New algorithmic-based digital filter processing system for real-time continuous blood pressure measurement and analysis in conscious rats

A new algorithmic-based digital filter processing system for real-time continuous blood pressure (BP) measurement and analysis in freely-moving conscious rats has been developed. Real-time recognition of BP waveforms, real-time noise rejection and determination of representative waveform indexes (WIs) at indicated time points using digital filters and Smirnov's rejection test were realized with this system. Digital filters were applied for two different purposes: waveform segmentation and smoothing the calculations of representative WIs. Smirnov's rejection test was used for real-time noise rejection and yielded an accurate rejection rate of 99.99%. The result was that the digital filter processing and Smirnov's rejection test realized accurate real-time BP measurement and analysis in freely-moving conscious rats using a personal computer.     

Effect of oral health care program on the oral function of the elderly

In order to prepare a new prevention program under the long term care insurance from the fiscal year 2006, we have organized an oral health care program for the elderly in a town of Kagoshima prefecture. We conducted a series of oral health education, i.e., instruction on brushing and flossing, and oral function exercises. Before and after the three months program, we evaluated the unstimulated and stimulated salivary flow rate, the counts of S. mutans, the counts of repetitive saliva swallowing test (RSST), bilateral bite force and the number of permanent teeth and artificial teeth. According to the results, a statistically significant improvement was observed in RSST and the unstimulated and stimulated salivary flow rate, but not in the S. mutans level and bite force. The present research suggests the effectiveness of the oral health care program for the aged. A larger sized and longer period intervention will be necessary in order to validate our findings.     

Lymphokine-activated killer cell activity of peripheral blood,spleen, regional lymph node,and tumor infiltrating lymphocytes in gastric cancer patients

Lymphokine-activated killer (LAK) cell activity of peripheral blood mono-nuclear cells (PBM), spleen cells (SPC), regional lymph node cells (LNC), and tumor-infiltrating lymphocytes (TIL), induced by activation with in-terleukin 2 (IL 2) for 4 days, was evaluated in patients with gastric carcinoma. TIL exhibited the lowest LAK activity and the cytotoxicity of LNC was significantly lower than that of either PBM or SPC. There was no difference between PBM and SPC. Then, there were significant correlations of LAK activity among PBM, SPC, and LNC, whereas poor correlations were observed in the cytotoxicity between TIL and PBM, SPC, or LNC. Phenotypic analysis of each cell population was performed before and after activation with IL 2. Before culture, the cells mediating natural killer (NK) activity such as CD16⁺, CD56⁺, and CD57⁺ cells were few in LNC and TIL. However, CD56⁺ and CD57⁺ cells in TIL were increased after culture. Then, CD4⁺ Leu8⁺ and CD8⁺ CD11⁺ cells, which identify suppressor cell function, were not elevated in LNC or TIL, as compared to that in PBM or SPC. Further, the proportions of OKIa1⁺ and CD25⁺ cells expressing T-cell activation and IL 2 receptor were uniformly increased in all cell populations after culture. These results indicate the differential reactivity of each lymphocyte population to IL 2 and fundamental dysfunction of LNC and, especially TIL, suggesting the specific influence of the local tumor environment on the lymphocyte function in the area in patients with gastric carcinoma. © Wiley-Liss, Inc.     

Clinical Features of Fecal Immunochemical Test-Negative Colorectal Lesions based on Colorectal Cancer Screening among Asymptomatic Participants in Their 50s

Objective: To improve the efficacy of colorectal cancer (CRC) screening, decreasing the occurrence of interval cancers is essential. Most interval CRCs develop from fecal immunochemical test (FIT)-negative CRC. This study examined the clinical characteristics of FIT-negative advanced neoplasms (AN) and sessile serrated lesions (SSL), which are main candidate precursors of FIT-negative CRC, and the eligibility criteria for total colonoscopy (TCS) screening following negative FIT. Methods: Asymptomatic participants in their 50s were divided into two groups. The FIT-negative group underwent TCS following negative FIT, and the TCS-only group underwent TCS without FIT. One endoscopist reviewed the endoscopic images. Plausible risk factors for colorectal polyps were extracted. The clinical features of AN and SSL were compared between the groups. Result: Of 2,437 participants, 56.2% were included in the FIT-negative group. No between-group differences were recorded for the prevalence of different colorectal polyp types. By multivariate analysis, a significantly lower adjusted odds ratio (AOR) of AN was shown in women, and significantly higher AORs of AN were found for aging, smoking, and a family history of CRC. The AOR of SSL was higher for smokers. The proportion of AN in the right colon was higher in the FIT-negative group. No between-group differences were recorded for SSL. Conclusion: FIT screening was less likely to detect CRC and certain precancerous lesions in the right colon. Combining annual FIT with TCS for the high-risk population based on a scoring system, may detect FIT-negative CRC and colorectal polyps, thus, reducing interval cancer.     

Adaptor protein CRK induces epithelial–mesenchymal transition and metastasis of bladder cancer cells through HGF/c‐Met feedback loop

We have previously reported that an adaptor protein CRK, including CRK‐I and CRK‐II, plays essential roles in the malignant potential of various aggressive human cancers, suggesting the validity of targeting CRK in molecular targeted therapy of a wide range of cancers. Nevertheless, the role of CRK in human bladder cancer with marked invasion, characterized by distant metastasis and poor prognosis, remains obscure. In the present study, immunohistochemistry indicated a striking enhancement of CRK‐I/‐II, but not CRK‐like, in human bladder cancer tissues compared to normal urothelium. We established CRK‐knockdown bladder cancer cells using 5637 and UM‐UC‐3, which showed a significant decline in cell migration, invasion, and proliferation. It is noteworthy that an elimination of CRK conferred suppressed phosphorylation of c‐Met and the downstream scaffold protein Gab1 in a hepatocyte growth factor‐dependent and ‐independent manner. In epithelial–mesenchymal transition‐related molecules, E‐cadherin was upregulated by CRK elimination, whereas N‐cadherin, vimentin, and Zeb1 were downregulated. A similar effect was observed following treatment with c‐Met inhibitor SU11274. Depletion of CRK significantly decreased cell proliferation of 5637 and UM‐UC‐3, consistent with reduced activity of ERK. An orthotopic xenograft model with bioluminescent imaging revealed that CRK knockdown significantly attenuated not only tumor volume but also the number of circulating tumor cells, resulted in a complete abrogation of metastasis. Taken together, this evidence uncovered essential roles of CRK in invasive bladder cancer through the hepatocyte growth factor/c‐Met/CRK feedback loop for epithelial–mesenchymal transition induction. Thus, CRK might be a potent molecular target in bladder cancer, particularly for preventing metastasis, leading to the resolution of clinically longstanding critical issues.     

CpG oligodeoxynucleotides potentiate the antitumor activity of anti‐BST2 antibody

Numerous monoclonal antibodies (mAb) targeting tumor antigens have recently been developed. Antibody‐dependent cellular cytotoxicity (ADCC) and antibody‐dependent cellular phagocytosis (ADCP) via effector cells such as tumor‐infiltrating natural killer (NK) cells and macrophages are often involved in mediating the antitumor activity of mAb. CpG oligodeoxynucleotides (ODN) have a potent antitumor activity and are considered to increase tumor infiltration of NK cells and macrophages. Our group previously reported significant antitumor activity of anti‐bone marrow stromal antigen 2 (BST2) mAb against BST2‐positive endometrial cancer cells through ADCC. In this study, we evaluated the synergistic antitumor activity of combination therapy with anti‐BST‐2 mAb and CpG ODN using SCID mice and elucidated the mechanisms underlying this activity. Anti‐BST2 mAb and CpG ODN monotherapy had a significant dose‐dependent antitumor activity (P = 0.0135 and P = 0.0196, respectively). Combination therapy with anti‐BST2 mAb and CpG ODN had a significant antitumor activity in SCID mice (P < 0.01), but not in NOG mice. FACS analysis revealed significantly increased numbers of NK cells and macrophages in tumors treated with a combination of anti‐BST2 mAb and CpG ODN and with CpG ODN alone in SCID mice (P < 0.05 and P < 0.01, respectively). These results suggested that the combination therapy with anti‐BST2 mAb and CpG ODN has a significant antitumor activity and induces tumor infiltration of NK cells and macrophages. Combination therapy with CpG ODN and anti‐BST2 mAb or other antitumor mAb depending on ADCC may represent a new treatment option for cancer.     

Milrinone inhibits sympathetic-mediated tachycardia by a postjunctional action independent of cyclic AMP.

In pithed rats with stimulated sympathetic outflow, the phosphodiesterase inhibitor milrinone (0.3 mg/kg, i.v.) decreased the peak tachycardiac response produced by both sympathetic nerve stimulation (15 s at 0.5-3 Hz) and norepinephrine administration (0.3-5 micrograms/kg, i.v.). However, another phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX, 0.5 mg/kg, i.v.) had no effect on the peak tachycardic response to sympathetic stimulation. Similarly, in isolated rat atria, milrinone (9 mumol/L) inhibited the tachycardia produced by norepinephrine, whereas IBMX (1 mumol/L) had no effect. The inhibitory effect of milrinone on sympathetic responses was not due to changes in norepinephrine release since milrinone (9 mumol/L) increased norepinephrine release in isolated rat atria incubated with [3H]norepinephrine. When the duration of the tachycardia (rather than the peak tachycardic response) produced by sympathetic nerve stimulation was measured, it was found to be prolonged by both milrinone and IBMX, suggesting that in this case cyclic AMP was involved. Furthermore, in contrast to its inhibitory effects on norepinephrine-induced tachycardia in rat atria, milrinone enhanced the tachycardia produced by the adenylate cyclase activator forskolin. These results suggest that milrinone has complex actions on sympathetic control of heart rate and that beta-adrenoceptor tachycardia occurs by mechanisms dependent on and independent of cyclic AMP.     

Changes in surgical strategies for peptic ulcers before and after the introduction of H2-receptor antagonists and endoscopic hemostasis

A total of 902 surgical patients with peptic ulcer disease were evaluated to clarify the effects of H₂-receptor antagonists and endoscopic hemostasis on surgical treatment. Following the introduction of these treatments to our institute in 1982, the number of operations performed annually decreased by 40%, or 36 cases per year. However, a remarkable increase in the frequency of surgical emergency intervention since 1982 was concurrently observed, with the ratio of emergency procedures to the total number of operated cases increasing to 72.5% in the last 5 years of the study. Moreover, intractability as an indication for surgery decreased to 34.1%, compared with an increase in the number of patients with bleeding and perforated ulcers requiring operation. There were 13 postoperative deaths recorded (1.4%). All of the deaths were in patients who had undergone emergency surgery in poor health. Of these 13 patients, 10 had bleeding ulcers. A study of bleeding ulcers for which endoscopic hemostasis had been unsuccessful revealed that shock on admission and a concomitant medical condition had been evident in all the patients who died, and in 52.2% and 30.4% of the survivors, respectively. The current study suggests that the frequency of high-risk patients requiring surgery is increasing since the introduction of H₂-receptor antagonists and endoscopic hemostasis, and thus, prompt surgical treatment and intensive management for such patients is essential.