Tetrahydrobiopterin (BH4) is an essential cofactor for endothelial nitric oxide (NO) synthase. Guanosine 5′-triphosphate cyclohydrolase-I (GTPCH-I) is a key limiting enzyme for BH4 synthesis. In the present in vitro study, we investigated whether peroxisome proliferator-activated receptor α (PPAR-α) agonist fenofibrate could recouple eNOS by reversing low-expression of intracellular BH4 in endothelial cells and discussed the potential mechanisms. After human umbilical vein endothelial cells (HUVECs) were treated with lipopolysaccharide (LPS) for 24 hours, the levels of cellular eNOS, BH4 and cell supernatant NO were significantly reduced compared to control group. And the fluorescence intensity of intracellular ROS was significantly increased. But pretreated with fenofibrate (10 umol/L) for 2 hours before cells were induced by LPS, the levels of eNOS, NO, and BH4 were significantly raised compared to LPS treatment alone. ROS production was markedly reduced in fenofibrate group than LPS group. In addition, our results showed that the level of intracellular GTPCH-I detected by western blot was increased in a concentration-dependent manner after being treated with fenofibrate. These results suggested that fenofibrate might help protect endothelial function and against atherosclerosis by increasing level of BH4 and decreasing production of ROS through upregulating the level of intracellular GTPCH-I.

SUMMARYIntroduction: Fenofibrate, an agonist of peroxisome proliferator-activated receptor-α (PPAR-α), has a vascular protective effect. Aims: We investigated the effect of the PPAR-α agonist on coronary artery endothelial function in patients with hypertriglyceridemia. Methods: Fifty-eight patients with hypertriglyceridemia were divided into two groups: control (no treatment; n = 23) and fenofibrate treatment (n = 35), 200 mg/d, for 6 months. The patients had undergone rest and adenosine treatment to induce hyperemia for quantification of coronary flow velocity reserve (CFVR) by noninvasive Doppler echocardiography before treatment and at 6-month follow-up. Pulse wave velocity (PWV) was measured before treatment and at 6-month follow-up. Results: CFVR was significantly improved with fenofibrate treatment as compared with baseline level and control group (3.14 ± 0.36 vs. 2.80 ± 0.58 and 2.79 ± 0.65, P < 0.01 and 0.05, respectively), with no difference between baseline levels and untreated controls. In addition, at 6 months, plasma level of homocysteine was significantly increased with fenofibrate treatment as compared with at baseline and control group (median 18.13 [range 14.46-22.02] μmol/L vs. 14.09 [12.01-18.81] and 13.34 [9.69-17.06] μmol/L, P < 0.001 and 0.01, respectively). Furthermore, at 6 months, PWV was significantly decreased with fenofibrate treatment as compared with control group (1446 ± 136 cm/s vs. 1570 ± 203 cm/s, P < 0.05). Conclusions: Treatment with PPAR-α agonist fenofibrate significantly improved CFVR and arterial stiffness in patients with hypertriglyceridemia. This endothelial protective effect may be reduced in part by the side effect of increasing homocysteine.

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ObjectivesTo develop and validate a predictive model for evaluating in-hospital mortality risk in elderly patients with community-acquired pneumonia.SettingTwo tertiary care hospitals with 2000 beds and 1000 beds respectively in Beijing, China.ParticipantsElderly patients (age ≥ 65 years) with community-acquired pneumonia admitted to the Department of Internal Medicine of the two hospitals from January 2010 to December 2019 or from January 2019 to December 2019 respectively.DesignIt was a retrospective study. After dividing the data set into training and validation sets, we created a mortality model that included patient demographics, hospitalization time, hospital outcome, and various clinical conditions associated with hospitalization. We then applied the model to the validation set.Main outcome measuresIn-hospital mortality.ResultsThe training cohort included 2,466 patients admitted to the one hospital, while the validation cohort included 424 patients at the other hospital. The overall in-hospital mortality rate was 15.6%. In the multivariable model, age, respiratory failure, heart failure, and malignant tumors were associated with mortality. The model had excellent discrimination with AUC values of 0.877 and 0.930 in the training and validation cohorts, respectively.ConclusionsThe predictive model to evaluate in-hospital mortality in elderly patients with community-acquired pneumonia, which was established based on administrative data, provides a simple tool for physicians to assess the prognosis of elderly patients with community-acquired pneumonia in Beijing.Strengths and limitations of this studyThe clinical data collected were obtained from a large retrospective cohort over a 10-year period, resulting in good reliability.The model based on administrative data can help healthcare workers determine the prognosis and outcomes of elderly patients of CAP, especially in resource limited regions in China.Our main outcome was in-hospital mortality, not 30-day mortality or longer.All included cases were collected from inpatient, outpatient and emergency patients were not included.The model was only verified in two hospitals in Beijing and further verification should be conducted in other areas and different levels of hospitals.