Interleukin-4 stimulates proliferation of endometriotic stromal cells

Several lines of evidence indicate that the Th2 immune response is associated with endometriosis. Although an increased concentration of interleukin (IL)-4, a typical Th2 cytokine, has been reported in endometriotic tissues, the implication of this for endometriosis has not been determined. To investigate a possible role of IL-4 in the development of endometriosis, we examined the presence of IL-4-producing cells in endometriotic tissues and the effect of IL-4 on proliferation of endometriotic stromal cells. Endometriotic stromal cells were isolated from endometriotic tissues obtained from women undergoing surgery for endometrioma. Immunohistochemistry of endometriotic tissues revealed that IL-4-positive cells were abundant in the stroma. The effect of IL-4 on proliferation of endometriotic stromal cells was studied using cell counting and BrdU incorporation assays. IL-4 (0.1 to 10 ng/ml) significantly increased cell number and BrdU incorporation in a dose-dependent manner, and the proliferative effect of IL-4 was inhibited by anti-IL-4 receptor antibody. IL-4-induced activation of mitogen-activated protein kinases in endometriotic stromal cells was examined by Western blotting. IL-4 induced phosphorylation of p38 mitogen-activated protein kinase, stress-activated protein kinase/c-Jun kinase, and p42/44 mitogen-activated protein kinase and inhibitors of these kinases suppressed IL-4-induced proliferation of endometriotic stromal cells. These findings suggest that proliferation of endometriotic stromal cells induced by locally produced IL-4 is involved in the development of endometriosis.     

Measurement of the apparent diffusion coefficient in the liver: is it a reliable index for hepatic disease diagnosis?

Purpose The aim of this study was to determine the validity of the hepatic apparent diffusion coefficient (ADC) measurement. The influence of differences in measured location and administration of Buscopan (hyoscine butylbromide) for ADC were assessed. Materials and methods SENSE-DWI (b = 0, 500) was obtained before and after Buscopan administration to 30 patients suspected of having a liver tumor. In this sequence, respiration gating was employed, but cardiac triggering was not. ADC measurement was performed in the hepatic parenchyma of both right and left lobes in selected slices. A statistical analysis was performed to estimate the correlation among ADC, measured location, Buscopan, and pulse rate. The images were visually evaluated to categorize the subcardiac signal loss in the left lobe. Results The ADC showed higher values in the left lobe than in the right lobe in both pre- and postloaded studies (P < 0.001). In a comparison between ADCs in the pre- and postloaded studies, the differences were not significant in the left lobe (P = 0.93) or the right lobe (P = 0.41). No correlation was noted between ADCs and the pulse rate. Visual evaluation revealed that the subcardiac signal loss was more prominent in the postloaded study. Conclusion ADC measurement of the left hepatic lobe was far more incorrect than that of the right lobe if cardiac gating was not employed. The administration of Buscopan worsened the image quality of the left lobe and made visual evaluation difficult. This article was presented at the Japan Radiological Society meeting in 2005.     

Dynamic enhanced MRI predicts chemosensitivity in breast cancer patients

BACKGROUND: Primary chemotherapy for breast cancer is effective as postoperative adjuvant therapy. However, one of the critical disadvantages was a treatment delay for patients with progressive disease. The present study attempts to clarify quantitative parameters on MRI which can be used to predict the sensitivity to treatment in breast cancer patients. METHODS: The subjects consisted of 26 patients with invasive ductal breast cancer who received primary chemotherapy before surgery. The mean maximum tumor dimension was 3.3cm, and 21 cases had nodal involvements. Three cases demonstrated histological grade 3. Dynamic enhanced MRI was evaluated at three different time periods; prior to, in the midst of preoperative chemotherapy, and just before the initial operation. The signal intensity ratio (SIR) and early contrast uptake (ECU) were calculated, as well as the correlation between these dynamic data and the tumor reduction rates were analyzed retrospectively. P-values of less than 0.05 were considered to indicate statistically significant. RESULTS: Responders to chemotherapy had the significantly higher SIR and ECU values than non-responders (p=0.0454 and 0.0334, respectively). ECU value significantly decreased as tumor reduction by chemotherapy (p=0.0028). Pathological tumor dimension was significantly correlated with the tumor size estimated on presurgical MRI (p<0.0001). CONCLUSIONS: Our current series demonstrated the significant correlation between pretreatment MRI data and tumor reduction by chemotherapy in breast cancer patients. With these results, it seems possible to define good and non-responders prior to treatment.     

Myocardial nerve fibers are preserved in MPTP-treated mice, despite cardiac sympathetic dysfunction

Recently, we reported a profound depletion of cardiac sympathetic nerve fibers in Parkinson's disease (PD). This cardiac sympathetic denervation is a characteristic hallmark of PD. Cardiac sympathetic dysfunction was also observed in 1-methyl-4-phenyl-1,2,3,6-tetrahydroxypyridine (MPTP)-treated mice, a model of PD. Although binding assay showed a decreased density of norepinephrine transporter (NET) in the hearts of the mice, their histopathological alterations have not been demonstrated. In this study, we investigated hearts of MPTP-treated mice with immunohistochemical method and Western blot analyses. MPTP-treated mice showed significant decreases in the contents of cardiac noradrenaline and dopamine, suggesting the sympathetic dysfunction. Synaptophysin-, tyrosine hydroxylase- or NET-immunoreactive nerve fibers were abundant in the hearts of control mice and MPTP-treated mice, without apparent differences between the two groups. Western blot analyses also showed no difference in the amounts of these proteins. Myocardial nerve fibers were well preserved in MPTP-treated mice, despite apparent cardiac sympathetic dysfunction.     

Hypolipidemic effect of Shoyu polysaccharides from soy sauce in animals and humans

Soy sauce (Shoyu) is a traditional Japanese fermented seasoning and is available worldwide. We investigated the effects of Shoyu polysaccharides (SPS) prepared from soy sauce on hyperlipidemia in vitro and in vivo. First, SPS inhibited pancreatic lipase. Second, in experiments with animals, it was found that SPS reduced serum triacylglycerol (TG) elevation induced by high-fat diets. Third, in a 2-week placebo-controlled parallel group study, healthy men (TG <150 mg/dl) were treated with 600 mg of SPS (n=5) or placebo (n=5) every day. After 2 weeks, serum TG elevation was significantly (P<0.05) lower in the SPS-treated group than in the placebo-treated group after 6 h of a high-fat diet. Fourth, in a 4-week randomized, double-blind, placebo-controlled parallel group study, hyperlipidemic men (TG >150 mg/dl) were treated with 600 mg of SPS (n=15) or placebo (n=15) daily. After 4 weeks, serum TG levels in the SPS-treated group were significantly (P<0.05) lower than the baseline (0 week). In conclusion, SPS of soy sauce reduce lipid absorption, and soy sauce is a potentially promising seasoning for the treatment of hyperlipidemia through food.     

Recognition of forked and single-stranded DNA structures by human RAD18 complexed with RAD6B protein triggers its recruitment to stalled replication forks

Post-replication DNA repair facilitates the resumption of DNA synthesis upon replication fork stalling at DNA damage sites. Despite the importance of RAD18 and polymerase η (Polη) for post-replication repair (PRR), the molecular mechanisms by which these factors are recruited to stalled replication forks are not well understood. We present evidence that human RAD18 complexed with RAD6B protein preferentially binds to forked and single-stranded DNA (ssDNA) structures, which are known to be localized at stalled replication forks. The SAP domain of RAD18 (residues 248–282) is crucial for binding of RAD18 complexed with RAD6B to DNA substrates. RAD18 mutated in the SAP domain fails to accumulate at DNA damage sites in vivo and does not guide DNA Polη to stalled replication forks. The SAP domain is also required for the efficient mono-ubiquitination of PCNA. The SAP domain mutant fails to suppress the ultraviolet (UV)-sensitivity of Rad18 -knockout cells. These results suggest that RAD18 complexed with RAD6B is recruited to stalled replication forks via interactions with forked DNA or long ssDNA structures, a process that is required for initiating PRR.     

Computer-assisted diagnostic system for neurodegenerative dementia using brain SPECT and 3D-SSP

Purpose  To develop a computer-assisted automated diagnostic system to distinguish among Alzheimer disease (AD), dementia with Lewy bodies (DLB), and other degenerative disorders in patients with mild dementia. Methods  Single photon emission computed tomography (SPECT) images with injection of N-Isopropyl-p-[¹²³I]iodoamphetamine (IMP) were obtained from patients with mild degenerative dementia. First, datasets from 20 patients mild AD, 15 patients with dementia with DLB, and 17 healthy controls were used to develop an automated diagnosing system based on three-dimensional stereotactic surface projections (3D-SSP). AD- and DLB-specific regional templates were created using 3D-SSP, and critical Z scores in the templates were established. Datasets from 50 AD patients, 8 DLB patients, and 10 patients with non-AD/DLB type degenerative dementia (5 with frontotemporal dementia and 5 with progressive supranuclear palsy) were then used to test the diagnostic accuracy of the optimized automated system in comparison to the diagnostic interpretation of conventional IMP-SPECT images. These comparisons were performed to differentiate AD and DLB from non-AD/DLB and to distinguish AD from DLB. A receiver operating characteristic (ROC) analysis was performed. Results  The area under the ROC curve (Az) and the accuracy of the automated diagnosis system were 0.89 and 82%, respectively, for AD/DLB vs. non-AD/DLB patients, and 0.70 and 65%, respectively, for AD vs. DLB patients. The mean Az and the accuracy of the visual inspection were 0.84 and 77%, respectively, for AD/DLB vs. non-AD/DLB patients, and 0.70 and 65%, respectively, for AD vs. DLB patients. The mean Az and the accuracy of the combination of visual inspection and this system were 0.96 and 91%, respectively, for AD/DLB vs. non-AD/DLB patients, and 0.70 and 66%, respectively, for AD vs. DLB patients. Conclusion  The system developed in the present study achieved as good discrimination of AD, DLB, and other degenerative disorders in patients with mild dementia as the commonly performed visual inspection of conventional SPECT images. A combination of visual inspection and this system is helpful in the differential diagnosis of patients with mild dementia.     

Continuous drip infusion of low dose cytarabine and etoposide with granulocyte colony-stimulating factor for elderly patients with acute myeloid leukaemia ineligible for intensive chemotherapy

BACKGROUNDS AND OBJECTIVES: The optimal strategy for the management of elderly patients with acute myeloid leukaemia (AML) is still controversial. We previously reported the effectiveness of low dose cytarabine (Ara-C) and etoposide (VP-16) (AV therapy) for those elderly AML patients ineligible for intensive chemotherapy. We initiated the present feasibility study to improve the efficacy by using glanulocyte-colony stimulating factor (G-CSF) with AV therapy (AVG therapy). PATIENTS AND METHODS: The eligibility for enrolment was AML patients according to the World Health Organization (WHO) criteria who were over 60 years of age and who had difficulty in tolerating intensive chemotherapy due to their poor performance status (PS) or some comorbidities. They were given continuous drip infusion of Ara-C (20 mg/body) and VP-16 (50 mg/body) for 7-14 days, and were also simultaneously administered G-CSF (150 microg/m2) once daily. RESULTS: The median age of consecutively enrolled 25 patients was 73 years. Eighteen (72%) patients achieved complete remission (CR). The 1-year overall survival (OS) and the 3-year OS rates were 69% and 22%, respectively. The 1-year disease free survival (DFS) rate in CR patients was 44%. The major regimen related toxicities of grade 3 or 4 were only febrile neutropenia in 15 patients (60%). No regimen-related mortality was observed. CONCLUSION: AVG therapy was therefore found to be an effective and well-tolerated regimen for remission induction in elderly AML patients with poor PS or comorbidity.     

A multicenter phase I trial of interferon-beta and temozolomide combination therapy for high-grade gliomas (INTEGRA Study)

A multicenter phase I clinical trial, namely, Integrated Japanese Multicenter Clinical Trial: A Phase I Study of Interferon-beta and Temozolomide for Glioma in Combination with Radiotherapy (INTEGRA Study), is being conducted for patients with high-grade glioma in order to evaluate the safety, feasibility and preliminary clinical effectiveness of the combination of interferon-beta and temozolomide. The primary endpoint is incidence of adverse events. The secondary endpoints are progression-free survival time and overall survival time. In addition, objective tumor response will be evaluated in a subpopulation of patients with the measurable disease. The reduction rate of tumor will be calculated according to Response Evaluation Criteria In Solid Tumors for measurable tumors as determined by magnetic resonance imaging. Subsequently, the overall response will be evaluated based on the results of measurable and non-measurable tumors. Ten newly diagnosed and 10 recurrent patients will be enrolled in this study.