The Effect of Endovascular Treatment of Renal Artery Stenoses on Coexistent Aneurysms Associated with Fibromuscular Dysplasia.

PURPOSE: Endovascular data on patients with coexistent renal artery stenosis (RAS) and renal artery aneurysm (RAA) caused by fibromuscular dysplasia (FMD) are scarce, and the outcomes from RAS-specific treatment on RAA remain unclear. This study aimed to evaluate the safety and effectiveness of RAS-specific endovascular management in patients with coexisting RAA caused by FMD. MATERIALS AND METHODS: Clinical and endovascular data on 19 patients with coexistent RAS and RAA caused by FMD who underwent RAS-specific endovascular therapy were analyzed prospectively. An RAA located within 10 mm of the RAS was defined as a stenosis-related RAA (SRAA), and long-term outcomes were evaluated. RESULTS: Nineteen patients (24 RASs and 30 RAAs) underwent endovascular therapy. Twenty-one RASs were treated with balloon angioplasty alone, whereas 3 RASs were treated with stent implantation. None of the RAAs were treated directly. During an average of 4.2 years ± 3.2 of follow-up, systolic and diastolic blood pressures decreased from 183.0 mm Hg ± 19.5 and 120.2 mm Hg ± 19.0 to 127.9 mm Hg ± 10.3 and 80.9 mm Hg ± 6.9, respectively; the number of antihypertensive medications reduced from 1.7 ± 1.0 to 0.8 ± 0.3 (for all, P < .001). The serum creatinine level remained stable. The maximum diameter of all RAAs decreased from 14.6 mm ± 9.7 to 11.3 mm ± 8.4 (P < .001). There was a significant difference in the improvement rate of the maximum diameter between SRAAs (65.0%, 13 of 20) and non-SRAAs (20.0%, 2 of 10) (P = .019). CONCLUSIONS: RAS-specific endovascular therapy is safe and effective and possibly aids in preventing RAA progression in patients with FMD with coexistent RAS and RAA.

Association between red blood cell distribution width-to-albumin ratio and prognosis of patients with acute myocardial infarction.

BACKGROUND: Red blood cell distribution width (RDW) and albumin level were considered to be related to the prognosis of patients with acute myocardial infarction (AMI). This study aims to investigate the correlation between RAR and 90-day mortality in AMI patients. METHODS: Data of AMI patients were obtained from the Medical Information Mart for Intensive Care III (MIMIC-III) database. According to the median, RAR < 4.32 was regarded as low RAR level group, and RAR ≥ 4.32 as high RAR level group; low RDW level group was defined as < 14.00%, and high RDW level group as ≥ 14.00%; albumin < 3.30 g/dL was low level group, and albumin ≥ 3.30 g/dL as high level group. The outcome was the mortality rate within 90 days after admission to ICU. Univariate and multivariate Cox models were performed to determine the relationship between RAR and 90-day mortality in AMI patients with hazard ratio (HR) and 95% confidence interval (CI). Stratification analyses were conducted to explore the effect of RAR on 90-day mortality in different subgroups of age, gender, simplified acute physiology score II (SAPS II), elixhauser comorbidity index (ECI) score, treatment modalities and white blood cell. RESULTS: Of the total 2081 AMI patients, 543 (26.09%) died within 90-day follow-up duration. The results showed that high RAR (HR = 1.65, 95% CI 1.34-2.03) and high RDW levels (HR = 1.31, 95% CI 1.08-1.61) were associated with an increased risk of death in AMI patients, and that high albumin level was related to a decreased risk of death (HR = 0.77, 95%CI 0.64-0.93). The relationship of RAR level and the mortality of AMI patients was also observed in the subgroup analysis. Additionally, the finding indicated that RAR might be a more effective biomarker for predicting 90-day mortality of AMI patients than albumin, RDW. CONCLUSION: RAR may be a potential marker for the prognostic assessment of AMI, and a high RAR level was correlated with increased risk of 90-day mortality of AMI patients.

Selective inhibition of phosphodiesterase 7 enzymes reduces motivation for nicotine use through modulation of mesolimbic dopaminergic transmission.

Background: About 5 million people die from diseases related to nicotine addiction and tobacco use each year. Nicotine-induced increase of corticomesolimbic dopaminergic (DAergic) transmission and hypodopaminergic conditions occurring during abstinence are important for maintaining drug-use habits. Methods: We examined the notion of re-equilibrating DAergic transmission by inhibiting phosphodiesterase 7 (PDE7), an intracellular enzyme highly expressed in the corticomesolimbic circuitry and responsible for the degradation of cyclic adenosine monophosphate (cAMP), the main second messenger modulated by DA receptor activation. Results: Using selective PDE7 inhibitors, we demonstrated in male rats that systemic PDE7 enzyme inhibition reduced nicotine self-administration and prevented reinstatement to nicotine seeking evoked by cues or by the pharmacological stressor yohimbine. The effect was also observed by direct application of the PDE7 inhibitors into the nucleus accumbens (NAc) shell but not into the core. Inhibition of PDE7 resulted in increased DA- and cAMP-regulated neuronal phosphoprotein (DARPP-32) and cAMP response element-binding protein (CREB) and their phosphorylated forms in the NAc. It also enhanced the DA D1 receptor agonism-mediated effects, indicating potentiation of protein kinase A (PKA)-dependent transmission downstream of D1 receptor activation. In electrophysiological recordings from DA neurons in the lateral posterior ventral tegmental area (VTA), the PDE7 inhibitors attenuated the spontaneous activity of DA neurons. This effect was exerted through the potentiation of D1 receptor signaling and the subsequent facilitation of γ-aminobutyric acid (GABA) transmission. The PDE7 inhibitors did not elicit conditioned place preference and did not induce intravenous self-administration, indicating lack of reinforcing properties. Conclusions: PDE7 inhibitors have the potential to treat nicotine abuse.SIGNIFICANCE STATEMENTThe World Health Organization (WHO) estimates that there are 1.25 billion smokers worldwide, representing one third of the global population over the age of 15. Nicotine-induced increase of corticomesolimbic dopaminergic (DAergic) transmission and hypodopaminergic conditions occurring during abstinence are critical for maintaining drug-use habits. Here we demonstrate that nicotine consumption and relapse to nicotine seeking are attenuated by re-equilibrating DAergic transmission through inhibition of phosphodiesterase 7 (PDE7), an intracellular enzyme responsible for the degradation of cyclic adenosine monophosphate (cAMP), the main second messenger modulated by DA receptor activation. PDE7 inhibition may represent a novel treatment approach to aid smoking cessation.

Correlation of the prognostic value of FNDC4 in glioblastoma with macrophage polarization.

BACKGROUND: Glioblastoma is among the most malignant tumors in the central nervous system and characterized by strong invasion and poor prognosis. Fibronectin type III domain-containing 4 (FNDC4) plays various important roles in the human body, including participating in cellular metabolism and inflammatory responses to cardiovascular diseases, influencing immune cells, and exerting anti-inflammatory effects; however, the role of FNDC4 in glioblastoma has not been reported. METHODS: In this study, bioinformatics databases, including TCGA, CGGA, GTEx, and TIMER, were used to analyze the differential expression of FNDC4 genes and cell survival, in addition to investigating its relationship with immune cell infiltration. Additionally, we overexpressed FNDC4 in glioblastoma cell lines U87 and U251 by lentiviral transfection and detected changes in proliferation, cell cycle progression, and apoptosis. Following collection of monocytes from the peripheral blood of healthy individuals and transformation into M0 macrophages, we performed flow cytometry to detect the polarizing effect of exogenous FNDC4, as well as the effect of FNDC4-overexpressing glioblastoma cells on macrophage polarization in a co-culture system. RESULTS: We identified that significantly higher FNDC4 expression in glioblastoma tissue relative to normal brain tissue was associated with worse prognosis. Moreover, we found that FNDC4 overexpression in U87 and U251 cells resulted in increased proliferation and affected the S phase of tumor cells, whereas cell apoptosis remained unchanged. Furthermore, exogenous FNDC4 inhibited the M1 polarization of M0 macrophages without affecting M2 polarization; this was also observed in glioblastoma cells overexpressing FNDC4. CONCLUSIONS: FNDC4 expression is elevated in glioblastoma, closely associated with poor prognosis, and promoted the proliferation of glioblastoma cells, affected the S phase of tumor cells while inhibiting macrophage polarization.

Characteristics of four-limb blood pressure and brachial-ankle pulse wave velocity in Chinese patients with Takayasu arteritis.

Purpose: Takayasu arteritis (TA) is a rare disease, which is frequently misdiagnosed or its diagnosis can be missed. This study aimed to analyse the characteristics of four-limb blood pressure (4LBP) and brachial-ankle pulse wave velocity (baPWV) in patients with TA, which could be useful in disease detection.Materials and Methods: We consecutively enrolled 182 patients with TA at Fuwai Hospital between January 2013 and January 2016. Pulse pressure (PP), pulsatile index (PI), inter-arm systolic blood pressure (SBP) difference (IASBPD), inter-leg SBP difference (ILSBPD), ankle-brachial index (ABI), baPWV, and inter-side baPWV difference (ΔbaPWV) were analysed and compared with those of age-, sex-, and SBP-matched participants without cardiovascular diseases.Results: In the TA group, the diastolic blood pressure was lower (67.4 ± 23.7 vs 84.1 ± 15.0 mmHg), PP was larger (69.7 ± 23.6 vs 53.7 ± 10.6 mmHg), PI was higher (1.3 ± 2.1 vs. 0.6 ± 0.1 mmHg), IASBPD was larger (18.2 ± 24.1 vs 4.2 ± 3.3 mmHg), and ILSBPD was larger (10.7 ± 15.0 vs 5.3 ± 4.1 mmHg) than those of the controls (all p < 0.01). Moreover, the proportions of PP >70 mmHg (36.8% vs 4.4%), PI > 1.0 (40.1% vs 2.2%), IASBPD >15 mmHg (34.6% vs. 0%), highest ABI >1.4 (17.6% vs. 0%), ILSBPD >15 mmHg (14.8% vs. 3.3%), lowest ABI < 0.9 (24.7% vs 2.2%), and ΔbaPWV > 185 cm/s (28.6% vs. 1.1%) were significantly greater in the TA group than in the control group (all p < 0.01). Approximately 80.8% of patients with TA (vs. 10.4% of controls) presented with at least one of these seven parameters (p = 0.000).Conclusion: The characteristics of 4LBP and baPWV in most patients with TA were abnormal, which helped us perform non-invasive primary screening and comprehensive evaluation of vascular lesions in such patients.

In daily life, many people measure the blood pressure of the arm but measuring the blood pressure of a single arm is inadequate because some hypertension and vascular diseases cannot be detected this way. Synchronous limb blood pressure measurements may be used to close this gap. Measuring synchronous limb blood pressure is very convenient and helps patients understand the value of limb blood pressure and examine many other useful parameters, such as the blood pressure differences between the two arms and two legs, as well as the ankle arm index. These values and derived parameters can also help detect many vascular diseases.Takayasu arteritis is a rare disease in young women. However, the aorta and branches of these patients are narrow or occluded. Patients often experience vague and ambiguous symptoms, such as hypertension or dizziness, so they are likely to be overlooked or misdiagnosed.Our study summarises the results of synchronous limb blood pressure measurements in patients with Takayasu arteritis and compares their results with those of a control population. Synchronous limb blood pressure measurements are easy and convenient and can detect vascular problems, which may improve the ability to diagnose Takayasu arteritis.

Andrographis paniculata and Its Main Bioactive Ingredient Andrographolide Decrease Alcohol Drinking and Seeking in Rats Through Activation of Nuclear PPARγ Pathway.

BACKGROUND AND AIMS: Andrographis paniculata is an annual herbaceous plant which belongs to the Acanthaceae family. Extracts from this plant have shown hepatoprotective, anti-inflammatory and antidiabetic properties, at least in part, through activation of the nuclear receptor Peroxisome Proliferator-Activated Receptor-gamma (PPAR γ). Recent evidence has demonstrated that activation of PPARγ reduces alcohol drinking and seeking in Marchigian Sardinian (msP) alcohol-preferring rats. METHODS: The present study evaluated whether A. paniculata reduces alcohol drinking and relapse in msP rats by activating PPARγ. RESULTS: Oral administration of an A. paniculata dried extract (0, 15, 150 mg/kg) lowered voluntary alcohol consumption in a dose-dependent manner and achieved ~65% reduction at the dose of 450 mg/kg. Water and food consumption were not affected by the treatment. Administration of Andrographolide (5 and 10 mg/kg), the main active component of A. paniculata, also reduced alcohol drinking. This effect was suppressed by the selective PPARγ antagonist GW9662. Subsequently, we showed that oral administration of A. paniculata (0, 150, 450 mg/kg) prevented yohimbine- but not cues-induced reinstatement of alcohol seeking. CONCLUSIONS: Results point to A. paniculata-mediated PPARγactivation as a possible therapeutic strategy to treat alcohol use disorder.

Upregulation of 6-phosphofructo-2-kinase (PFKFB3) by hyperactivated mammalian target of rapamycin complex 1 is critical for tumor growth in tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterized by the benign tumor formation in multiple organs. The main etiology of TSC is the loss-of-function mutation of TSC1 or TSC2 gene, which leads to aberrant activation of mammalian target of rapamycin complex 1 (mTORC1). In this research, we found a significant increase of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) expression in Tsc1-/- and Tsc2-/- mouse embryonic fibroblasts (MEFs) compared with the control cells. Inhibition of mTORC1 led to a dramatic decrease of PFKFB3 expression, indicating PFKFB3 regulation by mTORC1. Moreover, suppression of mTORC1 inhibited the expression of PFKFB3 in rat uterine leiomyoma-derived Tsc2-null ELT3 cells and human tumor cells. Furthermore, we identified hypoxia-inducible factor 1α (HIF-1α) as a mediator transmitting the signal from mTORC1 to PFKFB3. Depletion of PFKFB3 inhibited proliferation and tumorigenicity of Tsc1- or Tsc2-deficient cells. In addition, combination of rapamycin with PFK15, a PFKFB3 inhibitor, exerts a stronger inhibitory effect on cell proliferation of Tsc1- or Tsc2-null MEFs than treatment with single drug. We conclude that loss of TSC1 or TSC2 led to upregulated expression of PFKFB3 through activation of mTORC1/HIF-1α signaling pathway and co-administration of rapamycin and PFK15 may be a promising strategy for the treatment of TSC tumors as well as other hyperactivated mTORC1-related tumors.

Tripping Avoidance Lower Extremity Exoskeleton Based on Virtual Potential Field for Elderly People.

Tripping is a common problem that everyone faces when walking. This paper mainly focuses on a lower limb exoskeleton that can help those weak in joints to avoid tripping when negotiating stairs or stepping over obstacles. This method does not need a camera or map reconstruction to recognize the obstacles and plan paths. The exoskeleton applies an impedance controller to follow and control the pilot's movements. A virtual potential field is proposed to help the robot regulate the pilot's motion and avoid kicking the obstacles appearing in front of the pilot's foot during walking. Simulation and experiments show that this method works effectively and could help the elderly and those affected by joint weakness avoid tripping when walking.

Clinical features, laboratory findings and treatment of juxtaglomerular cell tumors: a systemic review.

Juxtaglomerular cell tumors (JGCTs) or reninoma are rare kidney tumors leading to secondary hypertension, and the non-specific clinical manifestations bring about challenges to the diagnosis. This study is to summarize the clinical features, laboratory findings, and treatment of JGCTs. The PubMed, EMBASE database, and manual search were utilized to find all cases, and 158 reports containing 261 patients were identified. Data on patients' demographics, clinical features, diagnostic methods, and treatment options were collected and analyzed. JGCTs occurred predominantly in female patients (female to male ratio, 2.1:1). The median age of patients was 25 years (IQR:18-34 years). Hypertension (97.24%) was the cardinal manifestation. Hypokalemia was reported in 78.71% (159/202) of subjects, and normal serum potassium accounted for 20.79% (42/202). In cases with assessed plasma renin activity (PRA) levels, the median PRA was 7.89 times the upper limit of normal (IQR:3.58-14.41), and 3.82% (5/131) of cases in the normal range. Tumors were detected in 97.8% (175/179) computed tomography (CT), 94.7% (72/76) magnetic resonance imaging (MRI), and 81.5% (110/135) ultrasound, respectively. For 250/261 patients undergoing surgical procedures, 89.14% (197/221), 94.94% (150/158), and 100% (131/131) of patients were restored to normal blood pressure, PRA, and serum potassium, respectively. JGCTs are commonly associated with hypertension, hypokalemia, and hyperreninemia, whereas patients with normotension, normokalemia, and PRA should be systematically pursued after drug-elution lasting for 2 weeks. CT and MRI are more sensitive imaging diagnostic methods. The blood pressure and biochemical parameters of most patients returned to normal after surgery.

Insight into the mechanism of nitrogen sufficiency conversion strategy for microalgae-based ammonium-rich wastewater treatment.

The strategy of nitrogen sufficiency conversion can improve ammonium nitrogen (NH4+-N) removal with microalgal cells from ammonium-rich wastewater. We selected and identified one promising isolated algal strain, NCU-7, Chlorella sorokiniana, which showed a high algal yield and tolerance to ammonium in wastewater, as well as strong adaptability to N deprivation. The transition from N deprivation through mixotrophy (DN, M) to N sufficiency through autotrophy (SN, P) achieved the highest algal yields (optical density = 1.18 and 1.59) and NH4+-N removal rates (2.5 and 4.2 mg L-1 d-1) from synthetic wastewaters at two NH4+-N concentrations (160 and 320 mg L-1, respectively). Algal cells in DN, M culture obtained the lowest protein content (20.6%) but the highest lipid content (34.0%) among all cultures at the end of the stage 2. After transferring to stage 3, the lowest protein content gradually recovered to almost the same level as SN, P culture on the final day. Transmission electron microscopy and proteomics analysis demonstrated that algal cells had reduced intracellular protein content but accumulated lipids under N deprivation by regulating the reduction in synthesis of protein, carbohydrate, and chloroplast, while enhancing lipid synthesis. After transferring to N sufficiency, algal cells accelerated their growth by recovering protein synthesis, leading to excessive uptake of NH4+-N from wastewater. This study provides specific insights into a nitrogen sufficiency conversion strategy to enhance algal growth and NH4+-N removal/uptake during microalgae-based ammonium-rich wastewater treatment.

Cebranopadol, a novel long-acting opioid agonist with low abuse liability, to treat opioid use disorder: Preclinical evidence of efficacy.

Maintenance therapy with buprenorphine and methadone is the gold standard pharmacological treatment for opioid use disorder (OUD). Despite these compounds demonstrating substantial efficacy, a significant number of patients do not show optimal therapeutic responses. The abuse liability of these medications is also a concern. Here we used rats to explore the therapeutic potential of the new long-acting pan-opioid agonist Cebranopadol in OUD. We tested the effect of cebranopadol on heroin self-administration and yohimbine-induced reinstatement of heroin seeking. In addition, we evaluated the abuse liability potential of cebranopadol in comparison to that of heroin under fixed ratio 1 (FR1) and progressive ratio (PR) operant self-administration contingencies. Oral administration of cebranopadol (0, 25, 50 µg/kg) significantly attenuated drug self-administration independent of heroin dose (1, 7, 20, 60µg/inf). Cebranopadol also reduced the break point for heroin (20 µg/inf). Finally, pretreatment with cebranopadol significantly attenuated yohimbine-induced reinstatement of drug seeking. In abuse liability experiments under FR1 contingency, rats maintained responding for heroin (1, 7, 20, 60µg/inf) to a larger extent than cebranopadol (0.03, 0.1, 0.3, 1.0, 6.0µg/inf). Under PR contingency, heroin maintained responding at high levels at all except the lowest dose, while the break point (BP) for cebranopadol did not differ from that of saline. Together, these data indicate that cebranopadol is highly efficacious in attenuating opioid self-administration and stress-induced reinstatement, while having limited abuse liability properties. Overall, the data suggest clinical potential of this compound for OUD treatment.

Augmented ERO1α upon mTORC1 activation induces ferroptosis resistance and tumor progression via upregulation of SLC7A11.

BACKGROUND: The dysregulated mechanistic target of rapamycin complex 1 (mTORC1) signaling plays a critical role in ferroptosis resistance and tumorigenesis. However, the precise underlying mechanisms still need to be fully understood. METHODS: Endoplasmic reticulum oxidoreductase 1 alpha (ERO1α) expression in mTORC1-activated mouse embryonic fibroblasts, cancer cells, and laryngeal squamous cell carcinoma (LSCC) clinical samples was examined by quantitative real-time PCR (qRT-PCR), western blotting, immunofluorescence (IF), and immunohistochemistry. Extensive in vitro and in vivo experiments were carried out to determine the role of ERO1α and its downstream target, member 11 of the solute carrier family 7 (SLC7A11), in mTORC1-mediated cell proliferation, angiogenesis, ferroptosis resistance, and tumor growth. The regulatory mechanism of ERO1α on SLC7A11 was investigated via RNA-sequencing, a cytokine array, an enzyme-linked immunosorbent assay, qRT-PCR, western blotting, IF, a luciferase reporter assay, and a chromatin immunoprecipitation assay. The combined therapeutic effect of ERO1α inhibition and the ferroptosis inducer imidazole ketone erastin (IKE) on mTORC1-activated cells was evaluated using cell line-derived xenografts, LSCC organoids, and LSCC patient-derived xenograft models. RESULTS: ERO1α is a functional downstream target of mTORC1. Elevated ERO1α induced ferroptosis resistance and exerted pro-oncogenic roles in mTORC1-activated cells via upregulation of SLC7A11. Mechanically, ERO1α stimulated the transcription of SLC7A11 by activating the interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) pathway. Moreover, ERO1α inhibition combined with treatment using the ferroptosis inducer IKE exhibited synergistic antitumor effects on mTORC1-activated tumors. CONCLUSIONS: The ERO1α/IL-6/STAT3/SLC7A11 pathway is crucial for mTORC1-mediated ferroptosis resistance and tumor growth, and combining ERO1α inhibition with ferroptosis inducers is a novel and effective treatment for mTORC1-related tumors.

Neoadjuvant chemotherapy for nonmetastatic esophago-gastric adenocarcinomas: a systematic review and meta-analysis.

OBJECTIVE: A systematic review and meta-analysis was performed to investigate the efficacy of neoadjuvant chemotherapy for nonmetastatic esophago-gastric adenocarcinomas. METHODS: Electronic databases were searched systematically from January 1980 to July 2012 and a total of 2,587 patients from 17 randomized controlled trials were subjected to meta-analysis. The odds ratios (ORs) for overall survival (OS) and progression-free survival (PFS) were calculated. RESULTS: Seventeen randomized controlled trials were obtained and various comparisons of treatment approaches were performed. Randomized controlled trials detected no differences in these comparisons: R0 resection for neoadjuvant chemotherapy versus none; Preoperative chemotherapy versus surgery alone: 3-year OS, 5-year OS, 5-year OS in Europe, 3-year PFS; Preoperative chemotherapy plus postoperative chemotherapy versus postoperative chemotherapy: 1-year OS, 5-year OS; Preoperative chemotherapy versus preoperative chemoradiotherapy: 3-year OS. Randomized controlled trials detected significant differences in these comparisons: Preoperative chemotherapy plus postoperative chemotherapy versus surgery alone: 3-year and 5-year PFS, 5-year OS; Subgroup analysis examining preoperative chemotherapy versus surgery alone: 5-year OS in Asia; Preoperative chemotherapy versus postoperative chemotherapy: 1-year OS. CONCLUSION: The current limited evidence suggests that preoperative chemotherapy can be applied to patients with nonmetastatic esophago-gastric adenocarcinomas (specifically, advanced esophago-gastric cancer). However, the results should be interpreted with caution because of the statistically low power and the heterogeneity among study designs; therefore, our results need validations in future studies.

Pregabalin reduces cocaine self-administration and relapse to cocaine seeking in the rat.

Pregabalin (Lyrica™) is a structural analog of γ-aminobutyric acid (GABA) and is approved by the FDA for partial epilepsy, neuropathic pain and generalized anxiety disorders. Pregabalin also reduces excitatory neurotransmitter release and post-synaptic excitability. Recently, we demonstrated that pregabalin reduced alcohol intake and prevented relapse to the alcohol seeking elicited by stress or environmental stimuli associated with alcohol availability. Here, we sought to extend these findings by examining the effect of pregabalin on cocaine self-administration (0.25 mg/infusion) and on cocaine seeking elicited by both conditioned stimuli and stress, as generated by administration of yohimbine (1.25 mg/kg). The results showed that oral administration of pregabalin (0, 10 or 30 mg/kg) reduced self-administration of cocaine over an extended period (6 hours), whereas it did not modify self-administration of food. In cocaine reinstatement studies, pregabalin (10 and 30 mg/kg) abolished the cocaine seeking elicited by both the pharmacological stressor yohimbine and the cues predictive of cocaine availability. Overall, these results demonstrate that pregabalin may have potential in the treatment of some aspects of cocaine addiction.

Association of lactate detection with in-hospital mortality in critically ill patients with acute myocardial infarction: a retrospective cohort study.

OBJECTIVES: To assess the associations of lactate level or lactate clearance at different time points with in-hospital mortality in critically ill patients with acute myocardial infarction (AMI). DESIGN: A cohort study. SETTING: The Medical Information Mart for Intensive Care III database. PARTICIPANT: 490 AMI patients. INTERVENTION: None. PRIMARY AND SECONDARY OUTCOME MEASURES: In-hospital mortality of patients. RESULTS: In total, 120 (24.49%) patients died at the end of follow-up. After adjusting for confounders, increased risk of in-hospital mortality in patients with AMI was observed in those with high lactate level (24 hours) (HR=1.156, 95%CI: 1.002 to 1.333). Increased lactate clearance (24 hours) was correlated with a decreased risk of in-hospital mortality in patients with AMI (HR=0.995, 95% CI: 0.994 to 0.997). The area under the curves (AUCs) of lactate level (24 hours) and lactate clearance (24 hours) were 0.689 (95% CI: 0.655 to 0.723) and 0.672 (95% CI: 0.637 to 0.706), respectively. The AUC of lactate level (24 hours) and lactate clearance (24 hours) was higher than lactate level (baseline). CONCLUSIONS: Increased lactate level (24 hours) was associated with an elevated risk of in-hospital mortality in patients with AMI and increased lactate clearance (24 hours) was correlated with a decreased risk of in-hospital mortality in patients with AMI despite the age and genders.

Pescadillo ribosomal biogenesis factor 1 reduction suppresses tumour growth and renders chemosensitivity of head and neck squamous cell carcinoma.

BACKGROUND: As one of the most devastating cancers, head and neck squamous cell carcinoma (HNSCC) has a short survival time and poor prognosis. Pescadillo ribosomal biogenesis factor 1 (PES1) plays a critical role in the progression of numerous cancers. However, its role and underlying mechanisms in HNSCC remain unclear. METHODS: A variety of bioinformatic approaches were used to identify the expressions, prognostic and diagnostic value of PES1 in HNSCC. qRT-PCR, immunofluorescence (IF) assay, western blotting and immunohistochemical (IHC) were used to evaluate the expression of PES1 in HNSCC cell lines and clinical tissues. PES1 was knocked down in TU177 and FaDu cells which have high PES1 expression. The effects of PES1 on cell proliferation and tumour growth in HNSCC were elevated by colony formation, CCK8 assays and tumorigenicity assay in nude mice. The effects on cisplatin (CDDP) sensitivity upon silencing of PES1 were assessed using a patient-derived xenograft (PDX) model. RESULTS: PES1 expression was an independent prognostic factor for HNSCC and negatively associated with the overall survival rate. Silencing of PES1 reduces HNSCC cell proliferation and tumour growth. Moreover, PES1 inhibition significantly sensitises HNSCC cells to cisplatin. Furthermore, we found a PES1 has a high correlation with c-Myc and plays an essential role in the tumour immune microenvironment. CONCLUSION: Our findings suggest that PES1 is associated with tumour growth and drug resistance and served as a potential cancer marker for diagnosis and a putative therapeutic target for HNSCC.

Enhancing algal growth and nutrient recovery from anaerobic digestion piggery effluent by an integrated pretreatment strategy of ammonia stripping and flocculation.

Anaerobic digestion piggery effluent (ADPE) with a quite high ammonium (NH4 +) concentration and turbidity (dark brown color) generally requires high dilution before microalgae cultivation, owing to its NH4 + toxicity and color inhibition to algal growth. An integrated pretreatment strategy of ammonia stripping and chemical flocculation may be a more practical pretreatment procedure for enhancing algae yield and nutrient recovery from anaerobic digestion piggery effluent. In this study, we determined the optimum pretreatment strategy of anaerobic digestion piggery effluent for subsequent microalgae cultivation and nutrient recovery. The results showed that the integrated anaerobic digestion piggery effluent pretreatment strategy of high-temperature ammonia stripping and chemical flocculation at a mixed dosage of 2 g L-1 polyaluminum chloride (PAC) and 40 mg L-1 cationic polyacrylamide (C-PAM), and 50 mg L-1 ammonium nitrogen (NH4 +-N) enrichment provided maximum algal yield (optical density = 1.8) and nutrient removal (95.2%, 98.7%, 99.3%, and 78.5% for the removal efficiencies of total nitrogen, NH4 +-N, total phosphorus, and chemical oxygen demand, respectively) from anaerobic digestion piggery effluent. The integrated pretreatment strategy is expected to become a more practical pretreatment procedure for enhancing algae yield and nutrient recovery from anaerobic digestion piggery effluent.

Cebranopadol, a novel long-acting opioid agonist with low abuse liability, to treat opioid use disorder: Preclinical evidence of efficacy.

The gold standard pharmacological treatment for opioid use disorder (OUD) consists of maintenance therapy with long-acting opioid agonists such as buprenorphine and methadone. Despite these compounds having demonstrated substantial efficacy, a significant number of patients do not show optimal therapeutic responses. Moreover, the abuse liability of these medications remains a major concern. Cebranopadol, is a new, long-acting pan-opioid agonist that also activates the nociception/orphanin FQ NOP receptor. Here we used rats to explore the therapeutic potential of this agent in OUD. First, in operant intravenous self-administration experiments we compared the potential abuse liability of cebranopadol with the prototypical opioid heroin. Under a fixed ratio 1 (FR1) contingency, rats maintained responding for heroin (1, 7, 20, 60 µg/inf) to a larger extent than cebranopadol (0.03, 0.1, 0.3, 1.0, 6.0 µg/inf). When the contingency was switched to a progressive ratio (PR) reinforcement schedule, heroin maintained responding at high levels at all except the lowest dose. Conversely, in the cebranopadol groups responding decreased drastically and the break point (BP) did not differ from saline controls. Next, we demonstrated that oral administration of cebranopadol (0, 25, 50 µg/kg) significantly attenuated drug self-administration independent of heroin dose (1, 7, 20, 60 µg/inf). Cebranopadol also reduced the break point for heroin (20 µg/inf). Furthermore, in a heroin self-administration training extinction/reinstatement paradigm, pretreatment with cebranopadol significantly attenuated yohimbine stress-induced reinstatement of drug seeking. Together, these data indicate that cebranopadol has limited abuse liability compared to heroin and is highly efficacious in attenuating opioid self-administration and stress-induced reinstatement, suggesting clinical potential of this compound for OUD treatment.

Improving algal growth in an anaerobic digestion piggery effluent by fungal pretreatment: Process optimization, the underlying mechanism of fungal decolorization, and nitrogen removal.

Anaerobic digestion piggery effluent (ADPE) shows high chromaticity and ammonium levels, severely inhibiting algal growth. Fungal pretreatment has great potential for decolorization and nutrient removal from wastewater, which coupled with microalgal cultivation may be a reliable strategy for sustainable ADPE resource utilization. In this study, we selected and identified two locally isolated eco-friendly fungal strains for ADPE pretreatment, and fungal culture conditions were optimized for decolorization and ammonium nitrogen (NH4+-N) removal. Subsequently, the underlying mechanisms of fungal decolorization and nitrogen removal were investigated, and the feasibility of using pretreated ADPE for algal cultivation was explored. The results showed that two fungal strains were identified as Trichoderma harzianum and Trichoderma afroharzianum, respectively, presenting good growth and decolorization performance for ADPE pretreatment. The optimized culture conditions were as follows: 20% ADPE, 8 g L-1 glucose, initial pH 6, 160 rpm, 25-30 °C, and 0.15 g L-1 initial dry-weight. ADPE decolorization was mainly caused by fungal biodegradation of color-related humic substances through manganese peroxidase secretion. The removed nitrogen was completely converted into fungal biomass as nitrogen assimilated, ca. 90% of which was attributed to NH4+-N removal. The pretreated ADPE significantly improved algal growth and nutrient removal, demonstrating the feasibility of developing an eco-friendly fungi-based pretreatment technology.

Ground Contact Force and Moment Estimation for Human-Exoskeleton Systems Using Dynamic Decoupled Coordinate System and Minimum Energy Hypothesis.

Estimating the contact forces and moments (CFMs) between exoskeletons' feet and the ground is a prerequisite for calculating exoskeletons' joint moments. However, comfortable, portable, and high-precision force sensors for CFM detection are difficult to design and manufacture. In addition, there are many unknown CFM components (six force components and six moment components in the double-support phase). These reasons make it challenging to estimate CFMs precisely. In this paper, we propose a novel method for estimating these CFMs based on a proposed dynamic decoupled coordinate system (DDCS) and the minimum energy hypothesis. By decomposing these CFMs into a DDCS, the number of unknowns can be significantly reduced from twelve to two. Meanwhile, the minimum energy hypothesis provides a relatively reliable target for optimizing the remaining two unknown variables. We verify the accuracy of this method using a public data set about human walking. The validation shows that the proposed method is capable of estimating CFMs. This study provides a practical way to estimate the CFMs under the soles, which contributes to reducing the research and development costs of exoskeletons by avoiding the need for expensive plantar sensors. The sensor-free approach also reduces the dependence on high-precision, portable, and comfortable CFM detection sensors, which are usually difficult to design.