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Background: Indications for adjuvant chemotherapy for advanced gastric cancer are determined based on the pathological diagnosis. However, macroscopic diagnoses have been reported as predictors of peritoneal recurrence and survival. This study investigated the predictability of peritoneal recurrence and survival based on macroscopically (sT) and pathologically (pT) diagnosed serosal invasion to identify more sensitive predictors of peritoneal recurrence., Methods: This study included 396 patients who underwent R0 resection without adjuvant chemotherapy with S-1 in the JCOG0110 study. Tumor depth limited to the subserosa (SS) was defined as serosal invasion negative (T-), while tumors with serosal invasion (SE, SI) were defined as serosal invasion positive (T+). The predictability of peritoneal recurrence based on sT and pT was evaluated using the Fine and Gray model. Cox regression analyses were performed for overall survival (OS) and relapse-free survival (RFS) with sT or pT as covariates., Findings: A total of 150 patients (37.9%) were sT+ and 82 (26.3%) were pT+. Sixty-two patients (15.7%) were sT+/pT+, 88 (22.2%) were sT+/pT-, 20 (5.1%) were sT-/pT+, and 226 (57.1%) were sT-/pT-. Both sT and pT were found to be independent predictors of peritoneal recurrence, OS, and RFS. The 5-year RFS rates of sT+/pT+, sT+/pT-, sT-/pT+, and sT-/pT-patients were 45.2%, 63.6%, 55.0%, and 81.8%, respectively., Conclusion: Intraoperatively diagnosed macroscopic serosal invasion showed a similar predictive value for peritoneal recurrence as pathologically diagnosed serosal invasion. The establishment of a novel staging system incorporating macroscopic serosal invasion is recommended., Competing Interests: Declaration of competing interest MT reports lecture fees from Taiho Pharmaceutical, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol-Myers Squibb, Yakult Honsha, Takeda Pharmaceutical, Eli Lilly Japan KK, Pfizer Pharmaceutical, Daiichi Sankyo, Johnson and Johnson, Medtronic Japan, Intuitive Japan, Olympus outside the submitted work. JM reports the funding from National Cancer Center, Japan and the Ministry of Labour and Welfare, Japan for the present study, and personal fees from Chugai Pharmaceutical, outside the submitted work. TS reports personal fees from Taiho Pharma, Chugai Pharma, Ono Pharma, Eli Lilly, outside the submitted work. TY reports grants from Eli Lilly japan, personal fees from MSD, BMS, Ono, Taiho, Lilly, Chugai, Pfizer, Nihon Kayaku, Terumo, Otsuka, Myarisan, EA pharma, Astra-Zeneca, Covidien, Johnson and Johnson outside the submitted work. NB received a research grant from Ono and Takeda and honorarium from Taiho, Ono, Bristol-Myers Squibb outside the submitted work. MS reports lecture fees from Taiho Pharmaceutical and Eli Lilly, travel support from Eli Lilly outside the submitted work, and has served as Chairman of the board of directors of the Japan Gastric Cancer Association and member of the Guideline committee of the Japan Gastric cancer Association during the study period. All the other authors declare no competing interests. Red lines represent serosal invasion positive and blue lines represent serosal invasion negative. The C-index was calculated using the Fine and Gray model., (Copyright © 2022 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: UVB radiation is the main source of sunburn and skin cancers. Apoptosis eliminates photodamaged cells, and is thus important for preventing epidermal carcinogenesis. The cytoplasmic regulatory protein p62/A170/sequestosome 1 (p62) molecule is involved in a variety of cellular and signaling pathways. p62 is known to be and important in autophagy, but its role in UVB-induced apoptosis remains to be clarified., Objective: To investigate the role of p62 against UVB-induced apoptotic changes, using mouse embryonic fibroblasts (MEFs) derived from p62 homozygous knockout (p62(-/-)) mice., Methods: p62(-/-) and wild-type (p62(+/+)) mice and MEFs were subjected to UVB irradiation, and the resultant apoptosis was analyzed using flow cytometry, quantitative real-time PCR, and western blots., Results: Apoptosis was decreased in the p62(-/-) MEFs compared to p62(+/+) MEFs in response to UVB treatment. Compared with p62(+/+) MEFs, p62(-/-) MEFs expressed significantly more Bcl-2 and less Bax, and showed increased Src and Stat3 phosphorylation. Our results show that p62 regulates apoptotic pathways by modifying critical signaling intermediates such as Src and Stat3., Conclusion: p62 deficiency [corrected] reduces UVB-induced apoptosis by modulating intrinsic apoptotic signaling through Src phosphorylation., (Copyright © 2016 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.)

Background: Exposure of skin to long-wave UV radiation (UVA) increases the cellular levels of reactive oxygen species (ROS), which have been linked to apoptosis induction through the damage of lipids, proteins, and nucleic acids. Peroxiredoxin I (Prx I) is one of a family of antioxidant proteins that plays a protective role against oxidative damage; however the role of Prx I in UVA-induced damage remains to be clarified., Objective: Here we investigated the protective role of Prx I against UVA-induced changes using mouse embryonic fibroblasts (MEFs) derived from Prx I homozygous knockout (Prx I (-/-)) mice., Methods: Prx I (-/-) and wild-type (Prx I (+/+)) MEFs were subjected to UVA irradiation, and the resulting apoptosis was analyzed using flow cytometry, quantitative real-time PCR, and western blotting., Results: Prx I (-/-) MEFs showed enhanced sensitivity to UVA treatment, exhibiting increased apoptosis and ROS production compared to Prx I (+/+) MEFs. Consistent with the increase in apoptosis, p53 expression was significantly higher, while Bcl-2, Bcl-xL, and Nrf2 expressions were all lower in Prx I (-/-) versus (+/+) MEFs. The UVA-induced inflammatory response was upregulated in Prx I (-/-) MEFs, as indicated by increased expressions of IκB, TNFα, and IL-6. Evidence was presented indicating that Prx I impacts these pathways by modifying critical signaling intermediates including p53, IκB, and Nrf2., Conclusion: Our results indicate that Prx I plays a protective role against UVA-induced oxidative damage by controlling ROS accumulation. Both the UVA-induced apoptotic and inflammatory signals were found to be modulated by Prx I., (Copyright © 2013 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.)

Proliferation and differentiation in the epidermis must be tightly regulated. This regulation is known to involve a range of transcription factors, including pituitary tumor transforming gene 1 (PTTG1), a ubiquitously distributed transcription factor that regulates keratinocyte proliferation and differentiation. Psoriasis is a common but refractory skin disorder, the pathophysiology of which is characterized by hyperproliferation and impaired differentiation in the epidermis. The present study was conducted to clarify the less well-known roles of PTTG1 in the pathophysiology of psoriasis, focusing on its relationship with tumor necrosis factor-α (TNF-α), which is a critical mediator of the disease. The levels of PTTG1 expression were increased in the psoriatic epidermis. Overexpression of PTTG1 resulted in the overproduction of TNF-α, and TNF-α itself had an inductive effect on PTTG1 expression, suggesting that their expression may involve autoinduction. Moreover, overexpression of PTTG1 involved augmented the expression of cyclin A and B1 proteins in both cultured keratinocytes and the psoriatic epidermis. Therefore, enhanced expression of PTTG1 in the psoriatic epidermis may result in aberrant regulation of the cell cycle and impaired differentiation via the interplay between PTTG1 and TNF-α.

The epidermis is a self-renewing tissue, the homeostasis of which is dependent upon the tight balance between proliferation and differentiation based on appropriate regulation of the cell cycle. The cell cycle regulation is dependent on the interactions among a number of cell cycle regulatory molecules, including the pituitary tumor-transforming gene 1 (PTTG1), also known as securin, a regulator of sister chromatid separation and transition from metaphase to anaphase. This study was conducted to clarify the less-known functions of PTTG1 in the epidermis by the use of keratinocytes cultured under two-dimensional (2D) or three-dimensional (3D) conditions. Forced overexpression of PTTG1 caused upregulation of cyclin B1, cyclin-dependent kinase 1 (CDK1), and c-Myc, resulting in enhanced proliferation and suppression of early differentiation without apparent alterations in terminal differentiation, and the exogenous PTTG1 was downregulated in association with cell cycle exit. In contrast, depletion of PTTG1 caused their downregulation and constrained proliferation with retention of differentiation capacity. These findings suggested that PTTG1 could alter the proliferation status by modulating the expression levels of the other cell cycle regulatory proteins, and excess PTTG1 primarily affects early differentiation of keratinocytes under the stability regulation associated with cell cycle exit.

Fourteen commercially available particle-packed columns and a monolithic column for hydrophilic interaction liquid chromatography (HILIC) were characterized in terms of the degree of hydrophilicity, the selectivity for hydrophilic-hydrophobic substituents, the selectivity for the regio and configurational differences in hydrophilic substituents, the selectivity for molecular shapes, the evaluation of electrostatic interactions, and the evaluation of the acidic-basic nature of the stationary phases using nucleoside derivatives, phenyl glucoside derivatives, xanthine derivatives, sodium p-toluenesulfonate, and trimethylphenylammonium chloride as a set of samples. Principal component analysis based on the data of retention factors could separate three clusters of the HILIC phases. The column efficiency and the peak asymmetry factors were also discussed. These data on the selectivity for partial structural differences were summarized as radar-shaped diagrams. This method of column characterization is helpful to classify HILIC stationary phases on the basis of their chromatographic properties, and to choose better columns for targets to be separated. Judging from the retention factor for uridine, these HILIC columns could be separated into two groups: strongly retentive and weakly retentive stationary phases. Among the strongly retentive stationary phases, zwitterionic and amide functionalities were found to be the most selective on the basis of partial structural differences. The hydroxyethyl-type stationary phase showed the highest retention factor, but with low separation efficiency. Weakly retentive stationary phases generally showed lower selectivity for partial structural differences., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Yin-Yang-1 (YY1) is a member of the GLI-Krüppel family of transcription factors, and both YY1 mRNA and protein expression have been identified in a number of different tissues and cell types suggesting that it is expressed both constitutively and ubiquitously. In epidermal tissue, however, we reported previously that YY1 protein is expressed at high levels in undifferentiated basal keratinocytes and is downregulated during differentiation toward the suprabasal layers. This differential expression pattern during keratinocyte differentiation suggests that YY1 may have an important role in regulating keratinocyte differentiation. In this study, we examined the role of YY1 in differentiation of the human keratinocyte cell line HaCaT using air-liquid interface three-dimensional culture. The constitutive overexpression of YY1 in HaCaT cells during air exposure-induced differentiation resulted in an undifferentiated phenotype, thickening of the stratified layers, suppression of differentiation marker expression, and retention of proliferative activity. These findings suggested that YY1 may have an important role in maintenance of the undifferentiated phenotype of keratinocytes in the basal epidermal layer, and that reduction of YY1 expression in the suprabasal layers may allow keratinocytes to differentiate and move toward the upper layers of the epidermis.

Much of the cell injury caused by ultraviolet A (UVA) irradiation is associated with oxidative stress. Quercetin is a major natural polyphenol that is known to protect cells from UVA-induced damage. Here, we investigated the molecular mechanism of this protection. Quercetin pretreatment strongly suppressed UVA-induced apoptosis in human keratinocyte HaCaT cells, markedly increased protein levels of the transcription factor Nrf2, induced the expression of antioxidative genes, and dramatically reduced the production of reactive oxygen species following UVA irradiation. Importantly, these beneficial effects were greatly attenuated by downregulating Nrf2 expression. Thus, quercetin protects cells from UVA damage mainly by elevating intracellular antioxidative activity via the enhanced accumulation of a transcription factor for antioxidant genes, Nrf2.

Objective: We aimed to assess the effects of age, comorbidity, and disease-specific functions on utility scores derived from three methods on prostate cancer., Methods: A total of 330 Japanese prostate cancer patients were asked to answer self-administered questionnaires. Community-weighted utility scores were derived from the EuroQoL-5D (EQ-5D) and the Short Form-36 (SF-36), while the patient's directly elicited utility score was derived from time trade-off technique. Univariate and multivariate analyses were performed to examine the relation between covariates and utility scores. We assigned age, the Index of Co-existent Disease, and disease-specific functions including sexual, urinary, bowel, and hormonal function as covariates., Results: Bowel and hormonal function were related to utility scores, while age and sexual function were not. Comorbidities were more closely related to utility scores derived from EQ-5D and SF-36., Conclusions: These results contribute to an understanding of which factor has an impact on utility scores in patients with prostate cancer.

UV radiation is an important environmental factor in the pathogenesis of skin aging and cancer. Many harmful effects of UV radiation are associated with generation of reactive oxygen species. Cellular antioxidants prevent the occurrence and reduce the severity of UV-induced photoaging and diseases of the skin. The transcription factor Nrf2 (NF-E2-related factor 2) and its negative regulator protein, Keap1 (Kelch-like-ECH-associated protein 1), are central regulators of cellular antioxidant responses. We used nrf2-null mice to investigate the roles of the Nrf2-Keap1 system in protection of skin from harmful effects of UVB irradiation. A single irradiation with UVB induced stronger and longer lasting sunburn reaction in nrf2-null mice. Histological changes, including epidermal necrosis, dermal edema, inflammatory cell infiltration, sunburn cell formation, TUNEL-positive apoptotic cell formation, and accumulation of oxidative DNA products such as 8-hydroxy-2'-deoxyguanosine after UVB irradiation, were more prominent in nrf2-null mice. These findings indicate that the Nrf2-Keap1 pathway plays an important role in protection of the skin against acute UVB reactions, including cutaneous cell apoptosis and oxidative damage. However, there were no significant differences in skin carcinogenesis between nrf2-null and wild-type mice exposed to chronic UVB irradiation, suggesting that there is a complex and subtle balance between factors promoting and preventing photocarcinogenesis. Journal of Investigative Dermatology (2008) 128, 1773-1779; doi:10.1038/sj.jid.5701245; published online 17 January 2008.

Ultraviolet (UV) radiation is one of the most important environmental factors involved in the pathogenesis of skin aging and cancer. Many harmful effects of UV radiation are associated with the generation of reactive oxygen species, and cellular antioxidants act to prevent the occurrence and reduce the severity of UV-induced skin disorders. Transcription factor NF-E2-related Factor 2 (Nrf2) and its cytoplasmic anchor protein Kelch-like-ECH-associated protein 1 (Keap1) are central regulators of the cellular antioxidant response. In this study, we investigated the effects of UV irradiation on the activation of Nrf2 in dermal fibroblasts. We found that UVA irradiation, but not UVB, causes nuclear translocation and accumulation of Nrf2 by a factor of 6.5 as compared with unirradiated controls. The nuclear accumulation of Nrf2 induced by UVA was enhanced by the photosensitizer hematoporphyrin. To evaluate the protective role of Nrf2 against UVA radiation, we examined UVA-induced apoptosis using dermal fibroblasts derived from nrf2 or keap1 gene knockout mice. Whereas disruption of nrf2 increased the number of apoptotic cells following UVA irradiation by 1.7-fold, disruption of keap1 decreased the apoptotic cell number by half as compared with wild-type controls. These findings thus demonstrate that the Nrf2-Keap1 pathway plays an important role in the protection of the skin against UVA irradiation.

Loricrin is a major component of the epidermal cornified cell envelope, and is expressed only in terminally differentiated keratinocytes. This cell differentiation-specific expression pattern suggests specific suppression of loricrin gene expression in undifferentiated keratinocytes as well as its activation in differentiated keratinocytes. We identified a negative regulatory sequence element in the first intron of the mouse loricrin gene involved in suppression of loricrin gene expression in undifferentiated keratinocytes. A database search indicated that this sequence contained the putative inverted Yin-Yang 1 (YY1)-binding motif. Constructs with point mutations in the putative YY1-binding motif showed increased reporter activity, indicating that YY1 negatively regulates loricrin gene transcription. Co-transfection experiments using a YY1 expression vector revealed that YY1 represses loricrin promoter activity. Western blotting and immunohistochemical analyses indicated that YY1 is more abundant in undifferentiated than in differentiated keratinocytes. These findings suggest that YY1 contributes to specific loricrin gene expression in differentiated keratinocytes by suppression of its transcription in undifferentiated keratinocytes. Furthermore, we demonstrated that forced expression of YY1 in differentiated keratinocytes results in specific downregulation of expression of other early and late differentiation markers.

Type 2 oculocutaneous albinism (OCA2) is an autosomal recessive disorder that results from mutations in the P gene that codes one of the melanosomal proteins, the function of which remains unknown. In this paper, we report the frequency of OCA2, 8%, among the Japanese albino population, six novel mutations containing four missense substitutions (P198L, P211L, R10W, M398I), and two splice site mutations (IVS15+1 G>A, IVS24-1 G>C). One of them, R10W, was within the putative signal peptide at the N-terminal of the P protein. This is the first report on the frequency of OCA2 in the Japanese albino population.

Background: Retrograde cerebral perfusion (RCP) is a simple technique and is expected to provide cerebral protection. However, its optimum management and limitations remain unclear. Transcranial Doppler has been used to monitor cerebral perfusion. Using this Doppler technique, we compared cerebral blood flow for RCP with that for selective cerebral perfusion., Methods: Thirty-two consecutive patients underwent elective surgical repair of an aortic aneurysm involving the aortic arch at Kyushu University Hospital. Retrograde cerebral perfusion was used in 15 patients and selective cerebral perfusion, in 17 patients. Continuous measurement of middle cerebral artery blood flow velocities was performed by transcranial Doppler technique., Results: Retrograde middle cerebral artery blood flow velocities during RCP could be measured in only 3 patients, whereas middle cerebral artery blood flow velocities during selective cerebral perfusion could be measured in all but 1 woman. The increase in middle cerebral artery blood flow velocities after RCP was significantly greater than that after selective cerebral perfusion., Conclusions: The measurement of middle cerebral artery blood flow velocities with transcranial Doppler technique is practicable during selective cerebral perfusion but difficult during RCP. The increase in middle cerebral artery blood flow velocities after RCP indicates reactive hyperemia and reflects the critical decrease in cerebral blood flow during this type of perfusion.

Background: No method has been available to assess the right ventricular (RV) pressure-volume relation in the operating room or intensive care unit. Left ventricular cross-sectional area measured by echocardiography using the technology of automated border detection has been used to construct left ventricular pressure-area (P-A) loops. In the human right ventricle, however, this approach has not been validated., Methods: We recorded RV P-A loops in 14 patients in the intensive care unit using transesophageal echocardiography. Multiple RV P-A loops were obtained by reducing preload with intravenous nitroglycerin, thereby elucidating the end-systolic P-A relation., Results: With an incremental dose of dobutamine, the slope of the RV end-systolic P-A relation increased (from 4.56+/-2.42 to 7.34+/-3.62 mm Hg/cm2, p<0.01), with no change in the x-axis intercept, which implied increased contractility. Furthermore, in the operating room we validated the use of RV cross-sectional area as a surrogate for RV volume by demonstrating the close correlation between the stroke area (maximal RV area minus minimal RV area) and stroke volume (r = 0.962; p<0.0001)., Conclusions: Transesophageal echocardiography with automated border detection is a promising tool for elucidating RV function through the analysis of RV P-A loops.

Background: Lazaroid, a series of 21-aminosteroids, has been shown to reduce free-radical-mediated injury after ischemia and reperfusion. Recent in vitro studies have demonstrated that, among the various compounds studied, the most efficient agent was U74500A. The question is whether these findings apply to the whole heart experiencing ischemia-reperfusion injury. In this study we compared the myocardial protective effects of U74006F, the only clinical candidate, and U74500A., Methods: An isolated rabbit heart preparation perfused with the blood from a support rabbit was used. All hearts were divided into three groups according to the administration of U74500A (4 mg/kg, group A; n = 7), U74006F (4 mg/kg, group F; n = 7), or solvent (group S; n = 7) to the donor rabbit before preservation. After 24 hours of preservation with University of Wisconsin solution at 0 degrees C, all hearts were perfused with cross-circulated blood for 60 minutes with the Langendorff mode followed by 40 minutes in the working mode., Results: After 10 minutes of reperfusion the serum lipid peroxide levels were significantly (p < 0.05) lower in group A (0.62+/-0.31 nmol/mL) than those in group S (2.1+/-1.3 nmol/mL) and group F (1.0+/-0.6 nmol/mL). The aortic flow rate at 10 mm Hg of left atrial pressure was significantly higher in group A (164+/-37 mL/min) than that of other groups (71+/-28 mL/min in group S and 97+/-28 mL/min in group F). There were no significant differences in high-energy phosphate levels after reperfusion among the three groups., Conclusion: These data imply that U74500A inhibits lipid peroxidation and prevents ischemia-reperfusion injury more efficiently than U74006F.

Monocytes/macrophages exert a series of important functions in vivo. To facilitate detailed investigation of their functional capacity and the mechanism leading to their differentiation, several cell lines have been established from primary material. We present here a new human monoblastic cell line, designated UG3. UG3 cells are characterized by the following features. (1) UG3 cells harbor the t(9;11)(p22;q23) translocation that results in fusion of the MLL and the AF9 genes and produce the corresponding AF9-MLL and MLL-AF9 fusion transcripts. (2) UG3 cells rely on the presence of exogenous growth factors for viability and proliferation, such as interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), or macrophage colony-stimulating factor (M-CSF). (3) When cultured in the presence of G-CSF, UG3 cells differentiate along the granulocytic lineage, as evidenced by segmentation of nuclei and positive staining for neutrophilic alkaline phosphatase and peroxidase. (4) When cultured in the presence of GM-CSF or M-CSF, UG3 cells differentiate into mature macrophages while preserving surface expression of CD14 and CD68 and also start to release cytokines into cell-culture supernatants. Under these culture conditions, UG3 cells also take up acetylated LDL. (5) When cultured in the presence of M-CSF and IL-4, UG3 cells differentiate into osteoclast-like multinucleated giant cells capable of bone resorption and display tartrate-resistant acid phosphatase (TRAP) activity. UG3 cells thus provide features to qualify them as a useful model to further investigate the mechanism underlying these processes and also to further elucidate the functional role of mature monocytes/macrophages or osteoclasts.

We studied the molecular genetic basis of a C1 inhibitor deficiency in a patient with type I hereditary angioneurotic edema using both the polymerase chain reaction and nucleotide sequencing. A single nucleotide change (T-->A) at the GT 5' donor splice recognition motif in the seventh intron of the C1 inhibitor gene was detected. A restriction site analysis of the C1 inhibitor gene in the patient's family indicated that this mutation is correlated with a decreased level of C1 inhibitor activity. A northern blot analysis demonstrated C1 inhibitor mRNA to have a normal size, but its contents were reduced by about 50% compared with a normal subject. As the donor splice site is essential for an excising of the intron during mRNA processing, aberrant mRNA splicing may cause a rapid degradation of the transcript, thus resulting in the onset of hereditary angioneurotic edema.

We examined eosinophil-colony stimulating activity in blister fluid or serum obtained from patients with bullous pemphigoid using the methylcellulose semi-solid hematopoietic stem cell culture system, and demonstrated that the blister fluid of patients with bullous pemphigoid generated strong eosinophil-colony stimulating activity. This evidence suggests that eosinophil-colony stimulating activity in blister fluid probably influences the induction of eosinophilia in bullous pemphigoid.

We show that in two cell lines of human squamous cell carcinoma (SCC) which slightly express intercellular adhesion molecule-1 (ICAM-1), the expression is enhanced not only by interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) but also by interleukin-1 (IL-1) and lipopolysaccharide (LPS). This expression is totally dependent on the increase of ICAM-1 mRNA. This evidence contrasts with previously reported findings indicating that, in human cultured keratinocytes, ICAM-1 expression is induced by IFN-gamma and TNF-alpha, and not by either IL-1 or LPS. This result suggests that various cytokines or agents easily enhance ICAM-1 expression in SCC cell lines, and may explain the clinical finding that ICAM-1 expression increases according to the progression of malignant tumors.

Thymidylate synthetase (TS) and thymidine kinase (TK) are key enzymes in de novo and salvage pathways for pyrimidine nucleotide synthesis, respectively. A high incidence of colorectal adenocarcinomas with varied grades of cell differentiation can be induced by 1,2-dimethylhydrazine (DMH) in rats. The marked increases of TS and TK activities were found in the poorly and well-differentiated adenocarcinomas of the colon, respectively. Oral administration of 1-(2-tetrahydrofuryl)-5-fluorouracil in combination with uracil (UFT) markedly reduced the number and accumulated area of colonic carcinomas, and TS activity in the poorly differentiated adenocarcinomas. A potential balance between the de novo and the salvage pathways for pyrimidine nucleotide synthesis was suggested to be related with the histopathological grades of cell differentiation. Suppression of colonic TS activity by UFT administration reduced the colonic carcinogenesis and the potency of the poorly differentiated adenocarcinomas of the colon.

Background: Steroid use during cardiac operations may reduce the risk of postperfusion lung syndrome, but both cardiopulmonary bypass and steroids are immunosuppressive. The synergistic effects of the bypass and steroids on patients' immunologic activities, hemodynamics, and metabolisms during and after heart operations have not been clarified systematically., Methods: Twenty-four patients undergoing valve replacement were studied in a randomized, double-blind trial. Twelve of these patients (S group) received bolus methylprednisolone, 20 mg/kg body weight, and the remaining 12 patients (C group) received a placebo intravenously before and after bypass. Blood cell count, C-reactive protein, lymphocyte surface markers (CD3, CD4, CD8, CD16, and CD20), phytohemagglutinin response, interleukin-2 production, and natural killer cell activity were examined on admission through day 7. Cardiac output, blood gas, electrolyte, lactate, and serum glucose levels were examined perioperatively., Results: The peak white blood cell count in the S group was higher than that in the C group (analysis of variance: p [group] = 0.0436). The peak C-reactive protein level was higher in the C group than in the S group (p [group] < 0.0001). From the analysis of the surface markers, the steroid increased the natural killer cells before and soon after bypass (p [group] = 0.0117), and later tended to increase the CD4+ T and B cells during the postoperative recovery period. The phytohemagglutinin response in both groups decreased after bypass (p [time] < 0.0001), but the steroid caused exaggerated decreases before (p < 0.01 by Student's t test) and soon after (p < 0.001) bypass in the S group (analysis of variance: p [group] = 0.0127). The interleukin-2 production was suppressed by bypass alone after the bypass in the C group, but was further suppressed by the steroid before and after bypass in the S group (p [group] = 0.0446). The cardiac index, water balance, electrolytes, arterial oxygen tension, and timing of extubation were not different between the groups. In contrast, the glucose (p [group] = 0.0486) and lactate (p [group] = 0.0525) levels were higher in the S group than those in the C group., Conclusions: T-cell functions are synergistically suppressed by cardiopulmonary bypass and high-dose methylprednisolone in heart operations. The hemodynamic benefits of the steroid are negligible, whereas glucose tolerance is worsened by the steroid during bypass.

Background: The superior-septal approach provides an excellent view of the mitral valve and therefore has received considerable interest. However, the safety of this approach is controversial because it requires division of the sinus node artery in most cases., Methods: Postoperative cardiac rhythms were analyzed in 152 consecutive patients who underwent mitral valve procedures between January 1992 and February 1995 with a conventional right lateral left atriotomy (group 1, n = 69) or the superior-septal approach (group 2, n = 83). Follow-up ranged from 2 to 38 months, and the mean follow-up was 16.1 months in group 1 and 13.8 months in group 2., Results: The mortality rate was similar in the two groups (1.4% in group 1 and 1.2% in group 2), and the causes of death were not related to the left atriotomy. At discharge, 96% of the patients in group 1 who were in sinus rhythm preoperatively and 78% of those in group 2 remained in sinus rhythm. At the last follow-up, 88% of these patients in group 1 and 83% in group 2 remained in sinus rhythm. Among the patients in atrial fibrillation or junctional rhythm before operation, 12% in group 1 and 11% in group 2 had regained sinus rhythm at the last follow-up. There were no significant differences in these values., Conclusions: Although the incidence of dysrhythmias was higher with the superior-septal approach in the early postoperative period, this approach provides an excellent operative view of the mitral valve and similar results in terms of late postoperative cardiac rhythms as the right lateral left atriotomy.

We describe selective cerebral perfusion techniques for repair of the aortic arch in neonates. These techniques may help protect the brain from ischemic injury caused by a cessation of cerebral perfusion for aortic arch reconstruction in patients with hypoplastic left heart syndrome or interrupted aortic arch.

Background: Lipid peroxidation is known to contribute to ischemia-reperfusion injury. U74500A is a 21-aminosteroid (lazaroid) that prevents lipid peroxidation without corticoid side effects. We examined the effect of U74500A on lung preservation using a canine orthotopic single left lung transplantation model., Methods: Twelve adult mongrel dogs underwent left lung allotransplantation. The lungs of the donor dogs were flushed with University of Wisconsin solution (50 ml/kg). Six donor dogs were pretreated with U74500A (5 mg/kg intravenously) before preservation (group L, n = 6), whereas those dogs without pretreatment served as controls (group C, n = 6). Allografts were stored in University of Wisconsin solution for 24 hours at 1 degrees C. Left single lung transplantations were performed by means of standard technique. Before reperfusion, recipients in group L received another dose of U74500A. Arterial blood gas analysis and hemodynamic measurements were made by occluding the right pulmonary artery to evaluate the transplanted left lung function at a inspired oxygen fraction of 1.0. Serum lipid peroxide level was measured after 2 hours of reperfusion., Results: Arterial oxygen tension, arterial carbon dioxide tension, and left pulmonary vascular resistance at 6 hours after reperfusion were significantly better in group L than in group C (arterial oxygen tension: 510 +/- 66 and 219 +/- 149 mm Hg; arterial carbon dioxide tension: 47 +/- 16 and 68 +/- 14 mm Hg; left pulmonary vascular resistance: 2412 +/- 826 and 3904 +/- 1251 dyn center dot sec/cm5, group L and group C, respectively). Serum lipid peroxide level was significantly lower in group L (0.25 +/- 0.24 nmol/ml) than in group C (0.92 +/- 0.53)., Conclusions: The administration of U74500A prevented lipid peroxidation and preserved pulmonary allograft function after 24 hours of ischemia.

It has been established that, even after syngeneic bone marrow transplantation, animals treated with immunosuppressive drugs may suffer from graft-versus-host disease, showing autoimmune-like symptoms. Although the major effector cells are known to be T-cell subsets, detailed characterization of such T cells remains to be investigated. In the present study, we characterized them, especially as to whether they are thymus-derived T cells or extrathymic T cells, and how self-reactive clones were distributed among the above T-cell subsets. BALB/c mice (Mls-1b2a) were irradiated (9 Gy), subjected to bone marrow transplantation, and then treated with cyclosporin A (CsA) for 6 weeks. From 2 weeks after the cessation of CsA, these mice displayed signs of GVH disease. The major target organs included the liver and colon. Two-color staining for CD3 and IL-2R beta was applied to identify CD3-IL-2R beta+ NK cells, CD3-intermediate +IL-2R beta+ cells (i.e., intermediate CD3 or TCR cells of extrathymic origin) and CD3-high+IL-2R beta- cells (i.e., high CD3 cells of thymic origin). It was demonstrated that the major expanding lymphocytes were intermediate TCR cells and that self-reactive clones (V beta 3+ and V beta 11+ cells in this strain of mice) were confined to this population. Interestingly, these self-reactive clones had ability to respond to immobilized anti-V beta 3 and anti-V beta 11 mAbs. Liver MNC in mice with GVH disease which contained the highest proportion of intermediate TCR cells were able to mediate the adoptive transfer of GVH disease to other irradiated (6.5 Gy) mice. Intermediate TCR cells also showed potent cytotoxic activity against syngeneic leukemia cells. These results suggest that intermediate TCR cells are the major effector cells for the induction of syngeneic GVH disease.

Background: Preoperative autologous blood donation is one of the most effective methods to avoid homologous blood transfusion in cardiac operations. However, there have been few reports about the safety and efficacy of autologous blood donation in children., Methods: Since 1986, we have instituted a blood conservation program including preoperative autologous blood donations in children. Eighty children as young as 3 years old (mean +/- SD, 8.6 +/- 3.9 years) and weighing as little as 12.3 kg (29.2 +/- 14.5 kg) were enrolled in the program, and 735 +/- 388 mL of blood was donated during an average of 3.1 +/- 1.5 phlebotomies before the operations., Results: Two episodes of mild vasovagal reaction were observed in 2 patients as a complication of the phlebotomy. Seventy-six percent of the collected blood was stored by cryopreservation; the remaining 24% was preserved by liquid storage. Seventy-eight of these patients (97.5%) underwent operations using cardiopulmonary bypass. Seventy-five patients (94%) were operated on successfully without the need for a homologous blood transfusion. As for the other 5 patients, 2 received only platelet concentrate., Conclusion: Preoperative autologous blood donation is a safe and effective method to avoid homologous blood transfusion in pediatric cardiac operations.

A simplified Manouguian's aortic annular enlargement for aortic valve replacement with prosthetic valve was performed in a patient with severe aortic stenosis and mild regurgitation by preserving both the anterior mitral leaflet and the left atrial roof intact. This method minimized the operative risk by avoiding injury to the mitral valve, while inserting a possibly two-size-larger prosthetic valve. The inserted prosthetic valve was positioned parallel to the original aortic valve. Moreover, the incision from the top of the commissure between the noncoronary cusp and left coronary cusp through the interventricular fibrous trigone appears to be easily extended into the exact center of the anterior mitral leaflet if further enlargement is required.

We describe a case in which a left ventricular-coronary sinus communication through a dissecting ventricular septal aneurysm developed after a redo mitral valve replacement. The outlet orifice of the communication was located in the side wall of the ostium of the coronary sinus. Both the communication and the aneurysm were successfully dealt with by performing a right atriotomy and by opening the aneurysm from its outlet orifice.

We describe two cases of coronary artery spasm that occurred during open heart operations and were treated by coronary artery bypass grafting. Vasodilators and calcium antagonists were infused directly into the right coronary artery via the side branch of the saphenous vein graft. Both patients were weaned successfully from cardiopulmonary bypass.

Twenty infants with interrupted aortic arch associated with various intracardiac anomalies underwent primary complete repair using pulsatile high-flow cardiopulmonary bypass with a short period of circulatory arrest. Age at repair ranged from 11 to 126 days (mean age, 43 days). Weight ranged from 2.2 to 5.5 kg (mean weight, 3.4 kg). Associated cardiac lesions included ventricular septal defect (14 patients), truncus arteriosus (3), transposition of the great arteries (2), and aortopulmonary window (1 patient). Left ventricular outflow tract obstruction was relieved in 2 patients. The aortic arch was reconstructed with a polytetrafluoroethylene graft in 7 patients and by direct anastomosis in the most recent 11 patients. An arterial cannulation method has been devised to facilitate direct anastomosis between the ascending aorta and the descending aorta, to lessen circulatory arrest time, and to prevent dangerous laceration and postoperative narrowing of the thin, small ascending aorta at the cannulation site. Two patients died, a surgical mortality rate of 10%. There has been one late death, which was due to severe truncal valve insufficiency. The other patients are doing well with a mean follow-up of 3 years 6 months. Restenosis of the direct anastomosis has not been noted in any patient. However, subaortic stenosis with pressure gradients of 30 to 40 mm Hg developed in 3 patients. In conclusion, one-stage repair including direct anastomosis for the aortic arch reconstruction and repair of all coexisting intracardiac defects is thought to be the treatment of choice.

Hemoconcentration for the establishment of no-donor blood transfusion in open heart surgery was assessed in regard to both the saving of protein and platelets and the exclusion of free hemoglobin. Two different types of hemoconcentrator were compared: the ultrafilter (group I, 6 patients) and the Cell Saver (group II, 6 patients). The total serum protein level, expressed as the percent recovery of the preoperative value, after hemoconcentration was significantly higher in group I (group I versus group II: total serum protein, 118% versus 87% [p less than 0.05]; fibrinogen, 77% versus 50% [p less than 0.01]; immunoglobulin, 83% versus 60% [p less than 0.01]). The platelets also seemed to be well preserved after hemoconcentration in group I. Although the exclusion of free hemoglobin from plasma was inferior in group I compared with group II, the postoperative plasma free hemoglobin level did not increase in group I. We conclude that use of the Cell Saver in nontransfusion cardiopulmonary bypass might cause a severe depletion of various proteins and that the ultrafilter is both safer and more useful if employed routinely.

Using a method of our own design, we evaluated intraoperatively the function of prosthetic heart valves. The changing hemodynamics induced by a stress test were assessed by simultaneously measuring the mean transvalvular pressure gradient and the stroke volume. The effective orifice area (EOA) of the valves was determined for each stroke by computer analysis, and this value was compared with the actual orifice area. Data were collected from 19 patients undergoing aortic or mitral valve replacement or both with 17 St. Jude Medical and 12 Ionescu-Shiley valves. The mean pressure gradient increased with tachycardia and an increase in mean left atrial pressure in the mitral position, but decreased with a decrease in cardiac output and peak left ventricular pressure in the aortic position. The St. Jude Medical valve had a smaller mean pressure gradient than the Ionescu-Shiley bioprosthesis. For both valves, the EOA increased with valve size. The St. Jude Medical valve had a greater EOA than the Ionescu-Shiley bioprosthesis, regardless of the valve size (p less than 0.005). However, the performance of prosthetic leaflets was better with the Ionescu-Shiley bioprosthesis than with the St. Jude Medical mechanical valve (p less than 0.001). This method involving computer analysis of each cardiac cycle proved to be useful for evaluating prosthetic heart valve function in the presence of changing hemodynamics.