Progressive functional deterioration in the cochlea is associated with age-related hearing loss (ARHL). However, the cellular and molecular basis underlying cochlear aging remains largely unknown. Here, we established a dynamic single-cell transcriptomic landscape of mouse cochlear aging, in which we characterized aging-associated transcriptomic changes in 27 different cochlear cell types across five different time points. Overall, our analysis pinpoints loss of proteostasis and elevated apoptosis as the hallmark features of cochlear aging, highlights unexpected age-related transcriptional fluctuations in intermediate cells localized in the stria vascularis (SV) and demonstrates that upregulation of endoplasmic reticulum (ER) chaperon protein HSP90AA1 mitigates ER stress-induced damages associated with aging. Our work suggests that targeting unfolded protein response pathways may help alleviate aging-related SV atrophy and hence delay the progression of ARHL.
Mice ; Animals ; Transcriptome ; Aging/metabolism* ; Cochlea ; Stria Vascularis ; Presbycusis

Objective: To investigate the association between the urinary arsenic level and serum total testosterone in Chinese men aged 18 to 79 years. Methods: A total of 5 048 male participants aged 18 to 79 years were recruited from the China National Human Biomonitoring (CNHBM) from 2017 to 2018. Questionnaires and physical examinations were used to collect information on demographic characteristics, lifestyle, food intake frequency and health status. Venous blood and urine samples were collected to detect the level of serum total testosterone, urinary arsenic and urinary creatinine. Participants were divided into three groups (low, middle, and high) based on the tertiles of creatinine-adjusted urinary arsenic concentration. Weighted multiple linear regression was fitted to analyze the association of urinary arsenic with serum total testosterone. Results: The weighted average age of 5 048 Chinese men was (46.72±0.40) years. Geometric mean concentration (95%CI) of urinary arsenic, creatinine-adjusted urinary arsenic and serum testosterone was 22.46 (20.08, 25.12) μg/L, 19.36 (16.92, 22.15) μg/g·Cr and 18.13 (17.42, 18.85) nmol/L, respectively. After controlling for covariates, compared with the low-level urinary arsenic group, the testosterone level of the participants in the middle-level group and the high-level group decreased gradually. The percentile ratio (95%CI) was -5.17% (-13.14%, 3.54%) and -10.33% (-15.68%, -4.63). The subgroup analysis showed that the association between the urinary arsenic level and testosterone level was more obvious in the group with BMI<24 kg/m² group (P_interaction=0.023). Conclusion: There is a negative association between the urinary arsenic level and serum total testosterone in Chinese men aged 18 to 79 years.
Humans ; Male ; Arsenic/urine* ; Creatinine ; East Asian People ; Testosterone/blood* ; Urinalysis ; Adolescent ; Young Adult ; Adult ; Middle Aged ; Aged

OBJECTIVE: The study aimed to analyze the applicability of the World Health Organization's exclusionary guidelines for Urinary creatinine (Ucr) in the general Chinese population, and to identify Ucr related factors. METHODS: We conduct a cross-sectional study using baseline data from 21,167 participants in the China National Human Biomonitoring Program. Mixed linear models and restricted cubic splines (RCS) were used to analyze the associations between explanatory variables and Ucr concentration. RESULTS: The geometric mean and median concentrations of Ucr in the general Chinese population were 0.90 g/L and 1.01 g/L, respectively. And 9.36% samples were outside 0.3-3.0 g/L, including 7.83% below the lower limit and 1.53% above the upper limit. Middle age, male, obesity, smoking, higher frequency of red meat consumption and chronic kidney disease were associated significantly with higher concentrations of Ucr. Results of the RCS showed Ucr was positively and linearly associated with body mass index, inversely and linearly associated with systolic blood pressure, diastolic blood pressure, triglycerides level, and glomerular filtration rate, and were non-linearly associated with triiodothyronine. CONCLUSION The age- and gender-specific cut-off values of Ucr that determine the validity of urine samples in the general Chinese population were recommended. To avoid introducing bias into epidemiologic associations, the potential predictors of Ucr observed in the current study should be considered when using Ucr to adjust for variations in urine dilution.
Middle Aged ; Male ; Humans ; Creatinine ; Cross-Sectional Studies ; Asian People ; Glomerular Filtration Rate ; China

Objective: To evaluate the long-term outcomes, failure patterns and prognostic factors of definitive radiotherapy in patients with cervical esophageal carcinoma (CEC). Methods: We retrospectively reviewed the clinical data of 148 CEC patients who treated with definitive radiotherapy in Cancer Hospital of Chinese Academy of Medical Sciences from January 2001 to December 2017. The median radiation dose was 66 Gy (59.4-70 Gy) and 33.1% of patients received concurrent chemotherapy. The Kaplan-Meier method was used to calculate survival rates. The log rank test was used for survival comparison and univariate prognostic analysis. The Cox model was used for multivariate prognostic analysis. Results: The median follow-up time was 102.6 months. The median survival time, 2- and 5-year overall survival (OS) were 22.7 months, 49.9% and 28.3%. The median, 2- and 5-year progression-free survival were 12.6 months, 35.8% and 25.8%. The 2- and 5-year locoregional recurrence-free survival were 59.1% and 50.8%. The 2- and 5-year distant metastases-free survival were 74.6% and 65.9%. Multivariate analysis showed that EQD(2)>66 Gy was the only independent prognostic indicator for OS (P=0.040). The median survival time and 5-year OS rate significantly improved in patients who received EQD(2)>66 Gy than those who received≤66 Gy (31.2 months vs. 19.2 months, 40.1% vs. 19.1%, P=0.027). A total of 87 patients (58.8%) developed tumor progression. There were 50 (33.8%), 23 (15.5%) and 39 (26.4%) patients developed local, regional recurrence and distant metastases, respectively. Eleven patients (7.4%) underwent salvage surgery, and the laryngeal preservation rate for entire group was 93.9%. Conclusions: Definitive radiotherapy is an effective treatment for cervical esophageal carcinoma with the advantage of larynx preservation. Local recurrence is the major failure pattern. EQD(2)>66 Gy is associated with the improved overall survival.
Humans ; Retrospective Studies ; Esophageal Neoplasms/pathology* ; Carcinoma/drug therapy* ; Prognosis ; Treatment Outcome ; Chemoradiotherapy/methods* ; Radiotherapy Dosage

Objective: To investigate the role of inflammatory biomarkers in the relationship between blood lead levels and blood pressure changes. Methods: A total of 9 910 people aged 18-79 years who participated in the China National Human Biomonitoring in 2017-2018 were included in this study. A self-made questionnaire was used to collect demographic characteristics, lifestyle and other information, and the data including height, weight and blood pressure were determined through physical examination. Blood and urinary samples were collected for the detection of blood lead and cadmium levels, urinary arsenic levels, white blood cells, neutrophils, lymphocytes, and hypersensitive C-reactive protein (hs-CRP). Weighted linear regression models were used to evaluate the associations between blood lead, inflammatory biomarkers and blood pressure. Mediation analysis was performed to investigate the role of inflammation in the relationship between blood lead levels and blood pressure changes. Results: The median (Q₁, Q₃) age of all participants was 45.4 (33.8, 58.4)years, including 4 984 males accounting for 50.3%. Multivariate logistic regression model analysis showed that after adjusting for age, gender, residence area, BMI, education level, smoking and drinking status, family history of hypertension, consumption frequency of rice, vegetables, and red meat, fasting blood glucose, total cholesterol, triglycerides, blood cadmium and urinary arsenic levels, there was a positive association between blood lead levels, inflammatory biomarkers and blood pressure (P<0.05). Each 2.71 μg/L (log-transformed) increase of the lead was associated with a 2.05 (95%CI: 0.58, 3.53) mmHg elevation in systolic blood pressure (SBP), 2.24 (95%CI: 1.34, 3.14) mmHg elevation in diastolic blood pressure (DBP), 0.25 (95%CI: 0.05, 0.46) mg/L elevation in hs-CRP, 0.16 (95%CI: 0.03, 0.29)×10⁹/L elevation in white blood cells, and 0.11 (95%CI: 0.02, 0.21)×10⁹/L elevation in lymphocytes, respectively. Mediation analysis showed that the levels of hs-CRP significantly mediated the association of blood lead with SBP, with a proportion about 3.88% (95%CI: 0.45%, 7.32%). The analysis also found that the levels of hs-CRP and neutrophils significantly mediated the association of blood lead with SBP, with a proportion about 4.10% (95%CI: 1.11%, 7.10%) and 2.42% (95%CI: 0.07%, 4.76%), respectively. Conclusion: This study suggests that inflammatory biomarkers could significantly mediate the association of blood lead levels and blood pressure changes.
Adult ; Male ; Humans ; Blood Pressure/physiology* ; C-Reactive Protein/analysis* ; Lead ; Arsenic/analysis* ; Cadmium ; Biomarkers ; Hypertension/epidemiology* ; China/epidemiology*

OBJECTIVES: To study the consistency between nasopharyngeal aspirates (NPA) and bronchoalveolar lavage fluid (BALF) in pathogen detection in children with pneumonia METHODS: A retrospective analysis was performed on the data of pathogens detected in 533 children with pneumonia from February 2017 to March 2020. The paired McNemar's test was used to compare the difference in pathogen detection between NPA and BALF groups. The RESULTS: NPA had a sensitivity of 28%, a specificity of 74%, a positive predictive value of 14%, and a negative predictive value of 91% in detecting bacteria, and a CONCLUSIONS There is poor consistency between NPA and BALF in the detection of bacteria and viruses, and clinicians should be cautious in diagnosing lower respiratory tract infection based on bacteria or viruses detected in NPA. There is moderate consistency between NPA and BALF in the detection of
Bronchoalveolar Lavage Fluid ; Child ; Humans ; Mycoplasma pneumoniae ; Pneumonia ; Pneumonia, Mycoplasma ; Respiratory Tract Infections ; Retrospective Studies

Objective:Comparing with the external fixator technique, investigate the clinical effect of fixator-assisted plating technique for treatment distal femoral valgus deformity in adolescent.Methods:A retrospective analysis of the relevant data of 22 patients (25 limbs) with acute correction of distal femoral valgus deformities from July 2015 to June 2019, according to the difference of the final fixation, they were divided two groups. The fixator-assisted plating group, including 8 patients (9 limbs), 5 boys and 3 girls, 5 left and 2 right, 1 bilateral, the physis were closed in 4 cases and opened in 4 cases, age 14.04±1.99 years (11.7-18 years). The external fixator group, including 14 patients (16 limbs), 6 boys and 8 girls, 8 left and 4 right, 2 bilateral, the physis were closed in 9 cases and opened in 5 cases, age 13.33±1.88 years (10.1-16.5 years). Measuring the mechanical axis deviation (MAD) and the mechanical lateral distal femur angle (mLDFA) in full length standing AP view X-ray of the lower limb pre and post operation. Recording the changed of limb length discrepancy (LLD) before and after surgery and the knee range of motion at 6 weeks, 3 months, 6 months and the last follow up post operation. The Kolcaba comfort status scale was used to evaluate the comfort of two groups at 2 weeks, 6 weeks, 3 months, 6 months and the last follow up. Meanwhile recorded the healing time of osteotomy sites and the complications.Results:The difference in general information between the two groups was not statistically significant. The fixator-assisted plating group followed up mean 26 months (range, 12-40 months), the healing time were 4.00±0.66 months, the mLDFA mean 73.33°±4.12° before surgery and 87.89°±1.69° after surgery and there was significant difference ( t=10.582, P<0.05). The external fixator group followed up mean 36 months (range, 22-42 months), the healing time were 4.00±0.66 months, the mLDFA mean 73.31°±3.95° before surgery and 87.31°±1.54° after surgery and there was significant difference ( t=14.118, P<0.05). The MAD were in the normal range in all patients after surgery, and there were no significant difference about healing time of the osteotomy sites and postoperative mLDFA between the two groups ( t=1.514, P=0.150; t=0.845, P=0.411). Comparing with the knee function, the fixator-assisted plating group was better at 6 weeks, 3 months, 6 months after surgery but there was no difference at the last follow up. Also, the fixator-assisted plating group felt more comfortable at 2 weeks, 6 weeks, 3 months, 6 months and there was no difference at the last follow up. All the patients with external fixator have mild pin sites infection and there were no obvious complications in patients with plate. Conclusion:The fixator-assisted plating technique can accurately correct the valgus deformity with satisfactory healing of the osteotomy in distal femoral compare with the external fixator technique, but the patients feel more comfortable and the knee joint function recovers faster and no risk of pin site infection, the clinical results was satisfactory with fewer complication.

OBJECTIVE: To evaluate the safety and efficacy of allogeneic natural killer (NK) cells in the treatment of primary hepatocellular carcinoma (HCC), and to elucidate the mechanism of NK cells therapy. METHODS: Twenty-one patients with primary HCC treated with allogeneic NK cells at the Fifth Medical Center of the PLA General Hospital were followed up for 1 year. Peripheral blood mononuclear cells (PBMCs) were isolated from patient-related donors and cultured in vitro for 15 days and infused to the patients in two consecutive days. Clinical data and laboratory data were collected and analyzed, including survival, clinical features, imaging changes, hematology, immunology, and biochemical indicators to evaluate the safety and efficacy of allogeneic NK cell therapy. The changes of peripheral blood lymphocyte subsets after treatment were also analyzed to explore the possible anti-tumor mechanisms. RESULTS: (1) Of the 21 patients with primary HCC, 11 patients were treated once, 5 patients were treated twice, and 5 patients were treated 3 times. After allogeneic NK cells infusion, 10 patients had fever, 1 patient had slight hepatalgia and 1 patient had slight headache, no other adverse events occurred including acute and chronic graft-versus-host disease (GVHD). They resolved spontaneously within 8 hours without other treatment. (2) The total disease control rate was 76.2% during one-year follow-up. Among them, the patients with Barcelona clinic liver cancer (BCLC) stage A had a disease control rate of 100%, stable disease (SD) in 10 cases; BCLC stage B patients had a disease control rate of 60%, partial response (PR) in 1 case, and SD 2 in cases; BCLC stage C patients had a disease control rate of 50%, complete response (CR) in 1 case, and 2 cases of PR. (3) The frequencies of NK cells and CD8+ T cells in peripheral blood were significantly lower than that before at 24 hours after treatment, and the frequencies of CD4+ T cells and CD4/CD8 were significantly higher than the baseline. CONCLUSION Allogeneic NK cells have good safety and efficacy in the treatment of primary HCC. The anti-tumor effect of the allogeneic NK cells may play an important role in the activation of the patient's natural immune system and delay disease progression, suggesting that allogeneic NK cells combined with sorafenib may be a very effective treatment for advanced HCC, and further large-sample multicenter randomized controlled clinical trials are needed to validate this result.
Carcinoma, Hepatocellular ; Graft vs Host Disease ; Humans ; Killer Cells, Natural ; Leukocytes, Mononuclear ; Liver Neoplasms

The aim of this paper was to screen the active targets of Schizonepetae Herba and Saposhnikoviae Radix in the treatment of ulcerative colitis by means of network pharmacology,and to investigate their mechanism of action. The effective components of Schizonepetae Herba and Saposhnikoviae Radix were screened out by traditional Chinese medicine systematic pharmacological( TCMSP)database,with oral bioavilability( OB) ≥30% and drug-like( DL) ≥18% selected as the thresholds. Target PPI network was built between the main components and their corresponding targets. One hundred and eighty-two human genes corresponding to the medicine target sites were obtained from Uniprot database; 3 874 genes corresponding to ulcerative colitis were obtained from Genecard database.A total of 115 intersection genes were screened from disease genes and medicine genes,and the PPI interaction analysis was conducted by using String tool. Disease-target PPI network was drawn by using Cytoscape software,and component-target-disease network was constructed. One hundred and eight nodes and 1 882 connections were found,and then Cytoscape software was used to merge the networks and filter the core network for gene GO function analysis and KEGG pathway enrichment analysis. The mechanism of Schizonepetae Herba and Saposhnikoviae Radix was then verified by animal experiment. Gene GO functional analysis suggested that biological process,molecular functions and cell components were involved,and it was found that ulcerative colitis might be related to transcription factor activity,and cytokine receptor binding,etc. Gene KEGG pathway enrichment analysis showed that the mechanism of ulcerative colitis might be associated with TNF and Toll-like receptors( TLRs) signaling pathway-mediated cytoinflammatory factors interleukin-1( IL-1) and interleukin-6( IL6). The possible mechanism of the effective components of Schizonepetae Herba and Saposhnikoviae Radix in treating ulcerative colitis might be related to intervening the cytokine receptor binding of TNF and TLRs signaling pathways,reducing the transcription of nuclear factor-kappaB( NF-κB),and inhibiting the secretion of intestinal inflammatory factors IL-1 and IL-6.
Animals ; Apiaceae/chemistry* ; Colitis, Ulcerative/drug therapy* ; Databases, Genetic ; Drugs, Chinese Herbal/therapeutic use* ; Humans ; Interleukins/metabolism* ; Lamiaceae/chemistry* ; Medicine, Chinese Traditional ; Phytotherapy ; Plant Roots/chemistry* ; Protein Interaction Mapping ; Signal Transduction ; Software ; Toll-Like Receptors/metabolism*

OBJECTIVETo investigate the role of MT-ND1 m.3635G>A mutation in the pathogenesis of Leber's hereditary optic neuropathy (LHON).

METHODSBiochemical characteristics including the activity of complex Ⅰ, ATP production and oxygen consumption rate among lymphoblastoid cell lines derived from 3 carriers, 3 affected matrilineal relatives of the families and 3 controls were compared.

RESULTSComparison of mitochondrial functions in lymphoblastoid cell lines of the carriers, patients and controls showed a 51.0% decrease in the activity of complex Ⅰ in patients compared with controls (P<0.05). The m.3635G>A mutation has resulted in decreased efficiency of ATP synthesis (P<0.05). Comparison of oxygen consumption rate showed that the basal OCR (P<0.05), ATP-linked OCR (P<0.05) and the maximum OCR (P<0.05) have all reduced to some extent compared with the controls.

CONCLUSIONThese results showed that m.3635G>A, as a LHON-associated mutation, can lead to mitochondrial dysfunction.

Adenosine Triphosphate ; genetics ; Asian Continental Ancestry Group ; genetics ; Female ; Humans ; Male ; Mitochondria ; genetics ; Mutation ; genetics ; NADH Dehydrogenase ; genetics ; Optic Atrophy, Hereditary, Leber ; genetics ; Pedigree