Association of non-steroidal anti-inflammatory drug use with encephalopathy development: An analysis using the United States Food and Drug Administration Adverse Event Reporting System (FAERS) and Japanese Adverse Drug Event Report (JADER) databases.

Encephalopathy is the most severe complication of various common infections, including influenza and herpes, and it often results in death or severe neurological disability. The risk factors for viral encephalopathy include non-steroidal anti-inflammatory drug (NSAID) use; however, studies on NSAID-related encephalopathy are limited. In this study, we aimed to investigate the characteristics of NSAID-related encephalopathy. We investigated the incidence of NSAID-related encephalopathy using data from the United States Food and Drug Administration Adverse Event Reporting System (FAERS) and Japanese Adverse Drug Event Report (JADER) databases containing reports on spontaneous adverse effects (AEs) published by the Pharmaceuticals and Medical Devices Agency. We used these databases to detect AEs based on reported odds ratios. By separating suspicious drugs, concomitant drugs, and drug interactions involving NSAIDs, we investigated the relationship between encephalopathy pathology and AEs of NSAIDs. Significant encephalopathy signals were detected for loxoprofen and etodolac in the FAERS database and loxoprofen in the JADER database. In the JADER database, significant encephalopathy signals in loxoprofen-treated patients were detected in 70-79-year-old, ≥80-year-old, influenza viral infection, and herpes virus infection groups. Significant encephalopathy signals in patients with herpes virus infection were detected in the ≥80-year-old and loxoprofen-treated groups. Regarding the involvement of loxoprofen in the development of encephalopathy, the JADER database listed loxoprofen as a suspect drug, without indicating any concomitant drug interactions. In conclusion, our findings suggest that loxoprofen and etodolac may be associated with viral encephalopathy. Accordingly, prudence is recommended when using loxoprofen in older individuals with viral infections.

Melanopsin signalling in mammalian iris and retina.

Non-mammalian vertebrates have an intrinsically photosensitive iris and thus a local pupillary light reflex (PLR). In contrast, it is thought that the PLR in mammals generally requires neuronal circuitry connecting the eye and the brain. Here we report that an intrinsic component of the PLR is in fact widespread in nocturnal and crepuscular mammals. In mouse, this intrinsic PLR requires the visual pigment melanopsin; it also requires PLCß4, a vertebrate homologue of the Drosophila NorpA phospholipase C which mediates rhabdomeric phototransduction. The Plcb4(-/-) genotype, in addition to removing the intrinsic PLR, also essentially eliminates the intrinsic light response of the M1 subtype of melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (M1-ipRGCs), which are by far the most photosensitive ipRGC subtype and also have the largest response to light. Ablating in mouse the expression of both TRPC6 and TRPC7, members of the TRP channel superfamily, also essentially eliminated the M1-ipRGC light response but the intrinsic PLR was not affected. Thus, melanopsin signalling exists in both iris and retina, involving a PLCß4-mediated pathway that nonetheless diverges in the two locations.

Employment status among non-retired cancer survivors in Japan.

Employed cancer patients confront some challenges as they attempt to return to work after treatment. We aimed to identify correlates of return to work for cancer survivors in Japan, with an emphasis on employment status. Participants were 260 patients (aged <65 years) who had received a cancer diagnosis ≥ 1 year previously and who were employed at the time of diagnosis. Participants completed questionnaires at consultations at any Regional Cancer Center Hospitals in Yamagata, Japan between 28 November 2011 and 9 December 2011. Logistic regression analysis was used to identify correlates of return to work. Data cross-tabulation was used to evaluate relationships to workplace and income-changes by employment status. A high proportion of patients (75.8%) had returned to work. Non-regularly employed survivors were less likely to return to work (odds ratio = 5.03; 95% confidence interval, 1.18-21.35). Individuals with poor health, advanced-stage tumours, of advanced age and women were significantly less likely to return to work. Only 52.8% of non-regular employees continued to be employed, and their income decreased by as much as 61.1%. Social and financial support policies should be organised based on more intensive study of employment circumstances.

Root surface strain during canal shaping and its influence on apical microcrack development: a preliminary investigation.

AIM: To determine the root surface strain (RSS) generated during root canal shaping and its effects on apical microcrack development. METHODOLOGY: Twenty-five extracted human mandibular premolars were selected and decoronated. The teeth were instrumented with either the ProTaper (PT) or WaveOne (WO) (Dentsply Maillefer) NiTi rotary systems (n = 10 per group) or used as controls (n = 5). Instrumented root canals were enlarged to ProTaper F4 (size 40, 0.06 taper) or using WaveOne LARGE (size 40, 0.08 taper) instruments according to the manufacturer's instructions. An electrical strain gage (KFG02-120-C1-16, Kyowa Dengyo, Tokyo, Japan) was fixed on the proximal root surface and connected to a strain amplifier via a bridge box in order to measure RSS. During canal shaping, the strain output of the amplifier was recorded. The instantaneous RSS induced by each instrument and the maximum RSSs were determined. All teeth were then stained with contrast media and imaged with micro-computed tomography (micro-CT) at an isotropic resolution of 10 µm to detect microcracks. The mean maximum RSS values (microstrain) and mean number of microcracks recorded for both groups were tested for statistical significance using Mann-Whitney U-test. Presence/absence of microcracks in both groups was compared by chi-square tests. RESULTS: Increased baseline RSS from strain accumulation during canal shaping was observed, with similar maximum RSS (mean ± SD) for PT (416.6 ± 185.1 µstrain) and WO (398.2 ± 163.8 µstrain) (P = 0.94). The interevaluator reliability for microcrack detection using micro-CT had a kappa value of 0.998. Compared to the PT group, there was a trend for fewer samples with microcracks in the WO group (P = 0.051). On the micro-CT images, apical microcracks were detected in 20 PT and 11 WO samples (P = 0.10). The microcracks were observed in the buccolingual direction in all WO and 81% of PT samples. No vertical root fractures were found. The maximum RSS obtained during canal shaping was poorly correlated with the number of microcracks found (R(2)  = 0.093). CONCLUSIONS: Based on these preliminary data, canal shaping appears to cause apical microcracks regardless of the type of rotary instrument motion. Contrast-enhanced micro-CT was able to identify microcracks in roots.

Diagnostic usefulness of FDG-PET/CT in advanced malignant lymphoma of the uterus: report of two cases.

Summary Malignant lymphoma of the uterus is difficult to diagnose because of its rarity and nonspecific symptoms. However, recently, 18F-fluoro-2-deoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) has become an important non-invasive diagnostic tool for the management of lymphoma patients. The authors report two cases of malignant lymphoma of the uterus, in which FDG-PET/CT was useful for diagnosis. Examination using ultrasonography or magnetic resonance imaging (MRI) demonstrated a normal-sized uterus and normal endometrium, but FDG-PET/CT showed FDG accumulation in the uterine body in both cases. Endometrial biopsy revealed diffuse large B-cell lymphoma, and chemotherapy with rituximab, cyclophosphamide, adriamycin, vincristine, and prednisone (R-CHOP) was initiated immediately. Primary malignant lymphoma of the female genitalia is reported to be rare. The present authors' experience with FDG-PET/CT suggests that malignant lymphoma of the female genitalia (including metastasis) may not be as rare as previously reported. Uterine malignant lymphoma may be overlooked by the examination of ultrasound, CT, or MRI.

Clinical efficacy and treatment persistence of monthly minodronate for osteoporotic patients unsatisfied with, and shifted from, daily or weekly bisphosphonates: the BP-MUSASHI study.

UNLABELLED: This multi-center, prospective, open-label, observational study evaluated the effects of once-monthly minodronate (50 mg) on treatment persistence, bone turnover markers, bone mineral density, low back pain, and upper gastrointestinal symptoms in outpatients with osteoporosis previously treated with daily or weekly bisphosphonate products. INTRODUCTION: The purposes of this study were to investigate the effects of once-monthly oral minodronate (MIN 50 mg) on bone turnover markers and bone mineral density, low back pain, and upper gastrointestinal symptoms, as well as preference for and treatment persistence of MIN 50 mg among Japanese osteoporosis patients currently treated with daily or weekly bisphosphonates. METHODS: Study patients were allocated based on their preference to either the Switch group (patients willing to switch over to MIN 50 mg) or the Continue group (patients wanting to continue their current therapies). Patients' treatment persistence and satisfaction levels with the therapies were assessed using a self-administered questionnaire. The study endpoints were serum TRACP-5b, serum P1NP, bone mineral density, upper gastrointestinal symptoms, and low back pain. RESULTS: In total, 264 and 133 patients were allocated into the Switch and Continue groups, respectively. Approximately, 65 % of patients were willing to switch to MIN 50 mg, with the predominant reason being "less frequent dosing more convenient." Treatment persistence was significantly higher in the Switch group (MIN 50 mg) than the Continue group. Almost all patients with abnormal bone metabolism markers demonstrated normalization after switchover. MIN 50 mg alleviated low back pain and upper gastrointestinal symptoms induced by prior bisphosphonate use. CONCLUSIONS: MIN 50 mg alleviates low back pain, reduces bone turnover markers and increases bone density, and induces fewer upper gastrointestinal symptoms after switchover from prior bisphosphonate products, and therefore, it may provide patients with a more convenient treatment option and enhance long-term treatment persistence.

Do Tetranychus urticae males avoid mating with familiar females?

The two-spotted spider mite, Tetranychus urticae, usually lives in kin groups under common webs. Because only the first mating results in fertilisation in female T. urticae, adult males guard quiescent deutonymph females, those at the stage immediately before maturation, to ensure paternity. Therefore, the cost of precopulatory guarding time seems considerable for males. Moreover, the fitness indices of daughters from intra-population crosses were significantly lower than those of daughters from inter-population crosses, indicating that inbreeding depression exists in T. urticae. Therefore, we hypothesised that T. urticae males should be choosy in guarding familiar females to avoid inbreeding depression. Furthermore, webs should be a key element of the environment shared by familiar individuals. In this study, we demonstrated the inbreeding avoidance mechanism of T. urticae males in relation to webs produced by familiar females (known webs) or unfamiliar females (unknown webs). Regardless of surrounding webs (known or unknown), males preferred unfamiliar to familiar females. We further examined whether males detect unfamiliar females by their webs. When males had experienced a female's web without encountering that female, they subsequently preferred females that did not produce the surrounding webs in which the choice experiment was conducted. Results suggest that putative kin recognition for inbreeding avoidance in T. urticae males is based on the relationship between webs and females, and not on the discrimination of webs in shared environments.

Ultrasound-guided platelet-rich plasma injections for the treatment of common peroneal nerve palsy associated with multiple ligament injuries of the knee.

PURPOSE: Peroneal nerve palsy in traumatic knee dislocations associated with multiple ligament injuries is common. Several surgical approaches are described for this lesion with less-than-optimal outcomes. The present case represents the application of plasma rich in growth factors (PRGF) technology for the treatment of peroneal nerve palsy with drop foot. This technology has already been proven its therapeutic potential for various musculoskeletal disorders. Based on these results, we hypothesized that PRGF could stimulate the healing process of traumatic peroneal nerve palsy with drop foot. METHODS: The patient was a healthy 28-year-old man. He suffered peroneal nerve palsy with drop foot after multiple ligament injuries of the knee. PRGF was prepared according to the manufactured instruction. Eleven months after the trauma with severe axonotmesis, serial intraneural infiltrations of PRGF were started using ultrasound guidance. The therapeutic effect was assessed by electromyography (EMG), echogenicity of the peroneal nerve under ultrasound (US) and manual muscle testing. RESULTS: Twenty-one months after the first injection, not complete but partial useful recovery is obtained. He is satisfied with walking and running without orthosis. Sensitivity demonstrates almost full recovery in the peroneal nerve distribution area. EMG controls show complete reinnervation for the peroneus longus and a better reinnervation for the tibialis anterior muscle, compared with previous examinations. CONCLUSION: Plasma rich in growth factors (PRGF) infiltrations could enhance healing process of peroneal nerve palsy with drop foot. This case report demonstrates the therapeutic potential of this technology for traumatic peripheral nerve palsy and the usefulness of US-guided PRGF. LEVEL OF EVIDENCE: V.

Evaluation of primary prophylaxis with granulocyte colony-stimulating factor for epithelial ovarian cancer.

PURPOSE: Primary prophylaxis with G-CSF has been used to minimize myelosuppression caused by anticancer agents and to avoid severe neutropenia. The authors retrospectively examined the value of primary prophylaxis using granulocyte colony-stimulating factor (G-CSF) for epithelial ovarian cancer. MATERIALS AND METHODS: From 2001 to 2010, 105 patients with ovarian cancer receiving chemotherapy in the present hospital were divided into two groups: one received primary prophylaxis with G-CSF and the other did not receive it in compliance with the guidelines for G-CSF usage. The incidence of febrile neutropenia (FN), degree of neutropenia, frequency of G-CSF administration, number of days of hospitalization, progression-free survival (PFS), and overall survival (OS) were evaluated. RESULTS: Neutrophils decreased almost equally and the length of hospitalization was not significantly lower between the groups. Five-year PFS or OS showed no significant difference either. CONCLUSIONS: Primary prophylaxis with G-CSF in chemotherapy for epithelial ovarian cancer could be of low significance.

Critical review of 'Public domain application': a flexible drug approval system in Japan.

BACKGROUND: 'Public domain application' is a flexible drug approval system in Japan, similar to the fast track designation in the United States. METHODS: From 1999 to 2009, four drugs and three regimens received approval from `Public domain application'. The data from the review reports were extracted, and the reviewing process was critically re-evaluated. RESULTS: The study drugs were categorized into three groups according to the sizes of the studies and evidence levels in the original articles that were submitted. Carboplatin was categorized into the first group with a large number of study patients and a high evidence level; the review report had studies with more than 15 000 total patients and 8 phase III studies. The ifosfamide and vinblastine regimen was categorized into the second group, with a low number of study patients and a low evidence level; the review report had studies with less than 1000 total patients and 1 phase III study. Dacarbazine; cytarabine; methotrexate, vinblastine, doxorubicin, and cisplatin; bleomycin, etoposide, and cisplatin; and fludarabine were categorized into the remaining third group, with a moderate number of study patients and evidence level. CONCLUSIONS: Drugs with various backgrounds, including evidence levels and physicians' experiences, were approved via `Public domain application'. The approvals of most drugs were evaluated to be appropriate.

The effect of endodontic procedures on apical crack initiation and propagation ex vivo.

AIM: To evaluate the potential effects of endodontic procedures (instrumentation and filling) on crack initiation and propagation in apical dentine. METHODOLOGY: Forty extracted single-rooted premolars with two canals were selected, 1.5 mm of the apex was ground perpendicular to the long axis of the tooth and the surface polished. The specimens were divided into 4 groups. The buccal canals of groups A, B and C were enlarged to size 40 with manual K-files. Group A was filled with gutta-percha using lateral condensation and vertical compaction without sealer. Group B was filled with the same method as group A except only lateral condensation was used. Group C was left unfilled, while group D was left unprepared and unfilled. Images of the resected surface were taken after resection (baseline), after canal preparation, after filling and after 4-week storage. The images were then inspected for cracks originating from the canal. RESULTS: A significant effect of preparation on crack initiation (P < 0.05) and no significant effect of filling (P > 0.05) or 4-week storage on crack initiation (P > 0.05) was found (logistic regression). Fisher's exact test revealed a significant effect of filling on crack propagation (P < 0.05) and no effect of 4-week storage on crack propagation (P > 0.05). CONCLUSIONS: Root canal procedures can potentially initiate and propagate cracks from within the root canal in the apical region.

Mechanistic correlations between two itch biomarkers, cytokine interleukin-31 and neuropeptide ß-endorphin, via STAT3/calcium axis in atopic dermatitis.

BACKGROUND: Itch is the cardinal symptom of atopic dermatitis (AD). ß-Endorphin, a neuropeptide, is increased in both AD skin and sera. Interleukin (IL)-31, an itch-relevant cytokine, activates IL-31 receptors in keratinocytes. However, how IL-31 and ß-endorphin interact in AD skin remains elusive. OBJECTIVES: To investigate the mechanistic interaction of IL-31 and ß-endorphin in AD. METHODS: This was a prospective cross-sectional study. We recruited adult patients with AD and controls according to Hanifin's AD criteria. Serum levels of IL-31 and ß-endorphin were measured by enzyme-linked immunosorbent assay. Expressions of IL-31 receptor A (IL-31RA) and ß-endorphin in the skin were assessed by immunohistochemistry. Their expression in the skin and blood was compared and correlated in patients with AD and in controls. We also treated primary keratinocytes with IL-31 and measured calcium influx, ß-endorphin production and signalling pathways to define their mechanistic interactions. RESULTS: ß-Endorphin was increased in the supernatant from IL-31-treated keratinocytes. IL-31 receptor activation resulted in calcium influx and STAT3 activation; pretreatment with STAT3 inhibitor stopped the increase of ß-endorphin. Notably, either replacement of extracellular calcium or treatment with 2-aminoethoxydiphenyl borate, an inhibitor for the store-operated channel, blocked STAT3 activation. We found higher levels of blood ß-endorphin and IL-31, which were significantly correlated, in patients with AD. Moreover, IL-31RA and ß-endorphin were increased and colocalized both in AD human skin and TPA-painted mouse skin. CONCLUSIONS: IL-31 receptor activation in keratinocytes induces calcium influx and STAT3-dependent production of ß-endorphin. These results might contribute to an understanding of the regulatory mechanisms underlying peripheral itch.

[Metastatic lung tumor from colon cancer with cavitation: report of a case].

A 55-year-old man underwent rectal amputation for rectal cancer in August 2005. A tiny thin-walled cavity lesion in his left S1+2 was found on computed tomography (CT) of the chest in November 2008. The cavity lesion in the left S1+2 gradually increased in size over 3 months and positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) showed FDG accumulation at the lesion. Videoassisted thoracoscopic (VATS) wedge resection was performed to make a definite diagnosis in March 2009. The pathological findings revealed a metastatic lung tumor from the rectal cancer. It is necessary to consider the possibility of metastatic lung tumors in a case with the cavity lesions especially in patients with a history of colon cancer.

Periapical bone defects of root filled teeth with persistent lesions evaluated by cone-beam computed tomography.

AIM: To evaluate and categorize the bone defects of root filled teeth with persistent periapical lesions by cone-beam computed tomography (CBCT). METHODOLOGY: Slice images of 532 teeth with persistent periapical lesions were obtained by CBCT in 427 patients and were examined by two endodontists. The periapical lesions were categorized into five types according to the characteristics of the bone defect based on CBCT images. The prevalence of each type was determined and analysed statistically at a 5% significance level using logistic regression. RESULTS: Of the 532 teeth analysed, 67% had buccal or labial bone plate defects (type II), 4% palatal or lingual bone plate defects (type III), 7%'through and through' defects (type IV) and 10% apical root protrusions from the bone plate (type V). Mandibular teeth had a significantly greater prevalence of type I lesions (P=0.0005) and a significantly lower prevalence for types IV (P=0.041), V (P=0.001), V-1 (P=0.015) and V-2 (P<0.001) as compared to maxillary teeth. CONCLUSION: CBCT accurately identified the type of periapical bone defect in persistent lesions. Because 10% of the teeth had apical root protrusions, which could not be identified by periapical radiography, the diagnostic information obtained by CBCT was an essential component of the treatment planning process.

Contribution of atmospheric nitrate to stream-water nitrate in Japanese coniferous forests revealed by the oxygen isotope ratio of nitrate.

Evaluation of the openness of the nitrogen (N) cycle in forest ecosystems is important in efforts to improve forest management because the N supply often limits primary production. The use of the oxygen isotope ratio (delta(18)O) of nitrate is a promising approach to determine how effectively atmospheric nitrate can be retained in a forest ecosystem. We investigated the delta(18)O of nitrate in stream water in order to estimate the contribution of atmospheric NO(3) (-) in stream-water NO(3) (-) (f(atm)) from 26 watersheds with different stand ages (1-87 years) in Japan. The stream-water nitrate concentrations were high in young forests whereas, in contrast, old forests discharged low-nitrate stream water. These results implied a low f(atm) and a closed N cycle in older forests. However, the delta(18)O values of nitrate in stream water revealed that f(atm) values were higher in older forests than in younger forests. These results indicated that even in old forests, where the discharged N loss was small, atmospheric nitrate was not retained effectively. The steep slopes of the studied watersheds (>40 degrees ) which hinder the capturing of atmospheric nitrate by plants and microbes might be responsible for the inefficient utilization of atmospheric nitrate. Moreover, the unprocessed fraction of atmospheric nitrate in the stream-water nitrate in the forest (f(unprocessed)) was high in the young forest (78%), although f(unprocessed) was stable and low for other forests (5-13%). This high f(unprocessed) of the young forest indicated that the young forest retained neither atmospheric NO(3) (-) nor soil NO(3) (-) effectively, engendering high stream-water NO(3) (-) concentrations.

Incidence of accessory canals in Japanese anterior maxillary teeth following root canal filling ex vivo.

AIM: To investigate the vertical and horizontal distribution and the incidence of accessory canals in Japanese maxillary anterior teeth following root filling. METHODOLOGY: The study included maxillary teeth; 69 central incisors, 61 lateral incisors and 31 canines. After the canal systems had been dyed and root canal instrumentation had been carried out, all prepared canals were filled with gutta-percha without using sealer. Transparent specimens were then obtained and examined with a digital microscope for horizontal and vertical distributions of accessory canals. RESULTS: The incidence of teeth with accessory canals in the apical 3 mm was 46%, 29% and 38% for the maxillary central incisors, lateral incisors and canines, respectively. The horizontal distribution was mainly buccal for central incisors, palatal for lateral incisors and distal and palatal for canines. There was a significant difference (P < 0.05) between the apical 3 mm and the rest of the root (16%, 20% and 19% for the maxillary central incisors, lateral incisors and canines, respectively) in terms of the presence of accessory canals. CONCLUSIONS: A high percentage of accessory canals can be found in apical 3 mm of the root. The horizontal distribution of accessory canals differed amongst the tooth types studied.

The effect of working length and root canal preparation technique on crack development in the apical root canal wall.

AIM: To evaluate the effects of working length and root canal preparation technique on crack development in the apical root canal wall. METHODOLOGY: Seventy extracted mandibular premolars were mounted in a resin block with simulated periodontal ligaments and divided into seven groups according to preparation technique and working length: group A, step-back preparation with stainless steel files with working length set at the apical foramen and defined as root canal length (CL); group B, same as for A, except that the working length was CL-1 mm; group C, crown-down preparation with Profile instruments followed by an apical enlargement sequence with CL as working length and group D, same as for C, except that the working length was CL-1 mm. Groups E, F and G served as controls. Groups E and F were prepared only with the crown-down sequence up to CL and CL-1 mm, respectively. Group G was left unprepared. Digital images of the apical root surface (AS) were recorded before preparation, immediately after instrumentation and after removing the apical 1 mm (AS-1 mm) and 2 mm (AS-2 mm) of the root end. RESULTS: Working length significantly affected crack development at AS (P < 0.05). Preparation technique significantly affected crack development at AS-1 mm (P < 0.05). At AS-2 mm, there was no significant difference between preparation technique and working length in terms of crack development on the canal wall. CONCLUSION: Root canal preparation alone, regardless of the technique used, can potentially generate cracks on the apical root canal wall as well as the apical surface. Working 1- mm short of the apical foramen might produce fewer cracks in the apical region.

[Simultaneously treated thymoma and lung cancer; report of a case].

A 74-year-old man was admitted to our hospital in order to treat a mediastinal mass and 2 ground-glass attenuations in the right upper lobe detected by chest X-ray and computed tomography (CT). Partial resection of right lung and thymectomy were performed. The mediastinal mass and 2 ground-glass attenuations in the right upper lobe proved to be thymoma and bronchioloalveolar carcinomas, respectively by pathology.

Systemic delivery of IL-10 by an AAV vector prevents vascular remodeling and end-organ damage in stroke-prone spontaneously hypertensive rat.

Interleukin-10 (IL-10) ameliorates various T-helper type 1 cell-mediated chronic inflammatory diseases. Although the therapeutic benefits of IL-10 include antiatherosclerotic effects, pathophysiological effects of IL-10 on vascular remodeling in hypertension have not yet been elucidated. These studies were designed to determine whether sustained IL-10 expression, mediated by an adeno-associated virus (AAV) vector, prevents vascular remodeling and target-organ damage in the stroke-prone spontaneously hypertensive rat (SHR-SP)-an animal model of malignant hypertension. A single intramuscular injection of an AAV1 vector encoding rat IL-10 introduced long-term IL-10 expression. These IL-10-transduced rats had decreased stroke episodes and proteinuria, resulting in improved survival. Histological examination revealed a reduced level of deleterious vascular remodeling of resistance vessels in the brain and kidney of these rats. Immunohistochemical analysis indicated that IL-10 inhibited the enhanced renal transforming growth factor-beta expression and perivascular infiltration of monocytes/macrophages and nuclear factor-kappaB-positive cells normally observed in the SHR-SP. Four weeks after IL-10 vector injection, systolic blood pressure significantly decreased and this effect persisted for several months. Overall, AAV vector-mediated systemic IL-10 expression prevented vascular remodeling and inflammatory lesions of target organs in the SHR-SP. This approach provides significant insights into the prevention strategy of disease onset with unknown genetic predisposition or intractable polygenic disorders.

Phase I/II study of sequential therapy with irinotecan and S-1 for metastatic colorectal cancer.

BACKGROUND: Both irinotecan (CPT-11) and S-1 are active against colorectal cancer; however, as S-1 is a prodrug of 5-fluorouracil (5-FU), 5-FU and its metabolites might inhibit the antitumour effect of CPT-11. Therefore, we designed a sequential combination, in which CPT-11 infusion was given on day 1 and S-1 was given orally at 80 mg m(-2) per day on days 3-16 every 3 weeks. METHODS: Twelve patients entered the phase I study, and the recommended doses were determined as a CPT-11 dose of 150 mg m(-2) and an S-1 dose of 80 mg m(-2). RESULTS: In all, 36 patients entered the phase II study, of whom 4 and 16 had complete and partial responses. The overall response rate was 55.6% (95% confidence interval, 38.1-72.1%), and median progression-free survival was 7.7 months (95% confidence interval, 4.8-12.6 months). Grade 3 neutropenia was the most common haematological toxicity and occurred in 6.5% of 215 treatment courses. Grade 3 non-haematological toxicities included anorexia (1.4%) and diarrhoea (0.9%). There was no grade 4 toxicity of any kind. CONCLUSION: Our results suggest that this regimen is convenient, safe and promising, compared with conventional regimens for patients with metastatic colorectal cancer.