A novel small-molecule PCSK9 inhibitor E28362 ameliorates hyperlipidemia and atherosclerosis.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the epidermal growth factor precursor homologous domain A (EGF-A) of low-density lipoprotein receptor (LDLR) in the liver and triggers the degradation of LDLR via the lysosomal pathway, consequently leading to an elevation in plasma LDL-C levels. Inhibiting PCSK9 prolongs the lifespan of LDLR and maintains cholesterol homeostasis in the body. Thus, PCSK9 is an innovative pharmacological target for treating hypercholesterolemia and atherosclerosis. In this study, we discovered that E28362 was a novel small-molecule PCSK9 inhibitor by conducting a virtual screening of a library containing 40,000 compounds. E28362 (5, 10, 20 µM) dose-dependently increased the protein levels of LDLR in both total protein and the membrane fraction in both HepG2 and AML12 cells, and enhanced the uptake of DiI-LDL in AML12 cells. MTT assay showed that E28362 up to 80 µM had no obvious toxicity in HepG2, AML12, and HEK293a cells. The effects of E28362 on hyperlipidemia and atherosclerosis were evaluated in three different animal models. In high-fat diet-fed golden hamsters, administration of E28362 (6.7, 20, 60 mg·kg-1·d-1, i.g.) for 4 weeks significantly reduced plasma total cholesterol (TC), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C) and PCSK9 levels, and reduced liver TC and TG contents. In Western diet-fed ApoE-/- mice (20, 60 mg·kg-1·d-1, i.g.) and human PCSK9 D374Y overexpression mice (60 mg·kg-1·d-1, i.g.), administration of E28362 for 12 weeks significantly decreased plasma LDL-C levels and the area of atherosclerotic lesions in en face aortas and aortic roots. Moreover, E28362 significantly increased the protein expression level of LDLR in the liver. We revealed that E28362 selectively bound to PCSK9 in HepG2 and AML12 cells, blocked the interaction between LDLR and PCSK9, and induced the degradation of PCSK9 through the ubiquitin-proteasome pathway, which finally resulted in increased LDLR protein levels. In conclusion, E28362 can block the interaction between PCSK9 and LDLR, induce the degradation of PCSK9, increase LDLR protein levels, and alleviate hyperlipidemia and atherosclerosis in three distinct animal models, suggesting that E28362 is a promising lead compound for the treatment of hyperlipidemia and atherosclerosis.

Computational Analysis of Vibrational Spectra of Hydrogen Bonds in sII and sH Gas Hydrates.

The amount of energy in natural gas hydrates is thought to be equivalent to twice that of all other fossil fuels combined. However, economic and safe energy recovery has remained a challenge till now. To develop a novel method of breaking the hydrogen bonds (HBs) surrounding the trapped gas molecules, we investigated the vibrational spectra of the HBs of gas hydrates with structure types II and H. Two models of 576-atom propane-methane sII hydrate and 294-atom neohexane-methane sH hydrate were built. A first-principles density functional theory (DFT) method was employed using the CASTEP package. The simulated spectra were in good agreement with the experimental data. Compared with the partial phonon density of states of guest molecules, we confirmed that the experimental infrared absorption peak in the terahertz region mainly arose from HB vibrations. By removing the components of guest molecules, we found that the theory of two kinds of hydrogen bond vibrational modes applies. The use of a terahertz laser to enable resonance absorption of HBs (at about 6 THz, to be tested) may therefore lead to the rapid melting of clathrate ice and release of guest molecules.

Treatment and surveillance for non-muscle-invasive bladder cancer: a clinical practice guideline (2021 edition).

Non-muscle invasive bladder cancer (NMIBC) is a major type of bladder cancer with a high incidence worldwide, resulting in a great disease burden. Treatment and surveillance are the most important part of NIMBC management. In 2018, we issued "Treatment and surveillance for non-muscle-invasive bladder cancer in China: an evidence-based clinical practice guideline". Since then, various studies on the treatment and surveillance of NMIBC have been published. There is a need to incorporate these materials and also to take into account the relatively limited medical resources in primary medical institutions in China. Developing a version of guideline which takes these two issues into account to promote the management of NMIBC is therefore indicated. We formed a working group of clinical experts and methodologists. Through questionnaire investigation of clinicians including primary medical institutions, 24 clinically concerned issues, involving transurethral resection of bladder tumor (TURBT), intravesical chemotherapy and intravesical immunotherapy of NMIBC, and follow-up and surveillance of the NMIBC patients, were determined for this guideline. Researches and recommendations on the management of NMIBC in databases, guideline development professional societies and monographs were referred to, and the European Association of Urology was used to assess the certainty of generated recommendations. Finally, we issued 29 statements, among which 22 were strong recommendations, and 7 were weak recommendations. These recommendations cover the topics of TURBT, postoperative chemotherapy after TURBT, Bacillus Calmette-Guérin (BCG) immunotherapy after TURBT, combination treatment of BCG and chemotherapy after TURBT, treatment of carcinoma in situ, radical cystectomy, treatment of NMIBC recurrence, and follow-up and surveillance. We hope these recommendations can help promote the treatment and surveillance of NMIBC in China, especially for the primary medical institutions.

[Retracted] lncRNA XIST promotes the progression of laryngeal squamous cell carcinoma by sponging miR­144 to regulate IRS1 expression.

The authors wish to retract their research article entitled 'lncRNA XIST promotes the progression of laryngeal squamous cell carcinoma by sponging miR­144 to regulate IRS1 expression', published in Oncology Reports 43: 525­535, 2020. They have found that, having repeated several of the experiments, XIST expression does not appear to affect LSCC cell apoptosis. In addition, some of their original data had been lost due to computer damage. Therefore, all authors are in agreement that this paper published in Oncology Reports should be retracted to maintain the integrity of the scientific record. All the named authors on the paper agree to this retraction, and they sincerely apologize for any inconvenience that might result from the retraction of this article. [the original article was published in Oncology Reports 43: 525­535, 2020; DOI: 10.3892/or.2019.7438].

Single-nucleotide methylation specifically represses type I interferon in antiviral innate immunity.

Frequent outbreaks of viruses have caused a serious threat to public health. Previous evidence has revealed that DNA methylation is correlated with viral infections, but its role in innate immunity remains poorly investigated. Additionally, DNA methylation inhibitors promote IFN-I by upregulating endogenous retrovirus; however, studies of intrinsically demethylated tumors do not support this conclusion. This study found that Uhrf1 deficiency in myeloid cells significantly upregulated Ifnb expression, increasing resistance to viral infection. We performed whole-genome bisulfite sequencing and found that a single-nucleotide methylation site in the Ifnb promoter region disrupted IRF3 recruitment. We used site-specific mutant knock-in mice and a region-specific demethylation tool to confirm that this methylated site plays a critical role in regulating Ifnb expression and antiviral responses. These findings provide essential insight into DNA methylation in the regulation of the innate antiviral immune response.

Enhanced O-linked Glcnacylation in Crohn's disease promotes intestinal inflammation.

BACKGROUND: Treatment of Crohn's disease (CD) remains to be a challenge due to limited insights for its pathogenesis. We aimed to determine the role of O-Linked ß-N-acetylglucosamine (O-GlcNAc) in the development of CD and evaluate therapeutic effects of O-GlcNAc inhibitors on CD. METHODS: O-GlcNAc in intestinal epithelial tissues of CD, adherent-invasive Escherichia coli (AIEC) LF82-infected cells and mice was determined by immunoblot and immunohistochemistry. AIEC LF82 and dextran sulfate sodium were administrated into C57BL/6 mice for estabolishing inflammatory bowel disease model and for therapeutic study. FINDINGS: O-GlcNAc was increased in intestinal epithelial tissues of CD patients and AIEC LF82-infected mice. Infection of AIEC LF82 up-regulated the level of UDP-GlcNAc and increased O-GlcNAc in human colon epithelial HCT116 and HT-29 cells. We identified that IKKß and NF-κB were O-Glycosylated in AIEC LF82-treated cells. Mutations of IKKß (S733A) and p65 (T352A) abrogated the O-GlcNAc in IKKß and NF-κB and inhibited AIEC LF82-induced activation of NF-κB. Application of 6-diazO-5-oxO-L-norleucine, an agent that blocks the production of UDP-GlcNAc and inhibits O-GlcNAc, inactivated NF-κB in AIEC LF82-infected cells, enhanced the formation of autophagy, promoted the removal of cell-associated AIEC LF82, alleviated intestinal epithelial inflammation, and improved the survival of the colitis mice. INTERPRETATION: Intestinal inflammation in CD is associated with increased O-GlcNAc modification, which is required for NF-κB activation and suppression of autophagy. Targeting O-GlcNAc could be an effective therapy for inflammatory bowel disease. FUNDING: National Natural Science Foundation of China (Nos. 81573087 and 81772924) and International Cooperation Foundation of Jilin Province (20190701006GH).

lncRNA XIST promotes the progression of laryngeal squamous cell carcinoma by sponging miR­144 to regulate IRS1 expression.

The initiation and development of several types of cancer have been linked to long non­coding RNA (lncRNA) X inactive­specific transcript (XIST). Yet, the pattern of expression, function, as well as the molecular mechanism underlying XIST in laryngeal squamous cell carcinoma (LSCC) lack characterization. Therefore, the present study aimed to determine the function and putative mechanism of XIST in the development of LSCC. It was revealed that the level of XIST was significantly higher in LSCC tissues that were associated with advanced Tumor­Node­Metastasis (TNM) stage and the presence of lymph node metastasis. Furthermore, the ability of human LSCC TU212 cells to proliferate, form colonies, migrate and invade was significantly suppressed, while cell apoptosis was significantly increased following knockdown of XIST. Further investigation revealed that XIST knockdown increased the expression of microRNA­144 (miR­144) by acting as an endogenous sponge of miR­144. Inhibition of miR­144 caused a partial reversal of the inhibitory effects mediated following depletion of XIST in LSCC cells. Moreover, an miR­144 target called insulin receptor substrate 1 (IRS1) was significantly decreased by XIST depletion in LSCC cells. IRS1 expression was positively correlated with XIST expression in LSCC tissues. In addition, knockdown of XIST impaired tumor growth in vivo by regulating the miR­144/IRS1 axis. The present study demonstrated that the progression of LSCC is promoted by XIST sponging miR­144 to regulate IRS1 expression, suggesting that XIST can serve as a putative target in the therapy of LSCC.

Widowed status predicts poor overall survival of Chinese patients with prostate cancer.

BACKGROUND: Little is known about the influence of marital status on Chinese prostate cancer (PCa) patients. Marital status may have an impact on overall survival in Chinese men with prostate cancer. METHODS: We identified 4,208 Chinese patients diagnosed with PCa between 2004 and 2015 in the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate Cox proportional hazard models were used to determine the impact of marital status on the overall survival (OS) of Chinese PCa patients. Survival analysis was performed using the Kaplan-Meier method. Smoothing function and threshold effect analysis were performed to determine the turning points of variables. RESULTS: Univariate analysis demonstrated that marital status, prostate-specific antigen (PSA) category, surgery status, T stage, N stage, and M stage were associated with OS. Multivariate analysis further indicated that marital status, PSA category, surgery status, T stage, and M stage were independent risk factors of OS. Survival analysis demonstrated that the nonwidowed group had a better OS than the widowed group. The risk of poor OS increased rapidly with the PSA level up to the turning point 15.6 and 45.4 ng/mL in the nonwidowed group (HR =1.089; 95% CI: 1.064-1.115; P<0.0001) and the widowed group (HR =1.056; 95% CI: 1.028-1.084; P<0.001), respectively. CONCLUSIONS: In conclusion, this study demonstrated that widowed status greatly affects the OS of Chinese PCa patients. Altogether, this study highlights the importance of psychological intervention, especially for widowed Chinese PCa patients. Timely psychological intervention for widowed Chinese PCa patients might improve the survival outcomes of PCa.

Stress-Induced Metabolic Disorder in Peripheral CD4+ T Cells Leads to Anxiety-like Behavior.

Physical or mental stress leads to neuroplasticity in the brain and increases the risk of depression and anxiety. Stress exposure causes the dysfunction of peripheral T lymphocytes. However, the pathological role and underlying regulatory mechanism of peripheral T lymphocytes in mood disorders have not been well established. Here, we show that the lack of CD4+ T cells protects mice from stress-induced anxiety-like behavior. Physical stress-induced leukotriene B4 triggers severe mitochondrial fission in CD4+ T cells, which further leads to a variety of behavioral abnormalities including anxiety, depression, and social disorders. Metabolomic profiles and single-cell transcriptome reveal that CD4+ T cell-derived xanthine acts on oligodendrocytes in the left amygdala via adenosine receptor A1. Mitochondrial fission promotes the de novo synthesis of purine via interferon regulatory factor 1 accumulation in CD4+ T cells. Our study implicates a critical link between a purine metabolic disorder in CD4+ T cells and stress-driven anxiety-like behavior.

[Strategies of preserving urinary continence in transurethral plasmakinetic enucleation of the prostate for benign prostate hyperplasia].

OBJECTIVE: To explore the strategies of preserving urinary continence in transurethral plasmakinetic enucleation of the prostate (PKEP) for benign prostate hyperplasia (BPH). METHODS: We treated 65 BPH patients by PKEP with preservation of urinary continence (UC-PKEP), which involved protection of the external urethral sphincter in the beginning of surgery, proper preservation of the anterior lobe of the prostate to protect the internal urethral sphincter in the middle, and preservation of the integrity of the bladder neck towards the end. We compared the postoperative status of urinary continence of the patients with that of the 54 BPH cases treated by complete plasmakinetic enucleation of the prostate (Com-PKEP). RESULTS: All the operations were performed successfully with the urinary catheters removed at 5 days after surgery. In comparison with Com-PKEP, UC-PKEP achieved evidently lower incidence rates of urinary incontinence at 24 hours (31.49% vs 13.85%, P <0.05), 1 week (18.52% vs 4.62%, P <0.05), 2 weeks (14.81% vs 3.08%, P <0.05), 1 month (3.70% vs 1.54%, P >0.05), and 3 months (3.70% vs 0%, P >0.05) after catheter removal. Compared with the baseline, the maximum urinary flow rate (Qmax) was significantly improved postoperatively in both the Com-PKEP (ï¼»7.43 ± 3.26ï¼½ vs ï¼»20.58 ± 3.22ï¼½ ml, P <0.05) and the UC-PKEP group (ï¼»8.04 ± 2.28ï¼½ vs ï¼»20.66 ± 3.08ï¼½ ml, P <0.05). CONCLUSIONS: Transurethral PKEP is a safe and effective method for the management of BPH, during which the strategies of avoiding blunt or sharp damage to the external urethral sphincter in the beginning, properly preserving the anterior lobe of the prostate in the middle and preserving the integrity of the bladder neck towards the end may help to achieve rapid recovery of urinary continence.

Upregulation of miR-543-3p promotes growth and stem cell-like phenotype in bladder cancer by activating the Wnt/ß-catenin signaling pathway.

The Wnt/ß-catenin signaling pathway, which is strictly controlled by multiple negative regulators, has been reported commonly hyper activated and closely related to the progression of bladder cancer. However, how tumor cells override the negative regulatory effects to maintain constitutive activation of Wnt/ß-catenin signaling is still unclear. In the current study, we demonstrated that upregulation of miR-543-3p in bladder cancer activated Wnt/ß-catenin signaling by directly targeting Wnt inhibitory factor 1 (WIF1) and Dickkopf 1 (DKK1), which are important antagonist molecules of the Wnt/ß-catenin pathway. Expression of miR-543-3p was upregulated in both bladder cancer tissues and cells, and positively correlated with high-grade bladder cancer. Furthermore, ectopic overexpression of miR-543-3p promoted proliferation and inhibited apoptosis in bladder cancer cells. Notably, overexpression of miR-543-3p enhanced, while silencing miR-543-3p reduced, stem cell-like phenotype of bladder cancer cells. Therefore, our results suggest that miR-543-3p plays a significant role in promoting proliferation and stem cell-like phenotype in bladder cancer, which might be a potential target for anti-bladder cancer therapy.

Inhibition of HIF-1α Affects Autophagy Mediated Glycosylation in Oral Squamous Cell Carcinoma Cells.

Purpose. To validate the function of autophagy with the regulation of hypoxia inhibitor-induced glycosylation in oral squamous cell carcinoma cell. Methods. Human Tca8113 cell line was used to detect autophagy and glycosylation related protein expression by western blotting and immunofluorescence with HIF-1α inhibitor. Short interfering RNA (siRNA) transfection blocked human ATG12 and ATG1. Results. HIF-1α inhibitor PX-478 reduced the amount of LC3-II and LC3-I in Tca8113 cells. PX-478 decreased the expression of O-GlcNAc and OGT and increased OGA expression. The tendency of O-GlcNAc showed a similar pattern to OGT. PX-478 gradually decreased OGT expression in Tca8113 cells. Protein level of O-GlcNAc and OGT increased in ATG12 and ATG1 depletion. The expression of OGT decreased at first and then rose slowly with the treatment of Atg12 and Atg1 siRNA and PX-478 fluctuant. Autophagy affected the stability of OGT when HIF-1α signaling was blocked. Conclusions. Autophagy reduced by hypoxic stress inhibited. HIF-1α inhibitor decreased glycosylation. OGT became unstable in the absence of autophagy when HIF-1α signaling was blocked.

Splenic artery trunk embolization reduces the surgical risk of liver transplantation.

BACKGROUND: Portal hypertension is one of the most important clinical conditions that cause intraoperative intensive hemorrhage in cirrhotic patients undergoing liver transplantation. Pre-transplant portal decompression may reduce the intraoperative bleeding during liver transplantation. METHODS: Splenic artery trunk embolization (SATE) was performed one month prior to liver transplantation. Platelet count, prealbumin, international normalized ratio, and blood flow in the portal vein and hepatic artery were monitored before and one month after SATE. The measurements above were collected on admission and before surgery in the non-SATE patients, who served as controls. We also recorded the intraoperative blood loss, operating time, required transfusion, post-transplant ascites, and complications within three months after operation in all patients. RESULTS: SATE significantly reduced portal venous blood flow, increased hepatic arterial blood flow, normalized platelet count, and improved prealbumin and international normalized ratio in the patients before liver transplantation. Compared to the non-SATE patients, the pre-transplant SATE significantly decreased the operating time, intraoperative bleeding, post-transplant ascites and severe surgical complications. CONCLUSION: Pre-transplant SATE decreases portal pressure, improves liver function reserve, and reduces the surgical risk of liver transplantation effectively in patients with severe portal hypertension.

B7-H4 expression in bladder urothelial carcinoma and immune escape mechanisms.

B7-H4 is a recently identified member of the B7 family considered to negatively regulate the immune response, and has been associated with the occurrence and development of certain types of tumor. However, little is known regarding the importance of human B7-H4 expression in bladder urothelial carcinoma. In the present study, B7-H4 expression in the tissues and sera of patients with bladder urothelial carcinoma was investigated, along with the clinical significance. In addition, the effects of activated T-lymphocyte in vitro cytotoxicity in the BIU-87 bladder cancer cell line following the blockade of the B7-H4 signaling pathway were also analyzed. The results showed that in normal bladder tissues, B7-H4 was not detected, but in the bladder urothelial carcinoma tissue samples, B7-H4 was detected in 24/49 (49.0%) specimens. Additionally, positive B7-H4 expression was significantly associated with increased TNM stage and pathological grade (P<0.05). Compared with the healthy control group, the serum-B7-H4 (sB7-H4) concentrations in the patients were also significantly increased (P<0.05). The sB7-H4 concentrations in cases with high-grade histology were significantly higher than those in patients with low-grade histology (P<0.05). Following the blockade of the B7-H4 antigen in BIU-87 cells, the cytotoxic activity of activated T cells against such BIU-87 cells was significantly enhanced compared with that against the control BIU-87 cells. This occurred in a T cell density-dependent and blocking antibody dose-dependent manner. These observations suggest that B7-H4 is involved in tumor occurrence, and the development and immune escape of bladder urothelial carcinoma cells. Therefore, B7-H4 may be an important target in the diagnosis and/or treatment of bladder urothelial carcinoma.

miR-200c modulates ovarian cancer cell metastasis potential by targeting zinc finger E-box-binding homeobox 2 (ZEB2) expression.

This study was to investigate the effect of miR-200c on regulation of ovarian cancer cell metastasis potential and explore the underlying molecular events. qRT-PCR was used to analyze the level of miR-200c expression in 48 ovarian cancer and 30 normal ovarian tissue samples. pre-miR-200c was used to manipulate miR-200c expression in ovarian cancer cells for detection of changed phenotypes of tumor cells. Bioinformatics analysis was then used to predict target genes of miR-200c and GO and pathway analyses drew the miR-200c-related gene network. Luciferase reporter assay confirmed the target of miR-200c as ZEB2. Western blot was used to detect gene expressions in ovarian cancer cells. Level of miR-200c expression was much higher in ovarian cancer than in normal ovarian tissues, and miR-200c expression was inversely associated with advanced clinical stage and lymph node metastasis of ovarian cancer (p < 0.01). The database search predicted 186 miR-200c-targeting genes, and GO analysis showed that functions of these target genes were enriched in the protein binding and other biological processes. Furthermore, miR-200c expression inhibited ovarian cancer cell ES-2 migration and invasion capacity by suppression of ZEB2 expression (p < 0.01). Overexpression of miR-200c regulated E-cadherin and vimentin expression in ovarian cancer cells. This study demonstrated high miR-200c expression in ovarian cancer tissues and ZEB2 as a targeting gene of miR-200c, which mediated the effects of miR-200c on regulation of ovarian cancer cell migration and invasion capacity and epithelial-to-mesenchymal transition. Thus, targeting of miR-200c or ZEB2 may serve as a potential therapeutic strategy for control of ovarian cancer.

Recombinant adenovirus vector Ad-hIL-10 protects grafts from cold ischemia-reperfusion injury following orthotopic liver transplantation in rats.

BACKGROUND: Interleukin 10 (IL-10), a Th2 type cytokine, modulates inflammatory responses by inhibiting the production of proinflammatory cytokines. This study was designed to investigate the protective effects of adenovirus-mediated human IL-10 (Ad-hIL-10) gene transfer on protecting grafts from cold ischemia-reperfusion injury following orthotopic liver transplantation in rats. METHODS: Adenoviruses encoding hIL-10 or beta-galactosidase (Ad-lacZ) were injected via the superior mesenteric vein into prospective donor animals. The donor liver was harvested 48 hours after transduction, and stored for 12 hours at 4 degree centigrade in lactated Ringer's solution prior to transplantation. The rats were divided into saline, Ad-lacZ, and Ad-hIL-10 groups. Liver function test, histopathological examination, reverse transcriptase-polymerase chain reaction (RT-PCR), and Western blotting were performed at 24 hours after transplantation in the three groups. RESULTS: Liver function (ALT and AST) was significantly improved, and the Suzuki score was significantly decreased in the Ad-hIL-10 group. The levels of hepatic TNF-alpha, MIP-2, ICAM-1 mRNA, and NF-kappaB protein in the Ad-hIL-10 group were significantly decreased. The expression of hIL-10 mRNA was detected by RT-PCR in Ad-hIL-10-treated grafts but not in controls treated with saline or Ad-lacZ. CONCLUSIONS: Donor pretreatment with Ad-hIL-10 down-regulates the expression of proinflammatory cytokines TNF-alpha, MIP-2, and ICAM-1 mRNA. hIL-10 protects against hepatic cold ischemia-reperfusion injury, at least in part, by suppressing NF-kappaB activation and subsequent expression of proinflammatory mediators.

Induction of lymphocyte apoptosis in rat liver allograft by adenoviral gene transfection of human interleukin-10.

BACKGROUND/AIMS: Gene therapy can provide a possible avenue in organ transplantation to treat acute allograft rejection. This study was designed to investigate the effect of adenovirus-mediated human IL-10 (hIL-10) gene transfer on the apoptosis of infiltrating lymphocytes and examine the efficacy of hIL-10 gene transfer in combination with subtherapeutic doses of cyclosporine A (CsA) in a rat liver transplantation model. METHODS: Inbred male DA and LEW rats were used for liver donors and recipients, respectively. The rats were divided into saline, Ad-lacZ, CsA, Ad-hIL-10 and Ad-hIL-10 + CsA groups. Graft survival, histopathological, enzyme-linked immunosorbent assay, reverse transcriptase-polymerase chain reaction and flow cytometry were performed in liver specimens obtained from different time points after transplantation in the 5 groups. RESULTS: Ad-hIL-10 pretreatment inhibited allograft rejection, prolonged the survival of hepatic allografts, and downregulated the expression of IFN-gamma and IL-2 mRNA, with simultaneous upregulation of IL-4 mRNA. In addition, Ad-hIL-10 pretreatment upregulated the expression of Fas mRNA in the isolated graft-infiltrating lymphocytes and induced graft-infiltrating lymphocyte apoptosis. A single subtherapeutic dose of CsA acted synergistically with it. CONCLUSION: hIL-10 gene therapy induced alloreactive lymphocyte apoptosis via Fas/FasL pathway. hIL-10 gene transfection in combination with subtherapeutic doses of CsA facilitates the long-term survival of liver grafts.

Effect of periodontitis on susceptibility to atrial fibrillation in an animal model.

BACKGROUND: Inflammation is implicated in the pathophysiology of atrial fibrillation (AF). Periodontitis causes a general inflammatory response. Whether periodontitis is related to AF is unknown. OBJECTIVE: The aim of the study was to test the hypothesis that inflammation facilitates AF. METHODS: Twenty-two adult mongrel canines of either sex were used for this study. Periodontitis was induced in 12 dogs (periodontitis group) by tying 2-0 silk ligatures at the second premolar of mandibula. Ten healthy dogs were used as controls. Before the ligation procedure and on the day 30, 60, and 90 after ligation, an electrophysiologic evaluation was performed to measure atrial refractoriness and AF inducibility by delivering a single atrial extrastimuli in the high right atrium, atrial septum (AS), and coronary sinus (CS), respectively. Before each electrophysiologic study, blood samples were taken for determining the levels of C-reactive protein (CRP) and tumor necrosis factor-alpha (TNF-alpha). Animals were killed after 90 days. The hearts and mandibulae were harvested for morphological study, and the periodontal disease severity was quanti fi ed. RESULTS: Atrial effective refractory period (AERP) shortened, and AF inducibility increased progressively in the periodontitis group. At a drive length of 300 milliseconds, AERP in the CS was 126.7 +/- 13.0 milliseconds and 107.5 +/- 9.7 milliseconds after 60 and 90 days of ligation, respectively (vs 165.8 +/- 10.8 milliseconds at baseline; P < .001). By CS pacing, AF was induced in 5 and 10 of 12 dogs on day 60 and 90 after ligation, respectively (vs 1/12 at baseline; P < .05 and P < .01, respectively). Elevation of CRP and TNF-alpha occurred after 60 days of ligation (CRP, 13.42 +/- 2.21 mg/L vs control, 1.92 +/- 0.38 mg/L; P < .001; TNF-alpha, 9.85 +/- 1.72 mg/L vs control, 3.36 +/- 0.75 mg/L; P < .001) and reached the peak at the end of the study (CRP, 31.38 +/- 2.69 mg/L vs control, 1.99 +/- 0.40 mg/L; P < .001; TNF-alpha, 12.32 +/- 1.07 mg/L vs control, 3.24 +/- 0.53 mg/L; P < .001). There was a negative correlation between the levels of serum inflammatory factors and AERP values (P < .05). Alveolar bone level decreased in the periodontitis group (P < .001). The long axis (P < .001) of atrial cardiomyocytes including the right atrial appendage (25.50 +/- 3.58 microm vs 18.14 +/- 3.32 microm), AS (24.78 +/- 3.45 microm vs 17.47 +/- 2.57 microm), and left atrial appendage (31.90 +/- 4.80 microm vs 18.78 +/- 2.42 microm) from the periodontitis group was larger than the control group. The short axis of atrial cardiomyocytes was larger than the control group, too (P < .001). Inflammatory cells were more generally found in the atria of the periodontitis group (P < .001). Myolysis affected some atrial cardiomyocytes of the dogs with periodontitis. CONCLUSION: Periodontitis led to inflammatory responses in the atrial myocardium, which disturbed the structural and electrophysiologic properties of the atrium and facilitated AF.

Tensile force produced by a lipoma in the masseteric space possibly causing hyperostosis of the angle of the mandible.

BACKGROUND: A lipoma is a benign tumor which may occur in the adipose tissue of any part of the body. The tumor is most commonly found on the trunk and extremities. Although it is the most common tumor of mesenchymal origin in the head and neck, its incidence is relatively rare. Lipoma of the head and neck is usually located in subcutaneous tissue. It is rarely deep seated with osseous involvement and rarely occurs in children, especially below the age of 10. CASE REPORT: The case of a painless mass of one-year history in the right parotidomasseteric region of an eight-year-old boy is presented. The mass was revealed to be a classical lipoma in the masseteric space, possibly causing hyperostosis of the angle of the mandible. After removal of the mass and a spherical protuberance in the angle of the mandible, the boy recovered and no recurrence was noted after one-year follow-up. CONCLUSIONS: Hyperostosis is a rare phenomenon with lipoma. In this case, the hypothesis was posed that the tensile force produced by the lipoma in the masseteric space possibly caused hyperostosis of the angle of the mandible. To the authors' knowledge, a classical lipoma arising from the deep fascial space resulting in osseous change has not been described in the literature before.