Elevation of Serum Cytokine Profiles and Liver Metabolomic Normalization in Early Convalescence of COVID-19 Patients.

Coronavirus disease 2019 (COVID-19) has become a global public health concern. We aimed to study the cytokine profile during the convalescent phase and its association with liver functions. We performed a retrospective study to investigate the longitudinal dynamic serum cytokine, liver function, and metabolomic profiles, as well as their potential correlations, from the viral replication phase to early convalescence. Our results demonstrated that liver injury was common. Liver injury was significantly associated with higher levels of interleukin (IL)-6 and IL-10 (p < 0.05). However, alanine aminotransferase levels decreased during the first week after hospital discharge (p < 0.01). In parallel, T-cell and B-cell immune response-stimulating cytokine IL-4, but not IL-2, was significantly elevated (p < 0.05). Furthermore, interferon-γ (IFN-γ) and tumor necrosis factor-α (TFN-α) levels increased, in contrast to the decrease in IL-6 and IL-10 levels; liver function returned to normal. The metabolomic analysis supported active recovery during early convalescence of COVID-19 patients that had distinct metabolic profiles associated with the hepatic tricarboxylic acid cycle, amino acid metabolism, and lipid metabolism. In addition, we identified a metabolomic association of IL-4 with liver repair. Our findings suggest that discharged patients continue to recover from the physiological effects of COVID-19, and the association of IL-4, IL-6, and IL-10 levels with metabolic changes and liver function repair may have important implications for clinical manifestations and treatment of COVID-19.

Predictors of functional outcome and hemorrhagic complications in acute ischemic stroke patients treated with intravenous thrombolysis - A retrospective analysis
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Intravenous thrombolysis (IVT) with recombinant tissue plasminogen activator (rt-PA) within 4.5 hours is an effective and routine therapy for acute ischemic stroke (AIS). The purpose of the study was to identify predictors of functional outcome at 3 months and hemorrhagic complications after IVT. A total of 123 AIS patients treated with intravenous alteplase within 4.5 hours after stroke were enrolled. Baseline clinical characteristics, medication and disease history, radiographic and laboratory data were collected. The clinical functional outcome at 3 months was measured by the modified Rankin Scale dichotomized at 0 - 1 (favorable) vs. 2 - 6 (unfavorable). Hemorrhagic complications were measured within 36 hours after IVT. Univariate and multivariate analysis was applied in the study, and the logistic regression identified the predictors for functional outcome at 3 months and hemorrhagic complications within 36 hours. In univariate analysis, the favorable outcome was significantly associated with short hospitalization, low initial National Institute of Health Stroke Scale scores, previous smoking, previous statin use, and absence of post-stroke cerebral edema or pneumonia. Hemorrhagic complications were significantly associated with high initial NIHSS scores, low platelet count, high D-dimer level, previous atrial fibrillation, and onset seasons (except summer). Multivariate regression analyses identified that seasons (spring and summer), short hospital stays, and absence of post-stroke cerebral edema or pneumonia were the predictors of a favorable functional outcome. Meanwhile, seasons (except summer), low platelet count, and high D-dimer levels were correlation factors for prognosis of high hemorrhagic complications.
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Epidemiological and clinical characteristics of 266 cases of intracerebral hemorrhage in Hangzhou, China.

Ethnicity and socioeconomic factors can influence disease susceptibility, clinical presentation, and outcome. We investigated the clinical characteristics (age, sex, seasonal variation, lesion site, symptoms, complications, prognosis, and sequelae) and risk factors for intracerebral hemorrhage (ICH) in 266 cases treated at our hospital in Hangzhou City, China, from January 2011 to December 2011. Risk of ICH increased dramatically with age; only 4.3% of cases were <30 years old, while 44.4% were >60 years of age. Men outnumbered women by 2:1 (67.3% vs. 32.7%). Single hemorrhage was most often located in the cerebral lobes (37.2% of cases), basal ganglia (34.2%), thalamus (8.3%), cerebellum (6.8%), ventricle (1.5%), and brainstem (1.1%), while 10.9% of cases exhibited hemorrhages at multiple sites. Hypertension was also a major risk factor for ICH, as 47% of all patients were hypertensive and the percentage increased with age. In hypertensive patients, the most common hemorrhage site was the basal ganglia and ICH was often associated with thrombopenia. In patients with leukemia (all forms), most hemorrhages were lobar. Warfarin- and encephalic operation-associated ICHs were all lobar. Headache was the major symptom of occipital, temporal, and frontal lobe hemorrhage. Dizziness, nausea, and vomiting were the major symptoms of cerebellum hemorrhage. Limb dysfunction was the major symptom of thalamic and basal ganglia hemorrhage. Disturbed level of consciousness was the major symptom in multisite, ventricular, parietal lobe, and brainstem hemorrhage. Hyperspasmia occurred most often in lobar hemorrhage and blurred vision in occipital lobe hemorrhage. Hospital mortality was 24.4% (n=65) with a mean delay from presentation to death of (10.5±18.5) d. The majority of fatalities were cerebral hernia cases (58.5%) and these patients also had the shortest time to death [(2.9±3.5) d]. Mortality was 100% in brainstem ICH and hemorrhagic conversion of cerebral infarct. Thrombopenia-associated ICH also had a high mortality rate (81.0%), while patients with cerebrovascular malformations and cerebral aneurysms demonstrated a much better prognosis (46.2% recovery).

Synthesis and biological evaluation of 3-aryl-quinoxaline-2-carbonitrile 1,4-di-N-oxide derivatives as hypoxic selective anti-tumor agents.

A series of 3-aryl-2-quinoxaline-carbonitrile 1,4-di-N-oxide derivatives were designed, synthesized and evaluated for hypoxic and normoxic cytotoxic activity against human SMMC-7721, K562, KB, A549 and PC-3 cell lines. Many of these new compounds displayed more potent hypoxic cytotoxic activity compared with TX-402 and TPZ in the tumor cells based evaluation, which confirmed our hypothesis that the replacement of the 3-amine with the substituted aryl ring of TX-402 increases the hypoxic anti-tumor activity. The preliminary SAR revealed that 3-chloro was a favorable substituent in the phenyl ring for hypoxic cytotoxicity and 7-methyl or 7-methoxy substituted derivatives exhibited better hypoxic selectivity against most of the tested cell lines. The most potent compound, 7-methyl-3-(3-chlorophenyl)-quinoxaline-2-carbonitrile 1,4-dioxide (9h) was selected for further anti-tumor evaluation and mechanistic study. It also exhibited significant cytotoxic activity against BEL-7402, HepG2, HL-60, NCI-H460, HCT-116 and CHP126 cell lines in hypoxia with IC50 values ranging from 0.31 to 3.16 µM, and preliminary mechanism study revealed that 9h induced apoptosis in a caspase-dependent pathway.

[In vitro metabolic interaction between diphenytriazol and steroid hormone drugs].

AIM: To observe the metabolic interaction between diphenytriazol and steroid hormone drugs, and provide some useful information for clinical medication. METHODS: The steroid hormone drugs which may be co-administrated with diphenytriazol were selected, such as mifepriston, estradiol, medroxyprogesterone acetate, progesterone, norethisterone and so on. Diphenytriazol was incubated with each drug in rat liver microsome. The residual concentration of diphenytriazol or steroid hormone drugs in the microsomal incubates was determined by reversed-phase high-performance liquid chromatography, separately. The inhibition constants (K(i)) for each of them were calculated. RESULTS: The inhibition constant K(is) of diphenytriazol for the metabolism of mifepristone, estradiol, medroxyprogesterone acetate, progesterone and norethisterone were (201.3 +/- 1.0), (94 +/- 4), (128.7 +/- 2.2), (64 +/- 5) and (80 +/- 4) micromol x L(-1), respectively. The inhibition constants K(i) of steroid hormone drugs for the metabolism of diphenytriazol was (66.9 +/- 2.2) micromol x L(-1) for estradiol, (60.0 +/- 2.3) micromol x L(-1) for medroxyprogesterone acetate, (163 +/- 10) micromol x L(-1) for progesterone and (88 +/- 5) micromol x L(-1) for norethisterone, respectively. CONCLUSION: Diphenytriazol shows metabolism interaction with steroid hormone drugs such as estradiol, medroxyprogesterone acetate, progesterone and norethisterone.