Activation of trace amine-associated receptor 1 ameliorates PTSD-like symptoms.

Trace amine-associated receptor 1 (TAAR1) negatively modulates monoaminergic transmission in the mammalian brain and participates in many psychiatric disorders. Preclinical evidence indicate that selective TAAR1 agonists have anxiolytic effects and anti-stress properties. Post-traumatic stress disorder (PTSD) is an anxiety disorder triggered by experiencing or witnessing traumatic stressors. However, it remains unknown whether TAAR1 is involved in PTSD. Here, we investigated the role of TAAR1 in two PTSD animal models, including single prolonged stress (SPS)-induced impairment of fear extinction and stress-enhanced fear learning (SEFL). SPS decreased TAAR1 mRNA levels in the prefrontal cortex and ventral tegmental area. Acute treatment of the TAAR1 partial agonist RO5263397 attenuated SPS-induced anxiety-like behavior evaluated by the elevated-plus maze test. Compared to non-stressed animals, rats that experienced SPS showed higher freezing levels in the extinction retention test, indicating an impairment of fear extinction retention after SPS exposure. Acute and chronic treatment of RO5263397 ameliorated SPS-induced impairment of fear extinction retention. In the SEFL model, compared to the No-shock group, rats that experienced severe foot shock before fear conditioning showed higher freezing levels during the tests, indicating enhanced fear learning after stress exposure. Chronic treatment of RO5263397 partially attenuated the SEFL. Moreover, chronic treatment with the selective TAAR1 full agonist RO5166017 completely prevented the SEFL. Taken together, these data showed that pharmacological activation of TAAR1 could ameliorate PTSD-like symptoms. The present study thus provides the first evidence that TAAR1 might participate in the development of PTSD, and TAAR1 agonists could be potential pharmacological treatments for this disorder.

Antinociceptive effects of α2/α3-subtype selective GABAA receptor positive allosteric modulators KRM-II-81 and NS16085 in rats: behavioral specificity.

Recent studies suggest that amongst the GABAA receptor subtype heterogeneity, α2/α3 subunits of GABAA receptors mediate pain processing. Therefore, α2/α3-subtype selective GABAA receptor positive allosteric modulators (PAMs) may be candidate analgesics. Antinociceptive effects of α2/α3-subtype selective GABAA receptor PAMs have been reported, but the behavioral effects of these compounds have not been systematically evaluated. This study examined the behavioral effects of two α2/α3 subtype-selective GABAA receptor PAMs, KRM-II-81 and NS16085, in male rats. The antinociceptive effects of KRM-II-81 and NS16085 were examined using rat models of inflammatory (complete Freund's adjuvant) and neuropathic pain (chronic constriction injury). The effect of KRM-II-81 on affective pain was measured using the place escape/avoidance paradigm (PEAP). Rate-response of food-maintained operant responding, horizontal wire test, and the spontaneous alternation T-maze, were assessed to study the side-effect profiles of KRM-II-81 and NS16085. The benzodiazepine midazolam was used as a comparator in these studies. KRM-II-81 and NS16085 attenuated mechanical allodynia but not thermal hyperalgesia in both pain states, and their effects were attenuated by the benzodiazepine receptor antagonist flumazenil. KRM-II-81 attenuated affective pain-related behavior in the PEAP test. In the operant responding procedure and horizontal wire test, only midazolam produced significant effects at the dose that produced maximal antinociception. In the T-maze assay, only midazolam significantly decreased the percentage of alternation at an antinociceptive dose. Thus, KRM-II-81 and NS16085 but not midazolam selectively produced antinociceptive effects. Collectively, these data suggest that α2/α3-subtype selective GABAA PAMs could be a novel class of analgesics and warrant further investigation. Significance Statement This study demonstrates that α2/α3-subtype selective GABAA PAMs KRM-II-81 and NS16085 produce selective antinociceptive effects devoid of sedation, myorelaxation, cognitive impairment in two rat models of persistent pain. Unlikely classical benzodiazepines, this study supports the development of α2/α3-subtype selective GABAA PAMs as safe and novel analgesics for pain management.

Routes to high-performance layered oxide cathodes for sodium-ion batteries.

Sodium-ion batteries (SIBs) are experiencing a large-scale renaissance to supplement or replace expensive lithium-ion batteries (LIBs) and low energy density lead-acid batteries in electrical energy storage systems and other applications. In this case, layered oxide materials have become one of the most popular cathode candidates for SIBs because of their low cost and comparatively facile synthesis method. However, the intrinsic shortcomings of layered oxide cathodes, which severely limit their commercialization process, urgently need to be addressed. In this review, inherent challenges associated with layered oxide cathodes for SIBs, such as their irreversible multiphase transition, poor air stability, and low energy density, are systematically summarized and discussed, together with strategies to overcome these dilemmas through bulk phase modulation, surface/interface modification, functional structure manipulation, and cationic and anionic redox optimization. Emphasis is placed on investigating variations in the chemical composition and structural configuration of layered oxide cathodes and how they affect the electrochemical behavior of the cathodes to illustrate how these issues can be addressed. The summary of failure mechanisms and corresponding modification strategies of layered oxide cathodes presented herein provides a valuable reference for scientific and practical issues related to the development of SIBs.

Nickel Nanoparticles Protruding from Molybdenum Carbide Micropillars with Carbon Layer-Protected Biphasic 0D/1D Heterostructures for Efficient Water Splitting.

It remains a tremendous challenge to achieve high-efficiency bifunctional electrocatalysts for both the hydrogen evolution reaction (HER) and the oxygen evolution reaction (OER) for hydrogen production by water splitting. Herein, a novel hybrid of 0D nickel nanoparticles dispersed on the one-dimensional (1D) molybdenum carbide micropillars embedded in the carbon layers (Ni/Mo2C@C) was successfully prepared on nickel foam by a facile pyrolysis strategy. During the synthesis process, the nickel nanoparticles and molybdenum carbide were simultaneously generated under H2 and C2H2 mixed atmospheres and conformally encapsulated in the carbon layers. Benefiting from the distinctive 0D/1D heterostructure and the synergistic effect of the biphasic Mo2C and Ni together with the protective effect of the carbon layer, the reduced activation energy barriers and fast catalytic reaction kinetics can be achieved, resulting in a small overpotential of 96 mV for the HER and 266 mV for the OER at the current density of 10 mA cm-2 together with excellent durability in 1.0 M KOH electrolyte. In addition, using the developed Ni/Mo2C@C as both the cathode and anode, the constructed electrolyzer exhibits a small voltage of 1.55 V for the overall water splitting. The novel designed Ni/Mo2C@C may give inspiration for the development of efficient bifunctional catalysts with low-cost transition metal elements for water splitting.

Sodium Carbonate-Promoted Formation of 5-Amino-1,2,4-thiadiazoles and 5-Amino-1,2,4-selenadiazoles with Elemental Sulfur and Selenium.

Sodium carbonate-promoted facile synthesis of 5-amino-1,2,4-thiadiazoles and 5-amino-1,2,4-selenadiazoles with elemental sulfur and selenium, respectively, was developed. This method was carried out with O2 in the air as the green oxidant, and it has several advantages, including low cost, low toxicity, and stable sulfur and selenium sources, good to excellent yields with water as the sole byproduct, simple operation, and a broad substrate scope. Preliminary mechanistic studies indicate that the formation of the 1,2,4-thiadiazole ring and the 1,2,4-selenadiazole ring undergoes different processes.

Association between the ratio of dietary vitamin A to body weight and hypertension in children / 中国学校卫生

Objective@#To explore the relationship between the ratio of dietary vitamin A (VitA) to body weight and hypertension among children, so as to provide a reference for blood pressure control through dietary nutritional interventions and childhood hypertension prevention.@*Methods@#Utilizing the baseline survey and followup sample data from the Healthy Children Cohort established in urban and rural areas of Chongqing from 2014 to 2019, structured quantitative dietary questionnaire and selfdesigned questionnaire were used to investigate the information of dietary intake and socioeconomic characteristics of 15 279 children, as well as blood pressure, height, weight measurement. The ratio of dietary VitA to body weight was divided into four groups based on quartiles [≤P25(Q1), >P25~P50(Q2), >P50~P75(Q3), >P75(Q4)]. Generalized linear regression models and Logistic regression models were used to analyze the correlation between ratio of dietary VitA to body weight with blood pressure levels and prevalence of hypertension.@*Results@#The results of the 2014 baseline survey indicated that, after adjusting for confounding factors such as demographic indicators and nutritional intake, significant differences were observed in systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) among different groups categorized by the ratio of dietary VitA to body weight (F=157.57, 44.71, 95.92, P<0.01). The baseline ratio of dietary VitA to body weight in children exhibited a negative correlation with DBP, SBP and MAP at baseline and in 2019[baseline: β(95%CI)=-0.65(-0.89--0.42), -0.22(-0.42--0.01), -0.36(-0.56--0.16); 2019: β(95%CI)=-0.77(-1.34--0.19), -0.62(-1.21--0.02), -0.77(-1.34--0.19), P＜0.05]. Compared to Q1 group, the risk of hypertension decreased among children in Q4 at baseline and followup in 2019 [OR(95%CI)=0.63(0.49-0.81), 0.18(0.08-0.42), P<0.01].@*Conclusions@#The ratio of dietary VitA to body weight is significantly negatively correlated with blood pressure levels among children, and dietary VitA deficiency is an independent risk factor for hypertension among children. Measures should be taken to actively adjust childrens dietary nutrition and reduce the risk of childhood hypertension.

Genetic and phenotypic analysis of MYO15A rare variants associated with autosomal recessive hearing loss / 临床耳鼻咽喉头颈外科杂志

Objective:To analyze the phenotype and genotype characteristics of autosomal recessive hearing loss caused by MYO15A gene variants, and to provide genetic diagnosis and genetic counseling for patients and their families. Methods:Identification of MYO15A gene variants by next generation sequencing in two sporadic cases of hearing loss at Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine. The sequence variants were verified by Sanger sequencing.The pathogenicity of these variants was determined according to the American College of Medical Genetics and Genomics（ACMG） variant classification guidelines, in conjuction with clinical data. Results:The probands of the two families have bilateral,severe or complete hearing loss.Four variants of MYO15A were identified, including one pathogenic variant that has been reported, two likely pathogenic variants,and one splicing variant of uncertain significance. Patient I carries c. 3524dupA（p. Ser1176Valfs*14）, a reported pathogenic variant, and a splicing variant c. 10082+3G>A of uncertain significance according to the ACMG guidelines. Patient I was treated with bilateral hearing aids with satisfactory effect, demonstrated average hearing thresholds of 37.5 dB in the right ear and 33.75 dB in the left ear. Patient Ⅱ carries c. 7441_7442del（p. Leu2481Glufs*86） and c. 10250_10252del（p. Ser3417del）,a pair of as likely pathogenic variants according to the ACMG guidelines. Patient Ⅱ, who underwent right cochlear implantation eight years ago, achieved scores of 9 on the Categorical Auditory Performance-Ⅱ（CAP-Ⅱ） and 5 on the Speech Intelligibility Rating（SIR）. Conclusion:This study's discovery of the rare c. 7441_7442del variant and the splicing variant c. 10082+3G>A in the MYO15A gene is closely associated with autosomal recessive hearing loss, expanding the MYO15A variant spectrum. Additionally, the pathogenicity assessment of the splicing variant facilitates classification of splicing variations.

TAAR1 as an emerging target for the treatment of psychiatric disorders.

Trace amines, a group of amines expressed at the nanomolar level in the mammalian brain, can modulate monoamine transmission. The discovery of and the functional research on the trace amine-associated receptors (TAARs), especially the most well-characterized TAAR1, have largely facilitated our understanding of the function of the trace amine system in the brain. TAAR1 is expressed in the mammalian brain at a low level and widely distributed in the monoaminergic system, including the ventral tegmental area and substantial nigra, where the dopamine neurons reside in the mammalian brain. Growing in vitro and in vivo evidence has demonstrated that TAAR1 could negatively modulate monoamine transmission and play a crucial role in many psychiatric disorders, including schizophrenia, substance use disorders, sleep disorders, depression, and anxiety. Notably, in the last two decades, many studies have repeatedly confirmed the pharmacological effects of the selective TAAR1 ligands in various preclinical models of psychiatric disorders. Recent clinical trials of the dual TAAR1 and serotonin receptor agonist ulotaront also revealed a potential efficacy for treating schizophrenia. Here, we review the current understanding of the TAAR1 system and the recent advances in the elucidation of behavioral and physiological properties of TAAR1 agonists evaluated both in preclinical animal models and clinical trials. We also discuss the potential TAAR1-dependent signaling pathways and the cellular mechanisms underlying the inhibitory effects of TAAR1 activation on drug addiction. We conclude that TAAR1 is an emerging target for the treatment of psychiatric disorders.

The imidazoline I2 receptor agonist 2-BFI reduces abuse-related effects of morphine: self-administration and drug discrimination.

RATIONALE: Increasing evidence shows that imidazoline I2 receptor agonists enhance opioid-induced analgesia, suggesting that the combination of I2 receptor agonists with opioids could be a favorable strategy for pain control. However, the effect of I2 receptor agonists on the abuse liability of opioids is unknown. This study examined the impact of the I2 receptor agonist 2-BFI on some abuse-related behavioral effects of the opioid morphine in rats. OBJECTIVES: The von Frey filament test was used to determine the antinociceptive effects of 2-BFI (intravenous, i.v.) in a rat model of complete Freund's adjuvant (CFA)-induced inflammatory pain. IV self-administration was used to assess the reinforcing effects of 2-BFI alone and to assess the effects of non-contingent injections of 2-BFI (i.p.) on morphine self-administration. A two-lever drug discrimination paradigm in which rats were trained to discriminate 3.2 mg/kg morphine (i.p.) from saline was used to examine whether 2-BFI or another I2 receptor agonist 2-(4,5-dihydroimidazol-2-yl)quinoline hydrochloride (BU224) affected the discriminative stimulus effects of morphine. RESULTS: 2-BFI could not maintain reliable self-administration behavior in rats with no pain or CFA-treated inflammatory pain. However, pretreatment with 2-BFI (i.p.) produced dose-dependent decreases in the dose-effect curve of morphine self-administration. Both 2-BFI and BU224 did not substitute for morphine but significantly attenuated the discriminative stimulus effects of morphine. CONCLUSIONS: These results suggest that I2 receptor agonists do not enhance, but in fact appear to decrease, the abuse liability of opioids, further supporting the potential utility of I2 receptor agonist-opioid combination therapy for pain control.

Association between serum PCSK9 and coronary heart disease in patients with type 2 diabetes mellitus.

BACKGROUND AND AIMS: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is considered a new biomarker for atherosclerosis, but its ability to predict cardiovascular outcomes has been controversial. This study aimed to address the lack of data on PCSK9, coronary heart disease (CHD) severity, and major cardiovascular events (MACEs) in patients with type 2 diabetes mellitus (T2DM). METHODS: A total of 2984 T2DM patients underwent selective coronary angiography, and their serum PCSK9 levels were measured using enzyme-linked immunosorbent assay. Correlation and logistic regression analyses were performed to investigate the association between PCSK9 expression and CHD severity. This study used Cox regression analysis to assess the association between circulating PCSK9 levels and the risk of MACEs. RESULTS: Circulating PCSK9 levels were significantly higher in the CHD group than in the non-CHD group [554.62 (265.11) ng/mL vs. 496.86 (129.05) ng/mL, p < 0.001]. Circulating PCSK9 levels positively correlated with CHD severity (diseased vessels: r = 0.35, p < 0.001; Gensini score: r = 0.46, p < 0.001). Elevated PCSK9 levels are an independent risk factor for CHD risk and severity (CHD group vs. non-CHD group: OR = 2.829, 95% CI: 1.771-4.520, p < 0.001; three vessel disease group vs. one vessel disease group: OR = 4.800, 95% CI: 2.387-9.652, p < 0.001; high GS group vs. low GS group: OR = 5.534, 95% CI: 2.733-11.208, p < 0.001). Through a six-year follow-up and multivariate Cox regression analysis, elevated circulating PCSK9 levels were found to be independently associated with MACEs in all participants (HR: 3.416, 5% CI: 2.485-4.697, p < 0.001; adjusted HR: 2.780, 95% CI: 1.930-4.004, p < 0.001). CONCLUSIONS: Serum PCSK9 levels were positively correlated with multi-vessel CHD and Gensini score. Elevated circulating PCSK9 levels are an independent risk factor for CHD and increased incidence of MACEs in T2DM.

Current status of GABA receptor subtypes in analgesia.

Gamma-aminobutyric acid (GABA), a non-protein-producing amino acid synthesized from the excitatory amino acid glutamate via the enzyme glutamic acid decarboxylase, is extensively found in microorganisms, plants and vertebrates, and is abundantly expressed in the spinal cord and brain. It is the major inhibitory neurotransmitter in the mammalian nervous system. GABA plays crucial roles in the regulation of synaptic transmission, the promotion of neuronal development and relaxation, and the prevention of insomnia and depression. As the major inhibitory neurotransmitter, GABA plays pivotal roles in the regulation of pain sensation, which is initiated by the activation of peripheral nociceptors and transmitted to the spinal cord and brain along nerves. GABA exerts these roles by directly acting on three types of receptors: ionotropic GABAA and GABAC receptors and G protein-coupled GABAB receptor. The chloride-permeable ion channel receptors GABAA and GABAC mediate fast neurotransmission, while the metabotropic GABAB receptor mediates slow effect. Different GABA receptors regulate pain sensation via different signaling pathways. Here we highlight recent updates on the involvement of specific GABA receptors and their subtypes in the process of pain sensation. Further understanding of different GABA receptors and signaling pathways in pain sensation will benefit the development of novel analgesics for pain management by targeting specific GABA receptor subtypes and signaling pathways.

Clinical characteristics and acute complication of COVID-19 patients with diabetes: a multicenter, retrospective study in Southern China.

Aims: This study aims to describe the clinical characteristics, laboratory data and complications of hospitalized COVID-19 patients with type 2 diabetes mellitus (T2DM) since epidemic prevention and control optimization was adjusted in December 2022 in China. Methods: This retrospective multicenter study included 298 patients with confirmed type 2 diabetes mellitus with or without COVID-19. We collected data from the first wave of the pandemic in The Fifth Affiliated Hospital of Guangzhou Medical University, Loudi Central Hospital and The First People's Hospital of Xiangtan from December 1, 2022 to February 1, 2023. We extracted baseline data, clinical symptoms, acute complications, laboratory findings, treatment and outcome data of each patient from electronic medical records. Results: For among 298 hospitalized patients with type 2 diabetes, 136 (45.6%) were COVID-19 uninfected, and 162 (54.4%) were COVID-19 infected. We found that the incidence of cough, fatigue, fever, muscle soreness, sore throat, shortness of breath, hyposmia, hypogeusia and polyphagia (all p<0.01) were significantly higher in the exposure group. They showed higher levels of ketone (p=0.04), creatinine (p<0.01), blood potassium (p=0.01) and more diabetic ketoacidosis (p<0.01). Patients with COVID-19 less use of metformin (p<0.01), thiazolidinediones (p<0.01) and SGLT2 (p<0.01) compared with patients without COVID-19. Conclusion: COVID-19 patients with diabetes showed more severe respiratory and constitutional symptoms and an increased proportion of hyposmia and hypogeusia. Moreover, COVID-19 patients with diabetes have a higher incidence of acute complications, are more prone to worsening renal function, and are more cautious about the use of antidiabetic drugs.

Investigation of preclinical pharmacokinetics of N-demethylsinomenine, a potential novel analgesic candidate, using an UPLC-MS/MS quantification method.

N- Demethylsinomenine (NDSM), the in vivo demethylated metabolite of sinomenine, has exhibited antinociceptive efficacy against various pain models and may become a novel drug candidate for pain management. However, no reported analytical method for quantification of N- Demethylsinomenine in a biological matrix is currently available, and the pharmacokinetic properties of N- Demethylsinomenine are unknown. In the present study, an ultra-high performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS) method for quantification of N- Demethylsinomenine in rat plasma was developed and utilized to examine the preclinical pharmacokinetic profiles of N- Demethylsinomenine. The liquid-liquid extraction using ethyl acetate as the extractant was selected to treat rat plasma samples. The mixture of 25% aqueous phase (0.35% acetic acid-10 mM ammonium acetate buffer) and 75% organic phase (acetonitrile) was chosen as the mobile phases flowing on a ZORBAX C18 column to perform the chromatographic separation. After a 6-min rapid elution, NDSM and its internal standard (IS), metronidazole, were separated successfully. The ion pairs of 316/239 and 172/128 were captured for detecting N- Demethylsinomenine and IS, respectively, using multiple reaction monitoring (MRM) under a positive electrospray ionization (ESI) mode in this mass spectrometry analysis. The standard curve met linear requirements within the concentration range from 3 to 1000 ng/mL, and the lower limit of quantification (LLOQ) was 3 ng/mL. The method was evaluated regarding precision, accuracy, recovery, matrix effect, and stability, and all the results met the criteria presented in the guidelines for validation of biological analysis method. Then the pharmacokinetic profiles of N- Demethylsinomenine in rat plasma were characterized using this validated UPLC-MS/MS method. N- Demethylsinomenine exhibited the feature of linear pharmacokinetics after intravenous (i.v.) or intragastric (i.g.) administration in rats. After i. v. bolus at three dosage levels (0.5, 1, and 2 mg/kg), N- Demethylsinomenine showed the profiles of rapid elimination with mean half-life (T1/2Z) of 1.55-1.73 h, and extensive tissue distribution with volume of distribution (VZ) of 5.62-8.07 L/kg. After i. g. administration at three dosage levels (10, 20, and 40 mg/kg), N- Demethylsinomenine showed the consistent peak time (Tmax) of 3 h and the mean absolute bioavailability of N- Demethylsinomenine was 30.46%. These pharmacokinetics findings will aid in future drug development decisions of N- Demethylsinomenine as a potential candidate for pain analgesia.

Cross-Channel Constraints on Resonant Antikaon-Nucleon Scattering.

Chiral perturbation theory and its unitarized versions have played an important role in our understanding of the low-energy strong interaction. Yet, so far, such studies typically deal exclusively with perturbative or nonperturbative channels. In this Letter, we report on the first global study of meson-baryon scattering up to one-loop order. It is shown that covariant baryon chiral perturbation theory, including its unitarization for the negative strangeness sector, can describe meson-baryon scattering data remarkably well. This provides a highly nontrivial check on the validity of this important low-energy effective field theory of QCD. We show that the K[over ¯]N related quantities can be better described in comparison with those of lower-order studies, and with reduced uncertainties due to the stringent constraints from the πN and KN phase shifts. In particular, we find that the two-pole structure of Λ(1405) persists up to one-loop order reinforcing the existence of two-pole structures in dynamically generated states.

Distinct Effects of Methamphetamine Isomers on Limbic Norepinephrine and Dopamine Transmission in the Rat Brain.

Methamphetamine (METH) is a psychostimulant that primarily exerts its effects on the catecholamine (dopamine (DA) and norepinephrine (NE)) systems, which are implicated in drug addiction. METH exists as two distinct enantiomers, dextrorotatory (d) and levorotatory (l). In contrast to d-METH, the major component of illicit METH used to induce states of euphoria and alertness, l-METH is available without prescription as a nasal decongestant and has been highlighted as a potential agonist replacement therapy to treat stimulant use disorder. However, little is known regarding l-METH's effects on central catecholamine transmission and behavior. In this study, we used fast-scan cyclic voltammetry to elucidate how METH isomers impact NE and DA transmission in two limbic structures, the ventral bed nucleus of the stria terminalis (vBNST) and nucleus accumbens (NAc), respectively, of anesthetized rats. In addition, the dose-dependent effects of METH isomers on locomotion were characterized. d-METH (0.5, 2.0, 5.0 mg/kg) enhanced both electrically evoked vBNST-NE and NAc-DA concentrations and locomotion. Alternatively, l-METH increased electrically evoked NE concentration with minimal effects on DA regulation (release and clearance) and locomotion at lower doses (0.5 and 2.0 mg/kg). Furthermore, a high dose (5.0 mg/kg) of d-METH but not l-METH elevated baseline NE and DA concentrations. These results suggest mechanistic differences between NE and DA regulation by the METH isomers. Moreover, l-METH's asymmetric regulation of NE relative to DA may have distinct implications in behaviors and addiction, which will set the neurochemical framework for future studies examining l-METH as a potential treatment for stimulant use disorders.

Imaging and pathological diagnosis of primary intracranial malignant melanoma: A case report and literature review.

RATIONALE: Primary intracranial malignant melanoma (PIMM) is a rare malignant tumor that lacks specific clinical manifestations. Preoperative diagnosis is difficult to differentiate from meningiomas on computed tomography (CT) scans. Magnetic resonance imaging (MRI) usually shows typical characteristics with high signal intensity on T1WI and low signal intensity on T2WI. PIMM is highly invasive, insensitive to chemoradiotherapy, and has a poor prognosis. PATIENT CONCERNS: A 27-year-old woman was admitted to the hospital with a headache for 10 days. She did not experience nausea, vomiting, dizziness, or any other discomfort. A computerized tomography (CT) scan demonstrated a high-density mass in the left cerebellum with patchy calcification at the posterior edge, and heterogeneous enhancement was observed on a contrast-enhanced scan. MRI revealed typical characteristics of high signal intensity on T1WI and low signal intensity on T2WI. The signal characteristics of FLAIR were similar to those of T2WI, and diffusion-weighted imaging (DWI) sequence showed limited diffusion of the tumor. Magnetic resonance spectroscopy revealed increased choline (Cho) and decreased creatine (Cr) and N-acetyl aspartate (Naa) in the tumor. INTERVENTIONS: The patient underwent tumor resection and postoperative chemoradiotherapy and immunotherapy. PATHOLOGICAL DIAGNOSIS: Histological and Immunohistochemistry (IHC) tests confirmed the diagnosis of PIMM. In addition, genetic testing revealed GNAQ gene variation. OUTCOMES: No recurrence or complications were observed during the follow-up for 6 months. LESSONS: PIMM is rare, and its pathological diagnosis should be closely combined with clinical and medical history. GNAQ is a common variant of PIMM and is expected to be a therapeutic target.

Progress of therapeutic efficacy and predictive indicators of neoadjuvant chemoradiotherapy for locally advanced rectal cancer / 肿瘤研究与临床

The standard treatment for locally advanced rectal cancer is neoadjuvant chemoradiotherapy(nCRT) followed by surgery. The therapeutic efficacy of patients after nCRT differs greatly. Effective use of nCRT can accurately predict the efficacy and help patients avoid damage caused by excessive treatment. This article describes the main methods of current nCRT and newly proposed concepts, such as totally neoadjuvant therapy, summarzies its impact on the efficacy of locally advanced rectal cancer, introduces the potential predictive biomarkers of efficacy evaluation for nCRT and the latest advances in clinical, histological and molecular predictors, and discusses the potential value of efficacy prediction in nCRT .

Correlations of β-catenin expression with clinical efficacy of tyrosine kinase inhibitors and prognosis of advanced lung adenocarcinoma patients with epidermal growth factor receptor mutations / 肿瘤研究与临床

Objective:To investigate the correlations of β-catenin expression with the efficacy of tyrosine kinase inhibitor (TKI) and prognosis of patients with advanced lung adenocarcinoma harboring epidermal growth factor receptor (EGFR) mutations.Methods:The clinical data of 125 patients with stage Ⅲ B-Ⅳ lung adenocarcinoma who were treated with first-line EGFR-TKI treatment in the 901st Hospital of Joint Logistic Support Force of Chinese PLA from January 2016 to December 2019 were collected. The expression of β-catenin protein was detected by immunohistochemistry, and subtypes of EGFR mutations were detected by amplification refractory mutation system (ARMS). Correlations of β-catenin expression with clinicopathological features, efficacy of EGFR-TKI and prognosis were analyzed. Twenty-eight pairs of specimens were selected before EGFR-TKI treatment and after resistance to EGFR-TKI to observe the changes of β-catenin expression. Results:Among 125 advanced lung adenocarcinoma patients with EGFR mutations, there were 60 cases of EGFR 19 del, 55 cases of L858R mutation and 10 cases of rare sensitive mutation; 79 cases (63.2%) had reduced membranous expression of β-catenin, 66 cases (52.8%) had ectopic expression in cytoplasm and 28 cases (22.4%) had ectopic expression in nucleus. The positive rates of Napsin A protein in the groups with different abnormal expression patterns of β-catenin were lower than those in the corresponding normal expression groups (all P < 0.001). Patients with International Association for the Study of Lung Cancer (IASLC) grade Ⅲ showed more frequent translocation in cytoplasma and nucleus of β-catenin than patients with IASLC gradeⅠ-Ⅱ (ectopic expression in cytoplasm: χ2 = 3.99, P = 0.046,ectopic expression in nucleus: χ2 = 11.07, P = 0.001). The objective remission rate (ORR) in patients with reduced membranous expression of β-catenin and ectopic expression in nucleus was lower than that in patients with normal membranous expression ( χ2 = 4.66, P = 0.031) and negative ectopic expression in nucleus ( χ2 = 10.22, P = 0.001), and the disease control rate (DCR) in patients with ectopic expression in nucleus was lower than that in the corresponding normal expression group ( χ2 = 10.95, P = 0.001). Patients with ectopic expression of β-catenin in nucleus and cytoplasma had worse progression-free survival (PFS) and overall survival (OS) than the corresponding cytoplasmic and nuclear ectopic expression negative groups (both P < 0.05). Multivariate Cox regression analysis showed that nuclear β-catenin ectopic expression was an independent risk factor for both PFS and OS (PFS: HR = 2.088, 95% CI 1.331-3.274, P = 0.001; OS: HR = 3.656, 95% CI 1.795-7.444, P<0.001). β-catenin membranous expression was reduced in 11 of 28 tissue samples that underwent secondary biopsy compared with pre-treatment ( P = 0.049). Conclusions:β-catenin expression in advanced lung adenocarcinoma with EGFR-sensitive mutations can be used as a molecular marker to predict the efficacy of EGFR-TKI and prognosis of patients.

Clinical significance of hepatitis B virus DNA detection in screening patients with hepatitis B / 中华检验医学杂志

Objective:To explore the clinical significance of hepatitis B virus (HBV) DNA detection in screening patients with hepatitis B.Methods:Clinical data of 682 331 hepatitis B patients were retrospectively analyzed. The HBV DNA of these patients was detected in the Fifth Medical Center of the PLA General Hospital from January 2017 to December 2021, there were 481 159 males and 201 172 females in this cohort, the average age was (41.34±16.13) years. Patients were divided into HBV DNA positive group (219 879 cases) and HBV DNA negative group (462 452 cases). Clinical characteristics, data of five serologic markers of hepatitis B and hepatitis B surface antigen quantification (HBsAg-QN), liver function, alpha fetoprotein (AFP) and prothrombin time (PT) results were collected and analyzed and compared between the two groups.Results:The positive rate of HBV DNA was 32.22% (219 879/682 331) in this cohort. Among the different age groups, the positive rate of HBV DNA was the highest (40.34%, 128 038/317 380) in young people aged 18-44 years. The proportion of patients was lower among aged <1, 45-59 and ≥60 years patients in HBV DNA positive group than that in HBV DNA negative group, while the proportion of patients was higher among aged 1-17 and 18-44 years patients in HBV DNA positive group than that in HBV DNA negative group (all P<0.001). Among 2 291 <1-year-old infants tested for HBV DNA, 71 infants were HBV DNA positive. The positive rates of HBV DNA from 2017 to 2021 were 4.86% (27/556), 3.68% (14/380), 3.47% (17/490), 1.55% (6/386) and 1.46% (7/479) respectively, showing a downward trend year by year. The positive rate of HBV DNA in acute hepatitis B (AHB) patients was the highest (49.88%, 208/417) among 680 040 patients with hepatitis B. The proportion of AHB patients (0.09%, 208/219 808) and chronic hepatitis B (80.44%, 176 806/219 808) in HBV DNA positive group was higher than that in HBV DNA negative group [0.05% (209/460 232) and 65.45% (301, 216/460 232)], while the proportion of patients with HBV-related liver cirrhosis (11.28%, 24 793/219 808), HBV-related liver cancer (6.72%, 14 775/219 808), liver cancer surgery (1.39%, 3 055/219 808) and liver transplantation (0.08%, 171/219 808) were lower than that in HBV DNA negative group [22.99% (105 813/460 232), 7.25% (33 385/460 232), 3.50% (16 129/460 232) and 0.76% (3 480/460 232)] (all P<0.001). At the same time, positive rate of hepatitis B surface antigen (HbsAg), HBsAg-QN, hepatitis B e antigen (HbeAg), level of total bilirubin, total bilirubin, AFP and PT were higher in HBV DNA positive group than those in HBV DNA negative group, while the age, male ratio and albumin results in HBV DNA positive group were lower than those in HBV DNA negative group (all P<0.01). The HBV DNA loads were higher in HBsAg positive group, hepatitis B surface antibody positive group and HBeAg positive group than those in respective negative groups, while the HBV DNA loads were lower in hepatitis B e antibody positive group and hepatitis B core antibody positive group than those in respective negative groups (all P<0.001). Conclusions:The mother to child transmission rate of<1-year-old infants decreases year by year. HBV DNA is an important factor for the progression of hepatitis B disease. HBV DNA positive hepatitis B patients with higher HBsAg-QN values are more likely to have abnormal serum markers such as liver dysfunction. HBV DNA detection is therefore of clinical importance in screening patients with hepatitis B.

Clinical features and stroke etiology in 10 patients with bilateral middle cerebellar peduncle infarctions: a preliminary study / 中华神经科杂志

Objective:To characterize clinical and neuroimaging features, etiologies, and mechanisms of bilateral middle cerebellar peduncle (MCP) infarctions.Methods:Consecutive patients with bilateral MCP infarctions treated in the Beijing Tiantan Hospital, Capital Medical University between January 1, 2020 and April 30, 2022 were enrolled in this retrospective study. The demographic data, vascular risk factors, clincial manifestations and the National Institutes of Health Stroke Scale (NIHSS) scores were collected. Brain diffusion-weighted imaging was used to assess the regions of cerebral infarction, and the extracranial and intracranial segments of the vertebrobasilar artery were evaluated using magnetic resonance angiography, or computed tomography angiography. The stroke etiology and underlying mechanism were evaluated according to the Chinese Ischemic Stroke Subclassification.Results:Ten patients with bilateral MCP infarctions (8 men and 2 women) were analyzed ultimately. The onset age were 51.0-86.0 (64.8±11.4) years. NIHSS scores were 2.0-12.0 (4.9±2.9) points at admission. All patients had vascular risk factors, most of which were hypertension (10 cases) and dyslipoproteinemia (8 cases). The most common clinical manifestations were vertigo (10 cases), followed by ataxia (9 cases) and dysarthria (8 cases). Four cases were isolated bilateral MCP infarctions, while 6 patients were combined with other vertebrobasilar artery infarctions, 4 of which were combined with cerebellar hemisphere infarctions, consistent with the clinical symptoms. The etiology in all patients was large atherosclerosis (severe stenosis or occlusion of V4 segment of vertebral artery and anterior inferior cerebellar artery; 9 cases). Five patients were classified as hypoperfusion/impaired emboli clearance, while 4 patients were considered as artery-to-artery embolism, and 1 was considered as the parent artery (plaque or thrombosis) occluding penetrating artery.Conclusions:Bilateral MCP infarctions are an extremely rare cerebrovascular disease characterized by vertigo, ataxia, and dysarthria. Cerebral infarction can be isolated or often combined with cerebellar hemisphere infarction. The etiology was mostly stenosis or occlusion of V4 segment of vertebral artery and anterior inferior cerebellar artery.