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We examined the differences in interhemispheric functional correlation in the somatosensory system using coherence (Coh) analysis. Ten healthy adult volunteers served as subjects for this experiment. Vibratory stimulation (modulation frequency, 21 Hz) was given to each palm to record vibratory steady-state somatosensory evoked potentials (S-SEPs). S-SEPs were recorded from four electrodes placed at 2 cm posterior and anterior to C3 and C4, referred to an electrode at Fpz, respectively. For comparison, unstimulated S-SEPs were also recorded. A total of 50 responses of 1-s epochs was averaged and subjected to discrete fast Fourier transforms to yield the amplitudes of major harmonic components and Coh value. The Coh value between the two signals, x and y at each frequency f, was calculated as [Coh(xy)(f)](2)=[S(xy)(f)](2)/[S(xx)(f)xS(yy)(f)]. The amplitude at 21 Hz in the contralateral somatosensory area was significantly larger than that in the other electrodes. The interhemispheric Coh of the somatosensory area at 21 Hz was significantly lower than that in the unstimulated condition or intrahemispheric Coh. The initial somatosensory information is desynchronized. These findings indicate less significance of interhemispheric correlation as the first step of the vibratory information processing in the somatosensory cortex.

SummaryBackground Chemical peeling with salicylic acid in polyethylene glycol (PEG) vehicle is used clinically to improve the cosmetic appearance of skin that has been damaged by exposure to the sun. It is well known that cancers of the skin such as basal cell carcinoma and squamous cell carcinoma may be induced by the sun. However, the carcinogenic potential of chemical peeling agents has not been studied. Objectives To evaluate the effects of chemical peeling with 30% salicylic acid in PEG on skin tumour formation in treated vs. control mice. Methods To serve as a model of sun-damaged skin, hairless SKH/hr1 mice were irradiated with ultraviolet (UV) B for 14 weeks, with or without treatment every 2 weeks with 30% salicylic acid in PEG for a total of 18 weeks. Results Not only was the total number of tumours greatly reduced in the treated vs. the control mice, but skin tumour development was also slower in the treated vs. the control mice. At the final treatment, the fractions of T and B lymphocytes and natural killer cells from spleens of both groups of mice were comparable, and interferon-γ production did not differ. Conclusions Our findings suggest that chemical peeling with salicylic acid in PEG may help to prevent as well as to reduce the number of UVB-induced skin tumours.

Hyper-IgE syndrome (HIES) is a primary immunodeficiency disease characterized by recurrent infections and marked immunoglobulin (Ig)E elevation. To assess the proper T-cell defects of HIES, the cytokine profile of naturally activated T cells was compared between HIES, atopic dermatitis and chronic granulomatous disease (CGD). Intracellular flow cytometric analysis after in vitro stimulation showed no difference in the proportion of interferon (IFN)gamma- or interleukin 4 (IL-4)-producing T cells among these diseases. Quantitative polymerase chain reaction (PCR) for the cytokine genes was performed using circulating highly fractionated HLA-DR+ and HLA-DR- T cells. The IFNgamma/IL-4 or IFNgamma/IL-10 ratios were lower in HLA-DR+ T cells of HIES than in CGD (P = 0.0106, 0.0445), but did not differ between HIES and atopy. The transforming growth factor-beta (TGFbeta)/IL-4 ratio in HLA-DR+ T cells of HIES was lower than that of atopy (0.0106) or CGD (0.0062). The TGFbeta/IL-4 ratio in HLA-DR- T cells of HIES was also lower than that of atopy (0.0285). Stepwise logistic regression analysis identified TGFbeta/IL-4 ratios in HLA-DR+ (0.0001) or HLA-DR- (0.0086) T cells as the most powerful parameters to distinguish HIES from atopy and/or CGD. Serum IgE levels negatively correlated with IFNgamma/IL-4 (0.0108), IFNgamma/IL-10 (0.0254), or TGFbeta/IL-4 (0.0163) ratios in HLA-DR+, but not HLA-DR-, T cells. These results suggested that the in vivo activated T cells of HIES did not sufficiently express the IFNgamma and TGFbeta genes, which could affect IL-4-dependent IgE production. The reduced TGFbeta expression may involve the indigenous T-cell defects of HIES.

To clarify the content of support for healthy aging, we analyzed age-related changes in functional capacity and factors affecting the maintenance based on a health status survey in elderly people, and also evaluated the results of a survey on functional capacity, living habits, and health in leaders in elderly people's clubs.A questionnaire survey was carried out with (1) 1,000 randomly selected elderly subjects agedor = 65 years and (2) 122 leaders in elderly people's clubs to evaluate functional capacity according to The Tokyo Metropolitan Institute of Gerontology Index of Competence, feeling of happiness according to the morale scale established by Lawton, living habits, and health. Factors affecting functional capacity were identified by stepwise multiple longistic regression analysis. In addition, the elderly people's club leader group and an age- and sex-matched control group were compared.1) Functional capacity decreased with age, this being more marked in the females than in the males. In particular, Instrumental Activities of Daily Living markedly decreased in the females at late ages. 2) Stepwise multiple logistic regression analysis revealed the following positive and negative factors associated with the maintenance of a high functional capacity (functional capacity scoreor = 12). The positive factors were: 1. hobbies, 2. living with the spouse, 3. habitual exercise, 4. positive acceptance of aging, 5. psychological stability, 6. diets with consideration of nutritional balance, 7. busy life, and 8. talking with friends and acquaintances once a week or more. The negative factors were: 1. belonging to a higher age groups, 2. living alone, and 3. smoking. 3) In the elderly people's club leader group, the age-related decline was gradual, and functional capacity was maintained at later ages. The group leaders typically 1. had hobbies, 2. went out almost everyday, 3. exercised almost every day, 4. talked with friends and relatives almost every day, 5. had active roles, 6. were busy, and 7. considered themselves to be healthy more frequently than the control group. The leader group also showed 8. a higher total morale scale score and 9. a higher score for positive acceptance of aging as a subscale than the control group.Our results suggest that nutrition balance, habitual exercise, hobbies, social roles, frequent contacts with others, positive acceptance of aging, and psychological stability are important for maintaining functional capacity in the maintenance of functional capacity. Early preventive measures are necessary to combat decline in functional capacity, particularly regarding Instrumental Activities of Daily Living, in females at later ages.

The purpose of this study is to attempt to characterize patients with unfavorable clinical outcome by the relative mRNA levels of ABC transporter expression in their tumor samples and to examine whether relative mRNA levels of each of the ABC transporters can be a useful predictor of progression-free survival in advanced ovarian carcinoma.We examined tumor samples taken from 30 patients with primary serous papillary adenocarcinoma of the ovary for the expression of MDR1 and MRP1, MRP2, and MRP3 mRNA by using real-time reverse transcription-PCR, and we evaluated its correlation with clinical outcome. All 30 patients were divided into three groups according to clinical outcome after debulking surgery and platinum-based chemotherapy: 8 patients were classified into the unfavorable group; 11 were classified into the favorable group; and 11 were classified into intermediate group.The relative mRNA levels of MRP1 and MRP3 were significantly different among the three groups, and the mRNA levels of MRP1 and MRP3 in the unfavorable group were significantly higher than those in the favorable group by multiple comparison. The relative mRNA levels of MRP1 expression were significantly correlated with those of MRP3 expression. In the 30 patients with serous papillary adenocarcinoma, univariate and multivariate analysis demonstrated that the high relative mRNA levels of MRP1 expression were significantly correlated with a short period of progression-free survival.In patients with advanced ovarian serous papillary adenocarcinoma, these results suggest that patients with an unfavorable clinical outcome are characterized by increased levels of coordinated MRP1 and MRP3 mRNA expression in their tumor samples. Furthermore, a higher level of MRP1 mRNA expression can be a candidate for a useful predictor of a shorter period of progression-free survival.

We studied the effectiveness of risk-directed therapy for infants younger than 13 months of age with acute lymphoblastic leukaemia (ALL). Fifty-five infants were assigned to different treatment programs (from December 1995 to December 1998) on the basis of their MLL gene status at diagnosis. Forty-two cases (76.3%) had a rearranged MLL gene (MLL+) and were treated with remission induction therapy followed by sequential intensive chemotherapy, including multiple genotoxic agents (MLL9601 protocol). Haematopoietic stem cell transplantation (HSCT) was attempted if suitable donors were available. Thirteen infants (23.7%) were classified as MLL- and treated for 2.5 years with intensive chemotherapy for high-risk B-ALL (MLL9602 protocol). Complete remission was induced in 38 of the 42 infants (90.5%) with MLL+ ALL and in all 13 patients (100%) with MLL- disease. In the MLL+ subgroup, the estimated event-free survival (EFS) rate at 3 years post diagnosis was 34.0% +/- 7.5%, compared with 92.3% +/- 7.4% in the MLL- subgroup (overall comparison, P = 0.001 by log-rank analysis). Both age less than 6 months (hazard ratio = 6.87, 95% CI = 0.91-52.3; P = 0.013) and central nervous system (CNS) involvement at diagnosis (hazard ratio = 2.92 95% CI = 1.29-6.63; P = 0.015) were significant independent predictors of an inferior outcome. These findings indicate a strategic advantage in classifying infant ALL as either MLL+ or MLL- early in the clinical course and selecting therapy accordingly. Standard chemotherapy for high-risk B-lineage ALL appeared adequate for MLL- cases. Novel therapeutic initiatives are warranted for infants with MLL+ disease, particularly those with initial CNS leukaemic involvement or age less than 6 months, or both.

Objectives : The objective of the present study is to quantify the effects of voluntary muscle contraction of the small hand (abductor pollicis brevis, first dorsal interosseus (FDI)) and forearm muscles (extensor carpi radialis (ECR), extensor carpi ulnaris (ECU), flexor carpi radialis (FCR) and flexor carpi ulnaris (FCU)) on motor evoked potentials (MEPs). Methods : MEPs were recorded in 12 healthy subjects by a circular coil placed over the vertex at 1.2 times the resting motor threshold at different levels of the muscle contraction (0–100% of maximum voluntary contraction (MVC)). The effects of transcranial magnetic stimulation (TMS) on the onset latency, MEP area and silent period (SP) as a function of the %MVC were evaluated using a piecewise linear regression analysis. Results : The MEP areas for the small hand muscles were almost completely saturated at 20% of MVC. In contrast, the MEP areas for radial muscles (ECR, FCR) had a dual increase at 40% of MVC while the ulnar muscles (ECU, FCU) had a dual increase at 20% of MVC. A uniform latency shift (1.5–3 ms reduction) was observed in all muscles with a changing point at 10% of MVC. The SPs were the longest for FDI and were not significantly influenced by MVC for any muscles. Conclusions : The excitatory and inhibitory effects of TMS on the MEPs differed for the small hand and forearm muscles and also between the ulnar and radial muscles. These results probably resulted from the different degrees of direct corticomotoneuronal inputs to each muscle and the inherent properties of the spinal motoneurons.

It is necessary to estimate financial status to determine hospital management policy. The costs and revenues (financial balance) of each hospital division are one good index. However, it is difficult to calculate the financial balance for each division, since clinics and central services are intricately involved with each other There are no reports on a pragmatic method for calculating the financial balance. We devised a simple method based on proportional dividing. Consequently, one individual was able to complete the calculation for our hospital, which consists of 1300 beds and 23 clinics, without using the central hospital computer system.

BACKGROUND: Although many authors have investigated the prognostic factors of gastric cancer, there are few comprehensive studies on the prognosis of patients with extensive lymph node metastasis. The aim of this study was to clarify the prognostic factors of gastric cancer with extragastric lymph node metastasis, using multivariate analysis.METHODS: The study population consisted of 121 patients who had undergone radical gastrectomy and extended lymph node dissection (D2, D3) for gastric cancer with extragastric lymph node metastasis. We examined 18 clinicopathologic factors, including the type of gastrectomy, tumor size, depth of wall invasion, status of lymph node metastasis, and stage of disease. Survival rates were analyzed by the Kaplan-Meier and Mantel-Cox methods, and multivariate analysis was done using the Cox proportional hazards model.RESULTS: The overall 5-year survival rate was 32%, and the 5-year survival rate after curative gastrectomy was 37%. Overall survival rate was associated with the type of gastrectomy, stage of disease, operative curability, tumor size, depth of wall invasion, and anatomical distribution of positive nodes, whereas the survival rate after curative gastrectomy was correlated with the type of gastrectomy, stage of disease, tumor size, gross type, and depth of wall invasion. Independent prognostic factors were operative curability and depth of wall invasion, and survival after curative gastrectomy was influenced only by the depth of wall invasion (mucosa and submucosa [T1], muscularis and subserosa [T2] vs serosa [T3]).CONCLUSION: In patients with gastric cancer with extragastric lymph node metastasis, independent prognostic factors after gastrectomy were operative curability and depth of wall invasion. Long-term survival can be achieved when the patients have no serosal invasion (T1, T2) and are treated by curative gastrectomy.

Purpose: To investigate the factors that influence the visual-changing pattern in proliferative diabetic retinopathy even after successful vitrectomy. Methods: One hundred and forty-seven consecutive eyes were retrospectively reviewed for 6–48 (average 20) months, and were divided into the following 4 groups based on their changing pattern of vision: group A, the visual acuity improved postoperatively and maintained the maximal corrected vision throughout the observation period (n = 49); group B, the visual acuity improved postoperatively but deteriorated thereafter (n = 68); group C, the visual acuity remained the same as before operation (n = 17), and group D, the visual acuity deteriorated immediately after vitrectomy (n = 13). Various issues including systemic conditions, blood tests, preoperative ocular findings, the operative procedures and postoperative complications were reviewed based on the patient records. These issues were analyzed by Spearman’s rank correlation, χ2 test, an analysis of variance (ANOVA) and the Kruskal-Wallis test. Finally, the discriminate factors between groups A and B were examined by a stepwise logistic regression analysis. Results: The following tendencies were observed in all 4 groups: younger patients tended to show a better visual-changing pattern (p = 0.02); patients with younger age at diabetes onset had a better visual-changing pattern after vitrectomy (p = 0.001), and a lower hemoglobin (Hb) A1c level is associated with a better visual changing pattern (p = 0.017). Preoperative rubeosis and macular detachment were frequently found in groups C and D, as well as postoperative rubeosis, vitreous bleeding and retinal detachment. Finally, a stepwise logistic regression analysis showed both fibrovascular proliferation (p = 0.016) from the optic disc and postoperative macular disease (p = 0.0009) to be significant factors for differentiating group A from group B. Conclusions: In addition to the factors which have already been indicated to affect the visual outcome of a vitrectomy, preoperative findings such as optic disc fibrovascular proliferation and postoperative macular disease were found to affect the visual-changing pattern after a successful vitrectomy. The optimal timing of surgery is very important not only in order to obtain good visual acuity but also to maintain good vision even after a successful vitrectomy.

Using first- and second-generation branched-DNA probe assays (1st- and 2nd-bDNA), we investigated the predictors of favorable clinical response to interferon (IFN) treatment in patients with chronic HCV viremia. A total of 122 patients (85 genotype lb and 37 genotype 2a) with chronic HCV viremia received 24-week IFN-alpha treatment. Patients with sustained clearance of serum HCV RNA by polymerase chain reaction at six months after IFN treatment were defined as having a sustained response (SR). HCV RNA level was determined by 1st- and 2nd-bDNA assays prior to treatment. Mean HCV RNA level by 1st-bDNA was significantly higher in genotype lb patients [5.4 x 10(6) HCV genome equivalent (Meq)/ ml] than in genotype 2a patients (0.9 Meq/ml) (P0.05). There was no significant difference between patients with these genotypes in the level by 2nd-bDNA (1b: 5.2 Meq/ml and 2a: 3.1 Meq/ml). SR was achieved by 43 (35.2%) of 122 patients. Mean HCV RNA levels by both the 1st- and 2nd-bDNA of SR patients (1.0 and 1.9 Meq/ml) were significantly lower than those of non-SR patients (5.3 and 6.0 Meq/ml) (both P0.05). The SR rate in genotype 2a patients (59.5%) was significant higher than in genotype lb patients (24.7%) (P0.05). Stepwise logistic regression analysis showed that HCV RNA levelor = 1.0 Meq/ml by 2nd-bDNA (odds ratio = 7.6, compared to level1.0 Meq/ml, P0.05) was a significant predictive cutoff for SR. Using 2nd-bDNA, a significantly higher rate of SR was found in genotype lb patients with levelor = 1.0 Meq/ml (57.6%) than in those with level1.0 Meq/ml (3.8%) (P0.05). The SR rate of genotype 2a patients with level1.0 Meq/ml (68.6%) was somewhat higher than for those with levelor = 1.0 Meq/ml (52.4%). These findings suggested that, using 2nd-bDNA, a low HCV RNA level ofor = 1.0 Meq/ml was the most favorable marker of successful IFN treatment and that patients with genotype 2a, even those with level1.0 Meq/ml, had a high rate of SR to IFN treatment.

Our purpose is to demonstrate the relationship between microvessel density (MVD), vascular cuffing (VC), vascular endothelial growth factor (VEGF) expression and clinicopathological parameters in ovarian cancer. Surgical specimens from 105 primary ovarian cancers were examined for vascularization and VEGF expression by immunohistochemical staining. The higher MVD group (MVD≧70) and the positive VEGF group were associated with better progression-free survival only in early stages. The significant association of the MVD with better progression-free survival was recognized only in the patients with clear cell adenocarcinomas. The complete VC group showed a similar trend as MVD though there was no statistical difference. A multivariate analysis revealed MVD to correlate independently with progression-free survival. In ovarian carcinoma, MVD was found to be an independent prognostic factor. In addition, the higher MVD with clear cell adenocarcinoma had the better prognosis. The clinicopathological role of angiogenesis should be analyzed taking account of histologic type.

Background/Aims : To understand hepatic injury during the process of hepatitis viral infection, determination of liver-specific functions at molecular levels is critical. Because the transport of endogenous/exogenous toxic substances is an intrinsically important hepatic function, we examined whether expression of the ATP-binding cassette (ABC) transporter gene was affected in patients with hepatitis viral infection. Methods : To determine which ABC transporter was expressed differently in patients with hepatic viral infection, we assayed the expression of MDR1 , MDR3 , MRP1 , MRP2 , and MRP3 in non-cancerous regions in the liver of 42 patients with hepatic tumors using both quantitative RT-PCR and immunological staining analysis, and compared the hepatic expression levels between patients with hepatitis viral infection and non-infected controls. Results : Of the five ABC transporter genes studied, the mRNAs of MRP2 and MRP3 were highly expressed in the human liver. There was a significant reduction in MRP2 expression to 29% in the virus-infected liver. Treatment of hepatic cells with inflammatory cytokines resulted in decreased mRNA levels of MRP2 and decreased MRP2 promoter activity. Conclusions : The down-regulation of MRP2 might induce a failure in the transport of various genotoxic substances in the liver with hepatitis virus infection.

Background: Obesity in children is one of the risk factors for adulthood obesity, which then leads to the development of chronic diseases such as hypertension, hyperlipidemia and diabetes. In this study, we identified significant factors associating with the body mass index (BMI) at 3 years of age from the perinatal characteristics of children. Methods: A total of 588 children were included in the study. The BMI at 3 years of age was examined in conjuction with the possible variables such as parents’ smoking status during pregnancy, parents’ age at birth, gestational age, sibling number and live birth order, sex, birthweight, BMI at 1 month of age, weight gain during the first month of life and feeding method at 1 month of age. Results: Univariate analysis showed that birthweight (P

GH and IGF-I are important for physical growth. We measured serum levels of these factors in preterm infants. The study population (n = 81) was divided into three groups according to the gestational age. We evaluated differences in serum GH and IGF-I levels among groups with regard to physical growth and development of retinopathy of prematurity. Serum GH levels in extremely preterm infants born at

Cytomegalovirus (CMV) antigenemia and quantitative real-time polymerase chain reaction (PCR) were compared for monitoring of CMV reactivation after allogeneic stem cell transplantation. The number of CMV antigen-positive cells by the antigenemia assay and the level of CMV DNA by real-time PCR correlated well. The sensitivity and specificity of the antigenemia assay was 55.4% and 95.5%, respectively, using real-time PCR as the reference standard. The probability of positive antigenemia at day 100 was 76.5%, with a median of first detection at day 37 in 51 patients, compared with a positive PCR of 84.3% and day 33, respectively. When HLA-identical sibling donor transplant recipients and other donor transplant recipients were analyzed separately, there was no difference between the two tests. However, temporal patterns of first detection of CMV antigen-positive cells and CMV DNA differed between HLA-identical and alternative recipients; patients without CMV (29%) or with sporadic positive PCR results (14%) were more common in HLA-identical sibling transplants, whereas patients with simultaneous antigenemia and positive PCR occurred more in alternative transplants (48%). Two of 51 patients (4%) developed CMV colitis despite antigenemia-guided prophylaxis, but both were successfully treated with ganciclovir. Although PCR is more sensitive than antigenemia, both tests are useful in the early detection of CMV after allogeneic stem cell transplantation.

Diffuse intimal thickening (DIT) is a thickened intima present in human arteries before atherosclerosis develops and is considered to be related to atherogenesis. The purpose of this study was to clarify the systemic and age distributions of DIT. Coronary, cerebral, carotid, subclavian, iliac and abdominal organ arteries and the aorta were examined in 72 autopsy cases (aged 36 weeks of gestation to 30 years at death). DIT was found in the coronary arteries and aorta from 36 weeks of gestation and the first year of life, respectively. The intima/media (I/M) ratio of coronary arteries showed an age-dependent increase and was much greater than that of other muscular arteries, i.e., intracranial and extraparenchymal cerebral arteries and abdominal organ arteries. Aorta also demonstrated age-dependent as well as site-dependent increases of I/M ratio; the more distal the segments, the greater the ratio. Consequently, the abdominal aorta had the largest I/M ratio within the aorta. Other elastic arteries, i.e., carotid, subclavian and iliac arteries, showed trends similar to the distal portions of the aorta. Thus, DIT was strongly expressed from an early age in arteries that are considered to be prone to atherosclerosis. These findings suggest that the development of atherosclerosis depends at least partly on the degree of DIT.

We retrospectively analyzed 336 patients with primary chronic myelofibrosis from 203 medical institutes in Japan. Notwithstanding their heterogeneous treatments, the median survival in 298 patients that could be evaluated was 10.0 years. Average age at onset was 60.7 years. Men were affected 1.4 times more frequently than women. The factors associated with shorter survival included anemia, leukocytosis/leukocytopenia, thrombocytopenia, and increased blasts in the peripheral blood, and sex (male), age (>60), and the presence of symptoms. A new scoring system based on the peripheral blood findings (hemoglobin [Hb] level, platelet count, and rate of blast formation) at initial diagnosis clearly correlated with survival rate. Accordingly, patients could be categorized into 3 groups by severity grading. Through stepwise multivariate survival analysis, the significant prognostic factors were identified as the severity grading based on the new scoring system (P = .0002), age (P = .0024), sex (P = .0153), and Hb (P = .0198). Chromosomal abnormalities were found in 58 of 154 patients (38%), although these did not influence survival.

Several studies reported the morphology of calretinin-positive (CR+) neurons and nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) labeled or neuronal nitric oxide synthase-positive (nNOS+) neurons in the rodent hippocampus, where these neurons showed similar morphological features. In addition, a previous study reported the frequent colocalization of CR and NADPH-d in the rat hippocampus. In this study, we aimed to examine whether CR+ neurons and nNOS+ neurons belong to a same morphological subpopulation of GABAergic neurons in the mouse hippocampus. Neurons were immunocytochemically classified into three groups, i.e., CR+/nNOS-, CR-/nNOS+ and CR+/nNOS+ groups. The present morphometric analysis was performed in the mouse Ammon's horn, because CR+/nNOS+ neurons were rarely found in the mouse dentate gyrus. We selected three morphometric parameters, i.e., soma area, soma form factor (FF) and number of primary dendrites. Dunnett's post-hoc analysis revealed that soma area, soma FF and number of primary dendrites were significantly larger in CR-/nNOS+ group than in CR+/nNOS- and CR+/nNOS+ groups. The morphometric data of CR+/nNOS+ group were quite similar to those of CR+/nNOS- group. The morphometric multivariate logistic regression analysis revealed that these three morphometric parameters were independent significant variables to discriminate between CR+/nNOS- and CR-/nNOS+ groups, and the majority of CR+/nNOS- and CR-/nNOS+ groups were correctly classified from the morphometric features. The present results clearly indicate that CR+/nNOS- neurons and CR-/nNOS+ neurons belong to different morphological subpopulations, and lead us to speculate that they might play different functional roles in the hippocampal circuit. The further application of morphometric multivariate analysis would be valuable to understand the functional roles of chemically defined neurons in the various brain regions.

Co-stimulatory molecules of CD28, cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), and the newly identified inducible co-stimulator (ICOS) are expressed on cell surfaces and provide regulatory signals for T-cell activation. Their genes are candidate susceptibility genes for type 1 diabetes because they co-localize to Chromosome 2q33 with the IDDM12 locus. After determining the genomic structure and screening for polymorphisms of the ICOS gene, we performed association studies between newly identified polymorphisms of the ICOS gene, together with known polymorphisms of CD28 and CTLA-4 genes, and type 1 diabetes. The 49A/G dimorphism in exon 1 and the (AT)n in the 3' untranslated region of the CTLA-4 gene were significantly associated with type 1 diabetes. Evaluation of the CTLA-4 49A-3'(AT)n 86-bp haplotype frequency in patients and controls confirmed the results from the analysis of each polymorphic site. Dimorphism in intron 3 of the CD28 gene was associated with type 1 diabetes only in the early-onset group. In contrast, there was no association with the microsatellite polymorphisms in the ICOS gene or dimorphisms in the promotor region of CTLA-4. Of the three genes encoding co-stimulatory molecules, the CTLA-4 gene appears to confer risks for the development of type 1 diabetes.

This paper examines the baseline imbalance incidental to stratified random sampling in clinical trials. We assume that patients are randomly sampled from a stratum-specific population and assigned to either treatment or control groups. Prognostic factors not used for the stratification cause within-stratum patient heterogeneity. The patient heterogeneity is investigated with an analysis of the prognostic index, or the log-relative-hazard. An index V, used to measure the degree of baseline imbalance between the groups, is defined using the prognostic index. The degree of baseline imbalance resulting from the stratified random sampling of a population of heterogeneous patients is examined. A method to estimate the exact size of the stratified logrank test is developed and applied to data obtained from a cancer clinical trial.

The aim of this study was to evaluate the relationship between changes in abdominal fat areas and the baseline serum leptin levels of Japanese obese women during weight reduction. The study was performed on 100 obese female Japanese volunteers. We measured the BMI and abdominal fat areas (visceral, subcutaneous and total) by magnetic resonance imaging and determined the fasting serum leptin levels before and after a 3 month weight reduction program. We examined whether or not a relationship exists between the baseline leptin levels and the subsequent changes in the abdominal fat areas after a weight reduction program. Multiple linear regression analysis was performed to examine the relationship between the baseline leptin levels and changes in abdominal visceral, subcutaneous, and total fat areas, and demonstrated that the baseline leptin level was a significant predictive factor for changes in the abdominal visceral fat area in both pre and postmenopausal Japanese obese women. We thus concluded the relatively higher baseline leptin levels in Japanese obese women to be associated with a relatively smaller reduction in the amount of abdominal visceral fat after undergoing a weight reduction program.

BACKGROUND To the authors' knowledge detailed morphometric changes in lymph nodes with and without metastasis in patients with early gastric carcinoma remain undocumented. METHODS Histologic slides of 1847 lymph nodes dissected from 115 consecutive patients who underwent gastrectomy for early gastric carcinoma were examined histologically and measured using computer morphometry with the public domain National Institutes of Health Image program. Quantitative data were analyzed in relation to preoperative and intraoperative clinical assessments and postoperative pathologic diagnosis. RESULTS Metastasis was found in 11 lymph nodes (0.6%) from 8 patients (7.0%). Metastatic lymph nodes showed a mean maximum dimension of 4.8 mm, a mean area of 14.4 mm2, and a mean ratio of maximum/minimum dimension of 1.36; the corresponding values for nonmetastatic lymph nodes were 4.7 mm (P = 0.45), 13.2 mm2 (P = 0.13), and 1.66 (P = 0.10), respectively. The lymph node with a metastasis was not necessarily the largest of the dissected lymph nodes from each patient, and histologically each lymph node with a metastasis showed pericancerous fibrosis in > 10% of its area. The sensitivities of preoperative computed tomography, abdominal ultrasonography (US), endoscopic US, and intraoperative assessments to diagnose metastasis were 0%, 13%, 0%, and 13%, respectively, and the sensitivities of these modalities to detect lymph nodes > 10 mm in dimension were 18%, 10%, 3%, and 10%, respectively. CONCLUSIONS Digital quantitative analysis is useful and widely applicable to clinicopathologic evaluation. The diagnostic sensitivity of lymph node metastasis in patients with early gastric carcinoma in the current study was very low with preoperative and intraoperative assessments because lymph node metastases were small and showed subtle histologic changes of pericancerous fibrosis. Cancer 2000;88:2438–42. © 2000 American Cancer Society.

Objective. The purpose of this study was to clarify characteristic sonomorphologic features of parotid lesions statistically and to propose new criteria for the differential diagnosis. Study design. Eighty-six tumorous lesions were analyzed with regard to the following sonomorphologic features: boundary, shape, echo intensity level, distribution of internal echoes, and acoustic enhancement. Stepwise polychotomous logistic regression analysis was performed to assess characteristic sonographic features. As dependent variables, we used “pleomorphic adenoma,” “Warthin tumor,” “malignant tumors” and “other benign lesions”; as predictor variables, we used the aforementioned sonomorphologic features. Proportion of the occurrence of each dependent variable was calculated. Results. Lobular shape and homogeneous internal echoes predicted pleomorphic adenoma. A lesion with multiple anechoic areas would be Warthin tumor with very high sensitivity. Malignant tumors showed either heterogeneous internal echoes without characteristic structures or polygonal shape. Conclusions. These sonomorphologic features should be observed to make more exact differential diagnoses for operation and therapy planning. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;88:226-33)

BACKGROUND Newly developed therapies for early gastric carcinoma attempt to consider patients' quality of life, but the applicability and effectiveness of these treatments remain undetermined. METHODS Clinicopathologic data of 612 consecutive patients with early gastric carcinoma, all of whom were treated by D1 and D2 gastrectomy, were analyzed. Patients with and without lymph node metastases were compared in relation to age and gender distributions, surgical procedures, histopathology of the tumors, 5-year prognosis, and in reference to the preoperative and intraoperative assessments. RESULTS The overall incidence of lymph node metastases was 5.7%. Tumor depth and size were related to lymph node metastases judged by univariate and multivariate analyses. Patients with mucosal tumors showed no relation between metastatic rate and tumor size, whereas those with submucosal tumors showed an increasing metastatic rate with tumor size. In all cases but one, lymph node metastases were confined to lymph node stations defined as Group 1 locations. Preoperative endoscopic ultrasonography showed a 55% diagnostic accuracy in determining tumor depth and a 15% sensitivity in diagnosing lymph node metastases. CONCLUSIONS Patients with early gastric carcinoma may be candidates for endoscopic mucosal resection if their tumor is confined to the mucosa and measures < 1 cm in greatest dimension. Other limited resections including D1 gastrectomy or standard D2 gastrectomy based on tumor depth and size are appropriate. Based on the current study findings, the authors propose a useful algorithm for managing such patients. Cancer 1999;85:1500–5. © 1999 American Cancer Society.

Objective: To evaluate the association of somatic growth from birth through diagnosis with the development of childhood cancer. Methods: The weights and heights of 1718 children with cancers were determined and converted into standard deviation (SD) scores, both at birth and at diagnosis, by using the means and SD values of the general population. Results: Among patients with neuroblastoma and acute lymphoblastic leukemia, the percentages of children with body weight and height over mean + 2 SDs were significantly higher at diagnosis than the expected value in the general population. The percentage of children with neuroblastoma and body weight over mean + 2 SD increased significantly from birth through diagnosis ( P = .04). Although the medians of weight SD scores decreased from birth through diagnosis in patients with representative cancers except for neuroblastoma, the value significantly increased in patients with neuroblastoma diagnosed before 1 year of age ( P = .03), especially in those whose cancer was detected by mass screening at 6 months of age ( P Conclusions: Rapid somatic growth from birth through diagnosis in patients with neuroblastoma diagnosed before 1 year of age suggests a possible involvement of certain growth factors in these patients. (J Pediatr 1999;134:178-84)

BACKGROUND Angiogenesis is essential for tumor growth, progression, and metastases. Microvessel density (MVD), a measure of tumor angiogenesis, has been found to have prognostic significance in many tumor types for predicting metastasis and survival. METHODS Between 1979-1989, 56 cases of FIGO Clinical Stage I and II adenocarcinoma of the uterine cervix treated by hysterectomy were reviewed histologically. All hysterectomy specimens were stained immunohistologically for factor VIII-related antigen. MVD was counted in a x200 field ( 0.785 mm2 per field) in the most active area of neovascularization. Results were expressed as the highest number of microvessels identified within any single x200 field. MVD and several other prognostic parameters were examined for correlation with progression free survival (PFS) and overall survival (OS) by a multivariate analysis according to the Cox proportional hazards model. RESULTS In early adenocarcinoma of the uterine cervix, MVD was increased significantly in invasive areas compared with adjacent nonneoplastic areas (median: 62.5 [range, 30-105] vs. median: 36.5 [range, 23-47]; P = 0.0003). MVD also was significantly correlated with ascites cytology (P = 0.0377). There was no correlation between microvessel count and lymph node status, depth of invasion, disease stage, lymph-vascular space invasion, grade, or parametrial involvement. Patients with high MVD (≥ 75) had significantly worse PFS and OS than those with low MVD (< 75) (log rank test, P = 0.0180 and 0.0199, respectively). Multivariate analysis showed that MVD correlated significantly and independently with PFS and OS. CONCLUSIONS In adenocarcinoma of the cervix, MVD is an independent prognostic factor for PFS and OS. Cancer 1998;83:1384-1390. © 1998 American Cancer Society.

To clarify whether twin fetuses could be clustered quantitatively observing in utero cardiovascular system function, 71 twin-paired fetuses between 24 and 40 weeks' gestation were subjected. Cluster analysis was performed using four variables; end-diastolic dimension and fractional shortening in the right ventricle (EDD, FS), resistance index in the umbilical artery (RIUA) and urine production rate (UPR). Three different groups were revealed. In Cluster 1 (C1), larger fetuses showed a significant increase in both EDD and UPR, and a significant decrease in FS, while smaller fetuses had a significant increase in RIUA and a decrease in UPR. In Cluster 2 (C2), smaller fetuses showed a significant increase in RIUA. Cluster 3 (C3) showed no significant deviations in any variable when referring to singleton pregnancies. C1 had a higher perinatal mortality rate than either C2 or C3, with the cause of death being cardiac failure in larger fetuses and renal failure in smaller fetuses. The frequencies of discordancy, hemoglobin difference above 5 g/dl and monochorionic placenta in C1 were also higher than fetuses in C3. C2 also showed higher frequencies of discordancy and small-for-gestational age than C3 fetuses. In C2 and C3, respiratory insufficiency was found to be the cause of neonatal death. The results revealed that C1 consists of twins with both larger and smaller fetuses displaying cardiac failure with an increase in renal perfusion and a decrease in renal and placental perfusion, respectively, and C2 consists of twins with smaller fetuses having both placental insufficiency and intrauterine growth retardation. C3 consists of twins with both lager and smaller fetuses having normal circulation, when compared to singleton pregnancy.

The relationships of hypothalamically elicited emotional behaviors to their accompanying pathophysiological effects were examined as a model of how complex "emotional behaviors" may be related to fundamental psychosomatic disorders. Twenty-two unanesthetized adult cats were studied. EKG alterations and histological changes in the heart, stomach, adrenal glands, and thymus were related to the specific stereotypical emotional behaviors that could be elicited by hypothalamic stimulation in tamed subjects. Restlessness, threat, and searching-biting behaviors were evoked by electrical stimulation of the anteromedial, ventromedial, and lateral hypothalamus, respectively. The occurrence of cardiac arrhythmias, ST and/or T (ST-T) changes in the EKG, histological damage to myocardium, gastric erosion, and adrenal hyperplasia were generally observed in the restlessness and threat groups but not in the searching-biting group. The pathophysiological effects were similar in the restlessness and threat groups with no specific EKG change or organ effect attributable to either site of stimulation. Hypothalamically elicited restlessness or threat behaviors in cats are each associated with cardiac, gastric, and adrenal pathophysiologies.

BACKGROUND The postoperative intrahepatic recurrence of hepatocellular carcinoma (HCC) is high. It is difficult to distinguish whether the recurrence is metastatic or new primary lesion. To determine the malignant potential of HCC itself, we analyzed the risk factors associated with portal venous invasion since this is direct evidence of tumor invasiveness. METHODS Two hundred and thirty-two patients who underwent curative hepatectomy for HCC without preoperative treatments were included in this study, because preoperative treatment caused the tumor to undergo a variety of histologic change. We analyzed the risk factors linked to portal venous invasion by both univariate and multivariate analyses. RESULTS In an univariate analysis, tumors larger than 3 cm, high histologic grade (III or IV), the presence of fibrous capsule, necrosis, mitotic rate of more than 4/10 high power fields, peliotic change, presence of tumor giant cells, high platelet count, low level of indocyanine green retention rate at 15 minutes, and the absence of cirrhosis were significantly correlated with portal venous invasion. In multiple stepwise logistic regression analysis, tumors larger than 3 cm, high histologic grades, and the presence of fibrous capsule were strong predictors of portal venous invasion by HCC. CONCLUSIONS Because the blood vessels of the fibrous capsule were frequently invaded by cancer cells, it may have been possible to prevent postoperative metastatic recurrence if HCC were resected before becoming large enough to have a fibrous capsule. Cancer 1996;77:2022-31.

The immunohistochemical expression of bcl-2 and p53 proteins was evaluated in formalin-fixed, paraffin-embedded surgical specimens from 212 patients with primary gastric lymphoma. bcl-2 protein was found to be expressed in 145 specimens (68%). Among the 179 specimens with B-cell lymphoma of mucosa-associated lymphoid tissue (MALT), bcl-2 positivity decreased significantly as the histological grade advanced; bcl-2 was expressed in 93% of low-grade tumors, 88% of mixed-grade (low-grade with a focal high-grade component) tumors, and 44% of high-grade tumors (Cochran's linear trend test; P.001). p53 protein expression was detected in 43 of 212 cases (20%). Among the B-cell MALT lymphomas, p53 positivity increased significantly as the histological grade advanced; p53 was expressed in 6% of low-grade tumors, 12% of mixed-grade tumors, and 31% of high-grade tumors (Cochran's linear trend test; P.001). An inverse correlation was observed between the expression of bcl-2 and p53 in all 212 lymphomas (gamma = -0.531; P.05) as well as in all 179 B-cell MALT lymphomas (gamma = -0.671; P.01). Although the bcl-2 expression did not correlate with the patient survival, the p53 positive cases showed a significantly poorer prognosis compared with the p53 negative cases (log-rank test; P.05). These results suggest that the expression of bcl-2 and p53 may, therefore, be associated with the transition from low-grade to high-grade tumors in primary gastric lymphoma.

To understand the role of vascular endothelial growth factor (VEGF) in placental development, we examined immunohistochemically 56 placentae ranging from 6--41-weeks gestation using rabbit antibody to a synthetic multiple antigen peptide (MAP), composed of N-terminal amino acid residues 1--20 of human VEGF. In the present study, syncytiotrophoblast and invading extravillous trophoblasts ubiquitously expressed VEGF throughout gestation. However, the expression of VEGF in syncytiotrophoblasts was uneven in the first trimester and most intense at the sprouting sites. In addition, some stromal cells in the villi and decidual cells were also positive in the first trimester. A morphometrical analysis of the ratio of the VEGF-positive cell area to the capillary area in the terminal villi statistically revealed a critical point of change at 16 weeks' gestation. These results provide further evidence to support the hypothesis that VEGF, locally expressed by trophoblasts, stromal cells in villi and decidual cells, may play an important role in the physiological growth and function of the vascular system in the villous stroma and basal plate during placental development and maturation.

We titrated antibody to hepatitis C virus (anti-HCV) core of serum samples from 57 patients with chronic HCV infection, in an attempt to clarify the relationship between the level of HCV RNA and the outcome of interferon treatment. The patients studied were positive for both anti-HCV, by second-generation assay, and HCV RNA, by polymerase chain reaction, and had been treated with interferon for six months. Of the 57 patients, HCV RNA was eliminated in 16 by the time of discontinuation of interferon treatment (CR); in 19 this elimination was transient (PR) and for 22 elimination was nil (NR). The low HCV RNA level was accompanied by high titers of anti-HCV core while high HCV RNA levels were accompanied by low titers of anti-HCV core, with an inverse correlation (r = -0.322, P0.05). The mean titer of anti-HCV core before interferon treatment was 324 units in CR, 205 in PR, and 168 in NR, with a correlation ratio of 0.382 (P0.05). A decreased titer (more than 50%) was found in 68% of the CR. At the time of six-month follow-up, the anti-HCV core titers of CR had decreased by more than 50%, compared to pretreatment titers, while in PR and NR, there was an increase to above the pretreatment titers, without increases in HCV RNA levels or worsening of the hepatitis. In conclusion, quantitative assay for anti-HCV core is useful to assess the status of HCV replication.

Immune cell subsets, when measured by two-color flow cytometry in a population of 129 hemodialysis patients, showed significant variance from normal values. Lymphopenia, decreased absolute counts, and altered percentage values of immune cells were found. Increased proportions of CD3+, T cell receptor (TCR) alpha beta + cells and CD4+ T lymphocytes were present. An abnormally high percentage of a subset of activated TCR alpha beta + cells (alpha beta + DR+) was also seen in hemodialysis patients. The proportion of B lymphocytes was found to be significantly lower as compared with controls. Relative values for TCR gamma delta+cells, both for activated (gamma delta + DR+) and nonactivated (gamma delta + DR-) subsets, as well as for CD8+ lymphocytes and natural killer cells did not vary from those of normal controls. Also, the CD4+/CD8+ ratio showed no significant change. Analysis of absolute counts of the investigated immune cell populations revealed significantly decreased numbers for the majority of subsets, as a result of the preexisting lymphocytopenia, characteristic of end-stage renal disease. We conclude that profound quantitative alterations of immune cells, including TCR+T cells subsets, exist in hemodialysis patients. These account, at least in part, for the immune dysregulation associated with chronic renal failure.

This paper describes the design of a Microsoft Excel Program which interactively creates attractive and outstanding survival curves. This program enables medical researchers to easily create quality presentation graphs of survival curves and obtain high quality slides and prints, which can be inserted in papers or used directly at medical meetings. Through the use of vertical bars, this program can display the exact points where censored cases occur on survival curves, making it possible to monitor censoring patterns between groups. Furthermore, this program can also create survival curves based on the proportional hazards model for specific patterns of covariate values, given estimated regression coefficients and baseline survival function. This program may be a most useful and effective tool in creating medical research papers containing survival analysis.

In literature database searching, we show that it is necessary to use plural databases for a more improved search. We also compare the results of a single database search with that of multiple database search in the domain of Japanese life sciences. We searched the MEDLINE and EMBASE using the same search terms. There were some differences in the results, owing to differences in the journals and recording methods. We herein show some of the differences in the journals contained in both databases. Furthermore, we show the differences in the number of papers derived from the same journal. Next, as an example of a practical search, we selected some universities in Japan, searched both databases regarding papers published from these universities and then merged the results by hand. According to our results, only 63% of all papers were common to both databases.

We have developed a visual field quantification system that can accurately quantify the measurement results by the Goldmann Perimeter (GP). This system calculates the plural indexes introduced in published papers. In recent years, several isopter quantification methods have been proposed. In these methods, the isopters are digitized and the data are input into a computer, after which a computer program evaluates the changes in the isopters quantitatively. However, each program is only able to evaluate private indexes. We have developed a system that quantifies data using multiple methods. This system used five methods that have been introduced in published papers. With this system, a physician can analyze GP data with multiple methods and can diagnose diseases accurately. We have already input about 2500 GP recording papers into the computer by this system. We then calculated the plural indexes, and visualized the temporal changes in the perimetry.

Background: Acute lymphoblastic leukemia (ALL) in infants represent 2.5% to 5% of all childhood ALL, and has an inferior therapeutic outcome compared to that of older children. Among several risk factors, rearrangement in MLL gene is most closely associated with this poor outcome. This is the first series of cooperative group trials stratifying ALL in infants with MLL gene status. Procedure: Infants with ALL, age less than 12 months, were registered on two consecutive multi-center trials designated MLL96 and MLL98. All the patients were tested for MLL gene rearrangements by Southern Blot analysis and/or fluorescence in situ hybridization. According to the MLL gene status, patients with rearranged MLL gene were allocated to intensive chemotherapy followed by hematopoietic stem cell transplantation (HSCT), and those with germline MLL were treated with standard chemotherapy alone (total treatment duration was 83–85 weeks). In MLL98 study, treatment intensification and early use of HSCT were introduced compared to MLL96 study. Results: A total of 101 infants were enrolled between December 1995 and December 2002. Seventy-nine had rearranged MLL and 22 had germline MLL. Event-free survival (EFS) of all 101 infants with ALL was 52.0% at 5 years; 5-year EFS for MLL rearranged cases was 39.7%, and for MLL germline cases was 95.5% (p Conclusions: Risk stratification with MLL gene status was successful for infants with ALL. Excellent results were obtained for the germline MLL group using chemotherapy alone, and early introduction of allogeneic HSCT in first remission seemed effective for the MLL rearranged group. However, use of HSCT with less toxic conditioning regimens or development of effective chemotherapy including molecular target therapy are needed for MLL rearranged patients in order to avoid severe late effects for infants.