Background & Aims The efficacy of treatment of Helicobacter pylori infection has decreased steadily due to increasing resistance to clarithromycin, metronidazole, and levofloxacin. Resistance to amoxicillin is generally low, and high intragastric pH increases the efficacy of amoxicillin, so we investigated whether a combination of a high-dose proton-pump inhibitor and amoxicillin (dual therapy) was more effective than standard first-line or rescue therapies in eradicating H pylori. Methods We performed a large-scale, multi-hospital trial to compare the efficacy of a high-dose dual therapy (HDDT) with that of standard therapies in treatment-naïve (n=450) or treatment-experienced (n=168) patients with H pylori infection. Treatment-naïve patients were randomly assigned to groups given HDDT (rabeprazole 20 mg and amoxicillin 750 mg, 4 times/day for 14 days; group A1), sequential therapy for 10 days (group B1), or clarithromycin-containing triple therapy for 7 days (group C1). Treatment-experienced patients were randomly assigned to groups given HDDT for 14 days (group A2), sequential therapy for 10 days (B2), or levofloxacin-containing triple therapy for 7 days (C2). H pylori infection was detected using the 13C–urea breath test. We evaluated factors associated with treatment outcomes. Results In the intention-to-treat treat analysis, H pylori was eradicated in 95.3% of patients in group A1 (95% confidence interval [CI], 91.9%–98.8%), 85.3% in B1 (95% CI, 79.6%–91.1%), and 80.7% in group C1 (95% CI, 74.3%–87.1%). Infection was eradicated in 89.3% of patients in group A2 (95% CI, 80.9%–97.6%), 51.8% in group B2 (95% CI, 38.3%–65.3%), and 78.6% (95% CI, 67.5%–89.7%). The efficacy of HDDT was significantly higher than that of currently recommended regimens, irrespective of CYP2C19 genotype. Bacterial resistance to drugs was associated with treatment failure. There were no significant differences between groups in adverse events or patient adherence. Conclusions HDDT is superior to standard regimens as empiric first-line or rescue therapy for H pylori infection, with similar safety profiles and tolerability. ClinicalTrials.gov no: NCT01163435.

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Hypoxia, a common environmental condition, influences cell signals and functions. Here, we compared the effects of hypoxia (1% oxygen) and normoxia (air) on chondrogenic differentiation of human mesenchymal stem cells (MSCs). For in vitro chondrogenic differentiation, MSCs were concentrated to form pellets and subjected to conditions appropriate for chondrogenic differentiation under normoxia and hypoxia, followed by the analysis for the expression of genes and proteins of chondrogenesis and endochondral ossification. MSCs induced for differentiation under hypoxia increased in chondrogenesis, but decreased in endochondral ossification compared to those under normoxia. MSCs induced for differentiation were more resistant to apoptosis under hypoxia compared to those under normoxia. The hypoxia-dependent protection of MSCs from chondrogenesis-induced apoptosis correlated with an increase in the activation of the phosphatidylinositol 3-kinase (PI3K)/Akt/FoxO pathway. These results suggest that the PI3K/Akt/FoxO survival pathway activated by hypoxia in MSCs enhances chondrogenesis and plays an important role in preventing endochondral ossification.

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Multiple drug resistance (MDR) is a problem that seriously reduces the efficacy of many chemotherapy agents. One mechanism for MDR is increased acidification of endocytic vesicles and increased cytosol pH, so weak base chemotherapeutic agents, including doxorubicin, are trapped in endocytic vesicles and exhibit a drug resistant phenotype. Treatments that selectively reverse this accumulation may therefore reverse the MDR phenotype. Photochemical internalization (PCI) is a novel technology developed for site-specific enhancement of the therapeutic efficacy of macromolecules by selective photochemical rupture of endocytic vesicles and consequent release of endocytosed macromolecules into the cytosol. This study evaluates PCI for release of doxorubicin from endocytic vesicles in MDR cells. Two breast cancer cell lines, MCF-7 and MCF-7/ADR (the latter resistant to doxorubicin), were selected. They were found equally sensitive to photochemical treatment with the photosensitiser TPPS 2a (disulfonated meso-tetraphenylporphine) and light. On exposure to doxorubicin alone, the IC 50 (drug concentration for 50% reduction in colony formation) was 0.1 lM for MCF-7 and 1 lM for MCF-7/ADR. After PCI (photochemical treatment followed by doxorubicin), the IC 50 concentration was 0.1 lM for both cell lines. Comparable changes were seen with assay of cell viability using 3-(4,5-dimethyltiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). On fluorescence microscopy in MCF-7/ADR cells, doxorubicin localised in granules identified as lysosomes. After PCI, doxorubicin was released into the cytosol and entered cell nuclei, as was seen in MCF-7 cells without PCI. In conclusion, PCI reversed the MDR phenotype of doxorubicin resistant breast cancer cells by endolysosomal release of the drug. The technique is a promising new approach to tackling the problem of MDR. ' 2006 Wiley-Liss, Inc.Key words: photodynamic therapy; photochemical internalization; doxorubicin resistant breast cancer cells Multiple drug resistance (MDR) is a major clinical problem that seriously reduces the efficacy of many chemotherapy agents. The establishment of a MDR phenotype by cancer cells is a result of complex molecular events. The most extensively studied mechanism is the over-expression of cell surface efflux pumps (the ABCtransporter family P-glycoprotein, MDR-associated protein, etc.) that can successfully purge a wide spectrum of chemotherapeutic agents from cells, 1 thereby decreasing their intracellular accumulation. 2 Other possible mechanisms are mutation of the DNA topoisomerase, or altered intracellular distribution of anticancer drugs. 2,3 Inhibition of ABC-transporters as a method to reverse MDR in cancer patients has been studied extensively, but the results have generally been disappointing. First-generation agents (e.g. cyclosporin, verapamil) were limited by unacceptable toxicity, whereas secondgeneration agents (e.g. valspodar, biricodar) had better tolerability, but were confounded by unpredictable pharmacokinetic interactions and interactio...