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Introduction: We tested the hypothesis that apoptotic adipose-derived mesenchymal stem cells (A-ADMSC) are superior to healthy (H)-ADMSC in attenuating cecal ligation puncture (CLP)-induced sepsis-mediated lung and kidney injuries., Methods: Adult male rats divided into group 1 (sham controls), group 2 (CLP), group 3 [CLP + H-ADMSC administered at 0.5, 6, and 18 hours after CLP], and group 4 [CLP + A-ADMSC administered as in group 3] were sacrificed 72 hours after CLP with blood, lung, and kidney collected for studies., Results: White blood cell (WBC) count, circulating TNF-α and creatinine levels were higher in groups 2 and 3 than in groups 1 and 4 (all P < 0.001). Kidney and lung damage scores were highest in group 2, lowest in group 1, significantly higher in group 3 than in group 4 (all P < 0.0001). Protein expressions of inflammatory (ICAM-1, MMP-9, TNF-α, NF-κB), oxidative, and apoptotic (Bax, caspase-3, PARP) biomarkers were higher in groups 2 and 3 than groups 1 and 4, whereas anti-apoptotic (Bcl-2) and mitochondrial integrity (cytochrome-C) biomarkers were lower in groups 2 and 3 than in groups 1 and 4 (all P < 0.001). Expressions of anti-oxidant biomarkers at protein (GR, GPx, NQO-1, HO-1) and cellular (GR, GPx) levels were highest in group 4 (all P < 0.001). The number of inflammatory cells (CD3+) in lungs and levels of DNA damage marker (γ-H2AX) in kidneys were higher in groups 2 and 3 than in groups 1 and 4 (all P < 0.001)., Conclusions: A-ADMSC therapy was superior to H-ADMSC therapy in protecting major organs from damage in rats with CLP-induced sepsis syndrome.

Background: The current standard treatment for patients with metastatic gastric cancer (MGC) is systemic chemotherapy. For gastric cancer patients with ovarian metastases, i.e. Krukenberg tumors, it is not known whether metastasectomy is associated with additional benefits., Patients and Methods: All patients who were diagnosed with gastric cancer and ovarian metastases between March 2000 and July 2010 in a medical center were included in the current study. The clinicopathological features and the treatment records were reviewed in detail and their association with overall survival (OS) was analyzed., Results: A total of 85 patients were identified. Thirty five (41.2%) and 50 (58.8%) patients did and did not undergo metastasectomy of Krukenberg tumors, respectively. The performance status and the proportion of patients receiving subsequent systemic therapy were well-matched between the two groups. Regarding disease status, patients who underwent metastasectomy had significantly larger Krukenberg tumors, pronounced bilateral disease and less extensive metastases outside the ovaries than patients who did not undergo metastasectomy. Patients who underwent metastasectomy had a better OS [median=14.1 months; 95% confidence interval (CI)=8.6-19.6 months] than patients who did not undergo metastasectomy (median OS=8 months; 95% CI=5.6-10.4 months, p=0.001). There was no aberrant postoperative morbiditie rate observed, and the median length of hospital stay after metastasectomy alone was 6 days. Based on multivariate analysis, metastasectomy remained an independent predictor of better OS (hazard ratio=0.36, p=0.002). The administration of subsequent systemic therapy, the use of platinum-based chemotherapy, and a better performance status also predict a better OS., Conclusion: Metastasectomy of Krukenberg tumors may be associated with survival benefits in patients with MGC. Further prospective studies are warranted.

Background and Aim: We tested the hypothesis that obesity reduced circulating number of endothelial progenitor cells (EPCs), angiogenic ability, and blood flow in ischemic tissue that could be reversed after obesity control., Methods: 8-week-old C57BL/6J mice (n=27) were equally divided into group 1 (fed with 22-week control diet), group 2 (22-week high fat diet), and group 3 (14-week high fat diet, followed by 8-week control diet). Critical limb ischemia (CLI) was induced at week 20 in groups 2 and 3. The animals were sacrificed at the end of 22 weeks., Results: Heart weight, body weight, abdominal fat weight, serum total cholesterol level, and fasting blood sugar were highest in group 2 (all p<0.001). The numbers of circulating EPCs (C-kit/CD31+, Sca-1/KDR + and CXCR4/CD34+) were lower in groups 1 and 2 than in group 3 at 18 h after CLI induction (p<0.03). The numbers of differentiated EPCs (C-kit/CD31+, CXCR4/CD34+ and CD133+) from adipose tissue after 14-day cultivation were also lowest in group 2 (p<0.001). Protein expressions of VCAM-1, oxidative index, Smad3, and TGF-β were higher, whereas the Smad1/5 and BMP-2, mitochondrial cytochrome-C SDF-1α and CXCR4 were lower in group 2 than in groups 1 and 3 (all p<0.02). Immunofluorescent staining of CD31+ and vWF + cells, the number of small vessel (<15 μm), and blood flow through Laser Doppler scanning of ischemic area were lower in group 2 compared to groups 1 and 3 on day 14 after CLI induction (all p<0.001)., Conclusion: Obesity suppressed abilities of angiogenesis and recovery from CLI that were reversed by obesity control.

Background: The standard of chemotherapy regimens for advanced or metastatic gastric cancer and the clinical outcome were heterogeneous in Asian versus non-Asian countries. This study aimed to explore predictors of safety and efficacy of chemotherapy for patients with advanced or metastatic gastric cancer., Methods: Treatment group-based meta-analysis and met a regression were performed to analyze results of randomized trials published since 2005 for advanced or metastatic gastric cancer patients who received systemic chemotherapy as first-line treatment. Data were extracted and synthesized according to the Cochrane guidelines., Results: Twenty-five trials (8 Asian, 17 Western or international) with 56 treatment groups were analyzed. Asian trials reported a lower percentage of gastroesophageal junctional carcinoma, higher percentage of diffuse type histology, and more frequent use of second-line chemotherapy. Meta-analysis revealed significant heterogeneity both in treatment safety (grade 3–4 neutropenia and diarrhea) and efficacy [6-month progression-free survival(PFS) and 1-year overall survival (OS)]. Meta-regression analyses indicate that Asian trials are associated with an 8.2% lower incidence of grade 3–4 neutropenia and 2.1%lower incidence of grade 3–4 diarrhea. A lower percentage of patients with gastroesophageal junction carcinoma and the use of combination regimens predicted better PFS. The use of second-line chemotherapy predicts better 1-year OS,which will increase by 10% for every 10% increase inpatients who received second-line chemotherapy., Conclusion: Geographic region (Asian vs. non-Asian) is an independent predictor of safety in systemic therapy for gastric cancer.

An explorative study evaluates the efficacy of Helicobacter pylori (HP) eradication (HPE) therapy on early-stage gastric diffuse large B-cell lymphomas (DLBCLs) without features of mucosa-associated lymphoid tissue (MALT), the pure (de novo) DLBCLs, in comparison with its efficacy on high-grade transformed gastric MALT lymphomas, the DLBCL(MALT). In total, 50 patients of stage IE/IIE1 HP-positive gastric DLBCLs with frontline HPE treatment were included. HP infection was successfully eradicated in 100% (16/16) of the pure (de novo) DLBCL patients and 94.1% (32/34) of the DLBCL(MALT) patients. In total, 68.8% (11/16) of pure (de novo) DLBCL patients and 56.3% (18/32) of DLBCL(MALT) patients achieved complete pathologic remission (pCR) after HPE therapy. The median time to pCR was 2.1 months (95% confidence interval, 0.6%-3.7%) for pure (de novo) DLBCLs and 5.0 months (95% confidence interval, 2.8%-7.5%; P = .024) for DLBCL(MALT). At a median follow-up of 7.7 years, all patients with pCR after HPE therapy were alive and free of lymphomas, except for one patient with pure (de novo) DLBCL who died of lung cancer. Similar to DLBCL(MALT), a substantial portion of early-stage HP-positive gastric pure (de novo) DLBCLs remains HP-dependent and responds to antibiotic treatment. Prospective studies to validate the findings are warranted.

Background & Aims: Women with hepatitis B virus (HBV) infection usually have lower viral loads than men, reducing their risk of liver cancer. There are 2 androgen-responsive elements in the HBV enhancer I that contribute to higher viral titers in men. We investigated whether and how estrogen signaling affects progression of HBV infection., Methods: Ovariectomy and estrogen supplementation were used to evaluate the effect of estrogen on HBV titers in transgenic mice with replicating HBV in hepatocytes. The effect of estrogen signaling on transcription of HBV genes, and the mechanisms of regulation, were studied in HepG2 cells., Results: HBV titers increased in female mice after ovariectomy and decreased in male mice supplemented with estrogen. Hepatic expression of estrogen receptor (ER)-α was increased by estrogen exposure. In HepG2 cells, up-regulation of ER-α reduced HBV transcription, which required a specific region within enhancer I. Direct DNA binding of ER-α and histone deacetylase activity were not required for ER-α-mediated repression of HBV genes. Overexpression of hepatocyte nuclear factor (HNF)-4α, which binds to this region, overcame the repressive effect of ER-α. ER-α did not repress transcription of an HBV replicon with a mutant HNF-4α binding site within enhancer I. Coimmunoprecipitation assays showed an interaction between ER-α and HNF-4α; this interaction prevented HNF-4α binding to enhancer I and activation of HBV transcription., Conclusions: Estrogen can repress transcription of HBV genes by up-regulating ER-α, which interacts with and alters binding of HNF-4α to the HBV enhancer I. These findings might account for the lower viral load and reduced incidence of liver cancer in HBV-infected women than men., (Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background and Aim: Currently, no data on the optimal time point after acute ischemic stroke (IS) at which high-sensitivity C-reactive protein (hs-CRP) level is most predictive of unfavorable outcome. We tested the hypothesis that hs-CRP levels during both acute (48 h after IS) and convalescent (21 days after IS) phases are equally important in predicting 90-day clinical outcome after acute IS. We further evaluated the impact of erythropoietin (EPO), an anti-inflammatory agent, on level of hs-CRP after acute IS., Methods: Totally 160 patients were prospectively randomized to receive either EPO therapy (group 1, n = 80) (5,000 IU each time, subcutaneously) at 48 h and 72 h after acute IS, or placebo (group 2, n = 80). Serum level of hs-CRP was determined using ELISA at 48 h and on day 21 after IS and once in 60 healthy volunteers., Results: Serum level of hs-CRP was substantially higher in all patients with IS than in healthy controls at 48 h and day 21 after IS (all p < 0.001). Levels of hs-CRP did not differ between group 1 and 2 at 48 h and day 21 after IS (all p > 0.5). Multivariate analysis showed that hs-CRP levels (at 48 h and day 21) were independently predictive of 90-day major adverse neurological event (MANE) (defined as recurrent stroke, NIHSS≥8, or death) (all p < 0.03), whereas EPO therapy was independently predictive of reduced 90-day MANE (all p < 0.02)., Conclusion: EPO therapy which was independently predictive of freedom from 90-day MANE did not alter the crucial role of hs-CRP levels measured at 48 h and 21-day in predicting unfavorable clinical outcome after IS.

Aim: This study investigated the impact of the circulating galectin-3 level on the 30-day prognostic outcome in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI)., Methods: From May 2009 to March 2011, blood samples for assessment of the circulating galectin-3 level were collected from 196 consecutive STEMI patients treated by primary PCI and from 30 healthy volunteers., Results: The galectin-3 level was determined using ELISA. Our results demonstrated that the circulating level of galectin-3 was significantly higher in STEMI patients than in healthy control subjects (p<0.001). As compared with patients with galectin-3 <7.67 ng/mL, patients with galectin-3 ≥7.67 ng/mL were significantly older, had significantly lower left ventricular ejection fraction and significantly higher frequency of elevated white blood cell count, advanced Killip score (defined as ≥ score 3), congestive heart failure (defined as ≥ New York Heart Association Functional Class III), respiratory failure, unstable hemodynamics requiring a mechanical ventilator and intra-aortic balloon pump support, multiple vessel diseases and 30-day mortality (all p<0.04). Furthermore, multivariate analysis showed that elevated circulating level of galectin-3 was the strongest independent predictor of the combined 30-day major adverse clinical outcome (MACO) (defined as advanced CHF or 30-day mortality) (p<0.0001)., Conclusion: A high circulating galectin-3 level may serve as a useful biomarker for predicting 30-day MACO in patients with STEMI undergoing primary PCI.

Molecular biomarkers to determine the effectiveness of targeted therapies in cancer treatment have been widely adopted in colorectal cancer (CRC), but those to predict chemotherapy sensitivity remain poorly defined. We tested our hypothesis that KRAS mutation may be a predictor of oxaliplatin sensitivity in CRC. KRAS was knocked-down in KRAS-mutant CRC cells (DLD-1(G13D) and SW480(G12V)) by small interfering RNAs (siRNA) and overexpressed in KRAS-wild-type CRC cells (COLO320DM) by KRAS-mutant vectors to generate paired CRC cells. These paired CRC cells were tested by oxaliplatin, irinotecan and 5FU to determine the change in drug sensitivity by MTT assay and flow cytometry. Reasons for sensitivity alteration were further determined by western blot and real-time quantitative reverse transcriptase polymerase chain reaction (qRT -PCR). In KRAS-wild-type CRC cells (COLO320DM), KRAS overexpression by mutant vectors caused excision repair cross-complementation group 1 (ERCC1) downregulation in protein and mRNA levels, and enhanced oxaliplatin sensitivity. In contrast, in KRAS-mutant CRC cells (DLD-1(G13D) and SW480(G12V)), KRAS knocked-down by KRAS-siRNA led to ERCC1 upregulation and increased oxaliplatin resistance. The sensitivity of irinotecan and 5FU had not changed in the paired CRC cells. To validate ERCC1 as a predictor of sensitivity for oxaliplatin, ERCC1 was knocked-down by siRNA in KRAS-wild-type CRC cells, which restored oxaliplatin sensitivity. In contrast, ERCC1 was overexpressed by ERCC1-expressing vectors in KRAS-mutant CRC cells, and caused oxaliplatin resistance. Overall, our findings suggest that KRAS mutation is a predictor of oxaliplatin sensitivity in colon cancer cells by the mechanism of ERCC1 downregulation.

Depletion of β-catenin impairs regeneration of the rapid turn-over gut epithelial cells, but appears dispensable for that of the slow turn-over mature hepatocytes in mice until 1 y of age. As the life span of mature murine hepatocytes is about 400 d, we studied conditional β-catenin knockout mice (Alb-Cre;Ctnnb1(flx/flx)) until 20 mo of age to determine the function of β-catenin in the postnatal liver. β-catenin was absent from the hepatocytes of β-catenin knockout mice 4 wk after delivery. From 9 mo of age, hepatocytes were gradually replaced by newly formed β-catenin-positive hepatocytes, which constituted about 90% of hepatocytes at 18-20 mo of age. This process was accompanied by active proliferation of bile duct/ductule cells. β-catenin-positive hepatocytes exhibited elevated proliferation activity and expression of progenitor cell markers, but lower albumin and Cre. This might explain their intact β-catenin protein, and suggest their origins from hepatic progenitor cells. Liver tumors arose spontaneously from β-catenin-positive cells, and tumorigenesis was accelerated by hepatitis B X protein. These results indicate β-catenin critical for the regeneration of mature hepatocytes. Failure to regenerate mature hepatocytes results in proliferation of hepatic progenitor cells that are able to maintain liver function but are predisposed to form liver tumors.

Although t(11;18)(q21;q21), t(1;14)(p22;q32), and a few other genetic mutations are specific markers for the Helicobacter pylori (HP)-independent status of gastric mucosa-associated lymphoid tissue (MALT) lymphoma, the molecular mechanisms responsible for HP-independence of gastric MALT lymphoma without such translocations and mutations remain uncharacterized. In the present study, we describe the establishment and characterization of a novel MALT lymphoma cell line, MA-1, which was derived from a gastric MALT lymphoma which was negative for both t(11;18)(q21;q21) and t(1;14)(p22;q32); the patient had failed HP eradication therapy and chemotherapy. The cell morphology and the immunophenotype of this cell line were similar to that of the original gastric MALT lymphoma. Comparative genomic hybridization analysis showed no significant gene copy number changes. Spectral karyotyping displayed a near-diploid chromosome content (48 < 2n>XY), with at least 13 chromosome structural abnormalities. Furthermore, fluorescence in situ hybridization analyses disclosed the existence of three sub-clones, characterized by t(14;18)(q32;q21)/IGH-BCL2, t(14;18)(q32;q21)/IGH-MALT1, and the presence of both chromosomal translocations in the same cell, respectively; whereas amplification of the genes CRAD9, TRAF2, and BCL10 were not found. In conclusion, we have established the first human gastric MALT lymphoma cell line, which is characterized by unusual and complex chromosome translocations and will be useful to explore further the molecular mechanisms of HP-independence in gastric MALT lymphoma., (Copyright © 2011 Wiley-Liss, Inc.)

Background: It has been suggested that obesity adversely influences both the severity and the therapeutic responsiveness of chronic asthma. However, it is unclear if it also impacts acute situations., Methods: To determine whether adiposity worsens the clinical and physiological manifestations of acute asthma and limits therapeutic effectiveness of standard treatment, we contrasted signs, symptoms, medication use, arterial oxygen saturation, peak expiratory flow rate, and the bronchodilator response to standard doses of albuterol in 90 non-obese and 90 obese asthmatics as they presented for urgent care. Treatment and clinical decisions were systematized using published care paths and the peak flow was measured with standard techniques. Body mass index (BMI) was calculated according to consensus criteria., Results: Other than BMI (p < .001), there were no between-group differences in age, gender, race, signs, symptoms, pulse oximetry, or pre-presentation medication use. The pretreatment peak flow in the obese population was 22.4% higher on average (p = .007), but there were no differences in the distribution of severity (p = .38), the response to albuterol (p = .61), or admission-discharge ratios (p = .62)., Conclusions: Obesity does not adversely influence the severity or the resolution of acute episodes of asthma.

Purpose: Generalized absence seizures are characterized by bilateral spike-wave discharges (SWDs), particularly in the frontoparietal cortical region. In WAG/Rij and GAERS rats with absence epilepsy, recent evidence indicates that SWDs arise first from the lateral somatosensory cortex (LSC), that is, the cortical focus theory. To further understand the cortical role in SWD generation, two epileptic rat models were assessed., Methods: Two models, Long-Evans rats with spontaneous SWDs and Wistar rats with low-dose pentylenetetrazol-induced SWDs (20 mg/kg, i.p.), were administered intracortical or intrathalamic ethosuximide (ESM) or saline. Electroencephalographic recordings were analyzed before and after intracranial microinfusion to evaluate onset, frequency, and duration of SWDs., Key Findings: In both epileptic rat models, ESM in the LSC significantly reduced SWD number, shortened SWD duration, and delayed SWD onset compared to saline. By contrast, ESM in the medial somatosensory cortex had little effect compared to saline. Intrathalamic infusion of ESM only delayed SWD onset., Significance: These findings suggest that the LSC may be essential for the occurrence of SWDs. Our data support the cortical focus theory for the generation of absence seizures., (Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.)

Purpose: To evaluate the efficacy, safety and pharmacokinetic profiles of S-1, which composed of tegafur (FT, a prodrug of 5-FU), 5-chloro-2,4-dihydroxypyridine and potassium oxonate (Oxo), in Taiwanese advanced gastric cancer (AGC) patients., Methods: Patients with chemo-naïve, histologically confirmed AGC were eligible. S-1 was given orally at dose of 40, 50 or 60 mg, twice daily for patients with body surface <1.25, 1.25-1.5 and >1.5 m(2), respectively, on day 1-28 every 42 days/cycle., Results: Thirty-four patients were included. On intent-to-treat analysis, the overall response rate, median progression-free and overall survival were 35.3% [95% confidence interval (CI): 19.2-51.3%], 2.9 (95% CI: 2.4-5.8) months and 9.8 (95% CI: 6.1-NA) months, respectively. The most common grade 3-4 toxicities were anemia 23.5% and neutropenia 11.8%. There were two treatment-related mortality, which occurred in patients with suboptimal renal function underestimated by serum creatinine level at study entry. Single-dose pharmacokinetic study showed trend toward lower AUC(5-FU), and higher AUC(FT) and AUC(Oxo) comparing to most Western reports., Conclusions: The efficacy, toxicity and pharmacokinetic profiles of S-1 in current study are compatible with those from other Asian populations. Accurate renal function assessment and more closely monitoring is mandatory for S-1 therapy in patients with low body mass. Literature review suggests that, besides AUC(5-FU), AUC(Oxo) may also attribute to the difference in the compliance to S-1 between Asian and Caucasian populations.

mTOR (mammalian target of rapamycin) inhibitors were recently found to be effective in the treatment of various human non-Hodgkin's lymphomas (NHLs). We recently reported that RAD001, an mTOR inhibitor, suppressed the growth of lymphoma cells at concentrations much lower than those required for carcinomas. However, the basis for the enhanced sensitivity to RAD001 is unknown. Seven aggressive NHL cell lines and seven carcinoma cell lines were used in this study. Cell cycle was analysed by flow cytometry. pAKT (phosphorylated AKT) (Ser(473) and Thr(308)), p-p70S6K, p-4E-BP1, p-mTOR, p-eIF4E (phosphorylated eIF4E), cyclin A, cyclin E, cyclin D3, c-Myc and insulin receptor substrate-1 (IRS-1) protein expression were assessed by immunoblotting. The PI3K/AKT/mTOR (phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin) signalling pathway was constitutively expressed in all seven lymphoma cell lines. RAD001 down-regulated p-mTOR, p-p70S6K, p-4E-BP1, cyclin A, cyclin E, cyclin D3, and c-Myc, but did not affect IRS-1. In parallel with RAD001-induced inhibition of cell viability, a dose- and schedule- dependent down-regulation of pAKT and p-eIF4E expressions was demonstrated. In contrast, a compensatory activation of pAKT and p-eIF4E, was observed in seven carcinoma cells. These findings indicate that the basis for enhanced activity of mTOR inhibitors in NHL may be the lack of compensatory activation of AKT and eIF4E phosphorylation in lymphoma cells., (Crown Copyright © 2011. Published by Elsevier Ltd. All rights reserved.)

Purpose/objectives: To explore the association between quality of life (QOL) and type D personality, which is characterized by the traits of negative affectivity and social inhibition, and to further identify impacts of these traits after controlling for biophysical and psychological factors in colorectal cancer survivors., Design: Cross-sectional and correlational., Setting: Oncology and surgical outpatient clinics of a medical center in Taiwan., Sample: 124 patients diagnosed with colorectal cancer who had completed active treatment., Methods: Data were collected using a set of structured questionnaires to explore type D personality, biophysical and psychological factors, and QOL. Their associations were verified with Mann-Whitney U test and Spearman's rho correlation. Significant factors associated with QOL were identified with generalized estimating equations., Main Research Variables: Type D personality and QOL., Findings: Patients with type D personality experienced higher physical and psychological distress than those with non-type D personality. Social inhibition remained an important factor leading to impairment in the mental component of QOL after controlling for other associated factors. Negative affectivity was associated with fatigue intensity and interference of fatigue with life activities., Conclusions: Personality trait was found to be an important factor associated with QOL. The trait of social inhibition was a significant factor influencing mental aspects of QOL, whereas negative affectivity was associated with fatigue., Implications for Nursing: Assessing patients' personality, including negative affectivity and social inhibition, could help nurses to develop supportive groups or social networks for these patients and thereby improve QOL for cancer survivors.

The primary aim of the high-dose 5-fluorouracil (5-FU) and leucovorin (LV; HDFL48) phase I study was to determine the maximum tolerated dose and dose-limiting toxicity of 5-FU and LV with modified tri-monthly 48-h continuous infusion of high-dose 5-FU/LV in patients with metastatic colorectal cancer. The study also determined the pharmacokinetic parameters of 5-FU, especially steady-state plasma and bone marrow (BM) concentrations. Eligibility included serum triglyceride of more than or equal to 70 mg/dl, adequate BM function, and the major typical trial criteria. Sixteen patients who were enrolled received tri-monthly 5-FU at 2500 mg/m²/48 h/week (with 500 then 250 mg/m²/48 h/week escalation by a conventional 3-3 schema up to 3750 mg/m²/48 h/week) and LV at 300 mg/m²/48 h on days 1, 8, and 15 during a regular 28-day cycle. The maximum tolerated dose of 5-FU was 3750 mg/m²/48 h/week with this tri-monthly schedule. Dose-limiting toxicities were grade III neutropenia with more than 1-week delay of the next cycle, grade III mucositis, diarrhea, and hand-foot syndrome for more than 3 days. The regimen maintains significant concentration differences between steady-state plasma and BM concentrations (8.06 ± 6.39 vs. 2.89 ± 1.01 μmol/l, P=0.021) as measured by high-performance liquid chromatography. Toxicities were of minor grade and were tolerable, with minimal myelotoxicity significantly associated with low steady-state BM concentration. None had 5-FU-related hyperammonemic encephalopathy. Three patients had an objective partial response (18.8%, 95% confidence interval: 4-46%) and two of the 14 patients, who had failed HDFL24 (2600 mg/m²/24 h/week), had a partial response to HDFL48 (14.3% partial response, 95% confidence interval 2-43%). Median progression-free survival and overall survival were 4.1 months (range: 1.8-12.5) and 10.5 months (range: 2.7-32.1), respectively. The efficacy and low myelotoxicity of HDFL48 were attributed to the sustained adequate steady-state plasma concentration and an average 2.63-fold concentration gradient between plasma and BM compartments at steady state. The recommended 5-FU dose for use in future trials was 3500 mg/m²/48 h/week, with a fixed dose of LV at 300 mg/m²/48 h/week.

Objectives: Little is known about the outcomes of patients with Killip class III acute ST-segment elevation myocardial infarction in the reperfusion era. This study investigated the short- and long-term outcomes of these patients who underwent primary percutaneous coronary intervention., Methods: Between January 2002 and November 2009, a total of 1,278 consecutive patients with acute ST-segment elevation myocardial infarction underwent primary percutaneous coronary intervention. Of these patients, 230 (17.0%) with Killip III, 216 (16.9%) with Killip II, and 832 (65.1%) with Killip I upon presentation were prospectively recruited., Results: Angiographic study showed significantly lower final thrombolysis in myocardial infarction 3 flow in patients with Killip III compared with those with Killip II and I (83.5% vs. 94.9% vs. 95.7%, p<.0001). The incidence of multiple vessel disease was also notably higher in Killip III than in Killip II and I (65.7% vs. 13.9% vs. 53.8%, p<.001). Besides, the incidence of advanced congestive heart failure (defined as greater than or equal to New York Heart Association functional class 3) during hospitalization was remarkably higher in Killip III compared to Killip II and I (71.3% vs. 13.9% vs. 6.6%, p<.001). Furthermore, the 30-day mortality and 1-yr cumulative mortality were notably higher in Killip III than in Killip II and I (20.0% vs. 4.2% vs. 1.7%, p<.001 and 31.7% vs. 7.9% vs. 4%, p<.001, respectively). Multivariate analysis showed that Killip III was independently predictive of 30-day and 1-yr mortality (all p < .04)., Conclusion: Killip III remains strongly and independently predictive of 30-day and 1-yr mortality in ST-segment elevation myocardial infarction patients even undergoing primary percutaneous coronary intervention.

Background: Western values and culture have undermined concepts filial piety in Taiwan in recent decades. Extant literature has identified the strong influence of filial piety on the willingness of children to care for their parents when ill. Most elderly parents experience illness and suffer from various types and degrees of disabilities and thus need physical, psychological, social, and spiritual care. Less involvement by children in elderly care naturally impacts nursing care, social resource allocations, and economic support for disabled elderly., Purpose: The purpose of this study was to investigate differences in filial piety in three-generation families who live together. Understanding children's filial piety behavior can help nurses understand their willingness to accept responsibility for parental care and can help nurses assist with arranging appropriate home or institutional care for elderly patients., Methods: The study used a cross-sectional research design and snowball sampling. The data set was collected in a township in Central Taiwan and involved 128 participants from 49 households. The questionnaires included demographics, filial piety affection, perceived filial self-efficacy, and filial behavior., Results: Predicted variables for filial behavior included the following: being a member of an older generation, marital status, having positive filial piety affection, and having positive perceived filial self-efficacy. This study found that adults in the youngest group (G3-2 subgroup) who received care and feeding three or more times a week from a grandparent when 0 to 6 years of age had higher scores for filial piety affection toward their parents than their youngest group peers (G3-1 subgroup). The G3-2 subgroup's parents also had higher positive scores for the Filial Piety Affection and Perceived Filial Self-efficacy scales relative to their own parents., Conclusions/implications for Practice: Filial piety is a basic virtue and a traditional cultural value that is worth retaining. There is a need to give positive reinforcement to filial piety values through school education, better parenting, and development of good family relationships. Furthermore, government policy should work to encourage improved filial behavior in youth.

Purpose: To describe a procedural technique involving a combined antegrade femoral and retrograde tibial approach for treatment of complex popliteal and infrapopliteal occlusions, and to determine the safety and efficacy of this technique., Materials and Methods: From May 2008 to March 2010, seven patients presenting with critical limb ischemia received dual vascular access intervention in this institution. Five legs were treated via the retrograde tibial approach after failure of antegrade intervention. A dual access approach was planned and adopted in another two legs. The target vessels were located at popliteal or infrapopliteal arteries., Results: We successfully gained all retrograde tibial access sites and achieved 100% procedural success and immediate hemodynamic improvement. Five legs required stent implantation to optimize the procedural results. No major complication occurred at the tibial access site. During the follow-up period (11.3 ± 7.2, range 3-23 months), no patients required any major amputation; only one patient underwent a mid-foot amputation. The target vessel revascularization rate at 3 and 6 months was 0 and 28.6%, respectively., Conclusion: Dual vascular access was successfully used in a small number of selected patients and this technique may hold promise in improving the success rates in the treatment of complex popliteal and infrapopliteal occlusions., (Copyright © 2011 Wiley-Liss, Inc.)

Background: We investigated whether myocardium-derived conditioned medium (MDCM) is effective in preserving left ventricular (LV) function in a rat acute myocardial infarction (AMI) model., Methods: Adult male Sprague-Dawley (SD) rats (n = 36) randomized to receive either left coronary artery ligation (AMI induction) or thoracotomy only (sham procedure) were grouped as follows (n = 6 per group): Group I, II, and III were sham-controls treated by fresh medium, normal rat MDCM, and infarct-related MDCM, respectively. Group IV, V, and VI were AMI rats treated by fresh medium, normal MDCM, and infarct-related MDCM, respectively. Either 75 μL MDCM or fresh medium was administered into infarct myocardium, followed by intravenous injection (3 mL) at postoperative 1, 12, and 24 h., Results: In vitro studies showed higher phosphorylated MMP-2 and MMP-9, but lower α-smooth muscle actin and collagen expressions in neonatal cardiac fibroblasts treated with MDCM compared with those in the cardiac fibroblasts treated with fresh medium (all p < 0.05). Sirius-red staining showed larger collagen deposition area in LV myocardium in Group IV than in other groups (all p < 0.05). Stromal cell-derived factor-1α and CXCR4 protein expressions were higher in Group VI than in other groups (all p < 0.05). The number of von Willebrand factor- and BrdU-positive cells and small vessels in LV myocardium as well as 90-day LV ejection fraction were higher, whereas oxidative stress was lower in Group VI than in Group IV and Group V (all p < 0.05)., Conclusion: MDCM therapy reduced cardiac fibrosis and oxidative stress, enhanced angiogenesis, and preserved 90-day LV function in a rat AMI model.

This study evaluated the association between atrial fibrillation (AF) and 30-day clinical outcome in patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). Between January 2005 and October 2009, 783 consecutive patients with acute STEMI undergoing primary PCI were enrolled. Of these patients, 85 (10.9%) with AF during admission were categorized into group 1, while the remaining 698 (89.1%) with sinus rhythm during admission served as group 2. The results demonstrated that the incidence of advanced Killip score (defined as ≥ score 3) and advanced congestive heart failure (defined as ≥ NYHA class 3) were significantly higher, whereas the left ventricular ejection fraction (LVEF) was notably lower in group 1 than in group 2 (all P < 0.003). Additionally, the normal blood flow in the infarct-related artery was notably lower in group 1 than in group 2 (P = 0.003). Moreover, the incidences of new-onset stroke and 30-day mortality were remarkably higher in group 1 than in group 2 (all P < 0.003). Furthermore, Kaplan-Meier analysis demonstrated that the 30-day survival rate was markedly lower in AF patients than in those with sinus rhythm. However, multivariate stepwise Cox regression analysis demonstrated that the advanced Killip score and low LVEF were significantly and independently predictive of 30-day mortality (all P < 0.004). In conclusion, AF was significantly associated with 30-day mortality.

Background: Acid-sensing ion channel 3 (ASIC3) is a ligand-gated cation channel activated by extracellular protons. ASIC3(-/-) mice exhibit protection against age-dependent glucose intolerance with enhanced insulin sensitivity., Methods: To determine the association between ASIC3 genetic polymorphisms and insulin resistance in Taiwanese, 606 unrelated subjects with no history of cardiovascular disease were recruited during routine health examinations., Results: Six ASIC3 gene polymorphisms were genotyped and only the rs2288646 polymorphism was found associated with insulin resistance. Significantly lower fasting serum insulin levels and homeostasis model assessment of insulin resistance (HOMA-IR) index and significantly higher quantitative insulin sensitivity check index (QUICKI) were observed in subjects carrying the rs2288646-A allele than in the non-carriers (P=0.028, P=0.047 and P=0.031, respectively) after adjustment for age, gender, and body mass index (BMI). Significantly lower frequencies of the rs2288646-A-containing genotypes were found in insulin resistant subjects (P=0.023). By multivariate analysis, rs2288646 genotypes, age, BMI, fasting plasma glucose level, C-reactive protein level, and soluble intercellular adhesive molecule 1 level, were all independently associated with HOMA-IR index and QUICKI (all, P<0.05)., Conclusions: Our analysis indicated an independent association between an ASIC3 genetic polymorphism and insulin resistance in Taiwanese., (Copyright 2010 Elsevier B.V. All rights reserved.)

Background: Cancer-related acute disseminated intravascular coagulation (DIC) is uncommon, but it is a severe complication resulting in a very dismal prognosis. Choosing the appropriate chemotherapy agents to treat the underlying cancer and stop the acute DIC process effectively, while avoiding chemotherapy-induced myelosuppression which may contribute to bleeding-related mortality, is difficult. Acute DIC in breast cancer is a rare condition and is not well studied. Therefore, we designed this study to determine the clinical characteristics and effective treatment for breast cancer patients with acute DIC., Patients and Methods: From March 1996 to November 2008, patients with histologically proven breast cancer who presented with acute DIC at National Taiwan University Hospital were retrospectively analyzed., Results: Sixteen patients were included in the study. Thirteen patients with breast cancer-related acute DIC were treated with various kinds of chemotherapy, one with tamoxifen, and two with supportive care only. Four patients responded to treatment; three of the responders received vinorelbine with high-dose 5-fluorouracil and leucovorin (HDFL), the other received vinorelbine with cisplatin. The median survival of the responders and non-responders was 13 months and 0.5 month (p<0.001). There were no grade 3 or 4 hematologic or non-hematologic toxicities in the patients receiving vinorelbine-HDFL., Conclusion: Vinorelbine plus HDFL is considered a safe and effective palliative treatment of choice for breast cancer patients with acute DIC. Further prospective study is warranted.

Empirical research has shown that parent-child conflict is positively related to poor adjustment in adolescents; however, the underlying processes have not been adequately examined. To explore the possible mediating pathways, reciprocal filial belief and perceived threat were chosen to represent two likely mechanisms accounting for how parent-child conflict harms adolescents' perceptions of their relationship with their parents and their self-perceptions within their cognitive-appraisal framework. The former operates by attenuating children's affection towards their parents and the latter by lowering their self-perceptions. This study also distinguishes internalizing from externalizing problems in order to examine whether lower reciprocal filial belief more strongly mediates the relation between conflict with parents and adolescents' externalizing problems and whether perceived threat more strongly mediates the relation between conflict with parents and adolescents' internalizing problems. Hypotheses are as follows: (1) the more parent-child conflict adolescents report, the less reciprocal filial belief they recognize, which, in turn, leads to more maladjustments, especially externalizing ones; (2) the more parent-child conflicts adolescents report, the more threat they perceive, which, in turn, leads to more maladjustments, especially internalizing ones. Participants consisted of 603 Taiwanese adolescents (226 males and 377 females) aged 15 to 19 (average age = 16.95; SD = 0.78). Structural equation modelling analyses confirmed the hypotheses. However, the three direct effects of conflict on internalizing problems, aggression, and deviant behaviour were still significant. In addition, a greater effect of the paternal than the maternal role on the link between conflict and attenuated reciprocal filial belief, and between perceived threat and internalizing problems, was identified. Implications for understanding the mediation processes responsible for all indirect effects, even the subsidiary ones, and the greater impact of conflict with the father than with the mother are discussed. Limitations of the study and considerations for future research are also addressed. La recherche empirique a indiqué que le conflit parent-enfant est positivement lié à une faible adaptation chez les adolescents; cependant, les processus sous-jacents n'ont pas été adéquatement examinés. Pour explorer les trajectoires de médiation possibles, la croyance filiale réciproque et la menace perçue ont été sélectionnées afin de représenter deux méchanismes plausiblement responsables de comment le conflit parent-enfant nuit aux peceptions des adolescents de leur relation avec les parents ainsi que de leurs auto-perceptions dans le cadre de leur évaluation cognitive. Le premier fonctionne en atténuant l'affection des enfants envers leurs parents et le dernier fonctionne en diminuant leurs auto-perceptions. Cette étude distingue aussi les problèmes internalisés de ceux qui sont externalisés dans le but d'examiner si la plus faible croyance de filiation réciproque médie fortement la relation entre le conflit avec les parents et les problèmes externalisés des adolescents et si la menace perçue médie plus fortement la relation entre le conflit avec les parents et les problèmes internalisés des adolescents. Les hypothèses sont les suivantes: (1) plus il y a de conflit parent-enfant rapporté par les adolescents, moins il y aura de croyance filiale réciproque reconnue par les adolescents qui, en revanche, mènera à plus de mésadaptation surtout externalisée. L'échantillon incluait 603 participants (226 mâles et 377 femelles) âgés entre 15 et 19 ans (âge moyen = 16.95; SD = 0.78). Une analyse de modélisation par équation structurelle a confirmé les hypotheses. Cependant, les trois effets directs du conflit sur les problèmes internalisés, sur l'agression et sur le comportement déviant étaient toujours significatifs. De plus, nous avons observé un plus grand effet du rôle paternel plus que maternel sur le lien entre le conflit et la croyance filiale réciproque atténuée ainsi qu'entre la menace perçue et les problèmes internalisés. Les implications pour la compréhension des processus de médiation responsables pour tous les effets indirects, même ceux qui sont accessoires, et le plus grand impact du conflit avec le père plus qu'avec la mère sont discutés. Les limites de l'étude et les considérations pour la recherche future sont aussi abordées. La investigación empírica ha demostrado que el conflicto entre padres e hijos está positivamente relacionado con pobre ajuste en adolescentes; no obstante, el proceso subyacente no ha sido examinado adecuadamente. Para explorar posibles caminos, se eligieron la creencia filial recíproca y la amenaza percibida con el objetivo de representar dos posibles mecanismos explicativos de cómo el conflicto padres-hijos daña la percepción de los adolescentes de su relación con los padres y su auto-percepción dentro de su marco de valoración cognitiva. El primero actúa atenuando el afecto de los hijos hacia los padres y el último bajando su auto-percepción. Este estudio también distingue los problemas interiorizados de los exteriorizados para examinar si la baja creencia filial recíproca es un mediador más fuerte de la relación entre el conflicto con los padres y los problemas exteriorizados de los adolescentes y si la amenaza percibida es un mediador más fuerte de la relación entre el conflicto con los padres y los problemas interiorizados de los adolescentes. Se han planteado las siguientes hipótesis: (1) cuanto más conflicto entre padres e hijos refieran los adolescentes, menor será el reconocimiento de la creencia filial recíproca, lo cual llevará a inadaptación, sobre todo, exteriorizada; (2) cuanto más conflicto entre padres e hijos refieran los adolescentes, mayor será la amenaza percibida, lo cual llevará a mayor inadaptación, sobre todo interiorizada. La muestra consistió de 603 adolescentes taiwaneses (226 chicos y 377 chicas) entre 15 y 19 años de edad (media edad = 16.95; DT = 0.78). Los análisis de los modelos de ecuaciones estructurales confirmaron las hipótesis. Sin embargo, los tres efectos directos de los conflictos en la internalización de los problemas, agresión y comportamiento anormal seguían siendo significativos. Además, se identificó un efecto mayor del rol paternal en comparación con el rol maternal en la relación entre conflicto y la creencia filial reciproca atenuada y entre la amenaza percibida y la internalización de los problemas. Se discuten las implicaciones para la comprensión del proceso mediador responsable de todos los efectos indirectos, incluso los subsidiarios, y el mayor impacto del conflicto con los padres que con las madres. Igualmente, se discuten las limitaciones del estudio y las consideraciones para la investigación futura.

Background: The relationships among the circulating levels of endothelial progenitor cells (EPC), stromal cell-derived factor (SDF)-1alpha, interleukin (IL)-10 and outcome were examined in patients with ST-segment elevation acute myocardial infarction (ST-se AMI) undergoing primary coronary angioplasty., Methods and Results: Circulating levels of IL-10, SDF-1alpha, and EPCs [defined by staining markers: CD31/CD34 (E(1)) and KDR/CD34 (E(2))] were examined by ELISA and flow cytometry, respectively. The IL-10 level was higher, whereas the circulating level of EPCs (E(1-2)) was lower (all P<0.05) in AMI patients than in normal subjects. Additionally, the SDF-1alpha level was significantly and independently predictive of an increased level of circulating EPCs (E(1-2)) (P<0.0001). Furthermore, patients with a high SDF-1alpha level (>1,500 pg/ml) had lower left ventricular performance, higher Killip score (defined as >or=3), and increased 30-day mortality than those with low SDF-1alpha level (or=3 or 30-day mortality) (P<0.01)., Conclusions: The serum SDF-1alpha level is independently predictive of an increased level of circulating EPCs (E(1-2)). E(2) and IL-10 are major independent predictors of 30-day MACO in ST-se AMI patients undergoing primary coronary angioplasty.

The consensus definition of autonomy in the psychological literature emphasizes self-governance through free volition, not separation or independence from others. Since the concept of self may differ cross-culturally, several researchers have tried to incorporate types of self into the notion of autonomy; however, only the dual model of autonomy has been able to do this while retaining an emphasis on volition. The dual model describes two distinct forms of autonomy-individuating and relating-each with superior function in a specific domain of individual functioning. Individuating autonomy represents a volitional capacity to act against social constraints and offers a route to achieve an independent self-identity by expressing individualistic attributes and distinctions. Relating autonomy represents a volitional capacity to act by emphasizing the harmony of self-in-relation-to-others, the quality of interpersonal relationships, and self-transcendence. These two forms of autonomy have been shown to coexist at the individual level in a Taiwanese sample. This study takes the next step, with a cross-cultural test of the coexistence and domain superiority hypotheses of individuating and relating autonomy. Participants included 306 college students from Taiwan and 183 college students from the United States. Structural equation modelling by multigroup analyses confirmed the cross-cultural equivalence of the two-factor individuating autonomy and relating autonomy measurement model. Across both samples the two forms of autonomy were shown to be mutually inclusive and not exclusive or independent. The domain-superior function of each form of autonomy was also confirmed cross-culturally; each form of autonomy has a dominant, but not necessarily exclusive, domain of functioning. Specifically, individuating autonomy was more associated with intrapersonal than interpersonal domain dependent variables, while relating autonomy was more associated with interpersonal than intrapersonal domain dependent variables. Limitations of the study and considerations for future research are discussed.

Background: Skin rash is the most common toxicity of epidermal growth factor receptor (EGFR)-targeted therapy. This study investigated the clinical and genetic factors associated with this skin rash., Methods: Fifty-two non-small cell lung cancer patients enrolled in a clinical trial of first-line gefitinib treatment were genotyped for EGFR intron 1 CA repeat ([CA]n) polymorphism and single nucleotide polymorphisms at G-216T, C-191A, and R521K. The severity of skin rash was correlated with the genotypic and clinicopathological features., Results: Seventeen patients (32.7%) developed grade 2-3 skin rashes within 4 weeks of treatment (early G2/3 rash). In the multivariate logistic regression analysis, only the [CA]n genotype was correlated with early G2/3 rash; and this relationship was modified by age. Early G2/3 rash developed in 21% of patients with homozygous long allele (19-22 repeats, L) genotype, 31% with heterozygous short allele (15-18 repeats, S)/L genotype, and 71% with S/S genotype, respectively. The estimated logarithm of odds ratio (lnOR) for early G2/3 rash, as compared to S/S genotype, for S/L genotype was -0.038 multiplied by age (P=0.011); and the lnOR for L/L genotype was -0.050 multiplied by age (P=0.004). Early G2/3 rash was correlated with tumor response in the multiple logistic regression analysis (P=0.027). However, the [CA]n genotype was not significantly correlated with tumor response (P=0.35)., Conclusions: EGFR [CA]n genotype appears to be a useful predictive marker of the development of skin rashes with gefitinib treatment.

Background: This study tested the hypothesis that the baseline plasma level of myeloperoxidase (MPO) independently predicts risk of patients with ST-segment elevation (ST-se) acute myocardial infarction (AMI) undergoing primary percutaneous coronary intervention (PCI)., Methods and Results: Plasma MPO levels in 128 patients were examined by ELISA. They were significantly higher in AMI patients than in normal controls (P<0.0001). Patients with a high plasma MPO level (>or=1,150 ng/ml) had significantly higher white blood cell counts, a higher plasma level of oxidized low-density lipoprotein, higher peak MB fraction of creatine kinase level, significantly lower left ventricular ejection fraction, and significantly higher incidence of 30-day composite major adverse clinical events (MACE) (defined as Killip score>or=3, re-infarction, repeat PCI, or 30-day mortality) than those patients with low plasma MPO level (<1,150 ng/ml) (all P<0.001). Multiple stepwise logistic regression analysis demonstrated that high plasma MPO level (>or=1,150 pg/ml) was the most independent predictor of 30-day MACE (P<0.0001)., Conclusions: Plasma MPO level is a major independent inflammatory predictor of 30-day MACE in ST-se AMI patients. Evaluation of the circulating MPO level might improve the prediction of unfavorable clinical outcome following AMI.

We have recently demonstrated that nuclear expression of BCL10 predicts Helicobacter pylori (HP) independence of early-stage gastric diffuse large B-cell lymphoma (DLBCL) with histologic evidence of mucosa-associated lymphoid tissue (MALT). In this study, we examined the role of B cell-activating factor of TNF family (BAFF) in mediating BCL10 nuclear translocation and HP independence of gastric DLBCL (MALT). We used immunohistochemistry and immunoblotting to measure the expression of BAFF, pAKT, BCL3, BCL10, and NF-kappaB. Transactivity of NF-kappaB was measured by electromobility shift assay. In lymphoma samples from 26 patients with gastric DLBCL (MALT), we detected aberrant expression of BAFF in 7 of 10 (70%) HP-independent and in 3 of 16 (18.8%) HP-dependent cases (P = .015). BAFF overexpression was associated with pAKT expression (P = .032), and nuclear expression of BCL3 (P = .014), BCL10 (P = .015), and NF-kappaB (P = .004). In B-cell lymphoma Pfeiffer cells, BAFF activated NF-kappaB and AKT; the activated NF-kappaB up-regulated BCL10, and the activated AKT caused formation of BCL10/BCL3 complexes that translocated to the nucleus. Inhibition of AKT by LY294002 (a PI3K inhibitor) blocked BCL10 nuclear translocation, NF-kappaB transactivity, and BAFF expression. Our results indicate that autocrine BAFF signal transduction pathways may contribute to HP-independent growth of gastric DLBCL (MALT).

Bortezomib, a proteasome inhibitor, has been clinically approved for the treatment of myeloma and lymphoma. Here, we report a differential effect of bortezomib on apoptosis in four hepatocellular carcinoma (HCC) cell lines and identify the major molecular event that determines sensitivity. Although bortezomib inhibited proteasome activity to a similar extent in all HCC cell lines, it showed differential effects on their viability: Huh-7 (IC(50) 196 nmol/L), Sk-Hep1 (IC(50) 180 nmol/L), Hep3B (IC(50) 112 nmol/L), and resistant PLC5 (IC(50) >1,000 nmol/L). Bortezomib caused cell cycle arrest at G(2)-M phase in all HCC cells tested whereas apoptotic induction was found only in sensitive cells but not in PLC5 cells. No significant bortezomib-induced NF-kappaB changes were noted in Huh-7 and PLC5. Bortezomib down-regulated phospho-Akt (P-Akt) in a dose- and time-dependent manner in all sensitive HCC cells whereas no alterations of P-Akt were found in PLC5. Down-regulation of Akt1 by small interference RNA overcame the apoptotic resistance to bortezomib in PLC5 cells, but a constitutively activated Akt1 protected Huh-7 cells from bortezomib-induced apoptosis. Furthermore, bortezomib showed suppression of tumor growth with down-regulation of P-Akt in Huh-7 tumors but not in PLC5 tumors. Down-regulation of P-Akt represents a major molecular event of bortezomib-induced apoptosis in HCC cell lines and may be a biomarker for predicting clinical response to HCC treatment. Targeting Akt signaling overcomes drug resistance to bortezomib in HCC cells, which provides a new approach for the combinational therapy of HCC.

Although acute pulmonary embolism (PE) may give rise to certain electrocardiographic (ECG) changes, most of these changes have low sensitivity and specificity and are of limited value alone in the diagnosis. Possible ECG changes with acute PE include S(1)Q(3)T(3) pattern, atrial tachyarrhythmias, incomplete right bundle-branch block, or negative T wave over right and midprecordial leads. Elevation of ST segment is a rare ECG manifestation with PE. We present a case of PE that went unrecognized in the emergency department (ED). The patient presented with anterior chest pain and dyspnea, and ECG showed ST elevation in V3 through V6. The differential diagnosis included acute coronary syndrome and acute pericarditis. Echocardiography revealed dilatation and dysfunction of right ventricle. Emergent computed tomographic pulmonary angiography showed bilateral pulmonary artery thrombosis and confirmed the diagnosis. Thrombolytic therapy with tissue plasminogen activator was initiated, and symptoms subsided dramatically. We proposed that the ST elevation in anterolateral leads might be the reciprocal changes of myocardial strain in the interventricular septum or right ventricle lateral wall. In a patient with such a critical condition and a confusing ECG, echocardiography played an important role in the diagnostic procedure, enabling prompt therapeutic intervention.

Background: Ischemic mitral regurgitation indicates a poor prognosis after acute myocardial infarction (AMI). This study addresses the clinical characteristics and contribution of ischemic mitral regurgitation to the midterm survival rate of patients following first AMI in our institution., Methods: Between January 2000 and December 2002, patients who underwent 2-dimensional color Doppler echocardiographic quantitation of ischemic mitral regurgitation within 30 days after first myocardial infarction (MI) were analyzed., Results: During the study period, 519 patients were enrolled (mean age 62.7 +/- 12 years, 76% men). The population was divided into 2 groups based on the degree of mitral regurgitation (MR). Group A included 440 subjects with no MR (n = 41), trivial MR (n = 188), and mild MR (n = 211). Group B included 79 subjects with moderate MR (n = 64), and severe MR (n = 15). Group B patients were more likely to be older (p < 0.05), women (p < 0.01), and nonsmokers (p < 0.01). Group B had a higher prevalence of inferior wall MI (p < 0.01) and lateral wall MI (p < 0.01). After 6 months of follow-up, 57 deaths had occurred (42 in Group A and 15 in Group B). Group B had a lower survival rate than Group A 180 days post-AMI (19% vs. 9.79%, p < 0.01)., Conclusions: Post-AMI patients with significant ischemic mitral regurgitation were more likely to be older, female, and nonsmokers. There was a positive association between the severity of ischemic mitral regurgitation and inferior MI and lateral wall MI. The severity of ischemic mitral regurgitation showed a significant inverse relationship with the mid-term post-MI survival rate.

Background: Acute disseminated intravascular coagulation (DIC) occurring in patients with advanced gastric cancer (AGC) is a rare entity with a dismal prognosis. Conventional cytotoxic chemotherapy is usually not possible. Preliminary reports have suggested that non-myelosuppressive weekly 24-h infusion of high-dose 5-fluorouracil (5-FU) and leucovorin (HDFL) may be helpful., Patients and Methods: Between 1994 and 2005, AGC patients who presented with acute DIC and were initially treated with HDFL (5-FU 2600 mg/m2 plus leucovorin 300 mg/m2, 24-h infusion weekly) were reviewed., Results: Nineteen such patients were identified. After treatment with HDFL for a median of 4 weeks, 14 patients showed a response of the acute DIC. Eight of them subsequently received HDFL-based combination chemotherapy. The median survivals for the whole group, the DIC responders, and the 8 patients receiving subsequent combination chemotherapy were 3, 6, and 8 months, respectively., Conclusion: HDFL, as a safe initial treatment for AGC patients with acute DIC, provides the opportunity for further aggressive chemotherapy.

Background: Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is characterized by multifocality of the tumors, which often scatter over the mucosa of the stomach and adjacent upper gastrointestinal tract, and is therefore theoretically not curable by surgical resection., Methods: We conducted a long-term follow-up study of 14 patients who received surgical treatment for gastric MALT lymphoma. Tissues from the surgical margins of the resected stomach were analyzed by polymerase chain reaction-based amplification of the complementarity-determining region 3 of the IgH gene for the presence of residual tumors. T (11;18)(q21;q21), a marker of Helicobacter pylori-independent MALT lymphoma, was analyzed by reverse transcription polymerase chain reaction. All living patients were restaged, and rebiopsied if suspicious lesions were identified., Results: At a median follow-up of 11.5 years, only 1 patient had evidence of tumor recurrence. Three patients with molecularly proven residual tumors in the surgical margin remained disease-free at 9.6 to 11.6 years. Five patients with t(11;18)(q21;q21) in the tumor cells were disease-free at 9.2 to 12.6 years., Conclusion: Our results indicate that surgical resection is a highly curative treatment for gastric MALT lymphoma, even for patients with residual tumor cells in the surgical margins, and for patients with H. pylori-independent tumors. A revisit of surgical treatment for gastric MALT lymphoma is mandatory.

Background: This study tested the hypothesis that in the acute phase of myocardial infarction (MI), the circulating level of soluble CD40 ligand (sCD40L), an index of platelet activation, is predictive of angiographic morphologic features that indicate high-burden thrombus formation (HBTF) in the infarct-related artery (IRA)., Methods and Results: This prospective study included 162 consecutive patients: 64 with HBTF and 98 with low-burden thrombus formation (LBTF). All patients had a Killip's classification

Background: An elevated C-reactive protein (CRP) level plays a crucial role in cell biology of atherosclerosis and unstable plaque formation. However, direct evidence of CRP involvement in atherosclerotic plaque development and vulnerability is still limited. We hypothesized that CRP is present in the vulnerable plaques and that CRP staining intensity is stronger in vulnerable plaques compared to stable plaques., Methods: Directional coronary atherectomy (DCA) was performed on 58 patients with stable angina (group 1) and 40 patients with unstable angina (group 2). White blood cell (WBC) counts were measured prior to DCA. Immunohistochemical staining (IHCS) was performed to localize CRP in the atheroma. Staining intensity in macrophages and extracellular tissue was graded as: 0, no staining; 1+, < 30%; 2+, 30%-60%; 3+, > 60%., Results: The IHCS demonstrated that CRP staining - 1+ intensity in macrophages and extracellular tissue were significantly higher in group 1 than in group 2 patients (all p values < 0.0001). However, IHCS demonstrated that CRP staining a 2+ intensity in macrophages and extracellular tissue were significantly higher in group 2 than in group 1 patients (all p values < 0.0001). By multiple analysis, only stable angina was independently associated with CRP staining : 1+ intensity in both macrophages and extracellular tissue (p < 0.0001), whereas unstable angina and WBC counts were independent predictors of CRP staining > or = 2+ intensity in both macrophages and extracellular tissue (p < 0.0001)., Conclusion: CRP was frequently found in atherosclerotic plaques of patients with unstable angina. This analytical finding suggests that CRP directly mediates an inflammatory process in the atherosclerotic plaque.

This study assessed the clinical activity and safety of twice-weekly paclitaxel and cisplatin combined with 5-fluorouracil and leucovorin (TP-HDFL) in patients with recurrent or metastatic esophageal squamous cell carcinoma. The regimen, composed of paclitaxel 35 mg/m 1-h intravenous infusion on days 1, 4, 8 and 11; cisplatin 20 mg/m 2-h intravenous infusion on days 2, 5, 9 and 12; and 5-flourouracil 2000 mg/m and leucovorin 300 mg/m 24-h intravenous infusion on days 5 and 12; repeated every 21 days. Forty-one patients (median age 51), 15 with de-novo metastatic disease and 26 with recurrent disease, were enrolled. Grades 3-4 neutropenia, leukopenia and diarrhea occurred in 37.8, 29.4 and 14.2% of cycles, respectively. One patient died of invasive fungal infection. Three complete responses, 13 partial response and 13 stable diseases were observed. The intent-to-treat response rate was 39.0% (95% confidence interval: 24-54). The median progression-free and overall survival were 6.3 and 8.9 months (range 1-50+), respectively. Twice-weekly TP-HDFL has the activity and toxicity profile similar to the previously reported same three-drug combination for advanced esophageal cancer.

Background: The prognostic value of interleukin (IL)-10 in patients with ST-segment elevation acute myocardial infarction (ST-se AMI) is currently unclear. The purpose of this study was to test whether the serum IL-10 level can predict 30-day mortality in patients with ST-se AMI undergoing primary percutaneous coronary intervention (PCI)., Methods and Results: The study design was a prospective cohort study of 250 consecutive patients with ST-se AMI of onset <12 h who were undergoing primary PCI. Blood samples for serum IL-10 levels were collected in the catheterization laboratory following vascular puncture. The serum IL-10 level was also evaluated in 20 healthy and 30 at-risk control subjects. The mean serum level of IL-10 was significantly higher in the AMI patients than in either group of controls (all values of p<0.0001). Patients with a high serum IL-10 level (> or = 30 pg/ml) had a significantly lower left ventricular ejection fraction (LVEF) (defined as <50%), significantly higher incidence of cardiogenic shock, higher white blood cell (WBC) count, more advanced congestive heart failure (defined as New York Heart Association function classification of > or = 3), and increased 30-day mortality than those patients with a low serum IL-10 level (<30 pg/ml) (all values of p<0.0001). Multiple stepwise logistic regression analysis demonstrated that a high serum IL-10 level, together with low LVEF, high WBC count and unsuccessful reperfusion, was independently predictive of increased 30-day mortality (all values of p<0.005)., Conclusion: In patients with ST-se AMI, the serum IL-10 level is a major independent predictor of 30-day mortality and should be used for early risk stratification following acute myocardial infarction.

Background: The prognostic value of interleukin (IL)-18 in patients with ST-segment elevation acute myocardial infarction (STEMI) is currently unclear. Thus, the purpose of this study was to test whether the circulating IL-18 level can predict prognosis in patients with STEMI undergoing primary percutaneous coronary intervention (PCI)., Methods and Results: A prospective cohort study was conducted with 267 consecutive patients with STEMI of onset <12 h who were undergoing primary PCI. Blood samples for plasma IL-18 level were collected in the catheterization laboratory following vascular puncture. The plasma IL-18 level was also evaluated in 25 healthy and 30 at-risk control subjects. The plasma level of IL-18 was significantly higher in acute myocardial infarction (AMI) patients than in both groups of control subjects (all p<0.0001). Patients with high plasma IL-18 level (> or =560 pg/ml) had significantly higher peak creatine kinase-MB levels, higher incidence of cardiogenic shock upon presentation, significantly lower left ventricular ejection fraction (LVEF), lower successful reperfusion and significantly higher incidence of 30-day composite major adverse clinical events (MACE) (advanced congestive heart failure > or = class 3 or 30-day mortality) than those patients with low plasma IL-18 level (<560 pg/ml) (all p<0.0001). Multiple stepwise logistic regression analysis demonstrated that high plasma IL-18 level (> or =560 pg/ml) along with low LVEF (<50%) and cardiogenic shock were the most independent predictors of 30-day MACE (p<0.0001)., Conclusions: In patients with STEMI, plasma IL-18 level is a major independent inflammatory predictor of 30-day MACE. Evaluation of circulating IL-18 might improve the prediction of unfavorable clinical outcomes following AMI.

We report here on three patients who underwent biventricular pacing (BVP) for severe heart failure and the problems encountered with pseudo-bipolar left ventricular (LV) lead configuration. With this configuration, right ventricular anode capture with simultaneous biventricular stimulation was noted at higher output during the isolated LV pacing mode in these patients, which forced us to program the LV pacing to unipolar configuration in one patient. The implication of this phenomenon in sequential BVP therapy is discussed.

We recently reported that low-grade mucosa-associated lymphoid tissue lymphoma (MALToma) and diffuse large B-cell lymphoma (DLBCL) with MALToma (DLBCL[MALT]) of stomach are equally responsive to H. pylori eradication therapy (HPET) and that H. pylori-independent status is closely associated with nuclear translocation of BCL10. However, co-existing MALToma and DLBCL components of gastric DLBCL(MALT) may respond differentially to HPET and the underlying mechanism remains unclear. Tumour tissue samples from 18 patients with microdissectable co-existing MALToma and DLBCL cells were studied. The clonality of lymphoma cells was examined by polymerase chain reaction-based amplification of the CDR3 region of the IgH gene and confirmed by DNA sequence analysis. BCL10 expression was determined by immunohistochemistry. Differential response of co-existing MALToma and DLBCL to HPET was defined as complete eradication of one component while the other component remained. Five (27.8%) of the 18 patients showed different IgH gene rearrangements in the two components and three (60%) of these five patients had differential response of MALToma and DLBCL to HPET. By contrast, 13 patients showed identical IgH gene rearrangements and only one (8%) of them had differential response of the two components to HPET (p = 0.044). Further, all four patients with differential response of MALToma and DLBCL to HPET showed nuclear expression of BCL10 in the H. pylori-independent component and cytoplasmic expression of BCL10 in the H. pylori-dependent component while the expression patterns of BCL10 were identical in both of these components in the 14 patients who had similar tumour response to HPET. We conclude that different clonality is a common reason for the differential response of co-existing MALToma and DLBCL of gastric DLBCL(MALT) to HPET and that immunohistochemical examination of BCL10 expression may help to identify the co-existence of these components., (Copyright 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

The impact the metabolic syndrome (MetS) components on the severity of insulin resistance (IR) has not been reported. We enrolled 564 subjects with MetS and they were divided into quartiles according to the level of each component; and an insulin suppression test was performed to measure IR. In males, steady state plasma glucose (SSPG) levels in the highest quartiles, corresponding to body mass index (BMI) and fasting plasma glucose (FPG), were higher than the other three quartiles and the highest quartiles, corresponding to the diastolic blood pressure and triglycerides, were higher than in the lowest two quartiles. In females, SSPG levels in the highest quartiles, corresponding to the BMI and triglycerides, were higher than in all other quartiles. No significant differences existed between genders, other than the mean SSPG levels in males were greater in the highest quartile corresponding to BMI than that in the highest quartile corresponding to HDL-cholesterol levels. The factor analysis identified two underlying factors (IR and blood pressure factors) among the MetS variables. The clustering of the SSPG, BMI, triglyceride and HDLcholesterol was noted. Our data suggest that adiposity, higher FPG and triglyceride levels have stronger correlation with IR and subjects with the highest BMI have the highest IR.

Background: To test the feasibility of incorporating a twice-weekly paclitaxel (Taxol) and cisplatin regimen into concurrent chemoradiotherapy (CCRT), followed by surgery, for patients with locally advanced esophageal cancer., Patients and Methods: Patients with operable T3N0-1M0 or T1-3N1M0 esophageal cancer were enrolled. The CCRT regimen included paclitaxel (35 mg/m2 1 h on days 1 and 4/week), cisplatin (15 mg/m2 1 h on days 2 and 5/week), and radiotherapy (2 Gy on days 1-5/week). When the accumulated radiation dose reached 40 Gy, the feasibility of esophagectomy was evaluated in all patients. In patients for whom esophagectomy was not feasible, CCRT was continued to a dose of 60 Gy., Results: The majority of 97 patients enrolled had squamous cell carcinoma on histology (95%) and T3N1 disease by endoscopic ultrasonographic staging (90%). All patients received CCRT to 40 Gy. Sixty-one patients underwent surgery, and 26 patients continued definitive CCRT to 60 Gy. The intention-to-treat pathological complete response rate was 25% [24/97, 95% confidence interval (CI) 16-33]. At a median follow-up of 25.3 months, the median progression-free and overall survival was 15.6 and 28.8 months, respectively. The most common grade 3/4 toxic effects were leukopenia (30%), thrombocytopenia (10%), and diarrhea (15%)., Conclusions: CCRT with a twice-weekly paclitaxel and cisplatin regimen followed by esophagectomy is an active treatment of locally advanced esophageal cancer.

Background: Weekly paclitaxel and infusional high-dose 5-fluorouracil/leucovorin (HDFL) are both effective regimens for metastatic breast cancer (MBC) patients., Patients and Methods: A study was designed using weekly paclitaxel 90 mg/m(2) 1-hour infusion followed by 2,000 mg/m(2) 5-fluorouracil plus 300 mg/m(2) leucovorin 24-hour infusion on days 1, 8 and 15, repeated every 28 days, in patients who had previously received a > or =1 regimen for MBC. The dose of paclitaxel was adjusted in each cycle according to toxicity., Results: A total of 182 cycles were given to 28 patients. The doses of paclitaxel needed to be reduced only in 22 (12%) cycles. Forty-five cycles were skipped or delayed more than 7 days, mostly due to neutropenia, infection, or neurotoxicity. Twenty-five patients were evaluable for response. Four had complete response, 13 partial response, seven stable disease, and two progressive disease. The response rate was 60.7% (95% CI: 42.6-78.8). Median survival was 18.1 months (95% CI: 11.4-24.9), and progression-free survival seven months., Conclusion: Weekly paclitaxel plus infusional HDFL is an active and well tolerated regimen for pretreated MBC patients.

Background: The present study tested the hypothesis that when administered in conjunction with a PercuSurge device for treatment of acute myocardial infarction (AMI), intracoronary (IC) administration of nitroprusside (NTP) is safe and superior to IC administration of NTP alone or nitroglycerin (NTG) for reversing slow-flow or no-reflow, both of which occur frequently during primary percutaneous coronary intervention (PCI)., Methods and Results: Sixty-two patients with ST-segment elevation AMI of <12 h duration undergoing primary PCI were enrolled. When the final Thrombolysis In Myocardial Infarction (TIMI) flow was normal (TIMI-3), NTG 200 microg was administered first, followed by (5 min later) NTP 100 microg via an intra-guiding catheter. When final TIMI flow was