In Vitro and In Vivo Activities of CS-758 (R-120758), a New Triazole Antifungal Agent

The activity of CS-758 (R-120758), a new triazole antifungal agent, was evaluated and compared with those of fluconazole, itraconazole, and amphotericin B in vitro and with those of fluconazole and itraconazole in vivo. CS-758 exhibited potent in vitro activity against clinically important fungi. The activity of CS-758 against Candida spp. was superior to that of fluconazole and comparable or superior to those of itraconazole and amphotericin B. CS-758 retained potent activity against Candida albicans strains with low levels of susceptibility to fluconazole (fluconazole MIC, 4 to 32 microg/ml). Against Aspergillus spp. and Cryptococcus neoformans, the activity of CS-758 was at least fourfold superior to those of the other drugs tested. CS-758 also exhibited potent in vivo activity against murine systemic infections caused by C. albicans, C. neoformans, Aspergillus fumigatus, and Aspergillus flavus. The 50% effective doses against these infections were 0.41 to 5.0 mg/kg of body weight. These results suggest that CS-758 may be useful in the treatment of candidiasis, cryptococcosis, and aspergillosis.     

Incremental prognostic value of cardiac computed tomography angiography in asymptomatic aortic stenosis: Significance of aortic valve calcium score

Background

Cardiac computed tomography angiography (CCTA) provides the simultaneous evaluation of the aortic valve, myocardium, and coronary arteries. In particular, aortic valve calcium score (AVCS) can be accurately measured on the same scanning sequence used to measure coronary artery calcification, with no additional cost or radiation exposure. We sought to evaluate the prognostic value of CCTA measures, including AVCS, in asymptomatic aortic stenosis (AS).

Methods and results

Sixty-four initially asymptomatic patients with AS with a normal ejection fraction were prospectively enrolled and followed for median 29 (IQR = 18–50) months. During follow-up, 27 (42%) patients experienced cardiac events, including five cardiac deaths, eleven aortic valve replacements. Multivariate Cox proportional hazards analysis identified three CCTA measures as significant predictors of cardiac events: aortic valve area (per 0.1 cm² decrease; hazard ratio [HR]: 1.19, 95% confidence interval [CI]: 1.05–1.34); multi-vessel obstructive coronary artery disease (HR: 2.84, 95% CI: 1.10–7.32); and AVCS (per 100; HR: 1.09, 95% CI: 1.04–1.15). Kaplan–Meier analysis showed that patients with AVCS greater than or equal to the median value of 723 had significantly worse outcomes than those with AVCS less than 723 (p < 0.0001). The C-statistic value for cardiac events substantially increased when these CCTA measures were added to clinical characteristics plus echocardiographic peak transaortic velocity (0.913 vs. 0.702, p < 0.001).

Conclusions

In patients with asymptomatic AS, CCTA measures of valve area, coronary stenosis, and calcification severity provide independent and incremental prognostic value after accounting for the echocardiographic severity of stenosis.     

A Case of Early Gastric Cancer Manifesting as a Submucosal Tumor

Abstract: Gastric cancer manifesting as a submucosal tumor (SMT) is not common. A gastric barium meal and endoscopic studies performed on a 49-year-old male with epigastric pain, revealed an elevated lesion with bridging folds and central depression on the posterior wall of the lower body. An endoscopic ultrasonography (EUS) revealed a hypoechoic mass lesion within the submucosal layer. Due to an increase in the size of the tumor and its central depression during the subsequent year and a half, the patient was admitted for closer examination. Endoscopic biopsy material from the deeper layer, obtained by mucosal resection, revealed a poorly differentiated adenocarcinoma. Microscopic examination of the resected stomach showed a poorly differentiated adenocarcinoma within the submucosal layer, with considerable lymphocyte infiltration. Immunohistological examination disclosed marked T cell infiltration adjacent to the cancer cells. We suggest that considerable lymphocyte infiltration, particularly T cells, may have some role in the protective reaction against cancer cells. Our case was diagnosed as being cancer 18 months after the first endoscopic study. The biopsy material taken from the depression at the time of the first examination showed benign findings and a EUS revealed typical SMT. In the case of SMT shown by EUS to be a hypoechoic mass lesion in the submucosal layer, it is recommended that biopsy material be obtained from the deeper layer using methods available such as artificial ulcer formation.     

Ultrastructural analyses of pancreatic grafts preserved by the two-layer cold-storage method and by simple cold storage in University of Wisconsin solution

The two-layer cold storage method (TLM) using University of Wisconsin (UW) solution supplies sufficient oxygen to pancreatic grafts during preservation and extends pancreas preservation time to up to 96 h in the canine model. Simple cold storage in UW (UWM) on the other hand, preserves canine pancreas grafts for up to 72 h by preventing cell swelling, mainly because of its high osmotic pressure. The aim of this study is to analyze morphologically dog pancreatic grafts preserved by these two methods with their different mechanisms. Immediately after preservation of canine pancreata by TLM for 72 h and 96 h (group 1 and group 3, respectively), and by UWM for 72 h and 96 h (group 2 and group 4, respectively), tissue ATP levels were determined using high-performance liquid chromatography (HPLC), and detailed morphological analyses of intragraft components were performed using light- and electron microscopy. The mean areas of one mitochondrion and rough endoplasmic reticulum (RER) vacuolization were calculated by computer-graphic analyses using NIH image 1.62 f soft. The tissue ATP levels were significantly higher in groups 1 and 3 than groups 2 and 4 ( P < 0.05). Light microscopy demonstrated no marked difference among the 4 groups. By electron microscopy however, mitochondrial swelling and RER vacuolization were observed in acinar cells to various extents in the 4 groups. They were significantly more evident in group 2 than group 1 ( P < 0.05), and in group 4 than group 3 ( P < 0.05). In conclusion, TLM demonstrated excellent protection of intracellular organelles, mitochondria, and RER, up to 72-96 h. Well-maintained graft ATP levels in TLM groups may result in maintaining the integrity of intracellular organelle membranes as well as cellular membranes.     

Two-Stage Processing of Aesthetic Information in the Human Brain Revealed by Neural Adaptation Paradigm

Some researchers in aesthetics assume visual features related to aesthetic perception (e.g. golden ratio and symmetry) commonly embedded in masterpieces. If this is true, an intriguing hypothesis is that the human brain has neural circuitry specialized for the processing of visual beauty. We presently tested this hypothesis by combining a neuroimaging technique with the repetition suppression (RS) paradigm. Subjects (non-experts in art) viewed two images of sculptures sequentially presented. Some sculptures obeyed the golden ratio (canonical images), while the golden proportion were impaired in other sculptures (deformed images). We found that the occipito-temporal cortex in the right hemisphere showed the RS when a canonical sculpture (e.g. Venus de Milo) was repeatedly presented, but not when its deformed version was repeated. Furthermore, the right parietal cortex showed the RS to the canonical proportion even when two sculptures had different identities (e.g. Venus de Milo as the first stimulus and David di Michelangelo as the second), indicating that this region encodes the golden ratio as an abstract rule shared by different sculptures. Those results suggest two separate stages of neural processing for aesthetic information (one in the occipito-temporal and another in the parietal regions) that are hierarchically arranged in the human brain.     

Effect of the PPARG2 Pro12Ala Polymorphism and Clinical Risk Factors for Diabetes Mellitus on HbA1c in the Japanese General Population

Background

Although the peroxisome proliferator-activated receptor-γ2 (PPARG2) Pro12Ala gene variant is associated with diabetes mellitus, the associations and interactions of this polymorphism and known clinical risk factors with glycated hemoglobin (HbA1c) remain poorly understood. We investigated if carrying the Ala allele was inversely associated with HbA1c level and examined possible interactions.

Methods

This cross-sectional analysis used data collected from 1281 men and 1356 women aged 40 to 69 years who completed the baseline survey of the Japan Multi-Institutional Collaborative Cohort Study. PPARG2 polymorphism was determined by multiplex polymerase chain reaction (PCR)-based Invader assay. Multiple linear regression and ANCOVA were used to control for confounding variables (age, body mass index [BMI], energy intake, alcohol, smoking, physical activity, and family history of diabetes) and examine possible interactions.

Results

After adjustment, the Ala allele was significantly inversely associated with HbA1c in women but not in men. Older age, BMI, and family history of diabetes were associated with higher HbA1c in both sexes. When stratified by PPARG2 genotype, these associations were observed in subjects with the Pro12Pro genotype but not in Ala allele carriers. A significant interaction of genotype and BMI on HbA1c was observed in women. Older age, BMI, and family history of diabetes were significantly associated with high-normal HbA1c (≥5.7% NGSP), whereas PPARG2 polymorphism was not.

Conclusions

Although PPARG2 Pro12Ala polymorphism might attenuate associations between known risk factors and HbA1c level, it had a small effect on high-normal HbA1c, as compared with clinical risk factors, in the general population.Key words: peroxisome proliferator-activated receptor-γ2, polymorphism, glycated hemoglobin, interaction     

Serum hepatocyte growth factor and cancer mortality in an apparently healthy Japanese population

Background: In patients with cancer, hepatocyte growth factor (HGF) is elevated and is a predictor of prognosis. We investigated whether serum HGF was a predictive marker for cancer death in a population of community-dwelling Japanese.Methods: We studied 1492 apparently healthy Japanese adults who underwent health examinations in 1999. Those who reported a history of liver disease or malignancy on a baseline questionnaire were excluded, and plasma HGF was measured in the remaining 1470 participants, who were followed periodically for 10 years. Multivariate proportional hazards regression was used to estimate cancer mortality.Results: A total of 169 participants died during follow-up (61 from cancer, 32 from cerebrocardiovascular disease, and 76 from other diseases). Mean HGF at baseline was significantly higher among decedents than among survivors (0.26 ± 0.11 vs 0.23 ± 0.09 ng/ml, respectively; P < 0.01). The Cox proportional hazards model showed that age, systolic blood pressure, HGF (hazard ratio, 1.27; 95% CI, 1.06-1.52; P = 0.009), albumin level, smoking status, and creatinine were independent predictors of all-cause death. Age, HGF (hazard ratio, 1.31; 95% CI, 1.04-1.65; P = 0.02), and total cholesterol were independent predictive markers for cancer death.Conclusions: Serum HGF was a predictor of cancer death in an apparently healthy population of community-dwelling Japanese.     

Postoperative Elevation of Serum Pancreatic Secretory Trypsin Inhibitor

Postoperative transient elevations of serum pancreatic secretory trypsin inhibitor are reported for the first time. The elevations were independent of the surgical procedures or sites, and the maximum serum pancreatic secretory trypsin inhibitor was seen on the 2nd to 4th postoperative day. The elevation of pancreatic secretory trypsin inhibitor was significantly correlated with the length of the operation time and the volume of blood loss during the operation. The change of serum pancreatic secretory trypsin inhibitor was also significantly correlated with those of white blood cell count, alpha 1-antitrypsin, and fibrinogen.