Effects of edaravone against glomerular injury in rats with chronic puromycin aminonucleoside nephrosis

≪背景≫種々の病態により生じる酸化ストレスにより腎糸球体は組織学的な障害を受ける．Free radical scavengerであるエダラボンによる腎障害への保護効果はいくつか報告されている．この保護作用の機序を解明するため，我々は慢性 puromycine aminonucleoside (PAN) nephrosisモデルを用いて脂質過酸化のマーカーおよび腎組織学的検討を行った．≪方法≫慢性PANモデルは，PANを腹腔内投与し作成した（第1病日に130 mg/kg，腹腔内投与，第14病日に 60 mg/kg, 腹腔内投与）．ポジティブコントロール群(慢性PAN）(n＝4)，エダラボン投与群（慢性PAN＋Eda：Eda 3.0 mg/kg/day）（n＝4）の2群にグループ分けした．また，生理食塩水を腹腔内投与したwistarラット5匹をネガティブコントロール群とした．血液・尿を毎週採取し，実験終了日に麻酔下にラットより腎組織を採取した．≪結果≫慢性PAN＋Eda群では慢性PAN群に比べ，尿中アルブミン量および8-isoprostane排泄量の有意な低下を認めた(p＜0.01)．TBARSは，2群間で有意な差を認めなかった．組織学的検討では，慢性PAN＋Eda群がC-PAN群に比べ，糸球体障害度，4-hydroxy-2-nonenal（ 4-HNE）陽性面積(p＜0.01)，ED-1陽性細胞浸潤(p＜0.05)，アポトーシス細胞数の有意な減少(p＜0.05)を認めた．≪結論≫エダラボンのC-PAN群に対する投与により，尿中アルブミンを減少させ糸球体障害を改善することができた．慢性PANラットにおいて酸化ストレスおよび脂質過酸化に関連するマーカーは治療により減少し，マクロファージ浸潤および糸球体でのアポトーシス細胞の減少に相関していた．これら結果より，抗過酸化治療はC-PANにおいて糸球体障害軽減作用を有する可能性が示唆された． Excessive oxidants play roles in the pathogenesis of glomerular injury. Several studies have demonstrated protective effects of edaravone, a free radical scavenger, against renal injury. To clarify the protective effects of edaravone, we investigated changes in chemical markers of lipid peroxidation and renal histology in rats with chronic puromycin aminonucleoside (PAN) nephrosis (C-PAN). C-PAN was induced by intraperitoneal injections of PAN (130 mg/kg on day 1 and 60 mg/kg on day 14). Rats administered normal saline served as controls (n＝5). C-PAN rats were divided into two groups (each group: n＝4). In one group (C-PAN＋Eda), rats received 3.0 mg/kg/day of edaravone for five weeks. Blood and urinary samples were collected every week. Animals were sacrificed at the end of experiment for histological analysis. In C-PAN＋Eda rats, urinary excretion of albumin and 8-isoPGF2α were significantly decreased compared with that in C-PAN rats (p＜0.01), whereas levels of urinary thiobarbituric acid-reactive substances (TBARS) did not differ between the two groups. On histological examination, the scores for glomerular injury and area positive for 4-HNE were significantly lower in C-PAN＋Eda than in C-PAN rats (p＜0.05, p＜0.01, respectively). Infiltration of macrophages was also suppressed in C-PAN＋Eda rats. Edaravone treatment of C-PAN was able to decrease albuminuria and to ameliorate glomerular injury. Levels of several markers related to oxidative stress and lipid peroxidation were reduced after treatment, accompanied by reduction of macrophage infiltration and decrease in apoptotic cells in the glomeruli. These findings indicate that edaravone has protective effects against the glomerular injury observed in C-PAN nephrosis

Lumbar spinal stenosis: Assessment of cauda equina involvement by electrophysiological recordings

The objective of this study was to investigate the relationship between electrophysiological recordings and clinical as well as radiological findings in patients suggestive to suffer from a lumbar spinal stenosis (LSS). We hypothesise that the electrophysiological recordings, especially SSEP, indicate a lumbar nerve involvement that is complementary to the neurological examination and can provide confirmatory information in less obvious clinical cases. In a prospective cohort study, 54 patients scheduled for surgery due to LSS were enrolled in an unmasked, uncontrolled trial. All patients were assessed by neurological examination, electrophysiological recordings, and magnetic resonance imaging (MRI) of the lumbar spine. The electrophysiological recordings focused on spinal lumbar nerve involvement. Results: About 88% suffered from a multisegmental LSS and 91% of patients respectively complained of chronic lower back pain and/or leg pain for more than 3 months, combined with a restriction in walking distance. The neurological examination revealed only a few patients with sensory and/or motor deficits while 87% of patients showed pathological electrophysiological recordings (abnormal tibial SSEP in 78% of patients, abnormal H-reflex in 52% of patients). Conclusions: Whereas the clinical examination, even in severe LSS, showed no specific sensory-motor deficit, the electrophysiological recordings indicated that the majority of patients had a neurogenic disorder within the lumbar spine. By the pattern of bilateral pathological tibial SSEP and pathological reflexes associated with normal peripheral nerve conduction, LSS can be separated from a demyelinating polyneuropathy and mono-radiculopathy. The applied electrophysiological recordings, especially SSEP, can confirm a neurogenic claudication due to cauda equina involvement and help to differentiate neurogenic from vascular claudication or musculo-skeletal disorders of the lower limbs. Therefore, electro-physiological recordings provide additional information to the neurological examination when the clinical relevance of a radiologically-suspected LSS needs to be confirme

Score light

FinalistaAward-winningPostprint (published version

The Tobacco Control Scale as a research tool to measure country level tobacco control policy implementation

Introduction: The Tobacco Control Scale (TCS) was designed for advocacy purposes but has also been used as a research tool. In the present study, we characterized TCS use, its limitations and strengths, and critically assessed its use as a research instrument. Methods: We conducted an extensive search of the biomedical databases PubMed and Web of Science for the keyword 'tobacco control scale' in all fields. The search was limited to studies published in the period March 2006 to December 2019. Out of 69 hits, 32 studies met the inclusion criteria. Two reviewers independently extracted information from each publication regarding their general characteristics, publication and research aspects, and the characteristics of the use of the TCS. Results: We found that researchers have used the TCS as a tool to monitor tobacco control policies mainly in cross-sectional observational studies with ecological and multilevel designs directed to advocacy and the promotion of further research. Different outcomes, such as smoking prevalence and quit ratios, have been associated with tobacco control policy scores. The main reported limitations of the TCS were a low variance across countries and a failure to express enforcement and to incorporate the most recent legislation. Conclusions: The TCS has been commonly used to assess differences in outcomes according to tobacco control policies. However, there are still areas for improvement in its use in research regarding the lack of comparability of TCS scores across time. The lessons that have been learned should be used to adapt and expand the TCS overseas

Interaction Dynamics in Oscillator and Human-in-the-loop Systems.

This dissertation addresses control system analysis and system identification in three areas: error propagation in synchronization of harmonic oscillators, modeling of human active movement, and identification of human control strategies in manual pursuit tracking. 1) While most studies of synchronization in oscillator systems have focused on the existence of synchronous solutions in steady state, many problems pertaining to the transient dynamics have not been fully resolved. We extend the well-established theory of fundamental limitations to study the transient error propagation (string stability) in a string of synchronized harmonic oscillators. We first translate design requirements in terms of time-domain response and hardware limitations into a set of constraints on closed-loop frequency response. We further capture the conflict between string stability on the one hand and time-domain design requirements and hardware limitations on the other through a new Bode integral. 2) Modeling human active movement is a challenging problem not only because muscle has very sophisticated and highly nonlinear dynamics but also because neural and other signals internal to the body are difficult to observe directly. We seek a simple yet general and competent model to describe active movement in object manipulation tasks. Inspired by the Norton equivalent circuit in electrical engineering, we build a model based on the motion and force/torque signals that may be observed at the points of contact between the human body and the environment. The model consists of a motion source to represent a human's motor plan and a spring-mass-damper coupler to capture the time-varying driving point impedance of the human hand. The model is validated using occasional experimental trials in which a participant experiences unexpected loads in a grasp and twist task. 3) Although a large amount of literature has provided methods to identify feedback control in manual tracking tasks, very little research has been undertaken to experimentally identify feedforward control. We capitalize on the theory of fundamental limitations to study the link between a human's ability to simultaneously reject disturbances and perform pursuit tracking. We further develop an identification method to separate human feedback and feedforward control strategies in sinusoidal tracking tasks.PhDMechanical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/108853/1/ybo_1.pd

Assessment of Water Quality Index, Light Attenuation, and Nutrient Sequestering by Submerged Aquatic Vegetation in the Detroit River

This thesis assessed water quality – submerged aquatic vegetation interactions in the Detroit River. Submerged aquatic vegetation provides essential ecosystem services that support aquatic biodiversity and regulating ecosystem services such as carbon sinks, purifying water and nutrient cycling. Chapter 2 explored how degraded water quality in the Detroit River limits submerged aquatic vegetation via light limitation. A water quality index and light extinction coefficients were measured at 21 sites along with installation of in-situ water quality sondes at 4 sites to measure water quality at high temporal resolution. The river wide median euphotic depth was estimated to be 1.30 m, higher (1.34 m) at sites without tributary inflow compared sites that receive tributary inflow (0.83 m). Measured light extinction coefficients were correlated with water quality index scores. However, a multivariate PCA model predicting light extinction coefficient from chlorophyll a, turbidity and specific conductivity yielded the best prediction. Light attenuation appears to be driven by different water quality constitutes at different sites and over time. Chapter 3 tested nutrient drawdown by submerged aquatic vegetation at 5 wetlands. There was no evidence for phosphorus drawdown but nitrogen drawdown was apparent at one bed site. This thesis supports a conclusion for light limitation of submerged aquatic macrophytes at tributary influenced locations implying actions to improve tributary water quality will benefit the Detroit River. However, expanding macrophyte bed coverage is unlikely to address phosphorus reduction targets mandated for the Detroit River

Classifying Appliances Operation Modes Using Dynamic Time Warping (DTW) And K Nearest Neighbors (KNN)

In the Smart Grid environment, the advent of intelligent measuring devices facilitates monitoring appliance electricity consumption. This data can be used in applying Demand Response (DR) in residential houses through data analytics, and developing data mining techniques. In this research, we introduce a smart system approach that is applied to user\u27s disaggregated power consumption data. This system encourages the users to apply DR by changing their behaviour of using heavier operation modes to lighter modes, and by encouraging users to shift their usages to off-peak hours. First, we apply Cross Correlation to detect times of the occurrences when an appliance is being used. We then use two approaches to recognize the operation mode used: The Dynamic Time Warping (DTW), and Machine Learning using K-Means and K-Nearest Neighbors (KNN)

ANTIBODIES TO INFLIXIMAB IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE: CLINICAL AND MOLECULAR TARGETS

Infliximab was the first biological therapy to be approved for use in inflammatory bowel disease (IBD). Similar to other biological therapies, secondary loss of response to infliximab occurs in up to 50% of patients at 1 year follow up. In the case of infliximab, antibodies to infliximab (ATI) are likely to contribute towards secondary loss of response. This PhD thesis aims to identify the associated clinical outcomes of ATI, assess a strategy of infliximab dose escalation (DE) and to identify epitopes on infliximab using phage display. In a retrospective review of 214 patients, ATI were detected in 64% of patients during the first year of infliximab treatment. They were significantly associated with loss of clinical response, reduced infliximab levels and adverse drug reactions. Assessment of infliximab DE in 92 patients with subtherapeutic drug levels, showed it was effective at significantly increasing infliximab levels in those with and without ATI. DE was also associated with a high rate of clinical remission at 6 months. Pooled sera from eight patients with positive ATI and differing clinical outcomes was used for biopanning of two phage display libraries. Three distinct linear epitopes were heavily enriched from a novel whole gene fragment library (GFL), all mapped to complementarity determining regions of infliximab. Using a random peptide library (RPL), three different peptides were enriched. Using Pepsurf, a mimotope prediction programme, three conformational epitopes were predicted using the enriched peptides. One of the predicted epitopes from the RPL overlapped with a linear epitope selected from the GFL. In increasing our understanding of immunogenicity to infliximab, this may lead to an identification of an epitope associated with loss of response, a biomarker, and will help aid treatment decisions when ATI are detected