Telmisartan Alleviates Alzheimer's Disease-Related Neuropathologies and Cognitive Impairments.

BACKGROUND: Alzheimer's disease (AD) is the most common type of neurodegenerative disorder. There are few effective medications for halting the progression of AD. Telmisartan (TEL) is a widely used anti-hypertensive drug approved by FDA. Aside from treating hypertension, TEL has been revealed to provide protection against AD. However, the underlying mechanisms remain unclear. OBJECTIVE: To investigate the mechanisms underlying the beneficial effects of TEL against AD. METHODS: Eight-month-old APP/PS1 mice were administered with 5 mg/kg TEL once per day for 4 successive months. Nesting test, Y-maze test, and Morris water maze test were employed to assess the cognitive and executive functions. Neuronal and synaptic markers, amyloid-ß (Aß) pathology, neuroinflammation, and oxidative stress in the brains were measured. Specifically, components involved in Aß production and degradation pathway were analyzed to explore the mechanisms underlying the therapeutic effect of TEL against Aß pathology. The primary microglia were used to uncover the mechanisms underlying the anti-inflammatory effects of TEL in AD. Additionally, the preventive effect of TEL against AD were investigated using 4-month-old APP/PS1 mice. RESULTS: TEL treatment ameliorated cognitive and executive impairments, neuronal and synaptic injury, Aß pathology, neuroinflammation, and oxidative stress in APP/PS1 mice. The favorable effects of TEL on Aß pathology were achieved by inhibiting enzymatic Aß production and facilitating enzymatic and autophagic Aß degradation. Meanwhile, the anti-inflammatory effects of TEL were accomplished via microglial PPARγ/NLRP3 pathway. The administration of TEL prior to symptom onset prevented AD-related cognitive decline and neuropathologies. CONCLUSION: TEL represents a promising agent for AD prevention and treatment.

A cross-sectional study of the association between heavy metals and pan-cancers associated with sex hormones in NHANES 1999-2018.

Given the complexity of tumorigenesis, numerous studies have also shown that excessive exposure to heavy metals increases the risk of cancers and disrupts the secretion of sex hormones. However, the specific effects of heavy metals on cancers remain to be proven. To confirm the association between heavy metals and pan-cancer sex hormone levels among adults, 94,337 individuals from the National Health and Nutrition Examination Survey were assessed. We examined the associations between pan-cancers associated with sex hormones (ovarian, testicular, breast, and prostate cancers) and heavy metals in blood/urine. The methods (the WQS (weighted quantile sums) and SVYGLM (survey generalized linear model) regressions) were used to evaluate the association between sex hormone-related cancers and each metal category by incorporating covariates. To evaluate the overall effect of heavy metals and detect the dose-response relationship between the prevalence of pan-cancers associated with sex hormones and heavy metals, RCS (restricted cubic splines) were applied. Environmental exposure to heavy metals may be associated with pan-cancers associated with sex hormones in adults in the USA. Prostate cancer was inversely associated with blood cadmium while positively associated with blood lead, urinary tin, and thallium. Breast cancer was inversely associated with blood lead. Ovarian cancer was positively associated with blood cadmium. We also found a non-linear dose-response relationship between pan-cancers associated with sex hormones and heavy metals, which was non-parametric, using RCS models. The OR for breast cancer decreased along with the increase in lead concentration under approximately 20 µg/dl, while the OR for prostate cancer increased between urine thallium levels of approximately 0.17-1.1 ng/ml. Pan-cancers associated with sex hormones are associated with exposure to heavy metals. Considering the design of the NHANES study, further studies need to be conducted on other nationally representative surveys.

The Alzheimer's disease-associated gene TREML2 modulates inflammation by regulating microglia polarization and NLRP3 inflammasome activation.

Triggering receptor expressed on myeloid cells-like 2 (TREML2) is a newly identified susceptibility gene for Alzheimer's disease (AD). It encodes a microglial inflammation-associated receptor. To date, the potential role of microglial TREML2 in neuroinflammation in the context of AD remains unclear. In this study, APP/PS1 mice were used to investigate the dynamic changes of TREML2 levels in brain during AD progression. In addition, lipopolysaccharide (LPS) stimulation of primary microglia as well as a lentivirus-mediated TREML2 overexpression and knockdown were employed to explore the role of TREML2 in neuroinflammation in the context of AD. Our results show that TREML2 levels gradually increased in the brains of APP/PS1 mice during disease progression. LPS stimulation of primary microglia led to the release of inflammatory cytokines including interleukin-1ß, interleukin-6, and tumor necrosis factor-α in the culture medium. The LPS-induced microglial release of inflammatory cytokines was enhanced by TREML2 overexpression and was attenuated by TREML2 knockdown. LPS increased the levels of microglial M1-type polarization marker inducible nitric oxide synthase. This effect was enhanced by TREML2 overexpression and ameliorated by TREML2 knockdown. Furthermore, the levels of microglial M2-type polarization markers CD206 and ARG1 in the primary microglia were reduced by TREML2 overexpression and elevated by TREML2 knockdown. LPS stimulation increased the levels of NLRP3 in primary microglia. The LPS-induced increase in NLRP3 was further elevated by TREML2 overexpression and alleviated by TREML2 knockdown. In summary, this study provides the first evidence that TREML2 modulates inflammation by regulating microglial polarization and NLRP3 inflammasome activation. These findings reveal the mechanisms by which TREML2 regulates microglial inflammation and suggest that TREML2 inhibition may represent a novel therapeutic strategy for AD.

An alternative surgical technique for varicoceles: a preliminary experience of the microsurgical spermatic (distal end)-inferior or superficial epigastric vein anastomosis in symptomatic varicoceles associated with perineal pain.

Many therapies are effective in treating varicoceles, including dilation of the pampiniform plexus in males. The most common method of treatment is varicocelectomy. We aimed to assess an alternative technique (microsurgical spermatic [distal end]-superficial or inferior epigastric vein anastomosis) that preserves the normal blood flow pattern for varicocele treatment. We retrospectively analyzed 27 men with varicocele between October 2019 and July 2020. All patients underwent microsurgical spermatic (distal end)-superficial or inferior epigastric vein anastomosis. The prognosis was reviewed retrospectively with an additional survey conducted 3 months after surgery. The mean ± standard deviation of the age was 26.1 ± 7.3 years in patients with microsurgical spermatic (distal end)-superficial or inferior epigastric vein anastomosis. The maximum diameter of the varicocele vein, perineal pain score, sperm density, and forward movement of sperm improved over 3 months after surgery. Microsurgical spermatic (distal end)-superficial or inferior epigastric vein anastomosis is a safe and efficient surgical treatment for varicoceles.

Hemangioma of the prostate with retrograde ejaculation - a case report.

INTRODUCTION AND IMPORTANCE: Hemangioma of the prostate is rarely reported. We here describe a hemangioma of the prostate in a 31-year-old man. CASE PRESENTATION: The history, imaging characteristics, treatment and one year follow-up results were well documented. The chief complaint was retrograde ejaculation. A 3.1 cm × 2.9 cm mass in the prostate was detected by ultrasound. Transurethral resection of the prostate (TURP) was performed. CLINICAL DISCUSSION: Pathological examination revealed the mass was hemangioma. Immunohistochemical study found the tissue was SMA, CD34, CD31 positive, but D2-40 negative. Imaging feature combined with pathological result suggests the diagnosis of hemangioma of the prostate. One year follow-up revealed the patient was infertile. CONCLUSION: We suggest TURP should be performed to remove the hemangioma. Combined treatment is necessary to resolve the patient's infertility.

Clopidogrel with Aspirin versus Aspirin Alone following Intravenous Thrombolysis in Minor Stroke: A 1-Year Follow-Up Study.

OBJECTIVE: The objective of this study was to investigate the long-term effect of dual antiplatelet therapy (DAPT) using clopidogrel plus aspirin versus aspirin monotherapy after intravenous thrombolysis on functional outcomes in patients with minor stroke. METHODS: Patients with acute ischemic stroke with a National Institutes of Health Stroke Scale score ≤ 5 who received either DAPT or aspirin monotherapy following recombinant tissue plasminogen activator intravenous thrombolysis were studied. Data recorded between January 2017 and December 2020 were retrospectively analyzed. The primary efficacy outcome was functional improvement at 1 year, measured by a 1-point decrease across modified Rankin Scale (mRS) scores. Secondary outcomes included complete rehabilitation (mRS = 0), an excellent outcome (mRS = 0-1), and a favorable outcome (mRS = 0-2) at 1 year, as well as the rates of stroke recurrence and all-cause mortality within 1 year. RESULTS: A total of 238 patients were included, and follow-up data were available for 205 patients (86.1%). The distribution of 1-year outcomes on the mRS favored DAPT over aspirin monotherapy (adjusted common odds ratio (OR), 2.19; 95% confidence interval (CI), 1.12-4.28; p = 0.022). Patients who received DAPT, compared with those receiving aspirin alone, were more likely to achieve complete rehabilitation (adjusted OR, 2.44; 95% CI, 1.21-4.95; p = 0.013) at the 1-year follow-up. Additionally, the percentages of an excellent outcome and a favorable outcome did not differ, and the rates of stroke recurrence and all-cause mortality were comparable during the 1-year follow-up. CONCLUSIONS: Clopidogrel with aspirin following intravenous thrombolysis was associated with improved functional outcome at the 1-year follow-up for patients with minor stroke, and it did not increase the stroke recurrence rate and mortality.

Angiotensin-(1-7) Analogue AVE0991 Modulates Astrocyte-Mediated Neuroinflammation via lncRNA SNHG14/miR-223-3p/NLRP3 Pathway and Offers Neuroprotection in a Transgenic Mouse Model of Alzheimer's Disease.

OBJECTIVE: Emerging evidence suggests that brain angiotensin-(1-7) (Ang-(1-7)) deficiency contributes to the pathogenesis of Alzheimer's disease (AD). Meanwhile, our previous studies revealed that restoration of brain Ang-(1-7) levels provided neuroprotection by inhibition of inflammatory responses during AD progress. However, the potential molecular mechanisms by which Ang-(1-7) modulates neuroinflammation remain unclear. MATERIALS AND METHODS: APP/PS1 mice were injected intraperitoneally with AVE0991 (a nonpeptide analogue of Ang-(1-7)) once a day for 30 consecutive days. Cognitive functions, neuronal and synaptic integrity, and inflammation-related markers were assessed. Since astrocytes played a crucial role in AD-related neuroinflammation whilst long noncoding RNAs (lncRNAs) were reported to participate in modulating inflammatory responses, astrocytes of APP/PS1 mice were isolated for high-throughput lncRNA sequencing to identify the most differentially expressed lncRNA following AVE0991 treatment. Afterward, the downstream pathways of this lncRNA in the anti-inflammatory action of AVE0991 were investigated using primary astrocytes. RESULTS: AVE0991 rescued spatial cognitive impairments and alleviated neuronal and synaptic damage in APP/PS1 mice. The levels of Aß1-42 in the brain of APP/PS1 mice were not affected by AVE0991. By employing high-throughput lncRNA sequencing, our in vitro study demonstrated for the first time that AVE0991 suppressed astrocytic NLRP3 inflammasome-mediated neuroinflammation via a lncRNA SNHG14-dependent manner. SNHG14 acted as a sponge of miR-223-3p while NLRP3 represented a direct target of miR-223-3p in astrocytes. In addition, miR-223-3p participated in the AVE0991-induced suppression of astrocytic NLRP3 inflammasome. CONCLUSION: Our results suggest that Ang-(1-7) analogue AVE0991 inhibits astrocyte-mediated neuroinflammation via SNHG14/miR-223-3p/NLRP3 pathway and offers neuroprotection in APP/PS1 mice. These findings reveal the underlying mechanisms by which Ang-(1-7) inhibits neuroinflammation under AD condition and uncover the potential of its nonpeptide analogue AVE0991 in AD treatment.

Development and internal validation of a novel model and markers to identify the candidates for lymph node metastasis in patients with prostate cancer.

BACKGROUND: High-grade prostate cancer (PCa) has a poor prognosis, and up to 15% of patients worldwide experience lymph node invasion (LNI). To further improve the prediction lymph node invasion in prostate cancer, we adopted risk scores of the genes expression based on the nomogram in guidelines. METHODS: We analyzed clinical data from 320 PCa patients from the Cancer Genome Atlas database. Weighted gene coexpression network analysis was used to identify the genes that were significantly associated with LNI in PCa (n = 390). Analyses using the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases were performed to identify the activated signaling pathways. Univariate and multivariate logistic regression analyses were performed to identify the independent risk factors for the presence of LNI. RESULTS: We found that patients with actual LNI and predicted LNI had the worst survival outcomes. The 7 most significant genes (CTNNAL1, ENSA, MAP6D1, MBD4, PRCC, SF3B2, TREML1) were selected for further analysis. Pathways in the cell cycle, DNA replication, oocyte meiosis, and 9 other pathways were dramatically activated during LNI in PCa. Multivariate analyses identified that the risk score (odds ratio [OR] = 1.05 for 1% increase, 95% confidence interval [CI]: 1.04-1.07, P < .001), serum PSA level, clinical stage, primary biopsy Gleason grade (OR = 2.52 for a grade increase, 95% CI: 1.27-5.22, P = .096), and secondary biopsy Gleason grade were independent predictors of LNI. A nomogram built using these predictive variables showed good calibration and a net clinical benefit, with an area under the curve (AUC) value of 90.2%. CONCLUSIONS: In clinical practice, the application of our nomogram might contribute significantly to the selection of patients who are good candidates for surgery with extended pelvic lymph node dissection.

Psychological burden prediction based on demographic variables among infertile men with sexual dysfunction.

There has been increasing interest in the psycho-socio-relational and sexual disorders of infertility, as the risk of psychological burden among infertile men with sexual dysfunctions is significant. The purpose of this study was to develop and to validate a predictive model to estimate individual psychological burden among infertile men with sexual dysfunction and study the association between them. Comprehensive data were collected for infertile men (n = 480) who sought treatment for infertility in a reproductive medicine center between June 2012 and December 2013. Using independent predictors of psychological burden from the least absolute shrinkage and selection operator, univariable and multivariable analyses were developed into two models. Predictive accuracy was compared between the models. We explored the association between sexual dysfunction and psychological burden. A total of 480 patients were analyzed using 10-fold cross-validation. Independent predictors of psychological burden were incorporated into a model to measure anxiety (corrected-area under curve (AUC): 77.3%) and a model to measure depression (corrected-AUC: 70.2%). Anxiety and depression were both associated with erectile dysfunction (P < 0.05), with anxiety demonstrating the strongest association. Only anxiety was associated with premature ejaculation (P < 0.05). Premature ejaculation was not found to be associated with depression (P > 0.05). Predictive models for psychological burden among infertile men with sexual dysfunction are presented, and we found that there is an association between psychological burden and sexual dysfunction. According to the models, proper counseling and treatment of sexual dysfunction in infertile men may reduce the psychological burden, help attain natural pregnancy, and improve the quality of life.

Heparanase overexpression down-regulates syndecan-1 expression in a gallbladder carcinoma cell line.

Objective To discuss the relevance of heparanase and syndecan-1 and regulation of the heparanase-syndecan1 axis in the invasiveness of gallbladder carcinoma cells. Methods 1. Generation of a gallbladder cancer cell line overexpressing a heparanase (GBD-SD) transgene. 2. Western blot analysis of syndecan-1 levels of GBD-SD and control gallbladder carcinoma (GBC-SD) cells. 3. RT-PCR analysis of syndecan-1 mRNA levels of GBD-SD and GBC-SD. 4. Evaluation of invasion and migration of GBD-SD and GBC-SD cells. Results 1. Heparanase expression in GBD-SD cells was significantly increased. 2. The syndecan-1 mRNA level of GBD-SD cells was significantly lower compared with that of GBC-SD cells. 3. The syndecan-1 DNA copy number in GBD-SD cells was significantly lower compared with that of GBC-SD. 4. The invasiveness and migration of GBD-SD cells were significantly higher compared with GBC-SD cells. Conclusions 1. The expression of heparanase negatively correlated with that of syndecan-1 in a gallbladder carcinoma cell line. 2. The expression of heparanase and syndecan-1 in gallbladder carcinomas negatively correlated, similar to other tumours. 3. The heparanase/syndecan1 axis in gallbladder carcinoma plays an important role in the invasion and metastasis, thus providing a new therapeutic target. 4. Further research is required to identify the detailed mechanisms.

Hemodynamics in Transplant Renal Artery Stenosis and its Alteration after Stent Implantation Based on a Patient-specific Computational Fluid Dynamics Model.

BACKGROUND: Accumulating studies on computational fluid dynamics (CFD) support the involvement of hemodynamic factors in artery stenosis. Based on a patient-specific CFD model, the present study aimed to investigate the hemodynamic characteristics of transplant renal artery stenosis (TRAS) and its alteration after stent treatment. METHODS: Computed tomography angiography (CTA) data of kidney transplant recipients in a single transplant center from April 2013 to November 2014 were reviewed. The three-dimensional geometry of transplant renal artery (TRA) was reconstructed from the qualified CTA images and categorized into three groups: the normal, stenotic, and stented groups. Hemodynamic parameters including pressure distribution, velocity, wall shear stress (WSS), and mass flow rate (MFR) were extracted. The data of hemodynamic parameters were expressed as median (interquartile range), and Mann-Whitney U-test was used for analysis. RESULTS: Totally, 6 normal, 12 stenotic, and 6 stented TRAs were included in the analysis. TRAS presented nonuniform pressure distribution, adverse pressure gradient across stenosis throat, flow vortex, and a separation zone at downstream stenosis. Stenotic arteries had higher maximal velocity and maximal WSS (2.94 [2.14, 3.30] vs. 1.06 [0.89, 1.15] m/s, 256.5 [149.8, 349.4] vs. 41.7 [37.8, 45.3] Pa at end diastole, P= 0.001; 3.25 [2.67, 3.56] vs. 1.65 [1.18, 1.72] m/s, 281.3 [184.3, 364.7] vs. 65.8 [61.2, 71.9] Pa at peak systole, P= 0.001) and lower minimal WSS and MFRs (0.07 [0.03, 0.13] vs. 0.52 [0.45, 0.67] Pa, 1.5 [1.0, 3.0] vs. 11.0 [8.0, 11.3] g/s at end diastole, P= 0.001; 0.08 [0.03, 0.19] vs. 0.70 [0.60, 0.81] Pa, 2.0 [1.3, 3.3] vs. 16.5 [13.0, 20.3] g/s at peak systole, P= 0.001) as compared to normal arteries. Stent implantation ameliorated all the alterations of the above hemodynamic factors except low WSS. CONCLUSIONS: Hemodynamic factors were significantly changed in severe TRAS. Stent implantation can restore or ameliorate deleterious change of hemodynamic factors except low WSS at stent regions.