Eriocitrin Contained in Lemon Peel Ameliorates Disuse Muscle Atrophy by Suppressing the Expression of Atrogin-1 and MuRF-1 in Denervated Mice.

Unloading stress enhances oxidative stress, which in turn induces disuse muscle atrophy. This study evaluated the suppressive effect of lemon peel extract containing eriocitrin on muscle atrophy. Both lemon peel extract and eriocitrin suppressed weight loss in the gastrocnemius muscle under denervation in C57BL/6 mice. The mRNA level of ubiquitin ligases and their transcription factor were downregulated by eriocitrin. Eriocitrin inhibited the increase in lipid peroxidation and the ratio of glutathione disulfide/glutathione. These data suggest that eriocitrin ameliorated disuse muscle atrophy by suppressing the expression of ubiquitin ligase genes by its antioxidative effect.

Factors influencing physician decisions to discontinue treatment after onset of liver dysfunction: Post-hoc analysis of an all-case post-marketing surveillance study of iguratimod.

Objectives: Adverse drug reactions (ADRs) related to liver dysfunction are a common problem in patients with rheumatoid arthritis (RA) receiving iguratimod, but which patient subgroups go on to discontinue iguratimod treatment is unclear. A post-hoc analysis of a post-marketing surveillance study was performed to investigate factors influencing treatment continuation after the onset of liver dysfunction.Methods: Types of ADR were compared between patients in whom iguratimod treatment was discontinued or continued in accordance with the judgment of the patient's physician after the patient developed liver dysfunction as an ADR. Stepwise logistic regression analysis was also conducted to investigate factors associated with treatment discontinuation.Results: The multivariate analysis found that concomitant use of methotrexate (MTX) at >8 mg/week (vs. no use) was associated with a significantly lower risk of discontinuation (OR: 0.136; 95%CI: 0.030-0.620), and previous treatment with MTX (vs. no use) was associated with a significantly higher discontinuation risk (OR: 4.045; 95%CI: 1.098-14.908).Conclusion: Although concomitant use of MTX during iguratimod treatment does not appear to influence treatment discontinuation due to abnormal liver function, liver function tests are of importance to continued treatment in patients receiving iguratimod who have a history of MTX use.

Investigation of the predictors of the response to Iguratimod therapy: A post-hoc analysis of post-marketing surveillance study.

Objectives: The treatment response according to patient disease activity during Iguratimod therapy for rheumatoid arthritis has not been sufficiently assessed. A post-hoc analysis of post-marketing surveillance was performed. The treatment effect was evaluated using the European League against Rheumatism (EULAR) response criteria.Methods: Disease Activity Score (DAS) 28 was assessed at various time points. Patients showing a moderate or good response according to the EULAR response criteria at 24 weeks after the start of Iguratimod therapy were considered Responders. Propensity score matching was also performed, after which the factors with the greatest effect on the treatment evaluation were investigated.Results: The mean DAS28 at the start of administration and after 24 weeks was 4.31 and 2.52, respectively, in the Responder and 3.48 and 3.48, respectively, in the Non-responder. After propensity score matching for patient characteristics, the primary factors found to be related to being a Responder were concomitant use of methotrexate (MTX) with Iguratimod, and prior treatment with MTX before the start of Iguratimod.Conclusion: As factors related to the treatment effect, the concomitant use of MTX may contribute to achieving a better effect, and this study has shown that real-world are consistent with the results of clinical trials.

Safety and effectiveness of iguratimod in patients with rheumatoid arthritis: Final report of a 52-week, multicenter postmarketing surveillance study.

OBJECTIVES: We evaluated the long-term (52 weeks) safety and effectiveness of iguratimod (IGU) in patients with rheumatoid arthritis (RA). METHODS: This multicenter, prospective, observational study included all evaluable RA patients who received IGU since its market launch in 2012. We evaluated adverse events (AEs); adverse drug reactions (ADRs); ADRs of special interest, including liver and renal dysfunctions, interstitial lung disease, gastrointestinal and blood disorders, and infection; and change in Disease Activity Score 28-C-reactive protein (DAS28-CRP) at week 52. RESULTS: Safety and effectiveness were analyzed in 2666 and 1614 patients, respectively. The incidences of AEs, serious AEs, ADRs, and serious ADRs were 46.92, 7.35, 38.26, and 4.58%, respectively. The incidence of ADRs peaked at approximately 4 weeks of treatment. Subsequently, the ADR incidence did not increase over time. Improvement of RA activity was shown up to week 52. CONCLUSION: Long-term treatment with IGU in patients with RA resulted in a tolerable safety profile and an improvement in RA activity. IGU could be considered a useful treatment option for patients with RA.

Safety and effectiveness of 24-week treatment with iguratimod, a new oral disease-modifying antirheumatic drug, for patients with rheumatoid arthritis: interim analysis of a post-marketing surveillance study of 2679 patients in Japan.

OBJECTIVE: To determine the real-world safety and effectiveness of iguratimod (IGU) for rheumatoid arthritis (RA), a 52-week, Japanese, post-marketing surveillance study was conducted. An interim analysis at week 24 was performed. METHODS: This study included all RA patients who received IGU following its introduction to the market. All adverse events (AEs) and adverse drug reactions (ADRs) were collected. Effectiveness was evaluated by the change in Disease Activity Score 28-C-reactive protein (DAS28-CRP) from baseline to week 24. RESULTS: Safety was analyzed in 2679 patients. The overall incidences of AEs, ADRs, and serious ADRs were 38.41, 31.65, and 3.21%, respectively; the most commonly reported serious ADRs were pneumonia/bacterial pneumonia, interstitial lung disease, and Pneumocystis jiroveci pneumonia. Concomitant glucocorticoid use and comorbid conditions associated with respiratory disease were identified as risk factors for serious infections. Pulmonary alveolar hemorrhage and increased international normalized ratio of prothrombin time were observed with concomitant use of IGU and warfarin. The DAS28-CRP decreased from baseline to week 24. CONCLUSION: Although a safety concern was identified with concomitant use of IGU and warfarin, this real-world study showed no other new safety concerns and similar effectiveness to clinical trials. IGU is a new therapeutic option for RA patients.

Rabeprazole Coadministration Controls Ulcer Recurrence in Patients on Low-dose Aspirin Therapy: A Multicenter Prospective Study.

Objective To evaluate the efficacy and safety of rabeprazole coadministration with low-dose aspirin (LDA). Methods From 2015 to 2018, we conducted a large-scale, multicenter, prospective observational study to assess the safety and efficacy of treatment with rabeprazole (5 or 10 mg/day) in combination with LDA. Results The incidence of adverse reactions was 0.73% (11/1,513 patients), with no serious adverse reactions. We found no trend toward increases in the incidence of adverse reactions with increases in treatment duration. The cumulative recurrence rate of ulcers by Week 52 (Kaplan-Meier estimates) was 3.50% (range, 1.56-7.75%). No gastrointestinal bleeding was reported. Conclusion Rabeprazole in combination with LDA appears as safe and effective in real-world situations as in clinical trials.

Effectiveness of drug safety measures for reducing the incidence of adverse drug reactions: Post-hoc analysis of data from all-case surveillance of iguratimod using generalized estimating equations.

A post-marketing study was performed on all patients who had started treatment with iguratimod, a conventional synthetic disease-modifying antirheumatic drug approved in Japan. During the study period, various safety measures were implemented to reduce risks. We investigated the frequency of adverse drug reactions before and after implementation of each safety measure to examine the preventive effect of these measures. Post-hoc analysis was performed using data from all-case surveillance of iguratimod. The subjects were all of the patients receiving iguratimod for whom safety information was obtained. To identify the time after starting administration when adverse drug reactions were most likely to occur, a generalized linear mixed-effect model was applied for the period from initiation of administration until occurrence of reactions in each patient. The mean incidence of adverse drug reactions per patient was compared before and after the implementation of safety measures by using generalized estimating equations based on a two-sided test, 95% confidence interval, and 5% significance level. The number of patients treated with iguratimod was not related to changes in the number of patients with adverse drug reactions. After implementing precautions regarding co-administration with warfarin and liver dysfunction, the estimated mean incidence rate of adverse drug reactions (95% confidence interval) decreased significantly to 0.73 (0.59-0.90) and 0.72 (0.55-0.94), respectively. Accordingly, some of the implementation of safety measures significantly reduced adverse drug reactions. The effectiveness of safety measures implemented during the all-case surveillance of iguratimod was evaluated, revealing that early implementation of safety measures decreased the incidence of adverse drug reactions.

Therapeutic Response to Twice-daily Rabeprazole on Health-related Quality of Life and Symptoms in Patients with Refractory Reflux Esophagitis: A Multicenter Observational Study.

Objective To investigate the effect of twice-daily rabeprazole doses on health-related quality of life in refractory patients. Methods and Patients Reflux esophagitis patients with an insufficient response to once-daily proton pump inhibitor therapy (Los Angeles Classification grade A-D) received rabeprazole 10 mg or 20 mg twice daily for 8 weeks. The health-related quality of life (SF-8™) and symptoms, using the Frequency Scale for the Symptoms of Gastroesophageal reflux disease, were evaluated before treatment and at weeks 4 and 8. Endoscopy was performed at baseline and at weeks 8 and 32 where possible. The rabeprazole dose was determined by the attending physician. Results There were 1,796 patients analyzed for the efficacy of the twice-daily treatment. Of these cases, 1,462 were treated with rabeprazole 10 mg twice daily, and 334 were treated with rabeprazole 20 mg twice daily. The factors that affected the selection of the twice-daily rabeprazole dose by physicians were evaluated, and as expected, "endoscopic findings when treatment was started" had a strong effect on the selection of the rabeprazole dose. With both regimens, health-related quality of life and subjective symptoms were significantly improved at weeks 4 and 8 compared to baseline (p<0.001). The recurrence rate of erosive esophagitis at week 32 was 9.7% in rabeprazole twice daily-treated patients and 28.4% in proton pump inhibitor (PPI) once daily-treated patients. Both regimens were well tolerated. Conclusion Twice-daily treatment with rabeprazole improved the subjective symptoms and health-related quality of life in patients with refractory reflux esophagitis more effectively than the standard once-daily dose.

Endovascular operating suite: future directions for treating neurovascular disease.

OBJECT: The purpose of this study was to evaluate initial experiences in a surgical operating room (OR) with a multipurpose angiography unit, which offers integrated neurosurgical and radiological capabilities. METHODS: A specially designed biplane digital subtraction (DS) angiography system was installed in the neurosurgery OR. The new suite, which allows three-dimensional DS angiography with C-arm for computerized tomography and microsurgery capabilities, allows the neurosurgeon to perform a wide range of neurosurgical and endovascular procedures. Three hundred thirty-two procedures were performed in the endovascular OR between November 2003 and March 2005. Patients arriving in the emergency department were transferred to the endovascular OR without delay. The neurovascular team performed diagnostic angiography followed by endovascular interventional procedures or surgery. CONCLUSIONS: The newly designed endovascular OR facilitates safe and systemic treatment of neurovascular disease.

Imaging alterations due to squamous metaplasia in intracranial neurenteric cysts: A report of two cases.

Intracranial neurenteric cysts are rare congenital abnormalities with a broad imaging spectrum, and therefore are occasionally mistaken for other common intracranial cysts such as epidermoid and arachnoid cysts. We report two cases of neurenteric cysts in the posterior cranial fossa that were initially mistaken for other types of cysts. They exhibited signal intensity alterations in magnetic resonance imaging with significant volume expansion during their long-term observation. Both cases received surgical treatment because of clinical deterioration. Histologically, the cysts were lined by flattened or cuboidal epithelium, occasionally showing squamous metaplasia. Xanthogranulomatous inflammation and accumulation of cholesterol clefts, dry keratin and proteinaceous substance were observed in the cysts. These findings may indicate that chronic inflammation in neurenteric cysts induces squamous metaplasia, keratinization and high proteinaceous content, and causes MRI signal intensity alterations and volume expansion. We propose that MRI signal intensity alterations in neurenteric cysts may be a warning sign of their volume expansions, and thus require closer follow-up imaging and eventually surgical treatment.

BRAF V600E-mutated diffuse glioma in an adult patient: a case report and review.

Recent advances in genomic technology and genome-wide analysis have identified key molecular alterations that are relevant to the diagnosis and prognosis of brain tumors. Molecular information such as mutations in isocitrate dehydrogenase (IDH) genes or 1p/19q co-deletion status will be more actively incorporated into the histological classification of diffuse gliomas. BRAF V600E mutations are found frequently in circumscribed low-grade gliomas such as pleomorphic xanthoastrocytoma (PXA) and extra-cerebellar pilocytic astrocytoma, or epithelioid glioblastomas (E-GBM), a rare variant of GBM. This mutation is relatively rare in other types of diffuse gliomas, especially in adult onset cases. Here, we present an adult onset case of IDH wild-type/BRAF V600E-mutated diffuse glioma, evolving from grade III to grade IV. The tumor displayed atypical exophytic growth and had unusual histological features not fully compatible with, but indicative of PXA and E-GBM. We discuss differential diagnosis of the tumor, and review previously described diffuse gliomas with the BRAF V600E mutation.

Determining the Presence of Thin-Walled Regions at High-Pressure Areas in Unruptured Cerebral Aneurysms by Using Computational Fluid Dynamics.

BACKGROUND: Thin-walled regions (TWRs) of cerebral aneurysms are at high risk of rupture, and careful attention should be paid during surgical procedures. Despite this, an optimal imaging technique to estimate TWRs has not been established. Previously, pressure elevation at TWRs was reported with computational fluid dynamics (CFD) but not fully evaluated. OBJECTIVE: To investigate the possibility of predicting aneurysmal TWRs at high-pressure areas with CFD. METHODS: Fifty unruptured middle cerebral artery aneurysms were analyzed. Spatial and temporal maximum pressure (Pmax) areas were determined with a fluid-flow formula under pulsatile blood flow conditions. Intraoperatively, TWRs of aneurysm domes were identified as reddish areas relative to the healthy normal middle cerebral arteries; 5 neurosurgeons evaluated and divided these regions according to Pmax area and TWR correspondence. Pressure difference (PD) was defined as the degree of pressure elevation on the aneurysmal wall at Pmax and was calculated by subtracting the average pressure from the Pmax and dividing by the dynamic pressure at the aneurysm inlet side for normalization. RESULTS: In 41 of the 50 cases (82.0%), the Pmax areas and TWRs corresponded. PD values were significantly higher in the correspondence group than in the noncorrespondence group (P = .008). A receiver-operating characteristic curve demonstrated that PD accurately predicted TWRs at Pmax areas (area under the curve, 0.764; 95% confidence interval, 0.574-0.955; cutoff value, 0.607; sensitivity, 66.7%; specificity, 82.9%). CONCLUSION: A high PD may be a key parameter for predicting TWRs in unruptured cerebral aneurysms. ABBREVIATIONS: CFD, computational fluid dynamicsMCA, middle cerebral arteryPave, average pressurePD, pressure differencePmax, maximum pressureTWR, thin-walled regionWSS, wall shear stress.

Parallel insertion endoscopic technique for precise catheter placement in cystic craniopharyngiomas.

BACKGROUND: Total removal of craniopharyngioma is the most acceptable therapeutic modality; however, there are cases in which radical excision is not possible. To reduce the cystic component volume, an Ommaya reservoir catheter can be placed endoscopically. However, there are certain complications and risks with this type of maneuver, such as misplacement of the catheter, which may result in leakage of cyst contents or installed fluids such as bleomycin. Thus, accurate placement of intracystic catheter is extremely important. PATIENTS AND METHODS: The authors placed Ommaya reservoir catheters running over the outer surface of a transparent endoscopic sheath in three cases. RESULTS: This neuroendoscopic procedure permits easier manipulation of the catheter and precise placement of the catheter tip. This technique was useful for placement of Ommaya reservoir catheters. CONCLUSIONS: This new technique of catheter placement with neuroendoscopy is more accurate, safer, and less invasive.

Combined surgical and endovascular treatment of complex cerebrovascular diseases in the hybrid operating room.

BACKGROUND: Although most neurovascular diseases can be treated either by microsurgical or endovascular means, a subset of patients may require a combined approach. Patient transfer from the operating room (OR) to the angiosuite has been a fundamental drawback of this type of approach. OBJECTIVE: The purpose of this study is to report our clinical experience performing combined surgical and endovascular procedures for neurovascular diseases in the hybrid OR. METHODS: 29 patients with neurovascular diseases underwent combined endovascular and surgical procedures in a single session: 16 were scheduled combined treatment and 13 were emergency combined procedures. Of the emergency cases, three were rescue surgeries after endovascular complications. Three patients had ruptured intracranial aneurysms, eight had unruptured intracranial aneurysms, eight had arteriovenous malformations and eight had arteriovenous fistulae; two patients had either a spinal tumor or dural arteriovenous fistulae. RESULTS: All combined procedures were performed in a single session without changing the patient's surgical position. In cases of ruptured arteriovenous malformations or aneurysms with hematoma, an emergency embolization was performed to assist the surgical procedure. Combined superficial temporal artery-middle cerebral artery (STA-MCA) bypass followed by endovascular parent artery trapping were successfully performed for complex large or giant aneurysms. There were two periprocedural ischemic complications. Of the three patients who underwent surgical rescue after endovascular complications, two remained intact and one died despite immediate surgical procedures. CONCLUSION: A combined endovascular and surgical approach conducted in a hybrid OR provides a new strategy for the treatment of complex neurovascular diseases.

Robotic digital subtraction angiography systems within the hybrid operating room.

BACKGROUND: Fully equipped high-end digital subtraction angiography (DSA) within the operating room (OR) environment has emerged as a new trend in the fields of neurosurgery and vascular surgery. OBJECTIVE: To describe initial clinical experience with a robotic DSA system in the hybrid OR. METHODS: A newly designed robotic DSA system (Artis zeego; Siemens AG, Forchheim, Germany) was installed in the hybrid OR. The system consists of a multiaxis robotic C arm and surgical OR table. In addition to conventional neuroendovascular procedures, the system was used as an intraoperative imaging tool for various neurosurgical procedures such as aneurysm clipping and spine instrumentation. RESULTS: Five hundred one neurosurgical procedures were successfully conducted in the hybrid OR with the robotic DSA. During surgical procedures such as aneurysm clipping and arteriovenous fistula treatment, intraoperative 2-/3-dimensional angiography and C-arm-based computed tomographic images (DynaCT) were easily performed without moving the OR table. Newly developed virtual navigation software (syngo iGuide; Siemens AG) can be used in frameless navigation and in access to deep-seated intracranial lesions or needle placement. CONCLUSION: This newly developed robotic DSA system provides safe and precise treatment in the fields of endovascular treatment and neurosurgery.

Molecular rotor of Cs2([18]crown-6)3 in the solid state coupled with the magnetism of [Ni(dmit)2].

Nanoscale molecular rotors that can be driven in the solid state have been realized in Cs2([18]crown-6)3[Ni(dmit)2]2 crystals. To provide interactions between the molecular motion of the rotor and the electronic system, [Ni(dmit)2]- ions, which bear one S=1/2 spin on each molecule, were introduced into the crystal. Rotation of the [18]crown-6 molecules within a Cs2([18]crown-6)3 supramolecule above 220 K was confirmed using X-ray diffraction, NMR, and specific heat measurements. Strong correlations were observed between the magnetic behavior of the [Ni(dmit)2]- ions and molecular rotation. Furthermore, braking of the molecular rotation within the crystal was achieved by the application of hydrostatic pressure.

Cleavage of various peptides with pitrilysin from Escherichia coli: kinetic analyses using beta-endorphin and its derivatives.

Pitrilysin from Escherichia coli was overproduced, purified, and analyzed for enzymatic activity using 14 peptides as a substrate. Pitrilysin cleaved all the peptides, except for two of the smallest, at a limited number of sites, but showed little amino acid specificity. It cleaved beta-endorphin (beta-EP) most effectively, with a K(m) value of 0.36 microM and a k(cat) value of 750 min(-1). beta-EP consists of 31 residues and was predominantly cleaved by the enzyme at Lys(19)-Asn(20). Kinetic analyses using a series of beta-EP derivatives with N and/or C-terminal truncations and with amino acid substitutions revealed that three hydrophobic residues (Leu(14), Val(15), and Leu(17)) and the region 22-26 in beta-EP are responsible for high-affinity recognition by the enzyme. These two regions are located on the N- and C-terminal sides of the cleavage site in beta-EP, suggesting that the substrate binding pocket of pitrilysin spans its catalytic site.