Theta oscillons in behaving rats.

Recently discovered constituents of the brain waves-the oscillons-provide high-resolution representation of the extracellular field dynamics. Here we study the most robust, highest-amplitude oscillons that manifest in actively behaving rats and generally correspond to the traditional θ-waves. We show that the resemblances between θ-oscillons and the conventional θ-waves apply to the ballpark characteristics-mean frequencies, amplitudes, and bandwidths. In addition, both hippocampal and cortical oscillons exhibit a number of intricate, behavior-attuned, transient properties that suggest a new vantage point for understanding the θ-rhythms' structure, origins and functions. We demonstrate that oscillons are frequency-modulated waves, with speed-controlled parameters, embedded into a noise background. We also use a basic model of neuronal synchronization to contextualize and to interpret the observed phenomena. In particular, we argue that the synchronicity level in physiological networks is fairly weak and modulated by the animal's locomotion.

Theta oscillons in behaving rats.

Recently discovered constituents of the brain waves-the oscillons-provide high-resolution representation of the extracellular field dynamics. Here we study the most robust, highest-amplitude oscillons that manifest in actively behaving rats and generally correspond to the traditional θ-waves. We show that the resemblances between θ-oscillons and the conventional θ-waves apply to the ballpark characteristics-mean frequencies, amplitudes, and bandwidths. In addition, both hippocampal and cortical oscillons exhibit a number of intricate, behavior-attuned, transient properties that suggest a new vantage point for understanding the θ-rhythms' structure, origins and functions. We demonstrate that oscillons are frequency-modulated waves, with speed-controlled parameters, embedded into a noise background. We also use a basic model of neuronal synchronization to contextualize and to interpret the observed phenomena. In particular, we argue that the synchronicity level in physiological networks is fairly weak and modulated by the animal's locomotion.

Altered patterning of neural activity in a tauopathy mouse model.

Alzheimer's disease (AD) is a complex neurodegenerative condition that manifests at multiple levels and involves a spectrum of abnormalities ranging from the cellular to cognitive. Here, we investigate the impact of AD-related tau-pathology on hippocampal circuits in mice engaged in spatial navigation, and study changes of neuronal firing and dynamics of extracellular fields. While most studies are based on analyzing instantaneous or time-averaged characteristics of neuronal activity, we focus on intermediate timescales-spike trains and waveforms of oscillatory potentials, which we consider as single entities. We find that, in healthy mice, spike arrangements and wave patterns (series of crests or troughs) are coupled to the animal's location, speed, and acceleration. In contrast, in tau-mice, neural activity is structurally disarrayed: brainwave cadence is detached from locomotion, spatial selectivity is lost, the spike flow is scrambled. Importantly, these alterations start early and accumulate with age, which exposes progressive disinvolvement the hippocampus circuit in spatial navigation. These features highlight qualitatively different neurodynamics than the ones provided by conventional analyses, and are more salient, thus revealing a new level of the hippocampal circuit disruptions.

Phase I dose escalation and expansion study of golidocitinib, a highly selective JAK1 inhibitor, in relapsed or refractory peripheral T-cell lymphomas.

BACKGROUND: Relapsed or refractory peripheral T-cell lymphomas (r/r PTCLs) are a group of rare and aggressive diseases that lack effective therapies. Constitutive activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is reported to be associated with PTCLs. Golidocitinib is an oral, potent JAK1 selective inhibitor evaluated in a phase I/II multinational study in patients with r/r PTCLs. PATIENTS AND METHODS: Patients with r/r PTCLs were eligible. The primary objectives were to assess safety and tolerability of golidocitinib and to define its recommended phase II dose (RP2D). The secondary objectives were to evaluate its antitumor activity and pharmacokinetics (PK). RESULTS: A total of 51 patients were enrolled and received golidocitinib treatment at 150 or 250 mg once daily (QD). The median prior lines of therapies were 2 (range: 1-8). Golidocitinib was tolerated at both doses tested, while a higher incidence of serious adverse events and dose modifications at 250 mg were observed. The most common grade ≥3 drug-related treatment-emergent adverse events were neutropenia (27.5%) and thrombocytopenia (11.8%). An objective response rate of 39.2% and a complete response rate of 21.6% were observed. With median follow-up time of 14.7 and 15.9 months, the median duration of response (DoR) and progression-free survival were 8.0 and 3.3 months, respectively. Based on these data, 150 mg QD was defined as the RP2D. Golidocitinib demonstrated a favorable PK profile as an oral agent. Biomarker analysis suggested a potential correlation between JAK/STAT pathway aberrations and clinical activity of golidocitinib. CONCLUSIONS: In this phase I study, golidocitinib demonstrated an acceptable safety profile and encouraging antitumor efficacy in heavily pretreated patients with r/r PTCLs. These results support the initiation of the multinational pivotal study in patients with r/r PTCLs.

Preliminary clinical observations on autologous cultured skin fibroblasts transplantation in the treatment of keloids: a case report.

BACKGROUND: Keloids are benign skin lesions that gradually invade the surrounding normal tissue, and no treatment has proven curative. In our previous clinical practice of autologous cultured fibroblast transplantation, we found that fibroblast injection might have some effect on treating keloids, and we attempted to treat keloids by using fibroblast transplantation after obtaining the patient's approval. CASE REPORT: 1 patient was treated from March 2017 to June 2018. Autologous skin fibroblasts were separated from postauricular skin biopsy or resected keloid. They were cultured and expanded with exclusive methods. Cells (3×107/ml) within four or five passages were injected intradermally at the keloid at one-month intervals, 15 times in the patient. Shrink of the keloid on the patient was observed. The keloid became softer, flatter, and lighter in color after treatment. The elasticity of the keloid was also increased. The treatment effect was associated with the number of treatment sessions. CONCLUSIONS: This is the first report in which autologous fibroblast transplantation was used to treat keloids. Despite being only a single case experience, it suggests that keloid formation is a complex process in which still unknown factors may play a role.

Suvemcitug as second-line treatment of advanced or metastatic solid tumors and with FOLFIRI for pretreated metastatic colorectal cancer: phase Ia/Ib open label, dose-escalation trials.

BACKGROUND: Suvemcitug (BD0801), a novel humanized rabbit monoclonal antibody against vascular endothelial growth factor, has demonstrated promising antitumor activities in preclinical studies. PATIENTS AND METHODS: The phase Ia/b trials investigated the safety and tolerability and antitumor activities of suvemcitug for pretreated advanced solid tumors and in combination with FOLFIRI (leucovorin and fluorouracil plus irinotecan) in second-line treatment of metastatic colorectal cancer using a 3 + 3 dose-escalation design. Patients received escalating doses of suvemcitug (phase Ia: 2, 4, 5, 6, and 7.5 mg/kg; phase Ib: 1, 2, 3, 4, and 5 mg/kg plus FOLFIRI). The primary endpoint was safety and tolerability in both trials. RESULTS: All patients in the phase Ia trial had at least one adverse event (AE). Dose-limiting toxicities included grade 3 hyperbilirubinemia (one patient), hypertension and proteinuria (one patient), and proteinuria (one patient). The maximum tolerated dose was 5 mg/kg. The most common grade 3 and above AEs were proteinuria (9/25, 36%) and hypertension (8/25, 32%). Forty-eight patients (85.7%) in phase Ib had grade 3 and above AEs, including neutropenia (25/56, 44.6%), reduced leucocyte count (12/56, 21.4%), proteinuria (10/56, 17.9%), and elevated blood pressure (9/56, 16.1%). Only 1 patient in the phase Ia trial showed partial response, [objective response rate 4.0%, 95% confidence interval (CI) 0.1% to 20.4%] whereas 18/53 patients in the phase Ib trial exhibited partial response (objective response rate 34.0%, 95% CI 21.5% to 48.3%). The median progression-free survival was 7.2 months (95% CI 5.1-8.7 months). CONCLUSIONS: Suvemcitug has an acceptable toxicity profile and exhibits antitumor activities in pretreated patients with advanced solid tumors or metastatic colorectal cancer.

[A high relapse risk of chronic drug-induced liver injury is correlated with a greater severity of liver fibrosis].

OBJECTIVE: To construct a risk prediction model for relapse of chronic drug-induced liver injury (DILI) and explore the correlation between DILI relapse risk and liver fibrosis. METHODS: We retrospectively collected the clinical data of 1138 patients with chronic DILI hospitalized from January, 2017 to January, 2022, including 154 patients with and 984 without DILI relapse. Based on the results of univariable and multivariable logistic regression analyses, a risk prediction model for DILI relapse was constructed, evaluated for its discrimination and calibration using AUC value and Hosmer-Lemeshow test, and verified with a 200 times 5, 10 and 20 folds cross validation method. Spearman correlation analysis was used to evaluate the correlation between the new model and liver fibrosis, and its diagnostic efficiency for liver fibrosis was assessed by comparison with APRI and FIB-4 using ROC curve. RESULTS: The proportions of patients with S0, S1, S2, S3 and S4 liver fibrosis were 1.9%, 13.1%, 42.2%, 27.9% and 14.9% in the relapse group, respectively, as compared with 8.9%, 43.5%, 26.1%, 17.1% and 4.4% in the non-relapse group, respectively, showing severer liver fibrosis in patients with than those without DILI relapse. Multivariable logistic regression analysis identified LSM≥13.7 kPa (OR=4.35, 95%CI: 2.61-7.25, P < 0.001), CHE < 2500 U/L (OR=5.17, 95%CI: 2.13-12.53, P < 0.001), CHE of 2500-5000 U/L (OR=4.07, 95%CI: 2.75-6.01, P < 0.001), and AST > 2×ULN (OR=2.29, 95%CI: 1.38-3.80, P=0.001) as risk factors for relapse of chronic DILI. The ACLS model constructed based on these non-invasive indicators had an AUC value of 0.803 (95%CI: 0.78-0.83). The results of Hosmer-Lemeshow goodness of fit test (χ2=7.73, P=0.46) and the cross validation tests (average AUC of 0.803) all showed a good stability of the model. Spearman correlation analysis showed that ACLS score was positively correlated with the severity of liver fibrosis (rho=0.530, P < 0.001). At the optimal cut-off value of 3 points for diagnosing moderate liver fibrosis, the ACLS model had an AUC value of 0.78 (with specificity of 72.7% and sensitivity of 73.3%), demonstrating a better efficacy than that of APRI and FIB-4 (P < 0.001). At the cut-off value of 6 for severe liver fibrosis, the diagnostic efficacy of the model (AUC=0.83; specificity 75.7%, sensitivity 72.7%) was still better than that of APRI (P < 0.001) but comparable with that of FIB-4 (P=0.38). CONCLUSION: The patients at high risks of chronic DILI relapse have severer liver fibrosis and should be followed up regularly for timely aggressive treatment.

[Berberine inhibits erastin-induced ferroptosis of mouse hippocampal neuronal cells possibly by activating the Nrf2-HO-1/GPX4 pathway].

OBJECTIVE: To explore the mechanism by which berberine inhibits ferroptosis of mouse hippocampal neuronal cells (HT22). METHODS: Cultured HT22 cells were pretreated with 30 or 60 µmol/L berberine for 2 h before exposure to 0.5 µmol/L erastin for 8 h, and the cell proliferation, intracellular ferric iron level, changes in intracellular reactive oxygen species (ROS) and cell apoptosis were detected using CCK-8, Fe2+ fluorescent probe, fluorescent dye (DAPI) and fluorescent probe (H2DCFH-DA). RT-qPCR and Western blotting were used to detect the mRNA and protein expressions of Nrf2, HO-1 and GPX4 in the cells. We further tested the effects of treatments with 2 µmol/L ML385 (a Nrf2 inhibitor), 60 µmol/L berberine and erastin in the cells to explore the protective mechanism of berberine against erastin-induced ferroptosis in the neuronal cells. RESULTS: Treatment with 0.5 µmol/L erastin significantly lowered the viability of HT22 cells (P < 0.05) and increased the production of ROS, cell apoptosis rate and ferric iron level (P < 0.05). Pretreatment with 30 and 60 µmol/L berberine both significantly increased the vitality of erastin-exposed cells (P < 0.05) and lowered the levels of intracellular ROS and ferric iron content (P < 0.05). RT-qPCR and Western blotting showed that berberine obviously promoted the expressions of Nrf2, HO-1 and GPX4 in the cells (P < 0.05), and treatment with ML385 significantly inhibited the Nrf2-HO-1/GPX4 pathway, increased intracellular ROS and ferric iron contents and mitigated the protective effect of berberine against erastin-induced ferroptosis (P < 0.05). CONCLUSION: Berberine can inhibit erastin-induced ferroptosis in HT22 cells possibly by activating the Nrf2-HO-1/ GPX4 pathway.

[Non-surgical local treatment for pulmonary aspergilloma].

Pulmonary aspergilloma (PA) is usually secondary to pulmonary cavities. The main purpose of PA treatment is to prevent life-threatening hemoptysis. Many patients cannot tolerate surgical resection, which is considered the preferred treatment. Oral or intravenous antifungal therapy is less effective because PA usually does not invade the blood vessels of the pulmonary cavity. In this case, arterial embolization, local injection with drugs, and radiation therapy can be considered. This article will summarized various non-surgical local treatments for PA (hemoptysis) to refer clinical decision-making.

[The in vivo imaging of zebrafish for chemical vascular toxicity assessment].

Objective: To evaluate the vascular toxicity of chemicals by a real-time observation approach using the transgenic zebrafish. Methods: The spatiotemporal vascular alterations of transgenic zebrafish after chemical exposure were assessed by laser confocal microscopy and high-content screening analysis, respectively. Results: The method using Laser Confocal Microscopy (LCM) is easier to operate and yields high-resolution images, while it is lower throughput and inefficient. In contrast, high-content analysis (HCA) analysis obtains high-quality data of vascular toxicity manifesting whole blood vasculature, whereas it requires delicate operation procedures and advanced experimental conditions. Conclusion: Two kinds of zebrafish imaging methods each have advantages and disadvantages. LCM is suitable for the evaluation of a small number of chemicals. HCA, a cutting-edge technology, has great potential for chemical safety assessment allowing high throughput vascular toxicity tests of a good number of chemicals at a time.

Stability and dissipativity criteria for neural networks with time-varying delays via an augmented zero equality approach.

This work investigates the stability and dissipativity problems for neural networks with time-varying delay. By the construction of new augmented Lyapunov-Krasovskii functionals based on integral inequality and the use of zero equality approach, three improved results are proposed in the forms of linear matrix inequalities. And, based on the stability results, the dissipativity analysis for NNs with time-varying delays was investigated. Through some numerical examples, the superiority and effectiveness of the proposed results are shown by comparing the existing works.

[The Ophthalmology-centered medical industry in Suzhou in the Ming and the Qing Dynasties - from the Painting Album of Cityscapes and Business].

The Painting Album of Cityscapes and Business was finished in the early Qing Dynasty with realism. This painting album described the prosperity in business and everyday life in Suzhou during the late Ming and the early Qing Dynasties. They were drawn and painted retrospectively, ie, the content of the pictures was based on existing paintings handed down. In the painting album, more than ten medical-related elements were specifically depicted, such as traditional Chinese medicine clinics and pharmacies and seven ophthalmology-related elements including one clinic specialized in ophthalmology, two spectacle shops, two people wearing eyeglasses and three blind people. Up to now, no specialized ophthalmology clinics and spectacle shops have been found in earlier literature and paintings. It can be speculated that the Painting Album of Cityscapes and Business is the earliest album of paintings depicting clinics specialized in ophthalmology and spectacle shops in China. This painting album provides important information for the study of the medical industry in Suzhou in the late Ming and the early Qing Dynasties, particularly, in terms of ophthalmology-related diagnosis and treatment.

Melatonin protects against excessive autophagy-induced mitochondrial and ovarian reserve function deficiency though ERK signaling pathway in Chinese hamster ovary (CHO) cells.

Excessive autophagy-induced follicular atresia of ovarian granulosa cells might be one of the pathogenesis of Premature Ovarian Insufficiency (POI), and melatonin (MT) exerted many beneficial effects on mitochondria. However, there was little report regarding the beneficial effects of MT on excessive autophagy-induced mitochondrial and ovarian reserve function deficiency, and the mechanisms have not been clearly identified. Autophagy played a protective role in cells survival, however, high level of autophagy could lead to cell death. In this report, firstly, Chinese hamster ovary cell damage model stably expressing EGFP-LC3 was established. Next, we systematically investigated the protective effects of MT on mitochondrial and ovarian reserve function and molecular mechanisms using this cell damage model. Our results revealed that 10-9 M MT not only protected against the decline of anti-mullerian hormone (AMH) expression induced by excessive autophagy, but also rescued excessive autophagy-induced impairment of mitochondrial expression and mitochondrial membrane potential. Furthermore, MT protected against excessive autophagy-induced decrease of nucleus-encoded proteins including SDHA and mitofilin, and mitochondrial dynamic-related proteins including OPA1, MFN2, and DRP1. MT also decreased mitochondrial oxidative stress, increased antioxidant enzyme superoxide dismutase 2 (SOD2) expression and ameliorated the G2/M cell cycle arrest induced by excessive autophagy. Finally, MT inhibited excessive autophagy-induced activation of extracellular signal regulated kinase (ERK) signaling pathway. In conclusion, our study showed that MT rescued impairment of mitochondrial and ovarian reserve function, and production of mitochondrial ROS and cell cycle arrest induced by excessive autophagy through down-regulated ERK pathway, implying the potential therapeutic drug target for POI.

Do marginal abatement costs matter for improving air quality? Evidence from China's major cities.

This paper performs a two-stage analysis to investigate the trade-off between economic growth and pollution abatement. We first estimate the marginal abatement costs (MACs) of CO2, SO2, NOx, and particulate matter (PM) for 30 major Chinese cities from 2006 to 2015 via the shadow price approach under the directional distance function framework. The results show that the optimal directional vector is (11, -1, -1, -1, -1), which may indicate that increasing economic output is much more important than reducing the above undesirable outputs in these cities. Then, having examined the relationship between MACs and air quality by panel regression and dose-response analyses, we found ranges of positive and statistically significant treatment effects for the MACs of SO2 and PM on their respective concentrations. The overall results suggest that government officials in these cities may give precedence to economic growth over environmental protection.

Coverage and effectiveness of hypertension screening in different altitudes of Tibet autonomous region.

BACKGROUND: Tibet is an autonomous region in China located around an average altitude of 4500 m above sea level. Since 2012 the local government of Tibet has been providing free physical examinations, including screening for hypertension. However, the coverage and effectiveness of this free program have not been uncovered. This study aims to assess the coverage and effectiveness of hypertension screening and management program in 3 altitude levels of Tibet, and also the determinants of the success of the screening program. METHODS: A stratified cluster survey was conducted among 1636 residents aged 18 years or over in three different altitude areas in Tibet. We adjusted for age and sex based on national census data and used weighted logistic regression models to find factors associated with hypertension screening. RESULTS: The coverage of the hypertension screening program evaluated by participation rate in the previous screening was 94.9%, while 24.7% (95% CI: 22.1-27.3%) of them were diagnosed with hypertension. Females and alcohol drinkers were more likely to be screened. Among those diagnosed with hypertension, 28.7% had it under control. High altitude areas had a high proportion of controlled hypertension. The overall rate of controlled hypertension in high, moderate and low altitude areas was 35.1% (95% CI: 24.8-45.3%), 32.7% (95% CI: 22.2-43.2%) and 23.7% (95% CI: 14.7-32.6%), respectively. Younger aged persons were more likely to have better control of their hypertension. CONCLUSIONS: The coverage of hypertension screening in Tibet was high, especially in the low altitude areas. However, the effectiveness of hypertension control was low, indicating a need to implement the treatment adherence routines into the current screening interventions.

Controlled expression of lysis gene E by a mutant of the promoter pL of the thermo-inducible λcI857-pL system.

AIMS: To identify a lambda promoter pL mutant that could extend the thermal stability of the thermo-inducible λcI857-pR/pL system and to evaluate the effects of the modified system for the controlled expression of lysis gene E during the production of bacterial ghosts (BGs). METHODS AND RESULTS: The promoter pL mutant was identified by random mutagenesis and site-directed mutagenesis. The results showed that a T â†’ 35C mutation in the pL promoter was responsible for the phenotype alteration. Under the same induction conditions, the lysis rates of the modified lytic system on Escherichia coli and Salmonella enteritidis were significantly lower than that of the control, while the lysis rates of Escherichia coli with the thermo-inducible lytic system were significantly higher than that of S. enteritidis with the corresponding plasmid (P < 0·05). CONCLUSIONS: Increasing the heat stability of the thermo-inducible lytic systems decreased lysis efficiency during the production of BGs. There exist differences in the lysis efficiency of thermo-inducible lytic systems between different bacterial strains. SIGNIFICANCE AND IMPACT OF THE STUDY: These findings enrich current knowledge about modifications to thermo-inducible systems and provide a reference for the application of these modified systems for the production of BGs and controlled gene expression in bacteria.

[Efficacy and safety of eltrombopag in aplastic anemia: A multi-center survey in China].

Objective: To evaluate the safety and efficacy of eltrombopag combined with immunosuppressive therapy in patients with aplastic anemia (AA) in China. Methods: We investigated and analyzed the clinical data of AA patients from 14 hematological treatment centers who were treated with oral eltrombopag for at least 3 mon. Results: We enrolled 56 AA patients, including 19 treatment-naïve patients and 37 IST-refractory patients. The median administration period for eltrombopag was 7 (3-31) months, and the median maximum stable dosage was 75 mg/d (50-150 mg/d) . The 3-month hematological response (HR) rate was 60%, and the complete response (CR) rate was 30% in 10 SAA patients who were treated with first-line eltrombopag and standard IST (ATG+CsA) . Eight of 9 eltrombopag and CsA ± androgen first-line treated SAA patients responded (8/9, 89%) and 4 (44%) gave CR. The overall HR and CR rates were 79% and 52.6%, respectively, among these 19 patients by the end of the follow-up period. Of the 19 AA patients who were refractory to CsA ± androgen, 11 achieved HR (57.9%) at 3 mon, and the best HR rate was 44% in standard IST (ATG+CsA) refractory 18 patients after eltrombopag treatment. Fifty-one percent of the patients experienced mild or moderate adverse events, and gastrointestinal discomfort was the most common adverse effect reported by the study subjects. Conclusion: Adding Eltrombopag in first-line IST can accelerate the acquisition and improve the quality of hematological responses in AA patients. AA with relatively more residual hematopoietic cells may be well treated with eltrombopag and non-ATG IST. Eltrombopag can be used as salvage therapy for CsA±androgen refractory patients. Eltrombopag was generally safe and well tolerated by AA patients in China.

Long noncoding RNA SNHG7 represses the expression of RBM5 to strengthen metastasis of hepatocellular carcinoma.

Since this article has been suspected of research misconduct and the corresponding authors did not respond to our request to prove originality of data and figures, "Long noncoding RNA SNHG7 represses the expression of RBM5 to strengthen metastasis of hepatocellular carcinoma, by B.-Z. Sun, D.-G. Ji, Z.-X. Feng, Y. Wang, published in Eur Rev Med Pharmacol Sci 2019; 23 (13): 5699-5704-DOI: 10.26355/eurrev_201907_18307-PMID: 31298322" has been withdrawn. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/18307.

[Efficacy, safety and compliance of immunotherapy in the treatment of allergic rhinitis: a Meta-analysis].

Objective: By use of Meta analysis to compare efficacy, safety and compliance of subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) on allergic rhinitis (AR). Methods: Cochrane Library, Pubmed, Embase, CNKI Database, Wan Fang and Chinese Sci-tech Journal Database (from established time to May of 2018) were searched for trials about the AR treated by SCIT and SLIT. The relevant literatures were screened, and the randomized controlled studies were chosen. Nasal symptom scores, visual analogue scale (VAS) scores, adverse reactions and compliance were used as the outcome indicators, and the methodological quality of the literatures was evaluated strictly. The extracted data were analyzed by RevMan 5.3 and Stata 14 software. Results: A total of 20 randomized controlled studies were included, the overall quality of which was relatively high. No publication bias was found. There was no significant difference in nasal symptom scores, VAS scores and compliance between SCIT and SLIT (SMD value was 0.03, 0.14, respectively, RR=1.12; 95%CI value was -0.17-0.23, -0.03-0.31, 0.92-1.35, respectively, all P>0.05); SLIT group resulted in lower overall incidence of adverse reactions than that of SCIT group (RR=1.79, 95%CI: 1.42-2.26, P<0.05). Conclusion: Both SCIT and SLIT have similar eppecacy and compliance for treatment of AR, while adverse reactions are more frequently observed in SCIT.