HBB contributes to individualized aconitine-induced cardiotoxicity in mice via interfering with ABHD5/AMPK/HDAC4 axis.

The root of Aconitum carmichaelii Debx. (Fuzi) is an herbal medicine used in China that exerts significant efficacy in rescuing patients from severe diseases. A key toxic compound in Fuzi, aconitine (AC), could trigger unpredictable cardiotoxicities with high-individualization, thus hinders safe application of Fuzi. In this study we investigated the individual differences of AC-induced cardiotoxicities, the biomarkers and underlying mechanisms. Diversity Outbred (DO) mice were used as a genetically heterogeneous model for mimicking individualization clinically. The mice were orally administered AC (0.3, 0.6, 0.9 mg· kg-1 ·d-1) for 7 d. We found that AC-triggered cardiotoxicities in DO mice shared similar characteristics to those observed in clinic patients. Most importantly, significant individual differences were found in DO mice (variation coefficients: 34.08%-53.17%). RNA-sequencing in AC-tolerant and AC-sensitive mice revealed that hemoglobin subunit beta (HBB), a toxic-responsive protein in blood with 89% homology to human, was specifically enriched in AC-sensitive mice. Moreover, we found that HBB overexpression could significantly exacerbate AC-induced cardiotoxicity while HBB knockdown markedly attenuated cell death of cardiomyocytes. We revealed that AC could trigger hemolysis, and specifically bind to HBB in cell-free hemoglobin (cf-Hb), which could excessively promote NO scavenge and decrease cardioprotective S-nitrosylation. Meanwhile, AC bound to HBB enhanced the binding of HBB to ABHD5 and AMPK, which correspondingly decreased HDAC-NT generation and led to cardiomyocytes death. This study not only demonstrates HBB achievement a novel target of AC in blood, but provides the first clue for HBB as a novel biomarker in determining the individual differences of Fuzi-triggered cardiotoxicity.

Physical properties and hydration behavior of a fast-setting bioceramic endodontic material.

BACKGROUND: To investigate the physical properties and the hydration behaviour of the fast-setting bioceramic iRoot FS Fast Set Root Repair Material (iRoot FS) and three other endodontic cements. METHODS: iRoot FS, Endosequence Root Repair Material Putty (ERRM Putty), gray and white mineral trioxide aggregate (G-MTA & W-MTA), and intermediate restorative material (IRM) were evaluated. The setting time was measured using ANSI/ADA standards. Microhardness was evaluated using the Vickers indentation test. Compressive strength and porosity were investigated at 7 and 28 days. Differential scanning calorimetry (DSC) was employed for the hydration test. RESULTS: iRoot FS had the shortest setting time of the four bioceramic cements (p < .001). The microhardness values of iRoot FS, ERRM Putty and MTA increased at different rates over the 28 days period. At day one, ERRM Putty had the lowest microhardness of the bioceramic cements (p < .001), but reached the same level as MTA at 4, 7 and 28 days. The microhardness of iRoot FS was lower than that of W-MTA at 7 and 28 days (p < .05). The porosity of the materials did not change after 7 days (p < .05). The compressive strength values at 28 days were significantly greater for all bioceramic groups compared to those at 7 days (p < .01). ERRM Putty had the highest compressive strength and the lowest porosity of the evaluated bioceramic cements (p < .05), followed by iRoot FS, W-MTA, and G-MTA, respectively. DSC showed that iRoot FS hydrated fastest, inducing an intense exothermic reaction. The ERRM Putty did not demonstrate a clear exothermic peak during the isothermal calorimetry test. CONCLUSIONS: iRoot FS had a faster setting time and hydrating process than the other bioceramic cements tested. The mechanical properties of iRoot FS, G-MTA and W-MTA were relatively similar.

[Preliminary study on the efficacy and safety of oral sildenafil in pulmonary arterial hypertension in China].

OBJECTIVE: Sildenafil has been shown to be effective in pulmonary arterial hypertension (PAH). However, the impact of sildenafil on PAH has been under-investigated in China. The aim of the present study was to evaluate the efficacy and safety of oral sildenafil in PAH patients in China. METHODS: In this prospective, open-label and multi-center study, 90 patients were recruited from 14 centers to receive oral sildenafil (75 mg/d) for 12 weeks. They underwent a six-minute walk test (SMWT) and cardiac catheterization at the beginning and the end of 12 weeks. The primary endpoint was the changes in exercise capacity as assessed by SMWT. And the secondary endpoints included assessment of functional class, evaluation of cardiopulmonary hemodynamics and clinical deterioration (defined as death, transplantation and re-hospitalization for PAH). Drug safety and tolerability were also examined. RESULTS: There were 19 males and 71 females with an average age of 32.5 ± 12.1 years old (range: 18 - 61). Their etiologies were idiopathic (n = 15), related with congenital heart disease (n = 60), or related with connective tissue disease (n = 9) and chronic thromboembolic pulmonary hypertension (n = 6). Oral sildenafil significantly increased the SMWT distances [(342 ± 93) m vs. (403 ± 88) m, P < 0.001]. There was also remarkable improvement in Borg dyspnea score (2.9 ± 2.6 vs. 2.4 ± 2.0, P = 0.005). Furthermore, significant improvements in World Healthy Organization (WHO) functional class and cardiopulmonary hemodynamics were also found (mean pulmonary artery pressure, P < 0.001; cardiac index, P < 0.001; pulmonary vascular resistance, P < 0.001). Side effects were mild and consistent with other reports. CONCLUSION: This study confirms and extends previous studies. Oral sildenafil is both safe and effective for the treatment of adult PAH patients in China.

Diurnally Fluctuating pCO2 Modifies the Physiological Responses of Coral Recruits Under Ocean Acidification.

Diurnal pCO2 fluctuations have the potential to modulate the biological impact of ocean acidification (OA) on reef calcifiers, yet little is known about the physiological and biochemical responses of scleractinian corals to fluctuating carbonate chemistry under OA. Here, we exposed newly settled Pocillopora damicornis for 7 days to ambient pCO2, steady and elevated pCO2 (stable OA) and diurnally fluctuating pCO2 under future OA scenario (fluctuating OA). We measured the photo-physiology, growth (lateral growth, budding and calcification), oxidative stress and activities of carbonic anhydrase (CA), Ca-ATPase and Mg-ATPase. Results showed that while OA enhanced the photochemical performance of in hospite symbionts, it also increased catalase activity and lipid peroxidation. Furthermore, both OA treatments altered the activities of host and symbiont CA, suggesting functional changes in the uptake of dissolved inorganic carbon (DIC) for photosynthesis and calcification. Most importantly, only the fluctuating OA treatment resulted in a slight drop in calcification with concurrent up-regulation of Ca-ATPase and Mg-ATPase, implying increased energy expenditure on calcification. Consequently, asexual budding rates decreased by 50% under fluctuating OA. These results suggest that diel pCO2 oscillations could modify the physiological responses and potentially alter the energy budget of coral recruits under future OA, and that fluctuating OA is more energetically expensive for the maintenance of coral recruits than stable OA.

Oral sildenafil therapy for Chinese patients with pulmonary arterial hypertension: a multicenter study.

The impact of sildenafil on pulmonary arterial hypertension (PAH) in Chinese patients has been less investigated. A prospective, open-label, uncontrolled and multicenter study, therefore, was carried out to address this issue. Ninety patients with multicause-induced PAH received oral sildenafil (75 mg/day) for 12 weeks. The 6-minute walk test (SMWT) and cardiac catheterization were performed at the beginning and the end of the 12 weeks. The primary endpoint was the changes in exercise capacity assessed by the SMWT; the secondary endpoint included assessment of functional class, evaluation of cardiopulmonary hemodynamics, and clinical worsening. Drug safety and tolerability were also examined. The results showed that there was a significant improvement in SMWT distances (342 ± 93 m vs 403 ± 88 m, P < .0001), Borg dyspnea score (2.9 ± 2.6 vs 2.4 ± 2.0, P = .0046), World Health Organization functional class, and cardiopulmonary hemodynamics (mean pulmonary artery pressure, P < .0001; cardiac index, P < .0001; pulmonary vascular resistance, P < .0001) after 12 weeks of oral sidenafil therapy. Almost all enrolled patients did not experience significant clinical worsening. This study confirms and extends the findings of previous studies relating to effects of sildenafil on PAH, suggesting that oral sildenafil is safe and effective for the treatment of adult patients with PAH in the Chinese population.

Vena cava thrombosis after vena cava filter placement: Incidence and risk factors.

BACKGROUND: The objective of this study was to assess the clinical safety and efficacy of vena cava filter (VCF) placement, with particular emphasis on the incidence and risk factors of inferior vena cava thrombosis (VCT) after VCF placement. METHODS: Clinical data of patients with venous thromboembolism (VTE), with or without placement of VCF, were analyzed in a retrospective single-center audit of medical records from January 2005 to June 2009. The collected data included demographics, procedural details, filter type, indications, and complications. RESULTS: A total of 168 cases of VTE (82 with VCF; 86 without VCF) were examined. Over a median follow-up of 24.2 months, VCT occurred in 18 of 82 patients with VCFs (11 males, 7 females, mean age 55.4 years). In 86 patients without VCFs, VCT occurred in only 6 individuals (4 males, 2 females) during the study period. VCT was observed more frequently in patients fitted with VCFs than in those without VCFs (22% vs. 7.0%). CONCLUSIONS: The incidence of VCT in patients with VTE after VCF implantation was 22% approximately. Anticoagulation therapy should be continued for all patients with VCF placement, unless there is a specific contraindication. Almost all instances of VCT in patients with VCF implants in our study occurred after stopping anticoagulation treatment. The use of VCFs is increasing, and more trials are needed to confirm their benefit and accurately assess their safety.

[Changes in cerebral blood flow during mastication in patients receiving prosthesis insertion for repairing maxillary defect].

OBJECTIVE: To investigate the changes in cerebral blood flow in patients with maxillary defect treated with prosthesis insertion. METHODS: Thirty patients with maxillary defect receiving obturator prosthesis insertion were enrolled with another 30 subjects without dentition defect as the control. The cerebral blood flow rate was recorded before and at 5 and 10 min during mastication, and the results were analyzed statistically. RESULTS: There was no significant difference in Vs, Vd or Vm between the two groups at the time points for measurement. CONCLUSION: The blood supply by the middle cerebral artery is similar between the patients receiving obturator prosthesis insertion for maxillary defect and the subjects with full denture.

Impact of sildenafil therapy on pulmonary arterial hypertension in adults with congenital heart disease.

BACKGROUND: It has been demonstrated that sildenafil is effective in patients with pulmonary arterial hypertension (PAH). However, the impact of sildenafil on PAH in adults with congenital heart disease (CHD) has been less investigated. OBJECTIVE: In this prospective, open-label, uncontrolled and multicenter study, 60 patients with PAH related to CHD received oral sildenafil (75 mg/day) for 12 weeks. The enrolled patients underwent six-minute walk test (SMWT) and cardiac catheterization at the beginning and the end of the 12 weeks. The primary end point was the changes in exercise capacity assessed by SMWT; the secondary end point included assessment of functional class, evaluation of cardiopulmonary hemodynamics, and clinical worsening (defined as death, transplantation, and rehospitalization for PAH). Drug safety and tolerability were also examined. RESULTS: Oral sidenafil significantly increased SMWT distances (422.94 ± 76.95 m vs. 371.99 ± 78.73 m, P < 0.0001). There was also remarkable improvement in Borg dyspnea score (2.1 ± 1.32 vs. 2.57 ± 1.42, P = 0.0307). Moreover, significant improvements in World Healthy Organization (WHO) functional class and cardiopulmonary hemodynamics were also discovered (mean pulmonary artery pressure, P = 0.0002; cardiac index, P < 0.0001; pulmonary vascular resistance, P < 0.0001). Side effects in this study were mild and consistent with reported studies. None of the enrolled patients experienced significant clinical worsening. CONCLUSIONS: This study confirmed and extended previous studies. It suggested that oral sildenafil was safe and effective for the treatment of adult patients with CHD-related PAH.