Spirocyclohexadienone-Type Neolignans with Neuroprotective and Neurite Outgrowth Enhancing Activities from Magnolia liliiflora.

Three rare spirocyclohexadienone-type neolignans, magnoflorins A-C (1-3), and three known analogs (4-6), were isolated from the leaves of Magnolia liliiflora. Magnoflorin D (4) was obtained from natural resources for the first time. The chemical structures and absolute configurations of 1-4 were elucidated through detailed analysis of HR-ESI-MS, IR, 1 H, 13 C, and 2D NMR, and ECD experiments. The absolute configuration of 5 were characterized by X-ray crystallography in present study. Moreover, compounds 4 and 5 displayed moderate neuroprotective activity against corticosterone-induced PC12 cells injury at 20 µM with cell viability of 71.5±0.99 % and 73.0±1.42 %, respectively, compared to the model group with 60.83±0.93 %. Compound 6 could enhance neurite outgrowth of nerve growth factor (NGF)-induced PC12 cells at 10 µM with the differentiation rate of 11.98 %, compared with 20.49 % of 50 ng/ml NGF.

Low-Intensity Pulsed Ultrasound Enhanced Adipose-Derived Stem Cell-Mediated Angiogenesis in the Treatment of Diabetic Erectile Dysfunction through the Piezo-ERK-VEGF Axis.

Objectives: Erectile dysfunction is a major comorbidity of diabetes. Stem cell transplantation is a promising method to treat diabetic erectile dysfunction. In this study, we evaluated whether low-intensity pulsed ultrasound (LIPUS) could enhance the efficacy of adipose-derived stem cells (ADSCs) and investigated the underlying molecular mechanism. Materials and methods. Sixty 8-week-old male Sprague-Dawley rats were randomly divided into the normal control (NC) cohort or the streptozocin-induced diabetic ED cohort, which was further subdivided into DM, ADSC, LIPUS, and ADSC+LIPUS groups. Rats in the ADSC or ADSC+LIPUS group received ADSC intracavernosal injection. Rats in the LIPUS or ADSC+LIPUS group were treated with LIPUS. The intracavernous pressure (ICP) and mean arterial pressure (MAP) were recorded at Day 28 after injection. The corpus cavernosum tissues were harvested and subjected to histologic analysis and ELISA. The effects of LIPUS on proliferation and cytokine secretion capacity of ADSCs were assessed in vitro. RNA sequencing and bioinformatic analysis were applied to predict the mechanism involved, and western blotting and ELISA were used for verification. Results: Rats in the ADSC+LIPUS group achieved significantly higher ICP and ICP/MAP ratios than those in the DM, ADSC, and LIPUS groups. In addition, the amount of cavernous endothelium and cGMP level also increased significantly in the ADSC+LIPUS group. In vitro experiments demonstrated that LIPUS promoted proliferation and cell cycle progression in ADSCs. The excretion of cytokines such as CXCL12, FGF2, and VEGF was also enhanced by LIPUS. Bioinformatic analysis based on RNA sequencing indicated that LIPUS stimulation might activate the MAPK pathway. We confirmed that LIPUS enhanced ADSC VEGF secretion through the Piezo-ERK pathway. Conclusion: LIPUS enhanced the curative effects of ADSCs on diabetic erectile dysfunction through the activation of the Piezo-ERK-VEGF pathway. ADSC transplantation combined with LIPUS could be applied as a synergistic treatment for diabetic ED.

The Efficacy and Safety of Thrice vs Twice per Week Low-Intensity Pulsed Ultrasound Therapy for Erectile Dysfunction: A Randomized Clinical Trial.

BACKGROUND: A recent sham-controlled clinical study has shown that low-intensity pulsed ultrasound twice per week can safely and effectively treat patients with mild-to-moderate erectile dysfunction (ED). However, large-scale clinical trials are needed to verify its efficacy and safety and determine a reasonable treatment interval. AIM: To study whether low-intensity pulsed ultrasound therapy thrice per week is non-inferior to twice per week in patients with mild-to-moderate ED. METHODS: A randomized, open-label, parallel-group, non-inferiority clinical trial was conducted in 7 hospitals in China. A total of 323 patients with mild-to-moderate ED were randomized (1:1) into thrice per week (3/W) and twice per week (2/W) groups. Low-intensity pulsed ultrasound was applied on each side of the penis for 16 sessions. OUTCOMES: The primary outcome was response rate using the minimal clinically important difference in the International Index of Erectile Function (IIEF-EF) score at week 12. Secondary outcomes included Erection Hardness Score (EHS), Sexual Encounter Profile, Global Assessment Question, and Self Esteem and Relationship Questionnaire. RESULTS: Response rates in 3/W and 2/W groups were 62.0% and 62.5%, respectively. Treatment effect in the 3/W group was noninferior to that of the 2/W group, with rate difference lower bound of -0.01% [95% confidence interval -0.11 to 0.10%] within the acceptable margin (-14.0%). No significant difference was found among secondary outcomes. IIEF-EF score showed a significant increase from baseline in the 3/W group (16.8 to 20.7) and 2/W group (17.8 to 21.7), and the percentage of patients with EHS ≥3 increased in the 3/W (54.9% to 84.0%) and 2/W (59.5% to 83.5%) groups. There was no significant difference in response rate between the 2 groups after controlling for strata factors and homogeneous tests. No treatment-related adverse events were reported. CLINICAL IMPLICATIONS: Low-intensity pulsed ultrasound therapy displays similar efficacy and safety for mild-to-moderate ED when administered thrice or twice per week for 16 sessions. This study provides two options to suit patients' needs. STRENGTHS & LIMITATIONS: This is a large-sample, randomized, controlled, noninferiority trial study. Short-term follow-up and mostly younger patients are the main limitations. CONCLUSION: Low-intensity pulsed ultrasound therapy thrice and twice per week showed equivalent therapeutic effects and safety for mild-to-moderate ED in a young and generally healthy population. This therapy warrants further investigation of its potential value in rehabilitation of ED. Chen, H., Li Z., Li X., et al. The Efficacy and Safety of Thrice vs Twice per Week Low-Intensity Pulsed Ultrasound Therapy for Erectile Dysfunction: A Randomized Clinical Trial. J Sex Med 2022;19:1536-1545.

Primary malignant pericardial mesothelioma with a survival of 2.5 years: a case report.

Background: Primary malignant pericardial mesothelioma (PMPM) is a highly malignant tumor originating in the pericardium serosum with clinical manifestations presenting as constrictive pericarditis, with pericardial tamponade and heart failure. Malignant pericardial mesothelioma is rare and has a poor prognosis, with an average survival time of 6-10 months. Case Description: Herein, we report the case of a 57-year-old female who developed chest tightness and panic for no obvious reason. She was diagnosed with tuberculous pericarditis via multiple examinations including positron emission tomography/computed tomography (PET/CT), pleural biochemical routine, tuberculin purified protein derivative (PPD) test, T cell spot (T-SPOT) test, and echocardiography, and was experienced intermittent relief after anti-tuberculosis treatment. On 21 July, 2020, pericardiectomy was performed due to poor therapeutic effect, and the postoperative pathological diagnosis was malignant mesothelioma. After discussing treatment plans and considering the prognosis, the patient opted for palliative care. Subsequently, her symptoms gradually worsened, with chest tightness, shortness of breath, palpitations at rest, frequent arrhythmias, heart failure, cardiogenic shock, and multiple plasma chamber effusions. This case showed that the most common misdiagnosis of PMPM is tuberculous pericarditis, which needs to be differentiated from pleural mesothelioma with pericardial metastasis. Conclusions: The diagnosis of PMPM is usually made by pathologic surgery or histopathological examination to determine the specific disease location. In addition, pericardiocentesis fluid exfoliation cytology, imaging and echocardiography can assist diagnosis. Due to the lack of effective treatment for PMPM, timely surgery and postoperative adjuvant chemotherapy are needed to improve the quality of life of patients and prolong their survival time.

Same total normal forms sperm counts of males from Lhasa and Shanghai, China.

Male infertility may be caused by genetic and/or environmental factors that impair spermatogenesis and sperm maturation. High-altitude (HA) hypoxic environments represent one of the most serious challenges faced by humans that reside in these areas. To assess the influence of the plateau environment on semen parameters, 2,798 males, including 1,111 native Tibetans and 1,687 Han Chinese individuals living in the plains (HCILP) who underwent pre-pregnancy checkups, were enrolled in this study. The semen samples of males were evaluated to determine conventional sperm parameters, sperm morphology, and sperm movement. Reproductive endocrine hormones (REHs) were detected in 474 males, including 221 Tibetans and 253 HCILP. Due to recurrent abortions in partners, the DNA fragmentation index (DFI) of 133 native Tibetans and 393 HCILP individuals was further compared. Luteinizing hormone (LH) (4.94 ± 2.12 vs. 3.29 ± 1.43 U/L), prolactin (11.34 ± 3.87 vs. 8.97 ± 3.48 nmol/L), E2/T (0.22 ± 0.11 vs 0.11 ± 0.05), median total sperm motility (61.20% vs. 51.56%), and DFI (23.11% vs. 7.22%) were higher in males from plateau areas while median progressive motility (PR) (35.60% vs. 41.12%), total number of PR sperms (51.61 vs. 59.63 mil/ejaculate), percentage of normal form sperms (3.70% vs. 6.00%), curvilinear velocity (36.10 vs. 48.97 µm/s), straight-line (rectilinear) velocity (14.70 vs. 31.52 µm/s), estradiol (103.82 ± 45.92 vs. 146.01 ± 39.73 pmol/L), progesterone (0.29 ± 0.27 vs. 2.22 ± 0.84 nmol/L), testosterone (4.90 ± 1.96 vs. 14.36 ± 5.24 nmol/L), and testosterone secretion index (ratio of testosterone to LH) (33.45 ± 22.86 vs 145.78 ± 73.41) were lower than those in males from the plains. There was no difference in median total sperm number (157.76 vs. 151.65 mil/mL), sperm concentration (52.40 vs. 51.79 mil/mL), volume (3.10 vs. 3.10 mL), total normal form sperms (5.91 vs. 6.58 mil/ejaculate, p50), and follicle-stimulating hormone (FSH) levels (4.13 ± 2.55 U/L vs 3.82 ± 2.35 U/L) between the two groups of males. The REH and sperm parameters of males from HA hypoxic environments were adaptively altered. Although the total number of PR sperm decreased and DFI increased, the Tibetan population that lives at HAs has been found to grown continuously and rapidly. These results supplement prior findings regarding the impact of HA on male reproductive function.

PM2.5 constituents and mortality from a spectrum of causes in Guangzhou, China.

As the major constituents of PM2.5, carbonaceous constituents and inorganic ions have attracted emerging attentions on their health risks, particularly on cardiorespiratory diseases. However, evidences on the risks of PM2.5 constituents on other diseases (eg. nervous disease, genitourinary disease, neoplasms and endocrine disease) remain scarce. In our study, we firstly calculated residuals of PM2.5 constituents regressed on PM2.5 to remove the confounding effect of PM2.5. Then, generalized additive model (GAM) was used to assess impacts of residuals of PM2.5 constituents on mortality from 36 diseases (10 broad categories and 26 subcategories) during 2011-2015 in Guangzhou, China. Results of constituent-residual models showed that only EC, OC and NO3- were significantly associated with all-cause mortality, with per IQR change in corresponding constituent residuals related to percentage changes of 1.69% (95% CI: 0.42, 2.97), 1.94% (95% CI: 0.37, 3.54) and 2.59% (95% CI: 1.02, 4.18) at lag 03 days. All these pollutants were significantly associated with elevated mortality risk of cardiovascular disease, but only EC was significantly associated with respiratory mortality, and NO3- with endocrine disease and neoplasm. For more specific causes, the highest effect estimates of EC and NO3-were both observed on mortality from other form of heart disease, and OC on intentional self-harm, with estimates of 11.45% (95% CI: 2.74, 20.91), 12.59% (95% CI: 1.41, 25.02) and 18.01% (95% CI: 2.14, 36.36), respectively. Our findings highlighted that stricter emission control measures are still warranted to reduce air pollution level and protect the public health.

Estimating ground level PM2.5 concentrations and associated health risk in India using satellite based AOD and WRF predicted meteorological parameters.

PM2.5 concentrations in most of the Indian cities are in alarming levels. However, the current network of 308 monitoring stations are heterogeneously placed and do not cover many parts of the country. This limits the ability of agencies to measure the concentration which people are exposed to. In this study, ground level PM2.5 concentrations and the associated risk and mortality in India using satellite based AOD data for the year 2015 was estimated to identify the state specific number of more monitoring sites required. Results indicate that average PM2.5 concentrations were 89 µg/m3, which caused 1.61 million deaths including 0.34 million Chronic Obstructive Pulmonary Disease (COPD) deaths, 0.2 million Lung Cancer (LC) deaths, 0.53 million Ischemic Heart Disease (IHD) deaths and 0.70 million deaths due to Stroke. The years of life lost (YLL) per 1000 population due to exposure to PM2.5 indicated Delhi (North-India) to be severely affected by PM2.5 resulting in 227.47 years of life lost and was closely followed by Bihar (Eastern-India) (225.18), Rajasthan (Western-India) (225.05) and Uttar Pradesh (Northern-India) (213.16). Eastern India had the highest population weighted concentration (102.09 µg/m3) and contributed to 23.46% of premature mortality and was followed by Central (75.32 µg/m3) and Northern India (75.12 µg/m3), thus indicating severity of air pollution in India and need for its constant monitoring. As per Indian regulatory agency's guidelines, India still needs 1638 more air quality monitoring stations, of which North-Indian states require maximum number of additional stations i.e. 400, followed by 382 in eastern states.

Sensitive Detection of Ambient Formaldehyde by Incoherent Broadband Cavity Enhanced Absorption Spectroscopy.

Formaldehyde (HCHO) is the most abundant atmospheric carbonyl compound and plays an important role in the troposphere. However, HCHO detection via traditional incoherent broadband cavity enhanced absorption spectroscopy (IBBCEAS) is limited by short optical path lengths and weak light intensity. Thus, a new light-emitting diode (LED)-based IBBCEAS was developed herein to measure HCHO in ambient air. Two LEDs (325 and 340 nm) coupled by a Y-type fiber bundle were used as an IBBCEAS light source, which provided both high light intensity and a wide spectral fitting range. The reflectivity of the two cavity mirrors used herein was 0.99965 (1 - reflectivity = 350 ppm loss) at 350 nm, which corresponded with an effective optical path length of 2.15 km within a 0.84 m cavity. At an integration time of 30 s, the measurement precision (1σ) for HCHO was 380 parts per trillion volume (pptv), and the corresponding uncertainty was 8.3%. The instrument was successfully deployed for the first time in a field campaign and delivered results that correlated well with those of a commercial wet-chemical instrument based on Hantzsch fluorimetry (R2 = 0.769). The combined light source based on a Y-type fiber bundle overcomes the difficulty of measuring ambient HCHO via IBBCEAS in near-ultraviolet range, which may extend IBBCEAS technology to measure other atmospheric trace gases with high precision.

Sources and health risks of ambient polycyclic aromatic hydrocarbons in China.

Polycyclic aromatic hydrocarbons (PAHs) in the environment are of significant concerns due to their high toxicity to human health. PAHs measurements at limited air quality monitoring stations alone are insufficient to gain a complete understanding of ambient levels and public exposure of PAHs in China. This study simulated the concentrations of PAHs in China, identified the source contributions, and estimated the health risks. Anthropogenic emissions of 16 priority PAHs directly associated with health risks were generated from the global high-resolution PKU-FUEL-2007 inventory. Open biomass burning emissions were generated from the Fire Inventory from NCAR (FINN). PAHs concentrations in January, April, July, and October 2013 were simulated using the Community Multiscale Air Quality (CMAQ) model after incorporation of chemistry, partitioning, and deposition of PAHs. Predicted PAHs were in good agreement with seasonal and annual averaged observations from previous studies. The surface concentrations of 16-PAHs were higher in winter, with population weight average of 0.8 µg/m3 and peak value of 2.0 µg/m3 in urban areas in the North China Plain (NCP) and the Yangtze River Delta (YRD). Summer and spring exhibited lower concentrations of approximately 0.2 µg/m3 in most areas. The most important sources to PAHs were biomass burning and coal combustion in winter and industrial processes and oil and gas activities in summer. The cancer risk due to inhalation exposure of naphthalene (NAPH) and seven carcinogenic PAHs was significant, with the incremental lifetime cancer risk (ILCR) of >5 × 10-4 in many urban and industrial areas. Exposure to PAHs was estimated to result in 15,198 excess lifetime cancer cases in China. Oil and gas burning associated with transport, residential and commercial activities were major contributors to ILCR in China. Coal combustion was predominant in Shanxi but less important in other regions.

Characterization of Fine Particulate Matter and Associated Health Burden in Nanjing.

Particulate matter (PM) air pollution has become a serious environmental problem in Nanjing and poses great health risks to local residents. In this study, characteristics of particulate matter with an aerodynamic diameter less than 2.5 µm (PM2.5) over Nanjing were analyzed using hourly and daily averaged PM2.5 concentrations and meteorological parameters collected from nine national monitoring sites during the period of March 2014 to February 2017. Then, the integrated exposure-response (IER) model was applied to assess premature mortality, years of life lost (YLL) attributable to PM2.5, and mortality benefits due to PM2.5 reductions. The concentrations of PM2.5 varied among hours, seasons and years, which can be explained by differences in emission sources, secondary formations and meteorological conditions. The decreased ratio of PM2.5 to CO suggested that secondary contributions decreased while the relative contributions of vehicle exhaust increased from increased CO data. According to the values of attributable fractions (AF), stroke was the major cause of death, followed by ischemic heart disease (IHD), lung cancer (LC) and chronic obstructive pulmonary disease (COPD). The estimated total deaths in Nanjing due to PM2.5 were 12,055 and 10,771, leading to 98,802 and 87,647 years of life lost in 2014 and 2015, respectively. The elderly and males had higher health risks than youngsters and females. When the PM2.5 concentrations meet the World Health Organization (WHO) Air Quality Guidelines (AQG) of 10 µg/m³, 84% of the premature deaths would be avoided, indicating that the Nanjing government needs to adopt more stringent measure to reduce PM pollution and enhance the health benefits.

A single dose of dezocine suppresses emergence agitation in preschool children anesthetized with sevoflurane-remifentanil.

BACKGROUND: Emergence agitation (EA) is a common phenomenon in preschool children during emergence from general anesthesia. This study evaluated the safety and efficacy of dezocine for emergence agitation in preschool children anesthetized with sevoflurane-remifentanil. METHODS: A total of 100 preschool children, scheduled for elective laparoscopic repair of an inguinal hernia by high ligation of the hernia sac under sevoflurane-remifentanil anesthesia were randomized into two groups: Group C (n = 50) received Ringer's lactate 10 mL and Group D received Ringer's lactate 10 mL containing dezocine 0.1 mg/kg, postoperatively. RESULTS: Incidence of EA, defined as a score ≥ 3 on Aono's four point scale or Pediatric Anesthesia Emergence Delirium (PAED) score ≥ 10 in the PACU (10% vs. 76%) and the percentage of patients with severe EA (PAED score ≥ 13) (12% vs. 76%) were significantly lower in Group D compared to Group C (P < 0.05). Mean Children and Infants Postoperative Pain Scale (CHIPPS) score was significantly lower in Group D compared to Group C (1.2 ± 0.5 vs. 5.2 ± 0.6; P < 0.05). Patients need for fentanyl (18% vs. 4%) or propofol rescue (20% vs. 0) was significantly greater in Group C compared to Group D. No significant differences in other relative aspects after surgery between groups. CONCLUSION: Administration of dezocine 0.1 mg/kg decreased the incidence and severity of EA in preschool children that had undergone laparoscopic repair of an inguinal hernia by high ligation of the hernia sac under sevoflurane-remifentanil anesthesia. TRIAL REGISTRATION: A single dose of dezocine suppresses emergence agitation in preschool children anesthetized with sevoflurane-remifentanil effectively: A double-blind, prospective, randomized, controlled study, Chinese Clinical Trial Registry (ID: ChiCTR-IOR-16010033), retrospectively registered on November 21, 2016.

First Chemical Characterization of Refractory Black Carbon Aerosols and Associated Coatings over the Tibetan Plateau (4730 m a.s.l).

Refractory black carbon (rBC) aerosol is an important climate forcer, and its impacts are greatly influenced by the species associated with rBC cores. However, relevant knowledge is particularly lacking at the Tibetan Plateau (TP). Here we report, for the first time, highly time-resolved measurement results of rBC and its coating species in central TP (4730 m a.s.l), using an Aerodyne soot particle aerosol mass spectrometer (SP-AMS), which selectively measured rBC-containing particles. We found that the rBC was overall thickly coated with an average mass ratio of coating to rBC (RBC) of ∼7.7, and the coating species were predominantly secondarily formed by photochemical reactions. Interestingly, the thickly coated rBC was less oxygenated than the thinly coated rBC, mainly due to influence of the transported biomass burning organic aerosol (BBOA). This BBOA was relatively fresh but formed very thick coating on rBC. We further estimated the "lensing effect" of coating semiquantitatively by comparing the measurement data from a multiangle absorption photometer and SP-AMS, and found it could lead to up to 40% light absorption enhancement at RBC > 10. Our findings highlight that BBOA can significantly affect the "lensing effect", in addition to its relatively well-known role as light-absorbing "brown carbon."

Premature Mortality Attributable to Particulate Matter in China: Source Contributions and Responses to Reductions.

Excess mortality (ΔMort) in China due to exposure to ambient fine particulate matter with aerodynamic diameter ≤2.5 µm (PM2.5) was determined using an ensemble prediction of annual average PM2.5 in 2013 by the community multiscale air quality (CMAQ) model with four emission inventories and observation data fusing. Estimated ΔMort values due to adult ischemic heart disease, cerebrovascular disease, chronic obstructive pulmonary disease, and lung cancer are 0.30, 0.73, 0.14, and 0.13 million in 2013, respectively, leading to a total ΔMort of 1.3 million. Source-oriented CMAQ modeling determined that industrial and residential sources were the two leading sources of ΔMort, contributing to 0.40 (30.5%) and 0.28 (21.7%) million deaths, respectively. Additionally, secondary ammonium ion from agriculture, secondary organic aerosol, and aerosols from power generation were responsible for 0.16, 0.14, and 0.13 million deaths, respectively. A 30% ΔMort reduction in China requires an average of 50% reduction of PM2.5 throughout the country and a reduction by 62%, 50%, and 38% for the Beijing-Tianjin-Hebei, Jiangsu-Zhejiang-Shanghai, and Pearl River Delta regions, respectively. Reducing PM2.5 to the CAAQS grade II standard of 35 µg m-3 would only lead to a small reduction in mortality, and a more stringent standard of <15 µg m-3 would be needed for more remarkable reduction of ΔMort.

Randomized crossover trial of amoxapine versus vitamin B12 for retrograde ejaculation

ABSTRACT Objective To compare the efficacy and safety of amoxapine and vitamin B12 for treating retrograde ejaculation (RE). Materials and Methods Between May 2009 and November 2012, this open-label, randomized, crossover study enrolled 26 men suffering with RE at Department of Reproductive Medicine, Omori Hospital. Patients were randomly allocated into two groups (n=13 each). The amoxapine-B12 group received amoxapine (50 mg daily for 4 weeks, orally) followed (after a 1-week washout period) by vitamin B12 (500 μg three-times daily for 4 weeks). The B12-amoxapine group received the opposite regimen. All patients masturbated to ejaculation at least twice during each treatment period. The primary outcome was antegrade ejaculation of semen, as reported by the patient, on more than one occasion during either treatment period (defined as treatment success). Any adverse events were noted. Success rates were compared between treatments using Fisher’s exact test. Results One patient (B12-amoxapine group) withdrew for personal reasons (breakdown of marital relations); all other patients completed the study. Overall success rate was 88% (22/25). Success rate was higher for amoxapine than for vitamin B12 (80%, 20/25 vs 16%, 4/25; P<0.0001). 18 patients were responsive to amoxapine but not to vitamin B12, 2 patients were responsive to vitamin B12 but not amoxapine, 2 patients were responsive to both drugs, and 3 patients had no response to either drug. One patient (4%) reported sleepiness and 2 (8%) reported constipation while receiving amoxapine. No adverse events were reported during vitamin B12 treatment. Conclusions Amoxapine may be an effective, safe and well-tolerated therapy for RE.

Associations of mortality with long-term exposures to fine and ultrafine particles, species and sources: results from the California Teachers Study Cohort.

BACKGROUND: Although several cohort studies report associations between chronic exposure to fine particles (PM2.5) and mortality, few have studied the effects of chronic exposure to ultrafine (UF) particles. In addition, few studies have estimated the effects of the constituents of either PM2.5 or UF particles. METHODS: We used a statewide cohort of > 100,000 women from the California Teachers Study who were followed from 2001 through 2007. Exposure data at the residential level were provided by a chemical transport model that computed pollutant concentrations from > 900 sources in California. Besides particle mass, monthly concentrations of 11 species and 8 sources or primary particles were generated at 4-km grids. We used a Cox proportional hazards model to estimate the association between the pollutants and all-cause, cardiovascular, ischemic heart disease (IHD), and respiratory mortality. RESULTS: We observed statistically significant (p < 0.05) associations of IHD with PM2.5 mass, nitrate, elemental carbon (EC), copper (Cu), and secondary organics and the sources gas- and diesel-fueled vehicles, meat cooking, and high-sulfur fuel combustion. The hazard ratio estimate of 1.19 (95% CI: 1.08, 1.31) for IHD in association with a 10-µg/m3 increase in PM2.5 is consistent with findings from the American Cancer Society cohort. We also observed significant positive associations between IHD and several UF components including EC, Cu, metals, and mobile sources. CONCLUSIONS: Using an emissions-based model with a 4-km spatial scale, we observed significant positive associations between IHD mortality and both fine and ultrafine particle species and sources. Our results suggest that the exposure model effectively measured local exposures and facilitated the examination of the relative toxicity of particle species.

N6-Hydroperoxymethyladenosine: a new intermediate of chemical oxidation of N6-methyladenosine mediated by bicarbonate-activated hydrogen peroxide.

N6-Methyladenosine (m6A) represents a relatively abundant modification in eukaryotic RNA. Because m6A has similar properties to adenosine and a low reactivity, limited research has been focused on this nucleoside. In this study, we revealed an important intermediate in the oxidation of m6A through the bicarbonate-activated peroxide system. Over the course of oxidation, we found a new mechanism in which N6-hydroxymethyladenosine (hm6A), N6-formyladenosine (f6A) and N6-hydroperoxymethyladenosine (oxm6A) were intermediate products, and adenosine was the final product. In this study, oxm6A was isolated using HPLC and characterized by mass spectrometry, NMR and diphenyl-1-pyrenylphosphine (DPPP) fluorescence detection. This study provides a new modified nucleoside and demonstrates oxidative demethylation of m6A by reactive oxygen species at the nucleobase level and in RNA strands.

Congenital primary penile teratoma in a child.

Teratomas rarely present as a pediatric congenital primary penile mass. We describe a 14-month-old boy with a blister-like mass on his distal left penis. The subcutaneous mass measured 1.5 cm (length)×1.0 cm (width)×1.2 cm (height) on ultrasonography. There were clear margins between these structures and the lesion. At the age of 5 years, he received an extirpation surgery. Histologic analysis revealed that it was a mature teratoma. In our view, surgical resection should be the treatment of choice for a pediatric penile mass with the alertness of teratomas because of the possibility of malignant alteration and invasion of adjacent structures till unresectable.

A feedback loop in PPARγ-adenosine A2A receptor signaling inhibits inflammation and attenuates lung damages in a mouse model of LPS-induced acute lung injury.

Although peroxisome proliferator-activated receptor-γ (PPARγ) and adenosine A2A receptor (A2AR) are reported to be anti-inflammatory factors in acute lung injury (ALI), their internal link and synergic or antagonistic effect after activation are poorly understood. Here, we found that PPARγ and A2AR could upregulate the mRNA and protein expressions of each other in lung tissues of LPS-induced mouse ALI model and murine macrophages. Further investigation demonstrated that PPARγ upregulated A2AR expression by directly binding to a DR10 response element (-218 to -197) within A2AR gene promoter region. Instead of directly interacting with PPARγ, A2AR stimulated PPARγ expression via protein kinase A (PKA)-cAMP response element binding protein (CREB) signaling by provoking the binding of CREB to a cAMP responsive element (CRE)-like site in PPARγ gene promoter region. In addition, combination of PPARγ and A2AR agonists was found to exert obviously better effect on suppressing neutrophil infiltration and inflammatory cytokine expressions, attenuating lung edema, pathological changes and improving lung function of blood gas exchange than their single application. These findings reveal a novel functional positive feedback loop between PPARγ and A2AR signaling to potentialize their effect on inhibiting inflammation and attenuating lung damages in ALI. It suggests that targeting this PPARγ-A2AR signaling rather than PPARγ or A2AR alone may be a more attractive and efficient potential therapeutic strategy for ALI.

Chronic or high dose acute caffeine treatment protects mice against oleic acid-induced acute lung injury via an adenosine A2A receptor-independent mechanism.

The antagonism or genetic deletion of adenosine A(2A) receptors has been shown to exacerbate tissue damage in acute lung injury. Caffeine, a widely consumed behavioral drug, acts as a non-selective antagonist of A(2A) receptor and also has additional pharmacological effects. Thus, the protective vs. deleterious effects of caffeine in acute lung injury should be evaluated. In a murine oleic acid-induced model of acute lung injury, we found that chronic caffeine treatment by drinking water (0.1g/l or 0.25g/l for 2 weeks before acute lung injury) or acute caffeine treatment at high dose (i.p. 50mg/kg, injection, 30min before acute lung injury) significantly attenuated the lung edema, hemorrhage, neutrophil recruitment as well as the inflammatory cytokine tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1) expressions in both of the wild type (WT) and A(2A) receptor knockout (KO) mice. This profile was accompanied by increased cAMP levels and up-regulation of A2B receptor mRNAs in the lungs. In contrast, acute caffeine treatment at low dose (i.p. 5mg/kg or 15mg/kg, injection, 30min before acute lung injury) enhanced the inflammation and lung damage in WT mice with decreasing cAMP but not in A(2A) receptor KO mice. These results indicate that caffeine either enhances lung damage by antagonizing A(2A) receptor or exerts protection against lung damage via A(2A) receptor-independent mechanisms, depending on the timing of exposure (chronic vs. acute) and dose of administration (low vs. high). These findings provide new insight of caffeine in acute lung injury and highlight the potential benefit and strategy of caffeine intake or administration for preventing acute lung injury.

[Expression of hypoxia inducible factor-1alpha and relationship thereof to apoptosis related protein in non-small cell lung cancer].

OBJECTIVE: To investigate the expression of hypoxia inducible factor-1alpha (HIF-1alpha) and relationship thereof to survivin and Bax, apoptosis related proteins, in non-small cell lung cancer (NSCLC). METHODS: Immunohistochemistry was used in 52 specimens of NSCLC to detect the expression of HIF-1alpha, survivin and Bax. RESULTS: The positive rates of HIF-1alpha, survivin and Bax were 38.5% (20/52), 48.1% (25/52), and 42.3% (22/52) respectively. The higher the pathological stage of tumor, the higher expression rate of HIF-1alpha (chi2=8.271, P<0.05). The positive rate of HIF-1alpha expression of the patients with lymph node metastasis was higher than that of the patients without lymph node metastasis (chi2=6.370, P<0.05). However, HIF-1alpha expression had no relationship to the pathological type (chi2=0.561, P>0.05) and differentiation degree (chi2=0.326, P>0.05). Correlation analysis showed that the expression of HIF-1alpha was positively correlated with the surviving expression (gamma=0.496, P<0.05) and Bax expression (gamma=0.681, P<0.05). CONCLUSION: The expression of HIF-1alpha is related to the infiltration, metastasis, and apoptosis of NSCLC.