Comparison between use of direct oral anticoagulants and aspirin for risk of thromboembolism complications in patients undergoing total knee and hip arthroplasty: a systematic review and meta-analysis.

OBJECTIVE: Total knee and hip arthroplasty are one of the most commonly consistently successful surgeries in orthopedics worldwide. Literature has reported that depending upon the age and co-existing treatments, patients undergoing total knee and hip arthroplasty are often prone to increased risks of developing venous thromboembolic complications. In such cases, chemoprophylaxis with either direct oral anticoagulant therapy with factor-Xa inhibitors (i.e., rivaroxaban, apixaban, dabigatran) and aspirin are widely recommended. Recent surveys suggest that direct oral anticoagulants and aspirin have comparable efficacy. However, there is no consensus in the literature as to which drug is the safest. Therefore, in this review, we shall attempt to evaluate the comparative efficacy between direct oral anticoagulant drugs and aspirin in patients undergoing total joint arthroplasty. To compare risk of venous thromboembolism complications between use of direct oral anticoagulant drugs and aspirin in patients undergoing total knee and hip arthroplasty. MATERIALS AND METHODS: A sensitive and specific analysis of the literature was performed according to the Cochrane and written according to PRISMA guidelines (Supplementary Table I). Five electronic databases (Web of Science, Embase, CENTRAL, Scopus, and Medline) were evaluated. To compare the efficacy between the drugs we conducted a random-effect meta-analysis according to the outcome (bleeding complications, venous thromboembolism or pulmonary embolism) and overall mortality in patients undergoing total knee and hip arthroplasty. RESULTS: Overall, 993 studies were found of which 117 had their full texts evaluated. A total of 161,463 patients undergoing total joint arthroplasty with mean age equal 66.2 ± 5.0 years were identified in 14 studies. Higher risks of venous thromboembolism (OR: 1.56 95% CI 1.21-2.01), pulmonary embolism (OR: 1.63, 95% CI: 1.31 -2.04) and overall mortality (OR: 1.35, 95% CI 1.04-1.74) for patients receiving aspirin were verified as compared to direct oral anticoagulant drugs. Subsequently, we further observed that the risks of bleeding complications (OR: 0.89 95% CI 0.67-1.18) were insignificant. CONCLUSIONS: The study reports higher risks of venous thromboembolism, pulmonary embolism, and overall mortality for the patients receiving aspirin before undergoing.

Does prior arthroscopic procedure impact outcomes of knee arthroplasty? A systematic review and meta-analysis.

OBJECTIVE: Despite generally favorable outcomes following knee arthroscopy, a certain subset of patients inevitably develops progression of knee disease, necessitating subsequent total knee arthroplasty (TKA). Therefore, the evaluation of TKA outcomes following arthroscopy has emerged as a major area of research. The aim of the current review is to measure the impact of prior arthroscopy on functional and adverse outcomes following TKA. MATERIALS AND METHODS: Literature search was conducted in the databases including Medline, EMBASE, PubMed Central, ScienceDirect, Google Scholar and Cochrane library from inception until April 2021. Meta-analysis with random-effects model was conducted to calculate pooled odds ratio (OR) or standardized mean difference (SMD) with 95% confidence interval (CI) depending on the type of outcome. RESULTS: In total, 9 studies with 185,013 participants were included in the review. The majority of the studies were conducted in the USA and China. Almost all the studies had low quality as per Newcastle Ottawa (NO) scale. The pooled SMD for functional outcome was -0.19 [95%CI: -0.30 to -0.09], while the pooled OR for revision rate was 1.53 (95% CI: 1.21 to 1.92). In terms of postoperative complications, the pooled OR for stiffness was 1.55 (95% CI: 0.92-2.61), infection was 1.39 (95%CI: 1.17-1.67), aseptic loosening was 1.93 (95% CI: 1.19-3.11), VTE was 1.06 (95% CI: 0.83-1.35), and MUA was 1.33 (95% CI: 1.13-1.57) respectively. CONCLUSIONS: Prior arthroscopy has significant impact on the functional and adverse clinical outcomes following TKA. Surgeons need to develop a comprehensive intervention plan to manage these high-risk patients and reduce the rate of postoperative complications.

Impact of scan quality on the diagnostic performance of CCTA, SPECT, and PET for diagnosing myocardial ischemia defined by fractional flow reserve.

BACKGROUND: Scan quality can have a significant effect on the diagnostic performance of non-invasive imaging techniques. However, the extent of its influence has scarcely been investigated in a head-to-head manner. METHODS: Two-hundred and eight patients underwent CCTA, SPECT, and PET prior to invasive fractional flow reserve measurements. Scan quality was classified as either good, moderate, or poor. RESULTS: Distribution of good, moderate, and poor quality scans was; CCTA; 66%, 22%, 13%; SPECT; 52%, 38%, 9%; PET; 86%, 13%, 1%. Good quality CCTA scans possessed a higher specificity (75% vs. 31%, p = 0.001), positive predictive value (PPV, 71% vs. 51%, p = 0.050), and accuracy (80% vs. 60%, p = 0.009) compared to moderate quality scans, while sensitivity (94%) and negative predictive value (NPV, 88%) were similar to moderate and poor quality scans. Sensitivity (76%), NPV (84%), and accuracy (85%) of good quality SPECT scans was superior to those of moderate (41% p = 0.001, 56% p = 0.010, 70% p = 0.010) and poor quality (30% p = 0.003, 65% p = 0.069, 63% p = 0.038). Specificity (92%) and PPV (87%) of good quality SPECT scans did not differ from scans of diminished quality. Good quality PET scans exhibited high sensitivity (84%), specificity (86%), NPV (88%), PPV (81%) and accuracy (85%), which was comparable to scans of lesser quality. Good quality CCTA, SPECT, and PET scans demonstrated a similar diagnostic accuracy (p = 0.247). CONCLUSION: Diagnostic performance of CCTA, and SPECT is hampered by scan quality, while the diagnostic value of PET is not affected. Good quality CCTA, SPECT, and PET scans possess a high diagnostic accuracy.

Data on the impact of scan quality on the diagnostic performance of CCTA, SPECT, and PET for diagnosing myocardial ischemia defined by fractional flow reserve on a per vessel level.

Scan quality directly impacts the diagnostic performance of non-invasive imaging modalities as reported in a substudy of the PACIFC-trial: "Impact of Scan Quality on the Diagnostic Performance of CCTA, SPECT, and PET for Diagnosing Myocardial Ischemia Defined by Fractional Flow Reserve" [1]. This Data-in-Brief paper supplements the hereinabove mentioned article by presenting the diagnostic performance of CCTA, SPECT, and PET on a per vessel level for the detection of hemodynamic significant coronary artery disease (CAD) when stratified according to scan quality and vascular territory.

Whole-transcriptome sequencing of knee joint cartilage from osteoarthritis patients.

OBJECTIVES: The aim of this study was to provide a comprehensive understanding of alterations in messenger RNAs (mRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs) in cartilage affected by osteoarthritis (OA). METHODS: The expression profiles of mRNAs, lncRNAs, and circRNAs in OA cartilage were assessed using whole-transcriptome sequencing. Bioinformatics analyses included prediction and reannotation of novel lncRNAs and circRNAs, their classification, and their placement into subgroups. Gene ontology and pathway analysis were performed to identify differentially expressed genes (DEGs), differentially expressed lncRNAs (DELs), and differentially expressed circRNAs (DECs). We focused on the overlap of DEGs and targets of DELs previously identified in seven high-throughput studies. The top ten DELs were verified by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) in articular chondrocytes, both in vitro and in vivo. RESULTS: In total, 739 mRNAs, 1152 lncRNAs, and 42 circRNAs were found to be differentially expressed in OA cartilage tissue. Among these, we identified 18 overlapping DEGs and targets of DELs, and the top ten DELs were screened by expression profile analysis as candidate OA-related genes. WISP2, ATF3, and CHI3L1 were significantly increased in both normal versus OA tissues and normal versus interleukin (IL)-1ß-induced OA-like cell models, while ADAM12, PRELP, and ASPN were shown to be significantly decreased. Among the identified DELs, we observed higher expression of ENST00000453554 and MSTRG.99593.3, and lower expression of MSTRG.44186.2 and NONHSAT186094.1 in normal versus OA cells and tissues. CONCLUSION: This study revealed expression patterns of coding and noncoding RNAs in OA cartilage, which added sets of genes and noncoding RNAs to the list of candidate diagnostic biomarkers and therapeutic agents for OA patients.Cite this article: H. Li, H. H. Yang, Z. G. Sun, H. B. Tang, J. K. Min. Whole-transcriptome sequencing of knee joint cartilage from osteoarthritis patients. Bone Joint Res 2019;8:290-303. DOI: 10.1302/2046-3758.87.BJR-2018-0297.R1.

The association of coronary lumen volume to left ventricle mass ratio with myocardial blood flow and fractional flow reserve.

BACKGROUND: A diminished coronary lumen volume to left ventricle mass ratio (V/M) derived from coronary computed tomography angiography (CCTA) has been proposed as factor contributing to impaired myocardial blood flow (MBF) even in the absence of obstructive disease on invasive coronary angiography (ICA). METHODS: Patients underwent CCTA, and positron emission tomography (PET) prior to ICA. Matched global V/M, global, and vessel specific hyperaemic MBF (hMBF), coronary flow reserve (CFR), and, FFR were available for 431 vessels in 152 patients. The median V/M (20.71 mm3/g) was used to divide the population into patients with either a low V/M or a high V/M. RESULTS: Overall, a higher percentage of vessels with an abnormal hMBF and FFR (34% vs. 19%, p = 0.009 and 20% vs. 9%, p = 0.004), as well as a lower FFR (0.93 [interquartile range: 0.85-0.97] vs. 0.95 [0.89-0.98], p = 0.016) values were observed in the low V/M group. V/M was weakly associated with vessel specific hMBF (R = 0.148, p = 0.027), and FFR (R = 0.156, p < 0.001). Among vessels with non-obstructive CAD on ICA (361 vessels), no association between V/M and vessel specific hMBF nor CFR was noted. However, in the absence of obstructive CAD, V/M was associated with (R = 0.081, p = 0.027), and independently predictive for FFR (p = 0.047). CONCLUSION: Overall, an abnormal vessel specific hMBF and FFR were more prevalent in patients with a low V/M compared to those with a high V/M. Furthermore, V/M was weakly associated with vessel specific hMBF and FFR. In the absence of obstructive CAD on ICA, V/M was weakly associated with notwithstanding independently predictive for FFR.

Automated SPECT analysis compared with expert visual scoring for the detection of FFR-defined coronary artery disease.

PURPOSE: Traditionally, interpretation of myocardial perfusion imaging (MPI) is based on visual assessment. Computer-based automated analysis might be a simple alternative obviating the need for extensive reading experience. Therefore, the aim of the present study was to compare the diagnostic performance of automated analysis with that of expert visual reading for the detection of obstructive coronary artery disease (CAD). METHODS: 206 Patients (64% men, age 58.2 ± 8.7 years) with suspected CAD were included prospectively. All patients underwent 99mTc-tetrofosmin single-photon emission computed tomography (SPECT) and invasive coronary angiography with fractional flow reserve (FFR) measurements. Non-corrected (NC) and attenuation-corrected (AC) SPECT images were analyzed both visually as well as automatically by commercially available SPECT software. Automated analysis comprised a segmental summed stress score (SSS), summed difference score (SDS), stress total perfusion deficit (S-TPD), and ischemic total perfusion deficit (I-TPD), representing the extent and severity of hypoperfused myocardium. Subsequently, software was optimized with an institutional normal database and thresholds. Diagnostic performances of automated and visual analysis were compared taking FFR as a reference. RESULTS: Sensitivity did not differ significantly between visual reading and most automated scoring parameters, except for SDS, which was significantly higher than visual assessment (p < 0.001). Specificity, however, was significantly higher for visual reading than for any of the automated scores (p < 0.001 for all). Diagnostic accuracy was significantly higher for visual scoring (77.2%) than for all NC images scores (p < 0.05), but not compared with SSS AC and S-TPD AC (69.8% and 71.2%, p = 0.063 and p = 0.134). After optimization of the automated software, diagnostic accuracies were similar for visual (73.8%) and automated analysis. Among the automated parameters, S-TPD AC showed the highest accuracy (73.5%). CONCLUSION: Automated analysis of myocardial perfusion SPECT can be as accurate as visual interpretation by an expert reader in detecting significant CAD defined by FFR.

Association between Intracranial Atherosclerotic Calcium Burden and Angiographic Luminal Stenosis Measurements.

BACKGROUND AND PURPOSE: Calcification of the intracranial vasculature is an independent risk factor for stroke. The relationship between luminal stenosis and calcium burden in the intracranial circulation is incompletely understood. We evaluated the relationship between atherosclerotic calcification and luminal stenosis in the intracranial ICAs. MATERIALS AND METHODS: Using a prospective stroke registry, we identified patients who had both NCCT and CTA or MRA examinations as part of a diagnostic evaluation for ischemic stroke. We used NCCTs to qualitatively (modified Woodcock Visual Score) and quantitatively (Agatston-Janowitz Calcium Score) measure ICA calcium burden and used angiography to measure arterial stenosis. We calculated correlation coefficients between the degree of narrowing and calcium burden measures. RESULTS: In 470 unique carotid arteries (235 patients), 372 (79.1%) had atherosclerotic calcification detectable on CT compared with 160 (34%) with measurable arterial stenosis on CTA or MRA (P < .001). We found a weak linear correlation between qualitative (R = 0.48) and quantitative (R = 0.42) measures of calcium burden and the degree of luminal stenosis (P < .001 for both). Of 310 ICAs with 0% luminal stenosis, 216 (69.7%) had measurable calcium scores. CONCLUSIONS: There is a weak correlation between intracranial atherosclerotic calcium scores and luminal narrowing, which may be explained by the greater sensitivity of CT than angiography in detecting the presence of measurable atherosclerotic disease. Future studies are warranted to evaluate the relationship between stenosis and calcium burden in predicting stroke risk.

Incremental diagnostic value of epicardial adipose tissue for the detection of functionally relevant coronary artery disease.

BACKGROUND AND AIM: To determine the incremental diagnostic value of epicardial adipose tissue (EAT) volume in addition to the coronary artery calcium (CAC) score for detecting hemodynamic significant coronary artery disease (CAD). METHODS AND RESULTS: 122 patients (mean age 61 ± 10 years, 61% male) without a previous cardiac history underwent a non-contrast CT scan for calcium scoring and EAT volume measurements. Subsequently all patients underwent invasive coronary angiography (ICA) in conjunction with fractional flow reserve (FFR) measurements. A stenosis >90% and/or a FFR ≤0.80 were considered significant. Mean EAT volume and CACscore were 128 ± 51 cm(3) and 418 ± 704, respectively. The correlation between EAT volume and the CACscore was poor (r = 0.11, p = 0.24). Male gender (odds ratio [OR] 2.86, p = 0.01), CACscore ([cut-off value 100] OR 3.31, p = 0.003, and EAT volume ([cut-off value 92 cm(3)] OR 4.28, p = 0.01) were associated with flow-limiting disease. The multivariate model revealed that only male gender (OR 2.50, p = 0.045), CAC score (OR 3.60, p = 0.005), and EAT volume (OR 4.95, p = 0.02) were independent predictors of myocardial ischemia. Using the cut-off values of 100 (CAC score) and 92 cm(3) (EAT volume), sensitivity, specificity, negative predictive value, positive predictive value, and accuracy for detecting functionally relevant CAD as indicated by FFR were 71, 57, 77, 50 and 63% and 91, 29, 85, 44 and 52% for the CACscore and EAT volume, respectively. Adding EAT volume to the CAC score and cardiovascular risk factors did not enhance diagnostic performance for the detection of significant CAD (p = 0.57). CONCLUSION: EAT volume measurements have no diagnostic value beyond calcium scoring and cardiovascular risk factors in the detection of hemodynamic significant CAD.

Rebamipide attenuates autoimmune arthritis severity in SKG mice via regulation of B cell and antibody production.

Oxidative stress is involved in the pathophysiology of rheumatoid arthritis (RA). We investigated the therapeutic potential of rebamipide, a gastroprotective agent with a property of reactive oxygen species scavenger, on the development of inflammatory polyarthritis and the pathophysiological mechanisms by which rebamipide might confer anti-arthritic effects in SKG mice, an animal model of RA. Intraperitoneal (i.p.) injection of rebamipide attenuated the severity of clinical and histological arthritis. Rebampide treatment reduced the number of T helper type 1 (Th1), Th2, Th17, inducible T cell co-stimulator (ICOS)(+) follicular helper T (Tfh) transitional type (T2) and mature B cells in the spleen, but increased the number of regulatory T (Treg ), CD19(+) CD1d(high) CD5(high) , CD19(+) CD25(high) forkhead box protein 3 (FoxP3)(+) regulatory B (Breg ) cells, memory B cells, and transitional type 1 (T1) B cells. In addition, flow cytometric analysis revealed significantly decreased populations of FAS(+) GL-7(+) germinal centre B cells and B220(-) CD138(+) plasma cells in the spleens of rebamipide-treated SKG mice compared to controls. Rebamipide decreased germinal centre B cells and reciprocally induced Breg cells in a dose-dependent manner in vitro. Rebamipide-induced Breg cells had more suppressive capacity in relation to T cell proliferation and also inhibited Th17 differentiation from murine CD4(+) T cells. Together, these data show that i.p. administration of rebamipide suppresses arthritis severity by inducing Breg and Treg cells and suppressing Tfh and Th17 cells in a murine model of RA.

Predictors of renal relapse in Korean patients with lupus nephritis who achieved remission six months following induction therapy.

Renal relapse in patients with lupus nephritis (LN) is a risk factor for poor renal function. Therefore, there is a need to identify clinical and serological risk factors for renal relapse. A total of 108 patients with LN were enrolled in this study. All the subjects had achieved complete remission or partial remission following six months of induction therapy. We retrospectively analyzed their clinical and laboratory indices, final renal function, and kidney biopsy findings. The median follow-up period after LN diagnosis was 81 months. Renal relapse had occurred in 36 patients; it occurred in 38% and 46% of patients within five and 10 years after achievement of renal remission, respectively. There was no difference between the relapsed rate in patients with complete remission and that in those with partial remission. Clinical variables at LN onset and renal biopsy findings in the patients with sustained remission and relapsed patients were also not different. The probability of renal relapse was significantly higher in patients with an earlier age of onset of systemic lupus erythematosus (SLE) (≤ 28 years versus >28 years; HR 7.308, P=0.001), seronegativity for anti-Ro antibody (seronegativity versus seropositivity; HR 3.514, P=0.007), and seropositivity for anti-dsDNA antibody at six months after initiation of induction therapy (HR 8.269, P=0.001). Our study demonstrated that early onset of SLE, seronegativity for anti-Ro antibody and increased anti-dsDNA antibody following six months of induction therapy independently predict renal relapse among the LN patients.

Pancreatic adenocarcinoma upregulated factor, a novel endothelial activator, promotes angiogenesis and vascular permeability.

Pancreatic adenocarcinoma upregulated factor (PAUF) was recently reported to be a metastasis factor for pancreatic cancer cells. Here, we demonstrate a novel role for PAUF as a potent endothelial activator, promoting both angiogenesis and vascular permeability. Overexpression of PAUF in a mouse pancreatic cancer model resulted in increased tumor vascularity. Recombinant PAUF (rPAUF) enhanced proliferation, migration and capillary-like tube formation of human endothelial cells (ECs), consistently with increased neovascularization in vivo. rPAUF also increased endothelial permeability through the disruption of vascular endothelial-cadherin-facilitated cell-cell junctions in vitro and induced vascular leakage in mouse skin. These effects were attenuated upon treatment with an antibody against PAUF. Moreover, PAUF evoked a time- and dose-dependent activation of extracellular signal-regulated kinase (ERK)1/2, AKT and endothelial NO synthase (eNOS) in ECs, which are closely linked to rPAUF-induced angiogenesis. Finally, rPAUF upregulated the expression of C-X-C chemokine receptor 4 (CXCR4) in ECs and potentiated the in vitro and in vivo EC angiogenic responses to stromal cell-derived factor-1 (SDF-1), a ligand for CXCR4. Taken together, these data demonstrate that PAUF has a novel function in promoting angiogenesis and vascular permeability. Our findings suggest new possibilities for PAUF's role in the pathogenesis of angiogenesis-dependent diseases.

Rebamipide attenuates pain severity and cartilage degeneration in a rat model of osteoarthritis by downregulating oxidative damage and catabolic activity in chondrocytes.

OBJECTIVE: The objectives were to investigate the in vivo effects of treatment with rebamipide on pain severity and cartilage degeneration in an experimental model of rat osteoarthritis (OA) and to explore its mode of action. MATERIALS AND METHODS: OA was induced in rats by intra-articular injection of monosodium iodoacetate (MIA). Oral administration of rebamipide was initiated on the day of MIA injection, 3 or 7 days after. Limb nociception was assessed by measuring the paw withdrawal latency and threshold. We analyzed the samples macroscopically and histomorphologically, and used immunohistochemistry to investigate the expression of matrix metalloproteinase-13 (MMP-13), interleukin-1ß (IL-1ß), hypoxia-inducible factor-2α (HIF-2α), inducible nitric oxide synthase (iNOS), and nitrotyrosine in knee joints. Real-time quantitative reverse transcription-polymerase chain reaction was used to quantify the mRNA for catabolic and anticatabolic factors in human OA chondrocytes. RESULTS: Rebamipide showed an antinociceptive property and attenuated cartilage degeneration. Rebamipide reduced the expression of MMP-13, IL-1ß, HIF-2α, iNOS, and nitrotyrosine in OA cartilage in a dose-dependent manner. Nitrotyrosine expression in the subchondral bone region was decreased in the rebamipide-treated joints. mRNA expression of MMP-1, -3, and -13, and ADAMTS5 was attenuated in IL-1ß-stimulated human OA chondrocytes. By contrast, rebamipide induced the mRNA expression of tissue inhibitor of metalloproteinase-1 and -3. CONCLUSION: The results show the inhibitory effects of rebamipide on pain production and cartilage degeneration in experimentally induced OA. The suppression of oxidative damage and the restoration of extracellular matrix homeostasis of articular chondrocyte suggest that rebamipide is a potential therapeutic strategy for OA.

SPECT/PET myocardial perfusion imaging versus coronary CT angiography in patients with known or suspected CAD.

Stress SPECT myocardial perfusion imaging (MPI) is the most commonly utilized stress imaging technique for patients with suspected or known coronary artery disease (CAD) and has a robust evidence base including the support of numerous clinical guidelines. Gated SPECT is a well-established noninvasive imaging modalities that is a core element in evaluation of patients with both acute and stable chest pain syndromes. Over the past decade, PET has become increasingly used for the same applications. By comparison, cardiac computed tomography (CT) is a more recently developed method, providing non-invasive approaches for imaging coronary atherosclerosis and coronary artery stenosis. Non-contrast CT for imaging the extent of coronary artery calcification (CAC), in clinical use since the mid-1990's, has a very extensive evidence base supporting its use in CAD prevention. While contrast-enhanced CT for noninvasive CT coronary angiography (CCTA) is relatively new, it has already developed an extensive base of evidence regarding diagnosing obstructive CAD and more recently evidence has emerged regarding its prognostic value. It is likely that non-contrast CT or CCTA for assessment of extent of atherosclerosis will become an increasing part of mainstream cardiovascular imaging practices as a first line test. In some patients, further ischemia testing with MPI will be required. Similarly, MPI will continue to be widely used as a first-line test, and in some patients, further anatomic definition of atherosclerosis with CT will also be appropriate. This review will provide a synopsis of the available literature on imaging that integrates both CT and MPI in strategies for the assessment of asymptomatic patients for their atherosclerotic coronary disease burden and risk as well as symptomatic patients for diagnosis and guiding management. We propose possible strategies through which imaging might be used to identify asymptomatic candidates for more intensive prevention and risk factor modification strategies as well as symptomatic patients who would benefit from referral to invasive coronary angiography for consideration of revascularization.

VDUP1 potentiates Ras-mediated angiogenesis via ROS production in endothelial cells.

Vitamin D3 up-regulated protein 1 (VDUP1) is a tumor suppressor of which expression is reduced in a variety of cancer cells, and enforced expression inhibits the tumor cell proliferation. It inhibits the activity of thioredoxin, thus contributing cellular ROS generation. Since ROS is a critical factor for angiogenesis, we investigated the role of VDUP1 in angiogenesis and endothelial proliferation. The expression of VDUP1 was upregulated by overexpression of an oncogene, Ras. Enforced expression of VDUP1 increases ROS production and proliferation of Ras-overexpressing endothelial cells. Overexpression of VDUP1 increases the resistance to the anchorage-dependent cell death and tube formation of the Ras-overexpressing endothelial cell. In addition, the removal of ROS by ROS scavenger attenuates the effect of VDUP1 on tube formation. These results suggest that VDUP1 is involved in Ras-mediated angiogenesis via ROS generation in endothelial cells.

Lupus enteritis: clinical characteristics, risk factor for relapse and association with anti-endothelial cell antibody.

The study was undertaken to evaluate clinical and laboratory characteristics of patients with lupus enteritis and to investigate its association with anti-endothelial cell antibodies (AECAs). Systemic lupus erythematosus (SLE) patients who were admitted to Kangnam St. Mary's Hospital with complaints of acute abdominal pain from January 1990 to July 2006 were reviewed retrospectively. The clinical features, laboratory data and prognosis of these patients were analyzed. Among the 706 SLE patients admitted during the study period, 87 were found to admit for acute abdominal pain. Among them, 41 patients were identified with lupus enteritis. The SLE disease activity index score at admission and the mean prednisolone dose administered during the last three months prior to admission were significantly higher in patients with lupus enteritis than those with other causes (P < 0.001, P = 0.036). Serum anti-endothelial cell antibody (AECA-IgG) titer was also significantly higher in patients with lupus enteritis than those with other manifestations or healthy controls (P = 0.040, P < 0.001). Four out of 13 recurrent patients had pre-existing anti-phospholipid syndrome (APS), whereas only one out of 28 non-recurrent patients had pre-existing APS (P = 0.028). Most of the patients with lupus enteritis showed good response to high-dose intravenous steroids and there was no death directly associated with lupus enteritis.

Protein phosphatase 1 nuclear targeting subunit is a hypoxia inducible gene: its role in post-translational modification of p53 and MDM2.

p53, the most commonly mutated tumor suppressor gene in human cancers, is a master regulator of apoptosis in many types of cells. Recently, protein phosphatase-1 (PP1) has emerged as a key phosphatase of p53, which modulates the interaction of p53 with its regulatory protein mouse double minute 2 (MDM2) and transcriptional activity. In the present study, we demonstrate the potential role of PP1 nuclear targeting subunit (PNUTS) in regulating the phosphorylation and apoptotic activities of p53. Hypoxia significantly increased mRNA and protein expression of PNUTS in various cell lines concomitantly with increases in p53. Promoter analysis confirmed the presence of hypoxia response elements in the promoter region of the PNUTS gene, which respond to hypoxia and forced expression of hypoxia-inducible factor 1 alpha. Overexpression of PNUTS markedly increased cell death in response to hypoxia, with increased expression of Bax, an apoptosis-related gene induced by p53. Consistently, PNUTS increased the nuclear localization, phosphorylation, and transcriptional activity of p53 as well as the ubiquitin-dependent proteosomal degradation of MDM2. However, the W401A mutant form of PNUTS, which is incapable of binding to PP1, failed to induce these events. Taken together, our findings suggest that PNUTS may play an important role in controlling cell death in response to cellular stresses such as hypoxia through the post-translational modification of p53 and MDM2.