Association between excessive supraventricular ectopy and subclinical cerebrovascular disease: a population-based study.

BACKGROUND AND PURPOSE: The association between an increased supraventricular ectopic beat (SVEB) and subclinical cerebrovascular disease remains unclear. Given the emerging concept that an increased SVEB is a marker of atrial cardiomyopathy or atherosclerosis burden, we sought to determine whether excessive supraventricular ectopic activity (ESVEA) is associated with a higher burden of subclinical cerebrovascular disease in the middle-aged to older cohort with neither apparent stroke nor atrial fibrillation. METHODS: We conducted a cross-sectional population-based study of 462 men (mean age, 68.1 years) who underwent 24-h Holter electrocardiography and brain magnetic resonance imaging. ESVEA was defined as the presence of >10 SVEBs/h. Subclinical cerebrovascular diseases were defined as silent brain infarct (SBI), white matter hyperintensity (WMH) and intracranial atherosclerotic stenosis (ICAS). The association of ESVEA with the presence of subclinical cerebrovascular diseases was adjusted for potential confounding covariates. RESULTS: A total of 88 (19.0%) participants had ESVEA and 81 (17.5%), 91 (19.7%) and 109 (23.6%) had SBI, WMH and ICAS, respectively. In multivariable-adjusted Poisson regression with robust error variance, ESVEA was associated with the presence of WMH (relative risk, 1.58; 95% confidence interval, 1.06-2.36) and ICAS (relative risk, 1.49; 95% confidence interval, 1.02-2.18), but not with that of SBI (relative risk, 1.32; 95% confidence interval, 0.86-2.01). These associations were consistent when the graded distributions of subclinical cerebrovascular diseases were applied as outcomes in ordinal logistic regression. CONCLUSIONS: The ESVEA was independently associated with higher burdens of WMH and ICAS. This suggests that increased SVEBs might improve risk stratification of individuals at high risk of subclinical cerebrovascular disease and consequently apparent ischaemic stroke.

Associations of HLA class I alleles in Japanese patients with Crohn's disease.

Previous studies have suggested that the human leukocyte antigen (HLA) is involved in the etiology of Crohn's disease (CD); however, few reports are available on the association between HLA class I antigens and CD in Japan. In this study, we performed association analysis of HLA class I antigens in CD using 208 Japanese patients and 384 healthy controls. We identified novel positive associations between CD and HLA-A*02:01 (odds ratio (OR)=1.64, P=0.016) and HLA-A*02:07 (OR=2.31, P=0.0067) and confirmed previously reported positive associations between CD and HLA-Cw*14:02 (OR=2.18, P=0.0021) and HLA-B*51:01 (OR=1.70, P=0.033). We also identified novel negative associations between CD and HLA-A*24:02 (OR=0.60, P=0.0047) and HLA-B*07:02 (OR=0.38, P=0.0041). Although the associations were not significant after full Bonferroni correction, we suggested that HLA class I genes have dual functions, susceptibility and resistance in controlling the development of CD.

Ectopic cardiovascular fat in middle-aged men: effects of race/ethnicity, overall and central adiposity. The ERA JUMP study.

BACKGROUND/OBJECTIVES: Higher volumes of ectopic cardiovascular fat (ECF) are associated with greater risk of coronary heart disease (CHD). Identifying factors that are associated with ECF volumes may lead to new preventive efforts to reduce risk of CHD. Significant racial/ethnic differences exist for overall and central adiposity measures, which are known to be associated with ECF volumes. Whether racial/ethnic differences also exist for ECF volumes and their associations with these adiposity measures remain unclear. SUBJECTS/METHODS: Body mass index (BMI), computerized tomography-measured ECF volumes (epicardial, pericardial and their summation) and visceral adipose tissue (VAT) were examined in a community-based sample of 1199 middle-aged men (24.2% Caucasians, 7.0% African-Americans, 23.6% Japanese-Americans, 22.0% Japanese, 23.2% Koreans). RESULTS: Significant racial/ethnic differences existed in ECF volumes and their relationships with BMI and VAT. ECF volumes were the highest among Japanese-Americans and the lowest among African-Americans. The associations of BMI and VAT with ECF differed by racial/ethnic groups. Compared with Caucasians, for each 1-unit increase in BMI, African-Americans had lower, whereas Koreans had higher increases in ECF volumes (P-values<0.05 for both). Meanwhile, compared with Caucasians, for each 1-unit increase in log-transformed VAT, African-Americans, Japanese-Americans and Japanese had similar increases, whereas Koreans had a lower increase in ECF volumes (P-value<0.05). CONCLUSIONS: Racial/ethnic groups differed in their propensity to accumulate ECF at increasing level of overall and central adiposity. Future studies should evaluate whether reducing central adiposity or overall weight will decrease ECF volumes more in certain racial/ethnic groups. Evaluating these questions might help in designing race-specific prevention strategy of CHD risk associated with higher ECF.

Prognostic factors for survival in cervical cancer patients with bone metastasis.

PURPOSE: To investigate the prognostic factors for survival in uterine cervical cancer patients who developed bone metastasis. MATERIALS AND METHODS: Cervical cancer patients with bone metastasis who were treated at the present institute from April 1996 to September 2010 were identified from the authors' institutional tumor registries. Primary disease, follow-up, and recurrence data were collected and retrospectively reviewed. Univariate and multivariate analyses of prognostic factors for survival were performed. RESULTS: A total of 37 patients that developed cervical cancer bone metastasis were included in the authors' database. The median survival time after recurrence was 12 months. Univariate analysis revealed that patients with a disease-free interval (DFI) of ten months or less achieved significantly shorter survival after bone metastasis detection than those with a DFI of 11 months or more (median: 8.5 months versus 17 months, p < 0.0001). Multivariate analysis also showed that DFI of ten months or less was a significant predictor of short survival (p = 0.0018). CONCLUSIONS: The DFI was found to be independent prognostic factors for survival in cervical cancer patients who developed bone metastasis.

Intracellular bacteria recognition contributes to maximal interleukin (IL)-12 production by IL-10-deficient macrophages.

Interleukin (IL)-12 is a key factor that induces T helper cell type 1-mediated immunity and inflammatory diseases. In some colitis models, such as IL-10 knock-out (KO) mice, IL-12 triggers intestinal inflammation. An abundant amount of IL-12 is produced by intestinal macrophages in response to stimulation by commensal bacteria in IL-10 KO mice. Intact bacteria are more potent inducers of macrophage IL-12 production than cell surface components in this model. This suggested that cell surface receptor signalling and intracellular pathogen recognition mechanisms are important for the induction of IL-12. We addressed the importance of intracellular recognition mechanisms and demonstrated that signal transducers and activator of transcription 1 (STAT1) signalling activated bacterial phagocytosis and was involved in the induction of abnormal IL-12 production. In IL-10 KO mouse bone marrow-derived (BM) macrophages, Escherichia coli stimulation induced increased IL-12p70 production compared to lipopolysaccharide combined with interferon (IFN)-γ treatment. Significant repression of IL-12 production was achieved by inhibition of phagocytosis with cytochalasin D, and inhibition of de novo protein synthesis with cycloheximide. Induction of IFN regulatory factors-1 and -8, downstream molecules of STAT1 and the key transcription factors for IK-12 transcription, following E. coli stimulation, were mediated by phagocytosis. Interestingly, STAT1 was activated after stimulation with E. coli in IL-10 KO BM macrophages, although IFN-γ could not be detected. These data suggest that molecules other than IFN-γ are involved in hyper-production mechanisms of IL-12 induced by E. coli stimulation. In conclusion, enteric bacteria stimulate excessive IL-12p70 production in IL-10 KO BM macrophages via phagocytosis-dependent signalling.

Activity of pegylated liposomal doxorubicin for extragenital mullerian adenosarcoma with sarcomatous overgrowth: a case report and a review of the literature.

A 47-year-old woman was diagnosed with extragenital mullerian adenosarcoma with sarcomatous overgrowth. One month after her initial surgery, the patient developed pelvic recurrence, which was completely excised by surgery. However, one month later, the patient developed further recurrences in her pelvis and upper abdomen. A clinical complete response was achieved with three cycles of liposomal doxorubicin and is currently clinically free of disease. So far, including the present case, 23 cases of extragenital mulleian adenosarcoma have been reported in the English literature. Because of the rarity of the reported cases, there are no treatment guidelines based on a good level of evidence. In the current report, through a literature review, we provide information on the activity of pegylated liposomal doxorubicin for extragenital mullerian adenosarcoma with sarcomatous overgrowth.

IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn's disease.

BACKGROUND: A novel T helper (Th) cell lineage, Th17, that exclusively produces the proinflammatory cytokine interleukin 17 (IL17) has been reported to play important roles in various inflammatory diseases. IL23 is also focused upon for its potential to promote Th17. Here, the roles of the IL23/IL17 axis in inflammatory bowel diseases such as ulcerative colitis (UC) and Crohn's disease (CD) were investigated. METHODS: Mucosal samples were obtained from surgically resected specimens (controls, n = 12; UC, n = 17; CD, n = 22). IL17 production by isolated peripheral blood (PB) and lamina propria (LP) CD4(+) cells was examined. Quantitative PCR amplification was performed to determine the mRNA expression levels of IL17, interferon gamma (IFNgamma), IL23 receptor (IL23R) and retinoic acid-related orphan receptor gamma (RORC) in LP CD4(+) cells, and IL12 family members, such as IL12p40, IL12p35 and IL23p19, in whole mucosal specimens. The effects of exogenous IL23 on IL17 production by LP CD4(+) cells were also examined. RESULTS: IL17 production was higher in LP CD4(+) cells than in PB. Significant IL17 mRNA upregulation in LP CD4(+) cells was found in UC, while IFNgamma was increased in CD. IL23R and RORC were upregulated in LP CD4(+) cells isolated from both UC and CD. IL17 production was significantly increased by IL23 in LP CD4(+) cells from UC but not CD. Upregulated IL23p19 mRNA expression was correlated with IL17 in UC and IFNgamma in CD. CONCLUSIONS: IL23 may play important roles in controlling the differential Th1/Th17 balance in both UC and CD, although Th17 cells may exist in both diseases.

Induction of anti-VEGF therapy resistance by upregulated expression of microseminoprotein (MSMP).

Anti-vascular endothelial growth factor (VEGF) therapy has demonstrated efficacy in treating human metastatic cancers, but therapeutic resistance is a practical limitation and most tumors eventually become unresponsive. To identify microenvironmental factors underlying the resistance of cancer to antiangiogenesis therapy, we conducted genomic analyses of intraperitoneal ovarian tumors in which adaptive resistance to anti-VEGF therapy (B20 antibody) developed. We found that expression of the microseminoprotein, prostate-associated (MSMP) gene was substantially upregulated in resistant compared with control tumors. MSMP secretion from cancer cells was induced by hypoxia, triggering MAPK signaling in endothelial cells to promote tube formation in vitro. Recruitment of the transcriptional repressor CCCTC-binding factor (CTCF) to the MSMP enhancer region was decreased by histone acetylation under hypoxic conditions in cancer cells. MSMP siRNA, delivered in vivo using the DOPC nanoliposomes, restored tumor sensitivity to anti-VEGF therapy. In ovarian cancer patients treated with bevacizumab, serum MSMP concentration increased significantly only in non-responders. These findings imply that MSMP inhibition combined with the use of antiangiogenesis drugs may be a new strategy to overcome resistance to antiangiogenesis therapy.

Significance of measurement of serum trough level and anti-drug antibody of adalimumab as personalised pharmacokinetics in patients with Crohn's disease: a subanalysis of the DIAMOND trial.

BACKGROUND: Significance of monitoring adalimumab trough levels and anti-adalimumab antibodies (AAA) for disease outcome in Crohn's disease (CD) patients remained unclear. AIM: To evaluate the association of adalimumab trough levels and AAA at week 26 with clinical remission at week 52, the effect of azathiopurine on AAA and factors influencing trough levels in CD patients in the DIAMOND trial. METHODS: We performed this study using adalimumab trough levels, AAA at week 26 and 6-thioguanine nucleotide (TGN) in red blood cells at week 12. A multiple regression model and receiver operating analysis was performed to identify factors influencing adalimumab trough levels and AAA, and adalimumab thresholds for predicting disease activity. RESULTS: There was a significant difference of adalimumab trough level at week 26 between patients with disease remission and without at week 52 (7.7 ± 3.3 µg/mL vs 5.4 ± 4.3 µg/mL: P <.001). Adalimumab trough level of 5.0 µg/mL yielded optimal sensitivity and specificity for remission prediction (80.2% and 55.6%, respectively). AAA development at week 26 significantly affected remission at week 52 (P = .021), which was strongly associated with adalimumab trough levels. Female gender and increasing body weight were independently associated with low adalimumab trough levels, and female gender was associated with AAA development. A cut-off 6TGN level of >222.5 p mol/8 ×108 RBCs yielded sensitivity (100%) and specificity (60.6%) for AAA negativity. CONCLUSION: Adalimumab trough levels and AAA occurrence were significantly associated with clinical remission. Higher 6TGN affected AAA negativity. The combination therapy is beneficial in some relevant aspects for CD patients. (UMIN Registration No. 000005146).

Interferon-inducible gene family 1-8U expression in colitis-associated colon cancer and severely inflamed mucosa in ulcerative colitis.

Persistent severe inflammation in colonic mucosa is thought to cause the development of colon cancer in patients with ulcerative colitis (UC). However, predisposing genetic abnormalities have not been identified in this sequence. Using differential display PCR, we isolated cDNA fragments corresponding to mRNAs that were differentially expressed in colitis-associated cancer tissues and mucosa with mild inflammation in the colon of five UC patients. This molecular screening approach identified 60 cDNA fragments, and we sequenced 34 fragments. One cDNA fragment, which is identical to IFN-inducible gene family 1-8U, was strongly expressed in all five UC-associated cancers. 1-8U was also expressed in sporadic colon cancer tissues and colon cancer cell lines, but not in normal mucosa. This gene was strongly expressed in severely inflamed colonic mucosa of UC without colitis-associated colon cancer, although 1-8U expression was not related to the extent and duration of the disease. However, 1-8U was expressed in the colonic mucosa of all patients with chronic, continuously severe inflammation. These results indicated that IFN-inducible gene family 1-8U expression in inflamed colonic mucosa might be used as a preferential marker of colitis-associated colon cancer in UC.

Osteoclast-like cells express receptor activity modifying protein 2: application of laser capture microdissection.

Receptor activity modifying proteins (RAMPs) act as receptor modulators that determine the ligand specificity of receptors for the calcitonin (CT) family. The purpose of this study was to analyze the expression of RAMPs in osteoclast-like cells using the laser capture microdissection (LCM) technique. Mouse bone marrow and spleen cells were co-cultured on a film designed for LCM. After 10 days, 250 osteoclast-like cells were captured using the LCM system. Total RNA from these cells was used to synthesize cDNA and RT-PCR analysis was performed. Osteoclast-like cells expressed CT receptor (CTR), CT receptor-like receptor (CRLR) and RAMP2, but did not express RAMP1 or RAMP3. These results indicated (1) that a pure population of osteoclast-like cells can be prepared by LCM and gene expression of this population can be analyzed by RT-PCR and (2) that RT-PCR shows that osteoclast-like cells express RAMP2, CTR and CRLR, suggesting the potential for adrenomedullin binding to osteoclast-like cells. This is the first report that osteoclast-like cells express RAMP2.

Synthesis and activities of antitumor agents.

N-(2-Chloroethyl)-N-nitrosocarbamoyl derivatives of glycosylamines have been prepared. Six N-(2-chloroethyl)-N-nitrosoureas, including three disaccharide derivatives, were submitted to a determination of antitumor activity. All the compounds tested exhibited strong antitumor activity against leukemia L1210 in mice.

(2-Chloroethyl)nitrosourea congeners of amino acid amides.

Fourteen (2-chloroethyl)nitrosourea congeners of L-amino acid amides have been synthesized as potential antineoplastic agents. Almost all the congeners tested were found to be highly active against experimental leukemia L1210 in mice. The chemical decomposition rates of the congeners were measured in a buffered solution (pH 7.4) at 37 degrees C. Acute toxicities of some of the congeners were determined for mice. The congener of sarcosinamide shows the longest half-life (T0.5 = 329.7 min) and the lowest toxicity, LD50 = 392.0 mg/kg (ip) and 426.6 mg/kg (iv), in this series.

Correlation of nitrosourea murine bone marrow toxicity with deoxyribonucleic acid alkylation and chromatin binding sites.

All of the clinically available nitrosourea antitumor agents produce serious treatment-limiting bone marrow toxicity. A reduction in this toxicity can be achieved by attaching the chloroethylnitrosourea cytotoxic group to C2 (chlorozotocin) or C1 (1-(2-chloroethyl)-3-(beta-D-glucopyranosyl)-1-nitrosourea, GANU) of glucose. Both glucose analogs are less myelotoxic in mice than 1-(2-chloroethyl)-3-cyclohepyl-1-nitrosourea (CCNU) or 1-(4-amino-2-methylpyrimidin-5-yl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU), while retaining comparable antitumor activity against the murine L1210 leukemia. To define the nuclear mechanisms for this reduced myelotoxicity, alkylation of L1210 and murine bone marrow DNA was quantitated. With the use of the endonuclease micrococcal nuclease and DNase I, the sites of alkylation within the chromatin substructure were determined. Experiments were performed on L1210 leukemia or bone marrow cells that had been incubated in vitro for 2 hr with 0.1 mM [14C]chloroethyl drug. The quantitative alkylation of DNA by GANU was 1.3-fold greater in L1210, as compared to bone marrow, cells. This ratio of DNA alkylation is comparable to the 1.3 ratio we previously reported for chlorozotocin [L. C. Panasci, D. Green and P. S. Schein, J. clin. Invest. 64, 1103 (1979)]. In contrast, the ratio of alkylation (L1210:bone marrow DNA) for the myelotoxic ACNU was 0.66, similar to 0.59 for CCNU. Nuclease digestion experiments demonstrated that chlorozotocin and GANU preferentially alkylated internucleosomal linker regions of bone marrow chromatin, while nucleosome core particles were the preferred targets of CCNU and ACNU. The reduced myelotoxicity of chlorozotocin and GANU may be correlated with the advantageous ratio of L1210:bone marrow DNA alkylation and preferential alkylation of internucleosomal regions of bone marrow chromatin.

Prospective evaluation for upper gastrointestinal tract acute graft-versus-host disease after hematopoietic stem cell transplantation.

The incidence and clinical significance of upper gastrointestinal tract acute graft-versus-host disease (upper GI GVHD) were prospectively evaluated in 44 Japanese patients who underwent allogeneic (n = 26) or autologous (n = 18) stem cell transplantation. Endoscopic examination was routinely performed between days 20 and 50 post-transplant and when symptoms of upper GI and/or acute GVHD of other organs were present. The results were compared with the historical records of 49 allograft and 20 autograft recipients. The diagnosis of upper GI GVHD was confirmed by histologic findings of GVHD and persistent upper GI tract symptoms. The incidence of upper GI GVHD was 46% in the prospective allograft group, higher than in the retrospective group. Upper GI GVHD was not diagnosed in any autograft patients. Twelve of 19 patients with upper GI GVHD had skin GVHD, and two of the 12 had concurrent lower GI GVHD. Upper GI GVHD was successfully treated with steroids and did not progress to symptomatic lower GI GVHD. In addition, upper GI GVHD completely resolved without specific alteration in immunosuppressant therapy in six patients. No risk factors for upper GI GVHD could be identified. The presence of upper GI GVHD did not significantly affect early death rate, incidence of chronic GVHD, and overall survival. In conclusion, by the prospective evaluation of the upper GI tract by endoscopy we could accurately diagnose upper GI GVHD in half our allogeneic recipients. However, upper GI GVHD was successfully controlled with or without additional steroids in all cases and had little impact on transplant outcome.

Comparative investigation on use of (2''R)-4'-O-tetrahydropyranyl-adriamycin and adriamycin as intravesical chemotherapy for superficial bladder tumors.

An intravesical chemotherapeutic agent must be capable of being rapidly absorbed by the tumor cells and expressing its activity while undergoing little systemic absorption. A comparative investigation was conducted on (2''R)-4'-O-tetrahydropyranyl-doxorubicin (Adriamycin) (THP) and Adriamycin (ADM) from the above viewpoint using cultured MBT-2 and T-24 cell lines. From in vitro experimental systems, it is surmized that THP is taken up by bladder tumor cells more rapidly than ADM is, and that THP is thus able to exert its effect on the bladder tumor within a shorter time than that required by ADM. This pharmacokinetic advantage of THP was proved in an in vivo experimental system; that is, bladder tumor tissue which was established by implanting MBT-2 cells into the mouse (C3H/He) bladder was found to contain THP in a concentration approximately 1.9 times higher than the concentration of ADM. The amount of systemic absorption from the bladder was small in the case of both THP and ADM. THP should be useful as a new agent for intravesical chemotherapy.

Higher frequencies of numerical aberrations of chromosome 17 in primary gastric cancers are associated with lymph node metastasis.

We investigated the correlation between the frequency of numerical aberrations of chromosome 17 and clinicopathological features of gastric cancer. The copy number of chromosome 17 was examined with fluorescence in-situ hybridization (FISH) in frozen specimens from 100 primary gastric cancers. Chromosomal numerical aberrations were diagnosed as chromosomal loss (single signal) or gain (triple or more signals), in each cell. The frequency of numerical aberrations of chromosome 17 correlated significantly with the depth of invasion (P < 0.01), lymph node metastasis (P < 0.0001), lymphatic invasion (P < 0.001), and venous invasion (P < 0.01). Numerical aberrations of chromosome 17 were associated with lymph node metastasis in 32 early gastric cancers. Multiple regression analysis identified the depth of invasion and numerical aberrations of chromosome 17 as independent significant determinants of lymph node metastasis. Our findings suggest that alterations in chromosome 17 may be linked with tumor progression in primary gastric cancer. Our results also indicate that numerical aberrations of chromosome 17 detected by FISH provide important information about the malignant potential (in particular, lymph node metastasis) of primary gastric cancer.

BN-183B, a new antitumor antibiotic produced by Pseudomonas. Taxonomy, isolation, physico-chemical and biological properties.

BN-183B is a new antitumor antibiotic with chlorine in its molecule found in the culture broth of Pseudomonas sp. BN-183. The compound was weakly basic and isolated as a hydrochloride in a pure state. The molecular formula of its free base was determined as C14H20N2O6Cl2. The antibiotic showed not only strong antimicrobial activity against both Gram-positive and Gram-negative bacteria but also marked activity toward experimental tumors such as lymphoid leukemia L-1210 and lymphocytic leukemia P-388 in mice. No mutagenicity of BN-183B was noted.

SF-1771, a new antibiotic related to bleomycin.

A new antibiotic, substance SF-1771, has been isolated for the fermentation broth of Streptomyces toyocaensis SF-1771. The antibiotic is highly active against Gram-positive and -negative bacteria and effective against sarcoma 180 cells of ascites type in mice. It belonged to the phleomycin-bleomycin group antibiotics, but has been differentiated from the known antibiotics by the physiochemical properties, chromatographic behaviors and amino acid analysis.