Acute Adenoviral Infection Elicits an Arrhythmogenic Substrate Prior to Myocarditis.

BACKGROUND: Viral cardiac infection represents a significant clinical challenge encompassing several etiological agents, disease stages, complex presentation, and a resulting lack of mechanistic understanding. Myocarditis is a major cause of sudden cardiac death in young adults, where current knowledge in the field is dominated by later disease phases and pathological immune responses. However, little is known regarding how infection can acutely induce an arrhythmogenic substrate before significant immune responses. Adenovirus is a leading cause of myocarditis, but due to species specificity, models of infection are lacking, and it is not understood how adenoviral infection may underlie sudden cardiac arrest. Mouse adenovirus type-3 was previously reported as cardiotropic, yet it has not been utilized to understand the mechanisms of cardiac infection and pathology. METHODS: We have developed mouse adenovirus type-3 infection as a model to investigate acute cardiac infection and molecular alterations to the infected heart before an appreciable immune response or gross cardiomyopathy. RESULTS: Optical mapping of infected hearts exposes decreases in conduction velocity concomitant with increased Cx43Ser368 phosphorylation, a residue known to regulate gap junction function. Hearts from animals harboring a phospho-null mutation at Cx43Ser368 are protected against mouse adenovirus type-3-induced conduction velocity slowing. Additional to gap junction alterations, patch clamping of mouse adenovirus type-3-infected adult mouse ventricular cardiomyocytes reveals prolonged action potential duration as a result of decreased IK1 and IKs current density. Turning to human systems, we find human adenovirus type-5 increases phosphorylation of Cx43Ser368 and disrupts synchrony in human induced pluripotent stem cell-derived cardiomyocytes, indicating common mechanisms with our mouse whole heart and adult cardiomyocyte data. CONCLUSIONS: Together, these findings demonstrate that adenoviral infection creates an arrhythmogenic substrate through direct targeting of gap junction and ion channel function in the heart. Such alterations are known to precipitate arrhythmias and likely contribute to sudden cardiac death in acutely infected patients.

Descending dopaminergic pathway facilitates itch signal processing via activating spinal GRPR+ neurons.

A11 dopaminergic neurons regulate somatosensory transduction by projecting from the diencephalon to the spinal cord, but the function of this descending projection in itch remained elusive. Here, we report that dopaminergic projection neurons from the A11 nucleus to the spinal dorsal horn (dopaminergicA11-SDH ) are activated by pruritogens. Inhibition of these neurons alleviates itch-induced scratching behaviors. Furthermore, chemogenetic inhibition of spinal dopamine receptor D1-expressing (DRD1+ ) neurons decreases acute or chronic itch-induced scratching. Mechanistically, spinal DRD1+ neurons are excitatory and mostly co-localize with gastrin-releasing peptide (GRP), an endogenous neuropeptide for itch. In addition, DRD1+ neurons form synapses with GRP receptor-expressing (GRPR+ ) neurons and activate these neurons via AMPA receptor (AMPAR). Finally, spontaneous itch and enhanced acute itch induced by activating spinal DRD1+ neurons are relieved by antagonists against AMPAR and GRPR. Thus, the descending dopaminergic pathway facilitates spinal itch transmission via activating DRD1+ neurons and releasing glutamate and GRP, which directly augments GRPR signaling. Interruption of this descending pathway may be used to treat chronic itch.

Excitatory Projections from the Prefrontal Cortex to Nucleus Accumbens Core D1-MSNs and κ Opioid Receptor Modulate Itch-Related Scratching Behaviors.

Itch is an uncomfortable and complex sensation that elicits the desire to scratch. The nucleus accumbens (NAc) activity is important in driving sensation, motivation, and emotion. Excitatory afferents from the medial prefrontal cortex (mPFC), amygdala, and hippocampus are crucial in tuning the activity of dopamine receptor D1-expressing and D2-expressing medium spiny neurons (Drd1-MSN and Drd2-MSN) in the NAc. However, a cell-type and neural circuity-based mechanism of the NAc underlying acute itch remains unclear. We found that acute itch induced by compound 48/80 (C48/80) decreased the intrinsic membrane excitability in Drd1-MSNs, but not in Drd2-MSNs, in the NAc core of male mice. Chemogenetic activation of Drd1-MSNs alleviated C48/80-induced scratching behaviors but not itch-related anxiety-like behaviors. In addition, C48/80 enhanced the frequency of spontaneous EPSCs (sEPSCs) and reduced the paired-pulse ratio (PPR) of electrical stimulation-evoked EPSCs in Drd1-MSNs. Furthermore, C48/80 increased excitatory synaptic afferents to Drd1-MSNs from the mPFC, not from the basolateral amygdala (BLA) or ventral hippocampus (vHipp). Consistently, the intrinsic excitability of mPFC-NAc projecting pyramidal neurons was increased after C48/80 treatment. Chemogenetic inhibition of mPFC-NAc excitatory synaptic afferents relieved the scratching behaviors. Moreover, pharmacological activation of κ opioid receptor (KOR) in the NAc core suppressed C48/80-induced scratching behaviors, and the modulation of KOR activity in the NAc resulted in the changes of presynaptic excitatory inputs to Drd1-MSNs in C48/80-treated mice. Together, these results reveal the neural plasticity in synapses of NAc Drd1-MSNs from the mPFC underlying acute itch and indicate the modulatory role of the KOR in itch-related scratching behaviors.SIGNIFICANCE STATEMENT Itch stimuli cause strongly scratching desire and anxiety in patients. However, the related neural mechanisms remain largely unclear. In the present study, we demonstrated that the pruritogen compound 48/80 (C48/80) shapes the excitability of dopamine receptor D1-expressing medium spiny neurons (Drd1-MSNs) in the nucleus accumbens (NAc) core and the glutamatergic synaptic afferents from medial prefrontal cortex (mPFC) to these neurons. Chemogenetic activation of Drd1-MSNs or inhibition of mPFC-NAc excitatory synaptic afferents relieves the scratching behaviors. In addition, pharmacological activation of κ opioid receptor (KOR) in the NAc core alleviates C48/80-induced itch. Thus, targeting mPFC-NAc Drd1-MSNs or KOR may provide effective treatments for itch.

Mannitol and hyponatremia regulate cardiac ventricular conduction in the context of sodium channel loss of function.

Scn5a heterozygous null (Scn5a+/-) mice have historically been used to investigate arrhythmogenic mechanisms of diseases such as Brugada syndrome (BrS) and Lev's disease. Previously, we demonstrated that reducing ephaptic coupling (EpC) in ex vivo hearts exacerbates pharmacological voltage-gated sodium channel (Nav)1.5 loss of function (LOF). Whether this effect is consistent in a genetic Nav1.5 LOF model is yet to be determined. We hypothesized that loss of EpC would result in greater reduction in conduction velocity (CV) for the Scn5a+/- mouse relative to wild type (WT). In vivo ECGs and ex vivo optical maps were recorded from Langendorff-perfused Scn5a+/- and WT mouse hearts. EpC was reduced with perfusion of a hyponatremic solution, the clinically relevant osmotic agent mannitol, or a combination of the two. Neither in vivo QRS duration nor ex vivo CV during normonatremia was significantly different between the two genotypes. In agreement with our hypothesis, we found that hyponatremia severely slowed CV and disrupted conduction for 4/5 Scn5a+/- mice, but 0/6 WT mice. In addition, treatment with mannitol slowed CV to a greater extent in Scn5a+/- relative to WT hearts. Unexpectedly, treatment with mannitol during hyponatremia did not further slow CV in either genotype, but resolved the disrupted conduction observed in Scn5a+/- hearts. Similar results in guinea pig hearts suggest the effects of mannitol and hyponatremia are not species specific. In conclusion, loss of EpC through either hyponatremia or mannitol alone results in slowed or disrupted conduction in a genetic model of Nav1.5 LOF. However, the combination of these interventions attenuates conduction slowing.NEW & NOTEWORTHY Cardiac sodium channel loss of function (LOF) diseases such as Brugada syndrome (BrS) are often concealed. We optically mapped mouse hearts with reduced sodium channel expression (Scn5a+/-) to evaluate whether reduced ephaptic coupling (EpC) can unmask conduction deficits. Data suggest that conduction deficits in the Scn5a+/- mouse may be unmasked by treatment with hyponatremia and perinexal widening via mannitol. These data support further investigation of hyponatremia and mannitol as novel diagnostics for sodium channel loss of function diseases.

Protect the recurrent laryngeal nerves in US-guided microwave ablation of thyroid nodules at Zuckerkandl tubercle: a pilot study.

BACKGROUND: To evaluate the safety and efficacy of US-guided microwave ablation in patients with thyroid nodules at Zuckerkandl tubercle. METHODS: 103 consecutive patients with thyroid nodules at Zuckerkandl tubercle (ZTTN) were enrolled in this study from November 2017 to August 2021. Prior to the surgery or US-guided microwave ablation (MWA), preoperative ultrasound visualization of the recurrent laryngeal nerve (RLN) and ZTTN was performed, the size and the position relationship between them were observed. Patients were followed up at 1, 3, 6, and 12 months after MWA and the volume reduction rates (VRR) of the thyroid nodules were analyzed. RESULTS: All patients successfully had the RLN and ZTTN detected using ultrasound before surgery or ablation with a detection rate of 100%. For the 103 patients, the majority of ZTTN grades were categorized as grade 2, with the distance from the farthest outside of ZTTN to the outer edge of thyroid ranging between 6.0 and 10.0 mm. The position relationship between ZTTN and RLN was predominantly type A in 98 cases, with type D observed in 5 cases. After MWA, the median nodule volume had significantly decreased from 4.61 (2.34, 8.70) ml to 0.42 (0.15, 1.41) ml and the VRR achieved 84.36 ± 13.87% at 12 months. No nodules regrew throughout the 12-month follow-up period. Of the 11 patients experienced hoarseness due to RLN entrapment before ablation, 7 recovered immediately after separation of the RLN and ZTTN during MWA, 2 recovered after one week, and the other 2 recovered after two months. CONCLUSIONS: The RLN is closely related to ZTTN and mainly located at the back of ZTTN. The RLN can be separated from ZTTN by hydrodissection during MWA. US-guided MWA is a safe and effective treatment for ZTTN.

SARS-CoV-2 infection increases airway bleeding risk in patients after tracheostomies.

BACKGROUND: Airway bleeding events are a rare incident in SARS-CoV-2-infected patients after tracheostomies. We aimed to explore the correlation between airway bleeding and SARS-CoV-2 infection and evaluate the consistency of SARS-CoV-2 RNA test results in the upper and lower airway samples from patients after tracheostomies. METHODS: Forty-four patients after temporary or permanent tracheostomy were divided into a positive group (29 patients) and a negative group (15 patients) based on the SARS-CoV-2 RNA test results of their oropharyngeal swabs. The oropharyngeal and tracheal swabs of the positive group were re-collected for SARS-CoV-2 RNA detection. Demographic and clinical characteristics and airway bleeding events were recorded for all enrolled patients. RESULTS: Airway bleeding was reported in eleven patients of the positive group (11/29), with seven displaying bloody sputum or hemoptysis, and four featuring massive sputum crust formation in the trachea that resulted in dyspnea, and only one patient in the negative group (1/15), with a significant difference in the airway bleeding rate (37.9% vs. 6.7%, p < 0.05). The SARS-CoV-2 RNA test results showed a statistical difference in cycle threshold (Ct) values between oropharyngeal swabs and tracheal swabs (p < 0.05). CONCLUSIONS: After tracheostomies, patients are more susceptible to airway bleeding if they are infected with SARS-CoV-2. The findings signify that in addition to droplet transmission through tracheostoma, SARS-CoV-2 may infect the oropharynx by airborne and close contact transmission, and that given the higher viral load and longer infection time in the trachea, tracheal swabs are more reliable for SARS-CoV-2 detection in these patients.

Atmospheric Nitrogen Pollution Control Benefits the Coastal Environment.

Nitrogen is an essential nutrient and a major limiting element for the ocean ecosystem. Since the preindustrial era, substantial amounts of nitrogen from terrestrial sources have entered the ocean via rivers, groundwater, and atmospheric deposition. China serves as a key hub in the global nitrogen cycle, but the pathways, sources, and potential mitigation strategies for land-ocean nitrogen transport are unclear. By combining the CHANS, WRF-Chem, and WNF models, we estimated that 8 million tonnes (Tg) of nitrogen was transferred into the ocean in 2017 in China, with atmospheric deposition contributing 1/3. About half variation of the offshore chlorophyll concentration was explained by atmospheric deposition. The Bohai Sea was the hot spot of nitrogen input, estimated at 214 kg N ha-1, while other areas were around 25-51 kg N ha-1. The largest contributors are agricultural systems (4 Tg, 55%), followed by domestic sewage (2 Tg, 21%). Abatement measures could reduce nitrogen export to the ocean by 43%, and mitigating ammonia and nitrogen oxide emissions accounts for 33% of this reduction, highlighting the importance of addressing air pollution in resolving ocean pollution. The cost-benefit analysis suggests the priority of nitrogen reduction in cropland and transport systems for the ocean environment.

Early larval exposure to flumethrin induces long-term impacts on survival and memory behaviors of adult worker bees Apis mellifera.

Flumethrin has been supplied as an acaricide for Varroa mite control in world-wide apiculture due to its low lethal effects on honey bees. However, little is known about the effects of short-term flumethrin exposure in the larval stage on adult life stage of bees involving survival status, foraging and memory-related behaviors. Here, we found that exposure to flumethrin at 1 mg/L during larval stage reduced survival and altered foraging activities including induced precocious foraging activity, decreased foraging trips and time, and altered rotating day-off status of adult worker bees using the radio frequency identification system. Furthermore, larval exposure at 1 mg/L flumethrin influenced the correct proboscis extension responses of 7-day-old worker bees and decreased homing rates of 20-day-old worker bees, suggesting that 1 mg/L flumethrin exposure at larval stage could affect memory-related behaviors of adult bees; meanwhile, three genes related to memory (GluRA, Nmdar1 and Tyr1) were certainly down-regulated varying different flumethrin concentrations (0.01, 0.1, and 1 mg/L). Combined with transcriptomic sequencing, differentially expressed genes involved in olfactory memory of adult bees were completely down-regulated under flumethrin exposure. Our findings highlight the unprecedented impact of short-term exposure of insecticides on honey bees in long-term health monitoring under field conditions.

Synergistic resistance of honeybee (Apis mellifera) and their gut microorganisms to fluvalinate stress.

Fluvalinate is widely used in the control of Varroa destructor, but its residues in colonies threaten honeybees. The effect of fluvalinate-induced dysbiosis on honeybee-related gene expression and the gut microenvironment of honeybees has not yet been fully elucidated. In this study, two-day-old larvae to seven-day-old adult worker bees were continuously fed different amounts of fluvalinate-sucrose solutions (0, 0.5, 5, and 50 mg/kg), after which the expression levels of two immune-related genes (Hymenoptaecin and Defensin1) and three detoxication-related genes (GSTS3, CAT, and CYP450) in worker bees (1, 7, and 20 days old) were measured. The effect of fluvalinate on the gut microbes of worker bees at seven days old also was explored using 16S rRNA Illumina deep sequencing. The results showed that exposure of honeybees to the insecticide fluvalinate affected their gene expression and gut microbial composition. As the age of honeybees increased, the effect of fluvalinate on the expression of Hymenoptaecin, CYP450, and CAT decreased, and the abundance of honeybee gut bacteria was affected by increasing the fluvalinate concentration. These findings provide insights into the synergistic defense of honeybee hosts against exogenous stresses in conjunction with honeybee gut microbes.

Urinary continence in high-risk prostate cancer after robot-assisted radical prostatectomy.

PURPOSE OF REVIEW: Urinary incontinence is common postoperative complication following robot-assisted radical prostatectomy (RARP) in patients with prostate cancer (PCa). Despite the increasing adoption of RARP in the treatment of high-risk PCa (HRPC), concerns persist regarding the adequacy of reported continence outcomes in this subgroup. This review aims to illuminate the state of continence recovery in HRPC patients post-RARP. RECENT FINDINGS: Urinary continence (UC) recovery rates in HRPC was reported to be lower than the intermediate/low-risk counterparts from 6 to 24 months post-RARP. Predictive models showed that age, obesity, race, disease status, and surgical approaches represent predictors of continence recovery. Special techniques like NeuroSAFE technique and Retzius-Sparing approach also play a role in reducing incontinence also in the high-risk scenario. SUMMARY: RARP for HRPC appears to be associated with worse continence compared with other risk groups. A multimodality approach for prediction and prevention of incontinence after RARP is vital. Further research into this area is necessary to enhance continence recovery outcomes in HRPC patients undergoing RARP.

Metabolic profiling of Apis mellifera larvae treated with sublethal acetamiprid doses.

Acetamiprid is a neonicotinoid insecticide used in crop protection worldwide. Such widespread application can pose risks to pollinator insects, particularly to honeybees (Apis mellifera); therefore, the evaluation of the harmful effects of acetamiprid is necessary. Recent studies report behavior and gene expression dysfunction in honeybees, related to acetamiprid contamination. However, most studies do not consider potential metabolism disorders. To examine the effects of sublethal acetamiprid doses on the hemolymph metabolism of honeybees, worker bee larvae(2 days old) were fed with sucrose water containing different concentrations of acetamiprid (0, 5, and 25 mg/L) until capped (6 days old). The hemolymph (200 µL) of freshly capped larvae was collected for liquid chromatography-mass spectrometry (LC-MS). Overall, increasing acetamiprid exposure induced greater metabolic variations in worker bee larvae(treated groups compared to untreated). In the positive ion mode, 36 common differential metabolites in the acetamiprid-treated groups were screened from the identified differential metabolites. Of these, 19 metabolites were upregulated, and 17 were downregulated. 10 common differential metabolites were screened in the negative ion mode. 3 metabolites were upregulated, and 7 metabolites were downregulated. These common metabolites included traumatic acid, indole etc. These commonly differentiated metabolites were classified as compounds with biological roles, lipids, and phytochemical compounds, and others. The metabolic pathways of common differentiated metabolites with significant differences (P < 0.05) included the metabolism of tryptophan, purines, phenylalanine, etc. As the concentration of acetamiprid increased, the content of traumatic acid increased, the content of tryptophan metabolite l-kynurenine and indole decreased, and the content of lipids also decreased. Our results revealed that the damage to honeybee larvae increased when the acetamiprid solution formulations residue in their food had a concentration higher than 5 mg/L, causing metabolic disorders in various substances in larvae. Analysis of these metabolic processes can provide a theoretical basis for further research on the metabolism of acetamiprid-treated honeybees and elucidate the detoxification mechanisms.

Enhanced function of NR2C/2D-containing NMDA receptor in the nucleus accumbens contributes to peripheral nerve injury-induced neuropathic pain and depression in mice.

N-methyl-d-aspartate receptors (NMDARs) dysfunction in the nucleus accumbens (NAc) participates in regulating many neurological and psychiatric disorders such as drug addiction, chronic pain, and depression. NMDARs are heterotetrameric complexes generally composed of two NR1 and two NR2 subunits (NR2A, NR2B, NR2C and NR2D). Much attention has been focused on the role of NR2A and NR2B-containing NMDARs in a variety of neurological disorders; however, the function of NR2C/2D subunits at NAc in chronic pain remains unknown. In this study, spinal nerve ligation (SNL) induced a persistent sensory abnormity and depressive-like behavior. The whole-cell patch clamp recording on medium spiny neurons (MSNs) in the NAc showed that the amplitude of NMDAR-mediated excitatory postsynaptic currents (EPSCs) was significantly increased when membrane potential held at -40 to 0 mV in mice after 14 days of SNL operation. In addition, selective inhibition of NR2C/2D-containing NMDARs with PPDA caused a larger decrease on peak amplitude of NMDAR-EPSCs in SNL than that in sham-operated mice. Appling of selective potentiator of NR2C/2D, CIQ, markedly enhanced the evoked NMDAR-EPSCs in SNL-operated mice, but no change in sham-operated mice. Finally, intra-NAc injection of PPDA significantly attenuated SNL-induced mechanical allodynia and depressive-like behavior. These results for the first time showed that the functional change of NR2C/2D subunits-containing NMDARs in the NAc might contribute to the sensory and affective components in neuropathic pain.

Sublethal fluvalinate negatively affect the development and flight capacity of honeybee (Apis mellifera L.) workers.

Fluvalinate has been heavily used to control the pest Varroa destructor and residues in honeybee colony causing long-term exposure threat for bees. But, little is known about the lifetime trips and homing ability of worker bees under fluvalinate stresses during the development period. In this study, honeybees from 2-day-old larvae to 7-day-old adults were continuously fed with different concentrations of fluvalinate (0, 0.5, 5 and 50 mg/kg) and the effects of fluvalinate on the development of larvae were examined. And then, all the treated bees were reintroduced into the original source colony and were monitored, and the homing ability of 20 days old bees at 1000 and 2000 m away from the beehive were tested using the radio frequency identification (RFID). We found that fluvalinate significantly activates the superoxide dismutase (SOD) activities of larvae and 5 mg/kg fluvalinate reduced the homing rate of workers at 2000 m away from colony. 50 mg/kg fluvalinate reduced proportion of capped worker cells, activated Cytochrome P450 (CYP450) activity of larvae, affected the foraging times, influenced the homing rate and homing time of one trip at 2000 m away from colony. Our results showed that the larvae can activate the activities of SOD and detoxification enzymes in detoxification of fluvalinate and reduce the influence on honeybees. But, when the concentration is higher than 5 mg/kg fluvalinate, it is difficult for bees to detoxify fluvalinate completely, which affect the homing rate. The results reflect the potential risk for honeybees in the development stage continuously exposed to fluvalinate.

The negative effect of flumethrin stress on honey bee (Apis mellifera) worker from larvae to adults.

Flumethrin is a highly effective acaricide, but its lipophilic characteristic has some negative effects, such as accumulation in bee hives and bee products. However, studies on the survival stress of honey bees subsequent to chronic flumethrin exposure are limited. To answer this question, a study was carried out on the stress to honey bee (Apis mellifera) workers from larvae to adults by chronic exposure to sublethal concentrations of flumethrin. Three flumethrin treatment groups (1, 0.1, 0.01 mg/L) and one control group (with no added flumethrin) were established and divided the worker larvae into four groups. Then, starting with 2-day-old larvae, larvae and subsequent emerged worker bees of the four groups were orally fed with the corresponding concentrations of flumethrin until all the adult worker bees died, respectively. When the concentration was at 0.01 mg/L of flumethrin, the lifespan of adult worker bees decreased, and a down-regulation of detoxification-related genes (CYP450,GSTS) was induced in 1-day-old pupae. When it is at 0.1 mg/L flumethrin, the lifespan of adult worker bees was again shortened, and down-regulation of memory-related genes (GluRA1, Nmdar1, Tyr1) in 1-day-old pupae and gene Tyr1 in 1-day-old worker bees, detoxification-related genes (CYP450,GSTS) in 1-day-old pupae, and immunity genes (Defensin1, Hymenoptaecin) in 7-day-old worker bees were observed. When the concentration is at 1 mg/L flumethrin, lighter birth weight of newly emerged honeybee was found and deficiencies in olfactory learning and memory were observed in 7-day-old worker bees. Memory-related genes (GluRA1, Nmdar1, Tyr1) were down-regulated in 1-day-old pupae and genes (Nmdar1,Tyr1)in 1-day-old worker bees, as were detoxification-related genes (CYP450,GSTS) in 1-day-old pupae and gene CPY450 in 7-day-old worker bees, and immune genes (Defensin1, Hymenoptaecin) in 7-day-old worker bees. There was no significant difference in pupal weight, capping rate, emergence rate, expression of immune-related genes of 1-day-old pupae, expression of immune-related genes and detoxification-related genes of 1-day-old worker bees, expression of memory-related genes and detoxification-related gene GSTS of 7-day-old worker bees. These data provide an ominous warning about the unintended consequences on apiaries, and underscore the need for careful control of flumethrin residues in bee hives.

Overexpression of Ubiquitin-Conjugating Enzyme E2C Is Associated with Worsened Prognosis in Prostate Cancer.

To evaluate the role of ubiquitin-conjugating enzyme E2C (UBE2C) in prostate cancer (PCa) progression and prognosis, the TCGA and our PCa tissue microarray cohort were included in the study. Weighted gene co-expression network analysis (WGCNA) and non-negative matrix factorization were used to cluster patients and to screen genes that play a vital role in PCa progression (hub gene). Immunohistochemistry staining was used to evaluate the protein level of UBE2C in prostatic tissues. Through WGCNA, we found a gene co-expression module (named the purple module) that is strongly associated with the Gleason score, pathologic T stage, and biochemical recurrent status. Genes in the purple module are enriched in cell cycle and P53 signaling and help us to cluster patients into two groups with distinctive biochemical recurrent survival rates and TP53 mutation statuses. Further analysis showed UBE2C served as a hub gene in the purple module. The expression of UBE2C in PCa was significantly higher than that in paracancerous tissues and was remarkably associated with pathologic grade, Gleason score, and prognosis in PCa patients. To conclude, UBE2C is a PCa-progress-related gene and a biomarker for PCa patients. Therapy targeting UBE2C may serve as a promising treatment of PCa in the future.

Hypernatremia and intercalated disc edema synergistically exacerbate long-QT syndrome type 3 phenotype.

Cardiac voltage-gated sodium channel gain-of-function prolongs repolarization in the long-QT syndrome type 3 (LQT3). Previous studies suggest that narrowing the perinexus within the intercalated disc, leading to rapid sodium depletion, attenuates LQT3-associated action potential duration (APD) prolongation. However, it remains unknown whether extracellular sodium concentration modulates APD prolongation during sodium channel gain-of-function. We hypothesized that elevated extracellular sodium concentration and widened perinexus synergistically prolong APD in LQT3. LQT3 was induced with sea anemone toxin (ATXII) in Langendorff-perfused guinea pig hearts (n = 34). Sodium concentration was increased from 145 to 160 mM. Perinexal expansion was induced with mannitol or the sodium channel ß1-subunit adhesion domain antagonist (ßadp1). Epicardial ventricular action potentials were optically mapped. Individual and combined effects of varying clefts and sodium concentrations were simulated in a computational model. With ATXII, both mannitol and ßadp1 significantly widened the perinexus and prolonged APD, respectively. The elevated sodium concentration alone significantly prolonged APD as well. Importantly, the combination of elevated sodium concentration and perinexal widening synergistically prolonged APD. Computational modeling results were consistent with animal experiments. Concurrently elevating extracellular sodium and increasing intercalated disc edema prolongs repolarization more than the individual interventions alone in LQT3. This synergistic effect suggests an important clinical implication that hypernatremia in the presence of cardiac edema can markedly increase LQT3-associated APD prolongation. Therefore, to our knowledge, this is the first study to provide evidence of a tractable and effective strategy to mitigate LQT3 phenotype by means of managing sodium levels and preventing cardiac edema in patients.NEW & NOTEWORTHY This is the first study to demonstrate that the long-QT syndrome type 3 (LQT3) phenotype can be exacerbated or concealed by regulating extracellular sodium concentrations and/or the intercalated disc separation. The animal experiments and computational modeling in the current study reveal a critically important clinical implication: sodium dysregulation in the presence of edema within the intercalated disc can markedly increase the risk of arrhythmia in LQT3. These findings strongly suggest that maintaining extracellular sodium within normal physiological limits may be an effective and inexpensive therapeutic option for patients with congenital or acquired sodium channel gain-of-function diseases.

A preliminary study on ultrasound-guided percutaneous microwave ablation for palliative treatment of advanced head and neck malignancies.

OBJECTIVE: To evaluate the safety and efficacy of ultrasound (US)-guided percutaneous microwave ablation (UgPMWA) for palliative treatment of advanced head and neck malignancies. MATERIALS AND METHODS: This study includes 18 consecutive patients with advanced head and neck malignancies (n = 24), who have undergone UgPMWA for palliative treatment at our institution from December 2016 to April 2020. The maximum diameter and volume of the tumor were assessed by US, CT or MRI before microwave ablation (MWA), 1, 3 and 6 months after MWA and every 6 months thereafter. The quality of life was clinically assessed by the University of Washington Head and Neck Quality of Life questionnaire (UW-QOl). RESULTS: The success rate of tumor-targeting microwave antenna placement was 100%. No nerve injury and serious complications or death occurred during the perioperative period. The follow-up duration varied from 1 month to 38 months (11.56 ± 10.23 months) among patients. By the last follow-up before submission, the value of maximum diameter (5.00 ± 2.90 vs 3.28 ± 2.11 cm. p < 0.05) and tumor volume decreased significantly（74.35 ± 46.88 vs 47.45 ± 24.08 cm3. p < 0.05）respectively after palliative treatment with UgPMWA. UW-QOl of the patients was improved (59.24 ± 11.51 vs 69.84 ± 8.12, p < 0.05). CONCLUSION: UgPMWA is safe and effective for the palliative treatment of head and neck malignancies. Ultrasonic guidance can indicate an accurate location of the microwave antenna. It can also monitor the ablation area in real-time during the operation to avoid damage to surrounding normal tissues.

Thoracoscopic total laryngo-pharyngo-oesophagectomy for the pharyngoesophageal junction cancer: a single-center experience of multidisciplinary team.

PURPOSE: The aims of this study were to review the surgical experience and evaluate the feasibility of thoracoscopic total laryngo-pharyngo-oesophagectomy by multidisciplinary team in the patients with pharyngoesophageal junction cancer. METHODS: A total of 31 patients with pharyngoesophageal junction cancer who underwent thoracoscopic total laryngo-pharyngo-oesophagectomy with gastric pull-up reconstruction performed by a collaborative thoracic surgery and otolaryngology surgery team in our department from January 2009 to January 2019 were retrospectively analysed. Surgical experience, Postoperative morbidity, overall survival were evaluated. RESULTS: The median age was 62 years old. Among these patients, 20 had hypopharyngeal cancer, 11 had cervical oesophageal cancer. No patients died during the perioperative period, and the median operation time was 4 h 30 min. The mean hospital stay was 13 days. The rate of complications was 32.3%. There were two cases of anastomotic leakage, four cases of moderate pulmonary infection. The median follow-up period was 31 months. Four patients were lost to follow-up in the second and fourth years and were considered to have died at that time. The 3- and 5-year overall survival rates were 52.6% and 31.6%, respectively. CONCLUSION: As a salvage surgery, thoracoscopic total laryngo-pharyngo-oesophagectomy by multidisciplinary team can be performed with an acceptable level of perioperative morbidity and mortality, relatively good recovery, and acceptable survival outcome for patients with pharyngoesophageal junction cancer.

Intercellular Sodium Regulates Repolarization in Cardiac Tissue with Sodium Channel Gain of Function.

In cardiac myocytes, action potentials are initiated by an influx of sodium (Na+) ions via voltage-gated Na+ channels. Na+ channel gain of function (GOF), arising in both inherited conditions associated with mutation in the gene encoding the Na+ channel and acquired conditions associated with heart failure, ischemia, and atrial fibrillation, enhance Na+ influx, generating a late Na+ current that prolongs action potential duration (APD) and triggering proarrhythmic early afterdepolarizations (EADs). Recent studies have shown that Na+ channels are highly clustered at the myocyte intercalated disk, facilitating formation of Na+ nanodomains in the intercellular cleft between cells. Simulations from our group have recently predicted that narrowing the width of the intercellular cleft can suppress APD prolongation and EADs in the presence of Na+ channel mutations because of increased intercellular cleft Na+ ion depletion. In this study, we investigate the effects of modulating multiple extracellular spaces, specifically the intercellular cleft and bulk interstitial space, in a novel computational model and experimentally via osmotic agents albumin, dextran 70, and mannitol. We perform optical mapping and transmission electron microscopy in a drug-induced (sea anemone toxin, ATXII) Na+ channel GOF isolated heart model and modulate extracellular spaces via osmotic agents. Single-cell patch-clamp experiments confirmed that the osmotic agents individually do not enhance late Na+ current. Both experiments and simulations are consistent with the conclusion that intercellular cleft narrowing or expansion regulates APD prolongation; in contrast, modulating the bulk interstitial space has negligible effects on repolarization. Thus, we predict that intercellular cleft Na+ nanodomain formation and collapse critically regulates cardiac repolarization in the setting of Na+ channel GOF.

Conjunctival microcirculation is associated with cerebral cortex microcirculation in post-resuscitation mild hypothermia: A rat model.

OBJECTIVE: This study aimed to compare the changes in sublingual and conjunctival microcirculation occurring with cerebral cortex microcirculation changes during mild hypothermia in a rat model of cardiac arrest. METHODS: Twenty-four rats were randomized into mild hypothermia (M) or normothermia (C) groups. Ventricular fibrillation was electrically induced and left untreated for 8 minutes, followed by 8 minutes of cardiopulmonary resuscitation. The core temperature in group M reduced to 33 ± 0.5°C at 13 minutes after restoration of spontaneous circulation and was maintained for 8 hours. In group C, the core temperature was maintained at 37 ± 0.2°C. The hemodynamics and microcirculation in the sublingual region, bulbar conjunctiva, and cerebral cortex were measured at baseline and 1, 2, 3, 4, 6, and 8 hours after restoration of spontaneous circulation. RESULTS: The M group showed significantly worse sublingual microcirculation at 6 hours post-resuscitation. However, microcirculation in the conjunctiva and cerebral cortex at 3 hours post-resuscitation were better in the M group. In the M group, microcirculation in the cerebral cortex was significantly correlated with that in the conjunctiva but not the sublingual microcirculation. CONCLUSIONS: Changes in conjunctival microcirculation are closely related to cerebral cortex microcirculation during mild hypothermia, indicating that cerebral cortex microcirculation could be monitored by measuring conjunctival microcirculation.