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1.  Embryonic Lethality of Molecular Chaperone Hsp47 Knockout Mice Is Associated with Defects in Collagen Biosynthesis 
The Journal of Cell Biology  2000;150(6):1499-1506.
Triple helix formation of procollagen after the assembly of three α-chains at the C-propeptide is a prerequisite for refined structures such as fibers and meshworks. Hsp47 is an ER-resident stress inducible glycoprotein that specifically and transiently binds to newly synthesized procollagens. However, the real function of Hsp47 in collagen biosynthesis has not been elucidated in vitro or in vivo. Here, we describe the establishment of Hsp47 knockout mice that are severely deficient in the mature, propeptide-processed form of α1(I) collagen and fibril structures in mesenchymal tissues. The molecular form of type IV collagen was also affected, and basement membranes were discontinuously disrupted in the homozygotes. The homozygous mice did not survive beyond 11.5 days postcoitus (dpc), and displayed abnormally orientated epithelial tissues and ruptured blood vessels. When triple helix formation of type I collagen secreted from cultured cells was monitored by protease digestion, the collagens of Hsp47+/+ and Hsp47+/− cells were resistant, but those of Hsp47−/− cells were sensitive. These results indicate for the first time that type I collagen is unable to form a rigid triple-helical structure without the assistance of molecular chaperone Hsp47, and that mice require Hsp47 for normal development.
PMCID: PMC2150697  PMID: 10995453
gene targeting; extracellular matrix; collagen fibril; basement membrane; type I collagen
2.  Mechanism of impaired glucose-potentiated insulin secretion in diabetic 90% pancreatectomy rats. Study using glucagonlike peptide-1 (7-37). 
Journal of Clinical Investigation  1996;97(1):180-186.
Chronic hyperglycemia causes a near-total disappearance of glucose-induced insulin secretion. To determine if glucose potentiation of nonglucose secretagogues is impaired, insulin responses to 10(-9) M glucagonlike peptide-1 (GLP-1) (7-37) were measured at 2.8, 8.3, and 16.7 mM glucose with the in vitro perfused pancreas in rats 4-6 wk after 90% pancreatectomy (Px) and sham-operated controls. In the controls, insulin output to GLP-1 was > 100-fold greater at 16.7 mM glucose versus 2.8 mM glucose. In contrast, the increase was less than threefold in Px, reaching an insulin response at 16.7 mM glucose that was 10 +/- 2% of the controls, well below the predicted 35-40% fractional beta-cell mass in these rats. Px and control rats then underwent a 40-h fast followed by pancreas perfusion using a protocol of 20 min at 16.7 mM glucose followed by 15 min at 16.7 mM glucose/10(-9) M GLP-1. In control rats, fasting suppressed insulin release to high glucose (by 90%) and to GLP-1 (by 60%) without changing the pancreatic insulin content. In contrast, in Px the insulin response to GLP-1 tripled in association with a threefold increase of the insulin content, both now being twice normal when stratified for the fractional beta-cell mass. The mechanism of the increased pancreas insulin content was investigated by assessing islet glucose metabolism and proinsulin biosynthesis. In controls with fasting, both fell 30-50%. In Px, the degree of suppression with fasting was similar, but the attained levels both exceeded those of the controls because of higher baseline (nonfasted) values. In summary, chronic hyperglycemia is associated with a fasting-induced paradoxical increase in glucose-potentiated insulin secretion. In Px rats, the mechanism is an increase in the beta-cell insulin stores, which suggests a causative role for a lowered beta-cell insulin content in the impaired glucose-potentiation of insulin secretion.
PMCID: PMC507077  PMID: 8550831
3.  Eyebrow Reconstruction Using a Composite Skin Graft from Sideburns 
Supplemental Digital Content is available in the text.
Wide resection of malignant skin tumors in the upper orbital region often results in soft-tissue defects involving the eyebrow. We used composite skin grafts from the area around the sideburns for 1-stage reconstruction of skin and eyebrow defects. The results were aesthetically satisfying because the hair and shape of these regions were similar to those of the original eyebrow, and donor-site closure was easy with inconspicuous scar. The survival of full-thickness skin graft area of composite grafts from sideburn facilitates revascularization of thicker hair follicles in the graft and allows safe, natural eyebrow reconstruction.
PMCID: PMC4323394
4.  Prevalence of human cytomegalovirus, polyomaviruses, and oncogenic viruses in glioblastoma among Japanese subjects 
The association between human cytomegalovirus (HCMV) and glioblastoma multiforme (GBM) is becoming a new concept. However, information on the geographic variability of HCMV prevalence in GBM remains scarce. Moreover, the potential roles of various viruses, such as polyomaviruses and oncogenic viruses, in gliomagenesis remain unclear. Our aim was to investigate the prevalence of HCMV in GBM among Japanese patients. Furthermore, this was the first study that evaluated infection with four new human polyomaviruses in GBMs. This study also provided the first data on the detection of human papillomavirus (HPV) in GBM in the Eastern world.
We measured the number of various viral genomes in GBM samples from 39 Japanese patients using real-time quantitative PCR. The tested viruses included HCMV, Merkel cell polyomavirus, human polyomavirus (HPyV) 6, HPyV7, HPyV9, Epstein–Barr virus, human herpesvirus 8, and HPV. Our quantitative PCR analysis led to the detection of eight copies of the HCMV DNA mixed with DNA extracted from 104 HCMV-negative cells. The presence of HCMV and HPV genomes was also assessed by nested PCR. Immunohistochemical study was also carried out to detect HPV-derived protein in GBM tissues.
The viral DNAs were not detectable, with the exception of HPV, which was present in eight out of 39 (21%) GBMs. All HPV-positive cases harbored high-risk-type HPV (HPV16 and HPV18). Moreover, the HPV major capsid protein was detected in GBM tumor cells.
In contrast with previous reports from Caucasian patients, we did not obtain direct evidence in support of the association between HCMV and GBM. However, high-risk-type HPV infection may play a potential etiological role in gliomagenesis in a subset of patients. These findings should prompt further worldwide epidemiological studies aimed at defining the pathogenicity of virus-associated GBM.
PMCID: PMC4328287
Oncogenic viruses; HCMV; HPV; Polyomaviruses; Glioblastoma; Epidemiology
5.  A randomized controlled trial of endoscopic steroid injection for prophylaxis of esophageal stenoses after extensive endoscopic submucosal dissection 
BMC Gastroenterology  2015;15:1.
Esophageal stenosis following endoscopic submucosal dissection (ESD) is a serious adverse event that makes subsequent management more difficult.
This parallel, randomized, controlled, open-label study was designed to examine whether local steroid injection is an effective prophylactic treatment for esophageal stenoses following extensive ESD. This single center trial was conducted at the Keiyukai Hospital, a tertiary care center for gastrointestinal disease in Japan [University Hospital Medical Network Clinical Trial Registry (UMIN-CTR) on 15 September 2011 (UMIN000006327)]. Thirty-two patients with mucosal defects involving ≥75% of the esophageal circumference were randomized to receive a single dose of triamcinolone acetonide injections (n = 16) or be treated conventionally (n = 16). The primary outcome was the frequency of stricture requiring endoscopic dilatation; the surrogate primary endpoint was the number of dilatation sessions needed. Secondary outcomes included adverse event rates, the minimum diameter of the stenotic area and the duration of the course of dilatation treatments.
The frequency of stricture was not significantly different between the groups because of insufficient statistical power, but the number of dilatation sessions required was significantly less in the steroid group (6.1 sessions [95% confidence interval, CI 2.8–9.4] versus 12.5 [95% CI 7.1–17.9] sessions in the control group; P = 0.04). The perforation rate was similar in both groups. The minimum diameter of stenotic lumens was significantly greater in the treatment group than controls (11.0 mm versus 7.1 mm, respectively; P = 0.01). The perforation rate was not significantly different between the groups (1.0% versus 0.5% in the treatment and control group, respectively). Steroid injection was effective in cases of mucosal defects encompassing the entire esophageal circumference.
Prophylactic endoscopic steroid injection appears to be a safe means of relieving the severity of esophageal stenoses following extensive ESD.
PMCID: PMC4308850  PMID: 25609176
Esophageal stenosis; Steroid; Local injection; Endoscopic submucosal dissection (ESD); Early squamous cell carcinoma of esophagus
6.  Randomised phase II study comparing dose-escalated weekly paclitaxel vs standard-dose weekly paclitaxel for patients with previously treated advanced gastric cancer 
British Journal of Cancer  2013;110(2):271-277.
This randomised phase II trial compared dose-escalated weekly paclitaxel (wPTX) vs standard-dose wPTX for patients with previously treated advanced gastric cancer (AGC).
Ninety patients were randomised to a standard dose of wPTX (80 mg m−2) or an escalated dose of wPTX (80–120 mg m−2) to assess the superiority of overall survival (OS) with a one-sided alpha error of 0.3 and a power of 0.8.
The median OS showed a trend towards longer survival in the dose-escalated arm (11.8 vs 9.6 months; hazard ratio (HR), 0.75; one-sided P=0.12), although it was statistically not significant. The median progression-free survival (PFS) was significantly longer in the dose-escalated arm (4.3 vs 2.5 months, HR, 0.55; P=0.017). Objective response rate was 30.3% with dose escalation and 17.1% with standard dose (P=0.2). The frequency of all grades of neutropenia was significantly higher with dose escalation (88.7% vs 60.0%, P=0.002); however, no significant difference was observed in the proportion of patients experiencing grade 3 or more (40.9% vs 31.1%, P=0.34).
Dose-escalated wPTX in patients with pretreated AGC met our predefined threshold of primary end point, OS (P<0.3); however, it did not show a significantly longer OS. Progression-free survival was significantly better with dose escalation.
PMCID: PMC3899763  PMID: 24281004
gastric cancer; chemotherapy; paclitaxel; neutropenia
8.  Medial Frontal White and Gray Matter Contributions to General Intelligence 
PLoS ONE  2014;9(12):e112691.
The medial orbitofrontal cortex (mOFC) and rostral anterior cingulate cortex (rACC) are part of a wider neural network that plays an important role in general intelligence and executive function. We used structural brain imaging to quantify magnetic resonance gray matter volume and diffusion tensor white matter integrity of the mOFC-rACC network in 26 healthy participants who also completed neuropsychological tests of intellectual abilities and executive function. Stochastic tractography, the most effective Diffusion Tensor Imaging method for examining white matter connections between adjacent gray matter regions, was employed to assess the integrity of mOFC-rACC pathways. Fractional anisotropy (FA), which reflects the integrity of white matter connections, was calculated. Results indicated that higher intelligence correlated with greater gray matter volumes for both mOFC and rACC, as well as with increased FA for left posterior mOFC-rACC connectivity. Hierarchical regression analyses revealed that DTI-derived FA of left posterior mOFC-rACC uniquely accounted for 29%–34% of the variance in IQ, in comparison to 11%–16% uniquely explained by gray matter volume of the left rACC. Together, left rACC gray matter volume and white matter connectivity between left posterior mOFC and rACC accounted for up to 50% of the variance in general intelligence. This study is to our knowledge the first to examine white matter connectivity between OFC and ACC, two gray matter regions of interests that are very close in physical proximity, and underscores the important independent contributions of variations in rACC gray matter volume and mOFC-rACC white matter connectivity to individual differences in general intelligence.
PMCID: PMC4281236  PMID: 25551572
9.  Clinical neurophysiological assessment of sepsis-associated brain dysfunction: a systematic review 
Critical Care  2014;18(6):674.
Several studies have reported the presence of electroencephalography (EEG) abnormalities or altered evoked potentials (EPs) during sepsis. However, the role of these tests in the diagnosis and prognostic assessment of sepsis-associated encephalopathy remains unclear.
We performed a systematic search for studies evaluating EEG and/or EPs in adult (≥18 years) patients with sepsis-associated encephalopathy. The following outcomes were extracted: a) incidence of EEG/EP abnormalities; b) diagnosis of sepsis-associated delirium or encephalopathy with EEG/EP; c) outcome.
Among 1976 citations, 17 articles met the inclusion criteria. The incidence of EEG abnormalities during sepsis ranged from 12% to 100% for background abnormality and 6% to 12% for presence of triphasic waves. Two studies found that epileptiform discharges and electrographic seizures were more common in critically ill patients with than without sepsis. In one study, EEG background abnormalities were related to the presence and the severity of encephalopathy. Background slowing or suppression and the presence of triphasic waves were also associated with higher mortality. A few studies demonstrated that quantitative EEG analysis and EP could show significant differences in patients with sepsis compared to controls but their association with encephalopathy and outcome was not evaluated.
Abnormalities in EEG and EPs are present in the majority of septic patients. There is some evidence to support EEG use in the detection and prognostication of sepsis-associated encephalopathy, but further clinical investigation is needed to confirm this suggestion.
PMCID: PMC4277650  PMID: 25482125
10.  Draft Genome Sequence of Marine Flavobacterium Jejuia pallidilutea Strain 11shimoA1 and Pigmentation Mutants 
Genome Announcements  2014;2(6):e01236-14.
Here, we present the draft genome sequence of a novel carotenoid 2′-isopentenylsaproxanthin producer, Jejuia pallidilutea strain 11shimoA1, isolated from the surface of seaweed in Japan, and the ethyl methanesulfonate-induced pigmentation mutants. This genomic information will help to not only elucidate the 2′-isopentenylsaproxanthin biosynthetic pathway but also understand the evolution of flavobacteria.
PMCID: PMC4256183  PMID: 25477402
11.  Bacterial Symbionts of a Devastating Coffee Plant Pest, the Stinkbug Antestiopsis thunbergii (Hemiptera: Pentatomidae) 
Applied and Environmental Microbiology  2014;80(12):3769-3775.
Stinkbugs of the genus Antestiopsis, so-called antestia bugs or variegated coffee bugs, are notorious pests of coffee plants in Africa. We investigated the symbiotic bacteria associated with Antestiopsis thunbergii, a major coffee plant pest in Rwanda. PCR, cloning, sequencing, and phylogenetic analysis of bacterial genes identified four distinct bacterial lineages associated with A. thunbergii: a gammaproteobacterial gut symbiont and symbionts representing the genera Sodalis, Spiroplasma, and Rickettsia. In situ hybridization showed that the gut symbiont densely occupied the lumen of midgut crypts, whereas the Sodalis symbiont, the Spiroplasma symbiont, and the Rickettsia symbiont sparsely and sporadically infected various cells and tissues. Diagnostic PCR survey of 154 A. thunbergii individuals collected at 8 localities in Rwanda revealed high infection frequencies (100% for the gut symbiont, 51.3% for the Sodalis symbiont, 52.6% for the Spiroplasma symbiont, and 24.0% for the Rickettsia symbiont). These results suggest that the gut symbiont is the primary symbiotic associate of obligate nature for A. thunbergii, whereas the Sodalis symbiont, the Spiroplasma symbiont, and the Rickettsia symbiont are the secondary symbiotic associates of facultative nature. We observed high coinfection frequencies, i.e., 7.8% of individuals with quadruple infection with all the symbionts, 32.5% with triple infections with the gut symbiont and two of the secondary symbionts, and 39.6% with double infections with the gut symbiont and any of the three secondary symbionts, which were statistically not different from the expected coinfection frequencies and probably reflected random associations. The knowledge of symbiotic microbiota in A. thunbergii will provide useful background information for controlling this devastating coffee plant pest.
PMCID: PMC4054137  PMID: 24727277
12.  Net uptake of atmospheric CO2 by coastal submerged aquatic vegetation 
Global Change Biology  2014;20(6):1873-1884.
‘Blue Carbon’, which is carbon captured by marine living organisms, has recently been highlighted as a new option for climate change mitigation initiatives. In particular, coastal ecosystems have been recognized as significant carbon stocks because of their high burial rates and long-term sequestration of carbon. However, the direct contribution of Blue Carbon to the uptake of atmospheric CO2 through air-sea gas exchange remains unclear. We performed in situ measurements of carbon flows, including air-sea CO2 fluxes, dissolved inorganic carbon changes, net ecosystem production, and carbon burial rates in the boreal (Furen), temperate (Kurihama), and subtropical (Fukido) seagrass meadows of Japan from 2010 to 2013. In particular, the air-sea CO2 flux was measured using three methods: the bulk formula method, the floating chamber method, and the eddy covariance method. Our empirical results show that submerged autotrophic vegetation in shallow coastal waters can be functionally a sink for atmospheric CO2. This finding is contrary to the conventional perception that most near-shore ecosystems are sources of atmospheric CO2. The key factor determining whether or not coastal ecosystems directly decrease the concentration of atmospheric CO2 may be net ecosystem production. This study thus identifies a new ecosystem function of coastal vegetated systems; they are direct sinks of atmospheric CO2.
PMCID: PMC4237463  PMID: 24623530
air–water CO2 flux; blue carbon; carbon cycles; climate change; net ecosystem production; seagrasses
13.  Draft Genome Sequences of Marine Flavobacterium Nonlabens Strains NR17, NR24, NR27, NR32, NR33, and Ara13 
Genome Announcements  2014;2(6):e01165-14.
Here, we present the draft genome sequences of six carotenoid producers affiliated with Nonlabens spp. isolated from marine environments in both the northern and southern parts of Japan. The genomic information will help to elucidate the function and evolution of carotenoid synthetic gene clusters not only in the genus Nonlabens but also in the family Flavobacteriaceae.
PMCID: PMC4241665  PMID: 25395639
14.  Draft Genome Sequences of Marine Flavobacterium Algibacter lectus Strains SS8 and NR4 
Genome Announcements  2014;2(6):e01168-14.
Here, we present the draft genome sequences of a zeaxanthin-producing flavobacterium, Algibacter lectus strains SS8 and NR4, isolated from coastal sediment and rock surfaces in Hakodate, Japan, respectively. This genomic information represents the first Algibacter genome sequences, which will help us to elucidate the biology and evolution of Flavobacteriaceae bacteria.
PMCID: PMC4241666  PMID: 25395640
15.  Breast Reconstruction following Breast-conserving Surgery with a Subcutaneous Tissue Expander and Latissimus Dorsi Flap 
Corrective surgery following breast-conserving surgery is generally challenging due to severe fibrosis induced by postoperative radiotherapy. Although use of the latissimus dorsi myocutaneous flap offers a safe and reliable option, exposure of the skin paddle to the skin surface is often inevitable to achieve correction of nipple-areola complex malposition, leaving conspicuous, patchwork-like scars on the breast. In this report, we describe a 2-stage procedure using a subcutaneous tissue expander and the latissimus dorsi myocutaneous flap for the correction of both nipple-areola complex malposition and breast volume without skin paddle exposure. Although careful observation is necessary during skin expansion, this technique could offer an alternative option for patients undergoing corrective surgery following breast-conserving surgery.
PMCID: PMC4236376  PMID: 25426348
16.  Whole-Genome Analysis of Herbicide-Tolerant Mutant Rice Generated by Agrobacterium-Mediated Gene Targeting 
Plant and Cell Physiology  2014;56(1):116-125.
Gene targeting (GT) is a technique used to modify endogenous genes in target genomes precisely via homologous recombination (HR). Although GT plants are produced using genetic transformation techniques, if the difference between the endogenous and the modified gene is limited to point mutations, GT crops can be considered equivalent to non-genetically modified mutant crops generated by conventional mutagenesis techniques. However, it is difficult to guarantee the non-incorporation of DNA fragments from Agrobacterium in GT plants created by Agrobacterium-mediated GT despite screening with conventional Southern blot and/or PCR techniques. Here, we report a comprehensive analysis of herbicide-tolerant rice plants generated by inducing point mutations in the rice ALS gene via Agrobacterium-mediated GT. We performed genome comparative genomic hybridization (CGH) array analysis and whole-genome sequencing to evaluate the molecular composition of GT rice plants. Thus far, no integration of Agrobacterium-derived DNA fragments has been detected in GT rice plants. However, >1,000 single nucleotide polymorphisms (SNPs) and insertion/deletion (InDels) were found in GT plants. Among these mutations, 20–100 variants might have some effect on expression levels and/or protein function. Information about additive mutations should be useful in clearing out unwanted mutations by backcrossing.
PMCID: PMC4301741  PMID: 25378689
Acetolactate synthase; Gene targeting; Herbicide tolerance; Rice
17.  Factors predicting adverse events associated with pregabalin administered for neuropathic pain relief 
Pregabalin is an anticonvulsant drug that has been demonstrated to be effective in the treatment of neuropathic pain; however, data have indicated that the use of this drug is associated with adverse events, the frequency of which may vary according to the indication for which it is used. This retrospective study included 208 patients with neuropathic pain treated with pregabalin whose medical records were analyzed to identify factors associated with the occurrence of adverse events.
Pregabalin administration is occasionally abandoned due to adverse events such as somnolence, dizziness, unsteadiness, weight gain and edema. However, the exact causes of these differences in adverse events associated with pregabalin have not been elucidated.
To identify factors predicting adverse events associated with pregabalin administered for neuropathic pain.
The present study was a retrospective analysis involving 208 patients with neuropathic pain who had been treated with pregabalin in the pain clinic at the authors’ hospital between July 2010 and September 2011. Variables were extracted from the clinical records for regression analysis of factors related to the occurrence of adverse events associated with pregabalin administration. Multivariate logistic regression analysis was used to examine the relationship between various predictive factors and the adverse events.
Predictive factors were: duration of therapy (OR 1.684 [95% CI 1.179 to 2.406]; P=0.0042) for somnolence; nonsteroidal anti-inflammatory drugs (OR 0.132 [95% CI 0.030 to 0.578]; P=0.0072), age (OR 3.137 [95% CI 1.220 to 8.066]; P=0.0177) and maintenance dose (OR 0.437 [95% CI 0.217 to 0.880]; P=0.0205) for unsteadiness; serum creatinine (OR 6.439 [95% CI 1.541 to 26.902]; P=0.0107) for body weight gain; and neurotropin (OR 8.538 [95% CI 1.159 to 62.901]; P=0.0353) and serum creatinine (OR 6.912 [95% CI 1.118 to 42.726]; P=0.0375) for edema.
The results of the present study indicate that care is warranted regarding long durations of therapy for somnolence, advanced age rather than dose-dependent adverse events for unsteadiness, elevated serum creatinine level for weight gain, and elevated serum creatinine level and combination use of neurotropin for edema. The safety of the combined use of pregabalin and nonsteroidal anti-inflammatory drugs were also suggested.
PMCID: PMC4273715  PMID: 24945288
Adverse events; Body weight gain; Neuropathic pain; Pregabalin; Somnolence; Unsteadiness
18.  A novel approach to pseudopodia proteomics: excimer laser etching, two-dimensional difference gel electrophoresis, and confocal imaging 
Protocol exchange  2014;2014:2014.007.
Pseudopodia are actin-rich ventral cellular protrusions shown to facilitate the migration and metastasis of tumor cells. Here, we present a novel approach to perform pseudopodia proteomics. Tumor cells growing on porous membranes extend pseudopodia into the membrane pores. In our method, cell bodies are removed by horizontal ablation at the basal cell surface with the excimer laser while pseudopodia are left in the membrane pores. For protein expression profiling, whole cell and pseudopodia proteins are extracted with a lysis buffer, labeled with highly sensitive fluorescent dyes, and separated by two-dimensional gel electrophoresis. Proteins with unique expression patterns in pseudopodia are identified by mass spectrometry. The effects of the identified proteins on pseudopodia formation are evaluated by measuring the pseudopodia length in cancer cells with genetically modified expression of target proteins using confocal imaging. This protocol allows global identification of pseudopodia proteins and evaluation of their functional significance in pseudopodia formation within one month.
PMCID: PMC4192725  PMID: 25309719
pseudopodia; proteomics; excimer laser ablation; two-dimensional difference gel electrophoresis; confocal imaging
19.  Cerebral venous sinus thrombosis concomitant with leptomeningeal carcinomatosis, in a patient with epidermal growth factor receptor-mutated lung cancer 
Oncology Letters  2014;8(6):2489-2492.
A 64-year-old woman presented with dizziness, after two weeks of experiencing symptoms. Chest computed tomography revealed a peripheral nodule in her left upper lobe, and brain magnetic resonance imaging (MRI) demonstrated the presence of multiple brain masses. The patient underwent whole-brain radiotherapy based on a tentative diagnosis of lung cancer with multiple brain metastases. The diagnosis was confirmed by endobronchial biopsy as T4N3M1b, stage IV lung adenocarcinoma with an epidermal growth factor receptor mutation. On the 31st day of hospitalization, the patient developed severe headache. Subsequent magnetic resonance venography revealed defects in the superior sagittal, right sigmoid, and right transverse venous sinuses and the right internal jugular vein. Anticoagulation therapy with unfractionated heparin and warfarin was immediately administered following diagnosis of cerebral venous sinus thrombosis (CVST). Brain MRI demonstrated leptomeningeal gadolinium enhancement in front of the pons and medulla. Positive cerebrospinal fluid tumor cytology confirmed the diagnosis of leptomeningeal carcinomatosis. Following four weeks of antithrombotic therapy, complete thrombolysis was confirmed by magnetic resonance venography. Effective treatment with gefitinib was administered, and the patient survived for 10 months after the diagnosis of CVST and leptomeningeal carcinomatosis. Adequate early diagnosis and treatment of CVST enabled an excellent survival rate for the patient, despite leptomeningeal carcinomatosis. Following the development of headaches in patients with lung cancer, CVST, although rare, should be considered. Furthermore, following a diagnosis of CVST, leptomeningeal carcinomatosis should be investigated as an underlying cause.
PMCID: PMC4214432  PMID: 25364413
lung cancer; leptomeningeal carcinomatosis; cerebral venous sinus thrombosis; epidermal growth factor receptor-tyrosine kinase inhibitor; magnetic resonance imaging
20.  Topological Analysis for Arteriovenous Malformations via Computed Tomography Angiography: Part 2: Practical Application 
In a previous study, the authors outlined a technique for calculating the number of abnormal vascular loop structures described in 3-dimensional computed tomography angiography. To be developed into a quantitative evaluation method for soft-tissue arteriovenous malformations (AVMs), the concept needs assessment of validity.
Computed tomography angiography results of 19 soft-tissue AVMs and 18 control abdominal vessels are utilized. Enhanced vascular lumen regions over 120 HU were extracted by a region growing method and skeletonized into wire frame graph models. The number of vascular loop structures in graphs is calculated as 1 − [Number of nodes] + [Number of edges], and results are compared between AVM/control groups, pre-/postprogression, and pre-/posttreatment.
Average vascular lumen capacity of AVMs was 57.5 ml/lesion, and average number of vascular loops was 548 loops/lesion. Loop density of AVMs (weighted average, 9.5 loops/ml) exhibited statistically significant (P < 0.001) greater value than normal abdominal blood vessels (weighted average, 1.3 loops/ml). In all 4 cases without treatment, number of loops and loop density both increased. Particularly, number of loops increased greatly by 2 times or more in 3 cases. In all 7 cases with treatment, number of loops and vascular lumen capacity significantly (P = 0.0156) decreased. Particularly, number of loops showed clearer decrease in cases with entire lesion treatment than partial treatment.
Total number of described vascular loop structures and their density or volume well reflected the existence, progression, and remission of soft-tissue AVMs. Topological analysis can be expected to be developed into a quantitative evaluation for AVMs.
PMCID: PMC4229266  PMID: 25426390
21.  Roles of mast cells in the pathogenesis of inflammatory myopathy 
In addition to the pivotal roles of mast cells in allergic diseases, recent data suggest that mast cells play crucial roles in a variety of autoimmune responses. However, their roles in the pathogenesis of autoimmune skeletal muscle diseases have not been clarified despite their distribution in skeletal muscle. Therefore, the objective of this study is to determine the roles of mast cells in the development of autoimmune skeletal muscle diseases.
The number of mast cells in the affected muscle was examined in patients with dermatomyositis (DM) or polymyositis (PM). The susceptibility of mast cell-deficient WBB6F1-KitW/KitWv mice (W/Wv mice) to a murine model of polymyositis, C protein-induced myositis (CIM), was compared with that of wild-type (WT) mice. The effect of mast cell reconstitution with bone marrow-derived mast cells (BMMCs) on the susceptibility of W/Wv mice to CIM was also evaluated.
The number of mast cells in the affected muscle increased in patients with PM as compared with patients with DM. W/Wv mice exhibited significantly reduced disease incidence and histological scores of CIM as compared with WT mice. The number of CD8+ T cells and macrophages in the skeletal muscles of CIM decreased in W/Wv mice compared with WT mice. Engraftment of BMMCs restored the incidence and histological scores of CIM in W/Wv mice. Vascular permeability in the skeletal muscle was elevated in WT mice but not in W/Wv mice upon CIM induction.
Mast cells are involved in the pathogenesis of inflammatory myopathy.
PMCID: PMC4060256  PMID: 24636001
22.  Topological Analysis for Arteriovenous Malformations via Computed Tomography Angiography: Part 1: Mathematical Concepts 
Evaluating the progression of soft-tissue arteriovenous malformation (AVMs) is still problematic. To establish a quantitative method, we took a morphological approach.
Normal blood vessels in early-phase 3D-computed tomography angiography images are theoretically expected to be tree-like structures without loops, whereas AVM blood vessels are expected to be mesh-like structures with loops. Simplified to the utmost limit, these vascular structures can be symbolized with wire-frame models composed of nodes and connecting edges, in which making an extra loop always needs one more of edges than of nodes.
Total amount of abnormal vascular structures is estimated from a simple equation: Number of vascular loops = 1 − ([Number of nodes] − [Number of edges]).
Abnormalities of AVM vascular structures can be mathematically quantified using computed tomography angiography images.
PMCID: PMC4236366  PMID: 25426388
23.  Afferent vagal nerve stimulation resets baroreflex neural arc and inhibits sympathetic nerve activity 
Physiological Reports  2014;2(9):e12136.
It has been established that vagal nerve stimulation (VNS) benefits patients and/or animals with heart failure. However, the impact of VNS on sympathetic nerve activity (SNA) remains unknown. In this study, we investigated how vagal afferent stimulation (AVNS) impacts baroreflex control of SNA. In 12 anesthetized Sprague–Dawley rats, we controlled the pressure in isolated bilateral carotid sinuses (CSP), and measured splanchnic SNA and arterial pressure (AP). Under a constant CSP, increasing the voltage of AVNS dose dependently decreased SNA and AP. The averaged maximal inhibition of SNA was ‐28.0 ± 10.3%. To evaluate the dynamic impacts of AVNS on SNA, we performed random AVNS using binary white noise sequences, and identified the transfer function from AVNS to SNA and that from SNA to AP. We also identified transfer functions of the native baroreflex from CSP to SNA (neural arc) and from SNA to AP (peripheral arc). The transfer function from AVNS to SNA strikingly resembled the baroreflex neural arc and the transfer functions of SNA to AP were indistinguishable whether we perturbed ANVS or CSP, indicating that they likely share common central and peripheral neural mechanisms. To examine the impact of AVNS on baroreflex, we changed CSP stepwise and measured SNA and AP responses with or without AVNS. AVNS resets the sigmoidal neural arc downward, but did not affect the linear peripheral arc. In conclusion, AVNS resets the baroreflex neural arc and induces sympathoinhibition in the same manner as the control of SNA and AP by the native baroreflex.
Afferent vagal nerve stimulation resets the baroreflex neural arc and inhibits sympathetic nerve activity.
PMCID: PMC4270242  PMID: 25194023
Afferent nerve; carotid sinus baroreflex; sympathetic nerve activity; vagal nerve stimulation
24.  Tetrahydrobiopterin Has a Glucose-Lowering Effect by Suppressing Hepatic Gluconeogenesis in an Endothelial Nitric Oxide Synthase–Dependent Manner in Diabetic Mice 
Diabetes  2013;62(9):3033-3043.
Endothelial nitric oxide synthase (eNOS) dysfunction induces insulin resistance and glucose intolerance. Tetrahydrobiopterin (BH4) is an essential cofactor of eNOS that regulates eNOS activity. In the diabetic state, BH4 is oxidized to 7,8-dihydrobiopterin, which leads to eNOS dysfunction owing to eNOS uncoupling. The current study investigates the effects of BH4 on glucose metabolism and insulin sensitivity in diabetic mice. Single administration of BH4 lowered fasting blood glucose levels in wild-type mice with streptozotocin (STZ)-induced diabetes and alleviated eNOS dysfunction by increasing eNOS dimerization in the liver of these mice. Liver has a critical role in glucose-lowering effects of BH4 through suppression of hepatic gluconeogenesis. BH4 activated AMP kinase (AMPK), and the suppressing effect of BH4 on gluconeogenesis was AMPK-dependent. In addition, the glucose-lowering effect and activation of AMPK by BH4 did not appear in mice with STZ-induced diabetes lacking eNOS. Consecutive administration of BH4 in ob/ob mice ameliorated glucose intolerance and insulin resistance. Taken together, BH4 suppresses hepatic gluconeogenesis in an eNOS-dependent manner, and BH4 has a glucose-lowering effect as well as an insulin-sensitizing effect in diabetic mice. BH4 has potential in the treatment of type 2 diabetes.
PMCID: PMC3749361  PMID: 23649519
25.  Bacterial meningitis in the absence of cerebrospinal fluid pleocytosis: A case report and review of the literature 
Bacterial meningitis is typically diagnosed with a lumbar puncture, which usually reveals an elevated opening pressure and high white blood cell count. In this article, the authors report a case involving an 83-year-old woman who had normal cerebrospinal fluid findings on presentation, but who was subsequently found to have meningitis caused by Neisseria meningitidis. The authors discuss potential reasons for normal cerebrospinal fluid findings in the context of meningitis.
Elevation of cerebrospinal fluid (CSF) cell count is a key sign in the diagnosis of bacterial meningitis. However, there have been reports of bacterial meningitis with no abnormalities in initial CSF testing. This type of presentation is extremely rare in adult patients. Here, a case involving an 83-year-old woman who was later diagnosed with bacterial meningitis caused by Neisseria meningitidis is described, in whom CSF at initial and second lumbar puncture did not show elevation of cell counts. Twenty-six non-neutropenic adult cases of bacterial meningitis in the absence of CSF pleocytosis were reviewed. The frequent causative organisms were Streptococcus pneumoniae and N meningitidis. Nineteen cases had bacteremia and seven died. The authors conclude that normal CSF at lumbar puncture at an early stage cannot rule out bacterial meningitis. Therefore, repeat CSF analysis should be considered, and antimicrobial therapy must be started immediately if there are any signs of sepsis or meningitis.
PMCID: PMC4211346  PMID: 25371685
Bacterial meningitis; Lumbar puncture; Meningococcal meningitis; Neisseria meningitidis; Normal cerebrospinal fluid

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