Polar body genome transfer for preventing the transmission of inherited mitochondrial diseases.

Inherited mtDNA diseases transmit maternally and cause severe phenotypes. Currently, there is no effective therapy or genetic screens for these diseases; however, nuclear genome transfer between patients' and healthy eggs to replace mutant mtDNAs holds promises. Considering that a polar body contains few mitochondria and shares the same genomic material as an oocyte, we perform polar body transfer to prevent the transmission of mtDNA variants. We compare the effects of different types of germline genome transfer, including spindle-chromosome transfer, pronuclear transfer, and first and second polar body transfer, in mice. Reconstructed embryos support normal fertilization and produce live offspring. Importantly, genetic analysis confirms that the F1 generation from polar body transfer possesses minimal donor mtDNA carryover compared to the F1 generation from other procedures. Moreover, the mtDNA genotype remains stable in F2 progeny after polar body transfer. Our preclinical model demonstrates polar body transfer has great potential to prevent inherited mtDNA diseases.

Mas receptor activation facilitates innate hematoma resolution and neurological recovery after hemorrhagic stroke in mice.

BACKGROUND: Intracerebral hemorrhage (ICH) is a devastating neurological disease causing severe sensorimotor dysfunction and cognitive decline, yet there is no effective treatment strategy to alleviate outcomes of these patients. The Mas axis-mediated neuroprotection is involved in the pathology of various neurological diseases, however, the role of the Mas receptor in the setting of ICH remains to be elucidated. METHODS: C57BL/6 mice were used to establish the ICH model by injection of collagenase into mice striatum. The Mas receptor agonist AVE0991 was administered intranasally (0.9 mg/kg) after ICH. Using a combination of behavioral tests, Western blots, immunofluorescence staining, hematoma volume, brain edema, quantitative-PCR, TUNEL staining, Fluoro-Jade C staining, Nissl staining, and pharmacological methods, we examined the impact of intranasal application of AVE0991 on hematoma absorption and neurological outcomes following ICH and investigated the underlying mechanism. RESULTS: Mas receptor was found to be significantly expressed in activated microglia/macrophages, and the peak expression of Mas receptor in microglia/macrophages was observed at approximately 3-5 days, followed by a subsequent decline. Activation of Mas by AVE0991 post-treatment promoted hematoma absorption, reduced brain edema, and improved both short- and long-term neurological functions in ICH mice. Moreover, AVE0991 treatment effectively attenuated neuronal apoptosis, inhibited neutrophil infiltration, and reduced the release of inflammatory cytokines in perihematomal areas after ICH. Mechanistically, AVE0991 post-treatment significantly promoted the transformation of microglia/macrophages towards an anti-inflammatory, phagocytic, and reparative phenotype, and this functional phenotypic transition of microglia/macrophages by Mas activation was abolished by both Mas inhibitor A779 and Nrf2 inhibitor ML385. Furthermore, hematoma clearance and neuroprotective effects of AVE0991 treatment were reversed after microglia depletion in ICH. CONCLUSIONS: Mas activation can promote hematoma absorption, ameliorate neurological deficits, alleviate neuron apoptosis, reduced neuroinflammation, and regulate the function and phenotype of microglia/macrophages via Akt/Nrf2 signaling pathway after ICH. Thus, intranasal application of Mas agonist ACE0991 may provide promising strategy for clinical treatment of ICH patients.

Evaluation of the FPMC respiratory panel for detection of respiratory tract pathogens in nasopharyngeal swab and sputum specimens.

OBJECTIVES: The performance of the new Respiratory Pathogen panel (fluorescent probe melting curve, FPMC) for the qualitative detection of 12 organisms (chlamydia pneumoniae, mycoplasma pneumoniae, adenovirus, influenza A virus, influenza B virus, parainfluenza virus, rhinovirus, etc.) was assessed. METHODS: Prospectively collected nasopharyngeal swab (NPS) and sputum specimens (n = 635) were detected by using the FPMC panel, with the Sanger sequencing method as the comparative method. RESULTS: The overall percent concordance between the FPMC analysis method and the Sanger sequencing method was 100% and 99.66% for NPS and sputum specimens, respectively. The FPMC testified an overall positive percent concordance of 100% for both NPS and sputum specimens. The FPMC analysis method also testified an overall negative percent concordance of 100% and 99.38% for NPS and sputum specimens, respectively. CONCLUSIONS: The FPMC analysis method is a stable and accurate assay for rapid, comprehensive detecting for respiratory pathogens.

Internally Formed Preferences for Options only Influence Initial Decisions in Gambling Tasks, while the Gambling Outcomes do not Alter these Preferences.

All humans must engage in decision-making. Decision-making processes can be broadly classified into internally guided decision-making (IDM), which is determined by individuals' internal value criteria, such as preference, or externally guided decision-making (EDM), which is determined by environmental external value criteria, such as monetary rewards. However, real-life decisions are never made simply using one kind of decision-making, and the relationship between IDM and EDM remains unclear. This study had individuals perform gambling tasks requiring the EDM using stimuli that formed preferences through the preference judgment task as the IDM. Computational model analysis revealed that strong preferences in the IDM affected initial choice behavior in the EDM. Moreover, through the analysis of the subjective preference evaluation after the gambling tasks, we found that even when stimuli that were preferred in the IDM were perceived as less valuable in the EDM, the preference for IDM was maintained after EDM. These results indicate that although internal criteria, such as preferences, influence EDM, the results show that internal and external criteria differ.

Comparison of endoscopic resection therapies for rectal neuroendocrine tumors.

AIMS: This study was to evaluate and compare the efficacy and safety of endoscopic mucosal resection (EMR), clip-and-snare assisted endoscopic mucosal resection (CS-EMR), and endoscopic submucosal dissection (ESD) for the endoscopic resection of rectal NETs. MATERIAL AND METHODS: A retrospective analysis was performed on 47 patients with rectal NETs who underwent endoscopic treatment in The Second Affiliated Hospital of Soochow University. Manifestations of clinic pathological characteristics, complications, procedure time and hospitalization costs were studied. RESULTS: The complete resection rates with CS-EMR and ESD were significantly higher than those with EMR (CS-EMR vs. EMR, p = 0.038; ESD vs. EMR, p = 0.04), but no significant difference was found between the CS-EMR and ESD groups (p = 0.383). The lateral margin was less distant in the CS-EMR group than in the ESD group and there was no difference with regard to vertical margin (lateral margin distance, 1500 ± 3125 vs.3000 ± 3000 µm; vertical margin distance, 400 ± 275 vs.500 ± 500 µm). Compared to ESD, CS-EMR required less operation time (p < 0.01) and money (p < 0.01) and reduced the length of hospital stays (p < 0.01). CONCLUSIONS: The CS-EMR technique is more effective and efficient than EMR for small rectal NETs. In addition, CS-EMR reduces procedure time, duration of post-procedure hospitalization and decreases patients' cost compared to ESD while ensuring sufficient vertical margin distances.

Paradoxical Roles of Antioxidant Enzymes: Basic Mechanisms and Health Implications.

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated from aerobic metabolism, as a result of accidental electron leakage as well as regulated enzymatic processes. Because ROS/RNS can induce oxidative injury and act in redox signaling, enzymes metabolizing them will inherently promote either health or disease, depending on the physiological context. It is thus misleading to consider conventionally called antioxidant enzymes to be largely, if not exclusively, health protective. Because such a notion is nonetheless common, we herein attempt to rationalize why this simplistic view should be avoided. First we give an updated summary of physiological phenotypes triggered in mouse models of overexpression or knockout of major antioxidant enzymes. Subsequently, we focus on a series of striking cases that demonstrate "paradoxical" outcomes, i.e., increased fitness upon deletion of antioxidant enzymes or disease triggered by their overexpression. We elaborate mechanisms by which these phenotypes are mediated via chemical, biological, and metabolic interactions of the antioxidant enzymes with their substrates, downstream events, and cellular context. Furthermore, we propose that novel treatments of antioxidant enzyme-related human diseases may be enabled by deliberate targeting of dual roles of the pertaining enzymes. We also discuss the potential of "antioxidant" nutrients and phytochemicals, via regulating the expression or function of antioxidant enzymes, in preventing, treating, or aggravating chronic diseases. We conclude that "paradoxical" roles of antioxidant enzymes in physiology, health, and disease derive from sophisticated molecular mechanisms of redox biology and metabolic homeostasis. Simply viewing antioxidant enzymes as always being beneficial is not only conceptually misleading but also clinically hazardous if such notions underpin medical treatment protocols based on modulation of redox pathways.

Zinc Deficiency Exacerbates Behavioral Impediments and Dopaminergic Neuron Degeneration in a Mouse Model of Parkinson Disease.

BACKGROUND: Circulating zinc (Zn) concentrations are lower than normal in patients with Parkinson disease (PD). It is unknown whether Zn deficiency increases the susceptibility to PD. OBJECTIVES: The study aimed to investigate the effect of dietary Zn deficiency on behaviors and dopaminergic neurons in a mouse model of PD and to explore potential mechanisms. METHODS: Male C57BL/6J mice aged 8-10 wk were fed Zn adequate (ZnA; 30 µg/g) or Zn deficient (ZnD; <5 µg/g) diet throughout the experiments. Six weeks later 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was injected to generate the PD model. Controls were injected with saline. Thus, 4 groups (Saline-ZnA, Saline-ZnD, MPTP-ZnA, and MPTP-ZnD) were formed. The experiment lasted 13 wk. Open field test, rotarod test, immunohistochemistry, and RNA sequencing were performed. Data were analyzed with t-test, 2-factor ANOVA, or Kruskal-Wallis test. RESULTS: Both MPTP and ZnD diet treatments led to a significant reduction in blood Zn concentrations (PMPTP = 0.012, PZn = 0.014), reduced total distance traveled (PMPTP < 0.001, PZn = 0.031), and affected the degeneration of dopaminergic neurons in the substantia nigra (PMPTP < 0.001, PZn = 0.020). In the MPTP-treated mice, the ZnD diet significantly reduced total distance traveled by 22.4% (P = 0.026), decreased latency to fall by 49.9% (P = 0.026), and reduced dopaminergic neurons by 59.3% (P = 0.002) compared with the ZnA diet. RNA sequencing analysis revealed a total of 301 differentially expressed genes (156 upregulated; 145 downregulated) in the substantia nigra of ZnD mice compared with ZnA mice. The genes were involved in a number of processes, including protein degradation, mitochondria integrity, and α-synuclein aggregation. CONCLUSIONS: Zn deficiency aggravates movement disorders in PD mice. Our results support previous clinical observations and suggest that appropriate Zn supplementation may be beneficial for PD.

Interstitial lung disease in patients treated with poly (ADP-ribose) polymerase inhibitors (PARPi): analysis of results from clinical trials and the FDA Adverse Events Reporting System database.

OBJECTIVE: To evaluate the risk of interstitial lung disease associated with poly (ADP-ribose) polymerase inhibitors (PARPi) and characterize its clinical features. METHODS: We systematically reviewed phase III randomized clinical trials of interstitial lung disease related to PARPi and calculated Peto odds ratios (ORs) with 95% confidence intervals (CIs). Pharmacovigilance studies were conducted by collecting cases of PARPi-related interstitial lung disease from the FDA Adverse Events Reporting System and assessing disproportionalities by reporting ORs and information components. RESULTS: A total of five randomized clinical trials involving 2980 patients were included. Although PARPi showed a tendency to increase the risk of interstitial lung disease compared with controls, this difference was not significant (Peto OR: 4.92; 95% CI: 0.92 to 26.35). A total of 170 cases of interstitial lung disease related to PARPi were included, with a median latency of 99 days. PARPi had a significantly increased reporting of interstitial lung disease (reporting OR: 2.86; 95% CI: 2.46 to 3.33; information component (IC): 1.49; 95% CI: 1.28 to 1.74). Our sensitivity analyses showed strong robustness of the disproportionalities between PARPi as a class, olaparib, and interstitial lung disease. Some 91.9% of patients experienced discontinuation, 51.6% achieved remission, and no deaths were reported. CONCLUSION: Our pharmacovigilance study suggested increased reporting of interstitial lung disease related to PARPi particularly olaparib.

Factors associated with balance impairments in the community-dwelling elderly in urban China.

BACKGROUND: Identification of factors relevant to balance performance impairments in the elderly population was critical for developing effective interventions and preventions. However, there have been very limited data available based on large scale studies. The present study identified factors that independently contributed to performance impairments in overall balance, domains of static balance, postural stability, and dynamic balance, and individual items. METHODS: A total of 1984 community-dwelling Chinese elderly from urban areas of Shanghai were recruited. Information on demographic characteristic, exercise, and health status were collected with a face-to-face interview. Balance performances were assessed on site by trained investigators based on the X16 balance testing scale. To identify the effectors, ordinal logistic regression analysis was applied for overall balance, static balance, postural stability, and dynamic balance. Binary logistic regression analysis was used for 16 items. RESULTS: The community-dwelling elderly residents were aged from 60 to 97 years old. With increases of age, risks of impairments in overall balance increased gradually (ORs from 1.26 to 3.20, all P < 0.01). In the elderly with overweight and obesity, there was higher proportion of balance impairments compared to the elderly with normal BMI (OR = 1.26, P < 0.001). Regular exercise every week was associated with reduced risks of balance impairments (ORs from 0.63 to 0.73, all P < 0.001). Presences with vision lesion (ORs from 1.28 to 1.59, all P < 0.001), moderate hearing impairment (OR = 1.54, P < 0.001), somesthesis dysfunction (ORs from 1.59 to 13.26, all P < 0.001), and cerebrovascular disease (OR = 1.45, P = 0.001) were related to increased risks of balance impairments. Likewise, age, exercise, vision, hearing, somesthesis, and cerebrovascular disease were significantly associated with static balance, postural stability, and dynamic balance. Both overweight and obesity and underweight were associated with higher proportions of dynamic balance impairments. Regular exercise was significantly related to reduced risks of impairments in 15 out of the 16 items. CONCLUSIONS: In the elderly, age, overweight and obesity, exercise, vision, hearing, somesthesia, and cerebrovascular disease were dominant factors associated with impairments in overall balance, domains of static balance, postural stability, and dynamic balance, and most individual items. TRIAL REGISTRATION: Not applicable.

Risk factors of immune checkpoint inhibitor-associated acute kidney injury: evidence from clinical studies and FDA pharmacovigilance database.

BACKGROUND: Several risk factors of immune checkpoint inhibitors (ICIs)-associated acute kidney injury (AKI) have been reported sporadically. To identify the risk factors of ICIs-associated AKI in a large-scale population, therefore we conducted a systematic review and a real-world retrospective study. METHODS: We search literature concerning risk factors of ICIs-associated AKI in ClinicalTrials.gov and electronic databases (PubMed, Cochrane Library, Embase) up to January 2022. Meta-analysis was performed by using odds ratios (ORs) with 95%CIs. In a separate retrospective pharmacovigilance study by extracting data from US FDA Adverse Event Reporting System (FAERS) database, disproportionality was analyzed using the reporting odds ratio (ROR). RESULTS: A total of 9 studies (5927 patients) were included in the meta-analysis. The following factors were associated with increased risk of ICIs-associated AKI, including proton pump inhibitors(PPIs) (OR = 2.07, 95%CI 1.78-2.42), angiotensin-converting enzyme inhibitors (ACEIs)/ angiotensin receptor blockers (ARBs) (OR = 1.56, 95%CI 1.24-1.95), nonsteroidal anti-inflammatory drugs (NSAIDs) (OR = 1.29, 95%CI 1.01-1.65), diuretics (OR = 2.00, 95%CI 1.38-2.89), diabetes mellitus (OR = 1.28, 95%CI 1.04-1.57), genitourinary cancer (OR = 1.46, 95%CI 1.15-1.85), combination therapy of ICIs (OR = 1.93, 95%CI 1.25-2.97) and extrarenal immune-related adverse events(irAEs) (OR = 2.51, 95%CI 1.96-3.20). Furthermore, analysis from FAERS database verified that concurrent exposures of PPIs (ROR = 2.10, 95%CI 1.91-2.31), ACEIs/ARBs (ROR = 3.25, 95%CI 2.95-3.57), NSAIDs (ROR = 3.06, 95%CI 2.81-3.32) or diuretics (ROR = 2.82, 95%CI 2.50-3.19) were observed significant signals associated with AKI in ICIs-treated patients. CONCLUSIONS: Concurrent exposures of PPIs, ACEIs/ARBs, NSAIDs or diuretics, diabetes mellitus, genitourinary cancer, combination therapy, and extrarenal irAEs seem to increase the risk of AKI in ICIs-treated patients.

Evaluation of chemotherapy and radiotherapy in the adjuvant management of uterine carcinosarcoma: a population-based analysis.

PURPOSE: To evaluate the effects of adjuvant chemotherapy (CT) and radiotherapy (RT) on the survival of uterine carcinosarcoma (UCS) patients. METHODS: We analyzed 3207 patients with uterine carcinosarcoma without distant metastasis after surgery from 2004 to 2015 by utilizing data from the Surveillance, Epidemiology, and End Results database. Generally, cancer-specific survival (CSS) and overall survival (OS) outcomes were analyzed by Kaplan-Meier and Cox proportional hazards regression models. Further subgroup survival analysis was performed for those receiving RT and chemoradiotherapy (CRT). RESULTS: In general, both univariate and multivariate analyses showed that age, race, marital status, stage, lymph node metastasis, lymphadenectomy (LND), RT, and chemotherapy (CT) were associated with improved CSS and OS (P < 0.05). Further subgroup analysis showed that CRT exhibited a survival advantage over RT or CT alone in different groups. Various RT modalities, including brachytherapy (BT), external radiotherapy (EBRT), and EBRT + BT, were correlated with improved survival for patients aged 60-69 years with stage III-IV disease and lymph node metastasis. Patients with stage I-II disease aged > 70 years seemed to gain survival benefits from brachytherapy (BT) alone. BT with or without external radiotherapy was associated with improved survival for those who did not undergo lymphadenectomy. CONCLUSION: For UCS without distant metastasis after surgery, CRT should be considered. Regarding RT, BT alone is efficient in improving survival, especially for patients with stage I-II disease aged > 70 years old. EBRT alone does not show results in survival improvement for patients who did not undergo LND and those with lymph node metastasis. However, considering the limitation of SEER database, further studies with more large sample size and strict study design are needed to confirm it.

Pulmonary tuberculosis associated with immune checkpoint inhibitors: a pharmacovigilance study.

We examined case reports of immune checkpoint inhibitors (ICIs) associated pulmonary tuberculosis (PT) using data from the Food and Drug Administration Adverse Event Reporting System database. Disproportionality analysis was performed by using the reporting OR (ROR) with relevant 95% CI. A total of 74 cases of PT related to ICIs therapy were identified. ICIs were significantly associated with over-reporting frequencies of PT (ROR=3.16, 95% CI: 2.51 to 3.98), while the signal was differed between anti-programmed death-1/ligand-1 and anti-cytotoxic T lymphocyte antigen-4 agents. Most indications were lung cancer (64.9%), the median onset age was 70 years, the median time to onset of PT was 70 days, ICIs were discontinued in most cases (85.2%).

Magnifying endoscopic findings of early-stage poorly differentiated colorectal adenocarcinoma: a case report.

BACKGROUND: Colorectal poorly differentiated adenocarcinoma is rarely founded, especially in early-stage. Endoscopic features of early poorly differentiated colorectal cancer in magnifying endoscopy and chromoendoscopy haven't been clarified. CASE PRESENTATION: A 49-year-old man was referred to our hospital for endoscopic treatment of a lateral spread tumor located in the rectum. We performed pre-resection endoscopic examination for the patient. In magnifying endoscopy with crystal violet staining, the lesion showed irregular microvessels and turned out to be poorly stained with predominantly non-structural pit pattern and a few roundish pits scattered on the surface. The histology revealed a poorly differentiated adenocarcinoma of the rectum invading the deep submucosal layer with negative lymphovascular invasion. CONCLUSIONS: In this case report, we presented a case of poorly differentiated colorectal adenocarcinoma detected at an early stage, showing interesting endoscopic findings in magnifying endoscopy with crystal violet staining.

Ileus in patients treated with immune checkpoint inhibitors: A retrospective, pharmacovigilance study using Food and Drug Administration Adverse Event Reporting System database.

OBJECTIVE: Immune checkpoint inhibitors (ICIs) have been widely used in cancer treatment; however, some case reports suggested that ICIs treatment might result in ileus. This study aims to comprehensively reveal the relationship between ileus and ICIs treatment in real-world cases from Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). METHODS: Reports from January 1, 2011 to December 31, 2020 were extracted from the FAERS. ICIs-related adverse events in patients were defined as related to use of anti-programmed cell death protein 1 antibodies (PD-1, nivolumab and pembrolizumab), anti-programmed cell death-ligand 1 inhibitors (PD-L1, atezolizumab, durvalumab, avelumab, and cemiplimab), and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4, ipilimumab and tremelimumab). ICIs-related ileus cases were identified to characterize their clinical features. Reporting odds ratios (ROR) and information component (IC) were used to assess the relationship between ICIs and ileus. RESULTS: Among the 105 001 cases related to ICIs, 245 were reported with ICI-related ileus. The affected patients were mainly elderly (median age, 64.5 years) and male (58%, n = 143). The median onset for all cases was 36 (range 0-880) days, and no statistical difference was observed between monotherapy and combination therapy (PD-1 or PD-L1 plus CTLA-4) (p = 0.21). Most patients required drug withdrawal treatment (n = 113, 74%) and can achieve a recovered-resolved state (n = 72, 46%). All ICIs were significantly associated with ileus (ROR = 4.27, 95%Cl: 3.75-4.85; IC = 2.04, 95%Cl: 1.79-2.31). Ileus events were most commonly reported in PD-1 treatment (n = 164, ROR = 3.83, 95%Cl: 3.28-4.48; IC = 1.90, 95%Cl: 1.62-2.21). CONCLUSION: This pharmacovigilance database analysis suggested that ICIs are related to ileus. However, combination therapy may not speed up the onset of ileus.

An antisense Alu transposon insertion/deletion polymorphism of ALDH1A1 may functionally associate with Parkinson's disease.

BACKGROUND: Aldehyde dehydrogenase 1 (encoded by ALDH1A1) has been shown to protect against Parkinson's disease (PD) by reducing toxic metabolites of dopamine. We herein revealed an antisense Alu element insertion/deletion polymorphism in intron 4 of ALDH1A1, and hypothesized that it might play a role in PD.  METHODS: A Han Chinese cohort comprising 488 PD patients and 515 controls was recruited to validate the Alu insertion/deletion polymorphism following a previous study of tag-single nucleotide polymorphisms, where rs7043217 was shown to be significantly associated with PD. Functional analyses of the Alu element insertion were performed. RESULTS: The Alu element of ALDH1A1 was identified to be a variant of Yb8 subfamily and termed as Yb8c4. The antisense Yb8c4 insertion/deletion polymorphism (named asYb8c4ins and asYb8c4del, respectively) appeared to be in a complete linkage disequilibrium with rs7043217 and was validated to be significantly associated with PD susceptibility with asYb8c4ins serving as a risk allele (P = 0.030, OR = 1.224, 95% CI = 1.020-1.470). Multiple functional analyses including ALDH1A1 mRNA expression in blood cells of carriers, and reporters of EGFP and luciferase showed that the asYb8c4ins had a suppressive activity on gene transcription. Mechanistic explorations suggested that the asYb8c4ins induced no changes in CpG methylation and mRNA splicing of ALDH1A1 and appeared no binding of transcription factors. CONCLUSIONS: Our results consolidate an involvement of ALDH1 in PD pathogenesis. The asYb8c4 polymorphism may be a functional output of its linkage disequilibrium-linked single nucleotide polymorphisms.

A signal-off photoelectrochemical aptasensor for ultrasensitive 17ß-estradiol detection based on rose-like CdS@C nanostructure and enzymatic amplification.

Carbon-coated cadmium sulfide rose-like nanostructures (CdS@C NRs) were prepared via a facile solvothermal approach and used as the photoelectrochemical (PEC) sensing platform for the integration of functional biomolecules. Based on this, a novel "signal-off" PEC aptasensor mediated by enzymatic amplification was proposed for the sensitive and selective detection of 17ß-estradiol (E2). In the presence of E2, alkaline phosphatase-modified aptamer (ALP-apta) were released from the electrode surface through the specific recognition with E2, which caused the negative effect on PEC response due to the decrease of ascorbic acid (AA) produced by the ALP in situ enzymatic catalysis. The developed PEC aptasensor for detection of E2 exhibited a wide linear range of 1.0-250 nM, with the low detection limit of 0.37 nM. This work provides novel insight into the design of potential phoelectroactive materials and the application of signal amplification strategy in environmental analysis field.

Differential and paradoxical roles of new-generation antidepressants in primary astrocytic inflammation.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are commonly used new-generation drugs for depression. Depressive symptoms are thought to be closely related to neuroinflammation. In this study, we used up-to-date protocols of culture and stimulation and aimed to understand how astrocytes respond to the antidepressants. METHODS: Primary astrocytes were isolated and cultured using neurobasal-based serum-free medium. The cells were treated with a cytokine mixture comprising complement component 1q, tumor necrosis factor α, and interleukin 1α with or without pretreatments of antidepressants. Cell viability, phenotypes, inflammatory responses, and the underlying mechanisms were analyzed. RESULTS: All the SSRIs, including paroxetine, fluoxetine, sertraline, citalopram, and fluvoxamine, show a visible cytotoxicity within the range of applied doses, and a paradoxical effect on astrocytic inflammatory responses as manifested by the promotion of inducible nitric oxide synthase (iNOS) and/or nitric oxide (NO) and the inhibition of interleukin 6 (IL-6) and/or interleukin 1ß (IL-1ß). The SNRI venlafaxine was the least toxic to astrocytes and inhibited the production of IL-6 and IL-1ß but with no impact on iNOS and NO. All the drugs had no regulation on the polarization of astrocytic A1 and A2 types. Mechanisms associated with the antidepressants in astrocytic inflammation route via inhibition of JNK1 activation and STAT3 basal activity. CONCLUSIONS: The study demonstrated that the antidepressants possess differential cytotoxicity to astrocytes and function differently, also paradoxically for the SSRIs, to astrocytic inflammation. Our results provide novel pieces into understanding the differential efficacy and tolerability of the antidepressants in treating patients in the context of astrocytes.

Early verrucous cell carcinoma of the esophagus: a case report and endoscopic and histologic features.

BACKGROUND: Verrucous cell carcinoma of the esophagus (VCCE) is an extremely rare tumor and generally detected at advanced stage. Despite of its slow growth and well differentiation, it has very poor prognosis with high mortality. Therefore, early detection is a critical to improve patients' survival. However, no early cases of VCCE have been reported and the endoscopic features of early VCCE are not well described. We herein report the endoscopic and histologic features of an early VCCE. CASE PRESENTATION: A 54-year-old man with a history of excessive alcohol and tobacco use was admitted to our hospital because of chronic persistent swallowing dysfunction for six months. White light endoscopy revealed a flat lesion covered with scattered leukoplakia in the middle esophagus. Magnifying endoscopy with narrow-band imaging showed tiny irregular papillary microsurface structure. The lesion was considered as early esophageal cancer and completely resected with endoscopic submucosal dissection. Histological examination confirmed that the lesion was early VCCE which was limited within the mucosal lamina propria (m2). CONCLUSION: VCCE is rare with poor prognosis. This is a report of early VCCE and description of its endoscopic features which will contribute to early detection of these cancers.

Characteristics of balance performance in the Chinese elderly by age and gender.

BACKGROUND: Population aging has been an emerging public and health concern globally. Balance performance can be applied as an indicator of functional status and a predictor of health outcomes in the elderly. However, reference data of balance performance in the elderly generated from large scale studies have been very limited. In research and geriatric assessment settings, the age and gender specific data on balance performance are indispensable prerequisites for identifying subpopulation with and at risk of impairments and subsequently implementing targeted interventions in clinics and public health to improve their balance performance. METHODS: A total of 1984 elderly subjects aged 60 to 97 years from community settings in urban China were investigated. The balance performances together with 3 individual domains and 16 items were evaluated using the X16 balance testing scale. RESULTS: In the elderly, with age increases each item, individual domain, and overall balance performance scores decreased gradually. Meanwhile, individual variations of individual domains and overall balance performance were all increased over age. Relative to levels of 60- years, postural stability and overall balance performance decreased significantly since 65 years old, static balance and dynamic balance capacities started to decrease significantly since 70 years old. There was no significant difference in each balance domain and overall balance performance between men and women. Across age groups, portions of individuals able to perform task 4, 8 and 11 successfully were the lowest amongst their corresponding domains static balance, postural stability, and dynamic balance, respectively. Similar patterns were observed in both men and women. Balance performances were categorized into poor, fair, and good groups with scores of 0 to 10, 11 to 17, and 18 to 20, respectively. With increases of age, proportions with poor and fair balance capacities elevated stably. CONCLUSIONS: In the elderly, with advances in age, abilities of overall balance performance, individual domains of static balance, postural stability, and dynamic balance, and successful performances on specific tasks declined gradually and stably. The deterioration started to be obvious since 65-75 years. Men and women had similar patterns.

Procyanidin B3 alleviates intervertebral disc degeneration via interaction with the TLR4/MD-2 complex.

As a chronic musculoskeletal degeneration disease, intervertebral disc degeneration (IVDD) has been identified as a crucial cause for low back pain. This condition has a prevalence of 80% among adults without effective preventative therapy. Procyanidin B3 (Pro-B3) is a procyanidin dimer, which is widely present in the human diet and has multiple functions, such as preventing inflammation. But the inhibiting effect of Pro-B3 in IVDD development is still no known. Thus, our study aimed to demonstrate the therapeutical effect of Pro-B3 in IVDD and explain the underlying mechanism. In vitro studies, human nucleus pulposus (NP) cells were isolated and exposed in lipopolysaccharide (LPS) to simulate IVDD development. Pro-B3 pre-treatment inhibited LPS-induced production of inflammation correlated factors such as tumour necrosis factor α (TNF-α), interleukin-6 (IL-6), prostaglandin E2 (PGE2) and Nitric oxide (NO). On the other hand, LPS-medicated extracellular matrix (ECM) breakdown was blocked in Pro-B3 treated NP cells. Additionally, Pro-B3 treatment blocked the activation of NF-κB/toll-like receptor 4 pathway in LPS-exposed NP cells. Mechanistically, Pro-B3 could occupy MD-2's hydrophobic pocket exhibiting high affinity for LPS to intervene LPS/TLR4/MD-2 complex formation. In vivo, Pro-B3 treatment prevented the loss of gelatin NP cells and structural damage of annulus fibrosus in rat IVDD model. In brief, Pro-B3 is considered to be a treatment agent for IVDD.