The nucleolar MSP58 protein is a candidate oncogene implicated in modulating cellular proliferation and malignant transformation. In this study, we show that knocking-down MSP58 expression caused aneuploidy and led to apoptosis, whereas ectopic expression of MSP58 regulated cell proliferation in a context-dependent manner. Specifically, ectopic expression of MSP58 in normal human IMR-90 and Hs68 diploid fibroblasts, the H184B5F5/M10 mammary epithelial cell line, HT1080 fibrosarcoma cells, primary mouse embryonic fibroblasts (MEFs), and immortalized NIH3T3 fibroblasts resulted in induction of premature senescence, an enlarged and flattened cellular morphology, and increased senescence-associated β-galactosidase activity. MSP58-driven senescence was strictly dependent on the presence of functional p53, as revealed by the fact that normal cells with p53 knockdown by specific shRNA, or cells with a mutated or functionally impaired p53 pathway, were effective in bypassing MSP58-induced senescence. At least two senescence mechanisms are induced by MSP58. First, MSP58 activates the DNA damage response and p53/p21 signaling pathways. Second, MSP58, p53, and the SWI/SNF chromatin remodeling subunit, BRG1, form a ternary complex on the p21 promoter, and collaborate to activate p21. Additionally, MSP58 protein levels increased in cells undergoing replicative senescence and stress-induced senescence. Notably, the results of analyzing expression levels of MSP58 between tumors and matched normal tissues showed significant changes (both up- and downregulation) in its expression in various types of tumors. Our findings highlight new aspects of MSP58 in modulating cellular senescence, which suggests that MSP58 has both oncogenic and tumor-suppressive properties.

Central aortic systolic blood pressure (SBP-C) can be estimated from a cuff oscillometric waveform derived during the pulse volume plethysmography (PVP) by applying a device-specific aortic pressure-to-PVP waveform-generalized transfer function (A2P(GTF)). The present study compared the performance of an aortic-to-brachial pressure waveforms generalized transfer function (A2B(GTF)), which is independent of any PVP devices, with an A2P(GTF). Generalized transfer function of aortic-to-brachial (A2B(GTF)) and aortic-to-PVP (A2P(GTF)) were generated from the simultaneously obtained central aortic and brachial pressure waveforms recorded by a high-fidelity dual pressure sensor catheter, and the PVP waveform recorded by a customized noninvasive blood pressure monitor during cardiac catheterization in 40 patients, and were then applied in another 100 patients with simultaneously recorded invasive aortic pressure and noninvasively calibrated (using cuff SBP and diastolic blood pressures) PVP waveforms. The mean difference±s.d. between the noninvasively estimated and invasively recorded SBP-C was -2.1±7.7 mm Hg for A2B(GTF), which was not greater than that of -3.0±7.7 mm Hg for A2P(GTF)(P<0.01). In conclusion, SBP-C can be measured reliably using a noninvasive blood pressure monitor by applying either an A2P(GTF) or A2B(GTF) to a noninvasively calibrated PVP waveform. The performance of an A2B(GTF) is not inferior to that of an A2P(GTF).Journal of Human Hypertension advance online publication, 3 May 2012; doi:10.1038/jhh.2012.17.

Background: Although intravenous tissue-plasminogen activator (tPA) with a standard dose of 0.9 mg/kg is effective for patients with acute ischemic stroke, concerns have been raised for Asians. Objectives: We aimed to compare the safety and efficacy between low and standard dose for stroke thrombolysis. Patients/Methods: Consecutive patients receiving tPA treatment were recruited according to the pre-specified dosing policy from two medical centers in Taiwan: low-dose (0.7 mg/kg) at NCKUH from August 2006 to June 2009 or standard dose (0.9 mg/kg) at NCKUH from July 2009 to December 2010 and CCH from May 2008 to December 2010. The primary safety outcome was the occurrence of symptomatic intracerebral hemorrhage (sICHn). The secondary efficacy outcome was the proportion of patients with modified Rankin Scale (mRS) ≤ 1 at 3 months. Results: From August 2006 to December 2010, 261 patients were recruited, of whom 105 and 156 received low and standard doses respectively. The sICHn was non-significantly lower in the standard dose group than in the low dose group (2.6% vs. 4.8% respectively, p=0.34). Favorable outcome of mRS ≤ 1 at 3 months was similar (38.4% and 41.1%, respectively; p=0.676). A review of other case series of low vs. standard doses in Asians also showed comparable safety and efficacy. Conclusion: Our study, as well as other case series on Asians, revealed that standard dose thrombolysis for acute ischemic stroke in an Asian population carries no increased symptomatic intracerebral hemorrhage when compared with the low dose. © 2012 International Society on Thrombosis and Haemostasis.

Strontium ranelate is an effective drug that was developed for treating osteoporosis. Here, we report the case of a 62-year-old woman who developed headache and diffuse scalp hair loss 1 week after receiving strontium ranelate treatment for osteoporosis. The treatment was subsequently stopped because of the intractable headache. Nevertheless, the patient continued to lose hair for 6 weeks following treatment discontinuation. Histopathological analysis of scalp tissues revealed anagen effluvium. The patient's hair started regrowing slowly 2 months after treatment with strontium ranelate was discontinued.

Heat generated during implant osteotomy might lead to osteonecrosis and delayed bone repair, thus resulting in impaired early osseointegration and fixation of bone-anchoring devices. In this study, we proposed to overcome heat-induced injury to bone by fabricating core-shell polymeric biodegradable microspheres encapsulating a mitogenic factor, platelet-derived growth factor (PDGF), and a differentiation factor, simvastatin, in a simultaneous or sequential release profile. Microspheres encapsulating bovine serum albumin (BSA), PDGF, simvastatin, PDGF-in-core with simvastatin-in-shell, and simvastatin-in-core with PDGF-in-shell were delivered to fill standardized osteotomy sites on edentulous ridges of rat maxillae under irrigated or non-irrigated conditions. In the absence of irrigation, significant reduction of cell viability and increase in inflammation and sequestrum formation without evidence of osteogenesis were observed. Both PDGF and simvastatin deliveries facilitated cell viability and reduced osteonecrosis. Localized osteogenesis was seen under simvastatin treatment, while generalized but primitive osteogenesis was noted in PDGF-treated osteotomy sites. In addition, sequential PDGF-simvastatin delivery further augmented osteogenesis and promoted bone maturation. The results suggested that sequential PDGF-simvastatin delivery was an effective modality to prevent heat-induced complications and facilitate bone apposition after implant osteotomy, potentially favoring the early fixation of bone-anchoring devices and oral implant osseointegration.

BACKGROUND Chronic viral hepatitis is no longer a contraindication to renal transplantation (RT), owing to our better understanding of the hepatitis virus. Hepatitis patients may receive RT depending on their response to viral therapy. RT patients with hepatitis generally do not have an inferior prognosis compared with RT patients without the disease. Hepatic stellate cells (HSCs) are activated during chronic viral hepatitis. The role of HSCs in immunoregulatory effects in RT recipients has not been fully elucidated. METHODS We recruited 22 RT recipients with chronic viral hepatitis, who composed the chronic liver disease (CLD) group, and 25 disease-free recipients, who served as the control group. We retrieved their clinical data and collected serum to measure cytokine levels. To investigate the immunoregulatory effect of HSCs, we cocultured HSCs with allogeneic antigen-presenting cell-activated T cells (mixed lymphocyte reaction [MLR]) in Transwell plates. RESULTS The liver biopsy disclosed activation HSCs in 1 chronic hepatitis C virus recipient without treatment. Serum monocyte chemoattractant protein-1 (MCP-1) levels in the CLD group (41.6 ± 27.4 pg/mL) were significantly higher than those in the control group (28.1 ± 12.8 pg/mL; P =.008). There were similar levels of transforming growth factor-β1 (TGF-β1). In allogeneic MLR, HSCs inhibited T-cell activation through the soluble factors in the Transwell assays. There was a high level of MCP-1 in the supernates of the HSC group in the allogeneic MLR, but TGF-β1 was lower in HSCs cocultured with MLR than in the control group, except in the early period. CONCLUSIONS HSCs may play an immunoregulatory role in chronic viral hepatitis recipients to minimize the effect of immunosuppressants without affecting rejection. The immunomodulatory effects may be attributed to soluble factors in HSCs.

OBJECTIVES Kidney transplantation (KT) is associated with increased incidence of hypertension, hyperlipidemia, metabolic syndrome, and posttransplant diabetes mellitus that promote the development of coronary artery calcification (CAC). The aim of the current study was to elucidate the extent of CAC and its risk factors among KT patients. METHODS A cross-sectional study was performed to evaluate the severity of CAC in our KT patients. Multidetector computed tomography was performed to assess the coronary artery calcium score (CACS). Patients were further stratified according to the CACS as: group 1: 0-10, group 2: 11-100, group 3: 101-300, group 4: 301-1000, and group 5:>1000. Clinical as well as demographic data were compared among groups. Linear regression analysis was performed to determine factors that were associated with CAC. RESULTS A total of 99 patients were enrolled in the study. The mean age was 53.5 ± 11.8 years and duration of follow-up post-KT was 11.2 ± 5.9 years. The distribution of CACS in groups 1 through 5 was: 41.4%, 20.2%, 11.1%, 15.2%, and 12.1%, respectively. A significantly higher CACS was found in males, patients with pretransplant diabetes mellitus, older current age, older age at KT, hypertension, higher body weight, higher fasting plasma sugar level and lower high-density lipoprotein (HDL) cholesterol. Twenty-nine (29.3%) patients fulfilled criteria for metabolic syndrome (MS). The CACS was significantly higher in patients with MS than in those without MS. An incremental CACS was found to be correlated with increasing number of MS components (P =.003). Multivariate linear regression revealed that female gender, current age, hypertension, and HDL cholesterol were associated with CAC. CONCLUSION KT was associated with high CACS in a significant proportion of patients with long-term follow-up. Several risk factors were identified. Some of them were potentially treatable and should be taken into consideration in the management of KT recipients.

OBJECTIVES Adiponectin (APN) is an adipocyte-derived protein that has anti-inflammatory, anti-atherogenic, and insulin-sensitizing effects. Lower serum APN level is associated with various inflammatory and metabolic diseases in the general population. Kidney transplant (KT) recipients are at higher risk for developing several metabolic disorders, including metabolic syndrome (MS). The aim of the current study was to assess the change of APN level in KT recipients with and without MS. METHODS Prevalent KT recipients followed at our hospital were enrolled for the cross-sectional study of MS. The modified Adult Treatment Panel III criteria adopted for the Asian population were used to define MS. Overnight fasting blood samples were obtained for biochemistry and APN. APN was assayed with a commercially available enzyme-linked immunosorbent assay (ELISA) kit. The simplified Modification of Diet in Renal Disease (MDRD) equation was used for the calculation of estimated glomerular filtration rate (eGFR). Univariate and multivariate logistic regression were performed to determine parameters that were associated with serum APN level. RESULTS A total of 271 KT recipients (male:female = 133:138), with a mean age of 52.3 ± 12.6 years, were enrolled for the study of MS. The mean duration of follow-up posttransplantation was 9.02 ± 5.91 years. MS was found in 72 of 271 KT recipients (26.6%). Patients with MS were older, had significantly higher body weight, waist circumference, serum creatinine, fasting plasma sugar, and hemoglobin A1c, but lower serum APN level and eGFR than did patients without MS. Univariate logistic regression revealed the following variables were associated with APN level: MS, gender, body weight, body height, waist circumference, body mass index, serum creatinine, fasting blood sugar, triglyceride, high-density lipoprotein (HDL) cholesterol, and eGFR. Multivariate analysis revealed that gender, body weight, serum creatinine, triglyceride, and HDL cholesterol were associated with APN level. CONCLUSION Our results revealed that KT recipients with MS had significantly lower serum APN levels, even in the presence of lower eGFR, than those without MS.

BACKGROUND Genetic variations may affect posttransplantation metabolic syndrome and diabetes mellitus (PTDM), which is associated with greater morbidity and progressive impairment of both patient and graft survivals. The aim of this study was to evaluate several candidate gene polymorphisms for their association with the risk of developing PTDM. METHODS In April 1999, we enrolled 278 renal transplant participants, including 251 subjects free of diabetes and 27 with PTDM. We studied several candidate gene polymorphisms associated with diabetes: 4G/5G polymorphism of plasminogen activator inhibitor 1 (PAI-1) at -675; C/T polymorphism of interleukin-1beta (IL-1β) at -511; G/C polymorphism of IL-6 at 174; polymorphic XbaI of Glucose transporter 1 (GLUT1); and C/T polymorphism of methylenetetrahydrofolate redutase (MTHFR) at 677. RESULTS The PTDM group had an older mean age (47.6 ± 9.8 years), greater predominance of men (77.8%), higher number of chronic diseases (CDN ≥2, 96.3%), and more patients using tacrolimus-based immunosuppression (44.4%; P <.05). Using model A, a simple logistic regression, we observed that patients with the IL-6 G/G genotype experienced a lower risk of developing PTDM (odds ratio [OR], 0.08; 95% confidence interval [CI] 0.01-0.86), and multiple logistic regression models B and C, after adjusting for different variables, confirmed this observation (model B: OR, 0.05; 95% CI, 0.00-0.66). The IL-6 G/G genotype showed a borderline effect in model C (OR, 0.02; 95% CI, 0.00-1.16). There were no significant differences between the 2 groups in genotype variations of PAI-1, IL-1β, GLUT-1, and MTHFR. CONCLUSIONS The G/G genotype of IL-6 may play an important role to lower the risk for PTDM development.

Posttransplant new-onset diabetes mellitus (NODM) is an important complication among patients receiving immunosuppressants. It has a considerable impact on chronic allograft dysfunction. Calcineurin inhibitors have been implicated in the development of posttransplant NODM. Since high-risk candidates also undergo transplantation, prevention and control of posttransplant NODM is important. A 3-year postmarketing surveillance study is currently underway in Taiwan to evaluate the incidence and risk factors leading to development of NODM among de novo and maintenance solid-organ transplant patients receiving cyclosporine (CsA)-based immunosuppressive therapy. Concomitant therapy consisted of basiliximab, mycophenolate mofetil or enteric-coated mycophenolate sodium, and corticosteroids. Diabetes was diagnosed according to the American Diabetes Association criteria. This 6-month protocol-defined interim analysis included 101 patients (84 de novo, 17 maintenance) who received renal (n = 77), liver (n = 13), or heart (n = 11) transplantation. At the end of 6 months, 8/101 (7.92%) patients experienced NODM. The mean time to NODM was 3.05 months. No significant difference was observed between NODM and non-NODM patients for risk factors: age, body mass index, blood pressure, gender, high-density lipoproteins/triglycerides hdl/tg, and anti-hepatitis C virus. The composite endpoint of biopsy-proven acute rejection, graft loss, or death was reached in four patients, with a mean time to event of 3.81 months. Infections were noted in 34 subjects but, no malignancies. Among 389 adverse events reported in 91 patients (90.1%), the majority were of mild to moderate severity. Two deaths were reported: heart transplant recipients with acute rejection and cytomegalovirus meningitis with respiratory failure. Long-term enrollment with follow-up evaluation of these NODM patients up to 3 years will help evaluate the NODM incidence rates and exact graft survival and overall survival rates of CsA-treated transplant patients in Taiwan.