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OBJECTIVES: To compare initial treatment with and without corticosteroids for acute pancreatitis in dogs and investigate the therapeutic efficacy and prognosis. MATERIALS AND METHODS: Sixty‐five dogs were included in this non‐blinded, non‐randomised clinical study. Dogs with acute pancreatitis received treatment either with dose of 1 mg/kg/day prednisolone (n=45) or without prednisolone (n=20). Response to treatment was based on changes in the C‐reactive protein concentration, improvement in clinical signs, duration of hospitalisation, mortality and recurrence rate. RESULTS: From the third day of hospitalisation, C‐reactive protein concentration was significantly lower in the prednisolone group than that in the non‐prednisolone group. The number of days required to reach a C‐reactive protein concentration of

Background Triple negative breast cancer (TNBC) is highly malignant and prone to metastasis and relapse, and therefore has poorer prognosis than other sub-types. The mechanism of higher malignancy of TNBC has not been sufficiently elucidated. KLF4is reported to be a transcription factor that is associated with both tumor suppression and oncogenesis. We have reported that breast cancer patients with strong expression of KLF4 had better prognosis, especially in TNBC patients. And here we report that KLF4 negatively regulates the metastasis and growth of TNBC. Methods We assessed the expression levels of KLF4 in 84 patients with TNBC by immunohistochemical staining and studied the patterns of metastasis/recurrence clinicopathologically. The overall survival (OS) rate and the disease free survival (DFS) rate after surgery was calculated by Kaplan-Maier method. In addition, circulating tumor cells (CTCs) in the peripheral blood of TNBC patients were identified and compared with primary lesions in terms of KLF4 expression. Moreover, the expression of KLF4 was inhibited by transfecting cultured TNBC cells (MDA-MB231) with the small interfering RNA (siRNA) of KLF4 to analyze the effects of KLF4 on cell proliferation and epithelial-mesenchymal transition (EMT)-like changes. For the proliferation assay, measurements were made by MTT assays. Cell migration and invasion assays of KLF4 suppressed TNBC cells were also examined. Total RNA was extracted from these cells, cDNA was synthesized, and used for the quantitative polymerase chain reaction (qPCR) analysis. Results In the 84 TNBC patients, higher KLF4 expression was associated with significantly better OS and DFS. An analysis of KLF4 expression in CTCs of the TNBC patients showed that KLF4 expression was lower in CTCs than in primary cancer lesions. TNBC cells (MDA-MB231) that were transfected the KLF4 siRNA exhibited a greater ability to growth than controls. These cells also underwent EMT-like changes with reduced expression of epithelial factors such as E-cadherin. Treating these TNBC cells with eribulin resulted a reduction of the expression of stem cell/EMT markers. Conclusion TNBC patients with reduced KLF4 expression had poor outcomes. The results of our experiments suggest the expression of KLF4 is one of the important factors that inhibit the EMT and growth of TNBC. Citation Format: Nagata T, Sekine S, Arai M, Fujii T. KLF4 improve prognosis of triple negative breast cancer by suppression of epitherial mesenchymal transition [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-01-22.

The number of patients with dementia is increasing markedly, and effective treatment and methods for prevention are needed. Moderate exercise decreases the progression of dementia. We report a case of dementia presenting remarkable improvement in activities of daily living (ADL) through KAATSU training. The patient was a 78-year-old woman with brain atrophy detected by magnetic resonance imaging (MRI) at the age of 73. She had a remarkable decrease in ADL and vitality at the age of 76 and was diagnosed with frontotemporal dementia (FTD) at the age of 77. In initial presentation, she had a humpback and Parkinsonian gait. Her muscle strength in the abdomen, lower back, and thighs was remarkably decreased, and her trunk rotation and sense of equilibrium were also reduced. At first, the training protocol was low-intensity resistance exercises using self-weight workouts and KAATSU-walk training. For upper extremities exercises, dynamic movement using the truncal muscle group was performed, and for lower extremities exercises, the sense of equilibrium was stimulated using standing exercises. The load and degree of difficulty were increased gradually. The average 10-meter walk time, the number of steps, and the average timed up and go test time were lower after 6 months than after 2 months. The average bilateral femoral circumference increased after 6 months compared with after 2 months. In conclusion, a patient with FTD performed KAATSU training for 6 months and had a remarkable improvement in motor function. Thus, KAATSU training may be effective in improving ADL in patients with dementia.

The efficacy of the local application of recombinant human fibroblast growth factor-2 (FGF-2) in periodontal regeneration has been investigated. In this study, a randomized, double-blind, placebo-controlled clinical trial was conducted in 253 adult patients with periodontitis. Modified Widman periodontal surgery was performed, during which 200 µL of the investigational formulation containing 0% (vehicle alone), 0.2%, 0.3%, or 0.4% FGF-2 was administered to 2- or 3-walled vertical bone defects. Each dose of FGF-2 showed significant superiority over vehicle alone (p < 0.01) for the percentage of bone fill at 36 wks after administration, and the percentage peaked in the 0.3% FGF-2 group. No significant differences among groups were observed in clinical attachment regained, scoring approximately 2 mm. No clinical safety problems, including an abnormal increase in alveolar bone or ankylosis, were identified. These results strongly suggest that topical application of FGF-2 can be efficacious in the regeneration of human periodontal tissue that has been destroyed by periodontitis.

Japanese encephalitis virus (JEV) and West Nile virus (WNV) are emerging zoonotic arboviruses that have recently undergone intercontinental expansion. Both JEV and WNV are naturally transmitted between mosquito vectors and vertebrate reservoir hosts, including birds. A potential route of JEV introduction from Asia to western North America is via the Hawaiian archipelago, while the spread of WNV from mainland North America to Hawai'i is also considered an impending threat. We surveyed resident, non-native bird sera for antibodies to JEV and WNV on two Hawaiian Islands from 2004-2005. Three of 1,835 birds (0.16%) had evidence of antiflavivirus antibodies, demonstrating neutralizing activity to JEV and St. Louis encephalitis virus (SLEV). These detections could represent a limited transmission focus of either, or both, JEV and SLEV, or cross-reactive antibodies due to primary infection with an alternate flavivirus. Frequent air traffic from both Asia and North America to Hawai'i, along with the presence of probable competent vectors and amplifying vertebrate hosts in Hawai'i, increases the likelihood of introduction and maintenance of novel flaviviruses. Therefore, it is important to monitor for the presence of these viruses.

Greenbug, Schizaphis graminum (Rondani) (Hemiptera: Aphididae), was Þrst discov- ered damaging seashore paspalum (Paspalum vaginatum Swartz) turfgrass in November 2003 at Belle Glade, FL. Inquiries to several golf courses with seashore paspalum turf across southern Florida indicated infestation was wide spread by April 2004. Damage symptoms progress from water soaked lesions surrounding feeding sites within 24 h to chlorosis and necrosis of leaf tips within 96 h. Problems caused by greenbug feeding were initially misdiagnosed as fertilizer, disease, other insects, or water management problems because aphids were not previously found on warm season turfgrasses. Greenbug development and fecundity studies were conducted on six seashore paspalum varieties: OAloha,O OSeaDwarf,O OSeaGreen,O OSeaIsle,O OSeaWay,O and OSeaWolf.O Greenbug did not survive on OSeaWolf.O Development rates (mean SEM) ranged from 7.6 0.2 to 8.2 0.2 d on the remaining varieties. Greenbug longevity and fecundity on OAlohaO were signiÞcantly less than on the other varieties. The estimated intrinsic rate of natural increase (rm) for greenbug ranged from 0.24 to 0.26 across tested varieties. Values for net reproductive rate (Ro) ranged from 12.3 on OAlohaO to 40.4 on OSeaWay.O In feeding trials on indicator plants, the Florida isolate of greenbug exhibited a unique biotypic proÞle most commonly found on noncultivated grass hosts. It was virulent on the wheat variety GRS1201 that is resistant to the principal agricultural biotypes attacking small grains and to all currently available resistant sorghum varieties.

The objective of this research was to characterize clinical data packages (CDPs) of new drug applications (NDAs) using foreign data based on the International Conference on Harmonization (ICH) E5 guideline. Official review reports of NDAs approved in Japan between January 1999 and April 2005 were examined. Those NDAs considered by the official reviewers to be approved based on the ICH E5 guideline (E5-NDAs) were identified and classified into six categories of approval requirements in Japan. The details of pivotal clinical efficacy studies in the CDPs were examined. Forty-one NDAs were identified as E5-NDAs. Pivotal clinical studies conducted in Japan were required by the E5-NDAs, except for nine of those in which the foreign clinical studies reduced Japanese clinical studies in the CDPs. Given the differences in approval requirements among regions, the acceptability of foreign clinical data to Japanese approval is limited.

Idiopathic nodular glomerulosclerosis (ING) is characterized as diffuse nodular glomerulosclerotic lesions, closely resembling Kimmelstiel-Wilson lesions without diabetic mellitus. We report here three Japanese cases of ING and discuss the previous reports. The patients were 75-, 48- and 84-year-old males with a history of long-term hypertension. Laboratory examination revealed moderate proteinuria and mild renal dysfunction. Diabetes mellitus was excluded by repeated clinical and laboratory investigations. Renal histology revealed nodular glomerulosclerosis, and both afferent and efferent arteriolosclerosis in all patients. In electron microscopy, the glomerular basement membrane was markedly thick in all patients. A low-protein diet and potent anti-hypertensive treatment using angiotensin-converting enzyme inhibitors were initiated in all patients and urinary protein excretion significantly reduced without the progression of renal dysfunction. We reviewed 42 previously reported cases and our three cases. The analysis revealed that common clinical features of ING are being male (82.2%) of relatively advanced age (mean age 61.3 years), with hypertension (82.2%), mild renal dysfunction (mean serum creatinine 2.9 mg/dl) and moderate urinary protein excretion (mean 4.05 g/day). Common histopathological findings of ING are nodular glomerulosclerosis (100%), arterio-arteriolosclerosis (91.2 and 89.7%) and glomerular basement membrane thickening (85.7%). In conclusion, ING is one of the phenotypes of arteriosclerotic renal disease without diabetes mellitus. Severe arterio-arteriolosclerosis may contribute to the progression to glomerular nodular formation in ING. The combination of renin-angiotensin system inhibition and a low protein diet can be beneficial for the reduction of urinary protein excretion.

KAATSU training is a novel training, which is performed under conditions of restricted blood flow. It can induce a variety of beneficial effects such as increased muscle strength, and it has been adopted by a number of facilities in recent times. The purpose of the present study is to know the present state of KAATSU training in Japan and examine the incidence of adverse events in the field. The data were obtained from KAATSU leaders or instructors in a total of 105 out of 195 facilities where KAATSU training has been adopted. Based on survey results, 12,642 persons have received KAATSU training (male 45.4%, female 54.6%). KAATSU training has been applied to all generations of people including the young ( 80 years old). The most popular purpose of KAATSU training is to strengthen muscle in athletes and to promote the health of subjects, including the elderly. It has been also applied to various kinds of physical conditions, cerebrovascular diseases, orthopedic diseases, obesity, cardiac diseases, neuromuscular diseases, diabetes, hypertension and respiratory diseases. In KAATSU training, various types of exercise modalities (physical exercise, walking, cycling, and weight training) are used. Most facilities have used 5-30 min KAATSU training each time, and performed it 1-3 times a week. Approximately 80% of the facilities are satisfied with the results of KAATSU training with only small numbers of complications reported. The incidence of side effects was as follows; venous thrombus (0.055%), pulmonary embolism (0.008%) and rhabdomyolysis (0.008%). These results indicate that the KAATSU training is a safe and promising method for training athletes and healthy persons, and can also be applied to persons with various physical conditions.

We describe the case of a 51-year-old man with hepatitis C virus (HCV) infection and a 3-month history of facial edema. Laboratory tests upon admission for renal biopsy showed normal renal function and normocomplementemia. Serum HCV antibody (Ab) and cryoglobulin were positive. Renal biopsy specimens showed features of membranous glomerulonephritis. The likely cause was immune complex-mediated glomerulonephritis associated with HCV infection. Reports of similar cases in the literature show the normocomplementemia and negative or slightly positive cryoglobulins observed in our case as well as seropositivity for circulating immune complexes containing HCV RNA. In our case, electron microscopic examination of the subepithelial glomerular lesions revealed massive virus-like particles within unusual multilayers of electron-dense deposits (EDDs), suggesting the existence of HCV in the glomeruli. In the addition to the unique histopathological feature the presence of La/SS-B antibody in his serum indicated an abnormal immune response associated with HCV. We advise him to undergo the therapy with new type of IFN such as pegIFN-alpha2a and/or anti-viral agent like ribavirin to achieve clinical and histopathological improvement.

We have previously reported that voltage-dependent Ca 2+ (VDC) channels of rat melanotrophs are inhibited by prostaglandin E 2 (PGE 2 ). In this study, mechanisms involved in the inhibitory actions of PGE 2 receptors of rat melanotrophs were analysed using reverse transcriptase-polymerase chain reaction (RT-PCR), Ca 2+ -imaging and whole-cell, patch-clamp techniques with recently developed EP agonists, each of which is selective for the known four subclasses of EP receptors (EP 1-4 ). PGE 2 reversibly suppressed the cytosolic Ca 21 concentration ([Ca 2+ ] i ). The maximum reduction in [Ca 2+ ] i by PGE 2 was comparable to that by dopamine or to that by extracellular Ca 2+ removal. RT-PCR analysis of all four EP receptors revealed that EP 3 and EP 4 receptor mRNAs were expressed in the intermediate lobe. The effects of PGE 2 to suppress [Ca 2+ ] i were mimicked by the selective EP 3 agonist, ONO-AE-248, whereas three other EP agonists, ONO-DI-004 (EP 1 ), ONO-AE1-259 (EP 2 ) and ONO-AE1-329 (EP 4 ), had little or no effect on [Ca 2+ ] i . All four G-protein activated inward rectifying K + (GIRK) channel mRNAs were identified in intermediate lobe tissues by RT-PCR. Dopamine concentration-dependently activated GIRK currents, whereas PGE 2 did not activate GIRK currents, even at the concentration causing maximal inhibition of VDC channels. These results suggest that PGE 2 acts on EP 3 receptors to suppress Ca 2+ entry of rat melanotrophs by selectively inhibiting VDC channels of these cells. We have compared the possible cellular and molecular mechanisms of inhibition by dopamine and PGE 2 .

In the present study, the function of the somatosensory feedback system in postural control was investigated. For the sake of simplicity, the present study considered only balancing in the anteroposterior direction using the ankle strategy, in which the ankle moment is mainly used to maintain balance. To suppress the vestibular and visual feedback paths, a subject stood on a force-measuring platform with a fixed back support. Because the subject's body was immovable under these conditions, the subject controlled a computer model that simulated the subject's load at the ankles. Information about the sway angle of the model was fed through the somatosensory feedback path. Frequency response functions of the ankle moment in response to the sway angle were calculated. The experimental results suggest that the human somatosensory feedback system has derivative characteristics and, consequently, can maintain an upright posture by itself. The results were compared with those of previous studies on vestibular and visual feedback systems. The comparison reveals that subject-to-subject variance in the somatosensory system is significantly smaller than that in the other systems. This may indicate that the somatosensory feedback is the most automatic of the systems and plays a dominant role when a subject maintains an upright posture using the ankle strategy.

Twenty 2-thiopyrimidine nucleoside analogues were synthesized and examined for inhibitory activity against herpes simplex virus (HSV) type 1 and 2, varicella-zoster virus (VZV), human cytomegalovirus (HCMV) and thymidine kinase-deficient HSV (HSV-TK) replication in vitro. 2-thiouracil (thymine) arabinoside, 2′-deoxy-2-thiouridine (or 2-thiothymidine) and their 5-halogenated derivatives showed anti-HSV activity in both RPMI8226 (human B-lymphoblastoid cells) and MRC-5 (human embryo lung cells). 2′-deoxy-5-halogenated-2-thiocytidines were also inhibitory against HSV, whereas 2-thiocytosine arabinoside and its derivatives were not inhibitory against HSV replication, except 5-bromo and 5-iodo congeners (TN-31, TN-32). Substitution of the halogen atom at the 5-position of the pyrimidine rings to an atom with a higher molecular weight increased anti-HSV and VZV activities, except for the anti-HSV activity of 2-thiouracil arabinosides. 2′-deoxy-5-methyl-, and 2′-deoxy-5-iodo-2-thiouridines (TN-17, TN-44) showed the most potent anti-HSV activity, and 2′-deoxy-5-chloro- and 2′-deoxy-5-bromo-2-thiocytidines were potent inhibitors of VZV replication. However, none of the compounds inhibited HCMV and HSV-TK− replication. TN-31 and TN-32 were shown to inhibited HCMV and HSV-TK− as well as HSV and VZV replication. The cytotoxicity of the 2-thiopyrimidine nucleoside analogues was less than that of the 2-oxy-congeners of the compounds (5-iodo-2′-deoxyuridine, 5-iodo-2′-deoxycytidine, thymine arabinoside and cytosine arabinoside). The selectivity index of 2′-deoxy-5-iodo-2-thiouridine (TN-44) was higher than that of 5-iodo-deoxyuridine. TN-17 and TN-44 were not cytotoxic to resting or stimulated human peripheral blood mononuclear cells at 400 μ, although TN-32 was cytotoxic at a concentration of 20 μ.

The prevalence of Dirofilaria immitis in cats in Japan has been examined since 1957. Twenty surveys involving a total of 3775 cats, conducted in two islands of Japan (Honshu and Kyushu), were studied. The surveys evaluated both stray (3617) and house (158) cats. Presence of D. immitis was detected at necropsy. The results show a prevalence of D. immitis varying from 0.5 to 9.5% for stray cats and from 3.0 to 5.2% for house cats on the two islands.

Tumors at the cranial base in 2 cats (a 9 1/2-year-old, castrated male Chinchilla and a 7-year-old, castrated male American shorthair) were diagnosed as malignant craniopharyngioma. The tumor lesion was histopathologically divided into four parts: 1) a small acinus part, in which relatively large cells with a pale cytoplasm composed small acini; 2) a duct part, in which small cuboidal cells composed ducts; 3) a cyst part, in which there were large cysts lined with flat cells; and 4) a pavement part, in which large multiangular-shaped cells proliferated in a pavement pattern. The epithelial cells of some parts were positive for keratin by immunohistochemistry. Histopathologic findings of the present feline cases were identical to those of malignant craniopharyngioma in other animal species.

First we solve the relativistic Hartree problem for a finite nucleus: We obtain the relativistic single particle states of positive and negative energy nucleons in 16O, treating these nucleons on the equal footing, and compare the results with those of the mean field theory. We solve the simultaneous mean field equations as matrix equations on the wave packet basis. This method needs not rely on the derivative expansion to renormalize the divergent sums of the densities and of the energies of negative energy nucleons. The contribution of these nucleons suppresses the mean meson fields and increases the nuclear radius. Secondly, taking the positive energy nucleon state sector picture of a nucleus to elucidate the results of the above relativistic Hartree calculation, we derive the effective nuclear interactions between positive energy nucleons which are corrected by the N N vacuum polarizations. The polarizations suppress the meson exchange interactions and increase their ranges.

SynopsisThe incidence of cavum septum pellucidum (CSP), which has been widely regarded as a developmental anomaly of little clinical importance in neuropathology, was examined in 113 patients with affective disorders (69 with bipolar disorder and 44 with major depression), 40 schizophrenic patients, and 92 control subjects by magnetic resonance imaging (MRI). Significantly higher incidence of Grade 3–4 CSP (moderate to large) compared with the controls was found only in the schizophrenics. When a broader interpretation of CSP, including indeterminant (Grade 1) and small (Grade 2) CSP was used, three additional patients with bipolar disorder were found to have Grade 1–2 CSP, and the total prevalence of Grade 1–4 CSP in the patients with bipolar disorder was significantly higher than that in the control subjects but slightly lower than that in the schizophrenic patients. CSP was not observed in any patient with major depression. There were no differences between the patients with and without CSP in age, sex, education, or the duration of illness. These findings are consistent with the hypothesis that neurodevelopmental abnormality may be present in schizophrenia, and such an abnormality may also be present in some patients with bipolar disorder.

A specific procedure using high-performance liquid chromatography/particle beam mass spectrometry (HPLUPBMS) has facilitated determination of bromisovalum in human plasma and whole blood. Bromisovalum, a sedative and hypnotic, was effectively extracted with SepPak C,, cartridges and selectively determined by HPLUPBMS of EI mode. An originally synthesized 2-bromohexanoylurea served as the internal standard (IS). The calibration curve was linear over the concentration range 0.5-5.0 &g and the lower limit of detection was 0.1 r&g (10 ng at the time of direct injection). This method could be practically applied to detect bromisovalum in the whole blood of an autopsied individual.

Anti-ganglioside antibodies have been reported in various peripheral neuropathies, including Guillain-Barre syndrome (GBS), chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, Fisher syndrome, monoclonal gammopathy-associated neuropathy, and other idiopathic neuropathies. To our knowledge, there has been no report of anti-ganglioside-positive sarcoidosis. We report a 62-year-old man with acute weakness of the limbs and sensory disturbance of the right arm and trunk resembling GBS. Soluble interleukin-2 receptor and angiotensin-converting enzyme levels were elevated. Anti-ganglioside antibodies (immunoglobulin G anti-N-acetylgalactosaminyl-GD1a antibody [IgG anti-GalNAc-GD1a antibody]) were detected. Neurophysiological examination demonstrated axonal neuropathy. Bilateral hilar lymphadenopathy was demonstrated on a chest CT scan, and abnormal uptake of 67 Gallium was detected by scintigraphy. The ratio of CD4 to CD8 was elevated in bronchoalveolar lavage fluid. Noncaseating epithelioid cell granulomas were detected in a specimen obtained via transbronchial lung biopsy. Because intravenous immunoglobulin did not improve the symptoms, we commenced steroid pulse therapy followed by oral prednisolone therapy. After steroid therapy, he recovered fully. Because the findings in our patient fulfilled the criteria for neurosarcoidosis, we diagnosed his illness as probable neurosarcoidosis. To the best of our knowledge, this is the first patient with GBS-like-onset neurosarcoidosis positive for anti-IgG anti-GalNAc-GD1a antibody.

The goal of this study is to maintain a continuous level of exercise intensity around the aerobic threshold (AT) during riding on an electric motor assisted bicycle using a new control system of electrical motor assistance which uses the efficient pedaling rate of popular bicycles. Five male subjects participated in the experiment, and the oxygen uptake was measured during cycling exercise using this new pedaling rate control system of electrical motor assistance, which could maintain the pedaling rate within a specific range, similar to that in previous type of electrically assisted bicycles. Results showed that this new pedaling rate control system at 65 rpm ensured continuous aerobic exercise intensity around the AT in two subjects, and this intensity level was higher than that observed in previous type. However, certain subjects were unable to maintain the expected exercise intensity because of their particular cycling preferences such as the pedaling rate. It is necessary to adjust the specific pedaling rate range of the electrical motor assist control according to the preferred pedaling rate, so that this system becomes applicable to anyone who want continuous aerobic exercise.

On the basis of differential and density gradient centrifugation studies, the site of the uric acid degrading enzymes, urate oxidase and allantoinase, in amphibia was previously assigned to the hepatic peroxisomes. Using specific antibodies against frog urate oxidase and allantoinase, we have undertaken an immunocytochemical study of the localization of these two proteins in frog liver and kidney, and demonstrate that whereas urate oxidase is present in peroxisomes, allantoinase is localized in mitochondria. Urate oxidase and allantoinase were detected by immunoblot analysis in both frog liver and kidney. The subcellular localization of these two enzymes was ascertained by Protein A-gold immunocytochemical staining of Lowicryl K4M-embedded tissue. Peroxisomes in frog liver parenchymal cells and kidney proximal tubular epithelium contained a semi-dense subcrystalloid core, which was found to be the exclusive site of urate oxidase localization. Allantoinase was detected within mitochondria, but not in peroxisomes of hepatocytes or proximal tubular epithelium. No allantoinase was detected in the mitochondria of nonhepatic parenchymal cells in liver and of the cells lining the distal convoluted tubules of the kidney. These results demonstrate that, unlike rat kidney peroxisomes which lack urate oxidase, peroxisomes of frog kidney contain this enzyme. Contrary to previous assumptions, these studies also clearly establish that urate oxidase and allantoinase, the first two enzymes involved in uric acid degradation, are localized in different subcellular organelles in frog liver and kidney.

A strain of Fusarium solani was isolated from a dog showing many cutaneous and submucosal nodules and pyogranulomatous kidney lesions. Clinical isolates from this systemic infection were identified using microscopic examination and confirmed by molecular analysis.

Background Hawaii and the United States-affiliated Pacific islands (USAPI) host over 8 million travelers annually, most of whom originate in Asia, Australia, and the Americas where prevalence of oseltamivir resistance in 2009 pandemic influenza A (H1N1) has been reported to be 2.5–3.5%. Objective To survey a collection of samples from Hawaii and the USAPI that had tested positive for the 2009 pandemic influenza A (H1N1) virus by RTI-PCR to assess whether antiviral resistance emerged in these island communities during the 2009 H1N1 pandemic. Study design We examined RNA extracted from Hawaiian and USAPI cases for the neuraminidase H275Y mutation associated with oseltamivir resistance by pyrosequencing. Results Two hundred and sixty-three (263) 2009 pandemic influenza A (H1N1) positive specimens were tested and 263/263 (100%) were shown to lack the mutation most commonly associated with oseltamivir resistance. Conclusions There was no evidence of oseltamivir resistant A(H1N1)pdm09 virus during the 2009 pandemic in the Pacific islands despite considerable travel exposure. Geographic isolation, the lack of a “second wave” of pandemic influenza, judicious antiviral use, aggressive vaccination, and below average tourism due to the global economic crisis may have been contributing factors. Continued surveillance and vigilance is necessary to monitor unpredictable influenza activity.

Squirrel monkeys with induced canine distemper virus (CDV) encephalitis showed characteristic clinical signs such as seizures or myoclonus, with EEGs showing periodic synchronized discharge (PSD). Histopathologically, there was gliosis and neuronal degeneration diffusely distributed in both the gray and white matters in the subacute phase, the lesions resembling those found in childhood acute viral encephalitis and subacute sclerosing panencephalitis (SSPE). The auditory brain-stem response (ABR) changes were remarkable in the subacute phase, and the recovery of latency was correlated with survival. The visual evoked potential (VEP) abnormalities disappeared in the acute phase and appeared again with delayed latency in the subacute stage. One monkey which did not show clinical signs but had the pathological changes showed the VEP abnormality. These data suggest that the evoked potentials are helpful in judging the prognosis, and that this model is useful for the analysis of the pathogenesis of viral encephalitis.

Transgenic plants of lettuce cultivar (cv.) ‘South Bay’ were produced by using Agrobacterium tumefaciens vectors containing the β-glucuronidase (GUS) reporter gene and the NPT II gene for kanamycin resistance as a selectable marker. High frequency of transformation, based on kanamycin resistance and assays for GUS expression, was obtained with 24 to 72-h-old cotyledon explants cocultivated for 48 h with Agrobacterium tumefaciens. After the cocultivation period, the explants were placed in selection medium containing 50 or 100 mg l−1 of kanamycin, 100 mg l−1 cefotaxime and 500 mg l−1 carbenicillin for 10 days. Surviving explants were transferred every 14 days on shoot elongation medium. Progenies of R0 plants demonstrated linked monogenic segregation for kanamycin resistance and GUS activity.

The chemical nature of urinary stone protein is poorly understood. We have sequenced a cDNA of urinary calcium oxalate stone protein extracted with EDTA. cDNA sequences showed complete identity between urinary stone protein and human osteopontin. Osteopontin protein was detected by staining with Stains-All, which specifically stains phosphoproteins, and by digestion with the highly specific protease thrombin, demonstrating that urinary calcium oxalate stones consist of osteopontin protein. We used a technique of in situ hybridization to detect osteopontin mRNA in the kidney. In control rats, distal tubular cells were sporadically positive, and proximal tubular cells and glomeruli were negative for osteopontin mRNA. A rat model of stone formation was induced with glyoxylic acid. In stone-forming rats, staining of distal tubular cells was remarkably increased, but proximal tubular cells and glomeruli were still negative. Immunostaining for the osteopontin protein also revealed that epithelial cells of distal tubules were weakly positive in control rats and significantly increased in stone-forming rats, although proximal tubular cells and glomeruli were negative. Northern blot analysis showed a significant increase of osteopontin mRNA in stone-forming rats in proportion to the dosage and the duration of the stone-inducing drugs. These results show that osteopontin in the kidney is presumably involved in urinary stone formation as the stone matrix.

A liquid chromatographic (HPLC) method for simultaneous determination of thiamphenicol, florfenicol and chloramphenicol residues in muscles of animals and cultured fishes was developed. The drugs are extracted from minced muscles with ethyl acetate, and the extract is evaporated to dryness. The residue is dissolved with 3% NaCl and partitioned with n-hexane. The drugs are extracted with ethyl acetate, and after evaporation of the solvent, the residue is cleaned up by Sep-Pak Florisil cartridge. HPLC analysis is carried out on Chromatorex ODS column, and the drugs are quantitated by UV detector at 225 or 270 nm. The average recoveries of thiamphenicol, florfenicol and chloramphenicol added to muscles at 0.1 ppm were more than 74.1%. The detection limit was 1 ng for each drug standard, which corresponded to 0.01 ppm in muscies.

A high performance liquid chromatographic method (HPLC) for the determination of olaquindox, morantel, furazolidone, nitrofurazone and carbadox residues in swine muscles was developed. The drugs were extracted from muscles with acetonitrile and cleaned up by alumina column. HPLC analysis was carried out on an Inertsil C8 column with a mobile phase of acetonitrile-water-acetic acid (3:97:1), and the drugs were detected at 340 nm. The average recoveries of all drugs added to muscles at 0.1 ppm level were more than 75% and the detection limit of each drug was 0.03 ppm in muscles.

Purpose To determine if alteplase infusion for the treatment of loculated abdominopelvic abscesses requiring percutaneous catheter drainage was superior to saline solution infusion. Methods and Materials This study was a single-center prospective randomized trial. Patients with loculated abdominopelvic abscesses unsuccessfully drained by initial catheter placement were randomized to receive the fibrinolytic agent alteplase or normal saline solution. The amount of alteplase used to treat abscesses was 2 mg or 4 mg based on infusion volumes of 0–50 mL or 51–100 mL, respectively. Infusions were administered twice daily for 3 days. Computed tomography was performed before initiation of therapy and immediately after 3 days of infusions. Success was defined by removal of the catheter after drainage without recurrent abscess or surgical intervention within 30 days. Results A total of 20 patients were included in this study: 11 received alteplase and nine received normal saline solution. There was no significant difference in the distribution of sex ( P = .08) or age ( P = .29). Abscess resolution was achieved in nine of 11 alteplase-treated patients (80%) versus three of nine saline solution–treated patients (33%). However, one patient in each group required repeat intervention within 30 days, for overall success rates of 73% versus 22%, respectively ( P = .02). Having observed a significant difference in the primary outcome variable, the study was terminated early. Conclusions A 3-day course of twice-daily alteplase infusion therapy is superior to normal saline solution for the treatment of loculated abdominopelvic abscesses.

Renal deterioration often occurs in cases of infectious endocarditis (IE), but, IE- associated nephritis with rapidly progressive glomerulonephritis (RPGN) is rare. Patients with severe infection (e.g., IE) sometimes show positivity for cytoplasmic antineutrophil cytoplasmic antibodies (C-ANCA). Therefore, diagnosis and treatment are very difficult in cases of RPGN with IE and positivity for C-ANCA. Such cases are rare, only 12 have been reported in the English literature. Herein, we describe the case of a 50-year-old man who presented with RPGN with IE and tested positively for C-ANCA. He was referred to our hospital because of leg edema, purpura and renal dysfunction. Laboratory tests revealed serum creatinine elevation and positivity for C-ANCA and proteinase 3-specific (PR3)-ANCA. RPGN and acute renal failure were diagnosed. Hemodialysis and steroid therapy were started. Streptococcus oralis was isolated by blood culture. Transthoracic echocardiography revealed grade III mitral valve insufficiency with two vegetations. Therefore, IE was diagnosed. The steroid therapy was stopped, and antibiotic therapy was begun. Because there was no improvement, surgical therapy was performed. The operation was successful, but the patient died of brain hemorrhage. Our experience in this case indicates C/PR3-ANCA positive RPGN must be ruled out in patients with infectious disease, particularly IE, together with renal symptoms, and renal biopsy should be performed.

We investigated the role of visual feedback in human upright posture control. To make the role of vision clear, we compared the visual, vestibular and somatosensory feedback systems in their ability to perceive movement and suppress short- and long-term sway. First, we measured thresholds for the perception of movement Then effects of each feedback system to suppress short- and long-term sway were analyzed through posture control experiments, in which the available sensory input was limited. The visual and somatosensory thresholds were small ( 0.5 degree). The results of the posture control experiments suggested that the visual system contributed to suppression of sway in the frequency range below 0.4 Hz and the system had a minor effect in frequencies above 0.5 Hz. These results support our previous finding that the visual system does not allow a normal subject to maintain an upright posture by itself. The somatosensory system, on the other hand, suppressed body sway around 0.2 and 0.9 Hz. The higher frequency range might enable the system to maintain an upright posture by itself.

Twenty 5-alkyl-2-thiopyrimidine nucleosides were newly synthesized and examined for antiviral activities against herpes simplex virus (HSV), varicella-zoster virus (VZV) and human cytomegalovirus (HCMV). In this study, 2′-deoxy-5- alkyl-2-thiocytidine analogues had lower 50% effective concentration (EC50) values against HSV- 1, and 2/-deoxy-5-alkyl-2-thiouridine analogues showed lower EC50 against VZV than their congeners of arabinoside form. Among the compounds examined, 2′-deoxy-5-ethyl and 5-propyl- 2-thiocytidine (TN-53 and TN-54) were most potent and selective anti-HSV compounds. Their EC50s were 0.04 and 0.15 μM, and selectivity indexes were more than 7215 and 1849, respectively. On the other hand, 2′-deoxy-5-propyl-2-thiouridine (TN-51), 5-bromovinyl-2-thiouracil arabinoside (TN-65) and 5-styryl-2-thiouracil arabinoside (TN-67) were most potent and selective anti-VZV compounds. Their EC50s were 3.1, 3.8 and 2.6 μM for CaQu strain of VZV, respectively, and 2.1 to 3.0 times lower than that of acyclovir. All 2-thiopyrimidine nucleoside analogues did not show antiviral activities against thymidine kinase (TK) negative strains of HSV-1 and VZV. Only three 2-thiocytosine arabinoside compounds showed marginal anti-CMV activities (EC50s were 57–159 μM). All of the five alkyl-2-thio-pyrimidine nucleoside analogues examined were not cytotoxic to human lymphoblastoid cells (RPMI8226) and human embryonic fibroblast cells (MRC-5) at 240 μM (100 pg/ml) or more. Regarding the structure-activity relationship of 5-alkyl-2-thiopyrimidine nucleoside analogues, the following remarks will be noted. Elongation of 5-alkyl chain (methyl to ethyl) of 2-thiocytosine in both deoxyribosyl and arabinosyl nucleosides increased anti-HSV-1 activity but not anti-VZV activity. Furthermore, elongation of the same chain (ethyl to propyl) of 2-thiodeoxyuridine increased anti-VZV activity whereas it did not in the case of 2-thiouracil arabinosides.

5-Fluorouracil (5-FU) and 5′-deoxy-5-fluorouridine (5′-DFUR), a prodrug of 5-FU, are representative of the chemotherapeutic agents for colorectal adenocarcinomas. Pyrimidine nucleoside phosphorylase (PyNPase) catalyses the conversion of 5′-DFUR to 5-FU, the activated form. Murine adenocarcinoma CT26 cells were transfected with human PyNPase cDNA. The engineered transfectants producing PyNPase augmented the response to 5′-DFUR in vitro and in vivo . Animals were administered by means of intraperitoneal (i.p.) injection, and not orally, in order to obtain a better efficiency of absorption. The tumours of the transfected cells nearly all disappeared, even following treatment with quite a small amount of the anticancer agent. The animals injected with the tranfected cells were protected against subsequent challenge with the parental tumour cell line. These findings demonstrate that PyNPase gene transfection increases the sensitivity to 5′-DFUR, and thereby decreases the toxicity of the agent.

An otherwise healthy 20-year-old woman presented with an erythematous rash on her face as well as arthralgia and anemia. She also had systemic edema, proteinuria and hypertension. Laboratory data on admission showed hypocomplementemia, human parvovirus B 19 (HPV) DNA and both immunoglobulin (Ig) M and IgG antibodies to HPV in her serum. Renal biopsy specimens showed features of endocapillary glomerulonephritis under light microscopy. Electron microscopy showed massive subendothelial electron-dense deposits. No cause was probable other than immune complex-mediated glomerulonephritis associated with HPV infection. In a review of this and similar cases reported in the literature, several characteristic features come to light: female dominance, onset in the second or third decade of life, hypocomplementemia, histologic renal endocapillary and/or mesangioproliferative glomerulonephritis with subendothelial deposits and spontaneous recovery.

Disaster preparedness is one of the national priorities. In Japan, disaster medicine is defined as a part of the national medical plan initiated by Ministry of Health, Welfare and Labor. The Japan Medical Association is the largest professional physicians' group in Japan, and has contributed to all kinds of disaster relief work regionally and nation-wide for years. Based on past successes, the Japan Medical Association proposes a new disaster action plan named Japan Medical Association Team (JMAT). The primary mission of JMAT is to deploy to the disaster scene requested and work for disaster relief. JMAT covers the acute to sub-acute phase of disaster response, and also collaborate with other agencies. In the preparation and mitigation phases, the Japan Medical Association work for establishing mutual disaster aid partnerships, disaster plans, networks with other agencies, team building, disaster medicine training and education, etc. In Japan, the Disaster Medical Assistant Team (DMAT) has been established based on the experience of the 1995 Kobe Earthquake, when lots of preventable trauma deaths occurred because of delayed medical response. The mission of DMAT is to deploy to the scene immediately and triage/transfer the most serious disaster victims outside the scene for advanced medical care. DMAT covers the first 48 hours of disaster response phase, and then JMAT takes charge of the work. JMAT will also respond to chemical, biological, radiological and nuclear disasters, and international humanitarian work. The present issues of establishing JMAT are 1.training and education for Japan Medical Association members, 2.establising cooperation with other agencies, and 3.having presence at the Central Disaster Committee, Cabinet Office, Government of Japan.

IntroductionTrauma care is one of the key components of disaster medicine. However, it is difficult in Japan to gain extensive experience in trauma surgery, especially penetrating trauma. The Advanced Trauma Operative Management (ATOM) course was developed as a model for teaching operative trauma techniques to surgical residents, fellows, and attending surgeons as the number of these cases decreases in the US. In 2008, a new ATOM training site was established at Jichi Medical University in Japan, and as of December, 2010, five courses have been offered.MethodsThe ATOM course consists of lectures and a porcine operative experience. Comprehensive evaluation of ATOM was designed to assess participant learning in the cognitive, affective, and psychomotor domains. Data on the first 36 participants was retrospectively collected and analyzed.ResultsParticipants included: 20 expert trauma surgeons, and 16 general surgeons. All groups showed improvement in knowledge (pre-test score: 61.9 ± 16.4 (mean ± standard deviation), post-test score: 70.6 ± 16.5, p-value < 0.001) with results in the expert and fellow groups reaching statistical significance. Self-confidence also improved (pre-evaluation score: 65.4 ± 17.6, post-evaluation score: 82.0 ± 9.4, p-value < 0.001), with all groups reaching statistical significance.DiscussionThis course creates real operative situations in a standardized fashion that improves knowledge and operative confidence for trauma operations, which may be of great benefit in disaster medicine training.

Duchenne muscular dystrophy (DMD), the most common form of muscular dystrophy, is caused by lack of dystrophin. Exon skipping has been developed as a possible treatment of DMD and exon 45–55 skipping strategy could be one of goals of this therapy, partly because patients with exon 45–55 in-frame deletion have shown very mild skeletal muscle symptoms. Moreover, this strategy could theoretically rescue up to 63% of DMD deletion patients, however function of exon 45–55 deleted dystrophin is not well understood. To clarify the functional role of truncated dystrophin, we generated the transgenic (Tg) mice which expressed the exon 45–55 lacking human dystrophin and two Tg lines were established. We, then, mated Tg male mice with mdx female mice to get Tg/ mdx male mice and extensively analyzed the phenotypes. These Tg/ mdx mice expressed only truncated dystrophin, accompanied by recovery of the dystrophin–glycoprotein complex at the sarcolemma. The Tg/ mdx also showed improvement of the function, including serum creatine kinase level, muscle pathology and specific tetanic force, to a level of the wild type. These results suggest that truncated dystrophin with exon 45–55 deletion has a equivalent function to the full length dystrophin. On the other hand, atrophy of type2B fibers and increasing of type2A fibers were observed at 20weeks of Tg/ mdx mice. Moreover, the localization of neuronal NOS (nNOS) in Tg/ mdx was changed from sarcolemma to cytosol and nNOS itself was activated. This activation induced hyper-nitrosylation of the ryanodine receptor type-1 and Ca 2+ was constantly released from sarcoplasmic reticulum to cytosol. This Ca 2+ release might be related to the findings, up-reguletion of Atrogin-1 and MuRF1, which could induce muscle atrophy and PGC1 α , which could alter the muscle fiber types. This Tg/ mdx mouse could be also a very useful model for analyzing pathogenesis of BMD phenotypes.

Aim: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) such as gefitinib, erlotinib or afatinib are essential drugs for the treatment of advanced non-small cell lung cancer (NSCLC) with activating EGFR gene mutations. However, disease progression inevitably occurs around 10-12 months after EGFR-TKI treatment. Bevacizumab (Bmab) enhances the effect of cytotoxic chemotherapy with advanced NSCLC while it remains unknown whether Bmab enhances the effect of EGFR-TKIs on EGFR mutant NSCLC. We conducted a phase II trial to investigate the efficacy and safety of gefitinib when combined with Bmab as a first-line therapy in patients with advanced NSCLC harboring EGFR gene mutations. Methods: In this trial, 42 patients with PS 0 to 2 received daily gefitinib (250mg/body) and Bmab (15mg/kg, every 3 weeks). The primary endpoint was 1-year progression-free survival (PFS) rate, and the secondary endpoints included response rate, PFS time, overall survival (OS) time and toxicity. Results: The patients had a median age of 73 (range, 42-86), of whom 40% were male, 75% with PS 0-1, 79% in stage IV, and 21% with postoperative recurrence. As for the activating EGFR gene mutations, 57% of the patients had exon 19 deletion (del), 38% exon 21 point mutations (L858R), 2.5% exon 18 G719A, and 2.5% exon 21 G861Q. At the time of this analysis, 34 pts (81%) had dropped out of the protocol treatment, wherein 10 out of 42 pts (24%) discontinued it because of adverse events (AEs). The 1-year PFS rate was 56.7% (95% confidence interval: 39.9-70.5%), which did not meet the primary endpoint. The median PFS time (month) was 14.4 with a significant difference between those of exon 19 del (18.0) and L858R (9.4, p = 0.006). The objective response rate and disease control rate were 73.8% and 97.6%, respectively. The median OS was not yet reached. The severe AEs included grade 3 liver dysfunction (19%), hypertension (17%), acneiform (14%), proteinuria (7%), intracranial hemorrhage (3%), and grade 4 perforation of the digestive tract (3%), but no treatment-related death. Conclusions: Gefitinib in combination with Bmab as a first line therapy seems a favorable and well-tolerated treatment for patients with advanced NSCLC with activating EGFR gene mutations, especially for those with exon 19 del mutations. Disclosure: N. Nogami: Reseach funding; Astra Zeneca, Chugai-Pharma. Speaker fees for scientific meetings; Astra Zeneca, Chugai-Pharma; T. Kozuki: Reseach funding; Astra Zeneca, Chugai-Pharma. Speaker fees for scientific meetings; Astra Zeneca, Chugai-Pharma; N. Takigawa: Speaker fees for scientific meetings; Astra Zeneca, Chugai-Pharma; K. Hotta: Reseach funding; Astra Zeneca, Chugai-Pharma. Speaker fees for scientific meetings; Astra Zeneca, Chugai-Pharma; . Kiura: Reseach funding; Astra Zeneca, Chugai-Pharma. Speaker fees for scientific meetings; Astra Zeneca, Chugai-Pharma. All other authors have declared no conflicts of interest.

This study was designed to investigate the effects of cocaine-amphetamine-regulated transcript (CART), a recently discovered hypothalamic neuropeptide, on food intake, anxiety, oxygen consumption and gastric emptying in mice. Intracerebroventricular (i. c. v.) injection of CART (1 - 100 pmol) markedly reduced food intake in a dose-related manner. A significant decrease was observed 20 min after i. c. v. injection of CART and continued for four hours. In the elevated plus maze test, i. c. v. CART injection significantly raised the normal preference for the closed arms. Furthermore, the i. c. v. injection of CART significantly reduced oxygen consumption and gastric emptying rate. These results suggest that CART modulates feeding, emotion, and autonomic functions in mice.