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Background/Objectives The Japan-multimodal intervention trial for prevention of dementia (J-MINT) is intended to verify the effectiveness of multi-domain interventions and to clarify the mechanism of cognitive improvement and deterioration by carrying out assessment of dementia-related biomarkers, omics analysis and brain imaging analysis among older adults at high risk of dementia. Moreover, the J-MINT trial collaborates with partnering private enterprises in the implementation of relevant interventional measures. This manuscript describes the study protocol. Design/Setting Eighteen-month, multi-centered, randomized controlled trial. Participants We plan to recruit 500 older adults aged 65–85 years with mild cognitive impairment. Subjects will be centrally randomized into intervention and control groups at a 1:1 allocation ratio using the dynamic allocation method with all subjects stratified by age, sex, and cognition. Intervention The multi-domain intervention program includes: (1) management of vascular risk factors; (2) group-based physical exercise and self-monitoring of physical activity; (3) nutritional counseling; and (4) cognitive training. Health-related information will be provided to the control group every two months. Measurements The primary and secondary outcomes will be assessed at baseline, 6-, 12-, and 18-month follow-up. The primary outcome is the change from baseline to 18 months in a global composite score combining several neuropsychological domains. Secondary outcomes include: cognitive change in each neuropsychological test, incident dementia, changes in blood and dementia-related biomarkers, changes in geriatric assessment including activities of daily living, frailty status and neuroimaging, and number of medications taken. Conclusions This trial that enlist the support of private enterprises will lead to the creation of new services for dementia prevention as well as to verify the effectiveness of multi-domain interventions for dementia prevention. Electronic Supplementary Material Supplementary material is available for this article at 10.14283/jpad.2021.29 and is accessible for authorized users.

Although most patients in the intensive care unit (ICU) receive antibiotics, little is known about patterns of antibiotic use in ICUs in Japan. The objective of this study was to evaluate the pattern of antibiotic use in ICUs. A nationwide one-day cross-sectional surveillance of antibiotic use in the ICU was conducted three times between January 2011 and December 2011. All patients aged at least16 years were included. Data from 52 ICUs and 1148 patients were reviewed. There were 1028 prescriptions for intravenous antibiotics. Of 1148 patients, 834 (73%) received at least one intravenous antibiotic, and 575 had at least one known site of infection. Respiratory and intra-abdominal infections were the two most common types. Of 1028 prescriptions, 331 (34%) were for surgical or medical prophylaxis. Excluding prophylaxis, carbapenems were the most commonly prescribed agent. Infectious disease consultations, pre- and post-prescription antimicrobial stewardship, and ICU-dedicated antibiograms were available in 44%, 52%, 77%, and 21% of the ICUs, respectively. In logistic regression analysis adjusting for patient characteristics, treatment in a university hospital (adjusted odds ratio, 1.72; 95% CI, 1.05–2.84; P = 0.033) and an open ICU (adjusted odds ratio, 2.30; 95% CI, 1.02–5.17; P = 0.044) were significantly associated with greater likelihood of carbapenem use. An increase in the number of closed ICUs and more intensive care specialists may reduce carbapenem use in Japanese ICUs. Large-scale epidemiological studies of antimicrobial resistance in the ICU are needed.

The authors report on a rare case of maternal virilization during pregnancy caused by autosomal recessive P450 oxidore- ductase (POR) deficiency.A 24-year-old primigravida developed a deepening voice and hirsutism in the second trimester. Prenatal ultrasonography failed to detect any fetal abnormality and fetal growth was normal. POR deficiency was suspected, but the mother declined fetal genetic testing. A female neonate was delivered by cesarean section at 41 weeks' gestation.The neonate had skeletal abnormalities. Mutational analysis of the POR gene demonstrated homozygosity for c.1370 GA and p.R457H in the patient and heterozygosity in her parents. POR deficiency was confirmed in the neonate.POR deficiency should be suspected in cases of maternal virilization. Maternal urinary estriol, fetal magnetic resonance imaging, and parental genetic testing should be performed. Parental consent for fetal genetic testing should be sought to ensure prompt diagnosis and early treatment.

As a result of the RAINBOW trial, ramucirumab plus paclitaxel was established as a second-line treatment of advanced gastric cancer. Regarding the safety of ramucirumab plus paclitaxel in the Japanese, a subgroup analysis of the RAINBOW trial was conducted. The incidence of neutropenia was higher in Japanese patients. However, information is lacking concerning the safety of ramucirumab after marketing in Japanese patients. Therefore, the aim of this study was to evaluate the safety of ramucirumab in Japanese patients with advanced gastric cancer. The inclusion criteria were patients diagnosed with advanced gastric cancer who had commenced treatment with ramucirumab plus paclitaxel or paclitaxel only at Ogaki Municipal Hospital (Gifu, Japan) between January 2015 and December 2016. There were 26 patients in the ramucirumab plus paclitaxel group and 22 patients in the paclitaxel only group. Treatment-related adverse events were documented in 100.0% of the patients in the ramucirumab plus paclitaxel group (Grade 3-4, 73.1%) and 90.9 % of the patients in the paclitaxel only group (Grade 3-4, 45.5 %). The most frequently observed adverse event in both treatment groups was anemia. The second common adverse event was neutropenia. The incidence of neutropenia of Grade ≥3 was significantly higher in the ramucirumab plus paclitaxel group than in the paclitaxel only group. In conclusion, the incidence of neutropenia is high. However, we believe that ramucirumab plus paclitaxel can be safely administered.

Background Prospective evidence is inconsistent regarding the association between vegetable/fruit intake and the risk of gastric cancer. Methods In an analysis of original data from four population-based prospective cohort studies encompassing 191 232 participants, we used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of gastric cancer incidence according to vegetable and fruit intake and conducted a meta-analysis of HRs derived from each study. Results During 2 094 428 person-years of follow-up, 2995 gastric cancer cases were identified. After adjustment for potential confounders, we found a marginally significant decrease in gastric cancer risk in relation to total vegetable intake but not total fruit intake: the multivariate-adjusted HR (95% CI; P for trend) for the highest versus the lowest quintile of total vegetable intake was 0.89 (0.77–1.03; P for trend = 0.13) among men and 0.83 (0.67–1.03; P for trend = 0.40) among women. For distal gastric cancer, the multivariate HR for the highest quintile of total vegetable intake was 0.78 (0.63–0.97; P for trend = 0.02) among men. Conclusion(s) This pooled analysis of data from large prospective studies in Japan suggests that vegetable intake reduces gastric cancer risk, especially the risk of distal gastric cancer among men.

Background The prognosis in advanced hepatocellular carcinoma (HCC) with multiple intrahepatic metastases is extremely poor. Combination therapy with subcutaneous interferon (IFN) alfa and intraarterial 5-fluorouracil was reported to be effective against such advanced HCC. We describe results of debulking surgery followed by combination therapy with IFN alfa and 5-FU for massive HCC with multiple intrahepatic metastases. Methods In 27 HCC patients with massive tumors and multiple intrahepatic metastases, we performed combination therapy with IFN alfa and 5-FU after maximal liver tumor resection. Results Mean patient age was 63.3 years. Including intrahepatic metastases, tumors numbered 5 or more in 17 patients (63%). Portal or hepatic vein branches were invaded in 22 (81%). The mean maximum tumor diameter was 102 mm. Among 24 patients whose results were analyzed, an objective response by residual intrahepatic metastases was observed in 13 (54%; complete response in 12, and partial response in 1). Overall 1-, 3-, and 5-year survival was 73.2%, 38.7%, and 38.7%, respectively; 1-, 3-, and 5-year progression-free rates were 38.2%, 22.3%, and 22.3%. Conclusions Debulking surgery followed by IFN alfa and 5-FU combination chemotherapy offers possibility of long-term survival despite massive HCC with multiple intrahepatic metastases.

The aim of this study was to investigate the efficacy and safety of combination chemotherapy with weekly paclitaxel and 5-fluorouracil (5-FU) as first-line treatment in patients with advanced or recurrent gastric carcinoma. A total of 65 patients were treated with the following regimen, administered every 28 days; 5-FU 600 mg/m2 by 24-hour continuous infusion from days 1 through 5, and weekly paclitaxel 80 mg/m2 by 3-hour intravenous infusion on days 8, 14, and 21. A total of 272 cycles were conducted with a median of 4 (2-13) cycles per case. Out of 57 patients with measurable disease by RECIST criteria, there were 2 complete responses (3.5%), 20 partial responses (35.1%) and 25 cases with stable disease (43.9%). The overall response rate was 38.6% (95%CI: 26.0-51.2%). The median survival time and 1-year survival rates were 329 days and 47.4%, respectively. Both hematologic and non-hematologic toxicities were well tolerated.

Summary Objectives: The analysis of brain imaging data such as functional MRI often requires considerable computing resources, which in most cases are not readily available in many medical imaging facilities. This lack of computing power makes it difficult for researchers and medical practitioners alike to perform on-site analysis of the generated data. This paper presents a system that is capable of analyzing functional MRI data in real time with results available within seconds after data acquisition. Methods: The system employs remote computational servers to provide the necessary computing power. System integration is accomplished by an accompanying software package, which includes fMRI analysis tools, data transfer routines, and an easy-to-use graphical user interface. The remote analysis is transparent to the user as if all computations are performed locally. Results: The use of PC clusters in the analysis of fMRI data significantly improved the performance of the system. Simulation runs fully achieved real-time performance with a total processing time of 1.089 s per image volume (64 x 64 x 30 in size), much less than the per volume acquisition time set to 3.0 s. Conclusions: The results show the feasibility of using remote computational resources to enable on-demand real-time fMRI capabilities to imaging sites. It also offers the possibility of doing more intensive analysis even if the imaging site doesn’t have the necessary computing resources.

Background/purpose Washing the face with a mild cleanser is generally recommended for acne care. Occasionally, the general public has the misconception that acne is exacerbated by cleansers and furthermore it has concerns about inducing skin irritation and xerosis by intensive washing. Recently, we developed a new cleanser based on sodium laureth carboxylate and alkyl carboxylates (AEC/soap) that cleans sebum well without penetrating the stratum corneum. Methods We designed a controlled clinical trial conducted on adult Japanese males with moderate or less acne. Twenty subjects washed their faces with AEC/soap base cleanser twice a day for 4 weeks. Assessment of the efficacy was conducted prior to the start of the study, and at the end of weeks 2 and 4. Results Significant improvement of the acne was observed within 2 weeks, and acne lesions were not detectable in 25% of the subjects at week 4. Sebum secretion levels on the skin significantly increased on the forehead, but significantly decreased on the cheek which correlated with the improvement. No complaints of dryness or irritation occurred during the study. Conclusion Washing the face twice a day with facial cleanser based on AEC/soap is an effective care for moderate or less grade facial acne.

We describe four patients with generalized scaly and pustular skin lesions showing extensive neutrophilic infiltration in the subcorneal region of the epidermis. Immunofluorescence, immunoblot and enzyme-linked immunosorbent assay analyses detected IgG antibodies reacting exclusively with desmoglein 1, the pemphigus foliaceus antigen. This study indicates that pemphigus foliaceus may show prominent neutrophilic pustular skin lesions.

Hepatic veno-occlusive disease (VOD) is one of the most serious complications in patients receiving stem cell transplantation (SCT). However, the cause of VOD remained to be elucidated. Vascular endothelial growth factor (VEGF) has been reported to have various physiological effects including neovascularization and acceleration of vasopermeability. Because we postulated that VEGF could be one of the causative factors in VOD after SCT, serum VEGF levels were measured by ELISA in 50 patients receiving SCT. Six of the patients showed typical manifestations of VOD and four of them died due to VOD. The mean maximum serum VEGF level in the six patients with VOD was markedly increased compared to that in the patients without VOD (P < 0.001) and in normal controls (P < 0.001). Moreover, the mean maximum serum VEGF level in patients with VOD before conditioning chemoradiotherapy for SCT was also high compared to patients without VOD (P = 0.0012) in the same period. Similarly, serum VEGF levels were significantly higher in patients whose plasma protein C activities decreased below 40% (P < 0.001). during the clinical course of VOD after SCT, the increase of serum VEGF synchronized fairly well with the development of VOD. Since VEGF causes the expression of tissue factor on circulating monocyte/ macrophages and results in hypercoagulability, our observation suggests that in the patients with VOD who showed high serum VEGF it might account for the development of VOD. Furthermore, this observation may indicate a novel therapeutic strategy for prevention of VOD. Bone Marrow Transplantation (2001) 27, 1173–1180.

Allergic and chronic inflammation of the airway is regarded as the main pathogenesis of bronchial asthma, in which adhesion of inflammatory cells requires the expression of adhesion molecules. Thus, to clarify the role of fibronectin (FN) in the airway inflammation of bronchial asthma, FN levels in plasma and bronchoalveolar lavage fluid (BALF) from bronchial asthmatics were determined. FN concentrations in plasma and BALF were measured by enzyme-linked immunosorvent assay (ELISA) in 17 asthmatic patients and 10 healthy controls to elucidate the role of FN in allergic inflammation. The mean FN/albumin (Alb) level in the BALF of asthmatic patients was 2.973 micrograms/mg, which was significantly higher than that of healthy controls (0.727 microgram/mg). Non-atopic asthmatics showed a significantly higher level of FN in their BALF in comparison with atopic asthmatics, although the ratio of FN to albumin showed no significant difference. FN levels in BALF correlated significantly with total cell density (r = 0.71, P < 0.05) and alveolar macrophage density (r = 0.64, P < 0.05). FN levels in plasma did not correlate with those in BALF. In conclusion, increased FN in BALF, which was produced locally in the airways of asthmatic patients, is actively involved in the regulation of allergic inflammation.

This study investigated the relation between asthma attacks and levels of plasma fibronectin (FN) and serum eosinophilic cationic protein (ECP) in patients with bronchial asthma in order to clarify the role of FN in the airway inflammation of bronchial asthma. Plasma levels of FN were significantly higher (P < 0.025) in patients with bronchial asthma than in healthy controls. They were also significantly higher (P < 0.05) in non-atopic asthmatics than in atopic asthmatics. Furthermore, plasma FN was lower during the attack than the non-attack stage (P < 0.025), and a significant increase of plasma FN was noted (P < 0.05) in asthmatics who had more severe and more frequent attacks. Serum levels of ECP were significantly higher during the attack than the non-attack stage (P < 0.005). An increase of plasma FN in the non-attack stage after attacks showed a significant correlation (P < 0.05) with a decrease of serum ECP. These observations clearly indicate that the decrease in plasma FN associated with attacks is closely related to aggravation of airway inflammation, and that the increase in plasma FN in the non-attack stage reflects chronic airway inflammation. These results suggest that the fluctuation in plasma levels of FN may be one of the factors affecting allergic inflammation and attacks in bronchial asthma.

To confirm when the levator aponeurosis is disinserted and how the disinsertion is compensated for in growing children, the earliest and latest photographs of the same children were the subjects of a retrospective comparative study regarding upward displacement of the superior palpebral crease and the eyeball in the palpebral fissure. Ninety-four children (48 boys and 46 girls) were selected from 615 patients with cleft lip and palate who were followed for more than several years at our outpatient clinic and whose 58,000 photographs were digitized. The earliest and latest photographs of the patients were taken in primary gaze position; the former, taken at less than 3 years of age, and the latter, taken at more than 6 years of age, were selected for this study. The intervals between the two photographs ranged from 3 to 14 years (mean, 9.61 years; SD, 3.11). The superior palpebral crease moved upward parallel with the growth of the children (p0.0001) as well as with the length of the growth period (p = 0.0141). The lower eyelid did not move downward (p0.0001). The eyeball also displaced upward parallel with growth (p0.0001) and with the length of the growth period (p = 0.0302). The more the superior palpebral crease was displaced upward, the more the eyeball was displaced upward (p = 0.0005). The levator aponeurosis may be likely to disinsert from the tarsus in growing children, thus requiring compensatory, excessive contraction of the levator muscle, which may cause upward displacement of the superior palpebral crease. Subsequently, excessive contraction of the superior rectus muscle in conjunction of the levator muscle may rotate the eyeball upward, which may incline the head. When the head is not inclined in the primary gaze position, compensatory contraction of the inferior rectus muscle to maintain the horizontal visual axis may displace the eyeball upward in the orbit by means of the inferior suspensory ligament of Lockwood.

Vascular endothelial growth factor (VEGF) is a potent mitogen in endothelial cells, but little is known about its activity in other cell types. To clarify the role of VEGF in human dental pulp cells and pulp tissue, we investigated the effects of VEGF on the chemotaxis, proliferation, and differentiation of human dental pulp cells. VEGF induced a strong chemotactic response in human dental pulp cells in a dose-dependent manner. VEGF also marginally enhanced the proliferation of human dental pulp cells and induced an increase in alkaline phosphatase in human dental pulp cells. However, these effects of VEGF were not observed in reference to human skin fibroblasts. Analyses by the reverse-transcription/polymerase-chain-reaction method and flow cytometry showed that the mRNAs of two VEGF receptors, fms-like tyrosine kinase and kinase insert domain-containing receptor, were expressed in human dental pulp cells, whereas only fms-like tyrosine kinase mRNA was expressed in human skin fibroblasts. VEGF induced the activation of activator protein I (AP-1) and c-fos mRNA expression in human dental pulp cells. The AP-1 inhibitor curcumin strongly inhibited VEGF-induced alkaline phosphatase production in human dental pulp cells. In addition, VEGF antisense oligonucleotide suppressed the production of VEGF and alkaline phosphatase in human dental pulp cells. These results suggest that VEGF produced by human dental pulp cells acts directly upon human dental pulp cells in an autocrine manner, and may promote the chemotaxis, proliferation, and/or differentiation of human dental pulp cells via the utilization of kinase insert domain-containing receptor and in part through AP-1 by increasing c-fos.

A surgical resection of metastatic liver lesions from colorectal cancer contributes to an improved prognosis. However, the postoperative recurrence rate remains high, particularly in the residual liver. This is probably the result of the failure to detect small lesions. In the present study, we histologically examined the presence of intrahepatic micrometastases, which are considered to be related to recurrence in the residual liver. Intrahepatic micrometastases were histologically examined in 31 resected specimens of 25 patients undergoing a hepatic resection because of metastasis to the liver from colorectal cancer. Micrometastases were found in 14 of 25 cases (56.0%). They were located in the portal veins, central veins, sinusoid, and bile ducts. The longest distance from the main metastasis was 38.2 (mean 7.5 +/- 8.0) mm. The size of the macrometastases became larger, and the frequency of micrometastases and the distance of micrometastases from macrometastases had a tendency to increase. Continuous invasion of the macrometastases into the micrometastases through the vasculature or bile duct was also observed. These results suggested that some micrometastases observed in the metastatic liver from colorectal cancer were thus seeded from the primary lesions, while other micrometastases originated from the macrometastatic lesions as satellite lesions.

Synopsis Objective Sodium laureth sulphate (SLES) is an anionic detergent, which has been used globally for personal care products because of its mildness and good foaming ability. However, SLES is somewhat invasive and stimulatory to the skin, and many consumers with sensitive skin desire milder detergents for daily use skin cleansers. We enhanced the mildness of SLES by formulating it with sodium laureth carboxylate (AEC) and lauryl glucoside (LG). Methods In skin soak tests, 5% detergent solutions were applied to the forearms of 10 Japanese healthy volunteers for 30 min followed by washing with tap water once a day for 4 days. Twenty-four hours after the last treatment, cutaneous capacitance measurements and visual analyses were performed. In a controlled usage study, 16 Japanese healthy volunteers used the test body cleanser for 4 weeks. Assessment of efficacy and mildness was conducted prior to the start of the study and at the end of week 4 by cutaneous conductance, dermoscopic evaluation of the stratum corneum and visual assessment by a dermatologist. Results In soak tests, cutaneous capacitance was significantly decreased on the soap-treated region and on the SLES-treated region. No significant decrease was identified on the SLES/AEC/LG-treated region with less induction of erythema or dryness. In the controlled usage study, no significant changes in cutaneous conductance or texture or damage of corneocytes on the forearm and lower thigh were found. However, visual assessment revealed a significant decrease in scaling and erythema on the lower thigh after 4 weeks of usage with an improvement of the discomfort of the consumer. The favourability rating of this formulated detergent in several questionnaire items was very good. Conclusion The newly formulated skin cleanser with the combination of anionic surfactants SLES and AEC and the non-ionic surfactant LG provides a mild surfactant with a satisfactory cleansing activity for body washing. Resume Objectif Le laureth sulfate de sodium (SLES) est un detergent anionique, qui a ete utilise a l'echelle mondiale pour les produits de soins personnels en raison de sa douceur et d'une bonne capacite de former des mousse. Cependant, SLES est quelque peu invasive et irritant de la peau et de nombreux consommateurs ayant la peau sensible desirent des detergents doux pour les bases lavantes de tous les jours. Nous avons ameliore la douceur de SLES en le formulant avec le sodium laureth carboxylate (AEC) et le lauryl glucoside (LG). Methodes Dans les tests de trempage de la peau, des solutions detergentes a 5% ont ete appliquees sur les avant-bras de 10 volontaires japonais sains pendant 30 min, le tout suivi d'un lavage avec de l'eau du robinet, une fois par jour pendant 4 jours. Vingt- quatre heures apres le dernier traitement, des mesures d'impedance et des analyses visuelles cutanees ont ete realisees. Dans une etude sur l'utilisation controlee, 16 volontaires sains japonais ont utilise le nettoyant d'essai pour le corps pendant 4 semaines. L'evaluation de l'efficacite et de la douceur a ete realisee avant le debut de l'etude et a la fin de la semaine 4 par conductance cutanee, par l'evaluation dermoscopique de la couche cornee, et par l'evaluation visuelle par un dermatologue. Resultats Dans les tests de trempage, la capacitance cutanee etait significativement diminuee sur les zones traitees au savon ainsi que sur la region traitee au SLES. Aucune diminution significative a ete identifiee sur la region traitee a la combinaison AEC/LG SLES qui montrait aussi moins d'induction d'erytheme ou de secheresse. Dans l'etude de l'utilisation controlee, aucun changement significatif dans la conductance cutanee ou de la texture ou de dommages de corneocytes sur l'avant-bras et de la cuisse inferieure a ete trouve. Toutefois, une evaluation visuelle a revele une diminution significative de desquamation et de l'erytheme sur la cuisse inferieur apres 4 semaines d'utilisation avec une amelioration de l'inconfort ressenti par les consommateurs. La cote d'acceptation de ce detergent formule etait tres bon dans plusieurs items du questionnaire. Conclusion Le nettoyant pour la peau nouvellement formule avec la combinaison d' agents tensioactifs anioniques et SLES/AEC et le tensioactif non ionique LG fournit un agent tensio-actif doux, avec une activite de nettoyage satisfaisant pour le lavage des corps.

Treatment response to interferon alfa (IFNalpha) is described in three consecutive cases of two forms of Sjogren's syndrome associated neuropathy (SSN)-two with sensory ataxic ganglionopathy and one with sensorimotor neuropathy with demyelinating features. All responded well to IFNalpha in terms of neuropathic symptoms, sicca symptoms, antibody titres, and findings in salivary gland biopsy specimens. IFNalpha thus showed promise in treating both SSN and the underlying Sjogren's syndrome.

Idiopathic interstitial pneumonia (IIP) is a progressive and often fatal pulmonary disorder, and evaluating the prognosis of patients with IIP has never been sufficient. Accordingly, factors including clinical features, laboratory data, cellular components in bronchoalveolar lavage (BAL) fluid and response to corticosteroid therapy were analyzed in 35 patients with IIP whose median age of respiratory onset was 60 years (range; 37-77 years). Nineteen patients (54.3%) were in the active stage of IIP and 16 of them were treated with corticosteroids. Significant prognostic factors were the neutrophil percentage in BAL fluid, interstitial shadows on chest radiograph, pulmonary function, blood oxygen level, grade of dyspnea, and disease activity at the initial examination. Patients in the active stage showed higher proportions of neutrophils and eosinophils in BAL fluid than those in the non-active stage. Despite corticosteroid therapy, the survival of patients in the active stage was significantly shorter than those in the non-active stage. Fifty percent of the patients treated with corticosteroids were regarded as responders at 1 month after the initiation of therapy; however, there was no significant difference between responders and non-responders in terms of survival time. In conclusion, disease activity and neutrophils in BAL fluid may be important predictors of the prognosis of IIP.

Aim This study was conducted to clarify the management of perioperative infectious complications after adult living donor liver transplantation (LDLT). Patients and methods Fourteen adult LDLT patients were enrolled in this study. We examined the occurrence of infectious complications in these cases and the relationships of infectious complications to UNOS status and MELD score. Surveillance culture and immunoserologic analyses were performed. From the results of these analyses, we made a diagram of infection surveillance using a matrix of time and sampling site. Using the diagram, we chose sensitive antibiotics as soon as possible. Results The infection site and its pathogen were able to be detected in four (28.5%) patients, all of whom had MRSA infections, together with lung aspergillosis in one case, pseudomonas pneumonia in another, and both in another. Two patients died of lung aspergillosis. Bacteria detected in the airway tended to spread to other sites during the postoperative period. In all four patients in whom infectious diseases were detected, and in a fifth patient in whom the site of infection was not known, the UNOS status was 1. The MELD score was calculated in eight patients, six of whom had high MELD scores (>20). Conclusion Most cases were manageable by choosing and changing antibiotics and antifungal drugs according to the results of surveillance cultures twice a week. However, aspergillosis had an extremely poor prognosis. Patients with a high MELD score or low UNOS status, or both, showed poor prognosis; and in them, multiple drug resistance bacteria caused severe perioperative infectious complications.

This study sought to determine whether a prognostic score is a useful indicator of donor safety using 13 consecutive donors enrolled for liver transplantation. The donor operations were right hepatic lobectomies (n = 10) and left hepatic lobectomies (n = 3). The postoperative maximal level of serum total bilirubin was used to assess the magnitude of surgical stress. Variables such as donor age, percentage of liver resection (PLR), indocyanine green 15-minute retention rate (ICGR15), operative blood loss, operation time, prognostic score and graft weight were evaluated as predictors of the magnitude of surgical stress. The PLR and prognostic score (PS) were calculated according to the following formulae: PLR (%) = 100*Graft weight (g)/standard liver volume of the donor (mL); PS = -84.6 + 0.933*PLR (%) +1.11*ICGR15 (%) +0.999*age (years); Standard liver volume (mL) = 706.2*body surface area (m2) + 2.39. No serious complications occurred after the donor operations. Maximal bilirubin ranged from 1.9 to 10.9 mg/dL. There were no mortalities, although there were two morbidities, bile leakage and prolonged liver dysfunction. Postoperative hyperbilirubinemia was observed in two donors and in one Gilbert's syndrome donor. Linear regression analysis of each variable indicated poor correlations between those variables and maximal bilirubin. However, close correlations were seen between maximal bilirubin and both donor age and PS except for the three patients who showed postoperative hyperbilirubinemia. In these uneventful donors, statistical formulae were obtained as follows: maximal bilirubin (PMB) = 0.271 + 0.056*donor age (correlation coefficient 0.612, P.008), PMB = 1.541 + 0.059*PS (correlation coefficient 0.597, P.009). In conclusion, PS is useful to predict maximal bilirubin and to ensure donor safety.

Synchronous Paget's disease of breast and vulva is extremely rare and has only been reported in the literature in one other case.A 58-year-old postmenopausal woman was found to have crusting, bleeding, and discharge from left nipple, as well as vulvar pruritis at the same time. Biopsy of breast lesion demonstrated Paget's disease with an underlying foci of ductal carcinoma in-situ that required total mastectomy of left breast with sentinel node biopsy and breast reconstruction. For vulvar symptoms, the patient was initially diagnosed with dermatitis and topical ointment was prescribed. However, her symptoms persisted for the next several months, and she underwent vulvar biopsy that demonstrated Paget's disease. She underwent partial vulvectomy. Multiple episodes of recurrent vulvar Paget's disease were noted in the postoperative course that medical therapy with Imiquimod and a second partial vulvectomy was performed.Synchronous of breast and vulvar Paget's disease is presented. There was a delay in diagnosing vulvar Paget's disease in this experienced case. While coincidence of breast and vulvar Paget's disease is likely, ectopic mammary tissue in vulvar as well as secondary metastasis from a focal lesion of breast Paget's disease needs to be carefully evaluated whenever the patient complains of vulvar symptoms in the setting of breast Paget's disease.

Oral squamous cell carcinomas (SCCs) are malignant tumours that frequently invade the mandibular bone and bone invasion is a common clinical problem. Recent studies have revealed that bone resorption by osteoclasts is an important step in the process of bone invasion by oral SCCs. However, the cellular and molecular mechanisms of bone invasion by oral SCCs remain unclear. Oral SCCs invade the mandibular bone through an erosive, mixed or infiltrative pattern that correlates with clinical behaviours. The expressions of interleukin (IL)-6, IL-11, tumour necrosis factor (TNF) α and parathyroid hormone-related protein (PTHrP) were higher in the infiltrative pattern than in the erosive pattern. These cytokines lead to receptor activator of NF-κB ligand (RANKL) expression or osteoprotegerin (OPG) suppression not only in oral SCC cells but also in cancer stromal cells to induce osteoclastogenesis. Taken together, oral SCCs provide a suitable microenvironment for osteoclastogenesis to regulate the balance of RANKL and OPG. In this review, we introduce recent advances in the knowledge of the cellular and molecular mechanisms, by which oral SCC invades mandibular bone based on the recent findings of our lab and others.

The complete nucleotide sequence of alpha antigen secreted from Mycobacterium avium (A-alpha) was determined. The gene encodes 330 amino acids, including 40 amino acids for the signal peptide, followed by 290 amino acids for the mature protein with a molecular mass of 30,811 Da. This is the first sequence of A-alpha. Comparisons between A-alpha and alpha antigens of Mycobacterium leprae, Mycobacterium bovis BCG, and Mycobacterium kansasii showed highly homologous regions which suggested a conserved functional domain and two less-homologous regions. Serological analysis of recombinant A-alpha, expressed by a series of deletion constructs, indicated the possibility that A-alpha carries at least six B-cell epitopes. The three antigenic determinants were common to Mycobacterium tuberculosis, M. kansasii, and M. avium. The results also suggested the possibility that there are three species-specific epitopes.

The development and progression of thyroid tumors is signaled by phenotype-specific mutations of genes involved in growth control. Molecular events associated with undifferentiated thyroid cancer are not known. We examined normal, benign, and malignant thyroid tissue for structural abnormalities of the p53 tumor suppressor gene. Mutations were detected by single-strand conformation polymorphisms of PCR-amplified DNA, using primers bracketing the known hot spots on either exons 5, 6, 7, or 8. The prevalence of mutations was as follows: normal thyroid 0/6; follicular adenomas 0/31; papillary carcinomas 0/37; medullary carcinomas 0/2; follicular carcinomas 1/11; anaplastic carcinomas 5/6; thyroid carcinoma cell lines 3/4. Positive cases were confirmed by direct sequencing of the PCR products. All five anaplastic carcinoma tissues and the anaplastic carcinoma cell line ARO had G:C to A:T transitions leading to an Arg to His substitution at codon 273. In both tumors and cell lines, examples of heterozygous and homozygous p53 mutations were identified. The only thyroid carcinoma cell line in which p53 mutations were not detected in exons 5-8 had markedly decreased p53 mRNA levels, suggesting the presence of a structural abnormality of either p53 itself or of some factor controlling its expression. The presence of p53 mutations almost exclusively in poorly differentiated thyroid tumors and thyroid cancer cell lines suggests that inactivation of p53 may confer these neoplasms with aggressive properties, and further loss of differentiated function.

In previously reported retrospective analyses of uterine cervical carcinoma cases, HER2 was correlated with poor radiation sensitivity and poor treatment outcomes and HIF-1alpha was found to be an indicator of poor prognosis. To date, no prospective studies have been performed to evaluate the radiation sensitivity and treatment outcomes of patients with uterine cervical carcinoma relative to HER2 and HIF-1alpha expressions. We conducted a prospective evaluation of HER2 and HIF-1alpha in cases of locally advanced uterine cervical carcinoma treated with concurrent chemoradiotherapy.Between June 2005 and April 2008, 25 patients with locally advanced uterine cervical carcinoma were registered in this study, KGROG0501. Their clinical stages were Ib2/IIb/IIIb/IVa in 1/2/22/1 cases, respectively. Nineteen cases had squamous cell carcinoma and six had adenocarcinoma. HER2 expression and HIF-1alpha expression were analyzed using an immunohistochemical kit on pretreatment biopsied specimens. HIF-1alpha expression was studied using another commercial immunohistochemical kit on pretreatment biopsied specimens. The survival rates were compared between patients with and without positive HER2 and HIF-1alpha expressions.The 20-month survival of HER2(-) and HIF-1alpha(-) cases (n = 6) was 100% and that of HER2(+) and HIF-1alpha(+) cases (n = 4) was 37.5% (p = 0.0032).In this first prospective analysis of patients with uterine cervical carcinoma treated with concurrent chemoradiotherapy, concomitant expression of HER2 and HIF-1alpha was suggested to be a strong indicator of poor prognosis. A novel therapy including molecular targeted therapy such as anti-HER2 and anti-HIF-1alpha may be worth considering in patients with concomitant expression of HER2 and HIF-1alpha.

A 47-year-old Japanese man was transferred to our hospital because of acute-on-chronic hepatitis B virus infection. On admission, he was suffering from sepsis due to a catheter infection and respiratory failure caused by pulmonary edema and pneumonia, but, as a result of preoperative intensive care, we avoided septic shock. ABO-incompatible liver transplantation (ABO-I-LT) was performed. In accordance with our ABO-I-LT protocol, we administered, rituximab and performed plasma exchange, splenectomy as well as hepatic artery infusion. The patient was discharged 80 days after living donor transplantation (LDLT). However, 136 days after LDLT, he experienced recurrent respiratory failure due to severe pneumonia. At that time, the CD19(+) B-cell count in the peripheral blood flow remained below 1%. We suspected a mixed infection involving Streptococcus pneumonia, Pneumocystis carinii, and fungus. The cause of the complication was overwhelming postsplenectomy infection (OPSI). We started administration of sulfamethoxazole and trimethoprim, ciprofloxacin hydrochloride, and micafungin sodium therapy as well as gamma-globulin. Oxygenation improved gradually; the patient was discharged at 41 days after re-admission. Although this patient survived the OPSI, it was clear that some aspects of the ABO-I-LT protocol should also be altered.

Locally advanced uterine cervical carcinoma (LAUCC) treated with chemoradiotherapy is considered to be the standard treatment regimen. However, no evidence of its efficacy and safety has been obtained from the Japanese population. Furthermore, the total dose of Japanese radiation therapy protocol is less than that of the USA which indicated that chemoradiotherapy for LAUCC is better than radiation therapy alone by phase III clinical trials. Thus, the current phase II study was designed to evaluate chemoradiotherapy with a lower radiation dose for LAUCC using weekly nedaplatin effectively and safely in the Japanese population. Nedaplatin is a platinum drug and no hydration is required to infuse patients because it is less toxic on renal function. If this phase II trial is successful, chemoradiotherapy for LAUCC in out-patient clinics could be possible.Patients registered in the current study were found to have LAUCC based on the following criteria i) pathologically proven squamous cell carcinoma or adenocarcinoma, ii) FIGO clinical Stage Ib, IIa, IIb with bulky tumor (diameter40 mm assessed by pelvic magnetic resonance imaging) or pelvic lymph node swelling (diameter10 mm assessed by pelvic computed tomography); iii) FIGO clinical Stage IIIa, IIIb and IVa with no paraaortic lymph node swelling (diameter10 mm) observed by abdominal computed tomography; iv) age: 20-75 years; v) performance status: 0-2. The treatment protocol was as follows: Radiation therapy in a combination of external beam radiation therapy (total dose: 50 Gy-52 Gy/25-27 fractions with central shielding after 30-32 Gy) with high-dose rate intracavitary irradiation (24-30 Gy/4-6 fractions to point A). Chemotherapy applied in the current study was weekly nedaplatin infused intravenously (30 mg/mm2/time, once a week, total 150 mg/mm2/5 weeks). Sample size in the current study was 45 LAUCC patients recruited for three years at a single institution. This protocol was permitted by the ethics committee of Kitasato University Hospital.Ten patients were registered in this study between June 2005 and March 2006. The median age was 57.5 years (range 36-73). PS0 was five and PS1 was five. As for clinical stage, nine were IIIb and only one was IIb. Nine patients were proven to have squamous cell carcinoma and one adenocarcinoma. The median maximum tumor diameter was 62.5 mm (range 30-100 mm). As for initial response, eight had CR and two had PR (100% response rate). As for hematological acute morbidity, three were grade 2, six were grade 3, and one was grade 4.This initial analysis of the phase II study confirmed that concurrent chemoradiotherapy using nedaplatin is safe and efficacious, thus we decided to undergo further studies.

A 29-year-old man was referred to our hospital with fulminant hepatic failure (FHF) and stage III hepatic coma (somnolence and confusion). Living donor liver transplantation (LDLT) was planned for 2 days after admission to our hospital. However, on the day after admission, he lapsed into stage IV hepatic coma: no right reflexes and no response to pain stimuli. Emergency cranial computed tomography revealed a subarachnoid hemorrhage (SAH), but no aneurysm was seen on magnetic resonance angiography. We speculated that the cause of the SAH may have been bleeding of intracranial veins secondary to coagulopathy and overextension of a vein due to brain edema. We considered that only LDLT could improve the coagulopathy and brain edema. The patient recovered consciousness on postoperative day (POD) 2 and was finally discharged from the hospital without neurological deficit on POD 85. This case suggested that SAH is not a prohibiting factor for LDLT in an FHF patient if the cause of the SAH is venous bleeding.

Background We have demonstrated a culture bag system that is useful for pancreatic islet transplantation. To improve and simplify islet transplantation procedures from culture to transplantation, we developed a novel device specific for both islet culture and transplantation (TUBERO Device [TD]) using an oxygen-permeable material. Materials and Methods Porcine islets with 30 minutes warm ischemia time were cultured for 24 hours at 37°C in 5% CO 2 and humidified air under three different procedures: (1) ordinary culture flask, (2) culture bag suitable for platelets, and (3) TD. Loss of islets during culture, glucose-stimulated insulin release as an islet functional test, and ADP/ATP ratio as an index of islet viability tests were evaluated to compare the devices. TD was further applied in two clinical islet transplantations using non–heart-beating donors in Japan. Results The loss of islets during culture was considerably lower in the TD group. The stimulation index upon glucose challenge tests was significantly higher in the TD group than the others. The ADP/ATP ratio in TD group was significantly lower than that in the ordinary flask group, suggesting that the apoptotic islets were relatively lower among TD. Most importantly, TD was successfully applied both in the clinical islet cultures and in transplantation, resulting in excellent graft function. Conclusions We propose that the TD, a novel product, not only simplifies islet transplantation procedures, but also maintain the quality of isolated islets.

Aims Two-stage hepatectomy for multiple, bilobar liver metastases from colorectal cancer aimed to minimize liver failure risk by performing the second resection after regeneration, but impact of this strategy on volume of the future liver remnant (FLR) remained to be demonstrated. We compared two-stage hepatectomy with one stage following portal vein embolization (PVE) for multiple, bilobar liver metastases from colorectal cancer as to effects on volume of the FLR. Methods Forty-three patients undergoing major hepatectomy for multiple colorectal cancer metastases were divided retrospectively into patients undergoing hepatectomy following PVE (n = 21) and those undergoing two-stage hepatectomy (n = 22). Increases in FLR volume were compared. Results While the increase in the volume FLR averaged approximately 70 mL (302.6 mL before PVE vs. 370.9 mL after PVE) and the increase in the ratio of FLR to total liver volume averaged approximately 7.5% (30.2% to 37.5%) following PVE, first-stage hepatectomy increased FLR volume by approximately 100 mL (from 259.4 to 361.4), and the ratio, by 15% (26.9% to 41.6%). The FLR hypertrophy ratio relative to pre-procedure volume estimates in the two-stage group (50.2%) was twice that in the PVE group (25.3%). Conclusions Superiority of two-stage hepatectomy in hypertrophy of the FLR was confirmed.

Invasive pulmonary aspergillosis (IPA) occurs in 1.5 to 10% of liver transplant recipients. Of the fungal infections, IPA is the most difficult to treat and the most frequently life-threatening. However, the best treatment strategy remains controversial. The patient was a 53-year-old woman who underwent living donor liver transplantation (LDLT) because of subacute fulminant hepatic failure due to autoimmune hepatitis. Aspergillus fumigatus was detected in the sputum taken intraoperatively by bronchial suction. A computed tomogram of the lung 7 days after LDLT showed fungal balls in the left lung. IPA was diagnosed. Since the patient suffered from pulmonary edema postoperatively and fungal balls occupied a greater part of the left lung, conservative therapy using micafungin, amphotericin B, and itraconazole was first selected. However, the fungus balls did not completely disappear. Moreover, brain abscess probably resulting from IPA dissemination was detected. Lung resection was performed as reduction surgery, and salvage treatment using voriconazole was done for a brain abscess. Septate hyphae of Aspergillus fumigatus were identified in the lung specimen. We concluded that for patients with IPA after LDLT, pulmonary resection should be done as soon as possible before deterioration of IPA and complication due to acute cellular rejection.

Increased risk of early recurrence

It is difficult to predict the recurrence of colorectal liver metastasis after curative hepatectomy. We investigated the relationship between subsequent metastasis and both CEA protein and CEA mRNA (TaqMan PCR) diachronic levels.The subjects were 30 patients with colorectal liver metastases. Serum CEA protein and CEA mRNA assays were performed every month after hepatectomy.Metastasis recurred in 21 of the 30 patients. The CEA mRNA assay showed 26 cases with high (H) levels and 4 with low (L). Among the 15 patients whose protein levels were not elevated (NE group), 6 had recurrence; all 6 belonged to the mRNA H group. None of the 4 patients in the mRNA L group had recurrence. In the protein-elevated (E) group (DFI6 months) (n = 7), mRNA was elevated in 5 cases (71.4%) 6 months before recurrence, whereas protein was elevated in 1 case. The sensitivity, specificity and accuracy of CEA protein/mRNA for identifying recurrence were 71.4/100, 100/44.4, and 80/83.3%, respectively.CEA mRNA is more sensitive than CEA protein in detecting recurrence. CEA mRNA may be useful for identifying high-risk groups or detecting recurrence at an early stage, when the CEA protein level is still low.

Patients with prolapsing internal hemorrhoids were treated with a novel sclerosing agent (OC-108), and the results were compared with surgery of ligation and excision. This study included 20 years or older patients with prolapsing internal hemorrhoids who visited ten medical institutions in Japan from October 2000 to October 2002. Investigation on surgery was also performed. Comparing OC-108 and surgery in patients with third- and fourth-degree internal hemorrhoids according to the Goligher’s classification, for which surgery has been generally indicated, at 28 days after treatment, the disappearance rate of prolapse was similar between OC-108 and surgery, 94% (75/80 patients) and 99% (84/85 patients), respectively. The 1-year recurrence rate was 16% (12/73 patients) in the OC-108 group, and this value was satisfactory because of its less invasive nature while it was more or less higher compared with 2% (2/81 patients) in the surgery group. The incidences of pain and bleeding were lower in the OC-108 group. OC-108 is a useful alternative treatment for hemorrhoids.

This study assessed the usefulness of artificial liver support (ALS) for pretransplant patients with fulminant hepatic failure (FHF). Five patients (age 14 to 52 years, 3 men and 2 women) with FHF who were being prepared for living donor liver transplantation (LDLTx) were enrolled in this study. ALS included plasma exchange, using 40 to 50 units of fresh frozen plasma per session, and high-flow hemodiafiltration, using a high-performance polysulfone membrane. Variables such as circulatory and respiratory function, coma grade, and neurologic disorders were evaluated. Although systolic and diastolic blood pressures showed no statistical differences between pre-ALS and post-ALS, the difference in heart rates was statistically significant. After ALS initiation in the pre-LDLTx period, one of the three patients who needed mechanical ventilation was weaned from it. After LDLTx, all patients recovered neurologically; no neurologic disorder was observed. These results suggested that ALS could predict neurologic status after LDLTx. The difference in coma grades also achieved statistical significance. Our study indicates that short-term ALS is useful for improving circulatory and respiratory function prior to liver transplantation, as well as for predicting posttransplantation neurologic status. Although some patients recover by ALS alone, the survival rate of ALS-only patients is less than 50%. ALS prolongs intensive treatment, thus increasing both the risk of infection and the medical costs. Further investigation to determine a precise marker for liver regeneration will be needed to establish a consensus on the indications for long-term ALS. We conclude that ALS is useful to improve circulatory and respiratory functions among pretransplant patients, and to predict neurologic status after LDLTx.

The right margin of the caudate lobe is obscure. Therefore, a part of the caudate lobe (a part of the right side of the paracaval portion) seems almost always to remain with the right lobe graft during the standard harvesting procedure. We reviewed the intraoperative findings and the postoperative courses of donors and recipients of 11 consecutive living donor liver transplantations using right lobe grafts. Further, we used computed tomography during the postoperative course to investigate whether the remaining caudate lobe was present in the right lobe graft and whether it produced serious complications. Four recipients displayed an intraoperative bile leak from a remaining part of the caudate lobe after the completion of biliary reconstruction. With the exception of one case who developed repeated bile leakage from the same origin which eventually healed during a long-term postoperative course, Most recipients showed no postoperative biliary complications. Although a remaining caudate lobe was detected on postoperative computed tomography in all recipients, it produced no serious complications. In conclusion, a part of the right side of the paracaval portion of the caudate lobe almost always remains with a right lobe graft during the standard harvesting procedure. However, the implications of this phenomenon seem to be benign.

Tuberculosis, the leading cause of death among infectious diseases worldwide, is a major cause of lymphocytic exudative pleural effusion. T-helper 1 cytokines, including interferon-gamma (IFN-gamma), interleukin (IL)-12p40 and IL-18 are predominantly associated with cell-mediated immune responses, and play an important role in immunity to Mycobacterium tuberculosis.We studied 55 patients presenting with pleural effusion at the National Sanyo Hospital between April 2000 and September 2001 (42 men and 13 women; mean age 67 years). Twenty patients (36%) had tuberculous pleurisy, while 18 (33%) had malignant effusions and 17 (31%) had an effusion with another aetiology. Pleural fluid concentrations of IL-12p40 and IL-18 as well as IFN-gamma measured by enzyme-immunoassays.Concentrations of all three cytokines were significantly higher in tuberculous than other pleural effusions. Significant correlations were evident between IFN-gamma and IL-12. We found particularly high concentrations of IL-12p40 and IFN-gamma in tuberculous patients with high fever.The results indicate that T-helper 1 cytokines are involved in intrapulmonary cellular immune responses to M. tuberculosis, and suggest that the interactions between them may play an important role in the pathogenesis and severity of the pleural effusion. Understanding the development of this response may enhance our understanding of the pathogenesis of tuberculous pleural effusion and suggest new therapies.

Summary. Background: Vascular endothelial growth factor (VEGF) is an endothelial cell-specific potent mitogen that induces angiogenesis and microvascular hyperpermeability. Recently, it has been reported that megakaryocytes and platelets contain VEGF in their cytoplasm. Objectives: To elucidate and confirm the bioactivity and role of VEGF in platelets (platelet VEGF), which may be closely related to vascular thrombosis and atherosclerosis. Methods: The VEGF localization in megakaryocytes on bone marrow smears was analyzed by immunofluorescence and confocal laser scanning microscopic analysis. The intracellular VEGF expressed in platelets was determined by flow cytometric analysis. Platelet-rich plasma and washed platelets were used to analyze the secretion of VEGF during platelet aggregation by thrombin or gelatinase A (matrix metalloproteinase-2) stimulation. Immunohistochemical studies for VEGF in the thrombotic region were performed. Results and conclusions: Megakaryocytes and platelets are a very rich source of circulating VEGF. Gelatinase A, which is closely associated with vascular remodeling, enhances the VEGF levels released from platelets. VEGF was clearly detected in the fibrin nets of a thrombus. Taken together, platelet VEGF is bioactive as a direct angiogenic growth factor, and may play a very important role in wound healing and atherosclerosis in conjunction with other platelet cytokines such as platelet-derived growth factor, platelet-derived endothelial cell growth factor, transforming growth factor (TGF)-α, and TGF-β.

Background: The 72 kDa matrix metalloproteinase 2 (MMP-2) and the 92 kDa matrix metalloproteinase 9 (MMP-9) are type IV collagenases implicated in various aspects of inflammation including accumulation of inflammatory cells, tissue injury, and development of remodelling. The role of these enzymes in the pathogenesis of asthma exacerbations is unknown. Methods: Circulating levels of MMP-2 and MMP-9 proteins and the expression of their inhibitor, tissue inhibitor of metalloproteinase 1 (TIMP-1), were measured in 21 patients experiencing an asthma exacerbation and 21 age matched patients with stable asthma. Circulating gelatinolytic activity was compared during the asthma exacerbation and during subsequent convalescence by gelatin zymography in the same individuals. In addition, MMP-9 specific activity was quantified with a colorimetric assay which uses an artificial proenzyme containing a specific domain recognised by MMP-9 in the same paired samples. Results: A significant increase in the circulating level of MMP-9 was seen in patients with an asthma exacerbation compared with patients with stable asthma (202.9 (22.0) v 107.7 (9.9) ng/ml, p=0.0003). There were no significant differences in the circulating levels of MMP-2 or TIMP-1. Gelatin zymography identified two major circulating gelatinolytic activities corresponding to MMP-2 and MMP-9, and showed that asthma exacerbations are characterised by markedly increased MMP-9 activity with no significant change in MMP-2 activity compared with the activities during convalescence in the same individuals. Direct measurement showed that MMP-9 specific activity is significantly increased during asthma exacerbations compared with subsequent convalescence (269.6 (31.7) v 170.4 (12.6) ng/ml, p=0.0099). Conclusions: Asthma exacerbations are characterised by increased circulating MMP-9 activity. This increased activity may be related to exaggerated airway inflammation and airway remodelling.

Interleukin 6 (IL-6) is a pleiotropic cytokine with many physiological functions. The present study was designed to determine the expression of IL-6 and its receptor (IL-6R) in human gastric and colorectal cancers. Nine gastric- and nine colorectal cancer cell lines were analysed. The IL-6 gene was expressed in two gastric cancer cell lines and one colorectal cancer cell line; however, most of the cancer cell lines studied expressed the IL-6R gene. The level of IL-6 secretion in the gastric cancer cell lines correlated with the level of soluble IL-6R secretion, and was significantly higher (< approximately 100 pg/ml) than the level of IL-6 secretion in the colorectal cancer cell lines (< approximately 50 pg/ml). These results suggest that IL-6 may act in a paracrine fashion rather than an autocrine fashion in these cell lines.

N-acetylgalactosaminyl transferase-3 (GalNAc-T3) is an enzyme involved in the initial glycosylation of mucin-type O-linked proteins. In the present study, we used immunohistochemistry to examine GalNAc-T3 expression in 215 surgically resected non-small cell lung cancers. We analysed the biological and clinical importance of GalNAc-T3 expression, especially with regard to its potential as a prognostic factor. We found that normal bronchial epithelial cells, bronchial gland cells, and alveolar pneumocytes showed cytoplasmic immunostaining for GalNAc-T3. Low expression of GalNAc-T3, observed in 93 of 215 tumours (43.4%), was found more frequently in tumours from smokers than those from nonsmokers (P=0.001), in squamous cell carcinomas than nonsquamous cell carcinomas (P

In 1983, varicella zoster virus (VZV) disease was first recognized in the context of infection with the human immunodeficiency virus (HIV). Since that time, there have been many reports discussing the occurrence and clinical manifestations of hepes zoster in HIV-infected patients. We describe the development of prolonged herpes zoster in a patient with acquired immunodeficiency syndrome (AIDS) over the course of 104 days. Viral isolates at the three different clinical stages of the skin lesions were sensitive in vitro to acyclovir, and supposed to be a same strain by polymerase chain reaction (PCR) analysis. We also discuss an effective treatment for prolonged cases of zoster.

A case of familial cryptotia is presented, and the hereditary basis for this condition is discussed. Although, intuitively, the distribution of the intrinsic auricular muscle, the primary etiologic factor in cryptotia, must be determined genetically, further studies are needed to establish the mode of inheritance.

The present study was undertaken to investigate whether human chorionic gonadotropin (hCG) beta-core fragment (hCG beta cf) was directly produced by gestational trophoblastic tumors. Immunoreactivity of hCG beta cf was demonstrated in the extracts as well as in the culture media of hydatidiform mole tissues. It was also present in the extracts of choriocarcinoma tissues, and its molar concentration exceeded that of intact hCG. The presence of hCG beta cf was then confirmed by gel chromatography and Western blot analysis. Immunohistochemistry showed localization of hCG beta cf immunoreactivity to the syncytiotrophoblasts and scattered cells in the stroma of mole tissue, and to syncytiotrophoblastic cells in choriocarcinoma. Immunoreactivity of hCG beta cf was also detected in the sera of the patients with gestational trophoblastic disease, although the hCG beta cf/hCG ratio was less than one hundredth of that in the tissue extracts. Serial measurement of serum hCG beta cf levels after mole evacuation showed that they declined much more rapidly than those of hCG and became undetectable in the patients with subsequent spontaneous resolution, while hCG beta cf remained or became detectable before the rise of hCG was observed in the patients with subsequent persistent trophoblastic disease. Taken together, these results suggest that hCG beta cf is directly produced by gestational trophoblastic tumors, and monitoring of hCG beta cf in the serum after mole evacuation may be useful for early prediction of subsequent development of postmolar persistent trophoblastic disease.

A 65-year-old woman with primary breast carcinoma (T 3 N 0 M 0) received neoadjuvant chemotherapy consisting of 4 cycles of 50 mg.m-2 doxorubicin (ADM) and 60 mg.m-2 docetaxel (TXT). The patient received 50 mg.m-2 ADM and 60 mg.m-2 TXT intravenously on day 1 of each cycle every three weeks. The patient underwent transthoracic echocardiography and electrocardiography (ECG) before surgery and these results were normal. ECG showed bigeminy, trigeminy after intubation and incomplete AV block (Mobitz type II) during and after surgery. The patient recovered from these arrhythmias on the first postoperative day. Our data indicate one possibility that the management of anesthetic condition might easily induce the cardiac conduction abnormalities of this patient using ADM as neoadjuvant chemotherapy.

Docetaxel was effective as a second line neoadjuvant chemotherapy after failure of cyclophosphamide, epirubicin and 5-FU (CEF) in 2 cases of breast cancer. In Case 1, 4 cycles of trans-arterial neoadjuvant chemotherapy of docetaxel showed a PR effect after failure of 2 cycles of trans-arterial neoadjuvant chemotherapy with CEF. This patient died of pleuritis carcinomatosa 18 months after surgery for breast cancer (latissimus dorsi muscle myocutaneous flap after radical mastectomy). In Case 2, 6 cycles of neoadjuvant venous drip infusion of docetaxel resulted in a CR effect after failure of 2 cycles of transarterial neoadjuvant chemotherapy with CEF. This patient is alive and disease-free 27 months after the operation for breast cancer (same operation as for Case 1). Docetaxel was effective as neoadjuvant chemotherapy for patients after failure of trans-arterial neoadjuvant chemotherapy with CEF.

The aim of this study was to examine the enhancement of antitumor immunity of irradiated granulocyte macrophage-colony-stimulating factor (GM-CSF) gene-transduced mouse breast cancer cells.BALBMC mouse were vaccinated subcutaneously with saline or irradiated mouse breast cancer cells, BALBMC (1 x 10(6)/mouse), infected or not infected with recombinant adenovirus harboring GM-CSF gene on day-7. Mice were injected with parental cells (1 x 10(5)/mouse) on day 0.No mice vaccinated with irradiated GM-CSF producing BALBMC cells developed a tumor during the observation period of up to 16 weeks, whereas 100% of mice injected with saline developed a tumor.Our study demonstrates the feasibility of this immunotherapeutic approach as a novel adjuvant cancer therapy after surgery for breast cancer.