Effects of Exercise-Diet Therapy on Cognitive Function in Healthy Elderly People Evaluated by Deep Learning Based on Basic Blood Test Data.

BACKGROUND: Recent studies reported that vascular cognitive impairment in the elderly caused by arteriosclerosis plays an important role in cognitive disorders in both vascular dementia and Alzheimer's disease. In addition, systemic metabolic disorders such as oxygen metabolism dysfunction could be risk of dementia. Based on these findings, we have developed a deep neural network-based screening test (DNN-based test) of cognitive function using basic blood test data, which allowed prediction of cognitive function expressed by Mini Mental State Examination (MMSE) scores. AIM: Here, we investigated whether the DNN-based test could be applicable to assessment of the effects of exercise-diet on cognitive function. METHODS: We studied the following two groups: (1) seven subjects of the local fitness gym (68.6 ± 3.2 years old). We evaluated cognitive function by the DNN-based test using blood data before and after the intervention (for 3 months). These results were compared with the measured MMSE score. (2) we studied a total of 230 subjects (67.9 ± 7.4 years old) who were members of the Tsuminory health class (Apple classroom). We assessed cognitive function by the DNN-based test before and after the intervention (for 2 months). We compared the predicted MMSE scores by the DNN-based test before and after the 2-month intervention. RESULTS: In the first group, the MMSE score predicted by the DNN-based test increased from 27.1 ± 0.8 to 27.6 ± 0.7 after the intervention period (p = 0.024). The measured MMSE score also increased after exercise, but not significant (P = 0.28). In the second group, the exercise-diet therapy increased the predicted MMSE scores in 189 cases (p < 0.001). In contrast, the therapy significantly reduced the mean MMSE score (p < 0.001). DISCUSSION: The MMSE score predicted by the DNN-based test were increased by exercise-diet therapy in most subjects. The DNN-based test may be useful to monitor the effect of exercise-diet therapy on cognitive function aged people.

Effects of 20-Minute Intensive Exercise on Subjects with Different Working Memory Bases.

Continuous moderate-intensity aerobic exercise improves cognitive function including working memory (WM). We aimed to determine the differences in the effects of exercise on WM based on pre-exercise WM function and oxyhemoglobin (O2Hb) changes. We enrolled 12 healthy adult males who, after a 4-min rest and warm-up, performed a 20-min exercise regime at a workload corresponding to 50% of maximal oxygen consumption. They performed a pre- and postexercise two-back test, and the reaction times were recorded. Near-infrared spectroscopy was used to monitor the O2Hb concentration in the left prefrontal cortex during the exercise. Based on the pre-exercise reaction time, the subjects were allocated into either a fast group (FG) or a slow group (SG). The pre- and postexercise changes in the reaction time and time-to-peak O2Hb were compared. Further, we determined the relationship between the change in the reaction time and time-to-peak O2Hb. There was no significant change in the reaction time of the FG; however, that in the SG decreased significantly. The time-to-peak O2Hb in the FG was significantly less than that in the SG. These results showed differences in the changes of reaction time and O2Hb changes between the FG and SG.

Relationship Between Cognitive Dysfunction and Systemic Metabolic Disorders in Elderly: Dementia Might be a Systematic Disease.

Vascular cognitive impairment (VCI) plays an important role in dementia in elderly people, and refers to the contribution of vascular pathology to the entire spectrum of cognitive disorders, ranging from mild cognitive impairment to severe dementia, as well as the pathological spectrum, from 'pure' Alzheimer disease through degrees of vascular comorbidity to 'pure' vascular dementia. In the present study, we investigated the relationship between cognitive dysfunction and systemic metabolic disorders, by employing deep learning (DL). We studied 202 patients (73.4 ± 13.0 years), 94.6% of whom were undergoing treatment for lifestyle diseases, and 68.8% of whom had a history of cerebrovascular disorder. We evaluated cognitive dysfunction by performing a Mini Mental State Examination (MMSE). We performed general blood examination, including Complete Blood Count and Basic Metabolic Panel, and measured cerebral blood oxygenation in the prefrontal cortex (PFC) using time-resolved near infrared spectroscopy (TNIRS). We then used deep neural networks to assess the MMSE scores of the subjects based on the TNIRS parameters and the blood examination data, independently. Next, we compared predicted MMSE scores based on the TNIRS and the blood examination. There was a significant positive correlation between the TNIRS parameters and the blood examination data (r = 0.6, p < 0.01). These observations suggest that cognitive dysfunction in patients with VCI may be caused by combinations of systemic metabolic disorders such as energy and oxygen metabolisms and cerebral circulatory disturbance due to arteriosclerosis resulting from lifestyle-related diseases.

Thoracoscopic esophagectomy with extended lymph node dissection in the left lateral position: technical feasibility and oncologic outcomes.

The aim of this study was to estimate the technical and oncologic feasibility of video-assisted thoracoscopic radical esophagectomy (VATS) in the left lateral position. From January 2003 to December 2011, 132 patients with esophageal cancer underwent VATS. The mean duration of the thoracic procedure and the entire procedure was 294 ± 88 and 623 ± 123 minutes, respectively. Mean blood loss during the thoracic procedure and the entire procedure was 313 ± 577 and 657 ± 719 g, respectively. The mean number of dissected thoracic lymph nodes was 32.6 ± 12.9. There were four in-hospital deaths (3.0%); two patients (1.5%) died of acute respiratory distress syndrome and two patients (1.5%) died of tumor progression. Postoperative unilateral or bilateral recurrent laryngeal nerve (RLN) palsy, or pneumonia was found in 33 (25.0%), 21 (15.9%), and 27(20.5%) patients, respectively. The patients were divided into the first 66 patients who underwent VATS (Group 1) and the subsequent 66 patients (Group 2). The numbers of cases who underwent neoadjuvant or induction chemotherapy for T4 tumor and intrathoracic anastomosis were higher in Group 2 than in Group 1. The duration of the procedure, amount of blood loss, and the number of dissected thoracic lymph nodes were not different between the two groups. The total number of dissected lymph nodes was higher in Group 2 than in Group 1 (72.6 ± 27.8 vs. 62.6 ± 21.6, P = 0.023). The rate of bilateral RLN palsy was less in Group 2 than in Group 1 (7.6% vs. 24.2%, P = 0.042). The mean follow-up period was 38.7 months. Primary recurrence consisted of hematogenous, lymphatic, peritoneal dissemination, pleural dissemination, and locoregional in 15 (11.3%), 20 (15.1%), 3 (2.3%), 4 (3.0%), and 5 patients (3.8%), respectively. The rate of regional lymph node recurrence within the dissection field was only 4.5%. The prognosis of patients with lymph node metastasis was significantly poorer than that of patients without lymph node metastasis. However, the prognosis of the 11 cases that had metastasis only around RLNs was similar to that of node-negative cases. Thirteen patients with pathological remnant tumor (R1 or R2) did not survive longer than 5 years at present. The overall 5-year survival rate of stage I, II, and III disease after curative VATS was 82.2%, 77.0%, and 52.3%, respectively. Expansion of VATS criteria for patients after induction chemotherapy for T4 tumor or thoracoscopic anastomosis did not adversely affect the surgical results by experience. Although the VATS procedure is accompanied by a certain degree of morbidity including RLN palsy and pulmonary complications, VATS has an excellent locoregional control effect. In addition, the favorable survival after VATS shows that the procedure is oncologically feasible.

Granulocyte and monocyte adsorption apheresis as an effective treatment for Reiter disease.

Reiter disease (RD) is characterized by a triad of sterile arthritis, urethritis and conjunctivitis. The conditions occur concomitantly or sequentially, and are associated with mucocutaneous features such as circinate balanitis and stomatitis. Arthritis usually occurs in attacks followed by recovery, but it sometimes progresses to permanent damage of the affected joints. Because the symptoms of this disorder are attributable to activated neutrophils, we assessed the efficacy of granulocyte and monocyte adsorption apheresis (GCAP) in a 73-year-old man with RD who had skin rashes on his penis, scrotum and right hand, with severe arthralgia. The patient's skin rash and joint pain responded dramatically to five sessions of GCAP delivered at intervals of 5 days. We present a detailed description of the patient and discuss the mechanisms of GCAP, and suggest that GCAP may be useful for treating RD.

[Video-assisted thoracic surgery for pneumothorax in patients over fifty years of age].

BACKGROUND: Pneumothorax in middle-aged and elderly patients has various different features from young patients. We set out to investigate the outcome and usefulness of video-assisted thoracic surgery (VATS) in this group. PATIENTS AND METHODS: From January 1993 to August 2010, 168 patients underwent a total of 178 thoracoscopic surgeries. There were 160 men and 8 women with mean age of 67 (range, 50 to 85). The average duration of thoracic drainage before surgery was 7.4 days. We excised only responsible lesions as minimum degree of dissection as possible. When patients have intractable air leakage and chest computed tomography (CT) indicates severe pleural adhesions, pleurography should be performed to locate the site of air leakage and determine surgical approaches. One hundred and seventy patients were treated with the lateral approach, while 8 patients were successfully treated with the anterior approach. One hundred and fifty-one patients were treated with VATS alone, and 27 patients were treated with the combination of VATS and small thoracotomy. The duration of chest tube drainage, hospital stay, post-operative complication, outcome and recurrence were assessed. RESULTS: The air leakages stopped and all patients except for 2 patents were discharged without drainage tubes. Postoperative drainage time was 4.5 +/- 3.4 days. Postoperative hospital stay was 9.9 +/- 13.9 days. One patient died caused by perioperative myocardial infarction. Seventeen patients died of other diseases. Seven patients needed local hospital treatments and the recurrence rate was 3.9%. CONCLUSION: VATS for pneumothorax in patients over 50 years old is very useful by appropriate perioperative managements.

Genomic signatures of the evolution of defence against its natural enemies in the poisonous and medicinal plant Datura stramonium (Solanaceae).

Tropane alkaloids and terpenoids are widely used in the medicine and pharmaceutic industry and evolved as chemical defenses against herbivores and pathogens in the annual herb Datura stramonium (Solanaceae). Here, we present the first draft genomes of two plants from contrasting environments of D. stramonium. Using these de novo assemblies, along with other previously published genomes from 11 Solanaceae species, we carried out comparative genomic analyses to provide insights on the genome evolution of D. stramonium within the Solanaceae family, and to elucidate adaptive genomic signatures to biotic and abiotic stresses in this plant. We also studied, in detail, the evolution of four genes of D. stramonium-Putrescine N-methyltransferase, Tropinone reductase I, Tropinone reductase II and Hyoscyamine-6S-dioxygenase-involved in the tropane alkaloid biosynthesis. Our analyses revealed that the genomes of D. stramonium show signatures of expansion, physicochemical divergence and/or positive selection on proteins related to the production of tropane alkaloids, terpenoids, and glycoalkaloids as well as on R defensive genes and other important proteins related with biotic and abiotic pressures such as defense against natural enemies and drought.

Prospective randomized controlled study on the effects of perioperative administration of a neutrophil elastase inhibitor to patients undergoing video-assisted thoracoscopic surgery for thoracic esophageal cancer.

Sivelestat sodium hydrate (Ono Pharmaceutical Co., Osaka, Japan) is a selective inhibitor of neutrophil elastase (NE) and is effective in reducing acute lung injury associated with systemic inflammatory response syndrome (SIRS). We conducted a prospective randomized controlled study to investigate the efficacy of perioperative administration of sivelestat sodium hydrate to prevent postoperative acute lung injury in patients undergoing thoracoscopic esophagectomy and radical lymphadenectomy. Twenty-two patients with thoracic esophageal cancer underwent video-assisted thoracoscopic esophagectomy with extended lymph node dissection in our institution between April 2007 and November 2008. Using a double-blinded method, these patients were randomly assigned to one of two groups preoperatively. The active treatment group received sivelestat sodium hydrate intravenously for 72 hours starting at the beginning of surgery (sivelestat-treated group; n= 11), while the other group received saline (control group; n= 11). All patients were given methylprednisolone immediately before surgery. Postoperative clinical course was compared between the two groups. Two patients (one in each group) were discontinued from the study during the postoperative period because of surgery-related complications. Of the remaining 20 patients, 2 patients who developed pneumonia within a week after surgery were excluded from some laboratory analyses, so data from 18 patients (9 patients in each group) were analyzed based on the arterial oxygen pressure/fraction of inspired oxygen ratio, white blood cell count, serum C-reactive protein level, plasma cytokine levels, plasma NE level, and markers of alveolar type II epithelial cells. In the current study, the incidence of postoperative morbidity did not differ between the two groups. The median duration of SIRS in the sivelestat-treated group was significantly shorter than that in the control group: 17 (range 9-36) hours versus 49 (15-60) hours, respectively (P= 0.009). Concerning the parameters used for the diagnosis of SIRS, the median heart rates on postoperative day (POD) 2 were significantly lower in the sivelestat-treated group than in the control group (P= 0.007). The median arterial oxygen pressure/fraction of inspired oxygen ratio of the sivelestat-treated group were significantly higher than those of the control group on POD 1 and POD 7 (POD 1: 372.0 [range 284.0-475.0] vs 322.5 [243.5-380.0], respectively, P= 0.040; POD 7: 377.2 [339.5-430.0] vs 357.6 [240.0-392.8], P= 0.031). Postoperative white blood cell counts, serum C-reactive protein levels, plasma interleukin-1beta, tumor necrosis factor-alpha levels, and plasma NE levels did not differ significantly between the two groups at any point during the postoperative course, nor did serum Krebs von den Lungen 6, surfactant protein-A, or surfactant protein-D levels, which were used as markers of alveolar type II epithelial cells to evaluate the severity of lung injury. Plasma interleukin-8 levels were significantly lower in the sivelestat-treated group than in the control group on POD 3 (P= 0.040). In conclusion, perioperative administration of sivelestat sodium hydrate (starting at the beginning of surgery) mitigated postoperative hypoxia, partially suppressed postoperative hypercytokinemia, shortened the duration of SIRS, and stabilized postoperative circulatory status after thoracoscopic esophagectomy.

Learning of thoracoscopic radical esophagectomy: how can the learning curve be made short and flat?

Attainment of proficiency in video-assisted thoracoscopic radical esophagectomy (VATS) for thoracic esophageal cancer requires much experience. We have mastered this procedure safely under the direction of an experienced surgeon. After adoption of the procedure, the educated surgeon directed induction of this surgical procedure at another institution. We evaluated the efficacy of instruction during the induction period by comparing the results at the two institutions in which VATS had been newly induced. We defined the induction period as the time from the beginning of VATS to the time when the last instruction was carried out. From January 2003 to December 2007, 53 patients were candidates for VATS at Kanazawa University (institution 1). Of these, 46 patients underwent curative VATS by a single operator. We divided this period into three parts: the induction period of VATS, post-induction period, and proficient period when the educated surgeon of institution 1 directed the procedure at Maebashi Red Cross Hospital (institution 2). At institution 1, 12 VATS were scheduled, and nine procedures (75%) (group A) including eight instructions were completed during the induction period (from January 2003 to August 2004). Thereafter, VATS was performed without instruction. In the post-induction period, nine VATS were scheduled, and eight procedures (88.8%) (group B) were completed from September 2004 to August 2005. Subsequently, 32 VATS were scheduled, and 29 procedures (90.6%) (group C) were completed during the proficient period (from September 2005 to December 2007). The surgeon at Maebashi Red Cross Hospital (institution 2) started to perform VATS under the direction of the surgeon who had been educated at institution 1 from September 2005. VATS was completed in 13 (76.4%) (group D) of 17 cases by a single surgeon including seven instructions during the induction period at institution 2 from September 2005 to December 2007. No lethal complication occurred during the induction period at both institutions. We compared the results of VATS among four groups from the two institutions. There were no differences in the background and clinicopathological features among the four groups. The number of dissected lymph nodes and amount of thoracic blood loss were similar in the four groups (35 [22-52] vs 41 [26-53] vs 32 [17-69] vs 29 [17-42] nodes, P = 0.139, and 170 [90-380] vs 275 [130-550] vs 220 [10-660] vs 210 [75-543] g, P = 0.373, respectively). There was no difference in the duration of the thoracic procedure during the induction period at the two institutions. However, the duration of the procedure was significantly shorter in the proficient period of institution 1 (group C: 266 [195-555] minutes) than in the induction period of both institutions (group A: 350 [280-448] minutes [P = 0.005] and group D: 345 [270-420] mL [P = 0.002]). There were no surgery-related deaths in any of the groups. The incidence of postoperative complications did not differ among the four groups. Thoracoscopic radical esophagectomy can be mastered quickly and safely with a flat learning curve under the direction of an experienced surgeon. The educated surgeon can instruct surgeons at another institution on how to perform thoracoscopic esophagectomy. The operation time of thoracoscopic surgery is shortened by experience.

Prevention of neural tube defects by loss of function of inducible nitric oxide synthase in fetuses of a mouse model of streptozotocin-induced diabetes.

AIMS/HYPOTHESIS: Maternal diabetes during pregnancy increases the risk of congenital malformations such as neural tube defects (NTDs). Although the mechanism of this effect is uncertain, it is known that levels of nitric oxide synthase (NOS) and nitric oxide are elevated in embryos of a mouse model of diabetes. We postulated that overproduction of nitric oxide causes diabetes-induced congenital malformations and that inhibition of inducible NOS (iNOS) might prevent diabetic embryopathy. METHODS: Mice were rendered hyperglycaemic by intraperitoneal injection of streptozotocin. The incidence of congenital malformations including NTDs was evaluated on gestational day 18.5. We assessed the involvement of iNOS in diabetes-induced malformation by administering ONO-1714, a specific inhibitor of iNOS, to pregnant mice with streptozotocin-induced diabetic mice and by screening mice with iNOS deficiency due to genetic knockout (iNos(-/-)). RESULTS: ONO-1714 markedly reduced the incidence of congenital anomalies, including NTDs, in fetuses of a mouse model of diabetes. It also prevented apoptosis in the head region of fetuses, indicating that iNOS is involved in diabetes-related congenital malformations. Indeed, no NTDs were observed in fetuses of diabetic iNos(-/-) mice and the incidence of other malformations was also markedly reduced. CONCLUSIONS/INTERPRETATION: We conclude that increased iNOS activity during organogenesis plays a crucial role in the pathogenesis of diabetes-induced malformations and suggest that inhibitors of iNOS might help prevent malformations, especially NTDs, in diabetic pregnancy.

Alpha-lipoic acid reduces congenital malformations in the offspring of diabetic mice.

BACKGROUND: The mechanism of diabetes-induced congenital malformation remains to be elucidated. It has been reported that alpha-lipoic acid (LA) prevents neural tube defects (NTDs) in offsprings of rats with streptozotocin-induced diabetes. Here, we evaluate the protective effect of LA against diabetic embryopathy, including NTDs, cardiovascular malformations (CVMs), and skeletal malformations, in mice. METHODS: Female mice were rendered hyperglycemic using streptozotocin and then mated with normal male mouse. Pregnant diabetic or non-diabetic mice were treated daily with either LA (100 mg/kg body weight) or saline between gestational days 0 and 18. On day 18, fetuses were examined for congenital malformations. RESULTS: Plasma glucose levels on day 18 were not affected by LA treatment. No congenital malformations were observed either in the saline-treated or LA-treated non-diabetic group. In the saline-treated diabetic group, 39% of fetuses had external malformations and 30% had NTDs. In the LA-treated diabetic group, the corresponding proportions were 11 and 8%, respectively. LA treatment also decreased the incidence of CVMs from 30-3% and of skeletal malformations from 29-6%. CONCLUSIONS: We conclude that LA can reduce NTDs, CVMs and skeletal malformations in the offspring of diabetic mice at term delivery.

AKT induces senescence in primary esophageal epithelial cells but is permissive for differentiation as revealed in organotypic culture.

Epidermal growth factor receptor (EGFR) overexpression and activation is critical in the initiation and progression of cancers, especially those of epithelial origin. EGFR activation is associated with the induction of divergent signal transduction pathways and a gamut of cellular processes; however, the cell-type and tissue-type specificity conferred by certain pathways remains to be elucidated. In the context of the esophageal epithelium, a prototype stratified squamous epithelium, EGFR overexpression is relevant in the earliest events of carcinogenesis as modeled in a three-dimensional organotypic culture system. We demonstrate that the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway, and not the MEK/MAPK (mitogen-activated protein kinase) pathway, is preferentially activated in EGFR-mediated esophageal epithelial hyperplasia, a premalignant lesion. The hyperplasia was abolished with direct inhibition of PI3K and of AKT but not with inhibition of the MAPK pathway. With the introduction of an inducible AKT vector in both primary and immortalized esophageal epithelial cells, we find that AKT overexpression and activation is permissive for complete epithelial formation in organotypic culture, but imposes a growth constraint in cells grown in monolayer. In organotypic culture, AKT mediates changes related to cell shape and size with an expansion of the differentiated compartment.

[Extremely elderly patient in whom the pacing lead was implanted via the femoral vein].

We report on an extremely elderly patient in whom we were unable to insert a pacing lead via the subclavian or internal jugular vein because of a superior vena cava obstruction; we instead inserted the pacing lead via the femoral vein. The patient was a 98-year-old male. Thirty-nine years previously, pacemaker implantation was performed for complete atrioventricular block. Afterwards, pacemaker replacement and reimplantation had been performed a total of 15 times. The patient was recently admitted because of pacing failure. Pacemaker replacement was performed, but pacing was not possible because of disconnection of the pacing lead. Insertion of a new pacing lead was attempted via both subclavian veins and the right jugular vein but failed; this approach was abandoned and temporary pacing was done. Superior vena cava obstruction was noted on chest computed tomography (CT), and pacing lead insertion through the superior vena cava was deemed unfeasible. Myocardial electrode implantation was also considered, but general anesthesia was deemed problematic because of the patient's extreme age. A pacing lead was inserted via the right femoral vein, and the generator was implanted in the right lower abdomen. Postoperative pacing was satisfactory.

Petrous apex cholesterol granuloma treated via the endoscopic transsphenoidal approach.

Numerous surgical approaches have been used to treat petrous apex cholesterol granulomas. They are usually treated via the transtemporal- or middle fossa approach; some are managed endoscopically. We present a patient treated by the endoscopic transsphenoidal approach and review the literature.

Von Willebrand Factor Deposition and ADAMTS-13 Consumption in Allograft Tissue of Thrombotic Microangiopathy-like Disorder After Living Donor Liver Transplantation: A Case Report.

BACKGROUND: Thrombotic microangiopathy (TMA) pathogenesis after living donor liver transplantation (LDLT) is thought to be caused by release of unusually large von Willebrand factor multimers (UL-vWFMs) resulting from sinusoidal endothelial cell damage and induction of platelet adhesion and aggregation. A decrease in a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs-13 (ADAMTS-13) that cleave UL-vWFMs might cause excessive UL-vWFMs activity and result in platelet thrombus formation. However, this phenomenon has not undergone a full pathologic assessment. PROCEDURES: A 60-year-old man was diagnosed with hepatitis C-related end-stage cirrhosis. His son was the donor, and he underwent LDLT. On postoperative day 44, his laboratory findings met most TMA diagnostic criteria, and he was diagnosed with TMA-like disorder (TMALD). Localization of CD42b as a platelet marker, vWF, and ADAMTS-13 in allograft tissue of this patient were evaluated using immunohistochemistry. RESULTS: CD42b expression was observed as platelet aggregates attached to hepatocytes or within the hepatocyte cytoplasm, a morphology called extravasated platelet aggregation (EPA). vWF expression was observed mainly as deposited compact clusters, and ADAMTS-13 expression resembled distinct dots throughout the liver tissue. CONCLUSION: These findings suggest that EPA indicated sinusoidal endothelial cell damage followed by detachment, and vWF deposition resulted from UL-vWFM oversynthesis. ADAMTS-13 might be consumed in the allograft tissue to cleave UL-vWFMs, but ADAMTS-13 levels might be insufficient to cleave all the deposited UL-vWFMs. We present the case of an LDLT recipient diagnosed with TMALD using blood tests, which showed the presence of TMA pathogenesis in the allograft.

Antitumor activity of 1 M tegafur-0.4 M 5-chloro-2,4-dihydroxypyridine-1 M potassium oxonate (S-1) against human colon carcinoma orthotopically implanted into nude rats.

The purpose of this study was to establish a nude rat orthotopic (organ-specific) human colorectal cancer model as an in vivo secondary screen for general evaluation of new anticancer agents against colorectal cancer and to evaluate practically the antitumor activity of 1 M tegafur-0.4 M 5-chloro-2,4-dihydroxypyridine-1 M potassium oxonate (S-1), a new p.o. fluoropyrimidine, in comparison to 1 M tegafur-4 M uracil [(UFT) effective on colorectal tumor in clinical]. After implantation of KM12C, a human colorectal cancer cell line, into the subserosal layer of the colon as a single-cell suspension, extensive local tumor growth and invasion to both the mucosal and the serosal sides were observed in all rats. Metastatic foci were also formed in both lymph nodes and lungs following local tumor growth in all of them. Using this method, an equitoxic dose of S-1 (15 mg/kg/day) and UFT (30 mg/kg/day) was administered p.o. for 14 consecutive days from 7 days after tumor cell implantation. S-1 showed a higher tumor growth inhibition than UFT did [S-1, 57% (significantly different from the tumor weight of the untreated group at P < 0.05) and UFT, 18% (P > 0.05)]. When both drugs were administered to nude rats bearing KM12C injected into the cecal wall for 28 consecutive days at equitoxic doses, the mean survival in the S-1 group was 16 days longer than that in the untreated group (P < 0.01) but that in the UFT group was only 8 days longer (P > 0.05). After the administration of an equitoxic dose of both drugs, S-1 gave the higher levels than UFT in various pharmacokinetic parameters as follows: area under the curve 0-24 h of 5-fluorouracil in plasma (3.5-fold), area under the curve 0-24 h of 5-fluorouracil incorporated into RNA in the tumor (1.3-fold), and thymidylate synthase inhibition rate (percentage) in the tumor (about 20%). Collectively, these findings suggested that this orthotopic human colorectal tumor model in nude rats is useful to evaluate the clinical therapeutic efficacy of drugs or therapies for colorectal cancer, and that S-1 had a higher therapeutic effect on human colorectal tumor than UFT did.

Inferring phenotypic causal structures among meat quality traits and the application of a structural equation model in Japanese Black cattle.

Meat quality is one of the most important traits determining carcass price in the Japanese beef market. Optimized breeding goals and management practices for the improvement of meat quality traits requires knowledge regarding any potential functional relationships between them. In this context, the objective of this research was to infer phenotypic causal networks involving beef marbling score (BMS), beef color score (BCL), firmness of beef (FIR), texture of beef (TEX), beef fat color score (BFS), and the ratio of MUFA to SFA (MUS) from 11,855 Japanese Black cattle. The inductive causation (IC) algorithm was implemented to search for causal links among these traits and was conditionally applied to their joint distribution on genetic effects. This information was obtained from the posterior distribution of the residual (co)variance matrix of a standard Bayesian multiple trait model (MTM). Apart from BFS, the IC algorithm implemented with 95% highest posterior density (HPD) intervals detected only undirected links among the traits. However, as a result of the application of 80% HPD intervals, more links were recovered and the undirected links were changed into directed ones, except between FIR and TEX. Therefore, 2 competing causal networks resulting from the IC algorithm, with either the arrow FIR → TEX or the arrow FIR ← TEX, were fitted using a structural equation model () to infer causal structure coefficients between the selected traits. Results indicated similar genetic and residual variances as well as genetic correlation estimates from both structural equation models. The genetic variances in BMS, FIR, and TEX from the structural equation models were smaller than those obtained from the MTM. In contrast, the variances in BCL, BFS, and MUS, which were not conditioned on any of the other traits in the causal structures, had no significant differences between the structural equation model and MTM. The structural coefficient for the path from MUS (BCL) to BMS showed that a 1-unit improvement in MUS (BCL) resulted in an increase of 0.85 or 1.45 (an decrease of 0.52 or 0.54) in BMS in the causal structures. The analysis revealed some interesting functional relationships, direct genetic effects, and the magnitude of the causal effects between these traits, for example, indicating that BMS would be affected by interventions on MUS and BCL. In addition, if interventions existed in this scenario, a breeding strategy based only on the MTM would lead to a mistaken selection for BMS.

Ischemia reperfusion-facilitated sinusoidal endothelial cell injury in liver transplantation and the resulting impact of extravasated platelet aggregation.

BACKGROUND: The exact sequence of events leading to ultimate hepatocellular damage following ischemia/reperfusion (I/R) is incompletely understood. In this article, we review a mechanism of organ dysfunction after hepatic I/R or immunosuppressive treatment, in addition to the potential of liver sinusoidal endothelial cell (LSEC) protection and antiplatelet treatment for the suppression of hepatocellular damage. METHODS: A review of the literature, utilizing PubMed-NCBI, was used to provide information on the components necessary for the development of hepatocellular damage following I/R. RESULTS: It is well-established that LSECs damage following hepatic I/R or immunosuppressive treatment followed by extravasated platelet aggregation (EPA) is the root cause of organ dysfunction in liver transplantation. We have classified three phases, from LSECs damage to organ dysfunction, utilizing the predicted pathogenic mechanism of sinusoidal obstruction syndrome. The first phase is detachment of LSECs and sinusoidal wall destruction after LSECs injury by hepatic I/R or immunosuppressive treatment. The second phase is EPA, accomplished by sinusoidal wall destruction. The various growth factors, including thromboxane A2, serotonin, transforming growth factor-beta and plasminogen activator inhibitor-1, released by EPA in the Disse's space of zone three, induce portal hypertension and the progression of hepatic fibrosis. The third phase is organ dysfunction following portal hypertension, hepatic fibrosis, and suppressed liver regeneration through various growth factors secreted by EPA. CONCLUSION: We suggest that EPA in the space of Disse, initiated by LSECs damage due to hepatic I/R or immunosuppressive treatment, and activated platelets may primarily contribute to liver damage in liver transplantation. Endothelial protective therapy or antiplatelet treatment may be useful in the treatment of hepatic I/R following EPA.

Genetic relationships between internal diseases diagnosed at slaughter and carcass traits in Japanese Black cattle.

The objective of this paper was to estimate the genetic parameters of certain internal diseases (multifocal necrosis in the liver [MNL], bovine abdominal fat necrosis [BFN], and inflammation of the large intestine [ILI]) and to investigate relationships between the internal diseases and carcass traits (carcass weight [CW], rib eye area [REA], rib thickness [RT], subcutaneous fat thickness, and beef marbling score [BMS]). Records of the internal diseases and the carcass traits of 5,788 Japanese Black cattle were used for this study. The data for all the diseases were recorded as binary data as to whether the disease was observed (1) or not (0). Genetic parameters were estimated using linear and threshold animal models. The prevalence rates of MNL, BFN, and ILI were 16.1, 23.0, and 6.8%, respectively, and heritability estimates ± posterior SD were 0.18 ± 0.06, 0.28 ± 0.06, and 0.18 ± 0.06, respectively. The genetic correlations of MNL with BFN and ILI were -0.23 (P = 0.19) and -0.49 (P < 0.05), respectively. In contrast, the correlation between BFN and ILI was positive and high (0.96; < 0.05). The phenotypic correlations of the internal diseases with the carcass traits were weak and not different from 0 except for those of BFN and ILI with CW, REA, and RT, which were all negative (P < 0.05) and ranged from -0.21 (ILI and CW) to -0.05 (BFN and RT). The genetic correlations of MNL with the carcass traits were all weak and not significant. In contrast, the genetic correlations of BFN and ILI with CW, REA, and RT were all negative and significant (P < 0.05) between BFN and CW (-0.36) and between BFN and RT (-0.33). However, the genetic correlations for BFN and ILI with BMS were all positive at 0.21 P( = 0.16) and 0.39 (P < 0.05), respectively. The estimated heritability of the internal diseases suggests that they can be genetically improved. Genetic relationships of BFN and ILI with meat quantity traits were favorable for beef cattle breeding, because lower disease liabilities were associated with improved CW, REA, and RT for BFN and ILI. However, rather strong and unfavorable genetic relationships were found between BFN or ILI and BMS, which is related to meat quality. This suggests that selection for animals with superior BMS would increasingly lead to animals with higher liability to the internal diseases.