Showing papers by "Hokkaido University published in 2004"

Collagen Degradation by Host-derived Enzymes during Aging

Abstract: Incompletely infiltrated collagen fibrils in acid-etched dentin are susceptible to degradation. We hypothesize that degradation can occur in the absence of bacteria. Partially demineralized collagen matrices (DCMs) prepared from human dentin were stored in artificial saliva. Control specimens were stored in artificial saliva containing proteolytic enzyme inhibitors, or pure mineral oil. We retrieved them at 24 hrs, 90 and 250 days to examine the extent of degradation of DCM. In the 24-hour experimental and 90- and 250-day control specimens, we observed 5- to 6-microm-thick layers of DCM containing banded collagen fibrils. DCMs were almost completely destroyed in the 250-day experimental specimens, but not when incubated with enzyme inhibitors or mineral oil. Functional enzyme analysis of dentin powder revealed low levels of collagenolytic activity that was inhibited by protease inhibitors or 0.2% chlorhexidine. We hypothesize that collagen degradation occurred over time, via host-derived matrix metalloproteinases that are released slowly over time.

DJ-1 has a role in antioxidative stress to prevent cell death.

Abstract: Deletion and point (L166P) mutations of DJ-1 have recently been shown to be responsible for the onset of familial Parkinson's disease (PD, PARK7). The aim of this study was to determine the role of DJ-1 in PD. We first found that DJ-1 eliminated hydrogen peroxide in vitro by oxidizing itself. We then found that DJ-1 knockdown by short interfering RNA rendered SH-SY5Y neuroblastoma cells susceptible to hydrogen peroxide-, MPP+- or 6-hydroxydopamine-induced cell death and that cells harbouring mutant forms of DJ-1, including L166P, became susceptible to death in parallel with the loss of oxidized forms of DJ-1. These results clearly showed that DJ-1 has a role in the antioxidative stress reaction and that mutations of DJ-1 lead to cell death, which is observed in PD.

Mili, a mammalian member of piwi family gene, is essential for spermatogenesis.

Abstract: The piwi family genes, which are defined by conserved PAZ and Piwi domains, play important roles in stem cell self-renewal, RNA silencing, and translational regulation in various organisms. To reveal the function of the mammalian homolog of piwi, we produced and analyzed mice with targeted mutations in the Mili gene, which is one of three mouse homologs of piwi. Spermatogenesis in the MILI-null mice was blocked completely at the early prophase of the first meiosis, from the zygotene to early pachytene, and the mice were sterile. However, primordial germ cell development and female germ cell production were not disturbed. Furthermore, MILI bound to MVH, which is an essential factor during the early spermatocyte stage. The similarities in the phenotypes of the MILI- and MVH-deficient mice and in the physical binding properties of MILI and MVH indicate a functional association of these proteins in post-transcriptional regulation. These data indicate that MILI is essential for the differentiation of spermatocytes.

Lysophospholipid receptors: Signaling and biology

Abstract: ▪ Abstract Lysophospholipids (LPs), such as lysophosphatidic acid and sphingosine 1-phosphate, are membrane-derived bioactive lipid mediators. LPs can affect fundamental cellular functions, which include proliferation, differentiation, survival, migration, adhesion, invasion, and morphogenesis. These functions influence many biological processes that include neurogenesis, angiogenesis, wound healing, immunity, and carcinogenesis. In recent years, identification of multiple cognate G protein-coupled receptors has provided a mechanistic framework for understanding how LPs play such diverse roles. Generation of LP receptor-null animals has allowed rigorous examination of receptor-mediated physiological functions in vivo and has identified new functions for LP receptor signaling. Efforts to develop LP receptor subtype-specific agonists/antagonists are in progress and raise expectations for a growing collection of chemical tools and potential therapeutic compounds. The rapidly expanding literature on the LP re...

B7-H1 Expression on Non-Small Cell Lung Cancer Cells and Its Relationship with Tumor-Infiltrating Lymphocytes and Their PD-1 Expression

Abstract: Purpose: B7-H1/PD-L1 (B7-H1) and B7-DC/PD-L2 (B7-DC) are ligands for the receptor PD-1, which is known to negatively regulate T-cell activation. In the present study, we investigated the expression of B7-H1 and B7-DC in tumor specimens of non-small cell lung cancer and their relationships with clinicopathological variables and postoperative survival. Furthermore, we examined the correlation between B7-H1 expression on tumor cells and the number of tumor-infiltrating lymphocytes (TILs) or PD-1 expression on TILs. Experimental Design: The expression of B7-H1 and B7-DC in 52 surgically resected specimens of non-small cell lung cancer was evaluated immunohistochemically. Results: Expression of B7-H1 and B7-DC was focally observed in all non-small cell lung cancer tumor specimens. No relationship was found between the expression of B7-H1 or B7-DC and clinicopathological variables or postoperative survival. However, in the same sections evaluated, significantly fewer TILs were identified in B7-H1-positive tumor regions than in B7-H1-negative tumor regions in a subset of five patients ( P = 0.01). Moreover, the percentage of TILs expressing PD-1 was significantly lower in B7-H1-positive tumor regions than in B7-H1-negative tumor regions ( P = 0.02). Conclusions: The expression of B7-H1 on tumor cells in local areas reciprocally correlated with the number of TILs, and this may contribute to negative regulation in antitumor immune responses in non-small cell lung cancer.

Oncogenic mechanisms of the Helicobacter pylori CagA protein

Abstract: Infection with strains of Helicobacter pylori that carry the cytotoxin-associated antigen A (cagA) gene is associated with gastric carcinoma. Recent studies have shed light on the mechanism through which the cagA gene product, CagA, elicits pathophysiological actions. CagA is delivered into gastric epithelial cells by the bacterial type IV secretion system, where it deregulates the SHP2 oncoprotein. Intriguingly, CagA is noted for its variation, particularly at the SHP2-binding site, which could affect the potential of different strains of H. pylori to promote gastric carcinogenesis.

High Mechanical Strength Double‐Network Hydrogel with Bacterial Cellulose

Abstract: Double-network (DN) hydrogels with high mechanical strength have been synthesized using the natural polymers bacterial cellulose (BC) and gelatin. As-prepared BC contains 90 % water that can easily be squeezed out, with no more recovery in its swelling property. Gelatin gel is brittle and is easily broken into fragments under a modest compression. In contrast, the fracture strength and elastic modulus of a BC–gelatin DN gel under compressive stress are on the order of megapascals, which are several orders of magnitude higher than those of gelatin gel, and almost equivalent to those of articular cartilage. A similar enhancement in the mechanical strength was also observed for the combination of BC with polysaccharides, such as sodium alginate, gellan gum, and ι-carrageenan.

COPD in Japan : the Nippon COPD Epidemiology study

Abstract: Objectives: Despite high smoking rates, few prevalence studies of COPD have been performed in Asia. The Nippon COPD Epidemiology (NICE) Study used spirometry to measure prevalence of airflow limitation in Japanese adults. Methodology: Clinical, spirometric, and risk factor exposure data were collected on 2343 subjects aged ≥ 40 years who were demographically similar to the Japanese population. Airflow limitation was defined according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria (FEV1/FVC < 70%). Results: Prevalence of airflow limitation was 10.9%. Based upon GOLD severity criteria, 56% of these cases were found to be mild, 38% moderate, 5% severe, and 1% very severe. Airflow limitation was significantly more prevalent in males than females (16.4% vs. 5.0%; P 70 years; P < 0.001). Of note, airflow limitation was also found in 5.8% of non-smokers and 4.6% of those younger than age 60 years. Only 9.4% of cases with airflow limitation reported a previous diagnosis of COPD. Conclusions: Prevalence of airflow limitation in Japan is higher than previously reported, suggesting a high degree of under-recognition of COPD. The high prevalence of smoking coupled with an aging population threatens to further increase the burden of COPD, highlighting the need for enhanced screening efforts and interventions of prevention and treatment.

The use of uniaxial accelerometry for the assessment of physical-activity-related energy expenditure: a validation study against whole-body indirect calorimetry.

Abstract: Assessing the total energy expenditure (TEE) and the levels of physical activity in free-living conditions with non-invasive techniques remains a challenge. The purpose of the present study was to investigate the accuracy of a new uniaxial accelerometer for assessing TEE and physical-activity-related energy expenditure (PAEE) over a 24 h period in a respiratory chamber, and to establish activity levels based on the accelerometry ranges corresponding to the operationally defined metabolic equivalent (MET) categories. In study 1, measurement of the 24 h energy expenditure of seventy-nine Japanese subjects (40 (SD 12) years old) was performed in a large respiratory chamber. During the measurements, the subjects wore a uniaxial accelerometer (Lifecorder; Suzuken Co. Ltd, Nagoya, Japan) on their belt. Two moderate walking exercises of 30 min each were performed on a horizontal treadmill. In study 2, ten male subjects walked at six different speeds and ran at three different speeds on a treadmill for 4 min, with the same accelerometer. O2 consumption was measured during the last minute of each stage and was expressed in MET. The measured TEE was 8447 (SD 1337) kJ/d. The accelerometer significantly underestimated TEE and PAEE (91·9 (SD 5·4) and 92·7 (SD 17·8) % chamber value respectively); however, there was a significant correlation between the two values (r 0·928 and 0·564 respectively; P, 0·001). There was a strong correlation between the activity levels and the measured MET while walking (r 2 0·93; P, 0·001). Although TEE and PAEE were systematically underestimated during the 24 h period, the accelerometer assessed energy expenditure well during both the exercise period and the non-structured activities. Individual calibration factors may help to improve the accuracy of TEE estimation, but the average calibration factor for the group is probably sufficient for epidemiological research. This method is also important for assessing the diurnal profile of physical activity.

Anatomic reconstruction of the anteromedial and posterolateral bundles of the anterior cruciate ligament using hamstring tendon grafts

Abstract: Purpose: To develop and evaluate an anatomic reconstruction procedure of the posterolateral and anteromedial bundles of the anterior cruciate ligament (ACL). Type of study: Anatomic study and case series. Methods: The femoral attachment of the anteromedial and posterolateral bundles of the ACL was anatomically analyzed with 5 cadaveric knees. Using another 3 cadaveric knees, anatomic reconstruction of the posterolateral and anteromedial bundles was performed with the transtibial technique, and tunnel positioning and graft function in a range of knee motion was observed. Based on this anatomic study, an anatomic reconstruction procedure of the anteromedial and posterolateral bundles was developed using hamstring tendon autografts. This procedure was carried out in 57 consecutive patients with an ACL-deficient knee. The patients were followed-up for a minimum of 24 months. Results: We developed the arthroscopically assisted anatomic reconstruction procedure of the posterolateral and anteromedial bundles, involving a new method of creating the tibial and femoral tunnels for the posterolateral bundle. To visualize the femoral attachment of the posterolateral bundle, the medial infrapatellar portal was more useful than the lateral portal. In clinical results, the side-to-side difference of anterior laxity averaged 1.0 mm with a standard deviation of 0.9. Conclusions: The anatomic reconstruction of the anteromedial and posterolateral bundles using hamstring tendon autografts is clinically practical in the treatment for the ACL-deficient knee. Level of evidence: Level IV.

The decline and fate of an iron-induced subarctic phytoplankton bloom

Abstract: Iron supply has a key role in stimulating phytoplankton blooms in high-nitrate low-chlorophyll oceanic waters. However, the fate of the carbon fixed by these blooms, and how efficiently it is exported into the ocean's interior, remains largely unknown. Here we report on the decline and fate of an iron-stimulated diatom bloom in the Gulf of Alaska. The bloom terminated on day 18, following the depletion of iron and then silicic acid, after which mixed-layer particulate organic carbon (POC) concentrations declined over six days. Increased particulate silica export via sinking diatoms was recorded in sediment traps at depths between 50 and 125 m from day 21, yet increased POC export was not evident until day 24. Only a small proportion of the mixed-layer POC was intercepted by the traps, with more than half of the mixed-layer POC deficit attributable to bacterial remineralization and mesozooplankton grazing. The depletion of silicic acid and the inefficient transfer of iron-increased POC below the permanent thermocline have major implications both for the biogeochemical interpretation of times of greater iron supply in the geological past, and also for proposed geo-engineering schemes to increase oceanic carbon sequestration.

Fish invasion restructures stream and forest food webs by interrupting reciprocal prey subsidies

Abstract: Habitat alteration and biotic invasions are the two leading causes of global environmental change and biodiversity loss. Recent innovative experiments have shown that habitat disturbance can have drastic effects that cascade to adjacent ecosystems by altering the flow of resource subsidies from donor systems. Likewise, exotic species in- vasions could alter subsidies and affect distant food webs, but very few studies have tested this experimentally. Here we report evidence from a large-scale field experiment in northern Japan that invasion of nonnative rainbow trout (Oncorhynchus mykiss) interrupted reciprocal flows of invertebrate prey that drove stream and adjacent riparian forest food webs. Rainbow trout usurped terrestrial prey that fell into the stream, causing native Dolly Varden charr (Salvelinus malma) to shift their foraging to insects that graze algae from the stream bottom. This indirectly increased algal biomass, but also decreased biomass of adult aquatic insects emerging from the stream to the forest. In turn, this led to a 65% reduction in the density of riparian-specialist spiders in the forest. Thus, species invasions can interrupt flows of resources between interconnected ecosystems and have effects that propagate across their boundaries, effects that may be difficult to anticipate without in-depth understanding of food web relationships.

Biased biological functions of horizontally transferred genes in prokaryotic genomes.

Abstract: Horizontal gene transfer is one of the main mechanisms contributing to microbial genome diversification. To clarify the overall picture of interspecific gene flow among prokaryotes, we developed a new method for detecting horizontally transferred genes and their possible donors by Bayesian inference with training models for nucleotide composition. Our method gives the average posterior probability (horizontal transfer index) for each gene sequence, with a low horizontal transfer index indicating recent horizontal transfer. We found that 14% of open reading frames in 116 prokaryotic complete genomes were subjected to recent horizontal transfer. Based on this data set, we quantitatively determined that the biological functions of horizontally transferred genes, except mobile element genes, are biased to three categories: cell surface, DNA binding and pathogenicity-related functions. Thus, the transferability of genes seems to depend heavily on their functions.

CD8+ tumor-infiltrating lymphocytes together with CD4+ tumor-infiltrating lymphocytes and dendritic cells improve the prognosis of patients with pancreatic adenocarcinoma.

Abstract: ObjectiveRecent studies have demonstrated the importance of tumor immunity for a cancer patient's prognosis. In some types of cancer, it has been shown through immunohistochemical analysis that the existence of CD8+ tumor-infiltrating lymphocytes (TILs) is a crucial factor in determining prognosis.

Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome

Abstract: Deficient activities of multiple steroidogenic enzymes have been reported without and with Antley-Bixler syndrome (ABS), but mutations of corresponding cytochrome P450 enzymes have not been found. We identified mutations in POR, encoding P450 oxidoreductase, the obligate electron donor for these enzymes, in a woman with amenorrhea and three children with ABS, even though knock-out of POR is embryonically lethal in mice. Mutations of POR also affect drug-metabolizing P450 enzymes, explaining the association of ABS with maternal fluconazole ingestion.

Self-assembly of a silica–surfactant nanocomposite in a porous alumina membrane

Abstract: A mesoporous membrane composed of nanochannels with a uniform diameter has a potential use for precise size-exclusive separation of molecules. Here, we report a novel method to form a hybrid membrane composed of silica-surfactant nanocomposite and a porous alumina membrane, by which size-selective transport of molecules across the membrane becomes possible. The nanocomposite formed inside each columnar alumina pore was an assembly of surfactant-templated silica-nanochannels with a channel diameter of 3.4 nm; the channel direction being predominantly oriented along the wall of the columnar alumina pore. Molecules could be transported across the membrane including the silica-surfactant nanocomposite with a capability of nanometre-order size-exclusive separation. Our proposed membrane system has a potential use not only for separation science, but also catalysis and chip technologies.

Climatology and Interannual Variability of Arctic Cyclone Activity: 1948–2002

Abstract: Arctic cyclone activity is investigated in the context of climate change and variability by using a modified automated cyclone identification and tracking algorithm, which differs from previously used algorithms by single counting each cyclone. The investigation extends earlier studies by lengthening the time period to 55 yr (1948– 2002) with a 6-hourly time resolution, by documenting the seasonality and the dominant temporal modes of variability of cyclone activity, and by diagnosing regional activity as quantified by the cyclone activity index (CAI). The CAI integrates information on cyclone intensity, frequency, and duration into a comprehensive index of cyclone activity. Arctic cyclone activity has increased during the second half of the twentieth century, while midlatitude activity generally decreased from 1960 to the early 1990s, in agreement with previous studies. New findings include the following. 1) The number and intensity of cyclones entering the Arctic from the midlatitudes has incre...

MASSUGU2 Encodes Aux/IAA19, an Auxin-Regulated Protein That Functions Together with the Transcriptional Activator NPH4/ARF7 to Regulate Differential Growth Responses of Hypocotyl and Formation of Lateral Roots in Arabidopsis thaliana

Abstract: We have isolated a dominant, auxin-insensitive mutant of Arabidopsis thaliana, massugu2 (msg2), that displays neither hypocotyl gravitropism nor phototropism, fails to maintain an apical hook as an etiolated seedling, and is defective in lateral root formation. Yet other aspects of growth and development of msg2 plants are almost normal. These characteristics of msg2 are similar to those of another auxin-insensitive mutant, non-phototropic hypocotyl4 (nph4), which is a loss-of-function mutant of AUXIN RESPONSE FACTOR7 (ARF7) (Harper et al., 2000). Map-based cloning of the MSG2 locus reveals that all four mutant alleles result in amino acid substitutions in the conserved domain II of an Auxin/Indole-3-Acetic Acid protein, IAA19. Interestingly, auxin inducibility of MSG2/IAA19 gene expression is reduced by 65% in nph4/arf7. Moreover, MSG2/IAA19 protein binds to the C-terminal domain of NPH4/ARF7 in a Saccharomyces cerevisiae (yeast) two-hybrid assay and to the whole latter protein in vitro by pull-down assay. These results suggest that MSG2/IAA19 and NPH4/ARF7 may constitute a negative feedback loop to regulate differential growth responses of hypocotyls and lateral root formation.

Bioinspired Molecular Design of Light‐Harvesting Multiporphyrin Arrays

Abstract: Recent progress in fundamental studies on multiporphyrin arrays has provided structural parameters for the molecular design of artificial light-harvesting antennae which mimic the wheel-like antenna complexes of photosynthetic purple bacteria. Covalent and noncovalent approaches have been employed for the construction of artificial light-harvesting multiporphyrin arrays. Such arrays are categorized into ring-shaped, windmill-shaped, star-shaped, and dendritic architectures. In particular, dendritic multiporphyrin arrays have been proven to be promising candidates for both providing a large absorption cross-section and enabling the vectorial transfer of energy over a long distance to a designated point. Such molecular and supramolecular systems are also expected to be potent components for molecular electronics and photonic devices.

Prediction of respiratory tumour motion for real-time image-guided radiotherapy

Abstract: Image guidance in radiotherapy and extracranial radiosurgery offers the potential for precise radiation dose delivery to a moving tumour. Recent work has demonstrated how to locate and track the position of a tumour in real-time using diagnostic x-ray imaging to find implanted radio-opaque markers. However, the delivery of a treatment plan through gating or beam tracking requires adequate consideration of treatment system latencies, including image acquisition, image processing, communication delays, control system processing, inductance within the motor, mechanical damping, etc. Furthermore, the imaging dose given over long radiosurgery procedures or multiple radiotherapy fractions may not be insignificant, which means that we must reduce the sampling rate of the imaging system. This study evaluates various predictive models for reducing tumour localization errors when a real-time tumour-tracking system targets a moving tumour at a slow imaging rate and with large system latencies. We consider 14 lung tumour cases where the peak-to-peak motion is greater than 8 mm, and compare the localization error using linear prediction, neural network prediction and Kalman filtering, against a system which uses no prediction. To evaluate prediction accuracy for use in beam tracking, we compute the root mean squared error between predicted and actual 3D motion. We found that by using prediction, root mean squared error is improved for all latencies and all imaging rates evaluated. To evaluate prediction accuracy for use in gated treatment, we present a new metric that compares a gating control signal based on predicted motion against the best possible gating control signal. We found that using prediction improves gated treatment accuracy for systems that have latencies of 200 ms or greater, and for systems that have imaging rates of 10 Hz or slower.

Ecophysiological Interaction between Nitrifying Bacteria and Heterotrophic Bacteria in Autotrophic Nitrifying Biofilms as Determined by Microautoradiography-Fluorescence In Situ Hybridization

Abstract: Ecophysiological interactions between the community members (i.e., nitrifiers and heterotrophic bacteria) in a carbon-limited autotrophic nitrifying biofilm fed only NH4+ as an energy source were investigated by using a full-cycle 16S rRNA approach followed by microautoradiography (MAR)-fluorescence in situ hybridization (FISH). Phylogenetic differentiation (identification) of heterotrophic bacteria was performed by 16S rRNA gene sequence analysis, and FISH probes were designed to determine the community structure and the spatial organization (i.e., niche differentiation) in the biofilm. FISH analysis showed that this autotrophic nitrifying biofilm was composed of 50% nitrifying bacteria (ammonia-oxidizing bacteria [AOB] and nitrite-oxidizing bacteria [NOB]) and 50% heterotrophic bacteria, and the distribution was as follows: members of the alpha subclass of the class Proteobacteria (α-Proteobacteria), 23%; γ-Proteobacteria, 13%; green nonsulfur bacteria (GNSB), 9%; Cytophaga-Flavobacterium-Bacteroides (CFB) division, 2%; and unidentified (organisms that could not be hybridized with any probe except EUB338), 3%. These results indicated that a pair of nitrifiers (AOB and NOB) supported a heterotrophic bacterium via production of soluble microbial products (SMP). MAR-FISH revealed that the heterotrophic bacterial community was composed of bacteria that were phylogenetically and metabolically diverse and to some extent metabolically redundant, which ensured the stability of the ecosystem as a biofilm. α- and γ-Proteobacteria dominated the utilization of [14C]acetic acid and 14C-amino acids in this biofilm. Despite their low abundance (ca. 2%) in the biofilm community, members of the CFB cluster accounted for the largest fraction (ca. 64%) of the bacterial community consuming N-acetyl-d-[1-14C]glucosamine (NAG). The GNSB accounted for 9% of the 14C-amino acid-consuming bacteria and 27% of the [14C]NAG-consuming bacteria but did not utilize [14C]acetic acid. Bacteria classified in the unidentified group accounted for 6% of the total heterotrophic bacteria and could utilize all organic substrates, including NAG. This showed that there was an efficient food web (carbon metabolism) in the autotrophic nitrifying biofilm community, which ensured maximum utilization of SMP produced by nitrifiers and prevented buildup of metabolites or waste materials of nitrifiers to significant levels.

Living Donor Liver Transplantation for Adult Patients With Hepatocellular Carcinoma: Experience in Japan

Abstract: Liver transplantation (LTx) is theoretically an ultimate cure for hepatocellular carcinoma (HCC), achieving total removal of cancerous lesions and underlying liver cirrhosis.1 Through most of the 1980s, however, results of LTx for HCC were discouraging, with high recurrence rates and patient survival of only 30% at 3 years.2 In the early 1990s, Iwatsuki et al3 and Bisumuth et al4 determined clinicopathologic risk factors responsible for recurrence, which led to the development of the Milan criteria by Mazzafero et al.5 According to these criteria, LTx for HCC was limited to patients with solitary tumors up to 5 cm in diameter or with no more than 3 nodules, each 3 cm or less in diameter. Patients with extrahepatic spread and/or macrovascular invasion were ineligible. When the Milan criteria were instituted, the recurrence rate fell to 8%, and tumor-free patient survival at 4 years was 83%. With worldwide adoption of these criteria, 5-year survival rates rose to between 60% and 80%.6–8 The severe disparity between the demand for transplants and the supply of organs from deceased donors (DD), however, has meant that many HCC patients who might benefit from transplantation either die before an organ becomes available or must drop off the waiting list as the result of tumor progression.9–11 The number of annual deaths by HCC is estimated at >20,000 in the United States and at >30,000 in Japan.12,13 Living donor liver transplantation (LDLTx), initially invented for pediatric recipients,14,15 has been used recently in many adults with satisfactory results.16–21 In Japan, where use of DD organs is rare (only 24 deceased donor liver transplantations [DDLTx] have been performed in the last 6 years), LDLTx has become a common practice in the treatment of HCC. Reported herein are the results of this approach in 316 adult cases nationwide.

Efficacy, safety, and pharmacokinetics of multiple administration of infliximab in Behçet's disease with refractory uveoretinitis.

Abstract: OBJECTIVE: Behcet's disease (BD) with uveoretinitis is a chronic refractory disease accompanied by ocular attacks. As the decrease in visual acuity due to ocular attack is seriously life-threatening, development of a new drug is anticipated. Since tumor necrosis factor-a (TNF-a) is involved in the symptoms of BD, particularly the activity of ocular symptoms, suppression of TNF-a might be effective in treating BD with uveoretinitis. We conducted a clinical trial of infliximab, an anti-TNF-a chimeric monoclonal antibody, in patients with BD. METHODS: In this open label trial, the efficacy, safety, and pharmacokinetics of repeated administration of infliximab were evaluated in 13 patients with BD accompanied by refractory uveoretinitis. Infliximab was administered 4 times at Weeks 0, 2, 6, and 10 at doses of either 5 or 10 mg/kg by intravenous drip infusion. Frequency of ocular attacks was used as the primary index for evaluation of efficacy, with visual acuity and extraocular symptoms as secondary indices. RESULTS: The mean numbers of ocular attacks, converted to frequency per 14 weeks, were 3.96 times for the 5 mg/kg group and 3.79 times for the 10 mg/kg group during the observation period. Following treatment with infliximab, they decreased to 0.98 times and 0.16 times, respectively. A serious adverse event, tuberculosis, was observed in one case in the 10 mg/kg group. Serum infliximab concentration increased with dosage. CONCLUSION: Administration of infliximab in patients with BD with refractory uveoretinitis suppressed the frequency of ocular attacks, and multiple administration was well tolerated, suggesting that infliximab is effective for this condition.

Molecular Cloud Origin for the Oxygen Isotope Heterogeneity in the Solar System

Abstract: Meteorites and their components have anomalous oxygen isotopic compositions characterized by large variations in 18O/16O and 17O/16O ratios. On the basis of recent observations of star-forming regions and models of accreting protoplanetary disks, we suggest that these variations may originate in a parent molecular cloud by ultraviolet photodissociation processes. Materials with anomalous isotopic compositions were then transported into the solar nebula by icy dust grains during the collapse of the cloud. The icy dust grains drifted toward the Sun in the disk, and their subsequent evaporation resulted in the 17O- and 18O-enrichment of the inner disk gas.

The APP intracellular domain forms nuclear multiprotein complexes and regulates the transcription of its own precursor

Abstract: The physiological functions of the beta-amyloid precursor protein (APP) may include nuclear signaling. To characterize the role of the APP adaptor proteins Fe65, Jip1b, X11alpha (MINT1) and the chromatin-associated protein Tip60, we analyzed their interactions by confocal microscopy and co-immunoprecipitations. AICD corresponding to S3-cleaved APP bound to Fe65 that transported it to nuclei and docked it to Tip60. These proteins formed AICD-Fe65-Tip60 (AFT) complexes that were concentrated in spherical nuclear spots. gamma-Secretase inhibitors prevented AFT-complex formation with AICD derived from full-length APP. The APP adaptor protein Jip1b also transported AICD to nuclei and docked it to Tip60, but AICD-Jip1b-Tip60 (AJT) complexes had different, speckle-like morphology. By contrast, X11alpha trapped AICD in the cytosol. Induced AICD expression identified the APP-effector genes APP, BACE, Tip60, GSK3beta and KAI1, but not the Notch-effector gene Hes1 as transcriptional targets. These data establish a role for APP in nuclear signaling, and they suggest that therapeutic strategies designed to modulate the cleavage of APP affect AICD-dependent signaling.