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1.  Distinctive Tooth-Extraction Socket Healing: Bisphosphonate Versus Parathyroid Hormone Therapy 
Journal of periodontology  2013;85(1):24-33.
Patients with osteoporosis who receive tooth extractions are typically on either oral bisphosphonate or parathyroid hormone (PTH) therapy. Currently, the consequence of these therapies on hard- and soft-tissue healing in the oral cavity is not clearly defined. The aim of this study is to determine the differences in the therapeutic effect on tooth-extraction wound healing between bisphosphonate and PTH therapies.
Maxillary second molars were extracted in Sprague Dawley rats (n = 30), and either bisphosphonate (zoledronate [Zol]), PTH, or saline (vehicle control [VC]) was administered for 10 days (n = 10 per group). Hard-tissue healing was evaluated by microcomputed tomography and histomorphometric analyses. Collagen, blood vessels, inflammatory cell infiltration, and cathepsin K expression were assessed in soft tissue using immunohistochemistry, quantitative polymerase chain reaction, and immunoblotting.
Both therapies significantly increased bone fill and suppressed vertical bone loss. However, considerably more devital bone was observed in the sockets of rats on Zol versus VC. Although Zol increased the numbers of blood vessels, the total blood vessel area in soft tissue was significantly smaller than in VC. PTH therapy increased osteoblastic bone formation and suppressed osteoclasts. PTH therapy promoted soft-tissue maturation by suppressing inflammation and stimulating collagen deposition.
Zoledronate therapy deters whereas PTH therapy promotes hard- and soft-tissue healing in the oral cavity, and both therapies prevent vertical bone loss.
PMCID: PMC4245052  PMID: 23688101
Parathyroid hormone; tooth extraction; wound healing; zoledronic acid
2.  Regulation of gustatory physiology and appetitive behavior by the circadian clock in Drosophila melanogaster 
Current biology : CB  2010;20(4):300-309.
Circadian regulation of chemosensory processes is common in animals, but little is known about how circadian clocks control chemosensory systems or the consequences of rhythms in chemosensory system function. Taste is a major chemosensory gate used to decide whether or not an animal will eat, and the main taste organ in Drosophila, the proboscis, harbors autonomous circadian oscillators. Here we examine gustatory physiology, tastant-evoked appetitive behavior, and food ingestion to understand clock-dependent regulation of the Drosophila gustatory system.
Here we report that single-unit responses from labellar gustatory receptor neurons (GRNs) to attractive and aversive tastants show diurnal and circadian rhythms in spike amplitude, frequency and duration across different classes of gustatory sensilla. Rhythms in electrophysiological responses parallel behavioral rhythms in proboscis extension reflex (PrER). Molecular oscillators in GRNs are necessary and sufficient for rhythms in gustatory responses, and drive rhythms in G protein coupled receptor kinase 2 (GPRK2) expression that mediate rhythms in taste-sensitivity. Eliminating clock function in certain GRNs increases feeding and locomotor activity, mimicking a starvation response.
Circadian clocks in GRNs control neuronal output and drive behavioral rhythms in taste responses that peak at a time of day when feeding is maximal in flies. Our results argue that oscillations in GPRK2 levels drive rhythms in gustatory physiology and behavior, and that GRN clocks repress feeding. The similarity in gustatory system organization and feeding behavior in flies and mammals, and diurnal changes in taste sensitivity in humans, suggest that our results are relevant to the situation in humans.
PMCID: PMC4234688  PMID: 20153192
3.  Binding of a Third Metal Ion by the Human Phosphatases PP2Cα and Wip1 is Required for Phosphatase Activity 
Biochemistry  2013;52(34):10.1021/bi4005649.
The PPM phosphatases require millimolar concentrations of Mg2+ or Mn2+ to activate phosphatase activity in vitro. The human phosphatases PP2Cα (PPM1A) and Wip1 (PPM1D) differ in their physiological function, substrate specificity, and apparent metal affinity. A crystallographic structure of PP2Cα shows only two metal ions in the active site. However, recent structural studies of several bacterial PP2C phosphatases have indicated three metal ions in the active site. Two residues that coordinate the third metal ion are highly conserved, suggesting that human PP2C phosphatases may also bind a third ion. Here, isothermal titration calorimetry analysis of Mg2+ binding to PP2Cα distinguished binding of two ions to high affinity sites from the binding of a third ion with a millimolar affinity, similar to the apparent metal affinity required for catalytic activity. Mutational analysis indicated that Asp239 and either Asp146 or Asp243 was required for low-affinity binding of Mg2+, but that both Asp146 and Asp239 were required for catalysis. Phosphatase activity assays in the presence of MgCl2, MnCl2, or mixtures of the two, demonstrate high phosphatase activity toward a phosphopeptide substrate when Mg2+ was bound to the low-affinity site, whether Mg2+ or Mn2+ ions were bound to the high affinity sites. Mutation of the corresponding putative third metal ion-coordinating residues of Wip1 affected catalytic activity similarly both in vitro and in human cells. These results suggest that phosphatase activity toward phosphopeptide substrates by PP2Cα and Wip1 requires the binding of a Mg2+ ion to the low-affinity site.
PMCID: PMC3824971  PMID: 23906386
4.  Genetic variants and mutations of PPM1D control the response to DNA damage 
Cell Cycle  2013;12(16):2656-2664.
The Wip1 phosphatase is an oncogene that is overexpressed in a variety of primary human cancers. We were interested in identifying genetic variants that could change Wip1 activity. We identified 3 missense SNPs of the human Wip1 phosphatase, L120F, P322Q, and I496V confer a dominant-negative phenotype. On the other hand, in primary human cancers, PPM1D mutations commonly result in a gain-of-function phenotype, leading us to identify a hot-spot truncating mutation at position 525. Surprisingly, we also found a significant number of loss-of-function mutations of PPM1D in primary human cancers, both in the phosphatase domain and in the C terminus. Thus, PPM1D has evolved to generate genetic variants with lower activity, potentially providing a better fitness for the organism through suppression of multiple diseases. In cancer, however, the situation is more complex, and the presence of both activating and inhibiting mutations requires further investigation to understand their contribution to tumorigenesis.
PMCID: PMC3865055  PMID: 23907125
Wip1; PPM1D; genetic variants; mutations; human cancer; ATM; Chk2
5.  Rab35, acting through ACAP2 switching off Arf6, negatively regulates oligodendrocyte differentiation and myelination 
Molecular Biology of the Cell  2014;25(9):1532-1542.
Oligodendrocyte precursor cells differentiate into oligodendrocytes to form myelin sheaths. Rab35/ACAP2 and cytohesin-2 antagonistically control oligodendrocyte differentiation and myelination through Arf6 on/off regulation, presenting a unique way of regulating oligodendrocyte differentiation and myelination by a small GTPase network.
Oligodendrocyte precursor cells differentiate to produce myelin sheaths that insulate axons to ensure fast propagation of action potentials. Many aspects of differentiation are regulated by multiple extracellular signals. However, their intracellular signalings remain elusive. We show that Rab35 and its effector, ACAP2, a GTPase-activating protein that switches off Arf6 activity, negatively regulate oligodendrocyte morphological differentiation. Knockdown of Rab35 or ACAP2 with their respective small interfering RNAs promotes differentiation. As differentiation initiates, the activities of Rab35 and ACAP2 are down-regulated. The activity of Arf6, in contrast, is up-regulated. Arf6 knockdown inhibits differentiation, indicating that Rab35 and ACAP2 negatively regulate differentiation by down-regulating Arf6. Importantly, as differentiation proceeds, the activity of cytohesin-2, a guanine nucleotide exchange factor that switches on Arf6 activity, is up-regulated. Pharmacological inhibition of cytohesin-2 inhibits differentiation, suggesting that cytohesin-2 promotes differentiation by activating Arf6. Furthermore, using oligodendrocyte-neuronal cocultures, we find that knockdown of Rab35 or ACAP2 promotes myelination, whereas inhibition of cytohesin-2 or knockdown of Arf6 inhibits myelination. Thus Rab35/ACAP2 and cytohesin-2 antagonistically control oligodendrocyte differentiation and myelination through Arf6 regulation, presenting a unique small GTPase on/off switching mechanism.
PMCID: PMC4004601  PMID: 24600047
6.  Differential frontal involvement in shifts of internal and perceptual attention 
Brain stimulation  2012;6(4):675-682.
Perceptual attention enhances the processing of items in the environment, whereas internal attention enhances processing of items encoded in visual working memory. In perceptual and internal attention cueing paradigms, cues indicate the to-be-probed item before (pre-cueing) or after (retro-cueing) the memory display, respectively. Pre- and retro- cues confer similar behavioral accuracy benefits (pre-: 14–19%, retro-: 11–17%) and neuroimaging data show that they activate overlapping frontoparietal networks (1). Yet reports of behavioral and neuroimaging differences suggest that pre- and retro-cueing differentially recruit frontal and parietal cortices (1).
This study examined whether perceptual and internal attention are equally disrupted by neurostimulation to frontal and parietal cortices. We hypothesized that neurostimulation applied to frontal cortex would disrupt internal attention to a greater extent than perceptual attention.
Cathodal transcranial direct current stimulation (tDCS) was applied to frontal or parietal cortices. After stimulation, participants completed a change detection task coupled with either pre- or retro- cues.
Cathodal tDCS across site (frontal, parietal) hindered performance. However, frontal tDCS had a greater negative impact on the retro-cued trials demonstrating greater frontal involvement during shifts of internal attention.
These results complement the neuroimaging data and provide further evidence suggesting that perceptual and internal attention are not identical processes. We conclude that although internal and perceptual attention are mediated by similar frontoparietal networks, the weight of contribution of these structures differs, with internal attention relying more heavily on the frontal cortex.
PMCID: PMC3608701  PMID: 23266133
Internal attention; perceptual attention; working memory
8.  Anatomical variations in termination of the uncal vein and its clinical implications in cavernous sinus dural arteriovenous fistulas 
Neuroradiology  2014;56(8):661-668.
The aim of the study was to investigate the variations in the uncal vein (UV) termination and its clinical implication in cavernous sinus dural arteriovenous fistulas (CSDAVFs).
Biplane cerebral angiography in 80 patients (160 sides) with normal cerebral venous return (normal group) was reviewed with special interest in the termination of the UV. Frequency and types of uncal venous drainage from CSDAVFs in consecutive 26 patients were also analyzed.
In the normal group, the UV was identified in 118 sides (74 %). The UV terminated into cavernous sinus (CS) in 41 sides (34 %), the superficial middle cerebral vein (SMCV) in 58 sides (48 %), the laterocavernous sinus (LCS) in 15 sides (13 %), and the paracavernous sinus (PCS) in 4 sides (3 %). Cerebral venous blood via the UV draining into the CS directly (n = 41) or through the SMCV and/or the LCS (n = 45) was observed in 86 sides (54 %). Uncal venous drainage from CSDAVFs was found in 13 patients (50 %). The CSDAVFs drained directly into the UV in two patients, drained via LCS into the UV in two patients, and drained through the SMCV into the UV in the remaining nine patients. All cases were successfully treated by transvenous embolization with special attention given to uncal venous drainage.
There are several variations in UV termination according to the embryological development of the primitive tentorial sinus and the deep telencephalic vein. Careful attention should be paid to uncal venous drainage for the treatment of CSDAVFs.
PMCID: PMC4125747  PMID: 24878594
Cerebral vein; Dural arteriovenous fistula; Cerebral angiography
9.  A Novel Protein, CHRONO, Functions as a Core Component of the Mammalian Circadian Clock 
PLoS Biology  2014;12(4):e1001839.
Two independent studies, one of them using a computational approach, identified CHRONO, a gene shown to modulate the activity of circadian transcription factors and alter circadian behavior in mice.
Circadian rhythms are controlled by a system of negative and positive genetic feedback loops composed of clock genes. Although many genes have been implicated in these feedback loops, it is unclear whether our current list of clock genes is exhaustive. We have recently identified Chrono as a robustly cycling transcript through genome-wide profiling of BMAL1 binding on the E-box. Here, we explore the role of Chrono in cellular timekeeping. Remarkably, endogenous CHRONO occupancy around E-boxes shows a circadian oscillation antiphasic to BMAL1. Overexpression of Chrono leads to suppression of BMAL1–CLOCK activity in a histone deacetylase (HDAC) –dependent manner. In vivo loss-of-function studies of Chrono including Avp neuron-specific knockout (KO) mice display a longer circadian period of locomotor activity. Chrono KO also alters the expression of core clock genes and impairs the response of the circadian clock to stress. CHRONO forms a complex with the glucocorticoid receptor and mediates glucocorticoid response. Our comprehensive study spotlights a previously unrecognized clock component of an unsuspected negative circadian feedback loop that is independent of another negative regulator, Cry2, and that integrates behavioral stress and epigenetic control for efficient metabolic integration of the clock.
Author Summary
The circadian clock has a fundamental role in regulating biological temporal rhythms in organisms, and it is tightly controlled by a molecular circuit consisting of positive and negative regulatory feedback loops. Although many of the clock genes comprising this circuit have been identified, there are still some critical components missing. Here, we characterize a circadian gene renamed Chrono (Gm129) and show that it functions as a transcriptional repressor of the negative feedback loop in the mammalian clock. Chrono binds to the regulatory region of clock genes and its occupancy oscillates in a circadian manner. Chrono knockout and Avp-neuron-specific knockout mice display longer circadian periods and altered expression of core clock genes. We show that Chrono-mediated repression involves the suppression of BMAL1–CLOCK activity via an epigenetic mechanism and that it regulates metabolic pathways triggered by behavioral stress. Our study suggests that Chrono functions as a clock repressor and reveals the molecular mechanisms underlying its function.
PMCID: PMC3988004  PMID: 24736997
10.  Induction of Colonic Regulatory T Cells by Indigenous Clostridium Species 
Science (New York, N.Y.)  2010;331(6015):337-341.
CD4+ T regulatory cells (Tregs), which express the Foxp3 transcription factor, play a critical role in the maintenance of immune homeostasis. Here, we show that in mice, Tregs were most abundant in the colonic mucosa. The spore-forming component of indigenous intestinal microbiota, particularly clusters IV and XIVa of the genus Clostridium, promoted Treg cell accumulation. Colonization of mice by a defined mix of Clostridium strains provided an environment rich in transforming growth factor–β and affected Foxp3+ Treg number and function in the colon. Oral inoculation of Clostridium during the early life of conventionally reared mice resulted in resistance to colitis and systemic immunoglobulin E responses in adult mice, suggesting a new therapeutic approach to autoimmunity and allergy.
PMCID: PMC3969237  PMID: 21205640
11.  Survivin-responsive conditionally replicating adenovirus kills rhabdomyosarcoma stem cells more efficiently than their progeny 
Effective methods for eradicating cancer stem cells (CSCs), which are highly tumorigenic and resistant to conventional therapies, are urgently needed. Our previous studies demonstrated that survivin-responsive conditionally replicating adenoviruses regulated with multiple factors (Surv.m-CRAs), which selectively replicate in and kill a broad range of cancer-cell types, are promising anticancer agents. Here we examined the therapeutic potentials of a Surv.m-CRA against rhabdomyosarcoma stem cells (RSCs), in order to assess its clinical effectiveness and usefulness.
Our previous study demonstrated that fibroblast growth factor receptor 3 (FGFR3) is a marker of RSCs. We examined survivin mRNA levels, survivin promoter activities, relative cytotoxicities of Surv.m-CRA in RSC-enriched (serum-minus) vs. RSC-exiguous (serum-plus) and FGFR3-positive vs. FGFR3-negative sorted rhabdomyosarcoma cells, and the in vivo therapeutic effects of Surv.m-CRAs on subcutaneous tumors in mice.
Both survivin mRNA levels and survivin promoter activities were significantly elevated under RSC-enriched relative to RSC-exiguous culture conditions, and the elevation was more prominent in FGFR3-positive vs. FGFR3-negative sorted cells than in RSC-enriched vs. RSC-exiguous conditions. Although Surv.m-CRA efficiently replicated and potently induced cell death in all populations of rhabdomyosarcoma cells, the cytotoxic effects were more pronounced in RSC-enriched or RSC-purified cells than in RSC-exiguous or progeny-purified cells. Injections of Surv.m-CRAs into tumor nodules generated by transplanting RSC-enriched cells induced significant death of rhabdomyosarcoma cells and regression of tumor nodules.
The unique therapeutic features of Surv.m-CRA, i.e., not only its therapeutic effectiveness against all cell populations but also its increased effectiveness against CSCs, suggest that Surv.m-CRA is promising anticancer agent.
PMCID: PMC3925355  PMID: 24467821
Cancer stem cells; Conditionally replicating adenovirus; Fibroblast growth factor receptor 3; Gene therapy; Oncolytic adenovirus; Promoter; Rhabdomyosarcoma; Survivin; Tumor-initiating cell; Virotherapy
12.  Laterality of cervical disc herniation 
European Spine Journal  2012;22(1):178-182.
Cervical disc herniation (CDH) is found more frequently at the lower cervical spine than at the upper or middle level. However, there is scarcity of data about the laterality of CDH. The aim of this study is to detect the laterality of CDH.
We retrospectively evaluated preoperative computed tomography myelograms and magnetic resonance images of 75 cases of CDH who underwent single level anterior cervical discectomy and fusion at C4–5, C5–6, or C6–7 levels from 2008 to 2010 in our institute. Statistical analyses were performed using the Chi-square test.
Eleven cases were found at C4–5 level, 42 cases at C5–6 level, and 22 cases at C6–7 level. At C4–5 level, CDH was recognized at the right side in 2 cases, at the left side in 2 cases, and at the center in 7 cases. At C5–6 level, CDH was found at the right side in 20 cases and at the left side in 22 cases. At C6–7 level, CDH was found at the right side in 3 cases and at the left side in 19 cases with significantly high frequency of left-sided CDH (p < 0.025).
In this study, it was revealed that the left-sided CDH was more frequent than the right-sided CDH at C6–7 level.
PMCID: PMC3540298  PMID: 23149494
Cervical disc herniation; C6–7 level; Handedness; Laterality
13.  Lung Cancer: Epidemiology, Etiology, and Prevention 
Clinics in chest medicine  2011;32(4):10.1016/j.ccm.2011.09.001.
PMCID: PMC3864624  PMID: 22054876
Lung cancer; Tobacco smoking; Epidemiology; Carcinogens
14.  Dietary fructose enhances the incidence of precancerous hepatocytes induced by administration of diethylnitrosamine in rat 
Nonalcoholic fatty liver disease (NAFLD) is a risk for hepatocellular carcinoma (HCC), but the association between a high-fructose diet and HCC is not fully understood. In this study, we investigated whether a high-fructose diet affects hepatocarcinogenesis induced by administration of diethylnitrosamine (DEN).
Seven-week-old male Sprague–Dawley rats were fed standard chow (controls), a high-fat diet (54% fat), or a high-fructose diet (66% fructose) for 8 weeks. All rats were given DEN at 50 μg/L in drinking water during the same period. Precancerous hepatocytes were detected by immunostaining of the placental form of glutathione-S-transferase (GST-P). The number of GST-P-positive hepatocytes was assessed in liver specimens.
Serum levels of total cholesterol were similar among the three groups, but serum triglyceride, fasting blood glucose, and insulin levels were higher in the high-fructose group compared to the high-fat group. In contrast, hepatic steatosis was more severe in the high-fat group compared with the high-fructose and control groups, but the incidence of GST-P-positive specimens was significantly higher in the high-fructose group compared to the other two groups. The average number of GST-P-positive hepatocytes in GST-P positive specimens in the high-fructose group was also higher than those in the other two groups. This high prevalence of GST-P-positive hepatocytes was accompanied by higher levels of 8-hydroxydeoxyguanosine in serum and liver tissue.
These results indicate that dietary fructose, rather than dietary fat, increases the incidence of precancerous hepatocytes induced by administration of DEN via insulin resistance and oxidative stress in rat. Thus, excessive fructose intake may be a potential risk factor for hepatocarcinogenesis.
PMCID: PMC4029300  PMID: 24321741
Diethylnitrosamine; Fructose; Hepatocarcinogenesis; Nonalcoholic steatohepatitis; Placental form of glutathione-S-transferase
15.  Induction of p53-Dependent p21 Limits Proliferative Activity of Rat Hepatocytes in the Presence of Hepatocyte Growth Factor 
PLoS ONE  2013;8(11):e78346.
Hepatocyte growth factor (HGF), a potent mitogen for hepatocytes, enhances hepatocyte function without stimulating proliferation, depending on the physiological conditions. p53, a transcription factor, suppresses the cell proliferation by expressing p21WAF1/CIP1 in various tissues.
To investigate the mechanism through which the hepatocytes maintain mitotically quiescent even in the presence of HGF.
We studied the relationship between p53 and p21 expression and the effect of p53-p21 axis on hepatocyte proliferation in primary cultured rat hepatocytes stimulated by HGF. Hepatic p21 levels are determined serially after partial hepatectomy or sham operation in rats.
DNA synthesis was markedly increased by HGF addition in rat hepatocytes cultured at low density but not at high density. Cellular p53 levels increased in the hepatocytes cultured at both the densities. p21 levels were increased and correlated with cellular p53 levels in hepatocytes cultured at high density but not at low density. When the activity of p53 was suppressed by a chemical inhibitor for p53, cellular p21 levels were reduced, and DNA synthesis was increased. Similarly, p21 antisense oligonucleotide increased the DNA synthesis. In rats after partial hepatectomy, transient elevation of hepatic p21 levels was observed. In contrast, in sham-operated rats, hepatic p21 levels were increased on sustained time scales.
p53-related induction of p21 may suppress hepatocyte proliferation in the presence of HGF in the setting that mitogenic activity of HGF is not elicitable.
PMCID: PMC3817248  PMID: 24223793
16.  The hospital educational environment and performance of residents in the General Medicine In-Training Examination: a multicenter study in Japan 
It is believed that the type of educational environment in teaching hospitals may affect the performance of medical knowledge base among residents, but this has not yet been proven.
We aimed to investigate the association between the hospital educational environment and the performance of the medical knowledge base among resident physicians in Japanese teaching hospitals.
To assess the knowledge base of medicine, we conducted the General Medicine InTraining Examination (GM-ITE) for second-year residents in the last month of their residency. The items of the exam were developed based on the outcomes designated by the Japanese Ministry of Health, Labor, and Welfare. The educational environment was evaluated using the Postgraduate Hospital Educational Environment Measure (PHEEM) score, which was assessed by a mailed survey 2 years prior to the exam. A mixed-effects linear regression model was employed for the analysis of variables associated with a higher score.
Twenty-one teaching hospitals participated in the study and a total of 206 residents (67 women) participated and completed the exam. There were no residents who declined to participate in the exam. The mean GM-ITE score was 58 (standard deviation 8.4). The mixed-effects linear regression analysis showed that a higher PHEEM score was associated with a higher GM-ITE score (P = 0.02). Having a department of general medicine, and hospital location in a provincial community (versus an urban setting), were also shown to have a significant relationship with the higher score (P = 0.03, and P = 0.02, respectively).
We found that the performance of the medical knowledge base of resident physicians was significantly associated with the educational environment of their hospitals. Improvement of the educational environment in teaching hospitals might be crucial for enhancing the performance of resident physicians in Japan.
PMCID: PMC3733879  PMID: 23930077
outcome-based education; postgraduate medical education; educational environment; general medicine; provincial hospital
17.  Factors affecting the bond strength of denture base and reline acrylic resins to base metal materials 
Journal of Applied Oral Science  2013;21(4):320-326.
The shear bond strengths of two hard chairside reline resin materials and an auto-polymerizing denture base resin material to cast Ti and a Co-Cr alloy treated using four conditioning methods were investigated.
Material and Methods
Disk specimens (diameter 10 mm and thickness 2.5 mm) were cast from pure Ti and Co-Cr alloy. The specimens were wet-ground to a final surface finish of 600 grit, air-dried, and treated with the following bonding systems: 1) air-abraded with 50-70-µm grain alumina (CON); 2) 1) + conditioned with a primer, including an acidic phosphonoacetate monomer (MHPA); 3) 1) + conditioned with a primer including a diphosphate monomer (MDP); 4) treated with a tribochemical system. Three resin materials were applied to each metal specimen. Shear bond strengths were determined before and after 10,000 thermocycles.
The strengths decreased after thermocycling for all combinations. Among the resin materials assessed, the denture base material showed significantly (p<0.05) greater shear bond strengths than the two reline materials, except for the CON condition. After 10,000 thermocycles, the bond strengths of two reline materials decreased to less than 10 MPa for both metals. The bond strengths of the denture base material with MDP were sufficient: 34.56 MPa for cast Ti and 38.30 for Co-Cr alloy.
Bonding of reline resin materials to metals assessed was clinically insufficient, regardless of metal type, surface treatment, and resin composition. For the relining of metal denture frameworks, a denture base material should be used.
PMCID: PMC3881887  PMID: 24037070
Chromium-cobalt alloys; Denture base; Denture rebasing; Shear strength; Titanium
18.  CFD and PIV Analysis of Hemodynamics in a Growing Intracranial Aneurysm 
Hemodynamics is thought to be a fundamental factor in the formation, progression and rupture of cerebral aneurysms. Understanding these mechanisms is important to improve their rupture risk assessment and treatment. In this study we analyze the blood flow field in a growing cerebral aneurysm using experimental particle image velocimetry (PIV) and computational fluid dynamics (CFD) techniques. Patient-specific models were constructed from longitudinal 3D computed tomography angiography (CTA) images acquired at one-year intervals. Physical silicone models were constructed from the CTA images using rapid prototyping techniques and pulsatile flow fields were measured with PIV. Corresponding CFD models were created and run under matching flow conditions. Both flow fields were aligned, interpolated, and compared qualitatively by inspection and quantitatively by defining similarity measures between the PIV and CFD vector fields. Results showed that both flow fields were in good agreement. Specifically, both techniques provided consistent representations of the main intra-aneurysmal flow structures, and their change during the geometric evolution of the aneurysm. Despite differences observed mainly in the near wall region and the inherent limitations of each technique, the information derived is consistent and can be used to study the role of hemodynamics in the natural history of intracranial aneurysms.
PMCID: PMC3338124  PMID: 22548127
Cerebral aneurysms; hemodynamics; growth; computational fluid dynamics; particle image velocimetry
19.  Radiological findings in acute Haemophilus influenzae pulmonary infection 
The British Journal of Radiology  2012;85(1010):121-126.
The aim of this study was to assess pulmonary thin-section CT findings in patients with acute Haemophilus influenzae pulmonary infection.
Thin-section CT scans obtained between January 2004 and March 2009 from 434 patients with acute H. influenzae pulmonary infection were retrospectively evaluated. Patients with concurrent infection diseases, including Streptococcus pneumoniae (n=76), Staphylococcus aureus (n=58) or multiple pathogens (n=89) were excluded from this study. Thus, our study group comprised 211 patients (106 men, 105 women; age range, 16–91 years, mean, 63.9 years). Underlying diseases included cardiac disease (n=35), pulmonary emphysema (n=23), post-operative status for malignancy (n=20) and bronchial asthma (n=15). Frequencies of CT patterns and disease distribution of parenchymal abnormalities, lymph node enlargement and pleural effusion were assessed by thin-section CT.
The CT findings in patients with H. influenzae pulmonary infection consisted mainly of ground-glass opacity (n=185), bronchial wall thickening (n=181), centrilobular nodules (n=137) and consolidation (n=112). These abnormalities were predominantly seen in the peripheral lung parenchyma (n=108). Pleural effusion was found in 22 patients. Two patients had mediastinal lymph node enlargement.
These findings in elderly patients with smoking habits or cardiac disease may be characteristic CT findings of H. influenzae pulmonary infection.
PMCID: PMC3473957  PMID: 21224303
20.  Spinal ventral epidural arteriovenous fistulas of the lumbar spine: angioarchitecture and endovascular treatment 
Neuroradiology  2013;55(3):327-336.
Spinal ventral epidural arteriovenous fistulas (EDAVFs) are relatively rare spinal vascular lesions. We investigated the angioarchitecture of spinal ventral EDAVFs and show the results of endovascular treatment.
We reviewed six consecutive patients (four males and two females; mean age, 67.3 years) with spinal ventral EDAVFs treated at our institutions from May 2011 to October 2012. All patients presented with progressive myelopathy. The findings of angiography, including 3D/2D reformatted images, treatments, and outcomes, were investigated. A literature review focused on the angioarchitecture and treatment of spinal ventral EDAVFs is also presented.
The EDAVFs were located in the ventral epidural space at the L1–L5 levels. All EDAVFs were supplied by the dorsal somatic branches from multiple segmental arteries. The ventral somatic branches and the radiculomeningeal arteries also supplied the AVFs in two patients. The AVFs drained via an epidural venous pouch into the perimedullary vein in four patients and into both the perimedullary vein and paravertebral veins in two patients. Four cases without paravertebral drainage were treated by transarterial embolization with diluted glue, and two cases with perimedullary and paravertebral drainages were treated by transvenous embolization alone or in combination with transarterial embolization. An angiographic cure was obtained in all patients. Clinical symptoms resolved in two patients, markedly improved in three patients, and minimally improved in one patient.
In our limited experience, spinal ventral EDAVFs were primarily fed by somatic branches. EDAVFs can be successfully treated by endovascular techniques selected based on the drainage type of the AVF.
PMCID: PMC3582814  PMID: 23306215
Spinal artery; Arteriovenous fistula; Embolization; Spinal vein; Arteriovenous malformation
21.  DNA Methyltransferase Inhibitor Zebularine Inhibits Human Hepatic Carcinoma Cells Proliferation and Induces Apoptosis 
PLoS ONE  2013;8(1):e54036.
Hepatocellular carcinoma is one of the most common cancers worldwide. During tumorigenesis, tumor suppressor and cancer-related genes are commonly silenced by aberrant DNA methylation in their promoter regions. Zebularine (1-(β-D-ribofuranosyl)-1,2-dihydropyrimidin-2-one) acts as an inhibitor of DNA methylation and exhibits chemical stability and minimal cytotoxicity both in vitro and in vivo. In this study, we explore the effect and possible mechanism of action of zebularine on hepatocellular carcinoma cell line HepG2. We demonstrate that zebularine exhibits antitumor activity on HepG2 cells by inhibiting cell proliferation and inducing apoptosis, however, it has little effect on DNA methylation in HepG2 cells. On the other hand, zebularine treatment downregulated CDK2 and the phosphorylation of retinoblastoma protein (Rb), and upregulated p21WAF/CIP1 and p53. We also found that zebularine treatment upregulated the phosphorylation of p44/42 mitogen-activated protein kinase (MAPK). These results suggest that the p44/42 MAPK pathway plays a role in zebularine-induced cell-cycle arrest by regulating the activity of p21WAF/CIP1 and Rb. Furthermore, although the proapoptotic protein Bax levels were not affected, the antiapoptotic protein Bcl-2 level was downregulated with zebularine treatment. In addition, the data in the present study indicate that inhibition of the double-stranded RNA-dependent protein kinase (PKR) is involved in inducing apoptosis with zebularine. These results suggest a novel mechanism of zebularine-induced cell growth arrest and apoptosis via a DNA methylation-independent pathway in hepatocellular carcinoma.
PMCID: PMC3540068  PMID: 23320119
22.  Thoroughness of Mediastinal Staging in Stage IIIA Non-Small Cell Lung Cancer 
Journal of Thoracic Oncology  2012;7(1):188-195.
Guidelines recommend that patients with clinical stage IIIA non-small cell lung cancer (NSCLC) undergo histologic confirmation of pathologic lymph nodes. Studies have suggested that invasive mediastinal staging is underutilized, though practice patterns have not been rigorously evaluated.
We used the Surveillance, Epidemiology, and End Results-Medicare database to identify patients with stage IIIA NSCLC diagnosed from 1998 through 2005. Invasive staging and use of positron emission tomography (PET) scanning were assessed using Medicare claims. Multivariable logistic regression was used to identify patient characteristics associated with use of invasive staging.
Of 7583 stage IIIA NSCLC patients, 1678 (22%) underwent invasive staging. Patients who received curative intent cancer treatment were more likely to undergo invasive staging than patients who did not receive cancer specific therapy (30% vs. 9.8%, adjusted odds ratio [OR} 3.31, 95% CI 2.78–3.95). The oldest patients (age 85–94) were less likely to receive invasive staging than the youngest ((age 67–69) (27.6 % vs. 11.9%, OR 0.46, 95% CI 0.34–0.61)). Sex, marital status, income and race were not associated with the use of the invasive staging. The use of invasive staging was stable throughout the study period, despite an increase in the use of PET scanning from less than 10% of patients prior to 2000 to almost 70% in 2005.
Nearly 80% of Medicare beneficiaries with stage IIIA NSCLC do not receive guideline adherent mediastinal staging; this failure cannot be entirely explained by patient factors or a reliance on PET imaging. Incentives to encourage use of invasive staging may improve care.
PMCID: PMC3253367  PMID: 22134069
Non-small cell lung cancer; mediastinal staging; mediastinoscopy
23.  Pulmonary thin-section CT findings in acute Moraxella catarrhalis pulmonary infection 
The British Journal of Radiology  2011;84(1008):1109-1114.
Moraxella catarrhalis is an important pathogen in the exacerbation of chronic obstructive pulmonary disease. The aim of this study was to assess the clinical and pulmonary thin-section CT findings in patients with acute M. catarrhalis pulmonary infection.
Thin-section CT scans obtained between January 2004 and March 2009 from 292 patients with acute M. catarrhalis pulmonary infection were retrospectively evaluated. Clinical and pulmonary CT findings in the patients were assessed. Patients with concurrent infection including Streptococcus pneumoniae (n = 72), Haemophilus influenzae (n = 61) or multiple pathogens were excluded from this study.
The study group comprised 109 patients (66 male, 43 female; age range 28–102 years; mean age 74.9 years). Among the 109 patients, 34 had community-acquired and 75 had nosocomial infections. Underlying diseases included pulmonary emphysema (n = 74), cardiovascular disease (n = 44) or malignant disease (n = 41). Abnormal findings were seen on CT scans in all patients and included ground-glass opacity (n = 99), bronchial wall thickening (n = 85) and centrilobular nodules (n = 79). These abnormalities were predominantly seen in the peripheral lung parenchyma (n = 99). Pleural effusion was found in eight patients. No patients had mediastinal and/or hilar lymph node enlargement.
M. catarrhalis pulmonary infection was observed in elderly patients, often in combination with pulmonary emphysema. CT manifestations of infection were mainly ground-glass opacity, bronchial wall thickening and centilobular nodules.
PMCID: PMC3473838  PMID: 21123308
24.  Optimization of a Cyclic Peptide Inhibitor of Ser/Thr Phosphatase PPM1D (Wip1)† 
Biochemistry  2011;50(21):4537-4549.
PPM1D (PP2Cδ or Wip1) was identified as a wild type p53-induced Ser/Thr phosphatase that accumulates after DNA damage and classified into the PP2C family. It dephosphorylates and inactivates several proteins critical for cellular stress responses, including p38 MAPK, p53, and ATM. Furthermore, PPM1D is amplified and/or overexpressed in a number of human cancers. Thus, inhibition of its activity could constitute an important new strategy for therapeutic intervention to halt the progression of several different cancers. Previously, we reported the development of a cyclic thioether peptide with low micromolar inhibitory activity towards PPM1D. Here, we describe important improvements in the inhibitory activity of this class of cyclic peptides and also present a binding model based upon the results. We found that specific interaction of an aromatic ring at the X1 position and negative charge at the X5 and X6 positions significantly increased the inhibitory activity of the cyclic peptide, with the optimized molecule having Ki = 110 nM. To the best of our knowledge, this represents the highest inhibitory activity reported for an inhibitor of PPM1D. We further developed an inhibitor selective for PPM1D over PPM1A with Ki = 2.9 μM. Optimization of the cyclic peptide and mutagenesis experiments suggest that a highly basic loop unique to PPM1D is related to substrate specificity. We propose a new model for the catalytic site of PPM1D and inhibition by the cyclic peptides that will be useful both for the subsequent design of PPM1D inhibitors and for identification of new substrates.
PMCID: PMC3508689  PMID: 21528848
25.  Severe bleeding tendency caused by a rare complication of excessive fibrinolysis with disseminated intravascular coagulation in a 51-year-old Japanese man with prostate cancer: a case report 
Disseminated intravascular coagulation causes thrombotic tendency leading to multiple organ failure and occurs in a wide variety of diseases including malignancy. Disseminated intravascular coagulation is a latent complication in people with prostate cancer.
Case presentation
A 51-year-old Japanese man with advanced castration-resistant prostate cancer was admitted to our hospital because of extensive purpura and severe anemia. Prolonged plasma coagulation time, hypofibrinogenemia and normal platelet count suggested that a decrease in fibrinogen induced a bleeding tendency causing purpura. However, elevated plasma levels of thrombin-antithrombin complex, fibrin and/or fibrinogen degradation products and D-dimers, with positive fibrin monomer test, manifested disseminated intravascular coagulation and subsequent fibrinolysis. Plasma levels of thrombin-antithrombin complex, fibrin and/or fibrinogen degradation products and D-dimers decreased after administration of low-molecular-weight heparin. However, low fibrinogen and α2-antiplasmin levels were not improved and plasmin-antiplasmin complex did not decrease, which revealed excessive fibrinolysis complicated with disseminated intravascular coagulation. We suspected that prostate cancer cell-derived urokinase-type plasminogen activator caused excessive fibrinolysis. Administration of tranexamic acid for fibrinogenolysis was added together with high-dose anti-androgen therapy (fosfestrol) for prostate cancer. Thereafter, prostate-specific antigen and plasmin-antiplasmin complex decreased, followed by normalized fibrinogen and α2-antiplasmin levels, and the patient eventually recovered from the bleeding tendency. Immunohistochemical staining of the biopsied prostate tissue exhibited that the prostate cancer cells produced tissue factor, the coagulation initiator, and urokinase-type plasminogen activator.
This patient with rare complications of disseminated intravascular coagulation and excessive fibrinolysis is a warning case of potential coagulation disorder onset in patients with prostate cancer. We propose that combined administration of tranexamic acid and low-molecular-weight heparin together with high-dose anti-androgen therapy is a useful therapeutic option for patients with this complicated coagulation disorder.
PMCID: PMC3514400  PMID: 23130841
Castration-resistant prostate cancer; Disseminated intravascular coagulation; Excessive fibrinolysis; Low-molecular-weight heparin; Tranexamic acid

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