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Background: The intimal flap of aortic dissection may extend to the abdominal branches and probably lead to malperfusion syndrome. Renal malperfusion and renal atrophy are significantly related to patient outcomes. Purpose: To study the extent of the intimal flap and predisposing factors for renal atrophy in patients with aortic dissection. Material and Methods: From January 2001 to June 2008, 176 (137 men, aged 21-86 years, mean 51.9 years) of 225 subjects with aortic dissection and computed tomography (CT) met the inclusion criteria for this study. Of these 176 patients, 35 (19.9%) developed unilateral renal atrophy. A review of the CT was conducted to classify aortic branch vessel perfusion into three types: type 1, in which the branch vessels are perfused exclusively from the true lumen; type 2, in which the branches are perfused from both the true and false lumens; and type 3, in which the branches are perfused exclusively from the false lumen. Variables including age, gender, type of aortic dissection, type of perfusion of the abdominal branches, and the presence of thrombi in the false lumen were analyzed to determine whether these factors were related to the left or right side and global or focal renal atrophy. Results: Of 880 abdominal branches in 176 patients, 622 (70.7%) were classed as perfusion type 1, 50 (5.7%) as type 2, and 208 (23.6%) as type 3. Type 3 perfusion was most commonly observed in the left renal artery, at a frequency of 31.7% (66/208). Partial thrombosis in the false lumen above the level of the renal arteries was seen in 68.8% of patients; such thrombi and type 3 perfusion of the renal artery were significantly related to renal atrophy. The laterality (left or right) and extent (global or focal) of renal atrophy were not related to age, gender, type of aortic dissection, or perfusion type. Conclusion: Type 3 perfusion is most frequent in the left renal artery, and such perfusion and partial thrombi in the false lumen above the renal arteries are significantly related to the development of renal atrophy. [ABSTRACT FROM AUTHOR]

Objective: To prospectively compare the diagnostic potential of 3-T wholebody magnetic resonance imaging (WB-MRI) and integrated fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) (FDG-PET-CT), and their combined interpretation for the detection of residual/recurrent nasopharyngeal carcinoma (NPC).Methods: We enrolled 179 NPC patients at high risk of residual disease or with suspected recurrence. WB-MRI and FDG-PET-CT were obtained with an interval of <10 days.Results: Fifty-five (30.7%) patients were found to have residual/recurrent tumours. In a patient-based analysis, the sensitivity, specificity and diagnostic capability of WB-MRI were similar to those of FDG-PET-CT (90.9% vs. 87.3%, P=0.69; 91.1% vs. 90.3%, P>0.99; 0.929 vs. 0.924, P=0.83, respectively). Combined interpretation of WB-MRI with FDGPET-CT increased the sensitivity to 94.5%. A slight improvement in the diagnostic capability was obtained using a combined interpretation of WB-MRI and FDG-PET-CT over WB-MRI alone (0.952 vs. 0.929, P=0.22) and FDG-PET-CT alone (0.952 vs. 0.924, P=0.11).Conclusions: Three-Tesla WB-MRI achieved a similar diagnostic capability to FDGPET-CT for the detection of residual/recurrent NPC. Both techniques have different advantages, and their combined interpretation can yield a slightly higher diagnostic capability. In clinical practice, 3-T WB-MRI can offer an accurate and comprehensive assessment of residual/recurrent NPC. [ABSTRACT FROM AUTHOR]

We sought to prospectively evaluate the accuracy of 3.0-Tesla whole-body magnetic resonance imaging (WB-MRI) and integrated fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) (FDG-PETCT), and their combined interpretation for the assessment of distant-site status in 150 patients with untreated nasopharyngeal carcinoma (NPC). Eighteen (12%) patients were diagnosed as having distant malignancies (15 patients had distant metastases, and three distant synchronous tumours). On a patient-based analysis, WB-MRI and FDG-PET-CT showed similar sensitivity (77.8% vs 72.2%, P>0.999), specificity (98.5% vs 97.7%, P > 0.999) and diagnostic capability (0.905 vs 0.878, P = 0.669). Combined interpretation of WB-MRI and FDGPET-CT showed no significant benefit over either technique alone. In conclusion, 3.0-Tesla WB-MRI is a feasible, non-ionising technique that showed similar diagnostic capacity to FDG-PET-CT in assessing distant-site status in patients with untreated NPC and can be recommended as the first-line imaging technique for comprehensive evaluation of such patients. [ABSTRACT FROM AUTHOR]

We report 2 pediatric cases of small bowel obstruction due to a Meckel's diverticulum complicated with internal hernia. Abdominal multidetector computed tomograms with multiple planar reconstructions revealed a bridge-like lesion with inconspicuous mucosal folds in the right lower quadrant formed by adhesion of the tip of Meckel's diverticulum with the adjacent mesentery, with ileal loops converging at the "bridge" and engorged mesenteric vessels. These 2 cases highlight the feasibility of multidetector computed tomography, especially in the ED, in revealing this unusual etiology of small bowel obstruction. [ABSTRACT FROM AUTHOR]

Objective: To report the clinical and computed tomographic findings of 5 cases of left brachiocephalic vein perforation (LBCVP). Methods: The clinical and imaging features of 5 patients with LBCVP (1 woman, 4 men; mean age, 57.6 years) encountered over the last 2 decades were reviewed. Results: Etiologies included left jugular central catheter penetration in 2 patients, blunt trauma in 2, and idiopathic in 1. All patients manifested acute chest pain with a widened mediastinum on chest radiographs. Characteristic computed tomographic features included a cord-like hematoma along the course of the left brachiocephalic vein associated with a left upper anterior mediastinal hematoma (AMH). Three clinically stable patients with AMH smaller than 5 cm convalesced after conservative treatment and 2 clinically unstable patients with AMH bigger than 7 cm recovered well after surgery. Conclusions: Computed tomography is helpful in diagnosing LBCVP. Under close surveillance, patients with stable LBCVP with AMH smaller than 5 cm may be managed conservatively. However, emergency surgery is warranted if there are any signs of instability. [ABSTRACT FROM AUTHOR]

Background: This study investigates whether phloretin, a brain-edema inhibitor, can enhance the therapeutic effects of human-derived platelet-rich plasma (hPRP) in reducing brain hemorrhagic volume (BHV) and preserving neurological function in rodents following acute traumatic brain damage (TBD), Methods: Forty rats were divided into five groups: sham-control, TBD, TBD + phloretin (80 mg/kg/dose intraperitoneally at 30 minutes and on days 2/3 post-TBD), TBD + hPRP (80μL by left intra-carotid-artery injection at 3 hours post-TBD), and TBD + phloretin + hPRP. Cerebral tissues were harvested on day 28 post-TBD for analysis., Results: Brain MRI on day 28 showed the lowest BHV in the sham-control group and the highest in the TBD group. BHV was significantly lower in the phloretin + hPRP group compared to the phloretin or hPRP alone groups, which had similar BHV. Neurological function followed an inverse pattern to BHV. By day 28, protein levels of upstream (HGMB1, TLR-2, TLR-4, MyD88, Mal, TRAM, TRIF, TRAF6, IKK-α, IKK-ß, p-NF-κB) and downstream (IL-1ß, TNF-α, iNOS) inflammation signalings, apoptosis (caspase3, PARP), and fibrosis (Smad3, TGF-ß) biomarkers, as well as flow cytometric assessment of inflammatory cells (CD11b/c+, Ly6G+, PMO+) and early (AN-V+/PI-) and late (AN-V+/PI+) mononuclear-cell apoptosis, displayed patterns similar to BHV. The number of inflammatory (CD68+, MMP9+) and brain-swelling/myelin-damaged (AQP4+, GFAP+) mediators also followed this pattern, while neuronal-myelin (Doublecortin+, NeuN, nestin) mediators showed an inverse relationship with BHV (all p<0.0001)., Conclusion: Combined phloretin and hPRP therapy is superior to either treatment alone in protecting the brain against TBD, primarily by suppressing inflammatory signaling and brain-swelling biomarkers.

This study tested whether combined dapagliflozin and entresto would be superior to mere one therapy on protecting the residual renal function and integrity of kidney parenchyma in hypertensive kidney disease (HKD) rat. In vitro results showed that the protein expressions of oxidative-stress/mitochondrial-damaged (NOX-1/NOX-2/oxidized-protein/cytosolic-cytochrome-C)/apoptotic (mitochondrial-Bax/cleaved caspeases 3, 9)/cell-stress (p-ERK/p-JNK/p-p38) biomarkers were significantly increased in H 2 O 2 -treated NRK-52E cells than those of controls that were reversed by dapagliflozin or entresto treatment. Adult-male SD rats ( n  = 50) were equally categorized into group 1 (sham-operated-control), group 2 (HKD by 5/6 nephrectomy + DOCA-salt/25 mg/kg/subcutaneous injection/twice weekly), group 3 (HKD + dapagliflozin/orally, 20 mg/kg/day for 4 weeks since day 7 after HKD induction), group 4 (HKD + entresto/orally, 100 mg/kg/day for 4 weeks since day 7 after HKD induction), and group 5 (HKD + dapagliflozin + entresto/the procedure and treatment strategy were identical to groups 2/3/4). By day 35, circulatory levels of blood-urine-nitrogen (BUN)/creatinine and urine protein/creatinine ratio were lowest in group 1, highest in group 2, and significantly lower in group 5 than in groups 3/4, but no difference between groups 3/4. Histopathological findings showed the kidney injury score/fibrotic area/cellular expressions of oxidative-stress/kidney-injury-molecule (8-OHdG+/KIM-1+) exhibited an identical trend, whereas the cellular expressions of podocyte components (synaptopodin/ZO-1/E-cadherin) exhibited an opposite pattern of BUN level among the groups. The protein expressions of oxidative stress/mitochondrial-damaged (NOX-1/NOX-2/oxidized protein/cytosolic-cytochrome-C/cyclophilin-D)/apoptotic (mitochondrial-Bax/cleaved-caspase 3)/mitochondrial-fission (PINK1/Parkin/p-DRP1)/autophagic (LC3BII/LC3BI ratio, Atg5/beclin-1)/MAPK-family (p-ERK/p-JNK/p-p38) biomarkers displayed a similar pattern, whereas the protein expression of mitochondria-biogenesis signaling (SIRT1/PGC-1α-Mfn2/complex I-V) displayed an opposite pattern of BUN among the groups. In conclusion, combined dapagliflozin-entresto therapy offered additional benefits on protecting the residual kidney function and architectural integrity in HKD rat., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: This study tested the hypothesis that inflammatory and interleukin (IL)-17 signalings were essential for acute liver ischemia (1 h)-reperfusion (72 h) injury (IRI) that was effectively ameliorated by adipose-derived mesenchymal stem cells (ADMSCs) and tacrolimus., Methods: Adult-male SD rats (n = 50) were equally categorized into groups 1 (sham-operated-control), 2 (IRI), 3 [IRI + IL-17-monoclonic antibody (Ab)], 4 (IRI + tacrolimus), 5 (IRI + ADMSCs) and 6 (IRI + tacrolimus-ADMSCs) and liver was harvested at 72 h., Results: The main findings included: (1) circulatory levels: inflammatory cells, immune cells, and proinflammatory cytokines as well as liver-damage enzyme at the time point of 72 h were highest in group 2, lowest in group 1 and significantly lower in group 6 than in groups 3 to 5 (all p < 0.0001), but they did not differ among these three latter groups; (2) histopathology: the liver injury score, fibrosis, inflammatory and immune cell infiltration in liver immunity displayed an identical pattern of inflammatory cells among the groups (all p < 0.0001); and (3) protein levels: upstream and downstream inflammatory signalings, oxidative-stress, apoptotic and mitochondrial-damaged biomarkers exhibited an identical pattern of inflammatory cells among the groups (all p < 0.0001)., Conclusion: Our results obtained from circulatory, pathology and molecular-cellular levels delineated that acute IRI was an intricate syndrome that elicited complex upstream and downstream inflammatory and immune signalings to damage liver parenchyma that greatly suppressed by combined tacrolimus and ADMSCs therapy., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: To use convolutional neural network for fully automated segmentation and radiomics features extraction of hypopharyngeal cancer (HPC) tumor in MRI., Methods: MR images were collected from 222 HPC patients, among them 178 patients were used for training, and another 44 patients were recruited for testing. U-Net and DeepLab V3 + architectures were used for training the models. The model performance was evaluated using the dice similarity coefficient (DSC), Jaccard index, and average surface distance. The reliability of radiomics parameters of the tumor extracted by the models was assessed using intraclass correlation coefficient (ICC)., Results: The predicted tumor volumes by DeepLab V3 + model and U-Net model were highly correlated with those delineated manually (p < 0.001). The DSC of DeepLab V3 + model was significantly higher than that of U-Net model (0.77 vs 0.75, p < 0.05), particularly in those small tumor volumes of < 10 cm 3 (0.74 vs 0.70, p < 0.001). For radiomics extraction of the first-order features, both models exhibited high agreement (ICC: 0.71-0.91) with manual delineation. The radiomics extracted by DeepLab V3 + model had significantly higher ICCs than those extracted by U-Net model for 7 of 19 first-order features and for 8 of 17 shape-based features (p < 0.05)., Conclusion: Both DeepLab V3 + and U-Net models produced reasonable results in automated segmentation and radiomic features extraction of HPC on MR images, whereas DeepLab V3 + had a better performance than U-Net., Clinical Relevance Statement: The deep learning model, DeepLab V3 + , exhibited promising performance in automated tumor segmentation and radiomics extraction for hypopharyngeal cancer on MRI. This approach holds great potential for enhancing the radiotherapy workflow and facilitating prediction of treatment outcomes., Key Points: • DeepLab V3 + and U-Net models produced reasonable results in automated segmentation and radiomic features extraction of HPC on MR images. • DeepLab V3 + model was more accurate than U-Net in automated segmentation, especially on small tumors. • DeepLab V3 + exhibited higher agreement for about half of the first-order and shape-based radiomics features than U-Net., (© 2023. The Author(s).)

Background: This study tested whether combined dapagliflozin and entresto treatment would be superior to either one alone for preserving the left-ventricular ejection-fraction (LVEF) in rat after ischemia-reperfusion (IR) injury., Methods: Cell culture using H9C2 cells and IR injury in rat with dapagliflozin-entresto treatment were conducted in the present study., Results: In vitro flow-cytometric result showed that the intracellular and mitochondrial reactive oxygen species and mitochondrial permeability transition pore, and protein levels of oxidative-stress/DNA-damaged markers [NADPH-oxidase-1 (NOX-1)/NOX-2/oxidized-protein/γ-H2A-histone-family member X (γ-H2AX)] were significantly higher in hydrogen peroxide (H 2 O 2 ) (300μM)-treated H9C2 cells as compared with the controls that were significantly reversed in sacubitril/valsartan and dapagliflozin therapy in the same H 2 O 2 -treated condition, whereas the protein expressions of antioxidants [Sirtuin-1 (SIRT1)/SIRT3/superoxide dismutase/catalase/glutathione peroxidase) exhibited an opposite pattern among the groups (all p<0.001). Adult-male-Sprague-Dawley rat (n=40) were equally categorized into group 1 (sham-operated control), group 2 (IR), group 3 (IR+dapagliflozin/20mg/kg/orally at 3h and post-days 1/2/3 after IR), group 4 (IR+entresto/100mg/kg/orally at 3h and post-days 1/2/3 after IR) and group 5 (IR+dapagliflozin+entresto) and the hearts were harvested by day 3 after IR. The 3 rd day's LVEF was highest in group 1, lowest in group 2 and significantly higher in group 5 than in groups 3/4, but it was similar between the latter two groups (p<0.001). The protein expressions of oxidative-stress (NOX-1/NOX-2/oxidized protein), fibrotic (transforming-growth factor-ß/phosphorylated-Smad3), apoptotic [mitochondrial-Bax/cleaved-caspase-3/cleaved-poly (ADP-ribose) polymerase], mitochondria/DNA damaged (cytosolic-cytochrome-c/γ-H2AX), pressure-overload/heart-failure [brain natriuretic peptide (BNP)/ß-myosin heavy chain] and autophagic (ratio of meiotic cyclins CLB3-II/CLB3-I) biomarkers, and the upstream (high-mobility group box 1/Toll-like receptor-4/MyD88/phosphorylated-nuclear factor-κB and downstream [interleukin (IL)-1ß/IL-6/tumor necrosis factor-α] inflammatory signalings revealed an antithetical features of LVEF among the groups (all p<0.0001). The cellular levels of inflammatory (myeloperoxidase+/CD68+), pressure-overload/heart-failure (BNP+) and DNA-damage (γ-H2AX+) biomarkers as well as infarct area demonstrated an opposite pattern of LVEF among the groups (all p<0.0001)., Conclusion: Incorporated entresto-dapagliflozin treatment was superior to either one alone on protecting the heart against IR injury., Competing Interests: Conflicts of interest The authors declare that they have no conflicts of interest., (Copyright © 2022 Chang Gung University. Published by Elsevier B.V. All rights reserved.)

Objective: We aimed to develop a deep learning artificial intelligence (AI) algorithm to detect impacted animal bones on lateral neck radiographs and to assess its effectiveness for improving the interpretation of lateral neck radiographs., Methods: Lateral neck radiographs were retrospectively collected for patients with animal bone impaction between January 2010 and March 2020. Radiographs were then separated into training, validation, and testing sets. A total of 1733 lateral neck radiographs were used to develop the deep learning algorithm. The testing set was assessed for the stand-alone deep learning AI algorithm and for human readers (radiologists, radiology residents, emergency physicians, ENT physicians) with and without the aid of the AI algorithm. Another radiograph cohort, collected from April 1, 2020, to June 30, 2020, was analyzed to simulate clinical application by comparing the deep learning AI algorithm with radiologists' reports., Results: In the testing set, the sensitivity, specificity, and accuracy of the AI model were 96%, 90%, and 93% respectively. Among the human readers, all physicians of different subspecialties achieved a higher accuracy with AI-assisted reading than without. In the simulation set, among the 20 cases positive for animal bones, the AI model accurately identified 3 more cases than the radiologists' reports., Conclusion: Our deep learning AI model demonstrated a higher sensitivity for detection of animal bone impaction on lateral neck radiographs without an increased false positive rate. The application of this model in a clinical setting may effectively reduce time to diagnosis, accelerate workflow, and decrease the use of CT., (© 2023. The Author(s).)

Dengue virus (DENV) which infects about 390 million people per year in tropical and subtropical areas manifests various disease symptoms, ranging from fever to life-threatening hemorrhage and even shock. To date, there is still no effective treatment for DENV disease, but only supportive care. DENV nonstructural protein 1 (NS1) has been shown to play a key role in disease pathogenesis. Recent studies have shown that anti-DENV NS1 antibody can provide disease protection by blocking the DENV-induced disruption of endothelial integrity. We previously demonstrated that anti-NS1 monoclonal antibody (mAb) protected mice from all four serotypes of DENV challenge. Here, we generated humanized anti-NS1 mAbs and transferred them to mice after DENV infection. The results showed that DENV-induced prolonged bleeding time and skin hemorrhage were reduced, even several days after DENV challenge. Mechanistic studies showed the ability of humanized anti-NS1 mAbs to inhibit NS1-induced vascular hyperpermeability and to elicit Fcγ-dependent complement-mediated cytolysis as well as antibody-dependent cellular cytotoxicity of cells infected with four serotypes of DENV. These results highlight humanized anti-NS1 mAb as a potential therapeutic agent in DENV infection., Competing Interests: The authors have declared that no competing interests exist.

This study tested the hypothesis that valsartan (Val) and melatonin (Mel)-assisted adipose-derived mesenchymal stem cells (ADMSCs) preserved the residual renal function in chronic kidney disease (CKD) rat through promoting cellular-prior-protein (PrP C ) to upregulate PI3K/Akt/mTOR signaling and cell proliferation. In vitro study demonstrated that as compared with CKD-derived-ADMSCs, Val/Mel/overexpression of PrP C -treated CKD derived-ADMSCs significantly upregulated cell proliferation and protein expressions of PrP C and phosphorylated (p)-PI3K/p-Akt/p-mTOR, and downregulated oxidative stress (all p < 0.001). Rats (n = 42) were categorized into group 1 (sham-operated-control), group 2 (CKD), group 3 (CKD + ADMSCs/1.2 ×10 6 cells) + Mel/20 mg/kg/day), group 4 (CKD + siRNA-PrP C -ADMSCs/1.2 ×10 6 cells), group 5 (CKD + ADMSCs/1.2 ×10 6 cells + Val/20 mg/kg/day) and group 6 (CKD + Val + Mel). By day 35, the kidney specimens were harvested and the result showed that the protein expression of PrP C was highest in group 1, lowest in groups 2/4 and significantly lower in group 6 than in groups 3/5, but it was similar in groups 3/5 (all p < 0.0001). The protein expressions of cell-stress-signaling (p-PI3K/p-Akt/p-mTOR) and cell-cycle activity (cyclin-D1/clyclin-E2/Cdk2/Cdk4) exhibited an identical pattern, whereas the protein expressions of oxidative-stress (NOX-1/NOX-2)/mitochondrial fission (PINK1/DRP1)/apoptosis (cleaved-capsase3/cleaved-PARP) and fibrosis (TFG-ß/Smad3) as well as creatinine/BUN levels, ratio of urine-protein to urine-creatine and kidney-injured score exhibited an opposite pattern of PrP C among the groups (all p < 0.0001). In conclusion, Mel/Val facilitated-ADMSCs preserved renal architecture and function in CKD rat through promoting PrP C to regulate the cell proliferation/oxidative-stress/cell-stress signalings., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Phlebosclerotic colitis (PC) is a rare form of nonthrombotic colonic ischemia. This retrospective study analyzed the clinical findings and temporal CT changes in 29 PC patients with long-term follow-up., Methods: Twenty-nine patients with characteristic CT features of PC collected between 1997 and 2020 were stratified into the acute abdomen group (AA-group) (n = 10), chronic-progressive group (CP-group) (n = 14) and chronic-stable group (CS-group) (n = 5). Clinical and CT changes during follow-up, comorbidities and final outcomes were compared., Results: The AA-group exhibited a significantly thicker colonic wall and more involved segments and pericolic inflammation than the CP-group and CS-group on initial CT (p =  < 0.001-0.031). Seven patients in the AA-group who underwent right hemicolectomy had no recurrence during follow-up (mean ± SD, 7.1 ± 3.3 years), and the remaining three patients with renal or hepatic comorbidities who underwent conservative treatment died within 14 days. The CP-group showed significantly higher frequencies of chronic renal failure, urinary tract malignancies and liver cirrhosis than the AA-group (p = 0.005-0.008). In addition, CT follow-up (7.9 ± 4.3 years) showed significant increases in mesenteric venous calcifications, colonic wall thickening and involved colonic segments (p = 0.001-0.008) but conservative treatments were effective. The CS-group remained unchanged for years (8.2 ± 3.9 years)., Conclusions: Early surgery offered excellent prognosis in PC-related acute abdomen denoted by marked right colonic wall thickening and pericolic inflammation on CT. Conservative treatments with a wait-and-watch strategy were appropriate for CP-PC and CS-PC, albeit CP-PC harbored significant increases in calcifications, colonic wall thickening and affected segments in long-term CT follow-up., (© 2022. The Author(s).)

This study tested the hypothesis that melatonin (Mel) therapy preserved the brain architectural and functional integrity against ischaemic stroke (IS) dependently through suppressing the inflammatory/oxidative stress downstream signalling pathways. Adult male B6 (n = 6 per each B6 group) and TLR4 knockout (ie TLR4 -/- ) (n = 6 per each TLR4 -/- group) mice were categorized into sham control (SC B6 ), SC TLR4-/- , IS B6 , IS TLR4-/- , IS B6  + Mel (i.p. daily administration) and IS TLR4-/- + Mel (i.p. daily administration). By day 28 after IS, the protein expressions of inflammatory (HMBG1/TLR2/TLR4/MAL/MyD88/RAM TRIF/TRAF6/IKK-α/p-NF-κB/nuclear-NF-κB/nuclear-IRF-3&7/IL-1β/IL-6/TNF-α/IFN-γ) and oxidative stress (NOX-1/NOX-2/ASK1/p-MKK4&7/p-JNK/p-c-JUN) downstream pathways as well as mitochondrial-damaged markers (cytosolic cytochrome C/cyclophilin D/SRP1/autophagy) were highest in group IS B6 , lowest in groups SC B6 and SC TLR4-/- , lower in group IS TLR4-/- + Mel than in groups IS TLR4-/- and IS B6  + Mel and lower in group IS B6  + Mel than in group IS TLR4-/- (all P < .0001). The brain infarct volume, brain infarct area and the number of inflammatory cells in brain (CD14/F4-88) and in circulation (MPO+//Ly6C+/CD11b+//Ly6G+/CD11b+) exhibited an identical pattern, whereas the neurological function displayed an opposite pattern of inflammatory protein expression among the six groups (all P < .0001). In conclusion, TLR inflammatory and oxidative stress signallings played crucial roles for brain damage and impaired neurological function after IS that were significantly reversed by Mel therapy., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Acute liver ischaemia-reperfusion injury (IRI), commonly encountered during liver resection and transplantation surgery, is strongly associated with unfavourable clinical outcome. However, a prompt and accurate diagnosis and the treatment of this entity remain formidable challenges. This study tested the hypothesis that 31 P-magnetic resonance spectroscopy ( 31 P-MRS) findings could provide reliable living images to accurately identify the degree of acute liver IRI and melatonin-pretreated mitochondria was an innovative treatment for protecting the liver from IRI in rat. Adult male SD rats were categorized into group 1 (sham-operated control), group 2 (IRI only) and group 3 (IRI + melatonin [ie mitochondrial donor rat received intraperitoneal administration of melatonin] pretreated mitochondria [10 mg/per rat by portal vein]). By the end of study period at 72 hours, 31 P-MRS showed that, as compared with group 1, the hepatic levels of ATP and NADH were significantly lower in group 2 than in groups 1 and 3, and significantly lower in group 3 than in group 1. The liver protein expressions of mitochondrial-electron-transport-chain complexes and mitochondrial integrity exhibited an identical pattern to 31 P-MRS finding. The protein expressions of oxidative stress, inflammatory, cellular stress signalling and mitochondrial-damaged biomarkers displayed an opposite finding of 31 P-MRS, whereas the protein expressions of antioxidants were significantly progressively increased from groups 1 to 3. Microscopic findings showed that the fibrotic area/liver injury score and inflammatory and DNA-damaged biomarkers exhibited an identical pattern of cellular stress signalling. Melatonin-pretreated mitochondria effectively protected liver against IRI and 31 P-MRS was a reliable tool for measuring the mitochondrial/ATP consumption in living animals., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background: This study tested the hypothesis that combined hyperbaric oxygen (HBO) and autologous adipose-derived mesenchymal stem cell (ADMSC) therapy was superior to either alone at protecting renal function in rodents after acute ischemia-reperfusion (IR) injury., Methods and Results: Adult-male SD rats (n = 40) were equally categorized: group 1 (sham-operated control); group 2 (IR + 50 μg medium intra-renal artery administration); group 3 [IR + HBO (at 1.5 h and days 1 and 2 after IR)]; group 4 [IR + ADMSC (2.0×10 6 cells/5.0×10 5 /per each renal artery and 1.0×10 6 by intravenous injection at 1.5 h after IR]; and group 5 (IR + HBO-ADMSC). By 72 hr after IR, the circulating levels of BUN/creatinine and ratio of urine protein/creatinine were significantly highest in group 2, lowest in group 1, significantly increased in group 5 than in groups 3 and 4, but not different between latter two groups, whereas the circulating levels of EPCs and soluble-angiogenesis biomarkers (SDF-1α/HIF-1α) exhibited an opposite pattern to BUN/creatinine among the five groups (all P<0.001). The kidney injury score, ROS (fluorescent intensity of H 2 DCFDA dye in kidney), inflammation (F4/80+, CD14+ cells) and glomerular-tubular injury score (WT-1/KIM-1) displayed an identical pattern whereas the integrity of podocyte components exhibited an opposite pattern to BUN/creatinine among the five groups (all P<0.0001). The protein expressions of inflammatory (MMP-9/TNF-α/NF-κB/ICAM-1), oxidative-stress (NOX-1/NOx-2/oxidized protein) and apoptotic (mitochondrial-Bax/cleaved-caspase3/PARP) markers showed an identical pattern to BUN/creatinine (all P<0.001)., Conclusion: Combined ADMSC-HBO therapy was superior to either one alone at protecting the kidney from acute IR injury., Competing Interests: None., (AJTR Copyright © 2020.)

Background: This study tested the optimal time point for left intra-carotid arterial (LICA) administration of circulatory-derived autologous endothelial progenitor cells (EPCs) for improving the outcome in rat after acute ischemic stroke (IS)., Methods and Results: Adult male SD rats (n = 70) were equally categorized into group 1 (sham-operated control), group 2 (IS), group 3 (IS+EPCs/1.2 × 10 6 cells/by LICA administration 3 h after IS), group 4 (IS+EPCs/LICA administration post-day-3 IS), group 5 (IS+EPCs/LICA administration post-day-7 IS), group 6 (IS+EPCs/LICA administration post-day-14 IS), and group 7 (IS+EPCs/LICA administration post-day-28 IS). The brain infarct volume (BIV) (at day 60/MRI) was lowest in group 1, highest in group 2, and significantly progressively increased from groups 3 to 7, whereas among the IS animals, the neurological function was significantly preserved in groups 3 to 6 than in groups 2 and 7 post-day-60 IS (all P < 0.0001). By day 60, the endothelial cell markers at protein and cellular levels and number of small vessels exhibited an opposite pattern of BIV among the groups (all P < 0.0001). The protein and cellular levels of inflammation, and protein levels of oxidative stress, autophagy, and apoptosis were highest in group 2, lowest in group 1, and progressively increased from groups 3 to 7 (all P < 0.0001). The angiogenesis biomarkers at protein and cellular levels were significantly progressively increased from groups 1 to 3, then significantly progressively decreased from groups 4 to 7 (all P < 0.0001)., Conclusion: Early EPC administration provided better benefits on improving functional/image/molecular-cellular outcomes after acute IS in rat.

Background: This retrospective study evaluated the computed tomography (CT) features and clinical implications of a novel broken-crescent sign in patients with acute aortic intramural hematoma (IMH)., Methods: Out of 104 patients with aortic IMH encountered in our institution between 2003 and 2018, nine patients exhibited a positive broken-crescent sign, which was defined as a focal defect within the hyper-attenuating crescentic IMH on unenhanced CT, corresponding to a smooth out-bulging of the aortic lumen on enhanced study. The clinical findings, CT features, and outcomes of these nine patients were analyzed., Results: Of five males and four females (age range 48-84 years, mean 69.7 years), six had type A and three had type B IMH. Five patients who had medical treatment and stable status for 1 to 3 days suffered sudden death, two of whom showed ascending aortic rupture with hemopericardium in one and adventitial tear with outward spillage of IMH in another at follow-up CT. The other four patients had early surgical or endovascular management survived; two demonstrated ascending aorta ecchymosis with adventitial tear and intact intima at surgery. Our results support the supposition that aortic IMH complicated with adventitial tear and partial outward seepage of IMH may generate a broken-crescent sign in CT. Despite initially stable clinical status, the residual intact inner aortic wall carries a high risk of sudden aortic rupture., Conclusions: In patients with acute aortic IMH, identification of a broken-crescent sign in CT is highly suggestive of impending aortic rupture, and early aggressive treatment is mandatory.

This study traced intravenously administered induced pluripotent stem cell (iPSC)-derived mesenchymal stem cells (MSC) and assessed the impact of iPSC-MSC on preserving renal function in SD rat after 5/6 nephrectomy. The results of in vitro study showed that FeraTrack™Direct contrast particles (ie intracellular magnetic labelling) in the iPSC-MSC (ie iPS-MSC SPIONs ) were clearly identified by Prussian blue stain. Adult-male SD rats (n = 40) were categorized into group 1 (SC), group 2 [SC + iPS-MSC SPIONs (1.0 × 10 6 cells)/intravenous administration post-day-14 CKD procedure], group 3 (CKD), group 4 [CKD + iPS-MSC SPIONs (0.5 × 10 6 cells)] and group 5 [CKD + iPS-MSC SPIONs (1.0 × 10 6 cells)]. By day-15 after CKD induction, abdominal MRI demonstrated that iPS-MSC SPIONs were only in the CKD parenchyma of groups 4 and 5. By day 60, the creatinine level/ratio of urine protein to urine creatinine/kidney injury score (by haematoxylin and eosin stain)/fibrotic area (Masson's trichrome stain)/IF microscopic finding of kidney injury molecule-1 expression was lowest in groups 1 and 2, highest in group 3, and significantly higher in group 4 than in group 5, whereas IF microscopic findings of podocyte components (ZO-1/synaptopodin) and protein levels of anti-apoptosis ((Bad/Bcl-xL/Bcl-2) exhibited an opposite pattern to creatinine level among the five groups (all P < .0001). The protein expressions of cell-proliferation signals (PI3K/p-Akt/m-TOR, p-ERK1/2, FOXO1/GSK3β/p90RSK), apoptotic/DNA-damage (Bax/caspases8-10/cytosolic-mitochondria) and inflammatory (TNF-α/TNFR1/TRAF2/NF-κB) biomarkers displayed an identical pattern to creatinine level among the five groups (all P < .0001). The iPS-MSC SPIONs that were identified only in CKD parenchyma effectively protected the kidney against CKD injury., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

This study tested whether the soluble (s)ST2 is a superb biomarker predictive of moderate to severe cerebral-cardiac syndrome (CCS) (defined as coexisting National Institute of Health Stroke Scale (NIHSS) >8 and left-ventricular ejection fraction (LVEF) <60%) in patients after acute ischemic stroke (IS). Between November 2015 and October 2017, a total of 99 IS patients were prospectively enrolled and categorized into three groups based on NIHSS, i.e., group 1 (NIHSS ≤ 8, n = 66), group 2 (NIHSS = 9-15, n = 14) and group 3 (NIHSS ≥ 16, n = 19), respectively. Blood samples were collected immediately after hospitalization, followed by transthoracic echocardiographic examination. The results showed that the flow cytometric analysis for assessment of inflammatory biomarkers of TLR2+/CD14+cells, TLR4+/CD14+cells, Ly6g+/CD14+cells, and MPO+/CD14+cells, and ELISA assessment for circulatory level of sST2 were significantly higher in groups 2/3 than in group 1 (all p < 0.01). However, these parameters did not show significant differences between groups 2 and 3 (all p > 0.05). The LVEF was significantly lower in group 3 than in group 1 ( p < 0.001), but it displayed no difference between groups 1/2 or between groups 2/3. These inflammatory biomarkers ((TLR2+/CD14+cells// TLR4+/CD14+cells// MPO+/CD14+cells) and sST2)) were significantly positively correlated to NIHSS and strongly negatively correlated to LVEF (all p < 0.05). Multivariate analysis demonstrated that both MPO/CD14+cells >20% ( p = 0.027) and sST2 ≥ 17,600 ( p = 0.004) were significantly and independently predictive of moderate-severe CCS after acute IS. Receiver operating characteristic curve analysis demonstrated that sST2 was the most powerful predictor of CCS with a sensitivity of 0.929 and a specificity of 0.731 ( p < 0.001). In conclusion, sST2 is a useful biomarker for prediction of CCS severity in patients after acute IS., Competing Interests: receiver operating characteristic

Purpose: This study aimed to investigate the feasibility of diffusion tensor imaging (DTI) and T2-mapping to assess temporal renal damage in deoxycorticosterone acetate-salt (DOCA-salt) hypertensive rats and compare the results with histopathologic and immunohistochemical findings., Procedures: After baseline renal magnetic resonance imaging (MRI), 24 out of 30 uninephrectomized Sprague-Dawley rats with DOCA-salt-induced hypertension were divided equally into four groups. Group 1 had renal MRI at weeks 2, 4, 6, and 8, and groups 2, 3, and 4 had MRI at weeks 2, 4, and 6, respectively. The remaining 6 rats were used as sham controls. The renal cortex and outer and inner stripes of the outer medulla were examined over time using fractional anisotropy (FA), apparent diffusion coefficient (ADC), and T2-mapping, and the results were compared with baseline values. The degree of glomerular and tubular injury, endothelial cell thickening, hyaline arteriolosclerosis, macrophage infiltration, microcyst formation, and fibrosis in different zones at different time points in the DOCA-salt rats were compared with controls., Results: Compared with baseline values, DOCA-salt rats demonstrated a significant decrease in renal cortical FA from week 4 to week 8 (0.244 ± 0.015 vs 0.172 ± 0.014-0.150 ± 0.016, P = 0.018-0.002), corresponding to significantly more glomerular damage, arteriolosclerosis, macrophage infiltration, and fibrosis. The DOCA-salt rats had significantly increased cortical ADC and T2 values at weeks 6 and 8 (1.778 ± 0.051 × 10 -3  mm 2 /s vs 1.872 ± 0.058-1.917 ± 0.066 × 10 -3  mm 2 /s; 93.7 ± 4.9 ms vs 98.0 ± 2.9-100.7 ± 4.0 ms, respectively, all P < 0.05), consistent with excessively fluid-filled microcysts (aquaporin-2+). Despite DOCA-salt rats harbored markedly increased fibrosis in outer and inner stripes of the outer medulla at weeks 6 and 8, only nonsignificant decreases in FA were observed in comparison with the controls suggesting that only limited microstructural changes were present., Conclusions: Renal cortical FA is useful for the early detection and monitoring of renal damage in DOCA-salt hypertensive rats.

Purpose: In this prospective study, we sought to compare the clinical utility of fluorodeoxyglucose PET/MRI, MRI, and PET/CT in the detection of synchronous cancers and distant metastases in patients with oropharyngeal and hypopharyngeal squamous cell carcinoma (OHSCC)., Methods: We examined 198 consecutive patients with biopsy-proven OHSCC who agreed to receive chemoradiation. All patients underwent pretreatment PET/MRI and PET/CT on the same day. Patients were followed-up for a minimum of 12 months or until death. The McNemar's test and receiver-operating characteristic (ROC) curves were used to compare sensitivity/specificity and the diagnostic capabilities of PET/MRI, MRI, and PET/CT, respectively., Results: We identified 55 patients (27.7%) who had synchronous cancers and/or distant metastases (number of involved sites: 83). The results of site-based analysis revealed that the sensitivity of PET/MRI was 15.7% higher than that of MRI (73.5% versus 57.8%, p < 0.001) and 3.6% higher compared with PET/CT (73.5% versus 69.9%, p = 0.083), whereas the sensitivity of PET/CT was 12.1% higher than that of MRI (69.9% versus 57.8%, p = 0.012). On a patient-basis, ROC curve analysis demonstrated that PET/MRI yielded a greater area under curve than MRI (0.930 versus 0.905, p = 0.023). There were no significant differences in terms of diagnostic capability between MRI and PET/CT (0.905 versus 0.917, p = 0.469) and between PET/MRI and PET/CT (0.930 versus 0.917, p = 0.062)., Conclusions: In our cohort, PET/MRI showed a significantly higher diagnostic capability than MRI and no significant difference compared with PET/CT for the detection of synchronous cancers or distant metastases in patients with OHSCC.

Introduction: Duplications of the alimentary tract are a rare congenital malformation. Most of the cases are symptomatic and diagnosed before 2 years of age. Here, we report a young female presented with a huge abdominal mass, and colonic duplication was confirmed during laparotomy., Case Presentation: A 29-year-old female had chronic constipation treated with laxative agents. She presented to the emergency room with abdominal cramping for 3 days, accompanied with intermittent fever and vomiting. A huge movable abdominal mass was noted during physical examination. Computerized tomography showed a long segmental dilated bowel lumen with stool impaction and bowel wall thickening of the dilated lumen in the left abdomen, highly suggestive of a long tubular colon duplication. The patient underwent subtotal colectomy. Specimen subsequently confirmed the diagnosis for colonic duplication from cecum to sigmoid colon, and the duplicated colon was found on the antimesenteric side of the native colon. She had a stable postoperative course and was discharged 9 days later., Discussion: Duplications of the alimentary tract are a rare congenital anomaly. Colonic duplication is an even more unusual malformation of this type. It can be classified into cystic or tubular type according to the gross morphology and may or may not be associated with other congenital anomalies. Most common presentation includes abdominal distention, refractory constipation, and bowel obstruction like many other colorectal conditions. Thus, its indistinct symptoms make it difficult to be diagnosed preoperatively. The recommended treatment is surgical resection of the duplicated lumen along with the attached native colon.

This study tested the hypothesis that combined hyperbaric oxygen (HBO) and melatonin (Mel) was superior to either one for protecting the brain functional and parenchymal integrity from acute ischemic stroke (IS) injury. Adult-male Sprague-Dawley rats were divided into groups 1 (sham-operated control), 2 (IS), 3 (IS + HBO), 4 (IS + Mel), and 5 (IS + HBO-Mel). By day 28 after IS, the brain infarct area (BIA) was lowest in group 1, highest in group 2, significantly higher in groups 3 and 4 than in group 5, but not different between groups 3 and 4. The neurological function at day 7, 14, and 28 exhibited an opposite pattern to BIA among the 5 groups. The protein expressions of inflammatory (IL-1β/IL-6/iNOS/TNF-α/p-NF-κB), apoptotic (cleaved-caspase3/cleaved-PARP/mitochondrial Bax), mitochondrial/DNA-damaged (cytochrome-C/γ-H2AX), oxidative stress (NOX-1/NOX-2), and autophagy (i.e. ratio of CL3B-II/CL3B-I) biomarkers displayed an identical pattern of BIA among 5 groups. Cellular expressions of inflammation (F4/80+/GFAP+) and DNA-damaged biomarker (γ-H2AX+) exhibited an identical pattern, whereas the integrities of myelin sheath/neuron (MPB+/NeuN+), endothelial cell (CD31+/vWF+), and number of small vessels exhibited an opposite pattern of BIA among the 5 groups. Combined HBO-Mel therapy offered an additional benefit in protecting the brain against IS injury., (© 2019 American Association of Neuropathologists, Inc. All rights reserved.)

Endothelial cell (EC) dysfunction plays a crucial role for arterial obstructive disease. This study tested the therapeutic role of autologous endothelial progenitor cells (EPCs)/rosuvastatin-(Rosu)/valsartan-(Val) on repair of injured carotid ECs. Male Sprague-Dawley rats (n = 60) were categorized into five groups [sham-control (SC), left common carotid artery injury induced by balloon denudation (LCA BD ), LCA BD + Rosu (10 mg/kg/day), LCA BD + Val (20 mg/kg/day), and LCA BD + EPC (1.2 × 10 6 )]. By day 5, the LCA was harvested from each rat (n = 6/each time interval in group) after the procedure. Carotid-ring angiogenesis was significantly lower in LCA BD than the other groups (all P < 0.001). Compared with LCA BD , the number of EC was significantly higher in LCA BD treated with adipose-derived mesenchymal stem cells (ADMSCs) and more significantly higher in LCA BD treated with EPCs (all P < 0.001). Gene expression of EC (CD31/vWF), EPC (SDF-1α/CXCR4) and angiogenesis (VEGF/VEGF-receptor/angiopoietin/eNOS) and EC intercellular junction (VE-cadherin) biomarkers were significantly lower in LCA BD than in groups LCA BD + Rosu to LCA BD + EPC (all P < 0.001). Conversely, the gene expression of inflammatory (VCAM-1/MMP-9/TNF-α), oxidative-stress (NOX-1/NOX-2), apoptosis (cleaved caspase-3/PARP) and thrombin cofactor (thrombomodulin) biomarkers were significantly higher in LCA BD than in other groups (all P < 0.001). By day 14, the neointimal-layer area and cellular expressions of (CD40+/CD68+) were highest in LCA BD , lowest in SC, significantly higher in LCA BD + Val than in LCA BD + Rosu and LCA BD + EPC (all P < 0.001). In conclusion, EPCs were comparable to rosuvastatin and valsartan in upregulation of angiogenesis and repair of injured carotid ECs., Competing Interests: None.

This study tested the hypothesis that early administration of empagliflozin (Empa), an inhibitor of glucose recycling in renal tubules, could preserve heart function in cardiorenal syndrome (CRS) in rat. Chronic kidney disease (CKD) was caused by 5/6 subtotal nephrectomy and dilated cardiomyopathy (DCM) by doxorubicin (DOX) treatment. In vitro results showed that protein expressions of cleaved-caspase3 and autophagy activity at 24 h/48 h in NRK-52P cells were significantly upregulated by para-Creso treatment; these were significantly downregulated by Empa treatment. Flow cytometric analysis showed that annexin-V (i.e., early/late apoptosis) in NRK-52P cells expressed an identical pattern to cleaved-caspase3 between the two groups (all p < 0.001). Adult-male-SD rats (n = 18) were equally categorized into group 1 (sham-control), group 2 (CRS) and group 3 [CRS + Empa; 20 mg/kg/day]. By day-42 after CRS induction, left-ventricular ejection fraction (LVEF) level exhibited an opposite pattern, whereas LV end-diastolic dimension and creatinine level displayed the same pattern, to cleaved-caspase3 among the three groups (all p < 0.0001). In LV tissues, protein expressions of inflammatory (tumor-necrosis factor-α/nuclear-factor-κB/interleukin-1ß/matrix-metalloprotianse-9), oxidative stress (NOX-1/NOX-2/oxidized protein), apoptotic (mitochondrial-Bax/cleaved-caspase-3/cleaved-PARP), fibrotic (transforming-growth factor-ß/Smad3), DNA/mitochondrial-damage (γ-H2AX/cytosolic-cytochrome-C) and heart failure (brain natriuretic peptide (BNP) levels displayed an opposite pattern to LVEF among the three groups (all p < 0.0001). Additionally, cellular expressions of DNA-damage/heart-failure (γ-H2AX+//XRCC1+CD90+//BNP+) biomarkers and histopathological findings of fibrotic/condensed collagen-deposition areas and apoptotic nuclei showed an identical pattern, whereas connexin43 and small-vessel number exhibited an opposite pattern, to inflammation among the three groups (all p < 0.0001). In conclusion, Empa therapy protected heart and kidney against CRS injury., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

This study tested whether inducible pluripotent stem cell (iPSC)-derived mesenchymal stem cell (MSC) therapy could effectively protect kidney from acute ischemia (1 h) - reperfusion (5 day) injury (IRI). Male-adult SD-rats (n = 24) were equally categorized into groups 1 (sham-control), 2 [sham-control + iPSC-MSC (1.2 × 10 6 cells/rat)], 3 (IR only) and 4 (IR + iPSC-MSC). Blood urine nitrogen/creatinine levels and ratio of urine protein to creatinine, kidney weight and expressions of inflammation (TNF-α/NF-κB), oxidative-stress (NOX-1/NOX-2/oxidized protein) and apoptosis (mitochondrial-Bax/cleaved caspase-3/PARP) were significantly higher in group 3 than in groups 1, 2 and 4 and significantly higher in group 4 than in groups 1 and 2 (all P<0.0001), but showed no differences between groups 1 and 2, whereas the protein expressions of anti-inflammation (IL-4/IL-10) and endothelial (CD31/vWF) markers exhibited an opposite pattern to inflammation among the four groups (all P<0.0001). Protein expressions of angiogenesis (VEGF/CXCR4/SDF-1α) markers progressively increased from groups 1 to 4 (all P<0.0001). Cellular expressions of kidney injury score/DNA-damage (γ-H2AX)/apoptotic nuclei and glomerulus-tubular-damage (KIM/FSP-1) displayed an identical pattern to inflammation, whereas the cellular expressions of glomerulus-tubular-integrity (dystroglycan/podocin/p-cadherin/synaptopodin/ZO-1/fibronectin) revealed an opposite pattern to inflammation among the four groups (all P<0.0001). In conclusion, iPSC-derived MSC therapy effectively protected kidney against IRI., Competing Interests: None.

Purpose: This study aimed to investigate the potential of apparent diffusion coefficient (ADC) for monitoring adipose-derived mesenchymal stem cell (ADMSC) therapy of renal ischemic-reperfusion injury (IRI)., Procedures: After baseline magnetic resonance imaging (MRI), 36 Sprague-Dawley rats with bilateral renal IRI were divided equally as groups 1, 2, and 3 (non-treated rats) and groups 4, 5, and 6 (ADMSC-treated rats, with 2 million ADMSCs injected via the tail vein at 6 h after IRI). Groups 1 and 4, 2 and 5, and 3 and 6 were euthanized at days 1, 3, and 7, respectively, after renal MRI. The ratios of ADC at different time points to baseline values in the cortex, outer, and inner stripes of outer medulla (OSOM/ISOM), assessments of monocyte chemoattractant protein-1 (MCP-1), CD68+ cells, tubular cast formation, and degree of fibrosis in three zones over time were compared between the non-treated and ADMSC-treated rats., Results: Among three zones, the differences in cortical ADC and immunohistochemical changes between the non-treated and ADMSC-treated IRI rats over time were less obvious. Compared with the non-treated rats, the ADMSC-treated rats exhibited significantly higher ADC ratios of OSOM and ISOM at days 1 and 3 corresponding to significantly less MCP-1 staining, CD68+ cells, and tubular casts. From day 3 to day 7, coupling with the decrement of MCP-1 and CD68+ cells in IRI kidneys, the effect of cell density on ADC declined. By day 7, the ADMSC-treated rats showed significantly higher ADC ratios of ISOM than the non-treated IRI rats, indicating better recovery, which could be related to significantly fewer tubular casts and marked amelioration of fibrosis., Conclusions: We suggest ADC is a useful in vivo biomarker for monitoring ADMSC therapy of renal IRI.

Myocardial ischemia-reperfusion (IR) injury contributes to adverse cardiac outcomes after myocardial ischemia, cardiac surgery, or circulatory arrest. In this study, we evaluated the ability of combined SS31-mitochondria (Mito) therapy to protect heart cells from myocardial IR injury. Adult male SD rats ( n = 8/each group) were randomized: group 1 (sham-operated control), group 2 (IR, 30-min ischemia/72 h reperfusion), group 3 (IR-SS31 (2 mg intra-peritoneal injection at 30 min/24 h/48 h after IR)), group 4 (IR-mitochondria (2 mg/derived from donor liver/intra-venous administration/30 min after IR procedure)), and group 5 (IR-SS31-mitochondria). In H9C2 cells, SS31 suppressed menadione-induced oxidative-stress markers (NOX-1, NOX-2, oxidized protein) while it increased SIRT1/SIRT3 expression and ATP levels. In adult male rats 72 h after IR, left ventricular ejection fraction (LVEF) was highest in sham-operated control animals and lowest in the IR group. LVEF was also higher in IR rats treated with SS31-Mito than untreated IR rats or those treated with Mito or SS31 alone. Areas of fibrosis/collagen-deposition showed the opposite pattern. Likewise, levels of oxidative-stress markers (NOX-1, NOX-2, oxidized protein), inflammatory markers (MMP-9, CD11, IL-1β, TNF-α), apoptotic markers (mitochondrial-Bax, cleaved-caspase-3, PARP), fibrosis markers (p-Smad3, TGF-β), DNA-damage (γ-H2AX), sarcomere-length, and pressure/volume overload markers (BNP, β-MHC) all showed a pattern opposite that of LVEF. Conversely, anti-apoptotic (BMP-2, Smad1/5) and energy integrity (PGC-1α/mitochondrial cytochrome-C) markers exhibited a pattern identical to that of LVEF. This study demonstrates that the combined SS31-Mito therapy is superior to either therapy alone for protecting myocardium from IR injury and indicates that the responsible mechanisms involved increased SIRT1/SIRT3 expression, which suppresses inflammation and oxidative stress and protects mitochondrial integrity.

Purpose: To determine whether pretreatment in vivo 1H magnetic resonance (MR) spectroscopy at 3 Tesla (T) and 18F-FDG PET/CT can offer predictive power regarding the local control of oropharyngeal or hypopharyngeal squamous cell carcinoma (OHSCC) patients., Materials and Methods: 1 H MR spectroscopy was performed in addition to conventional MR imaging before definitive chemoradiotherapy in 58 patients with advanced OHSCC. The relationship of local control with the 1 H MR spectroscopy and 18 F-FDG PET/CT parameters was analyzed., Results: With a median follow-up of 17.6 months, 13 (22.4%) patients exhibited local failure; whereas the remaining 45 achieved local control. Kaplan-Meier analysis identified age > 60 years, creatine level on MRS ≦ 6.02 mM , glutamine and glutamate (Glx) level on MRS > 3.31 mM , and total lesion glycolysis (TLG) on 18 F-FDG PET/CT > 217.18 g/mL × mL as significant adverse predictors for 2-year local control. Multivariate Cox regression analysis showed that age (p=0.017), Glx level on MRS (p=0.021), and TLG on 18 F-FDG PET/CT (p=0.028) retained their independent prognostic significance. A scoring system was constructed based on the sum of these three factors. We found that patients with scores of 2-3 had significantly poorer local control rates than patients with scores of 0-1 (33.3% versus 86.8%, p=0.003)., Conclusion: We conclude that Glx on 1 H MR spectroscopy at 3 T was the independent prognostic factor for local control of OHSCC patients treated with chemoradiotherapy, and its combination with age and TLG may help identify a subgroup of patients at high risk for developing local failure., Competing Interests: CONFLICTS OF INTEREST The authors have declared no conflicts of interest.

This study tested the hypothesis that extracorporeal shock wave (ECSW) therapy could protect mouse brain from chronic cerebral hypoperfusion (CHP)-induced neuropathological changes in a bilateral carotid arterial stenosis (CAS) model. Adult-male C57BL/6 (B6) mice (n=36) were randomized into group 1 (sham-control), group 2 (CHP) and group 3 [CHP+ECSW (100 impulses at 0.15 mJ/mm 2 ) on day 5, 10 and 15 after CHP induction]. By day 60 after CHP induction, the white matter lesion, protein expressions of inflammatory (TNF-α/NF-κB/iNOS), oxidative-stress (NOX-1/NOX-2/NOX-4/nitrotyrosine), angiogenesis (eNOS/CD31), apoptotic (Bax/caspase-3/PARP), fibrotic (Smad3/TGF-ß) and mitochondrial-damaged (cytosolic cytochrome-C) biomarkers were significantly higher in group 2 than in groups 1 and 3, and significantly higher in group 3 than in group 1, whereas the protein expressions of anti-apoptotic (Bcl-2), anti-fibrotic (BMP-2/Smad1/5), and mitochondrial-integrity (mitochondrial cytochrome-C) biomarkers showed an opposite pattern to inflammation among the three groups (all P<0.0001). The cellular expressions of inflammatory (Iba-1/GFAP/CD14, F4/80), apoptotic (TUNEL-assay) and brain-damaged (γ-H2AX/AQP4) biomarkers showed an identical pattern to inflammation, whereas the cellular expressions of endothelial-cell (CD31/vWF), neuron/energy-integrity (NeuN/PGC-1α) and small-vessel density exhibited an opposite pattern to inflammation among the three groups (all P<0.0001). Cellular angiogenesis (VEGF/SDF-1α) significantly and progressively increased from groups 1 to 3 (all P<0.0001). In conclusion, ECSW therapy enhanced angiogenesis, inhibited molecular-cellular perturbations, and protected the white matter and neuron from CHP damage., Competing Interests: None.

This study tested the hypothesis that exendin-4 (Ex4) protects kidneys against ischemia-reperfusion (IR) injury mainly through upregulation of nuclear-factor erythroid 2-related factor 2 (Nrf2) signaling and downregulation of oxidative stress. Male-adult Sprague-Dawley rats (n=24) were equally divided into group 1 (sham-operated control), group 2 [IR only, ischemia (1 h)/reperfusion (72 h)] and group 3 (IR-Ex4, 10 μg/kg at 30 min, 24 h, 48 h after IR procedure). The in vitro study demonstrated that the protein expressions of phosphorylated (p)-Akt and Nrf2 were significantly progressively increased at time points of 0/0.5/1/3 h and 0/0.5/1/3/6/12/24 h, respectively in NRK-52E cells co-cultured with Ex4 (20 nM) (all P<0.0001). Additionally, the protein expressions of NOX-1/NOX2 were significantly increased, whereas p-Akt was significantly decreased in NRK-52E cells co-cultured with P-cresol (200 μM) that were significantly reversed after Ex4 treatment (all P<0.0001). As compared with baseline, the creatinine level, left/right kidney weight and MCP-1-positively stained area in the kidney parenchyma were significantly increased at 24 h after the IR procedure and significantly progressively decreased after that (all P<0.0001). By 27 h after IR, creatinine level/MCP-1 + area was significantly higher in group 2 than in groups 1 and 3, and significantly higher in group 3 than in group 1 (all P<0.0001). The numbers of Nrf2 +/NQO-1 + cells/SOD activity in kidney parenchyma were significantly lower in group 2 than in groups 1 and 3, and significantly lower in group 1 than in group 3 (all P<0.0001). In conclusion, Ex4 protected kidney from IR injury through upregulating antioxidants and downregulating inflammation/oxidative stress., Competing Interests: None.

We tested the hypothesis that allogenic adipose-derived mesenchymal stem cells (ADMSCs) alleviated brain death (BD)-induced remote organ damage and events of post heart-transplant acute rejection. To determine the impact of BD on remote organ damage, adult-male F344 rats (n=24) were categorized sham-control (SC), BD and BD MSC (allogenic ADMSC/1.2 × 10 6 cells/derived from F344 by intravenous transfusion 3 h after BD procedure). To determine the protective effect of allogenic ADMSCs, animals (n=8/each group in F344/Lewis) were categorized into groups BD-T(F344 heart transplanted into Lewis by 6h after BD), BD-T MSC(D1/3) (BD induction for 6h then heart transplantation, and allogenic ADMSCs transfusion at days 1 and 5 after heart transplantation), BD-T MSC(3h) (BD + ADMSC/1.2 × 10 6 cells at 3h and heart transplantation at 6h after BD) and BD-T MSC(3h, D1/3) [BD + ADMSC/1.2 × 10 6 cells at 3h and heart transplantation at 6h after BD, then ADMSC therapy by days 1/3]. At day 5 post procedure, liver, kidney and heart specimens showed higher molecular-cellular levels of inflammation, immune reaction, apoptosis and fibrosis in BD than in SC that were reversed in BD MSC (all P < 0.0001). These molecular-cellular expressions and circulating/splenic levels of innate/adoptive immune cells were higher in BD-T, lowest in BD-T MSC(3h, D1/3) and higher BD-T MSC(3h) in than BD-T MSC(D1/3) , whereas heart function showed an opposite pattern among the four groups (all P < 0.001). In conclusion, ADMSCs suppressed BD-caused remote organ damage and heart-transplant rejection., Competing Interests: CONFLICTS OF INTEREST The authors declare that they have no conflicts of interest.

Purpose: We sought to test the effectiveness of the application of a tailored anterior saturation band (ASB) to improve the image quality of pelvic magnetic resonance imaging (MRI) for assessing rectal cancer., Methods: A total of 165 patients with MRI assessment of rectal cancer between 2013 and 2015 were included. The image quality scores (4-point scale: 1, nondiagnostic through 4, excellent) of MRI without and with tailored ASBs were compared. Sensitivity, specificity, positive and negative predictive values, and accuracy of pelvic MRIs with and without a tailored ASB for T-staging in 65 patients with direct surgery and 67 patients with chemoradiotherapy before surgery were evaluated., Results: Two independent raters exhibited moderate-to-excellent interobserver agreements (κ = 0.529-0.879) in the grading of MRI image quality. Overall, the quality scores of sagittal and axial T2-weighted images with tailored ASBs were significantly improved compared with MRIs without ASBs (3.5 ± 0.3 vs. 2.7 ± 0.8 [mean ± SD]; P < .001, and 3.6 ± 0.3 vs. 2.8 ± 0.8; P < .001, respectively). The application of tailored ASBs in MRIs improved the averaged accuracies for staging of ≤ T2, T3, and T4 tumors from 87.7%, 78.5%, and 90.8% to 93.1%, 86.9%, and 97.7%, respectively. In post-chemoradiotherapy MRI follow-ups, the use of tailored ASBs also improved the average accuracies for staging of yT0, yT1-2, yT3, and yT4 tumors from 80.6%, 73.1%, 73.9%, and 91.0%, to 85.8%, 82.9%, 85.1%, and 94.0%, respectively., Conclusions: Application of a tailored ASB in pelvic MRI is effective in substantially reducing motion artifacts, significantly upgrading image quality, and improving accuracies of rectal tumor staging., (Copyright © 2017 Elsevier Inc. All rights reserved.)

This study tested the hypothesis that high-cholesterol diet (HCD)-induced fatty liver disease could be ameliorated by rosuvastatin (Ros) and propylthiouracil (PTU) therapy. Thirty-two Zealand rabbits were equally divided into group 1 (sham-control), group 2 (HCD for 8 weeks), group 3 [HCD-Ros (20 mg/kg/day administration after 4-week HFD for 4 weeks)], group 4 [HCD-PTU (0.1% PTU in drinking water) with treatment course as group 3]. Liver weight, fibrosis, collagen deposition area, and serum levels of AST/ALT were highest in group 2, lowest in group 1, and significantly higher in group 4 than group 3 (all P<0.0001). The levels of inflammatory (TNF-α/NF-κB/IL-1ß/IL-6/MMP-9/VCAM-1/PAI-1/TLR-4, MyD88/IL-12/IFN-γ), oxidative stress (NOX-1/NOX-2/oxidized protein), apoptotic (Bax/cleaved-capase-3/PARP), fibrotic (Smad-3/TGF-ß), and mitochondria-damaged (cytosolic-cytochrome-C) proteins showed an identical pattern, whereas antiapoptotic (Bcl-2), mitochondrial-integrity (mitochondrial-cytochrome-C) and antioxidative (SIRT1/SIRT3) biomarkers exhibited an opposite pattern to fibrosis among the four groups (all P<0.0001). The cellular expressions of inflammatory (Kupffer/CD14/CD44), α-fetoprotein-positively stained biomarkers, apoptotic nuclei and fat cells displayed an identical pattern to fibrosis (all P<0.0001). In conclusion, Ros-PTU therapy attenuated liver fibrosis, inflammatory reaction and generation of oxidative stress and fatty liver after HCD challenge in rabbits., Competing Interests: None.

This study tested the hypothesis that xenogeneic human umbilical cord-derived mesenchymal stem cell (HUCDMSC) therapy would improve survival rates in rats with acute respiratory distress-syndrome (ARDS, induction by 48 h inhalation of 100% oxygen) and sepsis-syndrome (SS, induction by cecal-ligation and puncture) (ARDS-SS). Adult-male Sprague-Dawley rats were categorized into group 1 (sham-controls), group 2 (ARDS-SS), group 3 [ARDS-SS+HUCDMSC (1.2 ×106 cells administered 1 h after SS-induction)], and group 4 [ARDS-SS+HUCDMSC (1.2 ×106 cells administered 24 h after SS-induction)]. The mortality rate was higher in groups 2 and 4 than in groups 1 and 3 (all p<0.0001). The blood pressure after 28 h was lower in groups 2, 3 and 4 (p<0.0001) than in group 1. Albumin levels and percentages of inflammatory cells in broncho-alveolar lavage fluid, and the percentages of inflammatory and immune cells in circulation, were lowest in group 1, highest in group 2, and higher in group 3 than group 4 (all p<0.0001). The percentages of inflammatory cells in ascites and kidney parenchyma showed identical patterns, as did kidney injury scores (all p<0.0001). EarlyHUCDMSC therapy reduced rodent mortality after induced ARDS-SS.

Objectives: We investigated the relationships of cystic nodal metastasis, human papillomavirus (HPV) status, and treatment failure patterns in patients with oropharyngeal squamous cell carcinoma (OPSCC) treated with chemoradiotherapy., Methods: We retrospectively reviewed pretreatment MRI and clinical courses of patients with OPSCC whose tumors were tested for HPV-induced p16 expression via immunohistochemistry and who completed chemoradiotherapy. Cervical cystic nodal metastasis and necrotic nodal metastasis were classified on MRI., Results: Of 98 patients eligible for analysis, 33 were p16-positive. Cystic nodal metastasis was significantly more prevalent in p16-positive than in p16-negative patients (39.4% versus 18.5%, respectively; p = 0.025). Necrotic nodal metastasis was significantly more prevalent in p16-negative than in p16-positive patients (73.8% versus 51.5%, respectively; p = 0.027). On multivariate analysis, necrotic nodal metastasis (odds ratio [OR] = 7.310, p = 0.011) was an independent predictor of regional failure, while advanced nodal stage (OR = 4.119, p = 0.022) and cystic nodal metastases (OR = 0.087, p = 0.026) were independent positive and negative predictors of distant failure, respectively., Conclusions: Cervical cystic and necrotic nodal metastases are associated with HPV-induced p16-positive and p16-negative OPSCC, respectively. Patients with necrotic nodal metastasis at presentation have an increased risk of regional failure. Distant failure is directly and inversely correlated with advanced nodal stage and cystic nodal metastasis, respectively.

We analyzed the effects of acute ischemia-reperfusion (KIR) injury on the status of kidney function and architecture in dipeptidyl peptidase4-difficient (DPP4 D ) rats and the effect of remote small bowel ischemia-reperfusion (BIR) preconditioning. DPP4-deficient (DPP4 D ) and normal Fischer344 (F344) rats were divided into 6 groups: (1) sham-F344, (2) sham-DPP4 D , (3) KIR-F344 (4) KIR-DPP4 D , (5) DPP4 D -KIR-extendin-9-39 and (6) BIR-KIR-F344. Blood creatinine and urea nitrogen levels and the urinary protein-to-creatinine ratio was higher in KIR-F344 rats than BIR-KIR-F344 or KIR-DPP4 D rats 72 h after acute KIR. Conversely, the circulating glucagon-like peptide 1 (GLP-1) levels were higher in BIR-KIR-F344 and KIR-DPP4 D than KIR-F344 rats after acute KIR. KIR-F344 rats showed greater inflammation, oxidative stress, apoptosis, DNA damage and kidney injury than other rat groups. Damage to the kidney architecture in KIR-F344 rats was greater than in BIR-KIR-F344 or KIR-DPP4 D rats. Expression of antioxidant proteins and GLP-1 receptor was higher in kidneys from KIR-DPP4 D and BIR-KIR-F344 than KIR-F344 rats, which suggests better intrinsic responses. We therefore suggest that elevated circulating GLP-1 levels due to DPP4 deficiency and BIR preconditioning protect kidney function and architecture during acute IR injury., Competing Interests: CONFLICTS OF INTEREST The authors declare that they have no conflicts of interest.

Although chronic kidney disease (CKD) is known to aggravate cardiovascular disease in the setting of cardiorenal syndrome (CRS), the impact of impaired cardiac function on the progression of CKD has seldom been reported. This study tested the impact of acute myocardial infarction on a rodent CKD model and the therapeutic effect of valsartan in this setting. Adult male Sprague-Dawley rats (n = 50) equally divided into group 1 (sham control), group 2 (CKD induced by 5/6 nephrectomy), group 3 (AMI by ligation of left coronary artery), group 4 (CKD+AMI), group 5 (CKD+AMI+valsartan, orally 10 mg/kg/day). By day 60, kidney injury score, creatinine levels, and ratio of urine to creatinine were highest in group 4 and lowest in group 1, significantly higher in group 4 than those in groups 2 and 5, and significantly higher in group 5 than those in group 2 (all p < 0.001). Protein expressions of inflammation (IL-1β/MMP-9), oxidative stress (NOX-1/NOX-2/oxidized protein, angiotensin-II receptor), apoptosis (Bax, cleaved caspase-3/PARP), fibrosis (Smad3/TGF-β), and kidney injured (KIM-1/FSP-1) markers showed an identical pattern, whereas anti-fibrosis (Smad5/BMP-2) indices exhibited an opposite pattern compared to that of creatinine level among all groups (all p < 0.01). Cellular expressions of inflammation (CD14/CD68), DNA-damage (γ-H2AX, CD90/XRCC1) and proximal-renal tubule (KIM-1) biomarkers displayed an identical pattern, whereas podocyte-integrity markers (podocin/ZO-1/p-cadherin/synaptopodin) showed a pattern opposite to that of creatinine level among all groups (all p < 0.001). In a rodent CKD setting, renal function impairment and parenchymal damage further deteriorated after AMI but were suppressed following valsartan treatment., Competing Interests: None.