Glucocorticoid receptor and serum‐ and glucocorticoid‐induced kinase‐1 in esophageal adenocarcinoma and adjacent Barrett's esophagus

Barrett's esophagus (BE) is a consequence of gastroesophageal reflux disease and is predisposed to esophageal adenocarcinoma (EAC). EAC is an exemplar model of inflammation‐associated cancer. Glucocorticoids suppress inflammation through glucocorticoid receptor (GR) and serum‐ and glucocorticoid‐induced kinase‐1 (Sgk1) expressions. Therefore, we immunolocalized GR and Sgk1 in EAC and the adjacent BE tissues and studied their association with clinical disease course in 87 patients with EAC who underwent surgical resection (N = 58) or endoscopic submucosal dissection (N = 29). Low GR and Sgk1 expressions in adjacent BE tissues were associated with adverse clinical outcomes (P = 0.0008 and 0.034, respectively). Patients with low Sgk1 expression in EAC cells exhibited worse overall survival (P = 0.0018). In multivariate Cox regression analysis, low GR expression in the adjacent nonmalignant BE tissues was significantly associated with worse overall survival (P = 0.023). The present study indicated that evaluation of GR and Sgk1 expressions in both the EAC cells and adjacent nonmalignant BE tissues could help to predict clinical outcomes following endoscopic and surgical treatments. In particular, the GR status in BE tissues adjacent to EAC was an independent prognostic factor.     

A quinol peroxidase inhibitor prevents secretion of a leukotoxin from Aggregatibacter actinomycetemcomitans

Takashima E, Yamada H, Yajima A, Shiomi K, ōmura S, Kiyoshi K. A quinol peroxidase inhibitor prevents secretion of a leukotoxin from Aggregatibacter actinomycetemcomitans. J Periodont Res 2009; doi: 10.1111/j.1600‐0765.2009.01211.x. © 2009 John Wiley & Sons A/S Background and Objective: Quinol peroxidase (QPO) catalyzes peroxidase activity using quinol in the respiratory chain as a substrate. Quinol peroxidase is essential for the secretion of leukotoxin (LtxA), which destroys leukocytes and erythrocytes in humans and is one of the major virulence factors of Aggregatibacter actinomycetemcomitans, which is associated with localized aggressive periodontitis. In the present study, we aimed to find a highly potent QPO inhibitor to attenuate the virulence of A. actinomycetemcomitans. Material and Methods: For screening of QPO inhibitors, QPO activity was measured kinetically by SpectraMax Plus with 96‐well UV plates. Three hundred compounds in the Kitasato Institute for Life Sciences Chemical Library were screened. Secretion of LtxA in the culture supernatant was examined by sodium dodecyl sulfate–polyacrylamide gel electrophoresis. Cytotoxicity against human promyelocytic leukemia cell line (HL‐60) cells from the culture supernatant was measured by Trypan Blue exclusion test. Results: The present study characterized ascofuranone as a highly potent inhibitor of QPO (K_i = 9.557 ± 0.865 nm ). Ascofuranone inhibited secretion of LtxA by A. actinomycetemcomitans in a dose‐dependent manner, making A. actinomycetemcomitans less pathogenic to HL‐60 cells. Conclusion: Quinol peroxidase inhibitors are promising candidates as alternative drugs for the treatment and prevention of the onset of localized aggressive periodontitis. Using ascofuranone as a seed compound, further study of QPO inhibitors could provide novel chemotherapeutic strategies for controlling localized aggressive periodontitis.     

Cross‐sectional analysis of germline BRCA1 and BRCA2 mutations in Japanese patients suspected to have hereditary breast/ovarian cancer

The prevalence of BRCA1/2 germline mutations in Japanese patients suspected to have hereditary breast/ovarian cancer was examined by a multi‐institutional study, aiming at the clinical application of total sequencing analysis and validation of assay sensitivity in Japanese people using a cross‐sectional approach based on genetic factors estimated from personal and family histories. One hundred and thirty‐five subjects were referred to the genetic counseling clinics and enrolled in the study. Full sequencing analysis of the BRCA1/2 gene showed 28 types of deleterious mutations in 36 subjects (26.7%), including 13 types of BRCA1 mutations in 17 subjects (12.6%) and 15 types of BRCA2 mutations in 19 subjects (14.1%). Subjects were classified into five groups and 22 subgroups according to their personal and family history of breast and/or ovarian cancer, and the prevalence of deleterious mutations was compared with previously reported data in non‐Ashkenazi individuals. Statistical analysis using the Mantel‐Haenszel test for groups I through IV revealed that the prevalence of Japanese subjects was significantly higher than that of non‐Ashkenazi individuals (P = 0.005, odds ratio 1.87, 95% confidence interval 1.22–2.88). Family history of the probands suffering from breast cancer indicated risk factors for the presence of deleterious mutations of BRCA1/2 as follows: (1) families with breast cancer before age 40 within second degree relatives (P = 0.0265, odds ratio 2.833, 95% confidence interval 1.165–7.136) and (2) families with bilateral breast cancer and/or ovarian cancer within second degree relatives (P = 0.0151, odds ratio 2.88, 95% confidence interval 1.25–6.64). (Cancer Sci 2008; 99: 1967–1976)     

Therapeutic results using high-dose-rate intracavitary irradiation in cases of cervical cancer

A comparison of the 5-year relative survival rates has been made between cases of cancer of the uterine cervix treated with 226Ra low-dose-rate intracavitary irradiation and those treated with 60Co high-dose-rate intracavitary irradiation (using the remote afterloading system, RALS). External irradiation using LINAC was also administered in both groups. The 5-year relative survival rates of the low-dose-rate cases were 82.6, 55.4, 49.0, and 18.2% in stage I, II, III, and IV cases, respectively, whereas they were 97.4, 55.1, 56.8, and 29.0% in the respective high-dose-rate cases. The differences between the two groups were not statistically significant. Delayed radiation complications of the rectum were frequent in both groups (approximately 14%) and those of the urinary bladder were somewhat less frequent (approximately 8%). The incidence of such complications did not differ significantly between the two groups.     

Usefulness of color Doppler sonography for assessing hemodynamics of free flaps for head and neck reconstruction

This report focuses on the monitoring of intraoperative and postoperative hemodynamics of free flaps for repair of head and neck defects by color Doppler sonography (CDS). The study group included 20 patients with head and neck cancer who underwent resection and reconstruction with free flaps. The hemodynamics in the feeding arteries of the flaps were measured during the following six stages: before surgery, immediately after microvascular anastomosis, and on postoperative days 1, 3, 5, and 7. The pulsatility index (PI) was used as the index for measuring changes in hemodynamics over time. Grafts showed the maximal PI immediately after vascular anastomosis. PI decreased over 3 to 7 days. Of the 20 patients, 1 patient in whom the hypopharynx was reconstructed with the radial forearm flap developed venous occlusion. This was diagnosed during the early stage using CDS, allowing the flap to be saved. CDS proved to be very useful for real-time observation of the hemodynamics in free flaps.     

A case presenting brain abscess with multiple infectious aneurysms

We report a case presenting a brain abscess with multiple infectious aneurysms. A 59-year-old man was transferred to our hospital suffering from left hemiparesis. MRI demonstrated a huge mass in the right frontal lobe with marked brain edema in the surrounding area. Diffusion-weighted image revealed heterogenous intensity, which is not typical in cases of brain abscess. Surgical removal was planned, and preoperative angiography was performed. Angiography demonstrated aneurysms at the distal branch of both the right middle cerebral artery and the anterior cerebral artery. These aneurysms were surgically resected, and the abscess was totally removed. Postoperative course was uneventful. Left hemiparasis was resolved, and there was no ischemic lesion seen on postoperative MRI. In the treatment of brain abscess, stereotactic aspiration has recently been preferred to removal by craniotomy. We conclude that cerebral angiography might be necessary to evaluate cerebrovascular complications including infectious aneurysms, in cases presenting atypical findings in neuroimaging study.     

Direct in vivo evidence of a vascular statin: a single dose of cerivastatin rapidly increases vascular endothelial responsiveness in healthy normocholesterolaemic subjects

AIMS: HMG-CoA reductase inhibitors (statins) have been demonstrated to have in vitro vascular effects. The aim of this study was to determine whether statins actually have in vivo vascular effects independent of their cholesterol-lowering effect. METHODS: We investigated the effect of a single dose of cerivastatin on vascular endothelial function by measuring flow-mediated dilatation of the brachial artery on ultrasound in 30 healthy volunteers with normal serum cholesterol concentrations. They were randomized to either placebo group (n = 15) or cerivastatin group (n = 15), and flow-mediated dilatation and endothelium-dependent dilatation were evaluated at before and 1 h, 3 h, 6 h, and 12 h after administration of placebo or cerivastatin. RESULTS: There were no differences in total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, malondialdehyde-LDL, and high-sensitivity C-reactive protein before and after administration of placebo or cerivastatin. Cerivastatin significantly increased flow-mediated dilatation at 3 h (P < 0.001), and this increase rapidly returned to the baseline level 6 h after administration. Endothelium--independent dilatation of brachial artery was not altered. CONCLUSIONS: A single dose of cerivastatin increased vascular endothelial responsiveness. Our data suggest that cerivastatin has a direct effect on the blood vessels that is independent of its lipid-lowering effect, and thus can be considered as a vascular statin.     

Dehydrotrametenolic acid induces preadipocyte differentiation and sensitizes animal models of noninsulin-dependent diabetes mellitus to insulin

We recently discovered that the triterpene acid compound dehydrotrametenolic acid promotes adipocyte differentiation in vitro and acts as an insulin sensitizer in vivo. This natural product has been isolated from dried sclerotia of Poria cocos WOLF (Polyporaceae), a well-known traditional Chinese medicinal plant. We examined the effects of dehydrotrametenolic acid on plasma glucose concentration in obese hyperglycemic db/db mice. Dehydrotrametenolic acid can reduce hyperglycemia in mouse models of noninsulin-dependent diabetes mellitus (NIDDM) and act as an insulin sensitizer as indicated by the results of the glucose tolerance test. These terpenoids and thiazolidine type of antidiabetic agents such as Ciglitazone, although structurally unrelated, share many biological activities: both induce adipose conversion, activate peroxisome proliferator-activated receptor gamma (PPAR gamma) in vitro, and reduce hyperglycemia in animal models of NIDDM. Dehydrotrametenolic acid is a promising candidate for a new type of insulin-sensitizing drug. This finding is very important for the development of insulin sensitizers that are not of the thiazolidine type.     

Tunicamycin inhibits NMDA and AMPA receptor responses independently of N-glycosylation

In a whole-cell patch-clamp configuration, currents through N-methyl- -aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor channels were monitored in cultured rat hippocampal neurons, and those currents were depressed to 25 and 28% of basal levels, respectively, by 3-min treatment with tunicamycin (10 μM), an inhibitor of protein N-glycosylation. Tunicamycin (10 μM) reduced amplitude of population spikes elicited in the dentate gyrus of rat hippocampal slices, reaching 78% of basal levels 60 min after the beginning of treatment, and long-term potentiation (LTP) of the perforant path was never induced in the presence of tunicamycin. Tunicamycin, thus, appears to serve as a modulator for NMDA and AMPA receptors, regardless of N-glycosylation, thereby inhibiting neurotransmission and LTP in the dentate gyrus.     

The effect of paroxetine on Taijinkyofusho: a report of three cases

Taijinkyofusho is a culture-related syndrome conceptualized in Japan. While previous studies suggest its psychopathological similarities to social phobia and obsessive-compulsive disorder, introspection regarding shame and low self-esteem is particularly linked to Japanese culture. We present three cases of Taijinkyofusho: Cases 1 and 2 show neurotic features while Case 3 shows delusional thoughts. Paroxetine was used for treatment but was productive in only the first two cases. Phobic and obsessive thought patterns were altered in Cases 1 and 2, suggesting that the significant core symptoms were responding to the treatment. In the future, large-scale pharmacological studies will be necessary to investigate treatment outcomes Taijinkyofusho. Such studies would contribute to providing information for effective treatment as well as for examining relationships between Taijinkyofusho and related disorders.