Relationship between Neurological Deterioration and Blood Pressure/Heart Rate Variability in Patients with Acute Cerebral Infarction

ObjectivesNeurological deterioration (ND) during hospitalization is an independent predictor of poor prognosis after stroke. Risk factors affecting early ND within 48 h post stroke have been intensively investigated, while few data are available on those for late ND after transfer to a wheelchair. Therefore, it was investigated whether hemodynamic factors may affect the late ND during hospitalization.Materials and methodsA retrospective study was conducted on 135 patients with atherothrombotic or cardiogenic cerebral infarction who were admitted to our hospital between April 1st, 2014 and July 31st, 2017. During hospitalization, average, maximum, and minimum values were determined for systolic blood pressure (sBP), diastolic BP (dBP), and heart rate (HR), respectively.135 patients were classified into two groups; ND (+) group, in which modified Barthel index score at the time of transfer to a wheelchair showed five points or more decrease between wheelchair transfer and discharge, and ND (?) group, which did not. Vital indices were compared between the two groups and subjected to ROC-curve analysis.ResultsThe ND (+) group included 32 patients, and the ND (?) 103. Significant differences were found between the groups in four items; sBPmin (p = 0.029), dBPmin (p = 0.019), HRave (p = 0.028), and HRmax (p < 0.01). The ND (+) group showed lower sBPmin and dBPmin, and higher HRave and HRmax than the ND (?) group.ConclusionsLate ND after transfer to a wheelchair is related to the vital indices during hospitalization and should be cautiously managed to prevent late ND     

First-Pass Arrival Interval of Ultrasound Contrast Medium in the Hepatic Artery and Portal Vein as a Marker for Assessment of Liver Transplant Recipients

BackgroundThis study measures the first-pass arrival times in the hepatic artery and portal vein of the transplanted liver using contrast-enhanced ultrasound (CEUS) and assess its correlation with graft performance in the early posttransplant period.MethodsThis study evaluated 35 liver transplant recipients who underwent CEUS examination within 1 month of transplant surgery. CEUS under contrast-specific harmonic imaging mode were recorded for 60 seconds immediately after intravenous administration of microbubble ultrasound contrast medium (Sonazoid, GE Healthcare, Oslo, Norway). The recorded video clips were reviewed by 2 readers to determine the first-pass arrival times in the hepatic artery and portal vein, and the difference between the 2 was defined as the arterial-portal arrival interval (APAI). Laboratory data on the same date of CEUS examination were collected as indicators to correlate with APAI.ResultsThe intra- and inter-rater reliability for APAI measurement were excellent, with intraclass correlation coefficients > .95. The mean APAI was 4.5 ± 1.8 seconds (range, 2.0-10.5 seconds). The APAI was positively correlated with the serum total bilirubin level (r = 0.357, P = .035) and negatively correlated with the platelet count (r = −0.354, P = .037). At the 5 second cutoff point, a total serum bilirubin of >8 mg/dL was reported in 5 of 11 patients (45.4%) with APAI of >5 seconds and in only 3 of 24 patients (12.5%) with APAI of <5 seconds (P < .05).ConclusionsThe APAI is a quantitative marker that links the hemodynamics and the clinical status of the liver graft.     

miR-146a-5p regulates autophagy and NLRP3 inflammasome activation in epithelial barrier damage in the in vitro cell model of ulcerative colitis through the RNF8/Notch1/mTORC1 pathway

Ulcerative colitis (UC) is a chronic inflammatory disease affecting the colon that can be influenced by microRNAs (miRNAs). This study aims to investigate the impact of miR-146a-5p on lipopolysaccharide (LPS)-induced Caco-2/HT-29 cell autophagy and NLRP3 inflammasome activation and the underlying mechanism, with the aim of identifying potential therapeutic targets. We used LPS to establish Caco-2/HT-29 cell models and measured cell viability by CCK-8. The levels of miR-146a-5p, RNF8, markers of NLRP3 inflammasome activation and autophagy, proteins involved in the Notch1/mTORC1 pathway, and inflammatory factors were assessed by RT-qPCR, Western blot, and ELISA. Intestinal epithelial barrier function was evaluated by measuring transepithelial electrical resistance. Autophagic flux was measured using tandem fluorescent-labeled LC3. miR-146a-5p was highly-expressed in LPS-induced Caco-2/HT-29 cells, and autophagy flux was blocked at the autolysosomal stage after LPS induction. Inhibition of miR-146a-5p suppressed NLRP3 inflammasome activation, reduced intestinal epithelial barrier damage, and facilitated autophagy inhibition in LPS-induced Caco-2/HT-29 cells. The autophagy inhibitor NH4Cl partially nullified the inhibitory effects of miR-146a-5p inhibition on NLRP3 inflammation activation. miR-146a-5p targeted RNF8, and silencing RNF8 partly abrogated the action of miR-146a-5p inhibition on promoting autophagy and inhibiting NLRP3 inflammasome activation. miR-146a-5p inhibition suppressed the Notch1/mTORC1 pathway activation by upregulating RNF8. Inhibition of the Notch1/mTORC1 pathway partially nullified the function of silencing RNF8 on inhibiting autophagy and bolstering NLRP3 inflammasome activation. In conclusion, miR-146a-5p inhibition may be a potential therapeutic approach for UC, as it facilitates autophagy of LPS-stimulated Caco-2/HT-29 cells, inhibits NLRP3 inflammasome activation, and reduces intestinal epithelial barrier damage by upregulating RNF8 and suppressing the Notch1/mTORC1 pathway.     

Identification of peptides presented through the MHC-II of dendritic cells stimulated with Mycobacterium avium

Mycobacterium avium (M. avium) represents a species of concern, because of its ability to modulate the host’s innate immune response, and therefore influence trajectory of adaptative immunity. Since eradicative response against mycobacteria, and M. tuberculosis/M. avium, relies on peptides actively presented on a Major Histocompatibility complex-II (MHC-II) context, we assessed paradoxical stimulation of Dendritic Cell resulting on immature immunophenotype characterized by membrane minor increase of MHC-II and CD40 despite of high expression of the pro-inflammatory tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) in supernatants. Identification of M. avium leucine rich peptides forming short α-helices shutting down Type 1T helper (Th1), contribute to the understanding of immune evasion of an increasingly prevalent pathogen, and may provide a basis for future immunotherapy to infectious and non-infectious disease.     

Sustained Release of Metformin via Red Blood Cell Accumulated Sulfenamide Prodrug

Metformin is a first-line antidiabetic drug to treat type 2 diabetes. It is rapidly eliminated from plasma but also accumulated into red blood cells (RBCs) from which it is slowly released back into plasma. The aim of the study was to evaluate whether the amount of metformin in the RBCs could be increased by a sulfenamide prodrug approach, which could provide longer duration of metformin in systemic circulation. Pharmacokinetic properties of metformin and its cyclohexyl sulfenamide prodrug were evaluated in plasma and in whole blood after intravenous and oral administration in rats. Once the sulfenamide prodrug reached the bloodstream, it was rapidly and efficiently accumulated into the RBCs, where it was converted to metformin by free thiols. The RBC–whole blood ratio of metformin was increased approximately from 42% to 96% when metformin was administered intravenously as its sulfenamide prodrug, and the proportion of metformin in the RBCs was found to be concentration and time independent. Because metformin was slowly liberated into plasma, the prodrug showed a sustained-release pharmacokinetic profile and longer plasma half-life for metformin after oral administration. Therefore, this sulfenamide prodrug has great potential to improve metformin therapy as the daily doses could be reduced.     

Preoperative neutrophil-to-lymphocyte ratio is a more valuable prognostic factor than platelet-to-lymphocyte ratio for nonmetastatic rectal cancer

Several combinations of inflammatory factors, including neutrophil-to- lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), have been reported to be prognostic factors in various malignant tumors, including colorectal cancer (CRC). The aim of this study was to evaluate the prognostic value of NLR and PLR for patients with rectal cancer (RC) who underwent curative surgery. Data from patients who underwent curative resection for RC were retrospectively reviewed. The cutoff for NLR and PLR was defined as 2.3 and 144 by receiver operating characteristic (ROC) curve. Overall survival (OS) and disease-free survival (DFS) were assessed using Kaplan-Meier method. Multivariable Cox regression model was used to evaluate the independent prognostic significance of variables. A total of 140 patients were eligible in the study. High NLR (> 2.3) and high PLR (> 144) both predicted lower OS and DFS according to Kaplan-Meier method. But in the multivariable Cox regression model, only the high NLR retained significance for reduced OS and DFS. According to Chi-square test, patients with higher NLR had larger tumor size and higher pN-stage. While PLR was only associated with the pN-stage. High preoperative NLR was shown to be a negative independent prognostic factor in patients undergoing resection for nonmetastatic RC. It may be helpful as a factor to guide the postoperative therapies.     

Photodecomposition,photomutagenicity and photocytotoxicity of retinyl palmitate under He–Ne laser photoirradiation and its effects on photodynamic therapy of cancer cells in vitro

ObjectiveOur aim was to study photodecomposition, photomutagenicity and cytotoxicity of retinyl palmitate (RP), a principal storage form of vitamin A in humans and animals, under He–Ne laser photoirradiation. Moreover, the effect of different concentrations and timing protocol of antioxidants on photodynamic therapy (PDT) is contradictory, so the effect of RP (as antioxidant) on the PDT cytotoxicity was studied.MethodsPhotomutagenicity was tested by Ames test. Photodecomposition was studied by UV–vis spectroscopy. Cytotoxicity was measured with MTT-assay. Moreover, the effect of PDT, using hematoporphyrin derivatives (HpD) as photosensitizer under He–Ne laser irradiation (10 J/cm²), was studied on HeLa cells either with or without RP (1–100 μM) which incubated with the cells for short or long incubation period (1 h or 24 h) prior to PDT.ResultsNo photodecomposition of RP alone was obseved whereas there is a little photodecomposition of RP only in presence of HpD under irradiation with He–Ne laser. Moreover, no photomutagenicity was observed in Salmonella typhimurium strains under laser irradiation in presence or absence of HpD. RP alone (1–100 μM) significantly decrease the viability of HeLa cells. Laser irradiation of HeLa cells pre-incubated with RP alone for 24 h showed further significant decrease in viability of the cells. While RP incubations for 1 h before PDT had slight effect on the cells, 24 h incubation before PDT enhanced the cytotoxicity of PDT on HeLa cells.ConclusionsRP can be used 24 h before PDT to enhance its effects. RP is not mutagenic under irradiation with He–Ne laser.     

Circulating tumor DNA/circulating tumor cells and the applicability in different causes induced hepatocellular carcinoma

In 2015, liquid biopsy was rated one of the top 10 breakthrough technologies of the year by MIT Technology Review. Liquid biopsy is a type of in vitro diagnostic method involving a noninvasive blood test. It is also a breakthrough technology used to detect tumors and cancers and assist in therapeutic strategies. The most widely used markers are circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA). Primary carcinoma of the liver is a malignancy of hepatocytes or intrahepatic biliary epithelial cells. The most common type of liver cancer is hepatocellular carcinoma (HCC), the causes of which mainly include infection with hepatitis B virus (HBV) and/or hepatitis C virus (HCV), alcohol abuse, aflatoxicosis, and nonalcoholic fatty liver disease/ nonalcoholic steatohepatitis. As there are few typical clinical characteristics during the early stage of the disease, early diagnosis of HCC is very challenging. However, CTCs and ctDNA carry tumor-specific information. Therefore, the detection and analysis of CTCs and ctDNA can provide evidence for the early diagnosis of HCC and guide treatment. Furthermore, several studies have indicated that different inducers of HCC cause different DNA mutations, and accordingly, detection of specific mutations in ctDNA will facilitate the determination of the HCC type and help physicians provide distinctive therapies.