A phase I study of S-1 combined with weekly cisplatin for metastatic gastric cancer in an outpatient setting

A dose-escalation study was conducted for patients with metastatic gastric cancer to determine the recommended dose of weekly intravenous (i.v.) cisplatin combined with a fixed dose of a new oral dihydropyrimidine dehydrogenase-inhibitory fluoropyrimidine, S-1, on an outpatient basis. Secondary endpoints were to define the toxicity profile and to determine tumour responses. S-1 was fixed at a dose of 70 mg/m(2)/day and was administered for 2 weeks followed by a 1-week rest. Three dose levels of cisplatin (10, 15 and 20 mg/m(2)) were studied. Cisplatin was infused over 30 min on days 1 and 8. 20 patients were enrolled. No dose-limiting toxicities (DLTs) were recorded during the administration of cisplatin up to 20 mg/m(2), except for grade 3 diarrhoea and stomatitis in one patient at dose level 3. No grade 4 adverse events occurred. However, grade 2 gastrointestinal adverse reactions, such as nausea and anorexia, were seen in 7 of 13 patients at dose level 3 within the first two treatment cycles. This was determined to be the maximum acceptable level that would not negate the advantages observed with use of an oral drug such as S-1. An objective tumour response was seen at all dose levels, and the overall response rate in the 18 patients evaluated was 61%. A higher response rate of 78% was observed in 9 patients who had received no prior chemotherapy. Oral S-1 with weekly cisplatin is a feasible and promising combination regimen that is appropriate for an outpatient setting. A randomised phase II study comparing this combination with S-1 alone in chemo-nai;ve patients is warranted.     

Hospital-acquired pneumonia in Japan may have a better mortality profile than HAP in the United States: a retrospective study

The characteristics of hospital-acquired pneumonia (HAP) are not well documented. In the present study we investigated the severity and mortality, microbiological profile, and the value of Gram staining in culture-confirmed HAP in a Japanese hospital by retrospective review conducted at a Japanese university hospital. Only culture-confirmed cases with good specimen quality were included in the analysis. The clinical characteristics of HAP, as well as the causative organisms, were investigated. Furthermore, the prognostic ability of existing prediction rules were evaluated for prediction of overall mortality. Forty-two cases were enrolled in this analysis. The majority of patients were admitted to the ICU (61.9 %), and 40.5 % had ventilator-associated pneumonia (VAP). The 30-day mortality was 23.8 %, which is less than that reported in the United States. Factors commonly known to be associated with worse outcome in the USA did not appear to influence the mortality from HAP in Japan. The most frequent causative organisms were methicillin-resistant Staphylococcus aureus (MRSA), followed by Pseudomonas spp. Sensitivity and negative predictive value of Gram staining were 89.4 and 85.7 %, respectively. SMART-COP predicted 30-day mortality with an area under the ROC curve (AUC) >0.7. The characteristics of HAP in Japan differ from HAP reported in the USA. In addition to lower mortality, we found both fewer ICU cases and VAP. Gram staining of good-quality specimens demonstrated promising sensitivity to predict the causative organisms. SMART-COP predicted mortality with appropriate ROC curve (AUC).     

Development of a disease-specific instrument to measure quality of life in patients with alopecia areata

Alopecia areata (AA) is a common hair loss disorder that frequently follows a chronic course. Although AA is apparently associated with disturbance of quality of life (QoL), no disease-specific instrument to measure the QoL has been developed. This study was conducted to develop a disease-specific self-administered instrument to measure AA patients' QoL (AAQ). A two-step cross-sectional study was conducted. Items were generated from qualitative interviews with five patients with AA (two men and three women, age 28±6.4 years). Then, a preliminary questionnaire was produced and delivered to the patients (n=122). The AAQ was examined in terms of statistical performance. The AAQ included 7 items in the following three subscales: 'restriction of activity', 'concealment' and 'adaptation'. The reliability of internal consistency was fair with Cronbach's alpha coefficients of 0.59-81 for each subscale. Confirmatory factor analysis and correlation analysis demonstrated that the AAQ had good construct validity. Interestingly, the AAQ was only correlated with subjective severity scores as rated by the patients, but not with objective disease severity assessed by investigators.     

Lack of association between serum paraoxonase-1 activity and residual platelet aggregation during dual anti-platelet therapy

High residual platelet aggregability during thienopyridine treatment occurs because of low levels of the active drug metabolite, and is associated with an increased rate of major adverse cardiovascular events. Recent findings suggest that paraoxonase-1 (PON1) is a major determinant for clopidogrel efficacy. The aim of this study was to assess the impact of serum PON1 activity on platelet aggregability in thienopyridine-treated patients. In 72 patients receiving treatment with aspirin and ticlopidine after acute coronary syndrome, various laboratory data including the formation of platelet aggregations induced by agonists were compared with serum PON1 activities, measured as paraoxonase and homocysteine thiolactone hydrolase (HTLase). Serum paraoxonase activity was significantly associated with HTLase activity (R = 0.4487, P < 0.0001). These PON1 activities were not correlated with any parameters for platelet aggregation, hypertension, sleep apnea, and diabetes mellitus. In contrast, serum PON1 activities seemed to be involved in cardiac function, with brain natriuretic peptide and ejection fraction being significantly correlated with serum HTLase activity (R = − 0.2767, P = 0.0214) and paraoxonase activity (R = 0.2558, P = 0.0339), respectively. Paraoxonase activity also demonstrated a significant association with increased levels of ankle-brachial index (R = 0.267, P = 0.0255). Serum PON1 activities did not influence platelet aggregability during treatment with thienopyridine. However, they might modulate cardiac function after acute coronary syndrome and progression of atherosclerosis.     

Genetic Polymorphisms of 17β-Hydroxysteroid Dehydrogenase 3 and the Risk of Hypospadias

IntroductionHypospadias is a common congenital anomaly caused by incomplete fusion of urethral folds. Development of the urethra and external genital system in the male fetus is an androgen-dependent process. In this regard, enzymes 17β-hydroxysteroid dehydrogenase type 3 (17βHSD3, encoded by HSD17B3) and steroid 5α-reductase type 2 (encoded by SRD5A2) play crucial roles.AimTo investigate the possible associations between common polymorphisms in HSD17B3 as well as well-known V89L polymorphism in SRD5A2 and risk of hypospadias.MethodsA case-control study was performed between 1999 and 2005. There were 89 Japanese boys with hypospadias and 291 newborn controls. We genotyped HSD17B3?1999T>C, +10A>G, +20A>G, +139G>A (V31I), +913G>A (G289S), and SRD5A2+336G>C (V89L) polymorphisms by allelic discrimination assay. We measured mRNA expression of the wildtype G289 allele and the mutant S289 allele of the HSD17B3 gene in the transfected human fetal kidney HEK293 cells.Main Outcome MeasuresAssessment of hypospadias including its severity and HSD17B3 and SRD5A2 genes using DNA blood samples: allele and genotype distribution of single nucleotide polymorphisms in these two genes in cases and controls.ResultsIn our study, the risk of hypospadias was significantly higher in subjects carrying homozygous HSD17B3+913A (289S) alleles (odds ratio [OR]: 3.06; 95% confidence interval [CI]: 1.38–6.76). The risk of severe hypospadias was much higher in these subjects (OR: 3.93; 95% CI: 1.34–11.49). The mRNA expression levels of HSD17B3 G289 were higher than those of HSD17B3 S289 mutant (P < 0.001). In addition, the risk of severe hypospadias increased in boys carrying the SRD5A2+336C (89L) allele (OR: 3.19; 95% CI: 1.09–9.36).ConclusionsThese results suggest that the HSD17B3 G289S polymorphism may be a potential risk modifier for hypospadias. Our findings provide evidence that a certain genotype related to androgen production may potentiate risk of hypospadias. Sata F, Kurahashi N, Ban S, Moriya K, Tanaka KD, Ishizuka M, Nakao H, Yahata Y, Imai H, Kakizaki H, Nonomura K, and Kishi R. Genetic polymorphisms of 17β-hydroxysteroid dehydrogenase 3 and the risk of hypospadias.     

Parametric imaging using contrast-enhanced ultrasound with Sonazoid for hepatocellular carcinoma

Purpose  

To clarify the usefulness of parametric imaging using contrast-enhanced ultrasound (CE-US) with Sonazoid by comparing parametric images of hepatocellular carcinoma (HCC) with histopathological findings.     

Gene yerP, Involved in Surfactin Self-Resistance in Bacillus subtilis

Surfactin is a cyclic lipopeptide biosurfactant. Transposon mutagenesis was performed in Bacillus subtilis strain 168, and a surfactin-susceptible mutant, strain 801, was isolated. Analysis of the region of insertion revealed that yerP was the determinant of surfactin self-resistance. YerP had homology with the resistance, nodulation, and cell division (RND) family proton motive force-dependent efflux pumps only characterized in gram-negative strains. The yerP-deficient strain 802, in which the internal region of the yerP gene of B. subtilis strain 168 was deleted, showed susceptibility to acriflavine and ethidium bromide. When strain 802 was converted to a surfactin producer by introducing a functional sfp which encodes a 4'-phosphopantetheinyl transferase and is mutated in B. subtilis strain 168, this yerP-deficient strain produced surfactin, although surfactin production was significantly reduced. The expression of yerP was at its maximum at the end of the logarithmic growth phase and was not induced by surfactin. yerP is the first RND-like gene characterized in gram-positive strains and is supposed to be involved in the efflux of surfactin.     

Inhibitory effects of resin composite containing bactericide-immobilized filler on plaque accumulation

OBJECTIVE: Previously, we have reported that incorporation of the antibacterial monomer 12-methacryloyloxydodecylpyridinium bromide (MDPB) was effective in immobilizing bactericide in the resin matrix, and an antibacterial composite without release of the agent could be achieved. In this study, an attempt was made to increase the density of bactericide immobilized in composite, and the inhibitory effects of this modified antibacterial composite on plaque accumulation were determined, focusing on the reliability of the effects and the mechanisms to affect the plaque formation. METHODS: An experimental composite containing immobilized bactericide at 2.83% was prepared by the incorporation of MDPB into a prepolymerized resin filler of control composite, and elution of antibacterial components and inhibition of in vitro plaque accumulation by Streptococcus mutans were determined. The inhibitory effects of the experimental composite on the attachment, glucan synthesis and growth of S. mutans on the surface were also examined in addition to the comparison of surface roughness and hydrophobicity with controls. The results were analyzed using the Student's t-test. RESULTS: The experimental composite had reproducible inhibitory effects against plaque accumulation compared with control (p<0.05), although it showed no elution of unpolymerized MDPB. The plaque-inhibitory effect of the experimental composite was found to depend upon the ability to inhibit the attachment, glucan synthesis, and growth of bacteria on its surface as no significant differences in the surface characteristics were obtained between control and experimental composites (p>0.05). SIGNIFICANCE: It was indicated that the experimental composite containing bactericide-immobilized filler has the possibility to be used clinically with an effective anti-plaque property.     

Aortic lesions in aspergillosis: histopathological study of two autopsy cases

The involvement of the aorta in aspergillosis is relatively rare, and its histopathological features have not been described in detail. In two autopsy cases of invasive aspergillosis in immunologically compromised patients with hematological disorders, the aspergillotic lesions of the aorta showed different characteristic histopathological features depending on the three layers of aortic wall. Intimal lesions were formations of the mural thrombus composed of aggregates of numerous fungal hyphae arranged perpendicularly to the aortic wall. In the media, smooth muscle cells were completely necrotic (anemic infarct of the media), while the framework of elastic fibers was well preserved, with only a few fungal hyphae detected. In the adventitia, an intense, partly granulomatous chronic inflammatory change with fibrosis was observed in association with mycotic embolic occlusion of the vasa vasorum. These histopathological changes were considered to represent one of the typical tissue reaction patterns in the wall of an elastic artery in aspergillosis.