic artery-to-pulmonary vessel fistula in hemoptysis patients.

OBJECTIVES: To investigate the clinical characteristics and outcomes on the success of bronchial arterial embolization (BAE) in patients with and without systemic artery-to-pulmonary vessel fistula (SA-PF) and to evaluate the feasibility of CTA in the assessment of SA-PF. METHODS: We retrospectively enrolled 420 consecutive patients that underwent BAE for hemoptysis control in our hospital from September 2011 to May 2019. The clinical characteristics, preprocedural CTA findings, BAE procedural findings, and follow-up outcomes were collected. Patients were divided into two groups according to DSA findings: patients with SA-PF and those without. RESULTS: A total of 184 (43.7%) patients presented with SA-PF. Pneumonia was less likely to be the concomitant condition in patients with SA-PF (p < 0.001). The mean number of culprit arteries per patient was significantly higher in patients with SA-PF compared to that in patients without SA-PF (p = 0.017). The SA-PF patients saw a greater probability of recurrence (HR: 2.782, 95% CI: 1.617-4.784, p < 0.001). SA-pulmonary venous fistula (SA-PVF) favored lower hemoptysis recurrence rate (HR: 0.199, 95%CI: 0.052-0.765, p = 0.019). SA-pulmonary artery fistula (SA-PAF) can be detected by optimized CTA protocol with a detection rate of 65.3% (49/75). CONCLUSIONS: The presence of SA-PF is an independent risk factor predicting early recurrence of hemoptysis after BAE. SA-PVF seems to be a protective factor for longer hemoptysis control compared to SA-PAF. Optimized preprocedural CTA is a reliable examination to identify SA-PAF. KEY POINTS: • The appearance of SA-PF is associated with a greater probability of early recurrent hemoptysis after bronchial artery embolization. • The presence of SA-PVF seems to be a protective factor for longer hemoptysis control after BAE compared to SA-PAF. • Optimized CTA protocol seems to be a promising auxiliary examination to detect SA-PAF.

Decreased mortality in acute respiratory distress syndrome patients treated with corticosteroids: an updated meta-analysis of randomized clinical trials with trial sequential analysis.

BACKGROUND: The possible benefits associated with corticosteroid treatment in acute respiratory distress syndrome (ARDS) patients are not fully known. We conducted an updated meta-analysis to assess the effect of corticosteroids in the treatment of patients with ARDS. METHODS: We systematically searched MEDLINE, Embase, and the Cochrane Library from inception to January 2021 via Ovid to identify randomized controlled trials evaluating the efficacy of glucocorticoids in the treatment of patients with ARDS. The primary outcome was hospital mortality. Secondary outcomes included the number of ventilator-free days at day 28, oxygenation improvement (PaO2/FIO2 ratios), and adverse events. RESULTS: Nine studies with 1371 participants were analyzed. The pooled analysis revealed that glucocorticoid use was associated with reduced mortality [relative risk (RR), 0.83; 95% confidence interval (CI) 0.74-0.93; P < 0.01; I2 = 37], and the statistical power was confirmed by trial sequential analysis. Glucocorticoids might also significantly increase the number of ventilator-free days at day 28 (mean deviation 3.66 days, 95% CI 2.64-4.68; P < 0.01) and improve oxygenation (standardized mean difference 4.17; 95% CI 2.32-6.02; P < 0.01). In addition, glucocorticoid use was not associated with increased risks of new infection (RR 0.84; 95% CI 0.70-1.01; P = 0.07) and hyperglycemia (RR 1.11; 95% CI 0.99-1.23; P = 0.06). CONCLUSIONS: The use of glucocorticoids might result in reduced mortality in patients with ARDS. Glucocorticoids might be recommended as an adjunct to standard care for ARDS; however, the optimal dose and duration of steroid therapy remains unknown and further studies are needed.

Bronchus-blocked ultrasound-guided percutaneous transthoracic needle biopsy (BUS-PTNB) for intubated patients with severe lung diseases.

BACKGROUND: Examinations based on lung tissue specimen can play a significant role in the diagnosis for critically ill and intubated patients with lung infiltration. However, severe complications including tension pneumothorax and intrabronchial hemorrhage limit the application of needle biopsy. METHODS: A refined needle biopsy technique, named bronchus-blocked ultrasound-guided percutaneous transthoracic needle biopsy (BUS-PTNB), was performed on four intubated patients between August 2020 and April 2021. BUS-PTNB was done at bedside, following an EPUBNOW (evaluation, preparation, ultrasound location, bronchus blocking, needle biopsy, observation, and withdrawal of blocker) workflow. Parameters including procedure feasibility, sample acquisition, perioperative conditions, and complications were observed. Tissue specimens were sent to pathological examinations and microbial tests. RESULTS: Adequate specimens were successfully obtained from four patients. Diagnosis and treatment were correspondingly refined based on pathological and microbial tests. Intrabronchial hemorrhage occurred in patient 1 but was stopped by endobronchial blocker. Mild pneumothorax happened in patient 4 due to little air leakage, and closed thoracic drainage was placed. During the procedure, peripheral capillary hemoglobin oxygen saturation (SPO2), blood pressure, and heart rate of patient 4 fluctuated but recovered quickly. Vital signs were stable for patient 1-3. CONCLUSIONS: BUS-PTNB provides a promising, practical and feasible method in acquiring tissue specimen for critically ill patients under intratracheal intubation. It may facilitate the pathological diagnosis or other tissue-based tests for intubated patients and improve clinical outcomes.

Multidetector computed tomography angiography prior to bronchial artery embolization helps detect culprit ectopic bronchial arteries and non-bronchial systemic arteries originating from subclavian and internal mammary arteries and improve hemoptysis-free early survival rate in patients with hemoptysis.

OBJECTIVES: To compare the average number of culprit arteries per patient, clinical success rate, and hemoptysis-free survival rate between hemoptysis patients with multidetector computed tomography (MDCT) angiography prior to bronchial artery embolization (BAE) and those without preprocedural MDCT angiography METHODS: This retrospective study was approved by the institutional review board with waiver of patient informed consent. From September 2012 to March 2017, 157 consecutive hemoptysis patients had been undergoing BAE. Among them, 106 patients received preprocedural MDCT angiography (MDCT group), while 51 patients did not receive preprocedural MDCT angiography (control group). The average number of culprit arteries per patient, clinical success rate, and hemoptysis-free survival rate were compared between the two groups. RESULTS: The average number of culprit ectopic bronchial arteries and that of non-bronchial systemic arteries originating from the subclavian and internal mammary arteries per patient in the MDCT group were both significantly higher than those in the control group (0.15 ± 0.51 vs 0.04 ± 0.20, p = 0.022, and 0.17 ± 0.56 vs 0.08 ± 0.39, p = 0.040, respectively). The clinical success rate of BAE with preprocedural MDCT angiography tended to be higher than that without MDCT angiography (97.2 vs 88.2%, p = 0.057). Importantly, patients in the MDCT group had a significantly higher hemoptysis-free early survival rate compared to those in the control group (96.1 vs 86.7%, p = 0.031). CONCLUSIONS: Preprocedural MDCT angiography helps detect culprit ectopic bronchial arteries and non-bronchial systemic arteries originating from subclavian and internal mammary arteries during BAE, and can improve the hemoptysis-free early survival rate, which could be recommended as a regular examination prior to BAE in patients with hemoptysis. KEY POINTS: • Preprocedural MDCT angiography helps detect culprit ectopic bronchial arteries and NBSAs originating from subclavian and internal mammary arteries during BAE. • Conducting MDCT angiography prior to BAE can improve hemoptysis-free early survival rate in hemoptysis patients.

Analysis of mutants from a genetic screening reveals the control of intestine and liver development by many common genes in zebrafish.

Both the intestine and liver develop from the endoderm, yet little is known how these two digestive organs share and differ in their developmental programs, at the molecular level. A classical forward genetic screen, with no gene bias, is an effective way to address this question by examining the defects of the intestine and liver in obtained mutants to assess mutated genes responsible for the development of either organ or both. We report here such a screen in zebrafish. ENU was used as the mutagen because of its high mutagenic efficiency and no site preference. Embryos were collected at 3.5 dpf for RNA whole mount in situ hybridization with a cocktail probe of the intestine marker ifabp and the liver marker lfabp to check phenotypes and determine their parental heterozygosis. A total of 52 F2 putative mutants were identified, and those with general developmental defects were aborted. To rule out non-inheritable phenotypes caused by high mutation background, F2 putative mutants were outcrossed with wild type fish and a re-screen in F3 generations was performed. After complementation tests between F3 mutants with similar phenotypes originating from the same F2 families, a total of 37 F3 mutant lines originated from 22 F2 families were identified after screening 78 mutagenized genomes. Classification of mutant phenotypes indicated that 31 out of the 37 mutants showed defects in both the intestine and liver. In addition, four "intestine specific mutants" and two "liver specific mutants" showed selectively more severe phenotype in the intestine and liver respectively. These results suggested that the intestine and liver share a substantial number of essential genes during both organs development in zebrafish. Further studies of the mutants are likely to shed more insights into the molecular basis of the digestive system development in the zebrafish and vertebrate.

Anti-virus activity and mechanisms of natural polysaccharides from medicinal herbs.

There has been a sudden increase in viral diseases, such as coronavirus disease 2019 (COVID-19), causing significant harm to human and animal well-being, as well as economic development. Medicinal herbs, with a history of thousands of years in clinical use, contain versatile polysaccharides as one of their primary compounds. This review offers an overview of the antiviral effects of polysaccharides from medicinal herbs on viruses in humans, poultry, swine and aquaculture in recent years. The mechanism of these antiviral polysaccharides, involved in hindering various stages of the viral life cycle thereby blocking virus infection, is summarized. The review also explores other underlying mechanisms of antiviral effects, such as enhancing the immune response, regulating inflammatory reactions, balancing gut flora, reducing oxidative stress, and suppressing apoptosis through various corresponding signaling pathways. The structure-function relationships discussed in this article also aid in understanding the antiviral mechanism of natural polysaccharides, indicating the need for more in-depth research and analysis. Natural polysaccharides from medicinal herbs have emerged as valuable resources in the fight against viral infections, exhibiting high effectiveness. This review emphasizes the promising role of polysaccharides from medicinal herbs as potential candidates for blocking viral infections in humans and animals.

International trends in pulmonary hypertension mortality between 2001 and 2019: Retrospective analysis of the WHO mortality database.

Background: There are limited published data on mortality trends in pulmonary hypertension (PH) worldwide. The objective of this study was to assess the PH-related mortality and time trends in the general population over the past 20 years. Material and methods: We used country-level PH mortality data from the World Health Organization (WHO) mortality database (2000-19), using the International Classification of Diseases, tenth revision (ICD-10) codes (I27.0, I27.2, I27.8, or I27.9). The average annual percentage changes (AAPCs) were calculated to describe mortality trends. Results: Fifty-four countries were included in this study. Between 2017 and 2019, the average age-standardized death rates (per 100,000) were 0.80 and 0.87 for males and females, respectively. Joinpoint analyses revealed a decreasing PH mortality trend for the overall population from 2000 to 2019 (AAPC -3.2 [95% confidence interval (CI) -4.1 to -2.4]), which was consistent between males and females (males: AAPC -5.3 [95% CI -6.2 to -4.4], females: AAPC -1.7 [95% CI -2.4 to -0.9]). When the estimates were stratified by etiology, we found that the mortality rates from idiopathic pulmonary arterial hypertension (I27.0) and pulmonary heart disease (unspecified, I27.9) had decreased significantly, while the mortality rates in other secondary PH (I27.2) and other specified pulmonary heart diseases (I27.8) had significantly increased. In addition, there were substantial differences in mortality rates and time trends across countries. Conclusion: Although an overall decrease in PH mortality trends over the past two decades, there were substantial differences across countries. For countries with high or rising mortality rates, more efforts are needed to reduce the mortality.

Imaging-Guided Percutaneous Endovascular Biopsy Applied in Patients with Pulmonary Artery Masses: A Review.

INTRODUCTION: Pulmonary artery (PA) masses are rare. Distinguishing PA tumours from embolism is sometimes difficult, and surgical biopsy is expensive and risky. We aimed to evaluate the efficacy of imaging-guided percutaneous endovascular biopsy (PEB) for obtaining tissues for histological diagnosis. METHODS: We searched Cochrane, Medline, Embase, and Web of Science for PEB trials involving patients with PA masses, published from the inception of the database until August 2023. RESULTS: We retrospectively reviewed 33 studies including 87 patients (median age 55 ± 69.3 years, 44 men) with PA masses who underwent a total of 110 PEBs. Of these patients, 34.5% (n = 38) underwent PEB-catheter aspiration (PEB-CA), 50.9% (n = 56) underwent PEB-forceps biopsy (PEB-FB) and 2.7% (n = 3) underwent PEB-directional atherectomy (PEB-DA). The most common histological aetiology of PA masses was mesenchymal tumours (n = 67, 75.9%). Tumour embolism (n = 6, 6.9%) and pulmonary embolism (n = 3, 3.4%) were the second and third most common types of PA masses, respectively. The technical success rates of PEB-CA, PEB-FB and PEB-DA were 92.1%, 94.6% and 100% (p = 0.796), respectively. Histopathological analysis provided clinical diagnostic success rates of 44.7%, 85.7% and 100% for PEB-CA, PEB-FB and PEB-DA (p < 0.001), respectively. In pairwise comparison, PEB-FB had a higher success rate in pathological diagnosis than PEB-CA (p = 0.000). Apart from one patient suffering from haemorrhagic cardiac tamponade, no other complications occurred. CONCLUSION: Imaging-guided PEB is a safe and effective technique for the early pathological diagnosis of PA masses.

Designing bifunctional NOP receptor-mu opioid receptor ligands from NOP receptor-selective scaffolds. Part I.

The nociceptin receptor (NOP) and its endogenous agonist, nociceptin/orphanin FQ (N/OFQ), members of the opioid receptor and peptide families respectively, modulate the pharmacological effects of classical opioids, particularly opioid-induced reward and nociception. We hypothesized that compounds containing both NOP and opioid receptor activity in a single molecule may have useful pharmacological profiles as non-addicting analgesics or as drug abuse medications. We report here our forays into the structure-activity relationships for discovering 'bifunctional' NOP-mu opioid receptor (MOP) ligands, starting from our NOP-selective scaffolds. This initial SAR suggests pharmacophoric elements that may be modified to modulate/increase opioid affinity, while maintaining high affinity for the NOP receptor, to result in potent bifunctional small-molecule NOP/MOP ligands.

Safety and efficacy of 12-week or longer indacaterol treatment in moderate-to-severe COPD patients: a systematic review.

BACKGROUND: This is a meta-analysis of the safety and efficacy of indacaterol in chronic obstructive pulmonary disease (COPD) with treatment duration of ≥12 weeks. METHODS: Randomized controlled trials (RCTs) reported in English (to September 30, 2012) were identified from PubMed, the Cochrane Library, Embase, websites, reference lists, and manual searches. Two reviewers independently assessed the quality of the trials and extracted information. RESULTS: Five RCTs were eligible. Five involved indacaterol, two salmeterol, one formoterol, and one tiotropium. Four studies had placebos. Using trough forced expiratory volume in 1 s as a measure of therapeutic effect, indacaterol was superior to the other ß2-agonists, tiotropium, and placebo at weeks 12, 26, and 52. Indacaterol had a greater effect on the transition dyspnoea index compared with placebo, formoterol, and salmeterol, but not open-label tiotropium. In reducing the as-needed use of salbutamol, indacaterol were superior to placebo, tiotropium, and formoterol, but not salmeterol (5, 95 % confidence interval (CI), -2.15, 12.15). Indacaterol improved St George's Respiratory Questionnaire scores more than placebo and open-label tiotropium, but not formoterol. Indacaterol seemed to cause more adverse events than placebo only at a dose of 600 µg daily and a duration of 52 weeks (risk ratio 1.15; 95 % CI, 1.04, 1.26). The total and serious adverse events and adverse events leading to discontinuation were comparable with open-label tiotropium and the ß2-agonists. CONCLUSIONS: Indacaterol is effective and well-tolerated as a bronchodilator for the maintenance of moderate to severe COPD.

Diabetic endothelial microangiopathy and pulmonary dysfunction.

Type 2 diabetes mellitus (T2DM) is a widespread metabolic condition with a high global morbidity and mortality rate that affects the whole body. Their primary consequences are mostly caused by the macrovascular and microvascular bed degradation brought on by metabolic, hemodynamic, and inflammatory variables. However, research in recent years has expanded the target organ in T2DM to include the lung. Inflammatory lung diseases also impose a severe financial burden on global healthcare. T2DM has long been recognized as a significant comorbidity that influences the course of various respiratory disorders and their disease progress. The pathogenesis of the glycemic metabolic problem and endothelial microangiopathy of the respiratory disorders have garnered more attention lately, indicating that the two ailments have a shared history. This review aims to outline the connection between T2DM related endothelial cell dysfunction and concomitant respiratory diseases, including Coronavirus disease 2019 (COVID-19), asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF).

Preclinical Characterization of XL092, a Novel Receptor Tyrosine Kinase Inhibitor of MET, VEGFR2, AXL, and MER.

The multi-receptor tyrosine kinase inhibitor XL092 has been developed to inhibit the activity of oncogenic targets, including MET, VEGFR2, and the TAM family of kinases TYRO3, AXL and MER. Presented here is a preclinical evaluation of XL092. XL092 causes a significant decrease in tumor MET and AXL phosphorylation (P < 0.01) in murine Hs 746T xenograft models relative to vehicle, and a 96% inhibition of VEGFR2 phosphorylation in murine lungs. Dose-dependent tumor growth inhibition with XL092 was observed in various murine xenograft models, with dose-dependent tumor regression seen in the NCI-H441 model. Tumor growth inhibition was enhanced with the combination of XL092 with anti-PD-1, anti-programmed death ligand-1 (PD-L1), or anti-CTLA-4 compared with any of these agents alone in the MC38 murine syngeneic model and with anti-PD-1 in the CT26 colorectal cancer survival model. In vivo, XL092 promoted a decrease in the tumor microvasculature and significant increases of peripheral CD4+ T cells and B cells and decreases in myeloid cells versus vehicle. Significant increases in CD8+ T cells were also observed with XL092 plus anti-PD-1 or anti-PD-L1 versus vehicle. In addition, XL092 promoted M2 to M1 repolarization of macrophages in vitro and inhibited primary human macrophage efferocytosis in a dose-dependent manner. In summary, XL092 was shown to have significant antitumor and immunomodulatory activity in animal models both alone and in combination with immune checkpoint inhibitors, supporting its evaluation in clinical trials.

MiR-124-3p targeting PDE4B attenuates LPS-induced ALI through the TLR4/NF-κB signaling pathway.

BACKGROUND: A large number of studies have found that microRNAs (miRNAs) and phosphodiesterase 4 (PDE4) are crucial regulators of inflammatory responses in acute lung injury (ALI). OBJECTIVE: This study will explore the protective effect of miR-124-3p on ALI and its related mechanism. METHODS: The ALI mouse model was established by intratracheal administration of lipopolysaccharide (LPS) and evaluated by haematoxylin and eosin (HE) staining, lung injury score, inflammation factors, polymorphonuclear leukocyte (PMN) count, total protein and lung wet weight/dry weight (W/D) ratio. MiR-124-3p was overexpressed in vivo by intratracheal administration of miR-agomir, and PDE4B was expressed at low level in vivo by intratracheal administration of a PDE4B inhibitor. The mRNA expression level was detected by qRT-PCR, and the protein expression level was detected by Western blot. The relationship between miR-124-3p and PDE4B was detected by dual-luciferase activity assay. RESULTS: We found that miR-124-3p was downregulated in LPS-induced ALI. Overexpression of miR-124-3p alleviated lung injury by inhibiting the Toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling pathway. Furthermore, we confirmed that miR-124-3p suppressed the TLR4/NF-κB signaling pathway by directly targeting PDE4B. CONCLUSION: miR-124-3p targeting PDE4B had a protective effect on LPS-induced ALI by inhibiting the TLR4/NF-κB signaling pathway.

Differential effects of nociceptin/orphanin FQ (NOP) receptor agonists in acute versus chronic pain: studies with bifunctional NOP/µ receptor agonists in the sciatic nerve ligation chronic pain model in mice.

1-(1-Cyclooctylpiperidin-4-yl)-indolin-2-one (SR14150) and 1-(1-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)piperidinl-4-yl)-indolin-2-one (SR16835) are moderately selective nociceptin/orphanin FQ (NOP) receptor agonists. In the [(35)S]guanosine 5'-O-(3-thiotriphosphate) assay in vitro, SR14150 is a partial agonist at both the NOP and µ-opioid receptors, whereas SR16835 is a full agonist at the NOP receptor and has low efficacy at µ receptors. These compounds were tested for antinociceptive and antiallodynic activity, using mice in chronic pain, subsequent to spinal nerve ligation (SNL) surgery. When administered subcutaneously to mice after SNL surgery, SR14150 but not SR16835 increased tail-flick latency, which was blocked by the opioid antagonist naloxone, but not by the NOP receptor antagonist (-)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (SB-612111). In contrast, both SR14150 and SR16835 had antiallodynic activity when mechanical allodynia was measured with von Frey monofilaments. This effect was completely blocked by SB-612111 but not by naloxone. On the other hand, morphine antinociception and antiallodynia were both blocked by naloxone and potentiated by SB-612111. These results indicate that, in mice, circuitry mediating antinociceptive activity in acute and chronic pain states is different. It is possible that during a chronic pain state, an up-regulated NOP system in the spinal cord leads to NOP receptor-mediated antiallodynia, which is blocked by NOP antagonists. However, supraspinal up-regulation could lead to an attenuation of morphine antinociception and antiallodynia, which can be alleviated by an NOP receptor antagonist. Thus, although neither NOP agonists nor antagonists are effective as analgesics in acute pain, they may have efficacy as analgesics, either alone or in combination with morphine, for treatment of chronic pain.

Nociceptin/orphanin FQ receptor activation attenuates antinociception induced by mixed nociceptin/orphanin FQ/mu-opioid receptor agonists.

Activation of brain nociceptin/orphanin FQ (NOP) receptors leads to attenuation of mu-opioid receptor (MOP receptor)-mediated antinociception. Buprenorphine, a high-affinity partial MOP receptor agonist also binds to NOP receptors with 80 nM affinity. The buprenorphine-induced inverted U-shaped dose-response curve for antinociception may be due to NOP receptor activation, given that, in the presence of the NOP receptor antagonist, 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J113397), or in NOP receptor knockout mice, buprenorphine has a steeper dose-response curve and acts as a full agonist. To further explore the involvement of the direct activation of NOP receptors by buprenorphine and other compounds that activate both NOP and MOP receptors, the antinociceptive effects of 1-(1-(2,3,3alpha,4,5,6-hexahydro-1H-phenalen-1-yl)piperidin-4-yl)-indolin-2-one. (SR16435), 3-ethyl-1-(1-(4-isopropylcyclohexyl)piperidin-4-yl)-indolin-2-one (SR16507), buprenorphine, pentazocine, and morphine, compounds with varying levels of MOP and NOP receptor affinity and efficacy, were assessed in mice using the tail-flick assay. The ability of the selective NOP receptor antagonist (-)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (SB-612111) to potentiate antinociception induced by the above compounds was examined to investigate whether activation of NOP receptors leads to attenuation of MOP receptor-mediated antinociception. SB-612111 potentiated antinociception induced by buprenorphine and the other mixed NOP/MOP receptor agonists SR16435 and SR16507. However, SB-612111 had no effect on pentazocine or morphine antinociception, two compounds with no NOP receptor-binding affinity. These results further support the hypothesis that activation of NOP receptors can lead to attenuation of MOP receptor-mediated antinociception elicited by mixed NOP/MOP receptor compounds such as buprenorphine, SR16435, and SR16507 and that, although buprenorphine has low efficacy in vitro, it has significant NOP receptor agonist activity in vivo.

Comparison of the antinociceptive and antirewarding profiles of novel bifunctional nociceptin receptor/mu-opioid receptor ligands: implications for therapeutic applications.

The nociceptin receptor (NOPr), a member of the opioid receptor family, is a target for the treatment of pain and drug abuse. Nociceptin/orphanin FQ (N/OFQ), the endogenous peptide for NOPr, not only modulates opioid antinociception, but also blocks the rewarding effects of several abused drugs, such as morphine, cocaine, and amphetamine. We hypothesized that NOPr agonists, with bifunctional activity at the mu-opioid receptor (MOPr), may function as nonaddicting analgesics or as drug abuse medications. Bifunctional small-molecule NOPr agonists possessing different selectivities and efficacies at MOPr were evaluated in an acute thermal antinociception assay, and for their ability to induce conditioned place preference (CPP) and their effect on morphine-induced CPP. 1-(1-Cyclooctylpiperidin-4-yl)-indolin-2-one) (SR14150), a high-affinity NOPr partial agonist, with low MOPr affinity and efficacy, produced analgesia that was naloxone-reversible. SR14150 did not induce CPP alone, nor did it attenuate morphine-induced CPP. 3-Ethyl-1-(1-(4-isopropylcyclohexyl)piperidin-4-yl)-indolin-2-one (SR16507), which has high affinity for both NOPr and MOPr, full agonist activity at NOPr, and partial agonist activity at MOPr, was also a potent analgesic and produced CPP alone, but also modestly attenuated morphine CPP. 1-(1-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)piperidinl-4-yl)-indolin-2-one (SR16835), a NOPr full agonist and low-affinity MOPr partial agonist, was not antinociceptive, did not produce CPP alone, but attenuated morphine CPP. Our results suggest that NOPr full-agonist activity is required to modulate opioid-induced reward, whereas a bifunctional NOPr/MOPr partial agonist profile may be suitable as a nonaddicting analgesic. The opioid-modulating effects of the NOPr ligands may be used effectively to produce better medications for treatment of drug abuse and pain.

CT-guided percutaneous transthoracic needle biopsy for paramediastinal and nonparamediastinal lung lesions: Diagnostic yield and complications in 1484 patients.

Computed tomography-guided percutaneous transthoracic needle biopsy (PTNB) is used for identifying paramediastinal lung lesions that cannot be diagnosed by bronchoscopy, but the diagnostic performance and complication rate are unreported.This retrospective study was approved by the institutional review board committee. A total of 1484 patients who underwent PTNB between April 2012 and April 2015 were enrolled. The cohort was divided into a paramediastinal (n = 195) and a nonparamediastinal group (n = 1289) based on lesion location. Diagnostic yield for malignancy and complication rates were analyzed in both groups. Univariate and multivariate logistic regression analysis was used to determine independent risk factors for hemoptysis complication in the paramediastinal group.Percutaneous transthoracic needle biopsy showed 95.6% (109/114) sensitivity and 100% (77/77) specificity for the diagnosis of lesions in the paramediastinal group, with similar accuracy (95.4%, 186/195) to that in the nonparamediastinal group (94.7%, 1221/1289; P = 0.699). Compared with PTNB for nonparamediastinal lesions, PTNB for paramediastinal lesions demonstrated a comparable pneumothorax rate (8.21% vs 8.69%; P = 0.823) and hemothorax rate (2.56% vs 1.47%; P = 0.261), and a higher hemoptysis rate (28.2% vs 19.4%; P = 0.005). Among 6 defined paramediastinal regions, the overall complication rate was the highest in the posterior region (42.4%) and the lowest in the paraventricular region (13.6%). Multivariate analysis revealed that lesion size of 2 to 3 cm (odds ratio [OR] 3.22), intrapulmonary length of needle path >2 cm (OR 8.85), and proximal to pulmonary artery (OR 10.33) were independent risk factors for hemoptysis in the paramediastinal group.Computed tomography-guided PTNB can diagnose paramediastinal lesions with high yield and acceptable complication rates. Given higher rate of hemoptysis in PTNB for paramediastinal lesions, more attention should be paid in cases with high risks.

Nucleic Acid Amplification Testing and Sequencing Combined with Acid-Fast Staining in Needle Biopsy Lung Tissues for the Diagnosis of Smear-Negative Pulmonary Tuberculosis.

BACKGROUND: Smear-negative pulmonary tuberculosis (PTB) is common and difficult to diagnose. In this study, we investigated the diagnostic value of nucleic acid amplification testing and sequencing combined with acid-fast bacteria (AFB) staining of needle biopsy lung tissues for patients with suspected smear-negative PTB. METHODS: Patients with suspected smear-negative PTB who underwent percutaneous transthoracic needle biopsy between May 1, 2012, and June 30, 2015, were enrolled in this retrospective study. Patients with AFB in sputum smears were excluded. All lung biopsy specimens were fixed in formalin, embedded in paraffin, and subjected to acid-fast staining and tuberculous polymerase chain reaction (TB-PCR). For patients with positive AFB and negative TB-PCR results in lung tissues, probe assays and 16S rRNA sequencing were used for identification of nontuberculous mycobacteria (NTM). The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy of PCR and AFB staining were calculated separately and in combination. RESULTS: Among the 220 eligible patients, 133 were diagnosed with TB (men/women: 76/57; age range: 17-80 years, confirmed TB: 9, probable TB: 124). Forty-eight patients who were diagnosed with other specific diseases were assigned as negative controls, and 39 patients with indeterminate final diagnosis were excluded from statistical analysis. The sensitivity, specificity, PPV, NPV, and accuracy of histological AFB (HAFB) for the diagnosis of smear-negative were 61.7% (82/133), 100% (48/48), 100% (82/82), 48.5% (48/181), and 71.8% (130/181), respectively. The sensitivity, specificity, PPV, and NPV of histological PCR were 89.5% (119/133), 95.8% (46/48), 98.3% (119/121), and 76.7% (46/60), respectively, demonstrating that histological PCR had significantly higher accuracy (91.2% [165/181]) than histological acid-fast staining (71.8% [130/181]), P < 0.001. Parallel testing of histological AFB staining and PCR showed the sensitivity, specificity, PPV, NPV, and accuracy to be 94.0% (125/133), 95.8% (46/48), 98.4% (125/127), 85.2% (46/54), and 94.5% (171/181), respectively. Among patients with positive AFB and negative PCR results in lung tissue specimens, two were diagnosed with NTM infections (Mycobacterium avium-intracellulare complex and Mycobacterium kansasii). CONCLUSION: Nucleic acid amplification testing combined with acid-fast staining in lung biopsy tissues can lead to early and accurate diagnosis in patients with smear-negative pulmonary tuberculosis. For patients with positive histological AFB and negative tuberculous PCR results in lung tissue, NTM infection should be suspected and could be identified by specific probe assays or 16S rRNA sequencing.