A novel long noncoding RNA-lncRNA-AABR07066529.3 alleviates inflammation, apoptosis, and pyroptosis by inhibiting MyD88 in lipopolysaccharide-induced myocardial depression.

Sepsis-induced myocardial depression (SIMD) is common in pediatric intensive care units and seriously threatens children's health. Recently, long noncoding RNAs (lncRNAs) have been showed to play important roles in various diseases; however, its role in SIMD is unclear. In this study, we used lipopolysaccharide (LPS)-treated rats and H9c2 cardiomyocytes to mimic SIMD in vivo and in vitro. We found that the expression of a novel lncRNA, we named lncRNA-AABR07066529.3, was elevated in LPS-induced rat heart tissue and H9c2 cardiomyocytes. In addition, LPS-induced inflammation, apoptosis, and pyroptosis were significantly exacerbated after lncRNA-AABR07066529.3 knockdown. Moreover, we found that myeloid differentiation factor 88 (MyD88) was upregulated in LPS-treated groups and was inhibited by lncRNA-AABR07066529.3. Besides, MyD88 knockdown abolished lncRNA-AABR07066529.3 silencing effects on inflammation, apoptosis, and pyroptosis induced by LPS in H9c2 cardiomyocytes. In our study, we found lncRNA-AABR07066529.3 exerted protective effects on LPS-induced cardiomyocytes by regulating MyD88 and might serve as a potential treatment target for SIMD.

ATIC-Associated De Novo Purine Synthesis Is Critically Involved in Proliferative Arterial Disease.

BACKGROUND: Proliferation of vascular smooth muscle cells (VSMCs) is a hallmark of arterial diseases, especially in arterial restenosis after angioplasty or stent placement. VSMCs reprogram their metabolism to meet the increased requirements of lipids, proteins, and nucleotides for their proliferation. De novo purine synthesis is one of critical pathways for nucleotide synthesis. However, its role in proliferation of VSMCs in these arterial diseases has not been defined. METHODS: De novo purine synthesis in proliferative VSMCs was evaluated by liquid chromatography-tandem mass spectrometry. The expression of ATIC (5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase), the critical bifunctional enzyme in the last 2 steps of the de novo purine synthesis pathway, was assessed in VSMCs of proliferative arterial neointima. Global and VSMC-specific knockout of Atic mice were generated and used for examining the role of ATIC-associated purine metabolism in the formation of arterial neointima and atherosclerotic lesions. RESULTS: In this study, we found that de novo purine synthesis was increased in proliferative VSMCs. Upregulated purine synthesis genes, including ATIC, were observed in the neointima of the injured vessels and atherosclerotic lesions both in mice and humans. Global or specific knockout of Atic in VSMCs inhibited cell proliferation, attenuating the arterial neointima in models of mouse atherosclerosis and arterial restenosis. CONCLUSIONS: These results reveal that de novo purine synthesis plays an important role in VSMC proliferation in arterial disease. These findings suggest that targeting ATIC is a promising therapeutic approach to combat arterial diseases.

TET2 Protects Against Vascular Smooth Muscle Cell Apoptosis and Intimal Thickening in Transplant Vasculopathy.

BACKGROUND: Coronary allograft vasculopathy (CAV) is a devastating sequela of heart transplant in which arterial intimal thickening limits coronary blood flow. There are currently no targeted therapies to prevent or reduce this pathology that leads to transplant failure. Vascular smooth muscle cell (VSMC) phenotypic plasticity is critical in CAV neointima formation. TET2 (TET methylcytosine dioxygenase 2) is an important epigenetic regulator of VSMC phenotype, but the role of TET2 in the progression of CAV is unknown. METHODS: We assessed TET2 expression and activity in human CAV and renal transplant samples. We also used the sex-mismatched murine aortic graft model of graft arteriopathy (GA) in wild-type and inducible smooth muscle-specific Tet2 knockout mice; and in vitro studies in murine and human VSMCs using knockdown, overexpression, and transcriptomic approaches to assess the role of TET2 in VSMC responses to IFNγ (interferon γ), a cytokine elaborated by T cells that drives CAV progression. RESULTS: In the present study, we found that TET2 expression and activity are negatively regulated in human CAV and renal transplant samples and in the murine aortic graft model of GA. IFNγ was sufficient to repress TET2 and induce an activated VSMC phenotype in vitro. TET2 depletion mimicked the effects of IFNγ, and TET2 overexpression rescued IFNγ-induced dedifferentiation. VSMC-specific TET2 depletion in aortic grafts, and in the femoral wire restenosis model, resulted in increased VSMC apoptosis and medial thinning. In GA, this apoptosis was tightly correlated with proliferation. In vitro, TET2-deficient VSMCs undergo apoptosis more readily in response to IFNγ and expressed a signature of increased susceptibility to extrinsic apoptotic signaling. Enhancing TET2 enzymatic activity with high-dose ascorbic acid rescued the effect of GA-induced VSMC apoptosis and intimal thickening in a TET2-dependent manner. CONCLUSIONS: TET2 is repressed in CAV and GA, likely mediated by IFNγ. TET2 serves to protect VSMCs from apoptosis in the context of transplant vasculopathy or IFNγ stimulation. Promoting TET2 activity in vivo with systemic ascorbic acid reduces VSMC apoptosis and intimal thickening. These data suggest that promoting TET2 activity in CAV may be an effective strategy for limiting CAV progression.

Genetic risk for major depressive disorder and loneliness in sex-specific associations with coronary artery disease.

Major depressive disorder (MDD) and loneliness are phenotypically and genetically correlated with coronary artery disease (CAD), but whether these associations are explained by pleiotropic genetic variants or shared comorbidities is unclear. To tease apart these scenarios, we first assessed the medical morbidity pattern associated with genetic risk factors for MDD and loneliness by conducting a phenome-wide association study in 18,385 European-ancestry individuals in the Vanderbilt University Medical Center biobank, BioVU. Polygenic scores for MDD and loneliness were developed for each person using previously published meta-GWAS summary statistics, and were tested for association with 882 clinical diagnoses ascertained via billing codes in electronic health records. We discovered strong associations with heart disease diagnoses, and next embarked on targeted analyses of CAD in 3893 cases and 4197 controls. We found odds ratios of 1.11 (95% CI, 1.04-1.18; P 8.43 × 10-4) and 1.13 (95% CI, 1.07-1.20; P 4.51 × 10-6) per 1-SD increase in the polygenic scores for MDD and loneliness, respectively. Results were similar in patients without psychiatric symptoms, and the increased risk persisted in females even after adjusting for multiple conventional risk factors and a polygenic score for CAD. In a final sensitivity analysis, we statistically adjusted for the genetic correlation between MDD and loneliness and re-computed polygenic scores. The polygenic score unique to loneliness remained associated with CAD (OR 1.09, 95% CI 1.03-1.15; P 0.002), while the polygenic score unique to MDD did not (OR 1.00, 95% CI 0.95-1.06; P 0.97). Our replication sample was the Atherosclerosis Risk in Communities (ARIC) cohort of 7197 European-ancestry participants (1598 incident CAD cases). In ARIC, polygenic scores for MDD and loneliness were associated with hazard ratios of 1.07 (95% CI, 0.99-1.14; P = 0.07) and 1.07 (1.01-1.15; P = 0.03), respectively, and we replicated findings from the BioVU sensitivity analyses. We conclude that genetic risk factors for MDD and loneliness act pleiotropically to increase CAD risk in females.

CaO-Nanoparticle-Enriched Polydopamine-Coated Hyper-Crosslinked Polymers as Heterogeneous Catalysts for the Transesterification of Vegetable Oils.

Biodiesel is an alternative fuel produced by the transesterification of vegetable oils in the presence of homogeneous or heterogeneous catalysts. Herein, we report the transesterification of vegetable oils using CaO nanoparticles supported on a polydopamine-coated hyper-crosslinked polymer, CaO@PDA-HCP as a heterogeneous catalyst. The effect of CaO-nanoparticle concentration (5-20 wt%) on catalysis performance was investigated, and the PDA-HCP surface was examined by X-ray diffraction, X-ray photoelectron spectroscopy, Fourier-transform infrared spectroscopy, field emission scanning electron microscopy, transmission electron microscopy, and energy dispersive X-ray spectroscopy. Basicity was shown to greatly influence the methyl ester content, and the best catalyst (15 wt% CaO) was demonstrated to be reusable without any loss of activity.

Lipocalin-Like Prostaglandin D Synthase but Not Hemopoietic Prostaglandin D Synthase Deletion Causes Hypertension and Accelerates Thrombogenesis in Mice.

Prostaglandin (PG) D2 is formed by two distinct PGD synthases (PGDS): lipocalin-type PGDS (L-PGDS), which acts as a PGD2-producing enzyme and as extracellular lipophilic transporter, and hematopoietic PGDS (H-PGDS), a σ glutathione-S-transferase. PGD2 plays an important role in the maintenance of vascular function; however, the relative contribution of L-PGDS- and H-PGDS-dependent formation of PGD2 in this setting is unknown. To gain insight into the function played by these distinct PGDS, we assessed systemic blood pressure (BP) and thrombogenesis in L-Pgds and H-Pgds knockout (KO) mice. Deletion of L-Pgds depresses urinary PGD2 metabolite (PGDM) by ∼35%, whereas deletion of H-Pgds does so by ∼90%. Deletion of L-Pgds, but not H-Pgds, elevates BP and accelerates the thrombogenic occlusive response to a photochemical injury to the carotid artery. HQL-79, a H-PGDS inhibitor, further depresses PGDM in L-Pgds KO mice, but has no effect on BP or on the thrombogenic response. Gene expression profiling reveals that pathways relevant to vascular function are dysregulated in the aorta of L-Pgds KOs. These results indicate that the functional impact of L-Pgds deletion on vascular homeostasis may result from an autocrine effect of L-PGDS-dependent PGD2 on the vasculature and/or the L-PGDS function as lipophilic carrier protein.

Measuring niacin-associated skin toxicity (NASTy) stigmata along with symptoms to aid development of niacin mimetics.

Though cardioprotective, niacin monotherapy is limited by unpleasant cutaneous symptoms mimicking dermatitis: niacin-associated skin toxicity (NASTy). Niacin is prototypical of several emerging drugs suffering off-target rubefacient properties whereby agonizing the GPR109A receptor on cutaneous immune cells provokes vasodilation, prompting skin plethora and rubor, as well as dolor, tumor, and calor, and systemically, heat loss, frigor, chills, and rigors. Typically, NASTy effects are described by subjective patient-reported perception, at best semi-quantitative and bias-prone. Conversely, objective, quantitative, and unbiased methods measuring NASTy stigmata would facilitate research to abolish them, motivating development of several objective methods. In early drug development, such methods might better predict clinical tolerability in larger clinical trials. Measuring cutaneous stigmata may also aid investigations of vasospastic, ischemic, and inflammatory skin conditions. We present methods to measure NASTy physical stigmata to facilitate research into novel niacin mimetics/analogs, detailing characteristics of each technique following niacin, and how NASTy stigmata relate to symptom perception. We gave niacin orally and measured rubor by colorimetry and white-light spectroscopy, plethora by laser Doppler flowmetry, and calor/frigor by thermometry. Surprisingly, each stigma's abruptness predicted symptom perception, whereas peak intensity did not. These methods are adaptable to study other rubefacient drugs or dermatologic and vascular disorders.

[Risk factors for the development of acute respiratory distress syndrome in children with measles].

OBJECTIVE: To study the risk factors for the development of acute respiratory distress syndrome (ARDS) in children with measles. METHODS: The clinical data of 55 children with measles were retrospectively studied. Of the 55 children, 11 were complicated by ARDS. The risk factors for the development of ARDS were investigated by univariate analysis and multivariate non-conditional logistic regression analysis. RESULTS: The univariate analysis showed that there were significant differences in the oxygen inhalation mode (nasal catheter/mask), the rate of sepsis, blood C-reactive protein (CRP) levels and lymphocyte counts at admission between the ARDS and non-ARDS groups (P<0.05). The presence of sepsis and higher blood CRP levels were identified as the major risk factors for the development of ARDS by the multivariate logistic regression analysis (OR=116.444, 1.050 respectively; P<0.05). CONCLUSIONS: The children with measles who have sepsis and higher blood CRP levels are at risk of ARDS.

[Short-term prognostic factors in children with acute liver failure].

OBJECTIVE: To investigate the factors that influence the short-term (6 months) prognosis in children with acute liver failure. METHODS: The clinical information of 53 children with acute liver failure treated between June 2008 and September 2013 was retrospectively analyzed. The patients were divided into survival group (n=21) and death group (n=32) according to their outcomes. The liver function parameters and incidence of complications were compared between the two groups, and multivariate logistic regression analysis was used to identify major factors affecting the short-term prognosis in these patients. RESULTS: There were significant differences between the death and survival groups in the indices of international normalized ratio (INR), blood ammonia and serum albumin (Alb), and complications such as hepatic encephalopathy, gastrointestinal hemorrhage, and multiple organ failure (P<0.05). Multivariate logistic regression analysis demonstrated that serum Alb, INR, and hepatic encephalopathy were the major factors affecting the short-term prognosis of acute liver failure (OR=0.616, 75.493 and 1210.727 respectively; P<0.05). CONCLUSIONS: INR, hepatic encephalopathy and serum Alb are the major factors that influence the short-term prognosis in children with acute liver failure.

Niacin, an old drug with a new twist.

Niacin (nicotinic acid) has been used for decades as a lipid-lowering drug. The clinical use of niacin to treat dyslipidemic conditions is limited by its side effects. Niacin, along with fibrates, are the only approved drugs which elevate high density lipoprotein cholesterol (HDLc) along with its effects on low density lipoprotein cholesterol (LDLc) and triglycerides. Whether niacin has a beneficial role in lowering cardiovascular risk on the background of well-controlled LDLc has not been established. In fact, it remains unclear whether niacin, either in the setting of well-controlled LDLc or in combination with other lipid-lowering agents, confers any therapeutic benefit and if so, by which mechanism. The results of recent trials reject the hypothesis that simply raising HDLc is cardioprotective. However, in the case of the clinical trials, structural limitations of trial design complicate their interpretation. This is also true of the most recent Heart Protection Study 2-Treatment of HDLc to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial in which niacin is combined with an antagonist of the D prostanoid (DP) receptor. Human genetic studies have also questioned the relationship between cardiovascular benefit and HDLc. It remains to be determined whether niacin may have clinical utility in particular subgroups, such as statin intolerant patients with hypercholesterolemia or those who cannot achieve a sufficient reduction in LDLc. It also is unclear whether a potentially beneficial effect of niacin is confounded by DP antagonism in HPS2-THRIVE.

[Clinical characteristics and drug resistance in children infected with Pseudomonas aeruginosa in the pediatric intensive care unit].

OBJECTIVE: To study the clinical characteristics of Pseudomonas aeruginosa (PA)-positive children in the pediatric intensive care unit, and to provide a basis for early diagnosis and reasonable treatment of PA infection. METHODS: The clinical data of 62 children infected with PA in the pediatric intensive care unit were retrospectively reviewed,including age, affected organs, fever duration, hospital stay duration, mechanical ventilation duration, prognosis, underlying diseases, mortality, culture results and drug sensitivity test results. RESULTS: Of the 62 PA-positive children, 25 (40%) were aged under 6 months and 47 (76%) under 2 years, with a median age of 28.8 months. Twenty-seven showed one positive result for sputum culture or endotracheal tube aspirates culture, 3 showed one positive result for blood culture, and 32 showed more than two positive results for blood, sputum or endotracheal tube aspirates cultures. On average, 2.8 organs were affected in each patient, with the respiratory system involved most frequently (58 patients, 94%). The mean fever duration was 7.3 days and the mean hospital stay duration was 34.2 days. In the 62 patients, 35 (57%) were cured and 17 (27%) died. Mechanical ventilation was administered to 51 patients (82%) for a mean duration of 13.4 days. Fifty-one patients (82%) had underlying diseases. The 17 (27%) children who died had a mean age of 17.4 months and a mean CRP level of 52.6 mg/L; 14 of them had increased or normal white blood cell count, and 3 had a decreased white blood cell count.The antibiotic sensitivity of PA was 72.6% for cefoperazone/sulbactam, 70.8% for meropenem, 49.1% for imipenem, 65.1% for ceftazidime, and 44.3% for piperacillin/tazobactam. There was complete resistance to cephazolin, cefuroxime and cefotaxime. CONCLUSIONS: The children under 2 years are prone to PA infection. Respiratory system involvements are common. Most of children infected with PA suffer from underlying diseases.The sensitivity of PA to common antibiotics is not high.

Cyclooxygenase-2-dependent prostacyclin formation and blood pressure homeostasis: targeted exchange of cyclooxygenase isoforms in mice.

RATIONALE: Cyclooxygenase (COX)-derived prostanoids (PGs) are involved in blood pressure homeostasis. Both traditional nonsteroidal antiinflammatory drugs (NSAIDs) that inhibit COX-1 and COX-2 and NSAIDs designed to be selective for inhibition of COX-2 cause sodium retention and elevate blood pressure. OBJECTIVE: To elucidate the role of COX-2 in blood pressure homeostasis using COX-1>COX-2 mice, in which the COX-1 expression is controlled by COX-2 regulatory elements. METHODS AND RESULTS: COX-1>COX-2 mice developed systolic hypertension relative to wild types (WTs) on a high-salt diet (HSD); this was attenuated by a PGI(2) receptor agonist. HSD increased expression of COX-2 in WT mice and of COX-1 in COX-1>COX-2 mice in the inner renal medulla. The HSD augmented in all strains urinary prostanoid metabolite excretion, with the exception of the major PGI(2) metabolite that was suppressed on regular chow and unaltered by the HSD in both mutants. Furthermore, inner renal medullary expression of the receptor for PGI(2), but not for other prostanoids, was depressed by HSD in WT and even more so in both mutant strains. Increasing osmolarity augmented expression of COX-2 in WT renal medullary interstitial cells and again the increase in formation of PGI(2) observed in WTs was suppressed in cells derived from both mutants. Intramedullary infusion of the PGI(2) receptor agonist increased urine volume and sodium excretion in mice. CONCLUSIONS: These studies suggest that dysregulated expression of the COX-2 dependent, PGI(2) biosynthesis/response pathway in the renal inner renal medulla undermines the homeostatic response to a HSD. Inhibition of this pathway may contribute directly to the hypertensive response to NSAIDs.

Hematopoietic prostaglandin D synthase (HPGDS): a high stability, Val187Ile isoenzyme common among African Americans and its relationship to risk for colorectal cancer.

Intestinal tumors in Apc(Min/+) mice are suppressed by over-production of HPGDS, which is a glutathione transferase that forms prostaglandin D(2) (PGD(2)). We characterized naturally occurring HPGDS isoenzymes, to see if HPGDS variation is associated with human colorectal cancer risk. We used DNA heteroduplex analysis and sequencing to identify HPGDS variants among healthy individuals. HPGDS isoenzymes were produced in bacteria, and their catalytic activities were tested. To determine in vivo effects, we conducted pooled case-control analyses to assess whether there is an association of the isoenzyme with colorectal cancer. Roughly 8% of African Americans and 2% of Caucasians had a highly stable Val187lle isoenzyme (with isoleucine instead of valine at position 187). At 37°C, the wild-type enzyme lost 15% of its activity in 1h, whereas the Val187Ile form remained >95% active. At 50°C, the half life of native HPGDS was 9min, compared to 42 min for Val187Ile. The odds ratio for colorectal cancer among African Americans with Val187Ile was 1.10 (95% CI, 0.75-1.62; 533 cases, 795 controls). Thus, the Val187Ile HPGDS isoenzyme common among African Americans is not associated with colorectal cancer risk. Other approaches will be needed to establish a role for HPGDS in occurrence of human intestinal tumors, as indicated by a mouse model.

Dietary α-linolenic acid diminishes experimental atherogenesis and restricts T cell-driven inflammation.

AIMS: Epidemiological studies report an inverse association between plant-derived dietary α-linolenic acid (ALA) and cardiovascular events. However, little is known about the mechanism of this protection. We assessed the cellular and molecular mechanisms of dietary ALA (flaxseed) on atherosclerosis in a mouse model. METHODS AND RESULTS: Eight-week-old male apolipoprotein E knockout (ApoE(-/-)) mice were fed a 0.21 % (w/w) cholesterol diet for 16 weeks containing either a high ALA [7.3 % (w/w); n = 10] or low ALA content [0.03 % (w/w); n = 10]. Bioavailability, chain elongation, and fatty acid metabolism were measured by gas chromatography of tissue lysates and urine. Plaques were assessed using immunohistochemistry. T cell proliferation was investigated in primary murine CD3-positive lymphocytes. T cell differentiation and activation was assessed by expression analyses of interferon-γ, interleukin-4, and tumour necrosis factor α (TNFα) using quantitative PCR and ELISA. Dietary ALA increased aortic tissue levels of ALA as well as of the n-3 long chain fatty acids (LC n-3 FA) eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid. The high ALA diet reduced plaque area by 50% and decreased plaque T cell content as well as expression of vascular cell adhesion molecule-1 and TNFα. Both dietary ALA and direct ALA exposure restricted T cell proliferation, differentiation, and inflammatory activity. Dietary ALA shifted prostaglandin and isoprostane formation towards 3-series compounds, potentially contributing to the atheroprotective effects of ALA. CONCLUSION: Dietary ALA diminishes experimental atherogenesis and restricts T cell-driven inflammation, thus providing the proof-of-principle that plant-derived ALA may provide a valuable alternative to marine LC n-3 FA.

Clinical characteristics of COVID-19 in family clusters: a systematic review.

BACKGROUND: Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread around the world and reports of children during early epidemic period showed features of family clusters. The aim of this study is to assess clinical profiles of COVID-19 in family clusters with children. METHODS: We performed a systematic literature review of English database (PubMed, Web of Science) and Chinese database (" www.cnki.net ", " www.cqvip.com " and " www.Wanfangdata.com.cn ") to identify papers on family clusters of COVID-19 with children and their family members. RESULTS: Eighteen studies involving 34 children and 98 adults from 28 families were included. Fever, cough and ground-grass opacity change of chest computed tomography (CT) were the dominant features, whereas proportion of asymptomatic infections for children was higher than adults with statistical significance (32.4% and 13.3%, respectively, P < 0.05). Median time of longer incubation period (10 days) and shorter duration of pharyngeal swab nucleic acid test positive period (11 days) were seen in children than adults (7 and 17 days, respectively) with statistical significance (P < 0.05). There were statistically significant differences in lymphopenia, increased C-reactive protein and abnormal chest CT between children and adult patients (P < 0.05). Twenty-seven families reported adults as first case of COVID-19 in family clusters. CONCLUSIONS: The same virus strain can cause milder disease in children compared with their caregivers. Children of COVID-19 were infected by adults in family during the early epidemic period. Asymptomatic patients can transmit the virus.

Electrospun Janus Beads-On-A-String Structures for Different Types of Controlled Release Profiles of Double Drugs.

A side-by-side electrospinning process characterized by a home-made eccentric spinneret was established to produce the Janus beads-on-a-string products. In this study, ketoprofen (KET) and methylene blue (MB) were used as model drugs, which loaded in Janus beads-on-a-string products, in which polyvinylpyrrolidone K90 (PVP K90) and ethyl cellulose (EC) were exploited as the polymer matrices. From SEM images, distinct nanofibers and microparticles in the Janus beads-on-a-string structures could be observed clearly. X-ray diffraction demonstrated that all crystalline drugs loaded in Janus beads-on-a-string products were transferred into the amorphous state. ATR-FTIR revealed that the components of prepared Janus nanostructures were compatibility. In vitro dissolution tests showed that Janus beads-on-a-string products could provide typical double drugs controlled-release profiles, which provided a faster immediate release of MB and a slower sustained release of KET than the electrospun Janus nanofibers. Drug releases from the Janus beads-on-a-string products were controlled through a combination of erosion mechanism (linear MB-PVP sides) and a typical Fickian diffusion mechanism (bead KET-EC sides). This work developed a brand-new approach for the preparation of the Janus beads-on-a-string nanostructures using side-by-side electrospinning, and also provided a fresh idea for double drugs controlled release and the potential combined therapy.

The Effect of Drug Heterogeneous Distributions within Core-Sheath Nanostructures on Its Sustained Release Profiles.

The sustained release of a water-soluble drug is always a key and important issue in pharmaceutics. In this study, using cellulose acetate (CA) as a biomacromolecular matrix, core-sheath nanofibers were developed for providing a sustained release of a model drug-metformin hydrochloride (MET). The core-sheath nanofibers were fabricated using modified tri-axial electrospinning, in which a detachable homemade spinneret was explored. A process-nanostructure-performance relationship was demonstrated through a series of characterizations. The prepared nanofibers F2 could release 95% of the loaded MET through a time period of 23.4 h and had no initial burst effect. The successful sustained release performances of MET can be attributed to the following factors: (1) the reasonable application of insoluble CA as the filament-forming carrier, which determined that the drug was released through a diffusion manner; (2) the core-sheath nanostructure provided the possibility of both encapsulating the drug completely and realizing the heterogeneous distributions of MET in the nanofibers with a higher drug load core than the sheath; (3) the thickness of the sheath sections were able to be exploited for further manipulating a better drug extended release performance. The mechanisms for manipulating the drug sustained release behaviors are proposed. The present proof-of-concept protocols can pave a new way to develop many novel biomolecule-based nanostructures for extending the release of water-soluble drugs.

Overexpression of Peroxisome Proliferator-Activated Receptor γ Coactivator 1-α Protects Cardiomyocytes from Lipopolysaccharide-Induced Mitochondrial Damage and Apoptosis.

Mitochondrial damage is considered one of the main pathogenetic mechanisms in septic cardiomyopathy. Peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) is critical for maintaining energy homeostasis in different organs and in various physiological and pathological states. It is also a key regulator gene in mitochondrial metabolism. In this study, we investigated whether regulation of the PGC-1α gene had protective effects on septic cardiomyopathy. We developed a rat model of septic cardiomyopathy. H9c2 myocardiocytes were treated with lipopolysaccharide (LPS) and PGC-1α expression measured. PGC-1α-overexpressing lentivirus was used to transfect H9c2 cells. ZLN005 was used to activate PGC-1α. The effect of the inhibition of PGC-1α expression on myocardial cell injury and its underlying mechanisms were also explored. Cell viability was measured by CCK-8 assay. Mitochondrial damage was determined by measuring cellular ATP, reactive oxygen species, and the mitochondrial membrane potential. An apoptosis analysis kit was used to measure cellular apoptosis. Mitochondrial DNA was extracted and real-time PCR performed. LC3B, mitochondrial transcription factor A (TFA), P62, Bcl2, and Bax were determined by immunofluorescence. LC3B, TFA, P62, Parkin, PTEN-induced putative kinase 1, and PGC-1α proteins were determined by Western blotting. We found mitochondrial damage and apoptotic cells in the myocardial tissue of rats with septic cardiomyopathy and in LPS-treated cardiomyocytes. PGC-1α expression was decreased in the late phase of septic cardiomyopathy and in LPS-treated cardiomyocytes. PGC-1α activation by ZLN005 and PGC-1α overexpression reduced apoptosis in myocardiocytes after LPS incubation. PGC-1α gene overexpression alleviated LPS-induced cardiomyocyte mitochondrial damage by activating mitochondrial biogenesis and autophagy functions. Our study indicated that mitochondrial damage and apoptosis occurred in septic cardiomyopathy and LPS-treated cardiomyocytes. The low expression level of PGC-1α protein may have contributed to this damage. By activating the expression of PGC-1α, apoptosis was reduced in cardiomyocytes. The underlying mechanism may be that PGC-1α can activate mitochondrial biogenesis and autophagy functions, reducing mitochondrial damage and thereby reducing apoptosis.

Patterns of Deterioration in Moderate Patients With COVID-19 From Jan 2020 to Mar 2020: A Multi-Center, Retrospective Cohort Study in China.

Background: Around the globe, moderate cases account for the largest proportion of all coronavirus disease 2019 (COVID-19) patients, and deteriorated moderate patients contribute the most in mortality. However, published articles failed to address the deterioration details of moderate cases, especially on when and how they deteriorated. Methods: All moderate COVID-19 patients hospitalized in Guangdong Province from January 14 to March 16, 2020, were included in this multicenter retrospective cohort study and were divided into deteriorated and non-deteriorated groups according to clinical status. Symptoms and demographic, therapeutic, and laboratory test result characteristics were collected to explore the features of disease deterioration. Results: Of 1,168 moderate patients included, 148 (13%) deteriorated to severe (130 cases) or critical (18 cases) status. Over 20% of the older subgroup (>50 years old) showed deterioration. The median time for deterioration was 11 days after onset [interquartile range (IQR) 9-14 days]. In addition, 12.2% severe cases could further develop to critical status after 3 days (IQR 2-6.5 days) of having a severe condition. Respiratory dysfunction and hypoxia were the major manifestations as disease deterioration, while 76 cases (52.1%) showed respiratory rate >30 breaths/min, 119 cases (80.4%) showed SaO2 <93%, 100 cases (67.5%) had 201 < PaO2/FiO2 < 300, and 27 cases (18.9%) had blood lactic acid >2.0 mmol/L. In view of multiple organ dysfunction, 87.8% of acute respiratory distress syndrome (ARDS), 20.2% of acute kidney injury (AKI), 6.8% of coagulopathy, 4% of acute heart failure (AHF), 3.4% of acute hepatic injury (AHI), and 5.4% of shock occurred in deteriorated patients, while organ injury occurred in the following sequence: ARDS, AKI, AHF, coagulopathy, AHI, and shock. Conclusions: The deteriorated pattern of moderate COVID-19 patients is characterized as the 11th day from onset (IQR 9-14 days) being an important time point of disease deterioration with further exacerbation to critical condition in 3 days (IQR 2-6.5 days), A RDS followed by AKI being the typical modes of sequential organ damage.

Epidemiological and Clinical Findings of Short-Term Recurrence of Severe Acute Respiratory Syndrome Coronavirus 2 Ribonucleic Acid Polymerase Chain Reaction Positivity in 1282 Discharged Coronavirus Disease 2019 Cases: A Multicenter, Retrospective, Observational Study.

BACKGROUND: Short-term recurrence of positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ribonucleic acid (RNA) polymerase chain reaction (PCR) in discharged coronavirus disease 2019 (COVID-19) patients attracts the public's concern. This study aimed to determine the clinical and epidemiological results of such patients. METHODS: This retrospective study was conducted on 32 designated hospitals for COVID-19 patients discharged from January 14 to March 10, 2020. After 28-day followed-up, patients who tested positive again for SARS-CoV-2 RNA and confirmed by reverse-transcriptase polymerase chain reaction were re-admitted to hospital for further treatments. All of the close contacts of patients who tested positive again were asked to self-segregate for 14 days. Data of epidemiology, symptoms, laboratory tests, and treatments were analyzed in those patients, and their close contacts were investigated. RESULTS: Of 1282 discharged patients, 189 (14.74%) tested positive again for SARS-CoV-2 RNA during 28-day follow-up. The median time from discharge to the next positive test was 8 days (interquartile range [IQR], 5-13). Patients in the group that tested positive again were younger (34 vs 45 years, P < .001) with a higher proportion of moderate symptoms (95.77% vs 84.35%, P < .001) in the first hospitalization than in the negative group. During the second hospitalization, all patients who tested positive again showed normal peripheral white blood cells and lymphocytes and no new symptoms of COVID-19; 78.31% further improved on chest computed tomography scan compared with the first discharge, yet 25.93% accepted antiviral therapy. The median time of re-positive to negative test was 8 days (IQR, 4-15). None of the close contacts developed COVID-19. CONCLUSIONS: Our data suggest that the short-term recurrence of positive SARS-CoV-2 RNA in discharged patients is not a relapse of COVID-19, and the risk of onward transmission is very low. This provides important information for managing COVID-19 patients.