Clonal Hematopoiesis and Cardiovascular Disease in Patients With Multiple Myeloma Undergoing Hematopoietic Cell Transplant.

Importance: There is a paucity of information on the association between clonal hematopoiesis of indeterminate potential (CHIP) and cardiovascular disease (CVD) in patients with cancer, including those with multiple myeloma (MM) undergoing hematopoietic cell transplant (HCT), a population at high risk of developing CVD after HCT. Objective: To examine the association between CHIP and CVD in patients with MM and to describe modifiers of CVD risk among those with CHIP. Design, Setting, and Participants: This was a retrospective cohort study of patients with MM who underwent HCT between 2010 and 2016 at City of Hope Comprehensive Cancer Center in Duarte, California, and had pre-HCT mobilized peripheral blood stem cell (PBSC) products cryopreserved and accessible for CHIP analyses. The study team performed targeted panel DNA sequencing to detect the presence of CHIP (variant allele frequency 2% or more). Main Outcomes and Measures: The primary end point was the 5-year cumulative incidence and risk for developing de novo CVD (heart failure, coronary artery disease, or stroke) after HCT. Results: Of 1036 consecutive patients with MM (580 male [56%]; median age, 60.0 years) who underwent a first autologous HCT, 201 patients had at least 1 CHIP variant (19.4%) and 35 patients had 2 or more variants (3.4%). The 5-year incidence of CVD was significantly higher in patients with CHIP (21.1% vs 8.4%; P < .001) compared with those without CHIP; the 5-year incidence among those with 2 or more variants was 25.6%. In the multivariable model, CHIP was associated with increased risk of CVD (hazard ratio [HR], 2.72; 95% CI, 1.70-4.39), as well as of individual outcomes of interest, including heart failure (HR, 4.02; 95% CI, 2.32-6.98), coronary artery disease (HR, 2.22; 95% CI, 1.06-4.63), and stroke (HR, 3.02; 95% CI, 1.07-8.52). Patients who had both CHIP and preexisting hypertension or dyslipidemia were at nearly 7-fold and 4-fold increased risk of CVD, respectively (reference: no CHIP, no hypertension, or dyslipidemia). Conclusion and Relevance: CHIP was significantly and independently associated with risk of CVD in patients with MM undergoing HCT and may serve as a novel biologically plausible biomarker for CVD in this cohort. Patients with MM and both CHIP and cardiovascular risk factors had an exceptionally high risk of CVD. Additional studies are warranted to determine if cardiovascular preventive measures can reduce CHIP-associated CVD risk.

The hyperthermic response to intra-preoptic area administration of agmatine in male rats.

Agmatine is an endogenous biogenic amine that exerts various effects on the central nervous system. The hypothalamic preoptic area (POA, thermoregulatory command center) has high agmatine immunoreactivity. In this study, in conscious and anesthetized male rats, agmatine microinjection into the POA induced hyperthermic responses associated with increased heat production and locomotor activity. Intra-POA administration of agmatine increased the locomotor activity, the brown adipose tissue temperature and rectum temperature, and induced shivering as demonstrated by increased neck muscle electromyographic activity. However, intra-POA administration of agmatine almost had no impact on the tail temperature of anesthetized rats. Furthermore, there were regional differences in the response to agmatine in the POA. The most effective sites for the microinjection of agmatine to elicit hyperthermic responses were localized in the medial preoptic area (MPA). Agmatine microinjection into the median preoptic nucleus (MnPO) and lateral preoptic nucleus (LPO) had a minimal effect on the mean core temperature. Analysis of the in vitro discharge activity of POA neurons in brain slices when perfused with agmatine showed that agmatine inhibited most warm-sensitive but not temperature-insensitive neurons in the MPA. However, regardless of thermosensitivity, the majority of MnPO and LPO neurons were not responsive to agmatine. The results demonstrated that agmatine injection into the POA of male rats, especially the MPA, induced hyperthermic responses, which may be associated with increased BAT thermogenesis, shivering and locomotor activity by inhibiting warm-sensitive neurons.

Emodin improves alveolar hypercoagulation and inhibits pulmonary inflammation in LPS-provoked ARDS in mice via NF-κB inactivation.

BACKGROUND: Alveolar hypercoagulation and pulmonary inflammation are important characteristics and they regulate each other in acute respiratory distress syndrome (ARDS). NF-κB pathway has been confirmed to be involved in regulation of this crosstalk. Emodin, a traditional Chinese herb, shows potent inhibitory effect on NF-κB pathway, but whether it is effective in alveolar hypercoagulation and pulmonary inflammation in ARDS remains to be elucidated. PURPOSE: The aim of this experiment was to evaluate the efficacy of emodin on LPS-provoked alveolar hypercoagulation and excessive pulmonary inflammation in ARDS, and its potential mechanism. METHODS: Mice ARDS was set up through LPS (40 µl, 4 mg/ml) inhalation. Male mice were randomly received with BPS, LPS only, LPS+ emodin (5 mg/kg, 10 mg/kg, 20 mg/kg, respectively) and BAY65-1942, an inhibitor of IKKß. After 48 h of LPS stimulation, pulmonary pathological injury, expressions of Tissue factor (TF), plasminogen activator inhibitor (PAI)-1, activated protein C (APC), collagen Ⅰ, collagen III, interleukin (IL) 8, IL-1ß and tumor necrosis factor (TNF)-α in lung tissues, as well as concentrations of antithrombin III (AT III), procollagen peptide type III (PIIIP), soluble thrombomodulin (sTM), thrombin antithrombin complex (TAT), myeloperoxidase (MPO) and the percentage of inflammatory cells in bronchoalveolar lavage fluid (BALF) were all determined. NF-κB pathway activation as well as NF-κB DNA binding activity in pulmonary tissue were simultaneously checked. RESULTS: LPS stimulation resulted in obvious lung injury, excessive inflammatory cells infiltration, which all were dose-dependently ameliorated by emodin. Expressions of TF, PAI-1, collagen Ⅰ and collagen III as well as IL-8, IL-1ß and TNF-α in pulmonary tissue were all elevated while APC decreased under LPS provocation, which were all reversed by emodin treatment in dose-dependent manner. LPS promoted the secretions of PIIIP, sTM, TAT and inhibited AT III production in BALF, and resulted in high levels of MPO and the percentage of inflammatory cells in BALF, all of which were significantly and dose-dependently attenuated while AT III production was increased by emodin. Meanwhile, emodin effectively inhibited NF-κB pathway activation and attenuated p65 DNA binding activity induced by LPS inhalation. Emodin and BAY-65-1942 had similar impacts in this experiment. CONCLUSIONS: Emodin improves alveolar hypercoagulation and fibrinolytic inhibition and depresses excessive pulmonary inflammation in ARDS mice in dose-dependent manner via NF-κB inactivation. Our data demonstrate that emodin is expected to be an effective drug in alveolar hypercoagulation and pulmonary inflammation in ARDS.

[Xuebijing improves clinical prognosis and reduces mortality in patients with acute paraquat poisoning: a Meta-analysis included 1 429 patients].

OBJECTIVE: To explore the therapeutic effect of Xuebijing on patients with acute paraquat poisoning (APP) by using systematic evaluation method. METHODS: PubMed, Cochrane Library, Embase, Wanfang database, China National Knowledge Infrastructure (CNKI), VIP database (VIP) and China Biology Medicine (CBM) were searched using the computers to find the literatures published about the Xuebijing injection for the treatment of APP. Randomized controlled trials (RCT) were retrieved from the establishment of the database to August 2019. Patients in experimental group were treated with Xuebijing injection combined with conventional treatment, while the patients in control group were only given conventional treatment. The patients' outcome included the 14-day mortality, arterial oxygen saturation (SaO2) and incidence of pulmonary fibrosis. In addition, the 6-month survival rate, alanine aminotransferase (ALT), serum creatinine (SCr), C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), malondialdehyde (MDA) and superoxide dismutase (SOD) between the two groups were compared. The literature data were extracted by two researchers independently, and the quality of the literatures was evaluated according to the Cochrane 5.1 handbook. The Meta-analysis was performed by using RevMan 5.3 software. The results stability of Meta-analysis was tested by sensitivity analysis. The publication bias was analyzed through drawing of funnel diagram. RESULTS: Twenty-seven RCT studies in total were enrolled, of which 26 were in Chinese and 1 was in English. A total of 1 429 patients were enrolled, among whom 726 were in experimental group and another 703 were in control group. Meta-analysis showed that compared with the control group, the 14-day mortality [relative risk (RR) = 0.62, 95% confidence interval (95%CI) was 0.54 to 0.72, P < 0.000 01] and incidence of pulmonary fibrosis (RR = 0.67, 95%CI was 0.53 to 0.85, P = 0.000 9) of patients in the experimental group were significantly lowered, while SaO2 at 7 days and 14 days were significantly increased [7 days: mean difference (MD) = 16.86, 95%CI was 9.89 to 23.83, P < 0.000 01; 14 days: MD = 16.51, 95%CI was 10.22 to 22.80, P < 0.000 01]. Compared with the control group, the survival rate within 6 months (RR = 1.55, 95%CI was 1.41 to 1.71, P < 0.000 01) and SOD (MD = 13.88, 95%CI was 7.43 to 20.33, P < 0.000 1) of patients in the experimental group were significantly increased, ALT at 14 days (MD = -78.35, 95%CI was -127.35 to -29.34, P = 0.000 5), SCr at 7 days and 14 days (7 days: MD = -135.13, 95%CI was -219.09 to -51.17, P = 0.002; 14 days: MD = -206.05, 95%CI = -290.13 to -121.96, P < 0.000 01), CRP (MD = -11.55, 95%CI was -17.77 to -5.33, P = 0.000 3), TNF-α (MD = -9.27, 95%CI was -15.48 to -3.96, P = 0.000 9) and MDA (MD = -1.27, 95%CI was -1.57 to -0.96, P < 0.000 01) were significantly lowered. The overall effect value of the parameters with high heterogeneity was not significantly changed after further Meta-analysis excluding any one of the studies, suggesting that the result was relatively stable. Funnel chart analysis was used to analyze the parameters from more than 10 articles enrolled, and it showed that there was publication bias. CONCLUSIONS: Xuebijing injection can reduce the mortality of patients with APP, which may because that it can improve liver and kidney function, reduce inflammation and oxidative stress damage, inhibit pulmonary fibrosis and increase oxygenation level.