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To describe the long-term health outcomes of patients with COVID-19 and investigate the potential risk factors. Clinical data during hospitalization and at a mean (SD) day of 249 (15) days after discharge from 40 survivors with confirmed COVID-19 (including 25 severe cases) were collected and analyzed retrospectively. At follow-up, severe cases had higher incidences of persistent symptoms, DLCO impairment, and higher abnormal CT score as compared with mild cases. CT score at follow-up was positively correlated with age, LDH level, cumulative days of oxygen treatment, total dosage of glucocorticoids used, and CT peak score during hospitalization. DLCO% at follow-up was negatively correlated with cumulative days of oxygen treatment during hospitalization. DLCO/VA% at follow-up was positively correlated with BMI, and TNF-α level. Among the three groups categorized as survivors with normal DLCO, abnormal DLCO but normal DLCO/VA, and abnormal DLCO and DLCO/VA, survivors with abnormal DLCO and DLCO/VA had the lowest serum IL-2R, IL-8, and TNF-α level, while the survivors with abnormal DLCO but normal DLCO/VA had the highest levels of inflammatory cytokines during hospitalization. Altogether, COVID-19 had a greater long-term impact on the lung physiology of severe cases. The long-term radiological abnormality maybe relate to old age and the severity of COVID-19. Either absent or excess of inflammation during COVID-19 course would lead to the impairment of pulmonary diffusion function.

Background Postoperative pain management is crucial for patients undergoing total knee arthroplasty (TKA). There have been many recent clinical trials on post-TKA peripheral nerve block; however, they have reported inconsistent findings. In this meta-analysis, we aimed to comprehensively analyze studies on post-TKA analgesia to provide evidence-based clinical suggestions. Methods We performed a computer-based query of PubMed, Embase, the Cochrane Library, and the Web of Science to retrieve related articles using neurothe following search terms: nerve block, nerve blockade, chemodenervation, chemical neurolysis, peridural block, epidural anesthesia, extradural anesthesia, total knee arthroplasty, total knee replacement, partial knee replacement, and others. After quality evaluation and data extraction, we analyzed the complications, visual analogue scale (VAS) score, patient satisfaction, perioperative opioid dosage, and rehabilitation indices. Evidence was rated using the Grading of Recommendations Assessment, Development, and Evaluation approach. Results We included 16 randomized controlled trials involving 981 patients (511 receiving peripheral nerve block and 470 receiving epidural block) in the final analysis. Compared with an epidural block, a peripheral nerve block significantly reduced complications. There were no significant between-group differences in the postoperative VAS score, patient satisfaction, perioperative opioid dosage, and rehabilitation indices. Conclusions Our findings demonstrate that the peripheral nerve block is superior to the epidural block in reducing complications without compromising the analgesic effect and patient satisfaction. Therefore, a peripheral nerve block is a safe and effective postoperative analgesic method with encouraging clinical prospects.

Key points During exercise, bradykinin (BK), a muscle metabolite in ischaemic muscles, exaggerates autonomic responses to activation of muscle afferent nerves in peripheral artery disease (PAD). We examined whether BK inhibits activity of KV 4 channels in muscle afferent neurons of PAD rats induced by femoral artery occlusion. We demonstrated that: 1) femoral occlusion attenuates KV 4 currents in dorsal root ganglion (DRG) neurons innervating the hindlimb muscles and decreases the threshold of action potential firing; 2) BK has a greater inhibitory effect on KV 4 currents in muscle DRG neurons of PAD rats; and 3) expression of KV 4.3 is downregulated in DRGs of PAD rats and inhibition of KV 4.3 significantly decreases activity of KV 4 currents in muscle DRG neurons. Femoral artery occlusion-induced limb ischaemia and/or ischaemia-induced metabolites (i.e. BK) inhibit activity of KV 4 channels in muscle afferent neurons and this is likely involved in the exaggerated exercise pressor reflex in PAD. Abstract Muscle afferent nerve-activated reflex sympathetic nervous and blood pressure responses are exaggerated during exercise in patients with peripheral artery diseases (PAD) and in PAD rats induced by femoral artery occlusion. However, the precise signalling pathways and molecular mediators responsible for these abnormal autonomic responses in PAD are poorly understood. A-type voltage-gated K+ (KV ) channels are quintessential regulators of cellular excitability in the various tissues. Among KV channels, KV 4 (i.e. KV 4.1 and KV 4.3) in primary sensory neurons mainly participate in physiological functions in regulation of mechanical and chemical sensation. However, little is known about the role of KV 4 in regulating neuronal activity in muscle afferent neurons of PAD. In addition, bradykinin (BK) is considered as a muscle metabolite contributing to the exaggerated exercise pressor reflex in PAD rats with femoral artery occlusion. Our data demonstrated that: 1) KV 4 currents are attenuated in dorsal root ganglion (DRG) neurons innervating the hindlimb muscles of PAD rats, along with a decreasing threshold of action potential firing; 2) KV 4 currents are inhibited by application of BK onto muscle DRG neurons of PAD rats to a greater degree; and 3) expression of KV 4.3 is downregulated in the DRGs of PAD rats and KV 4.3 channel is a major contributor to the activity of KV 4 currents in muscle DRG neurons. In conclusion, data suggest that femoral artery occlusion-induced limb ischaemia and/or ischaemia-induced metabolites (i.e. BK) inhibit the activity of KV 4 channels in muscle afferent neurons likely leading to the exaggerated exercise pressor reflex observed in PAD.

Objective Numerous neuroimaging studies have demonstrated that functional brain aberrations are associated with cognitive impairments in temporal lobe epilepsy (TLE). Here, we aimed to investigate the neural substrates of attention deficits by combining assessment of regional intrinsic brain activities with large-scale functional connectivity in patients with right TLE (rTLE). Methods Thirty-five patients with rTLE and 33 matched healthy controls were recruited. All participants completed the Attention Network Test (ANT) and resting-sate functional MRI (rs-fMRI) scans. The z-standardized fractional amplitude of the low-frequency fluctuation (zfALFF) approach was applied to evaluate the brain's intrinsic activity. The cerebral regions with significant zfALFF values were selected as seeds for subsequent functional connectivity analyses. A correlation analysis was performed between functional activity and clinical variables. Results Compared with the healthy control group, the patients showed decreased zfALFF in the right inferior temporal gyrus and bilateral superior parietal gyrus, and the right inferior temporal gyrus exhibited increased functional connectivity with the bilateral cerebellum-6/vermis-6 and decreased functional connectivity with right superior frontal gyrus. The ANT indicated that the rTLE group exhibited attention deficits. Furthermore, a positive correlation was found between the zfALFF value of the left superior parietal gyrus and alerting performance, while a negative correlation between the zfALFF value of the right superior parietal gyrus and disease duration. Conclusion This study demonstrated aberrant intrinsic cerebral activity and functional connectivity in the whole brain network, which may act as responsible and compensatory factors in attention deficits, especially further profoundly illuminated the compensatory role of cerebellum in patients with rTLE.

Objective To introduce our experience of laparoscopic uterovaginal anastomosis and operative outcomes following this technique and update the clinical management of congenital cervicovaginal atresia. Study design Between March 2015 and January 2019, twenty-three patients with congenital cervicovaginal atresia underwent laparoscopic uterovaginal anastomosis and Luohu procedure. Their clinical characteristics, surgical outcomes and follow-up data were retrospectively reviewed. Results The mean ± SD age of the cases was 16.4 ± 4.0 (11–26) years. All patients had a history of primary amenorrhea and cyclical abdominal pain, and the average delay in diagnosis from first symptoms was 33.5 ± 38 (1–156) months. Most of the patients had 1−3 cm long vaginal pouch. The operative procedure lasted 125 ± 32 (80–190) min. The average vaginal length at 1 month was 7.9 ± 1.3 (range 6–9) cm. All patients showed resumption of menstruation. The patients were followed for a mean of 27 ± 13 (12–56) months. During the follow-up, cervical stenosis did not occur in any of the cases. Conclusion Laparoscopic uterovaginal anastomosis with Luohu procedure provided a minimally invasive, safe, and effective surgical option for the patients with congenital cervicovaginal atresia. The technique is uncomplicated, easy to learn and perform, and provides a functional and anatomic satisfactory result. No special surgical instruments are required with this technique.

In peripheral artery disease patients, the blood supply directed to the lower limbs is reduced. This results in severe limb ischemia and thereby enhances pain sensitivity in lower limbs. The painful perception is induced and exaggerate during walking, and is relieved by rest. This symptom is termed by intermittent claudication. The limb ischemia also amplifies autonomic responses during exercise. In the process of pain and autonomic responses originating exercising muscle, a number of receptors in afferent nerves sense ischemic changes and send signals to the central nervous system leading to autonomic responses. This review integrates recent study results in terms of perspectives including how nerve growth factor affects muscle sensory nerve receptors in peripheral artery disease and thereby alters responses of sympathetic nerve activity and blood pressure to active muscle. For the sensory nerve receptors, we emphasize the role played by transient receptor potential vanilloid type 1, purinergic P2X purinoceptor 3 and acid sensing ion channel subtype 3 in amplified sympathetic nerve activity responses in peripheral artery disease.

Background The muscle relaxant methocarbamol is widely used for the treatment of muscle spasms and pain syndromes. To elucidate molecular mechanisms of its action, we studied its influence on neuromuscular transmission, on isometric muscle force, and on voltage-gated Na+ channels. Methods Neuromuscular transmission was investigated in murine diaphragm-phrenic nerve preparations and muscle force studied on mouse soleus muscles. Nav 1.4 channels and Nav 1.7 channels were functionally expressed in eukaryotic cell lines. Results Methocarbamol, at 2 mM, decreased the decay of endplate currents, slowed the decay of endplate potentials and reduced tetanic force of soleus muscles. The drug reversibly inhibited current flow through muscular Nav 1.4 channels, while neuronal Nav 1.7 channels were unaffected. Conclusions The study provides evidence for peripheral actions of methocarbamol on skeletal muscle. Muscular Na+ channels are a molecular target of methocarbamol. Since Nav 1.7 currents were unaffected, methocarbamol is unlikely to exert its analgesic effect by directly blocking Nav 1.7 channels.

Purpose The aim of this study was to develop a scale to quantify the negative life events of graduate students; and to identify the associations between negative life events and emotional disorders among them. Methods Based on a literature review, qualitative interviews and direct consultation with experts in relevant fields, the study served to identify the items that could be included in the Negative Life Events Scale for graduates (LES-GS). Psychometrics was used to analyze the items for reliability and validity. A cross-sectional survey was conducted in Changsha, China to explore the association between negative life events and emotional disorders among master's and PhD students. LES-GS, Patient Health Questionnaire-9 (PHQ-9), and the Generalized Anxiety Disorder Scale-7 (GAD-7) were utilized in the survey. Results The LES-GS exhibited acceptable reliability and validity. A total of 13.24% of master's and 16.60% of PhD students experienced moderate to severe depression symptoms. Additionally, a total of 9.04% of master's students and 15.47% of PhD students experienced moderate to severe anxiety symptoms. Among the master's students, five long-term events and one short-term event life events (these included "tension with family members"; "the graduation project is not going well"; "not interested in the major"; "poor relationship with partner or spouse", "long-term financial stress", and "dispute with the mentor") were associated with an increased likelihood of emotional disorders among them. Among the PhD students, "death of a close family member" and "the publication of academic papers fails to meet the graduation requirements" were associated with an increased likelihood of emotional disorders. Conclusion The LES-GS could be used to assess life events for graduate students. The treatment of emotional problems for the master's students and the doctorial students should be designed differently.

Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a widely prevalent problem with many complications, such as hypertension and cerebral vascular diseases. Atherosclerosis, whose most severe outcome is ischemic stroke, is reported being affected by OSAHS. The objective of this article is to investigate the differences of carotid atherosclerosis patients with or without OSAHS by a cross-sectional research. Patients diagnosed with carotid atherosclerosis by ultrasonography were recruited. They were requested to fill the primary screening OSAHS questionnaire. Patients with high tendency of OSAHS underwent polysomnography (PSG) tests into OSAHS group, and patients without OSAHS were into non-OSAHS group. Blood tests and medical history were collected. Carotid atherosclerosis severity was analyzed by carotid artery intima-media thickness (IMT), carotid plaque, blood flow velocity, etc. Differences between the two groups and subgroups were analyzed. A total of 242 carotid atherosclerosis patients were enrolled including 118 non-OSAHS patients (38 males and 80 females) and 124 OSAHS patients (40 mild, 32 moderate, and 52 severe). Significant differences were found in PSV-ICA and EDV-ICA on both sides (p

In patients with peripheral artery disease (PAD), the blood supply directed to the lower limbs is reduced. This results in severe limb ischemia and thereby intermittent claudicating which is characterized by pain in lower limbs that occurs with walking and is relieved by rest. Of note, PAD can extremely affect the quality of living of patients and increase high risk of coronary and cerebral vascular accidents. However, effective treatments of PAD are still challenging in clinics. A number of reports have demonstrated the beneficial effects of supervised exercise on symptoms of PAD patients. This review will summarize results obtained from recent human and animal studies, which include the abnormalities in sympathetic control of blood pressure response during exercise in PAD, and rationality of animal models used for study human PAD. Nonetheless, additional in-depth studies are necessary to better explore the underlying mechanisms of the exaggerated responses of sympathetic nerve and blood pressure in PAD at molecular and cellular levels.

DEAD (Asp-Glu-Ala-Asp) box RNA helicase 3 (DDX3X) is demonstrated to have crucial functions in the antiviral immune response. To our knowledge, little information focuses on the function of duck DDX3X. In this study, duck DDX3X (duDDX3X) was cloned and its role in the type I interferon (IFN) signaling pathway was investigated using duck embryo fibroblast (DEF) cells. Full-length duDDX3X cDNA encodes 652 amino acid residues and contains a DEADc domain and a HELICc domain. According to tissue distribution analysis, duDDX3X mRNA was widely expressed in different tissues, especially the spleen and the liver. Overexpression of duDDX3X in DEF cells induced IFN-β by activating transcription factors IRF1 and NF-κB. Knockdown of duDDX3X in DEF cells with siRNA significantly reduced IFN-β expression induced by poly(I:C), a double-stranded RNA (dsRNA) analog. Our results demonstrated that duck DDX3X was involved in the dsRNA-mediated type I IFN signaling pathway in DEF cells.

Macromolecular drugs, characterized by low stability and large molecular weight, still faced various difficulties by oral administration. And controlling drugs' release rate to reach the physiological concentration in the blood was recognized as one of the main challenges in this field but no studies are available so far. Thus, the objective of this study was to investigate the effect of insulin release rate on its in vitro and in vivo behavior when other obstacles (drug stability, mucus penetration and retention in gastrointestinal tract) was firstly overcome. Using n-butylcyanoacrylate (BCA) as the carrier, insulin-loaded Poly (n-butylcyanoacrylate) nanoparticles (Ins/PBCA NPs) were prepared by self-polymerization and the release rate of insulin was controlled by adjusting the mass ratio of Insulin/BCA. The NPs exhibited good stability in gastric fluid with controlled release in intestine and the release rate increased with the increase of Insulin/BCA mass ratio. All the Ins/PBCA NPs with different release rate showed excellent mucus penetration (>60%, 10 min) and strong gastrointestinal retention (~70%, 12 h). Especially, all the NPs showed promising hypoglycemic effect with the extent depending on drug release rate. Ins/BCA = 2/10 NPs exhibited fast hypoglycemic effect, while Ins/BCA = 2/15 NPs showed slow and outstanding performance. In conclusion, Ins/PBCA NPs could not only overcome the oral barriers of insulin delivery but also provide desired hypoglycemic effect by controlling insulin release rate.

BackgroundImmune cell infiltration in the tumor microenvironment (TME) affects tumor initiation, patients’ prognosis and immunotherapy strategies. However, their roles and interactions with genomics and molecular processes in hepatocellular carcinoma (HCC) still have not been systematically evaluated.MethodsWe performed unsupervised clustering of total 1000 HCC samples including discovery and validation group from available public datasets. Immune heterogeneity of each subtype was explored by multi-dimension analysis. And a support vector machine (SVM) model based on multi-omics signatures was trained and tested. Finally, we performed immunohistochemistry to verify the immune role of signatures.ResultsWe defined three immune subtypes in HCC, with diverse clinical, molecular, and genomic characteristics. Cluster1 had worse prognosis, better anti-tumor characteristics and highest immune scores, but also accompanied by immunosuppression and T cell dysfunction. Meanwhile, a better anti-PD1/CTLA4 immunotherapeutic response was predicted in cluster1. Cluster2 was enriched in TAM-M2 and stromal cells, indicating immunosuppression. Cluster3, with better prognosis, had lowest CD8 T cell but highest immune resting cells. Further, based on genomic signatures, we developed an SVM classifier to identify the patient’s immunological status, which was divided into Type A and Type B, in which Type A had poorer prognosis, higher T cell dysfunction despite higher T cell infiltration, and had better immunotherapeutic response. At the same time, MMP9 may be a potential predictor of the immune characteristics and immunotherapeutic response in HCC.ConclusionsOur work demonstrated 3 immune clusters with different features. More importantly, multi-omics signatures, such as MMP9 was identified based on three clusters to help us recognize patients with different prognosis and responses to immunotherapy in HCC. This study could further reveal the immune status of HCC and provide potential predictors for immune checkpoint treatment response.

Femoral artery occlusion in rats has been used to study human peripheral artery disease (PAD). Using this animal model, a recent study suggests that increases in levels of tumor necrosis factor-α (TNF-α) and its receptor lead to exaggerated responses of sympathetic nervous activity and arterial blood pressure as metabolically sensitive muscle afferents are activated. Note that voltage-dependent Na+ subtype NaV1.8 channels (NaV1.8) are predominately present in chemically sensitive thin fiber sensory nerves. The purpose of this study was to examine the role played by TNF-α in regulating activity of NaV1.8 currents in muscle dorsal root ganglion (DRG) neurons of rats with PAD induced by femoral artery occlusion. DRG neurons from control and occluded limbs of rats were labeled by injecting the fluorescent tracer DiI into the hindlimb muscles 5 days before the experiments. A voltage patch-clamp mode was used to examine TTX-resistant (TTX-R) NaV currents. Results were as follows: 72 h of femoral artery occlusion increased peak amplitude of TTX-R [1,922 ± 139 pA in occlusion ( n = 11 DRG neurons) vs. 1,178 ± 39 pA in control ( n = 10), means ± SE; P < 0.001 between the 2 groups] and NaV1.8 currents [1,461 ± 116 pA in occlusion ( n = 11) and 766 ± 48 pA in control ( n = 10); P < 0.001 between groups] in muscle DRG neurons. TNF-α exposure amplified TTX-R and NaV1.8 currents in DRG neurons of occluded muscles in a dose-dependent manner. Notably, the amplification of TTX-R and NaV1.8 currents induced by TNF-α was attenuated in DRG neurons with preincubation with respective inhibitors of the intracellular signaling pathways p38-MAPK, JNK, and ERK. In conclusion, our data suggest that NaV1.8 is engaged in the role of TNF-α in amplifying muscle afferent inputs as the hindlimb muscles are ischemic; p38-MAPK, JNK, and ERK pathways are likely necessary to mediate the effects of TNF-α.

Key points During exercise, the blood pressure (BP) response is exaggerated in peripheral artery disease (PAD). We examined whether heat treatment (HT) has beneficial effects on the exaggerated exercise pressor reflex in PAD rats. With HT (increase in basal muscle temperature of ∼1.5°C for 30 min, twice daily for three continuous days), the amplified BP response to muscle contraction is alleviated in PAD. We demonstrated that HT attenuates the enhancement of the BP response induced by stimulation of P2X in muscle afferent nerves of PAD rats. HT also attenuates the upregulation of the P2X3 and the increase in P2X currents in the muscle afferent neurons of PAD rats. Previous heat exposure plays a beneficial role in modifying the exaggeration of the exercise pressor reflex in PAD and a reduction in the activity of the P2X receptor pathway is probably a part of the mechanism mediating this improvement. Abstract The current study was performed to examine if heat treatment (HT) has beneficial effects on the exaggerated exercise pressor reflex in rats with peripheral artery disease (PAD). We further determined if the temperature-sensitive P2X receptor is involved in the effects of HT. The pressor response to static muscle contraction and α,β-methylene ATP (αβ-me ATP, a P2X agonist) was examined. Western blot analysis was used to determine the protein levels of P2X3 in the dorsal root ganglion (DRG), and the whole cell patch clamp was used to examine the amplitude of P2X currents in the DRG neurons. The basal muscle temperature (Tm ) was lower in PAD rats than in control rats. Tm was increased by ∼1.5°C and this increase was maintained for 30 min. This HT protocol was performed tweice daily for three continuous days. A greater blood pressure (BP) response to contraction was observed in PAD rats. HT attenuated the amplification of the BP response in PAD rats. HT also attenuated the enhancement of the BP response induced by the arterial injection of αβ-me ATP in PAD rats. In addition, HT attenuated the upregulation of the P2X3 and increased P2X currents in the DRG neurons of PAD rats. In conclusion, previous heat exposure plays an inhibitory role in modifying the exaggeration of the exercise pressor reflex in PAD and a reduction of the activity of the P2X receptor pathway is probably a part of mechanisms leading to the beneficial effects of HT.

Background Plastic bronchitis (PB) frequently occurs as a serious postoperative complication of the Fontan procedure. The definitive causes of PB are unknown. Case presentation Herein, we report a pediatric case of PB secondary to adenoviral infection. A 4-year-old girl was admitted to the general pediatric ward for cough since 2 weeks and fever since 11 days. Consolidated lesions were noted in the right upper and both lower lung lobes. Extracorporeal membrane oxygenation was performed because the patient’s respiratory failure remained unalleviated despite the use of a ventilator. Bronchial dendritic casts were extracted using flexible bronchoscopy, and the patient’s breathing improved. Pathological examination of the dendritic cast confirmed the diagnosis of type I PB. The exfoliated cells of sputum and cells from bronchoalveolar lavage fluid were positive for adenoviral antigen. Human adenovirus 7 was detected by next-generation sequencing of the bronchoalveolar lavage fluid. The patient recovered and was discharged 39 days after admission without recurrence of cough or wheezing. Conclusions PB due to human adenovirus 7 infection should be considered in children with persistent respiratory failure. Flexible bronchoscopy should be performed early to confirm diagnosis and to remove any airway obstruction.

Supplemental material, sj-docx-1-cll-10.1177_09636897211070238 for Cord-Blood Engraftment Using an Enhanced Dual-Conditioning Regimen for Malignant Hematologic Diseases by Jiahua Ding, Yongjun Fang, Rongfu Zhou, Yan Gu, Shengnan Du, Qin Lu and Qingqing Yue in Cell Transplantation

Objective: We aimed to explore functional connectivity (FC) and effective connectivity (EC) of the executive control networks (ECNs) and the default mode network (DMN) in patients with right-sided TLE (rTLE) by applying independent component analysis (ICA) and Granger causal analysis (GCA).Methods: Twenty-seven patients with rTLE and 20 healthy controls (HCs) matched for age, gender underwent resting-state functional magnetic resonance imaging and Attention Network Test (ANT).Results: The FC analysis showed compared to HCs, patients with rTLE demonstrated reduced FC strength in the right inferior parietal gyrus (IPG) and the right middle temporal gyrus (MTG). The left superior temporal gyrus (STG) displayed reduced FC values whereas the left thalamus revealed increased FC values in rTLE. ROI-wise GCA revealed that patients with rTLE displayed increased EC from the left thalamus to the left STG, and as well as enhanced EC from the right IPG to the right MTG compared to HCs. Voxel-wise GCA showed positive EC from the left thalamus to the left insula while the right middle occipital gyrus (MOG) exhibited increased EC to the right MTG in patients. The ANT results demonstrated executive dysfunction in patients compared to HCs. The increased FC in the left thalamus showed a negative association with ECF in patients.Conclusion: We speculated that recurrent seizures take effect on disruption among the brain networks, and self-modulation occurs simultaneously to compensate for cognitive decline. Our findings revealed new insights on the neuropathophysiological mechanisms of rTLE.

Objective: To observe the therapeutic effect of acupuncture-moxibustion at different intervals on persistent allergic rhinitis. Methods: A total of 90 patients conforming to the inclusion criteria were randomized into three groups named A, B and C by randomized block method. Patients in all three groups received the same treatment of acupuncture and herbal cake-partitioned moxibustion at the same acupoints, while the treatment frequency was different. Patients in group A received the treatment once a week, group B twice a week and group C three times a week, and all the treatment lasted for 4 weeks. The total nasal symptom score (TNSS), total ocular symptom score (TOSS) and Sino-nasal outcome test-20 (SNOT-20) were evaluated before and after treatment. The self-rating score of symptoms was evaluated during treatment and 2 weeks after treatment. Results: The total effective rate was 80.0% in group A, 93.3% in group B, and 100.0% in group C. The total effective rate in group A was statistically different from that in group B and group C (both P 0.05). After treatment, scores of TNSS, TOSS and SNOT-20 in all three groups dropped significantly, and statistically different from those before treatment (all P 0.05); after 4-week treatment, the score in group A was higher than that in group B and group C, and showed statistical significant (both P 0.05). Conclusion: All three protocols are effective for allergic rhinitis. With the increase of treatment frequency, the therapeutic efficacy with a treatment frequency of twice a week and three times a week is superior to that of once a week. Frequency of three times a week has a better long-term effect than once and twice a week, together with the least fluctuation of symptoms.

AIM: To evaluate the efficacy of recombinant human nerve growth factor-loaded amniotic membrane (rhNGF-AM) on corneal epithelial and nerve regeneration in rabbit model. METHODS: Freshly prepared human amniotic membrane (AM) were immersed into PBS buffer containing 100 or 500 μg/mL rhNGF for 15, 30, and 60min at 4℃. The in vitro release kinetics of rhNGF was measured with ELISA. For in vivo evaluation, the AM were immersed with 500 μg/mL rhNGF for 30min. Fifty-seven rabbits were selected to establish corneal epithelial defect model. In addition to the 19 rabbits in control group, 38 rabbits received AM transplantation with or without rhNGF after the removal of central epithelium. Corneal epithelial defect area, sub-epithelial nerve fiber density, corneal sensitivity, rhNGF contents in resident AM and corneas were measured after the surgery. RESULTS: rhNGF was sustained release from the AM within 14d in vitro, with the positive correlation with initial immersion concentration. The immersion of AM in 500 μg/mL rhNGF for 30min achieved the most stable release within 14d. After transplantation in rabbit cornea, a high concentration of rhNGF in resident rhNGF-AM and cornea was maintained within 8d. Corneal epithelial healing, nerve fiber regeneration and the recovery of corneal sensitivity were significantly accelerated after the rhNGF-AM transplantation when compared to simple AM transplantation (all P

Oryza longistaminata is an African wild rice species that possesses special traits for breeding applications. Self-incompatibility is the main cause of sterility in O. longistaminata, but here we demonstrated that its pollen vitality are normal. Lipid and carbohydrate metabolism were active throughout pollen development. In this study, we used I2-KI staining and TTC staining to investigate pollen viability. Aniline-blue-stained semithin sections were used to investigate important stages of pollen development. Tandem mass tags (TMT)-based quantitative analysis was used to investigate the profiles of proteins related to lipid and carbohydrate metabolism in 4-, 6-, and 8.5-mm O. longistaminata spikelets before flowering. Pollen was found to germinate normally in vitro and in vivo. We documented cytological changes throughout important stages of anther development, including changes in reproductive cells as they formed mature pollen grains through meiosis and mitosis. A total of 31,987 RNA transcripts and 8,753 proteins were identified, and 6,842 of the proteins could be quantified. RNA-seq and proteome association analysis indicated that fatty acids were converted to sucrose after the 6-mm spikelet stage, based on the abundance of most key enzymes of the glyoxylate cycle and gluconeogenesis. The abundance of proteins involved in pollen energy metabolism was further confirmed by combining quantitative real-time PCR with parallel reaction monitoring (PRM) analyses. In conclusion, our study provides novel insights into the pollen viability of O. longistaminata at the proteome level, which can be used to improve the efficiency of male parent pollination in hybrid rice breeding applications.

Background Neutrophilic asthmatics (NA) have less response to inhaled corticosteroids. We aimed to find out the predictor of treatment response in NA. Methods Asthmatics (n = 115) and healthy controls (n = 28) underwent clinical assessment during 6-month follow-up with standardized therapy. Asthmatics were categorized by sputum differential cell count. The mRNA expressions were measured by RT-qPCR for sputum cytokines (IFN-γ, IL-1β, IL-27, FOXP3, IL-17A, and IL-5). The protein of IL-1β in sputum supernatant was detected by ELISA. Reticular basement membranes (RBM) were measured in the biopsy samples. The role and signaling pathways of IL-1β mediating the epithelial-mesenchymal transition (EMT) process were explored through A549 cells. Results NA had increased baseline sputum cell IL-1β expression compared to eosinophilic asthmatics (EA). After follow-up, NA had less improvement in FEV1 compared to EA. For all asthmatics, sputum IL-1β mRNA was positively correlated with protein expression. Sputum IL-1β mRNA and protein levels were negatively correlated to FEV1 improvement. After subgrouping, the correlation between IL-1β mRNA and FEV1 improvement was significant in NA but not in EA. Thickness of RBM in asthmatics was greater than that of healthy controls and positively correlated with neutrophil percentage in bronchoalveolar lavage fluid. In vitro experiments, the process of IL-1β augmenting TGF-β1-induced EMT cannot be abrogated by glucocorticoid or montelukast sodium, but can be reversed by MAPK inhibitors. Conclusions IL-1β level in baseline sputum predicts the poor lung function improvement in NA. The potential mechanism may be related to IL-1β augmenting TGF-β1-induced steroid-resistant EMT through MAPK signaling pathways. Trial registration: This study was approved by the Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (IRB ID: 20150406).

Interleukin‐6 (IL‐6) via trans‐signaling pathway plays a role in modifying muscle sensory nerve‐exaggerated exercise pressor reflex in rats with ligated femoral arteries, but the underlying mechanisms are poorly understood. It is known that voltage‐gated potassium channel subfamily member Kv4 channels contribute to the excitabilities of sensory neurons and neuronal signaling transduction. Thus, in this study, we determined that 1) IL‐6 regulates the exaggerated exercise pressor reflex in rats with peripheral artery disease (PAD) induced by femoral artery ligation and 2) Kv4 channels in muscle dorsal root ganglion (DRG) neurons are engaged in the role played by IL‐6 trans‐signaling pathway. We found that the protein levels of IL‐6 and its receptor IL‐6R expression were increased in the DRGs of PAD rats with 3‐day of femoral artery occlusion. Inhibition of muscle afferents’ IL‐6 trans‐signaling pathway (gp130) by intra‐arterial administration of SC144, a gp130 inhibitor, into the hindlimb muscles of PAD rats alleviated blood pressure response to static muscle contraction. On the other hand, we found that 3‐day femoral occlusion decreased amplitude of Kv4 currents in rat muscle DRG neurons. The homo IL‐6/IL‐6Rα fusion protein (H. IL‐6/6Rα), but not IL‐6 alone significantly inhibited Kv4 currents in muscle DRG neurons; and the effect of H. IL‐6/6Rα was largely reverted by SC144. In conclusion, our data suggest that via trans‐signaling pathway upregulated IL‐6 in muscle afferent nerves by ischemic hindlimb muscles inhibits the activity of Kv4 channels and thus likely leads to adjustments of the exercise pressor reflex in PAD., Interleukin‐6 (IL‐6) regulates the exaggerated exercise pressor reflex in rats with peripheral artery disease (PAD) induced by femoral artery ligation. Kv4 channels in muscle dorsal root ganglion (DRG) neurons are engaged in the role played by IL‐6 trans‐signaling pathway.

Background Idiopathic pulmonary hemosiderosis (IPH) encompasses a rare and agnogenic group of diffuse alveolar capillary hemorrhagic diseases. Corticosteroid treatment is the globally preferred therapeutic strategy for IPH; however, it can cause immunodeficiency. Nocardia infection often occurs in immunocompromised patients and primarily involves the pleura and lungs. Herein, we describe a case of pediatric pulmonary Nocardia infection after the corticosteroid treatment of IPH. Case presentation A 7-year-old girl presented with chief complaints of pale complexion persisting for 1 year and a cough for 20 days. Abundant hemosiderin-laden macrophages were detected in the gastric juice, which supported the diagnosis of IPH. Uninterrupted doses of corticosteroids were administered during the last hospitalization. After nearly 2 months of corticosteroids therapy, the patient began to cough and produce a purulent sputum. Next-generation sequencing of the bronchoalveolar lavage fluid revealed Nocardia abscessus (N. abscessus) DNA. Linezolid was administered with good response, and the patient was discharged after 18 days of hospitalization. Her symptoms and pulmonary lesions had recovered, and the IPH appeared to be well-controlled with low dose of corticosteroids in follow-up. Conclusions Nocardia infection should be considered in the differential diagnoses for IPH patients receiving corticosteroid therapy, especially in patients with poor response to conventional empirical antibiotic therapy. Next-generation sequencing of bronchoalveolar lavage fluid may be used to quickly identify the Nocardia. Sulfonamides or linezolid are effective for pediatric pulmonary Nocardia infection.

Microecology is an emerging discipline in recent years. The female reproductive tract is an important microecological region, and its microecological environment can directly affect women’s cervical health. This meta-analysis aimed to analyze the effects of vaginal microecology on Human papillomavirus (HPV) infection and cervical intraepithelial neoplasia (CIN). PubMed and Web of Science were systematically searched for eligible publications from January 2000 to December 2017. Articles were selected on the basis of specific inclusion and exclusion criteria. The design and quality of all studies were evaluated using the Newcastle-Ottawa Scale (NOS). Odds ratios (ORs) with a 95% confidence interval (95% CI) were calculated. Thirteen eligible studies were selected to evaluate the association of vaginal microecology with HPV infection and CIN. The factors related to HPV infection were bacterial vaginosis (BV) (OR 2.57, 95% CI 1.78–3.71, PCandida albicans (VVC) (OR 0.63, 95% CI 0.49–0.82, P P P P

Large porous particles (LPPs) are well-known vehicles for drug delivery to the lungs. However, it remains uncertain whether or to which extent the in vitro drug release behavior of LPPs can be predictive of their in vivo performance (e.g., systemic exposure and therapeutic efficacy). With regard to this, three budesonide-loaded LPP formulations with identical composition but distinct in vitro drug release profiles were studied in vivo for their pharmacokinetic and pharmacodynamic behavior after delivery to rat lung, and finally, an in vitro/in vivo correlation (IVIVC) was established. All formulations reduced approximately 75% of the uptake by RAW264.7 macrophages compared with budesonide/lactose physical mixture and showed a drug release-dependent retention behavior in the lungs of rats. Likewise, the highest budesonide plasma concentration was measured for the formulation revealing the fastest in vitro drug release. After deconvolution of the plasma concentration/time profiles, the calculated in vivo drug release data were successfully utilized for a point-to-point IVIVC with the in vitro release profiles and the predictability of the developed IVIVC was acceptable. Finally, effective therapy was observed in an allergic asthma rat model for the sustained drug release formulations. Overall, the obtained in vitro results correlate well with the systemic drug exposure and the therapeutic performance of the investigated lung-delivered formulations, which can provide an experimental basis for IVIVC development in the pulmonary-controlled delivery system. STATEMENT OF SIGNIFICANCE: Large porous particles (LPPs) are well-known vehicles for drug delivery to the lungs. However, it remains uncertain whether or to which extent the in vitro drug release behavior of LPPs can be predicted by their in vivo performance (e.g., systemic exposure and therapeutic efficacy). With regard to this, three budesonide-loaded PLGA-based LPP formulations with identical composition but distinct in vitro drug release profiles were studied in vivo for their pharmacokinetic and pharmacodynamic behavior, and finally, an in vitro/in vivo correlation (IVIVC) was established. It was demonstrated that the influence of the in vitro drug release profile was obvious during lung retention, systemic exposure, and therapeutic efficacy measurements. An IVIVC (Level A) was successfully established for the budesonide-loaded LPPs delivered to the airspace of rats for the first time. Taken together, the present work will clearly support research and development activities in the field of controlled drug delivery to the lungs.

Acute respiratory distress syndrome (ARDS) is a uniform progression of overwhelming inflammation in lung tissue with extensive infiltration of inflammatory cells. Neutrophil apoptosis is thought to be a significant process in the control of the resolution phase of inflammation. It has been proved that 5-Aza-2′-deoxycytidine (Aza) can inhibit cancer by activating death-associated protein kinase 1 (DAPK1) to promote apoptosis. However, the effect of DAPK1 on neutrophil apoptosis is unclear, and research on the role of Aza in inflammation is lacking. Here, we investigated whether Aza can regulate DAPK1 expression to influence the fate of neutrophils in ARDS. In vitro, we stimulated neutrophil-like HL-60 (dHL-60) cells with different concentrations of Aza for different durations and used RNA interference to up- or downregulate DAPK1 expression. We observed that culturing dHL-60 cells with Aza increased apoptosis by inhibiting NF-κB activation to modulate the expression of Bcl-2 family proteins, which was closely related to the levels of DAPK1. In vivo, ARDS was evoked by intratracheal instillation of lipopolysaccharide (LPS; 3 mg/kg). One hour after LPS administration, mice were treated with Aza (1 mg/kg, i.p.). To inhibit DAPK1 expression, mice were intraperitoneally injected with a DAPK1 inhibitor. Aza treatment accelerated inflammatory resolution in LPS-induced ARDS by suppressing pulmonary edema, alleviating lung injury and decreasing the infiltration of inflammatory cells in bronchoalveolar lavage fluid (BALF). Moreover, Aza reduced the production of proinflammatory cytokines. However, administration of the DAPK1 inhibitor attenuated the protective effects of Aza. Similarly, the proapoptotic function of Aza was prevented when DAPK1 was inhibited either in vivo or in vitro. In summary, Aza promotes neutrophil apoptosis by activating DAPK1 to accelerate inflammatory resolution in LPS-induced ARDS. This study provides the first evidence that Aza prevents LPS-induced neutrophil survival by modulating DAPK1 expression. This study demonstrates a novel mechanism in neutrophil apoptosis. In vitro, 5-Aza-2′-deoxycytidine (Aza) promotes apoptosis by enhancing death-associated protein kinase 1 (DAPK1) expression and activity. In vivo, Aza treatment accelerates inflammatory resolution in lipopolysaccharide-induced acute respiratory distress syndrome by upregulating DAPK1 expression, resulting in apoptosis of neutrophils.

Mechanical ventilation-induced pulmonary fibrosis plays an important role in the high mortality rate of acute respiratory distress syndrome (ARDS). Resolvin D1 (RvD1) displays potent proresolving activities. Epithelial-mesenchymal transition (EMT) has been proved to be an important pathological feature of lung fibrosis. This study aimed to investigate whether RvD1 can attenuate mechanical ventilation-induced lung fibrosis. Human lung epithelial (BEAS-2B) cells were pretreated with RvD1 for 30 min and exposed to acid for 10 min before being subjected to mechanical stretch for 48 h. C57BL/6 mice were subjected to intratracheal acid aspiration followed by mechanical ventilation 24 h later (peak inspiratory pressure 22 cmH2O, positive end-expiratory pressure 2 cmH2O, and respiratory rate 120 breaths/min for 2 h). RvD1 was injected into mice for 5 consecutive days after mechanical ventilation. Treatment with RvD1 significantly inhibited mechanical stretch-induced mesenchymal markers (vimentin and α-smooth muscle actin) and stimulated epithelial markers (E-cadherin). Tert-butyloxycarbonyl 2 (BOC-2), a lipoxin A4 receptor/formyl peptide receptor 2 (ALX/FPR2) antagonist, is known to inhibit ALX/FPR2 function. BOC-2 could reverse the beneficial effects of RvD1. The antifibrotic effect of RvD1 was associated with the suppression of Smad2/3 phosphorylation. This study demonstrated that mechanical stretch could induce EMT and pulmonary fibrosis and that treatment with RvD1 could attenuate mechanical ventilation-induced lung fibrosis, thus highlighting RvD1 as an effective therapeutic agent against pulmonary fibrosis associated with mechanical ventilation.

BACKGROUND Thyroid cancer is a type of endocrine cancers with rapidly increased incidence. Recent studies have indicated long non-coding RNAs (lncRNAs) played crucial roles in thyroid cancer tumorigenesis and progression. However, the roles of most lncRNAs in thyroid cancer were still unclear. MATERIAL AND METHODS We used TCGA (The Cancer Genome Atlas), GSE50901, GSE29265, and GSE33630 datasets to analyze the expression pattern of ZFAS1 (ZNFX1 antisense RNA 1). The correlation between ZFAS1 and clinicopathological features in thyroid cancer was analyzed. Cell proliferation and cell cycle assays were used to validate the roles of ZFAS1 in thyroid cancer cell lines. DAVID (the database for annotation, visualization and integrated discover) system was used to perform GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis. The starBase datasets and Cytoscape was used to perform ceRNA (competitive endogenous RNA) network. RESULTS We demonstrated ZFAS1 was highly expressed in thyroid cancer compared to normal samples. Moreover, upregulation of ZFAS1 was positively correlated with clinicopathological features and poor prognosis in thyroid cancer. Functional validation showed knockdown of ZFAS1 suppressed cell proliferation and cell cycle in thyroid cancer cells. Bioinformatics analysis showed ZFAS1 was associated with translation, rRNA processing, intra-Golgi vesicle-mediated transport, ribosome, and ubiquitin-mediated proteolysis. CONCLUSIONS Our study suggested ZFAS1 could serve as a biomarker for thyroid cancer.

Gastric cancer (GC) is the fourth largest cancer in the world, with a 5-year survival rate of

Background Cholangiocarcinoma (CCA) represents a devastating malignancy characterized by high mortality, and notoriously problematic to diagnose. Recently, microRNAs (miRs) have been intensively investigated due to their potential usefulness from a tumor treatment perspective. Aims The current study was aimed to investigate whether miR-494 influences epithelial-mesenchymal transition (EMT), tumor growth and metastasis of CCA. Methods The regulatory miRNAs of WDHD1 in CCA expression chip were predicted, followed by determination of the miR-494 and WDHD1 expression in normal cholangiocyte tissues and CCA tissues. The related protein levels were determined. CCA cell migration, invasion, viability, and cell cycle distribution and the dosage-dependent effect of miR-494 on CCA cell growth were subsequently detected. Finally, tumorigenicity and lymph node metastasis (LNM) were measured. Results Initially, miR-194 affected the CCA development via negatively regulating WDHD1 and miR-494 which were downregulated while WDHD1 was upregulated in CCA. In addition, miR-494 overexpression elevated E-cadherin expression while decreased expressions of WDHD1, N-cadherin, Vimentin, Snail, Twist and MMP-9. Finally, overexpressed miR-494 was observed to suppress EMT, cell viability, migration, invasion, arrest cell cycle progression, tumor formation, and LNM while accelerating cell apoptosis in vivo. Conclusion This study indicated that miR-494 overexpression suppresses EMT, tumor formation and LNM while promoting CCA cell apoptosis through inhibiting WDHD1 in CCA.