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Purpose: To distinguish clinical factors that have time-varying (as opposed to constant) impact upon patient and graft survival among pediatric liver transplant recipients. Methods: Using national data from 2002 through 2013, we examined potential clinical and demographic covariates using Gray’s piecewise constant time-varying coefficients (TVC) models. For both patient and graft survival, we estimated univariable and multivariable Gray’s TVC, retaining significant covariates based on backward selection. We then estimated the same specification using traditional Cox proportional hazards (PH) models and compared our findings. Results: For patient survival, covariates included recipient diagnosis, age, race/ethnicity, ventilator support, encephalopathy, creatinine levels, use of living donor, and donor age. Only the effects of recipient diagnosis and donor age were constant; effects of other covariates varied over time. We retained identical covariates in the graft survival model but found several differences in their impact. Conclusion: The flexibility afforded by Gray’s TVC estimation methods identify several covariates that do not satisfy constant proportionality assumptions of the Cox PH model. Incorporating better survival estimates is critical for improving risk prediction tools used by the transplant community to inform organ allocation decisions. [ABSTRACT FROM AUTHOR]

The number of elderly patients diagnosed with hepatocellular carcinoma (HCC) is expected to increase. The present study aims to evaluate the role of age on treatments and outcome of HCC patients. 1530 patients firstly diagnosed with HCC were retrospectively included and classified as older (≥65 years, n = 318, 21%) and younger patients (<65 years, n = 1212, 79%). The two groups were compared with clinical characteristics, tumor burden, Barcelona Clinics Liver Cancer (BCLC) stage, treatments and long-term prognosis. Elderly patients were more HCV infected, had more diabetes, poorer performance status, and were less aggressively treated. The proportion of HCC within BCLC stage 0-A, B or C was similar between the two groups, but elderly patients were more presented with BCLC stage D. The overall survival of older patients was poorer compared to younger patients before and after propensity score matching. However, elderly patients were less often effectively treated with surgery and loco-regional therapies across different BCLC stages. After stratified by BCLC stages or treatments, older patients showed comparable long-term outcome to younger patients. Performance status, BCLC stages and effective treatments, rather than age, was independent factors determining prognosis in the whole cohort and only elderly patients by multivariate analysis. In conclusion, older could have comparable survival to younger patients within the same tumor stage or after similar treatments. Thus, equally active treatments should be encouraged to elderly patients. [ABSTRACT FROM AUTHOR]

Watermelon (Citrullus lanatus (Thunb.) Matsum. & Nakai) is a non-climacteric fruit. The modern sweet-dessert watermelon is the result of years of cultivation and selection for fruits with desirable qualities. To date, the mechanisms of watermelon fruit ripening, and the role of abscisic acid (ABA) in this process, has not been well understood. We quantified levels of free and conjugated ABA contents in the fruits of cultivated watermelon (97103; C. lanatus subsp. vulgaris), semi-wild germplasm (PI179878; C. lanatus subsp. mucosospermus), and wild germplasm (PI296341-FR; C. lanatus subsp. lanatus). Results showed that ABA content in the fruits of 97103 and PI179878 increased during fruit development and ripening, but maintained a low steady state in the center flesh of PI296341-FR fruits. ABA levels in fruits were highest in 97103 and lowest in PI296341-FR, but no obvious differences in ABA levels were observed in seeds of these lines. Examination of 31 representative watermelon accessions, including different C. lanatus subspecies and ancestral species, showed a correlation between soluble solids content (SSC) and ABA levels in ripening fruits. Furthermore, injection of exogenous ABA or nordihydroguaiaretic acid (NDGA) into 97103 fruits promoted or inhibited ripening, respectively. Transcriptomic analyses showed that the expression levels of several genes involved in ABA metabolism and signaling, including Cla009779 (NCED), Cla005404 (NCED), Cla020673 (CYP707A), Cla006655 (UGT) and Cla020180 (SnRK2), varied significantly in cultivated and wild watermelon center flesh. Three SNPs (-738, C/A; -1681, C/T; -1832, G/T) in the promoter region of Cla020673 (CYP707A) and one single SNP (-701, G/A) in the promoter of Cla020180 (SnRK2) exhibited a high level of correlation with SSC variation in the 100 tested accessions. Our results not only demonstrate for the first time that ABA is involved in the regulation of watermelon fruit ripening, but also provide insights into the evolutionary mechanisms of this phenomenon. [ABSTRACT FROM AUTHOR]

Background and Purpose: Recombinant tissue plasminogen activator (rtPA) is the only effective drug approved by US FDA to treat ischemic stroke, and it contains pleiotropic effects besides thrombolysis. We performed a meta-analysis to clarify effect of tissue plasminogen activator (tPA) on cerebral infarction besides its thrombolysis property in mechanical animal stroke. Methods: Relevant studies were identified by two reviewers after searching online databases, including Pubmed, Embase, and ScienceDirect, from 1979 to 2016. We identified 6, 65, 17, 12, 16, 12 and 13 comparisons reporting effect of endogenous tPA on infarction volume and effects of rtPA on infarction volume, blood-brain barrier, brain edema, intracerebral hemorrhage, neurological function and mortality rate in all 47 included studies. Standardized mean differences for continuous measures and risk ratio for dichotomous measures were calculated to assess the effects of endogenous tPA and rtPA on cerebral infarction in animals. The quality of included studies was assessed using the Stroke Therapy Academic Industry Roundtable score. Subgroup analysis, meta-regression and sensitivity analysis were performed to explore sources of heterogeneity. Funnel plot, Trim and Fill method and Egger’s test were obtained to detect publication bias. Results: We found that both endogenous tPA and rtPA had not enlarged infarction volume, or deteriorated neurological function. However, rtPA would disrupt blood-brain barrier, aggravate brain edema, induce intracerebral hemorrhage and increase mortality rate. Conclusions: This meta-analysis reveals rtPA can lead to neurological side effects besides thrombolysis in mechanical animal stroke, which may account for clinical exacerbation for stroke patients that do not achieve vascular recanalization with rtPA. [ABSTRACT FROM AUTHOR]

The factors driving the composition of gut microbiota are still only partly understood but appear to include environmental, cultural, and genetic factors. In order to obtain more insight into the relative importance of these factors, we analyzed the microbiome composition in subjects of Tibetan or Han descent living at different altitudes. DNA was isolated from stool samples. Using polymerase chain reaction methodology, the 16S rRNA V1–V3 regions were amplified and the sequence information was analyzed by principal coordinates analysis and Lefse analyses. Contrasting the Tibetan and Han populations both living at the 3600 m altitude, we found that the Tibetan microbiome is characterized by a relative abundance of Prevotella whereas the Han stool was enriched in Bacteroides. Comparing the microbiome of Han stool obtained from populations living at different altitudes revealed a more energy efficient flora in samples from those living at higher altitude relative to their lower-altitude counterparts. Comparison of the stool microbiome of Tibetan herders living at 4800 m to rural Tibetans living at 3600 m altitude shows that the former have a flora enriched in butyrate-producing bacteria, possibly in response to the harsher environment that these herders face. Thus, the study shows that both altitude and genetic/cultural background have a significant influence on microbiome composition, and it represents the first attempt to compare stool microbiota of Tibetan and Han populations in relation to altitude. [ABSTRACT FROM AUTHOR]

The central nervous system (CNS) insults may cause massive demyelination and lead to the release of myelin-associated proteins including its major component myelin basic protein (MBP). MBP is reported to induce glial activation but its effect on neurons is still little known. Here we found that MBP specifically bound to the extracellular surface of the neuronal plasma membrane and induced neurotoxicity in vitro. This effect of MBP on neurons was basicity-dependent because the binding was blocked by acidic lipids and competed by other basic proteins. Further studies revealed that MBP induced damage to neuronal membrane integrity and function by depolarizing the resting membrane potential, increasing the permeability to cations and other molecules, and decreasing the membrane fluidity. At last, artificial liposome vesicle assay showed that MBP directly disturbed acidic lipid bilayer and resulted in increased membrane permeability. These results revealed that MBP induces neurotoxicity through its direct interaction with acidic components on the extracellular surface of neuronal membrane, which may suggest a possible contribution of MBP to the pathogenesis in the CNS disorders with myelin damage. [ABSTRACT FROM AUTHOR]