Diagnostic Accuracy of Screening Arterial Spin-Labeling MRI Using Hadamard Encoding for the Detection of Reduced CBF in Adult Patients with Ischemic Moyamoya Disease.

BACKGROUND AND PURPOSE: Adult patients with ischemic Moyamoya disease are advised to undergo selective revascularization surgery based on cerebral hemodynamics. The purpose of this study was to determine the diagnostic accuracy of arterial spin-labeling MR imaging using Hadamard-encoded multiple postlabeling delays for the detection of reduced CBF in such patients. MATERIALS AND METHODS: Thirty-seven patients underwent brain perfusion SPECT and pseudocontinuous arterial spin-labeling MR imaging using standard postlabeling delay (1525 ms) and Hadamard-encoded multiple postlabeling delays. For Hadamard-encoded multiple postlabeling delays, based on data obtained from the 7 sub-boluses with combinations of different labeling durations and postlabeling delays, CBF corrected by the arterial transit time was calculated on a voxel-by-voxel basis. Using a 3D stereotaxic template, we automatically placed ROIs in the ipsilateral cerebellar hemisphere and 5 MCA territories in the symptomatic cerebral hemisphere; then, the ratio of the MCA to cerebellar ROI was calculated. RESULTS: The area under the receiver operating characteristic curve for detecting reduced SPECT-CBF ratios (<0.686) was significantly greater for the Hadamard-encoded multiple postlabeling delays-CBF ratios (0.885) than for the standard postlabeling delay-CBF ratios (0.786) (P = .001). The sensitivity and negative predictive value for the Hadamard-encoded multiple postlabeling delays-CBF ratios were 100% (95% confidence interval, 100%-100%) and significantly higher than the sensitivity (95% CI, 44%-80%) and negative predictive value (95% CI, 88%-97%) for the standard postlabeling delay-CBF ratio, respectively. CONCLUSIONS: ASL MR imaging using Hadamard-encoded multiple postlabeling delays may be applicable as a screening tool because it can detect reduced CBF on brain perfusion SPECT with 100% sensitivity and a 100% negative predictive value in adult patients with ischemic Moyamoya disease.

Rikkunshito simultaneously improves dyspepsia correlated with anxiety in patients with functional dyspepsia: A randomized clinical trial (the DREAM study).

BACKGROUND: Functional dyspepsia (FD), a heterogeneous disorder, involves multiple pathogenetic mechanisms. Developing treatments for FD has been challenging. We performed a randomized, placebo-controlled, double-blind clinical trial to determine the efficacy of rikkunshito, a Japanese herbal medicine, in FD patients. METHODS: FD patients (n = 192) who met the Rome III criteria without Helicobacter pylori infection, predominant heartburn, and depression were enrolled at 56 hospitals in Japan. After 2 weeks of single-blind placebo treatment, 128 patients with continuous symptoms were randomly assigned to 8 weeks of rikkunshito (n = 64) or placebo (n = 61). The primary efficacy endpoint was global assessment of overall treatment efficacy (OTE). The secondary efficacy endpoints were improvements in upper gastrointestinal symptoms evaluated by the Patient Assessment of Upper Gastrointestinal Disorders-Symptom Severity Index (PAGI-SYM), the Global Overall Symptom scale (GOS), and the modified Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (m-FSSG), and psychological symptoms evaluated by the Hospital Anxiety and Depression Scale (HADS). KEY RESULTS: Rikkunshito increased OTE compared to placebo at 8 weeks (P = .019). Rikkunshito improved upper gastrointestinal symptoms (PAGI-SYM, GOS, and m-FSSG) at 8 weeks, especially postprandial fullness/early satiety (P = .015 and P = .001) and bloating (P = .007 and P = .002) of the PAGI-SYM subscales at 4 weeks and 8 weeks. Improvement of HADS at 8 weeks (P = .027) correlated with those of PAGI-SYM (r = .302, P = .001), GOS (r = .186, P = .044), and m-FSSG (r = .462, P < .001), postprandial fullness/early satiety (r = .226, P = .014), dyspepsia (r = .215, P = .019), and PDS (r = .221, P = .016). CONCLUSION & INFERENCES: Rikkunshito may be beneficial for FD patients to simultaneously treat gastrointestinal and psychological symptoms.

Genetics in pulmonary arterial hypertension in a large homogeneous Japanese population.

Pulmonary arterial hypertension (PAH) is a rare but serious disease with a grave prognosis. Bone morphogenetic protein type 2 receptor (BMPR2) gene is a strong pathogenic factor for PAH. As a collaborative team from Kyorin University and Keio University in Japan, we have analyzed the BMPR2 gene in 356 probands and more than 50 family members, including secondary patients. Importantly, the study population is a racially, ethnically, and socially homogeneous population. In PAH patients, there is a high incidence of unique mutations in BMPR2, and several mutations are frequently observed in the Japanese population, suggesting that these common and recurring mutations may be highly pathogenic or have high penetrance, explaining why they are found frequently throughout the world. We have also mapped each breakpoint of exonic deletions/duplications and found that most break and rejoining points are in the Alu elements. Reviewing the distribution of the reported mutations on each exon of BMPR2 revealed that the number and frequency of mutations are imbalanced among exons. The penetrance of BMPR2 gene mutations was 3-fold higher in females than males. Full elucidation of BMPR2-mediated pathogenic mechanisms in PAH requires persistent efforts to achieve precision or individualized medicine as a therapeutic strategy for PAH.

The pruritogenic mediator endothelin-1 shifts the dendritic cell-T-cell response toward Th17/Th1 polarization.

Endothelin-1 (ET-1) is associated with skin diseases such as atopic dermatitis (AD) and psoriasis. ET-1 is enhanced in the skin of patients AD and psoriasis. In addition, plasma levels of ET-1 are elevated in AD and psoriasis. Although both AD and psoriasis are T-cell-mediated skin diseases, the association between ET-1 and the T-cell immune response has not been clarified. To evaluate the role of ET-1 in inflammatory skin disease, we sought to investigate the effects of ET-1 on the functions of dendritic cells (DCs) and subsequent immune responses. For this purpose, we immunohistochemically confirmed the upregulation of ET-1 in the epidermis of patients with AD or psoriasis. ET-1 directly induced phenotypic maturation of bone marrow-derived DCs (BMDCs). In addition, ET-1 augmented the production of several cytokines and allogeneic stimulatory capacity of BMDCs. Interestingly, ET-1-activated BMDCs primed T cells to produce Th1 and Th17 cytokines, but not Th2 cytokines. These findings indicate that ET-1 polarizes the DC-T-cell response toward Th17/1 differentiation and may augment the persistent course of inflammatory skin diseases.

Stability of cervical esophagogastrostomy via hand-sewn anastomosis after esophagectomy for esophageal cancer.

The aim of the present study is to evaluate the outcome of hand-sewn esophagogastric anastomosis during radical esophagectomy for esophageal cancer. The outcomes of 467 consecutive esophageal cancer patients who underwent cervical esophagogastric anastomosis using interrupted and double-layered sutures after radical esophagectomy via right thoracotomy or thoracoscopic surgery were retrospectively reviewed. Anastomotic leakage, including conduit necrosis, occurred in 11 of 467 patients (2.4%); 7 of 11 (63.6%) cases experienced only minor leakage, whereas the other four (36.4%) patients had major leakage that required surgical or radiologic intervention, including two patients of conduit necrosis. Anastomotic leakages were more frequently observed after retrosternal reconstruction compared with the posterior mediastinal route (P < 0.0001). The median time to healing of leakage was 40 days (range: 14-97 days). Two patients (2/467, 0.4%) died in the hospital due to sepsis caused by the leakage and conduit necrosis. Twelve patients (2.6%) developed anastomotic stenosis, which was improved by dilatation in all patients. Hand-sewn cervical esophagogastric anastomosis is a stable and highly safe method of radical esophagectomy for esophageal cancer.

Nucleotide-binding oligomerization domain 1 acts in concert with the cholecystokinin receptor agonist, cerulein, to induce IL-33-dependent chronic pancreatitis.

Nucleotide-binding oligomerization domain 1 (NOD1) fulfills important host-defense functions via its responses to a variety of gut pathogens. Recently, however, we showed that in acute pancreatitis caused by administration of cholecystokinin receptor (CCKR) agonist (cerulein) NOD1 also has a role in inflammation via its responses to gut commensal organisms. In the present study, we explored the long-term outcome of such NOD1 responsiveness in a new model of chronic pancreatitis induced by repeated administration of low doses of cerulein in combination with NOD1 ligand. We found that the development of chronic pancreatitis in this model requires intact NOD1 and type I IFN signaling and that such signaling mediates a macrophage-mediated inflammatory response that supports interleukin (IL)-33 production by acinar cells. The IL-33, in turn, has a necessary role in the induction of IL-13 and TGF-ß1, factors causing the fibrotic reaction characteristic of chronic pancreatitis. Interestingly, the Th2 effects of IL-33 were attenuated by the concomitant type I IFN response since the inflammation was marked by clear increases in IFN-γ and TNF-α production but only marginal increases in IL-4 production. These studies establish chronic pancreatitis as an IL-33-dependent inflammation resulting from synergistic interactions between the NOD1 and CCKR signaling pathways.

MALT1 Inhibition of Oral Carcinoma Cell Invasion and ERK/MAPK Activation.

The expression of mucosa-associated lymphoid tissue 1 (MALT1) that activates nuclear factor (NF)-κB in lymphocyte lineages is rapidly inactivated in oral carcinoma cells at the invasive front and the patients with worst prognosis. However, its mechanism to accelerate carcinoma progression remains unknown, and this study was carried out to examine the role in invasion. HSC2 oral carcinoma cells stably expressing wild-type MALT1 (wtMALT1) reduced the invasion of basement membrane matrices and collagen gels, and the dominant-negative form (∆MALT1)-expressing cells aggressively invaded into collagen gels. MALT1 decelerated proliferation and migration of cells and downregulated expression of matrix metalloproteinase 2 and 9, which were confirmed by short interfering RNA transfections. Reporter assays and immunoblot analysis showed that MALT1 does not affect the NF-κB pathway but inhibits ERK/MAPK activation. This was confirmed by endogenous MALT1 expression in oral carcinoma cell lines. Orthotopic implantation of ∆MALT1-expressing HSC2 cells in mice grew rapid expansive and invasive tongue tumors in contrast to an absence of tumor formation by wtMALT1-expressing cells. These results demonstrate that MALT1 suppresses oral carcinoma invasion by inhibiting proliferation, migration, and extracellular matrix degradation and that the ERK/MAPK pathway is a target of MALT1 and further suggests a role as a suppressor of carcinoma progression.

Randomised clinical trial: a dose-ranging study of vonoprazan, a novel potassium-competitive acid blocker, vs. lansoprazole for the treatment of erosive oesophagitis.

BACKGROUND: The potassium-competitive acid blocker vonoprazan (VPZ) has potent acid-inhibitory effects and may offer clinical advantages over conventional therapy for acid-related disorders. AIM: To investigate the efficacy and safety of VPZ in patients with erosive oesophagitis (EO). METHODS: In this multicentre, randomised, double-blind, parallel-group, dose-ranging study, patients ≥20 years with endoscopically confirmed EO [Los Angeles (LA) grades A-D] received VPZ 5, 10, 20 or 40 mg, or lansoprazole (LPZ) 30 mg once daily for 8 weeks. The primary endpoint was the proportion of healed EO subjects as shown by endoscopy at week 4. RESULTS: A total of 732 subjects received VPZ or LPZ. The proportion of healed EO subjects at week 4 was 92.3%, 92.5%, 94.4%, 97.0% and 93.2%, respectively, with VPZ 5, 10, 20 and 40 mg and LPZ 30 mg. All VPZ doses were non-inferior to LPZ when adjusted for baseline LA grades A/B and C/D. Among those with LA grades C/D, the proportions of healed EO subjects were 87.3%, 86.4%, 100%, 96.0% and 87.0%, respectively, with VPZ 5, 10, 20 and 40 mg and LPZ 30 mg. The incidence of adverse events was similar across the groups. CONCLUSIONS: Vonoprazan was effective and non-inferior to LPZ in healing EO. VPZ 20 mg or higher was highly efficacious for severe EO (LA grades C/D). VPZ was associated with no safety concern during this 8-week study, while there was a dose-dependent increase in serum gastrin. Once-daily VPZ 20 mg is the recommended clinical dose for treating EO.

Impairment of host resistance to helminthes with age in murine small intestine.

Age-associated alterations of Th2 immune responses against nematode parasites are largely unknown. We investigated primary and memory responses against two types of gastrointestinal nematode parasites, Heligmosomoides polygyrus (Hp) and Nippostrongylus brasiliensis (Nb), in aged mice. The small intestinal gene expression of Th2 cytokines was almost unchanged after primary (Nb and Hp) and secondary infection (Hp) in aged mice in contrast to strongly increased small intestinal gene expression of Th2 cytokines in young (3-month-old) mice. Mucus production decreased (Nb), and worm expulsion was impaired (Nb and Hp) compared with the young mice. Immunofluorescent staining revealed that after Hp infection, the number of alternatively activated macrophages, which are induced by Th2 cytokines, was lower in the aged mice. On the other hand, the number of CD4(+) T cells recruited to the worm cysts was normal compared with the young mice. These results suggest that migration of CD4(+) T cells to the host-parasite interface is not affected by ageing. Alterations in Th2 immune responses in aged mice might be due to inappropriate or insufficient activation of CD4(+) T cells in the submucosa.

Vision-based endoscope tracking for 3D ultrasound image-guided surgical navigation.

This work introduces a self-contained framework for endoscopic camera tracking by combining 3D ultrasonography with endoscopy. The approach can be readily incorporated into surgical workflows without installing external tracking devices. By fusing the ultrasound-constructed scene geometry with endoscopic vision, this integrated approach addresses issues related to initialization, scale ambiguity, and interest point inadequacy that may be faced by conventional vision-based approaches when applied to fetoscopic procedures. Vision-based pose estimations were demonstrated by phantom and ex vivo monkey placenta imaging. The potential contribution of this method may extend beyond fetoscopic procedures to include general augmented reality applications in minimally invasive procedures.

Adjunct antibiotic combination therapy for steroid-refractory or -dependent ulcerative colitis: an open-label multicentre study.

BACKGROUND: We previously demonstrated that antibiotic combination therapy is effective for induction and maintenance of ulcerative colitis (UC) remission. AIM: To assess whether antibiotic combination therapy is effective for active UC refractory to or dependent on steroids in a multicentre, open-label trial. METHODS: We enrolled 30 patients with steroid-refractory and 64 with steroid-dependent active UC. These patients received three-times-daily by mouth amoxicillin 500 mg, tetracycline 500 mg and metronidazole 250 mg, for two weeks, as well as conventional treatment. Symptom assessment and colonoscopic evaluation were performed before enrolment and at 3 and 12 months after treatment completion. Clinical response was defined as a Lichtiger symptom score decrease in ≥3 points and clinical remission as a score ≤4. RESULTS: Nineteen of the 30 steroid-refractory (63.3%) and 47 of the 64 steroid-dependent (73.4%) patients showed a clinical response within 2 weeks. At 3 and 12 months, 60% and 66.6% of steroid-refractory patients, and 56.3% and 51.6% of steroid-dependent patients, respectively, achieved clinical remission. In the steroid-dependent group, 39 of the 64 patients (60.9%) were able to stop steroid therapy and remained in remission for 3 months. Three (10%) steroid-refractory and four (6.3%) steroid-dependent patients underwent colectomy. CONCLUSIONS: This multicentre, long-term follow-up study suggests 2 week antibiotic combination therapy to be effective and safe in patients with active UC refractory to or dependent on steroids.

NOD2 downregulates colonic inflammation by IRF4-mediated inhibition of K63-linked polyubiquitination of RICK and TRAF6.

It is well established that polymorphisms of the caspase activation and recruitment domain 15 (CARD15) gene, a major risk factor in Crohn's disease (CD), lead to loss of nucleotide-binding oligomerization domain 2 (NOD2) function. However, a molecular explanation of how such loss of function leads to increased susceptibility to CD has remained unclear. In a previous study exploring this question, we reported that activation of NOD2 in human dendritic cells by its ligand, muramyl dipeptide (MDP), negatively regulates Toll-like receptor (TLR)-mediated inflammatory responses. Here we show that NOD2 activation results in increased interferon regulatory factor 4 (IRF4) expression and binding to tumor necrosis factor receptor associated factor 6 (TRAF6) and RICK (receptor interacting serine-threonine kinase). We then show that such binding leads to IRF4-mediated inhibition of Lys63-linked polyubiquitination of TRAF6 and RICK and thus to downregulation of nuclear factor (NF)-κB activation. Finally, we demonstrate that protection of mice from the development of experimental colitis by MDP or IRF4 administration is accompanied by similar IRF4-mediated effects on polyubiquitination of TRAF6 and RICK in colonic lamina propria mononuclear cells. These findings thus define a mechanism of NOD2-mediated regulation of innate immune responses to intestinal microflora that could explain the relation of CARD15 polymorphisms and resultant NOD2 dysfunction to CD.

Multimodal endoscopic treatment for delayed severe esophageal stricture caused by incomplete stent removal.

The usefulness of a covered self-expandable metallic stent for benign esophageal stricture and perforation was well established. In case of benign disease, early stent removal was recommended within 6-8 weeks after placement. A case with severe esophageal stricture caused by incomplete stent removal 7 years after stent placement for spontaneous esophageal rupture was reported. Residual stent fragments could be removed by step-by-step multimodal endoscopic treatment, producing satisfactory luminal diameter of the esophagus. In particular, stent trimming with argon plasma coagulation was safe and effective strategy. The endoscopic stent removal is minimally invasive and should be attempted before surgical intervention; however, it is most important to ensure early stent removal before tissue ingrowth or overgrowth can develop.

Ultrasound image-based endoscope localization for minimally invasive fetoscopic surgery.

The purpose of this work is to introduce an ultrasound image-based intraoperative scheme for rigid endoscope localization during minimally invasive fetoscopic surgery. Positional information of surgical instruments with respect to anatomical features is important for the development of computer-aided surgery applications. While most surgical navigation systems use optical tracking systems with satisfactory accuracy, there are several operation limitations in such systems. We propose an elegant framework for intraoperative instrument localization that does not require any external tracking system but uses an ultrasound imaging system and a computation scheme based on constrained kinematics of minimally invasive fetoscopic surgery. Our proposed algorithm simultaneously estimates endoscope and port positions in an online sequential fashion with standard deviation of 1.28 mm for port estimation. Robustness of the port estimation algorithm against external disturbance was demonstrated by intentionally introducing artificial errors to measurement data. The estimation converges within eight iterations under disturbance magnitude of 30 mm.

Threshold levels for wettability in nano- and micro-meter periodic structures.

The purposes of this study are to clarify the relationship between surface wettability and the pitch and size of periodic structures on the surface and to determine the thresholds at which the wettability switches from being hydrophobic to hydrophilic. To this various nano- and micro-meter scale periodic structures were fabricated. By applying a fine periodic structure to the surface, the wettability can be controlled between + 50° (hydrophobic) and -55° (hydrophilic). The pitch of the periodic structure at which the wettability switches from hydrophilic to hydrophobic was found to between 500 and 1,000 nm. Additionally, the height of the periodic structure at which the wettability switches from hydrophobic to hydrophilic was found to between 300 and 700 nm.

Inhibition of TGF-ß and EGF pathway gene expression and migration of oral carcinoma cells by mucosa-associated lymphoid tissue 1.

BACKGROUND: Expression of mucosa-associated lymphoid tissue 1 (MALT1) is inactivated in oral carcinoma patients with worse prognosis. However, the role in carcinoma progression is unknown. Unveiling genes under the control of MALT1 is necessary to understand the pathology of carcinomas. METHODS: Gene data set differentially transcribed in MALT1-stably expressing and -marginally expressing oral carcinoma cells was profiled by the microarray analysis and subjected to the pathway analysis. Migratory abilities of cells in response to MALT1 were determined by wound-healing assay and time-lapse analysis. RESULTS: Totally, 2933 genes upregulated or downregulated in MALT1-expressing cells were identified. The subsequent pathway analysis implicated the inhibition of epidermal growth factor and transforming growth factor-ß signalling gene expression, and highlighted the involvement in the cellular movement. Wound closure was suppressed by wild-type MALT1 (66.4%) and accelerated by dominant-negative MALT1 (218.6%), and the velocities of cell migration were increased 0.2-fold and 3.0-fold by wild-type and dominant-negative MALT1, respectively. CONCLUSION: These observations demonstrate that MALT1 represses genes activating the aggressive phenotype of carcinoma cells, and suggest that MALT1 acts as a tumour suppressor and that the loss of expression stimulates oral carcinoma progression.

Large current MOSFET on photonic silicon-on-insulator wafers and its monolithic integration with a thermo-optic 2 × 2 Mach-Zehnder switch.

n-channel body-tied partially depleted metal-oxide-semiconductor field-effect transistors (MOSFETs) were fabricated for large current applications on a silicon-on-insulator wafer with photonics-oriented specifications. The MOSFET can drive an electrical current as large as 20 mA. We monolithically integrated this MOSFET with a 2 × 2 Mach-Zehnder interferometer optical switch having thermo-optic phase shifters. The static and dynamic performances of the integrated device are experimentally evaluated.