Intestinal colonization and nosocomial spread of Clostridium difficile in pediatric cancer patients under long-term hospitalization

Clostridium difficile is a major causative agent of antimicrobial-associated diarrhea, and the leading cause of nosocomial diarrhea. We clarified intestinal colonization and nosocomial spread of C. difficile in pediatric cancer patients undergoing antineoplastic therapy during long-term hospitalization. Subjects were 10 children with pediatric malignant diseases admitted from November 2005 to December 2006, aged 5 to 15 years, who received antineoplastic agents. Stool specimens were examined at hospitalization, after each course of treatment with antineoplastic chemotherapy, and when symptoms such as diarrhea or fever occurred. While C. difficile was detected from stool specimens of 8 of 10 children during their hospital stay, 6 of these 8 children were negative for C. difficile on the day of their admission. These results demonstrate that the use of antimicrobial agents and antineoplastic agents lead to overgrowth of C. difficile in intestinal tract of pediatric cancer patients. Five of the 8 children carried toxin A-positive, toxin B-positive C. difficle and 2 were diagnosed with C. difficile-associated diarrhea (CDAD). This demonstrates that CDAD is not a rare infection in pediatric cancer patients. Nine C. difficile isolates from 8 children were analyzed by PCR ribotyping. Two isolates from 2 children were typed into the same type;banding patterns of the remaining 7 isolates from 6 children were unique.     

Mechanisms of the preventive effect of pilsicainide on atrial fibrillation originating from the pulmonary vein.

BACKGROUND: It has been shown that pilsicainide terminates atrial fibrillation (AF) by pharmacologic pulmonary vein (PV) isolation. However, whether it can prevent AF induction originating from the PV by the same mechanism is still uncertain. METHODS AND RESULTS: Rapid pacing from the left superior PV (LSPV) and the right atrial free wall (RAF) was performed to induce AF during electrical stimulation of both cervical vagal nerves in 6 anesthetized dogs and during the infusion of acetylcholine (ACh) in 8 isolated atria. Rapid pacing induced AF in all dogs, regardless of the pacing site, before pilsicainide. Pilsicainide (1 mg/kg) prevented AF during rapid pacing from the LSPV, with an impulse conduction block between the LSPV and the left atrial free wall (LAF). However, the same dose of pilsicainide did not prevent AF when pacing was performed from the RAF. Pilsicainide partially restored the action potential duration shortened by ACh infusion and prevented AF with an impulse conduction block at the LSPV-left atrial junction in all isolated preparations tested. CONCLUSION: The results suggest that (1) impulse conduction block at the LSPV-LA junction is the underlying mechanism of pilsicainide-induced prevention of vagally-induced AF originating from the LSPV and (2) pilsicainide is more effective at preventing AF originating from the LSPV than that from the RA.     

Anti-interleukin-6 receptor antibody therapy reduces vascular endothelial growth factor production in rheumatoid arthritis

OBJECTIVE: To investigate whether interleukin-6 (IL-6) is a regulator of vascular endothelial growth factor (VEGF) in rheumatoid arthritis (RA). METHODS: Serum VEGF levels in RA patients were assayed before and after 8 weeks or 24 weeks of maintenance therapy with humanized anti-IL-6 receptor monoclonal antibody (anti-IL-6R mAb). VEGF secreted by RA synovial fibroblasts cultured in the presence of IL-6, IL-1beta, and/or tumor necrosis factor alpha (TNFalpha) was measured. The inhibitory effect of anti-IL-6R mAb, recombinant IL-1 receptor antagonist (IL-1Ra), and anti-TNFalpha mAb on VEGF production was also examined. RESULTS: Serum VEGF levels in RA patients before anti-IL-6R mAb therapy were significantly higher than those in healthy controls (P < 0.0005). Treatment of RA patients with anti-IL-6R mAb normalized serum VEGF levels. In the in vitro study, IL-6 and IL-1beta each induced a slight amount of VEGF production in synovial cells, but TNFalpha did not. Although VEGF-inducing activity of these cytokines was not remarkable when they were added alone, IL-6 acted synergistically with IL-1beta or TNFalpha to induce VEGF production. There was no synergistic effect between IL-1beta and TNFalpha. In the presence of all of these cytokines, anti-IL-6R mAb eliminated the synergistic effect of IL-6, IL-1beta, and TNFalpha, while IL-1Ra or anti-TNFalpha mAb did not. CONCLUSION: Anti-IL-6R mAb therapy reduced VEGF production in RA. IL-6 is the pivotal cytokine that induces VEGF production in synergy with IL-1beta or TNFalpha, and this may be the mechanism by which IL-6 blockade effectively suppresses VEGF production in synovial fibroblasts.     

Effects of calcium antagonists on hepatic and systemic hemodynamics in awake portal hypertensive rats

The effects of the calcium antagonists diltiazem and nicardipine on portal pressure and splanchnic blood flow were studied in awake, unrestrained portal hypertensive rats. Portal hypertension was induced in rats by partial portal vein ligation. Hemodynamic measurements were done using the radiolabeled microsphere technique. In portal veinligated and sham-operated rats, intraarterial diltiazem and nicardipine reduced mean arterial pressure. No significant changes, however, were observed in portal pressure and cardiac index. In portal vein-ligated rats, diltiazem and nicardipine increased portal tributary blood flow. Portal tributary vascular resistance was also significantly decreased. The decrease in the hepatocollateral vascular resistance prevented an increase in portal pressure. In sham-operated rats, these changes were not observed. It is possible that the vascular responses to calcium antagonists are altered in portal vein-ligated rats. These findings demonstrate that the hemodynamic effects of calcium antagonists occur at two levels. First, the increase in portal tributary blood flow appears to be a selective effect on portal tributary vascular resistance. Secondly, the portal pressure does not increase in parallel with the increase in portal tributary blood flow because of a similar reduction in portocollateral vascular resistance.     

Silencing of LRRFIP1 enhances the sensitivity of gemcitabine in pancreatic cancer cells by activating JNK/c-Jun signaling

BackgroundThe epithelial-mesenchymal transition (EMT) in cancer cells has been shown to closely associate with the survival and drug resistance of cancer cells. We recently provided evidence that Wnt signal activator leucine-rich repeat in flightless-1-interacting protein 1 (LRRFIP1) regulates EMT in pancreatic cancer. LRRFIP1 silencing inhibits the translocation of β-catenin to the nucleus, which led to reverse EMT in cancer cells. It was suggested that LRRFIP1 was implicated in gemcitabine sensitivity by regulating EMT signaling.MethodsGemcitabine chemosensitivity was investigated in LRRFIP1-knockdown pancreatic cancer cells (PANC-1 and MIA Paca-2). In addition, the effects of LRRFIP1 knockdown on JNK/SAPK (stress activated-protein kinase) signaling and apoptosis were evaluated.ResultsLRRFIP1 silencing accelerates gemcitabine-induced caspase activity and cell death in pancreatic cancer cells. It was also revealed that gemcitabine-induced phosphorylation of c-Jun N-terminal kinase (JNK) and c-Jun were increased in LRRFIP1 knockdown cells. The activation of JNK/c-Jun in LRRFIP1-knockdown cells was significantly diminished by the inhibition of Rac activity. It was confirmed that the acquisition of gemcitabine sensitivity by LRRFIP1 silencing largely depends on the stimulation of JNK/SAPK (stress activated-protein kinase) signaling.ConclusionsOur findings suggest that reversing EMT and transient activation of JNK might be essential for the gemcitabine sensitivity in LRRFIP1 knockdown pancreatic cancer cells. Our discoveries highlight the potential role of LRRFIP1 in the chemosensitivity related to the regulation of EMT signaling.     

Impact of graft-versus-host disease on outcomes after allogeneic hematopoietic cell transplantation for adult T-cell leukemia: a retrospective cohort study

Allogeneic hematopoietic cell transplantation (HCT) is an effective treatment for adult T-cell leukemia (ATL), raising the question about the role of graft-versus-leukemia effect against ATL. In this study, we retrospectively analyzed the effects of acute and chronic graft-versus-host disease (GVHD) on overall survival, disease-associated mortality, and treatment-related mortality among 294 ATL patients who received allogeneic HCT and survived at least 30 days posttransplant with sustained engraftment. Multivariate analyses treating the occurrence of GVHD as a time-varying covariate demonstrated that the development of grade 1-2 acute GVHD was significantly associated with higher overall survival (hazard ratio [HR] for death, 0.65; P = .018) compared with the absence of acute GVHD. Occurrence of either grade 1-2 or grade 3-4 acute GVHD was associated with lower disease-associated mortality compared with the absence of acute GVHD, whereas grade 3-4 acute GVHD was associated with a higher risk for treatment-related mortality (HR, 3.50; P < .001). The development of extensive chronic GVHD was associated with higher treatment-related mortality (HR, 2.75; P = .006) compared with the absence of chronic GVHD. Collectively, these results indicate that the development of mild-to-moderate acute GVHD confers a lower risk of disease progression and a beneficial influence on survival of allografted patients with ATL.     

Severe insulin allergy successfully treated with continuous subcutaneous insulin infusion

Cervical necrotizing fasciitis and a descending mediastinal abscess of the neck following acute epiglottitis, life-threatening complications, is reported in a 43-year-old man with DM. The bacterial culture showed Peptostreptococcus anaerobius. The patient recovered after surgical debridement and broad-spectrum antibiotics therapy.     

Lymph Nodes Metastasis is a Risk Factor for Bone Metastasis From Extrahepatic Cholangiocarcinoma

Background/Aims: The rate and site of bone metastasis from cholangiocarcinoma as well as the prognosis are unclear. Therefore, we intend to make a comparative review of the background to bone metastasis, examine a high-risk group for bone metastasis and use the data towards the improvement in quality of life. Methodology: We studied 200 cases of cholangiocarcinoma resected in our division from January 2003 to April 2010. Results: Bone metastasis was confirmed in four cases (2.0%). The survival period after the diagnosis of bone metastasis ranged from 2.9 months to 21.6 months and the average was 6.7 months. We studied histopathological findings of bone metastasis, lymph node metastasis, lymphatic invasion, blood vessel invasion and perineural invasion (ly, v and pn) and found that all of four bone metastasis cases were positive for lymph node metastasis which was a statistically significant factor affecting bone metastasis. Conclusions: Since the number of cases we studied is small, it is difficult to determine whether lymph node metastasis is a risk factor for bone metastasis; however, we think it is necessary to take the probability of bone metastasis into consideration when we provide medical care to patients positive for lymph node metastasis.     

ASP6537, a novel highly selective cyclooxygenase-1 inhibitor,exerts potent antithrombotic effect without “aspirin dilemma”

Introduction

Aspirin inhibits both the cyclooxygenase (COX)-1-dependent production of thromboxane A₂ (TXA₂) in platelets and COX-2-dependent production of anti-aggregatory prostaglandin I₂ (PGI₂) in vessel walls, resulting in “aspirin dilemma.” Our objective is to investigate whether ASP6537 can overcome aspirin dilemma and exert a potent antithrombotic effect without a concurrent ulcerogenic effect.

Methods

We evaluated the inhibitory effects of ASP6537 on recombinant human COX-1 (rhCOX-1) and rhCOX-2 activities using a COX-1/2 selectivity test. To determine whether ASP6537 induces aspirin dilemma, we examined the effects of ASP6537 on in vitro TXA₂ and PGI₂ metabolite production from platelets and isolated aorta of guinea pigs, and on plasma concentrations of TXA₂ and PGI₂ metabolites in aged rats. Finally, we evaluated the antithrombotic effects and ulcerogenic activity of ASP6537 using an electrically induced carotid arterial thrombosis model and a gastric ulcer model in guinea pigs.

Results

The IC₅₀ ratios of rhCOX-2 to rhCOX-1 for ASP6537 and aspirin were > 142,000 and 1.63 fold, respectively. ASP6537 inhibited TXA₂ production more selectively than aspirin in in vitro and in vivo TXA₂/PGI₂ production studies. ASP6537 exerted a significant antithrombotic effect at ≥ 3 mg/kg, while aspirin tended to inhibit thrombosis at 300 mg/kg but it was not statistically significant. Further, ASP6537 did not induce ulcer formation at 100 mg/kg, whereas aspirin exhibited an ulcerogenic effect at doses of ≥ 100 mg/kg.

Conclusions

ASP6537 functions as a highly selective COX-1 inhibitor with a superior ability to aspirin for normalizing TXA₂/PGI₂ balance, and exerts antithrombotic effect without ulcerogenic effect.