bluuebunny/crossref_metadata_2025 huggingface dataset:
The μ-opioid receptor agonist DAMGO presynaptically suppresses solitary tract-evoked input to neurons in the rostral solitary nucleus
Authors: Boxwell Alison J. , Yanagawa Yuchio , Travers Susan P. , Travers Joseph B.
Published: March 2013

Taste processing in the rostral nucleus of the solitary tract (rNST) is subject to modulatory influences including opioid peptides. Behavioral pharmacological studies suggest an influence of μ-opioid receptors in rNST, but the underlying mechanism is unknown. To determine the cellular site of action, we tested the effects of the μ-opioid receptor agonist DAMGO in vitro. Whole cell patch-clamp recordings were made in brain stem slices from GAD67-GFP knockin mice expressing enhanced green fluorescent protein (EGFP) under the control of the endogenous promoter for GAD67, a synthetic enzyme for GABA. Neuron counts showed that ∼36% of rNST neurons express GABA. We recorded monosynaptic solitary tract (ST)-evoked currents (jitter ≤ 300 μs) in both GAD67-EGFP-positive (GAD67+) and GAD67-EGFP-negative (GAD67−) neurons with equal frequency (25/31; 22/28), but the inputs to the GAD67+ neurons had significantly smaller paired-pulse ratios compared with GAD67− neurons. DAMGO (0.3 μM) significantly suppressed ST-evoked currents in both cell types (mean suppression = 46 ± 3.3% SE), significantly increased the paired-pulse ratio of these currents, and reduced the frequency of spontaneous miniature excitatory postsynaptic currents but did not diminish their amplitude, indicating a presynaptic site of action. Under inhibitory amino acid receptor blockade, DAMGO was significantly more suppressive in GAD67+ neurons (59% reduction) compared with GAD67− neurons (35% reduction), while the reverse was true in normal artificial cerebrospinal fluid (GAD67+: 35% reduction; GAD67−: 57% reduction). These findings suggest that DAMGO suppresses activity in rNST neurons predominantly via a presynaptic mechanism, and that this effect may interact significantly with tonic or evoked inhibitory activity.
Unusual Root Canal Morphology of the Maxillary Second Molar: A Case Report
Authors: Şımşek Neslihan , Keleş Ali , Bulut Elçin Tekın
Published: March 2013

Introduction. This clinical case report presents the successful endodontic treatment of a maxillary second molar that has a mandibular molar-like anatomy with no palatal root and with each of its roots containing two separate root canals. Cone-beam computed tomography (CBCT) was used to confirm this unusual anatomy.Methods. A 34-year-old male patient was referred to the Department of Endodontics at Inonu University’s Faculty of Dentistry because of severe pain in his right maxillary second molar. Clinical and radiographic examinations identified unusual roots and root canals anatomy, and CBCT was planned in order to understand the nature of these variations. Cleaning and shaping procedures were performed using the crown down technique with Sybron Endo (Glendora, CA, USA) rotary instruments, and endodontic treatment was completed with gutta-percha cones and AH Plus resin sealers using the cold lateral compaction technique.Conclusions. The maxillary second molar exhibits aberrations and variations in terms of the numbers and configurations of its roots and root canals, and CBCT can be a useful imaging technique in endodontics.
Investigations on Performance and Emission Characteristics of Diesel Engine with Biodiesel (Jatropha Oil) and Its Blends
Authors: Pandhare Amar , Padalkar Atul
Published: March 2013

This paper presents the performance of biodiesel blends in a single-cylinder water-cooled diesel engine. All experiments were carried out at constant speed 1500 rpm and the biodiesel blends were varied from B10 to B100. The engine was equipped with variable compressions ratio (VCR) mechanism. For 100% Jatropha biodiesel, the maximum fuel consumption was 15% higher than that of diesel fuel. The brake thermal efficiency for biodiesel and its blends was found to be slightly higher than that of diesel at various load conditions. The increase in specific fuel consumption ranged from 2.75% to 15% for B10 to B100 fuels. The exhaust gas temperature increased with increased biodiesel blend. The highest exhaust gas temperature observed was 430°C with biodiesel for load conditions 1.5 kW, 2.5 kW, and 3.5 kW, where as for diesel the maximum exhaust gas temperature was 440°C. The CO2emission from the biodiesel fuelled engine was higher by 25% than diesel fuel at full load. The CO emissions were lower with Jatropha by 15%, 13%, and 13% at 1.5 kW, 2.5 kW, and 3.5 kW load conditions, respectively. TheNOxemissions were higher by 16%, 19%, and 20% at 1.5 kW, 2.5 kW, and 3.5 kW than that of the diesel, respectively.
Oyaksungisan, a Traditional Herbal Formula, Inhibits Cell Proliferation by Induction of AutophagyviaJNK Activation in Human Colon Cancer Cells
Authors: Yim Nam-Hui , Jung Young Pil , Kim Aeyung , Ma Choong Je , Cho Won-Kyung , Ma Jin Yeul
Published: March 2013

Oyaksungisan (OY) is a traditional herbal formula broadly used to treat beriberi, vomiting, diarrhea, and circulatory disturbance in Asian countries from ancient times. The effect of OY on cancer, however, was not reported until now. In this study, we have demonstrated that OY inhibits cell proliferation and induces cell deathviamodulating the autophagy on human colon cancer cells. In HCT116 cells, OY increased the ratio of LC3-II/LC3-I, a marker of autophagy, and treatment with 3-MA, an inhibitor of autophagy, and considerably reduced the formation of autophagosomes. In addition, OY regulated mitogen-activated protein kinase (MAPK) cascades; especially, JNK activation was closely related with autophagy effect by OY in HCT116 cells. Our results indicate that autophagy induction is responsible for the antiproliferative effect by OY, despite the weak apoptosis induction in HCT116 cells. In conclusion, OY might have a potential to be developed as an herbal anticancer remedy.
An Intelligent System Approach for Asthma Prediction in Symptomatic Preschool Children
Authors: Chatzimichail E. , Paraskakis E. , Sitzimi M. , Rigas A.
Published: March 2013

Objectives. In this study a new method for asthma outcome prediction, which is based on Principal Component Analysis and Least Square Support Vector Machine Classifier, is presented. Most of the asthma cases appear during the first years of life. Thus, the early identification of young children being at high risk of developing persistent symptoms of the disease throughout childhood is an important public health priority.Methods. The proposed intelligent system consists of three stages. At the first stage, Principal Component Analysis is used for feature extraction and dimension reduction. At the second stage, the pattern classification is achieved by using Least Square Support Vector Machine Classifier. Finally, at the third stage the performance evaluation of the system is estimated by using classification accuracy and 10-fold cross-validation.Results. The proposed prediction system can be used in asthma outcome prediction with 95.54 % success as shown in the experimental results.Conclusions. This study indicates that the proposed system is a potentially useful decision support tool for predicting asthma outcome and that some risk factors enhance its predictive ability.
Influence of Block of NF-Kappa B Signaling Pathway on Oxidative Stress in the Liver Homogenates
Authors: Kleniewska Paulina , Piechota-Polanczyk Aleksandra , Michalski Lukasz , Michalska Marta , Balcerczak Ewa , Zebrowska Marta , Goraca Anna
Published: March 2013

The aim of the present study was to assess whether BAY 11-7082, a nuclear factor-kappaB (NF-κB) inhibitor, influences the level of reactive oxygen species (ROS), tumor necrosis factor alpha (TNF-α), and NF-κB related signaling pathways in the liver. The animals were divided into 4 groups: I: saline; II: saline + endothelin-1 (ET-1) (1.25 μg/kg b.w., i.v.); III: saline + ET-1 (12.5 μg/kg b.w., i.v.); and IV: BAY 11-7082 (10 mg/kg b.w., i.v.) + ET-1 (12.5 μg/kg b.w., i.v.). Injection of ET-1 alone at a dose of 12.5 μg/kg b.w. showed a significant (P<0.001) increase in thiobarbituric acid reactive substances (TBARS) and hydrogen peroxide (H2O2) level and decrease (P<0.01) in GSH level (vs. control). ET-1 administration slightly downregulated gene expression of p65 of NF-κB but potently and in a dose-dependent way downregulated p21-cip gene expression in the liver. BAY 11-7082 significantly decreased TBARS (P<0.001), H2O2(P<0.01) and improved the redox status (P<0.05), compared to ET-1 group. The concentration of TNF-αwas increased in the presence of ET-1 (P<0.05), while BAY 11-7082 decreased TNF-αconcentration (P<0.01). Inhibition of IkBαbefore ET-1 administration downregulated gene expression of p21-cip but had no effect on p65.
Time of Day Does Not Modulate Improvements in Motor Performance following a Repetitive Ballistic Motor Training Task
Authors: Sale Martin V. , Ridding Michael C. , Nordstrom Michael A.
Published: March 2013

Repetitive performance of a task can result in learning. The neural mechanisms underpinning such use-dependent plasticity are influenced by several neuromodulators. Variations in neuromodulator levels may contribute to the variability in performance outcomes following training. Circulating levels of the neuromodulator cortisol change throughout the day. High cortisol levels inhibit neuroplasticity induced with a transcranial magnetic stimulation (TMS) paradigm that has similarities to use-dependent plasticity. The present study investigated whether performance changes following a motor training task are modulated by time of day and/or changes in endogenous cortisol levels. Motor training involving 30 minutes of repeated maximum left thumb abduction was undertaken by twenty-two participants twice, once in the morning (8 AM) and once in the evening (8 PM) on separate occasions. Saliva was assayed for cortisol concentration. Motor performance, quantified by measuring maximum left thumb abduction acceleration, significantly increased by 28% following training. Neuroplastic changes in corticomotor excitability of abductor pollicis brevis, quantified with TMS, increased significantly by 23% following training. Training-related motor performance improvements and neuroplasticity were unaffected by time of day and salivary cortisol concentration. Although similar neural elements and processes contribute to motor learning, training-induced neuroplasticity, and TMS-induced neuroplasticity, our findings suggest that the influence of time of day and cortisol differs for these three interventions.
Emu Oil Reduces Small Intestinal Inflammation in the Absence of Clinical Improvement in a Rat Model of Indomethacin-Induced Enteropathy
Authors: Abimosleh Suzanne M. , Tran Cuong D. , Howarth Gordon S.
Published: March 2013

Nonsteroidal-anti-inflammatory-drug (NSAID) enteropathy is characterized by small intestinal damage and ulceration. Emu Oil (EO) has previously been reported to reduce intestinal inflammation.Aim. We investigated EO for its potential to attenuate NSAID-enteropathy in rats.Methods. Male Sprague Dawley rats (n=10/group) were gavaged with Water, Olive Oil (OO), or EO (0.5 mL; days 0–12) and with 0.5 mL Water or the NSAID, Indomethacin (8 mg/kg; days 5–12) daily. Disease activity index (DAI), 13C-sucrose breath test (SBT), organ weights, intestinal damage severity (IDS), and myeloperoxidase (MPO) activity were assessed.P<0.05was considered significant.Results. In Indomethacin-treated rats, DAI was elevated (days 10–12) and SBT values (56%) and thymus weight (55%) were decreased, relative to normal controls. Indomethacin increased duodenum (68%), colon (24%), SI (48%), caecum (48%), liver (51%) and spleen (88%) weights, IDS scores, and MPO levels (jejunum: 195%, ileum: 104%) compared to normal controls. Jejunal MPO levels were decreased (64%) by both EO and OO, although only EO decreased ileal MPO (50%), compared to Indomethacin controls.Conclusions. EO reduced acute intestinal inflammation, whereas other parameters of Indomethacin-induced intestinal injury were not affected significantly. Increased EO dose and/or frequency of administration could potentially improve clinical efficacy.
Bifurcations of a Ratio-Dependent Holling-Tanner System with Refuge and Constant Harvesting
Authors: Liu Xia , Xing Yepeng
Published: March 2013

The bifurcation properties of a predator prey system with refuge and constant harvesting are investigated. The number of the equilibria and the properties of the system will change due to refuge and harvesting, which leads to the occurrence of several kinds bifurcation phenomena, for example, the saddle-node bifurcation, Bogdanov-Takens bifurcation, Hopf bifurcation, backward bifurcation, separatrix connecting a saddle-node and a saddle bifurcation and heteroclinic bifurcation, and so forth. Our main results reveal much richer dynamics of the system compared to the system with no refuge and harvesting.
The Treatment of Recurrent Urothelial Tumors of the Upper Urinary System and at Urostomy Site following Radical Cystectomy with Intraureteral Bacillus Calmette-Guérin and Cryotherapy
Authors: Demirtaş Abdullah , Yıldırım Yunus Emre , Ferahbaş Ayten , Akınsal Emre Can , Ekmekçioğlu Oguz , Tatlışen Atila
Published: March 2013

Urinary bladder carcinoma is the second most common cancer of the urinary system. The recurrence rate in the upper urinary system (UUS) for urothelial cancers is around 3% following radical cystectomy. The followup generally consists of imaging studies and urinary cytology, although there are no prospective data on the frequency, the mode, and the duration of followup. In patients carefully selected according to risk factors, kidney-sparing minimally invasive methods (ureteroscopic procedures, percutaneous approach, and local drug instillation) appear as contemporary alternatives for low-grade and low-stage primary UUS. In this paper, we present the patient who underwent radical cystectomy with urinary diversion ureterocutaneostomy, was diagnosed with widespread bilateral UUS tumors and recurrent tumor at the urostomy site at active followup, for which he was given local Bacillus Calmette-Guérin (BCG) and cryotherapy, and was followed by disease-free for 2 years thereafter.
Corneal Transplant Infection due toAlternaria alternata: A Case Report
Authors: Konidaris Vasileios , Mersinoglou Andreana , Vyzantiadis Timoleon-Achilleas , Papadopoulou Domniki , Boboridis Kostas G. , Ekonomidis Panagiotis
Published: March 2013

Purpose. To report a case ofAlternaria alternatakeratitis in a patient with a corneal transplant in her right eye due to bullous pseudophakic keratopathy.Methods. A 66-year-old female underwent a full-thickness keratoplasty in her right eye due to bullous pseudophakic keratopathy. Three weeks after keratoplasty, epithelial edema and a stromal opacity with an infiltrate and development of peripheral corneal opacities appeared. The diagnosis ofAlternaria alternatakeratitis was made.Results. The patient underwent a second keratoplasty, due to the corneal melting as a result of the fungal infection. She was also given combined antifungal treatment locally and systematically.Conclusion. Corneal transplantation alone would not have been sufficient to keep the fungus in the anterior portion of the eye. Combined antifungal treatment, locally and systematically, was important in attempting to prevent the further spread of the fungus to the interior of the eye. To our knowledge, the case presented here is only the second one in the literature concerning a keratomycosis due toAlternaria alternatacorneal transplant infection.
Pycnodysostosis: An Anaesthetic Approach to This Rare Genetic Disorder
Authors: Puri Rajeev , Saxena Arpita , Mittal Awak , Arshad Zia , Dwivedi Yogita , Chand Trilok , Mittal Apurva , Agrawal Archna , Prakash Jay , Pilendran Sathiyanarayanan
Published: March 2013

Pycnodysostosis (the Toulouse-Lautrec syndrome) is a rare autosomal-recessive disorder of osteoclast dysfunction. This disorder was first described by Maroteaux and Lamy in 1962. We describe anaesthetic management of a 35-year-old female having pyknodysostosis with fracture shaft left femur with anticipated difficult intubation. Therefore, spinal anesthesia was planned for her fracture fixation. The intra- and postoperative period remains uneventful.
Diversity of Mitochondrial Pathology in a Mouse Model of Axonal Degeneration in Synucleinopathies
Authors: Sekigawa Akio , Takamatsu Yoshiki , Sekiyama Kazunari , Takenouchi Takato , Sugama Shuei , Waragai Masaaki , Fujita Masayo , Hashimoto Makoto
Published: March 2013

There is mounting evidence for a role of mitochondrial dysfunction in the pathogenesis ofα-synucleinopathies such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In particular, recent studies have demonstrated that failure of mitochondrial quality control caused by loss of function of the PTEN-induced kinase 1 (PINK1, PARK6) Parkin (PARK2) pathway may be causative in some familial PD. In sporadic PD,α-synuclein aggregation may interfere with mitochondrial function, and this might be further exacerbated by leucine-rich repeat kinase 2 (LRRK2). The majority of these findings have been obtained inDrosophilaand cell cultures, whereas the objective of this paper is to discuss our recent results on the axonal pathology of brains derived from transgenic mice expressingα-synuclein or DLB-linked P123Hβ-synuclein. In line with the current view of the pathogenesis of sporadic PD, mitochondria abnormally accumulated inα-synuclein/LRRK2-immunopositive axonal swellings in mice expressingα-synuclein. Curiously, neither mitochondria nor LRRK2 was present in the swellings of mice expressing P123Hβ-synuclein, suggesting thatα- andβ-synuclein might play differential roles in the mitochondrial pathology ofα-synucleinopathies.
Assessment of Carotid Atherosclerosis in Type 2 Diabetes Mellitus Patients with Microalbuminuria by High-Frequency Ultrasonography
Authors: Zhang Yu-Hong , Gao Yuan , Mao Xin , Shang Jing , Su Ben-Li
Published: March 2013

The aim of this study is to evaluate carotid atherosclerosis in patients of type 2 diabetes mellitus with microalbuminuria (MA) by high-frequency ultrasonography. Two hundred and fifty patients of type 2 diabetes mellitus were divided into two groups according to urinary albumin excretion rate (UAER): normoalbuminuria group (130 cases) and microalbuminuria group (120 cases). The intimal-medial thickness (IMT) and the atherosclerotic plaques of carotid artery were observed in both groups by high-frequency ultrasound. Fasting blood glucose (FBG), hemoglobin A1c, and lipid profiles were measured. The values of IMT of microalbuminuria group were significantly higher than those of normoalbuminuria group (P<0.05). In univariate analysis, IMT was positively and significantly associated with age (r=0.265,P<0.05), waist circumference (r=0.263,P<0.05), body mass index (r=0.285,P<0.05), systolic blood pressure (r=0.276,P<0.05), UAER (r=0.359,P<0.05), HbA1c (r=0.462,P<0.05) and, duration of diabetes (r=0.370,P<0.05). In multivariate linear regression analysis, UAER and HbA1c were independent predictors of IMT (P<0.05for all). In the two groups, the rate of soft plaques was higher than that of dense plaques and calcified plaques. In conclusion, there is a significant association between microalbuminuria and IMT which is regarded as the early sign of carotid atherosclerosis in type 2 diabetic patients.
Chimerism-Based Experimental Models for Tolerance Induction in Vascularized Composite Allografts: Cleveland Clinic Research Experience
Authors: Siemionow Maria , Klimczak Aleksandra
Published: March 2013

The preclinical experimental models of vascularized composite allografts (VCAs) have been rapidly developed for the assessment of immunomodulatory protocols for clinical application. Recently, researchers have focused on immunomodulatory protocols which overcome the immunologic barrier between the allogeneic donor and recipient and may lead to tolerance induction. In order to test the feasibility of chimerism induction, experimental VCAs have been performed in different models including rodents, large animals, and nonhuman primates. These models differ in the complexity of transplanted tissue and in their responses to immunomodulatory protocols. In most applications, VCA contains multiple-tissue components; however, each individual component of CTA possesses unique immunologic characteristics that ultimately contribute to the chimerism induction and successful outcome of the VCA. Heterogenic character and complexity of tissue components in different VCA models determine the quality and robustness of donor-specific chimerism. As introduced in experimental studies, variable immunomodulatory options have been studied to achieve tolerance to VCA in rodents and large animal models allowing for widespread application in clinic. In this paper, based on our own experience, we have analyzed the current knowledge of tolerance-inducing strategies via chimerism induction in VCA experimental models in the context of immunomodulatory protocols and VCA complexity and their relevance and applicability to clinical practice.
On the Classification of Lattices Over Which Are Even Unimodular -Lattices of Rank 32
Authors: Henn Andreas , Hentschel Michael , Krieg Aloys , Nebe Gabriele
Published: March 2013

We classify the lattices of rank 16 over the Eisenstein integers which are even unimodular -lattices (of dimension 32). There are exactly 80 unitary isometry classes.
A Compound Fuzzy Disturbance Observer Based on Sliding Modes and Its Application on Flight Simulator
Authors: Wu Yunjie , Liu Youmin , Tian Dapeng
Published: March 2013

A compound fuzzy disturbance observer based on sliding modes is developed, and its application on flight simulator is presented. Fuzzy disturbance observer (FDO) is an effective method in nonlinear control. However, traditional FDO is confined to monitor dynamic disturbance, and the frequency bandwidth of the system is restricted. Sliding mode control (SMC) compensates the high-frequency component of disturbance while it is limited by the chattering phenomenon. The proposed method uses the sliding mode technique to deal with the uncompensated dynamic equivalent disturbance. The switching gain of sliding mode control designed according to the error of disturbance estimation is a small value. Therefore, the proposal also helps to decrease the chattering. The validity of the proposal method is confirmed by experiments on flight simulator.
Design, Dynamics, and Workspace of a Hybrid-Driven-Based Cable Parallel Manipulator
Authors: Zi Bin , Cao Jianbin , Zhu Zhencai , Mitrouchev Peter
Published: March 2013

The design, dynamics, and workspace of a hybrid-driven-based cable parallel manipulator (HDCPM) are presented. The HDCPM is able to perform high efficiency, heavy load, and high-performance motion due to the advantages of both the cable parallel manipulator and the hybrid-driven planar five-bar mechanism. The design is performed according to theories of mechanism structure synthesis for cable parallel manipulators. The dynamic formulation of the HDCPM is established on the basis of Newton-Euler method. The workspace of the manipulator is analyzed additionally. As an example, a completely restrained HDCPM with 3 degrees of freedom is studied in simulation in order to verify the validity of the proposed design, workspace, and dynamic analysis. The simulation results, compared with the theoretical analysis, and the case study previously performed show that the manipulator design is reasonable and the mathematical models are correct, which provides the theoretical basis for future physical prototype and control system design.
Efficacy and Safety of MLC601 (NeuroAiD®), a Traditional Chinese Medicine, in Poststroke Recovery: A Systematic Review
Authors: Siddiqui Fahad Javaid , Venketasubramanian Narayanaswamy , Chan Edwin Shih-Yen , Chen Christopher
Published: March 2013

Background: Subsequent to a pooled analysis of 2 trials, several more studies have been published assessing the benefit of MLC601 in stroke patients. Hence, it is timely to conduct an updated meta-analysis to frame the interpretation of the results of an ongoing large multicenter, randomized, double-blind, placebo-controlled study. Therefore, we conducted a systematic review of the efficacy of MLC601 in improving the recovery of stroke patients. Methods: PubMed® and the Cochrane Library® databases were searched for trials evaluating MLC601 in stroke patients. Primary outcome was functional independence, assessed by the Barthel Index or the Diagnostic Therapeutic Effects of Apoplexy scoring system, item 8. Secondary outcomes were improvement in functional independence scores, motor recovery, reduction in visual field defect and increase in cerebral blood flow. Two authors performed the article selection, appraisal and data extraction while resolving differences through discussion or consulting a third author. Data were analyzed in RevMan5®. Meta-analysis was conducted using a random effects model. Results: This review included 6 studies with overall low risk of bias but some clinical heterogeneity. MLC601 increased the chances of achieving functional independence after stroke compared to control treatments (risk ratio, 2.35; 95% CI, 1.31-4.23). No deaths and 4 serious adverse events were reported in the MLC601 group, although detail was sparse with inconsistent reporting. Conclusions: There is evidence that MLC601 as an add-on to standard treatment could be effective in improving functional independence and motor recovery and is safe for patients with primarily nonacute stable stroke.
Effect of Magnesium Supplementation on Carotid Intima-Media Thickness and Flow-Mediated Dilatation among Hemodialysis Patients: A Double-Blind, Randomized, Placebo-Controlled Trial
Authors: Mortazavi Mojgan , Moeinzadeh Firouzeh , Saadatnia Mohammad , Shahidi Shahrzad , McGee Jeanie C. , Minagar Alireza
Published: March 2013

Objectives: The aim of the present study was to determine the efficacy of oral magnesium (Mg) supplementation on endothelial function through evaluation of carotid intima-media thickness (cIMT), brachial artery flow-mediated dilatation (FMD), and C-reactive protein (CRP) among hemodialysis (HD) patients. Methods: This randomized, controlled, double-blind clinical trial consisted of 54 patients on HD. One group was treated orally with 440 mg of Mg oxide 3 times per week for 6 months (n = 29). The control group (n = 25) was given placebo using the same administration protocol. cIMT, FMD, serum calcium levels, phosphorus, lipid, CRP, and bicarbonate were measured at baseline and at 6 months in both groups. Results: At 6 months, cIMT was significantly decreased in the Mg group (0.84 ± 0.13 mm at baseline and 0.76 ± 0.13 mm at 6 months, p = 0.001). However, in the placebo group, cIMT was significantly increased (0.73 ± 0.13 and 0.79 ± 0.12 mm, respectively, p = 0.003). When hypertension, diabetes mellitus, smoking, hyperlipidemia, and systemic lupus erythematosus were controlled for in the analysis, the effect of Mg remained significant in both groups (p = 0.000). Conclusion: Our results indicate that Mg might not improve endothelial function (CRP level and FMD) and that a decreased cIMT as a marker of atherosclerosis may be due to the inhibition of calcification through the regulation parathormone, calcium, and phosphorus.
Defatted Milk Is Preferred by Mexican School-Age Children over Whole Milk in a Sensorial Study
Authors: Lara-Zamudio Yaveth , Villalpando Salvador , Shamah-Levy Teresa , Mundo-Rosas Verónica , Contreras-Manzano Alejandra , Lamadrid-Figueroa Hector
Published: March 2013

Objective: To compare the liking, flavor and texture of whole, partially defatted and defatted cow's milk using sensory tests. Materials and Methods: Children aged 6-16 years, living in indigenous boarding schools in the State of Hidalgo, Mexico, tested samples of whole, partially defatted and defatted cow's milk and answered a questionnaire that explored liking, flavor and texture through ad hoc designed scales. The differences in response proportions were analyzed by χ2 tests and multinomial logistic regression models. Results: Tests were completed by 165 children (79 girls and 86 boys). Rated by habitual consumers of whole, partially defatted and defatted milk, liking (70.6-77.8%, liked it very much), flavor (72.5-77.8%, very tasteful) and texture (41.3-54.9%, not creamy or watery) were better rated for defatted than for whole milk [liking (19.6-29.4%, p < 0.001, liked it very much), flavor (19.6-39.7%, p < 0.001, very tasty) and texture (27.5-39.2%, p < 0.05, not creamy or watery)]. The global preference was higher for defatted (74.5-81.0%) than for whole milk (6.3-15.7%, p < 0.001). Conclusions: Defatted milk (0.5%) can be introduced into public programs to reduce the saturated fat intake or control obesity in children older than 6 years in elementary schools.
Vitamin D Receptor Activators Upregulate and Rescue Podocalyxin Expression in High Glucose-Treated Human Podocytes
Authors: Verouti S.N. , Tsilibary E.C. , Fragopoulou E. , Iatrou C. , Demopoulos C.A. , Charonis A.S. , Charonis S.A. , Drossopoulou G.I.
Published: March 2013

Background: Vitamin D is beneficial in human and experimental chronic kidney disease, the leading cause of which is diabetic nephropathy. Vitamin D through its receptor, VDR, provides renal protection in diabetic nephropathy, but limited data exist about its effect on podocytes. Renal podocytes form the main filtration barrier possessing a unique phenotype maintained by proteins including podocalyxin and nephrin, the expression of which is suppressed in pathological conditions. Methods: We used immortalized human podocytes (human glomerular epithelial cells, HGEC) to assess podocalyxin and nephrin expression after treatment with 1,25-dihydroxyvitamin D3 (calcitriol) and its analogue paricalcitol. The involvement of VDR was investigated by silencing with hVDR-siRNA and ChIP analysis. Results: HGEC exhibit high glucose-mediated downregulation of podocalyxin and nephrin, loss of which has been linked with loss of the permselective renal barrier and proteinuria. Calcitriol and paricalcitol reversed high glucose-induced decrease of nephrin and significantly enhanced podocalyxin expression in podocytes cultured in high glucose. HGEC express VDR and retinoid X receptor (RXR). In the presence of calcitriol and paricalcitol, VDR expression was upregulated and VDR colocalized with RXR in the nucleus. VDR knockdown abolished the protective action of calcitriol and paricalcitol on podocalyxin expression indicating that podocalyxin activation of expression is partly mediated by VDR. Furthermore, VDR specifically regulates podocalyxin expression by bounding to a site upstream of the podocalyxin promoter. Conclusion: Vitamin D analogues maintain and, furthermore, re-activate the expression of specialized components of podocytes including podocalyxin, hence they provide protection against loss of the permselective renal barrier, with molecular mechanisms elucidated herein.
Role of Matrix Metalloproteinase-2 in Recovery after Tubular Damage in Acute Kidney Injury in Mice
Authors: Kaneko Tomohiro , Shimizu Akira , Mii Akiko , Fujita Emiko , Fujino Teppei , Kunugi Shinobu , Du Xuanyi , Akimoto Toshio , Tsuruoka Shuichi , Ohashi Ryuji , Masuda Yukinari , Iino Yasuhiko , Katayama Yasuo , Fukuda Yuh
Published: March 2013

Background/Aims: Matrix metalloproteinases (MMPs) are zinc endopeptidases that degrade extracellular matrix and are involved in the pathogenesis of ischemic damage in acute kidney injury (AKI). In the present study, we analyzed the role of MMP-2 in the repair process in ischemic AKI. Methods: AKI was induced in MMP-2 wild-type (MMP-2+/+) and MMP-2-deficient (MMP-2-/-) mice by 90-min renal artery clamping followed by reperfusion. Renal histology and the activity and distribution of MMP-2 were examined from day 1 to day 14. During the recovery from AKI, MMP-2+/+ mice were also treated with MMP-2/MMP-9 inhibitor. Results: In both MMP-2+/+ and MMP-2-/- mice, AKI developed on day 1 after ischemia/reperfusion with widespread acute tubular injury, but subsequent epithelial cell proliferation was evident on days 3-7. During the repair process, active MMP-2 and MMP-9 increased in regenerating tubular epithelial cells in MMP-2+/+ mice on days 7-14, and the tubular repair process was almost complete by day 14. On the other hand, in MMP-2-/- mice, less prominent proliferation of tubular epithelial cells was evident on days 3 and 7, and damaged tubules that were covered with elongated and immature regenerated epithelial cells were identified on days 7 and 14. Incomplete recovery of injured microvasculature was also noted with persistent macrophage infiltration. Similarly, treatment with MMP-2/MMP-9 inhibitor resulted in impaired recovery in MMP-2+/+ mice. Conclusion: MMP-2 is involved in tubular repair after AKI. The use of the MMP-2/MMP-9 inhibitor was a disadvantage when it was administered during the repair stage of ischemic AKI. Treatment with MMP inhibitor for AKI needs to be modified to enhance recovery from AKI.
Gremlin Is a Downstream Profibrotic Mediator of Transforming Growth Factor-Beta in Cultured Renal Cells
Authors: Rodrigues-Diez Raquel , Lavoz Carolina , Carvajal Gisselle , Rayego-Mateos Sandra , Rodrigues Diez Raul R. , Ortiz Alberto , Egido Jesús , Mezzano Sergio , Ruiz-Ortega Marta
Published: March 2013

Background/Aims: Chronic kidney disease is characterized by accumulation of extracellular matrix in the tubulointerstitial area. Fibroblasts are the main matrix-producing cells. One source of activated fibroblasts is the epithelial mesenchymal transition (EMT). In cultured tubular epithelial cells, transforming growth factor-β (TGF-β1) induced Gremlin production associated with EMT phenotypic changes, and therefore Gremlin has been proposed as a downstream TGF-β1 mediator. Gremlin is a developmental gene upregulated in chronic kidney diseases associated with matrix accumulation, but its direct role in the modulation of renal fibrosis and its relation with TGF-β has not been investigated. Methods: Murine renal fibroblasts and human tubular epithelial cells were studied. Renal fibrosis was determined by evaluation of key profibrotic factors, extracellular matrix proteins (ECM) and EMT markers by Western blot/confocal microscopy or real-time PCR. Endogenous Gremlin was targeted with small interfering RNA. Results: In murine fibroblasts, stimulation with recombinant Gremlin upregulated profibrotic genes, such as TGF-β1, and augmented the production of ECM proteins, including type I collagen. The blockade of endogenous Gremlin with small interfering RNA inhibited TGF-β1-induced ECM upregulation. In tubular epithelial cells Gremlin also increased profibrotic genes and caused EMT changes: phenotypic modulation to myofibroblast-like morphology, loss of epithelial markers and in-duction of mesenchymal markers. Moreover, Gremlin gene silencing inhibited TGF-β1-induced EMT changes. Conclusions: Gremlin directly activates profibrotic events in cul-tured renal fibroblasts and tubular epithelial cells. Moreover, endogenous Gremlin blockade inhibited TGF-β-mediated matrix production and EMT, suggesting that Gremlin could be a novel therapeutic target for renal fibrosis.
Development and Validation of Multiplex Real-Time PCR Assay for Noninvasive Prenatal Assessment of Fetal RhD Status and Fetal Sex in Maternal Plasma
Authors: Ordoñez Elena , Rueda Laura , Cañadas M. Paz , Fuster Carme , Cirigliano Vincenzo
Published: March 2013

Objective: Noninvasive prenatal detection of RhD status and fetal sex is becoming part of daily practice in clinical laboratories. We evaluated a high throughput procedure for automated DNA extraction and developed a multiplex real-time PCR (rt-PCR) for the simultaneous detection of three fetal loci in a single reaction to assess fetal sex and RhD status in maternal plasma. Methods: An automated DNA extraction method was evaluated together with a new multiplex rt-PCR assay for the simultaneous detection of exons 5 and 7 of the RHD gene together with the Y chromosome marker DYS14 in maternal plasma. The test was evaluated on 60 samples of known fetal genotype obtained from RhD-negative pregnant women before being applied prospectively on 158 consecutive clinical cases. Results were compared with newborn phenotypes. Results: Automated DNA extraction allowed successful analysis of all samples. DYS14 was detected in 118 cases (male fetuses) and both RHD exon 5 and 7 were detected in 148 samples. In 70 samples neither RHD exon 5 nor RHD exon 7 were detected (RhD-negative fetuses). Absence of all three sequences (female RhD-negative fetuses) was assessed in 33 samples. All prenatal results were in concordance with postnatal RhD status and fetal sex without false- positive or -negative results. Conclusion: The automated DNA extraction procedure coupled with a novel multiplex rt-PCR assay proved accurate, efficient and reliable allowing rapid and high throughput noninvasive determination of fetal sex and RhD status in clinical samples.
Carotid Intima-Media Thickness: A Novel Inflammatory Marker Which Should Not Be Assessed Alone!
Authors: Kurkluoglu Mustafa , Balta Sevket , Yesil Fahri Gurkan , Demirkol Sait , Tavlasoglu Murat , Arslan Zekeriya
Published: March 2013

No abstract available
Die Notwendigkeit unabhängiger klinischer Studien aus der Sicht des Instituts für Qualität und Wirtschaftlichkeit im Gesundheitswesen
Authors: Lange Stefan , Windeler Jürgen
Published: March 2013

Die Ergebnisse klinischer, möglichst randomisierter kontrollierter Studien (RCT) bilden das Rückgrat von Entscheidungen zur Zulassung von Arzneimitteln und von Nutzenbewertungen medizinischer Methoden. Während Zulassungsstudien von Arzneimitteln häufig zumindest einige der für eine Nutzenbewertung relevanten Fragen beantworten, ist die Situation bei nichtmedikamentösen therapeutischen Methoden und diagnostischen Verfahren eine gänzlich andere, weil es hier keine vergleichbar hohen Anforderungen an eine Markteinführung gibt. Insgesamt muss festgestellt werden, dass es in der Vergangenheit für Hersteller oder Anbieter von medizinischen Methoden keine ausreichenden (finanziellen) Anreize gab und auch weiterhin nicht gibt, klinische Studien zum patientenrelevanten Nutzen durchzuführen, sowohl bei Arzneimitteln als auch insbesondere im nichtmedikamentösen Bereich. Daraus resultiert eine Lücke von Studien, die mit ausreichender Ergebnissicherheit in einem angemessenen Vergleich Daten zum patientenrelevanten Nutzen bzw. Zusatznutzen einer medizinischen Methode liefern. In diesem Zusammenhang ist es zweitrangig, ob es sich dabei um «unabhängige» Studien handelt, zumal «Abhängigkeiten» nie ausgeschlossen werden können und dort, wo sie nicht durch die Deklaration eines Sponsorings leicht erkennbar sind, besonders problematisch werden können. Das Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG) ist gerne bereit und dabei, zusammen mit Interessierten dafür zu werben, dass für wichtige Studienprojekte von klinischen Forschergruppen, die die Kriterien einer qualitativ hochwertigen patientenorientierten klinischen Studie zu einer relevanten Fragestellung erfüllen, angemessene Fördermöglichkeiten geschaffen werden.
Klinische Studien in der Onkologie - 2013 und zukünftig
Authors: Wörmann Bernhard , Freund Mathias , Overkamp Friedrich , Ehninger Gerhard
Published: March 2013

Klinische Studien sind die Brücke zwischen Grundlagenforschung und Patientenversorgung. Sie sind die Basis der evidenzbasierten Medizin, das Rückgrat von Leitlinien. Die rasche Umsetzung von Erkenntnissen onkologischer Forschung in den letzten 40 Jahren war nur durch eine Vielfalt und einen Organisationsgrad klinischer Studien möglich, wie sie es in kaum einem anderen Gebiet der Medizin gibt. Aktuell ist diese Studienkultur in Deutschland gefährdet. Tiefgreifende Änderungen der politischen Rahmenbedingungen, unzureichende Finanzierung, neue Definition patientenrelevanter Endpunkte und veränderte Strukturen im ambulanten und stationären Bereich erfordern kritische Reflektion und neue Konzepte.
Is There a Role for N-Terminal Probrain-Type Natriuretic Peptide in Determining Volume Status in Haemodialysis Patients?
Authors: Kumar Sanjeev , Khosravi Maryam , Massart Annick , Davenport Andrew
Published: March 2013

Background/Aims: Natriuretic peptides have been reported to be a valuable biomarker for predicting cardiac events and mortality for haemodialysis patients. However, there has been a debate as to whether these biomarkers can be used to assess volume overload and help determine dry weight. Methods: We measured the N-terminal probrain natriuretic peptide (NTproBNP) in 366 stable haemodialysis outpatients with a corresponding pre- and post-dialysis multifrequency bioimpedance assessment of extracellular water (ECW)/total body water (TBW). Results: Median age was 61 years (46–73); 58.5% were male, 28.5% diabetic, and 37.7% Caucasoid; 71.1% had a history of hypertension, 8.4% of myocardial infarction, and 9.3% of coronary artery bypass surgery; dialysis vintage was 54 months (22–85.5), and urea reduction ratio was 73.4 ± 7.6%. Median post-dialysis NTproBNP was 179 pmol/l (68–535), pre-dialysis ECW/TBW was 0.393 ± 0.014, and post-dialysis ECW/TBW was 0.385 ± 0.015. On multivariate analysis log NTproBNP was associated with post-dialysis ECW/TBW (β 9.09, 95% CI 3.22–14.95, p = 0.003), mean arterial pressure (β 0.0087, 95% CI –0.0045 to –0.013, p = 0.000), and ultrafiltration rate (ml/kg· h; β 0.038, 95% CI 0.01–0.06, p = 0.001). Conclusion: In this study postdialysis NTproBNP values were correlated with direct assessments of volume status in haemodialysis patients, i.e. by ECW/TBW, or indirect measures of volume overload, i.e. ultrafiltration rate and post-dialysis mean arterial blood pressure. This suggests that serial NTproBNP values may aid clinical assessments of volume status in dialysis patients.
Covalently linking heparin to antithrombin enhances prothrombinase inhibition on activated platelets
Authors: Stevic Ivan , Chan Howard H. W. , Chander Ankush , Berry Leslie R. , Chan Anthony K. C.
Published: March 2013

Factor (F)Xa within the prothrombinase complex is protected from inhibition by unfractionated heparin (UFH), enoxaparin and fondaparinux. We have developed a covalent antithrombin-heparin complex (ATH) with enhanced anticoagulant activity. We have also demonstrated that ATH is superior at inhibiting coagulation factors when assembled on artificial surfaces. The objective of the present study is to determine the ability of ATH vs AT+UFH to inhibit FXa within the prothrombinase complex when the enzyme complex is assembled on the more native platelet system. Discontinuous inhibition assays were performed to determine final k 2-values for inhibition of FXa, FXa within the platelet-prothrombinase, or FXa within prothrombinase devoid of various components. Thrombin generation and plasma clotting was also assayed in the presence of resting/activated platelets ± inhibitors. Protection of FXa was not observed for ATH, whereas a moderate 60% protection was observed for AT+UFH. ATH inhibited platelet-prothrombinase ∼4-fold faster than AT+UFH. Relative to intact prothrombinase, rates for FXa inhibition by AT+UFH in prothrombinase complexes devoid of either prothrombin (II)/activated platelets/FVa were higher. However, inhibition by AT+UFH of prothrombinase devoid of FII yielded slightly lower rates compared to free FXa inhibition. Thrombin generation and plasma clotting was enhanced with activated platelets, while inhibition was better by ATH compared to AT+UFH, thus suggesting an overall enhanced anticoagulant activity of ATH against platelet-bound prothrombinase complexes.
A novel coagulation assay incorporating adherent endothelial cells in thromboelastometry
Authors: Zipperle Johannes , Holnthoner Wolfgang , Husa Anna-Maria , Nürnberger Sylvia , Redl Heinz , Schöchl Herbert , Schlimp Christoph J.
Published: March 2013

Following vascular injury or activation, endothelial cells (ECs) participate in the modulation of haemostasis and fibrinolysis. Viscoelastic tests (VETs) are a potent bedside monitoring tool that reports haemostatic parameters in real time. However, VETs neglect the influence of the surrounding endothelium. Our aim was therefore to establish an assay that incorporates ECs in a whole blood VET and to assess the impact of ECs on coagulation parameters. Outgrowth endothelial cells (OECs) and human umbilical vein endothelial cells (HUVECs) were seeded onto microbeads to create transferable EC-microcarriers. Microbeads were then added to citrated whole blood in the measurement cup of a thromboelastometry device (ROTEM). After the addition of CaCl2 (star-TEM®) to the blood sample (NATEM assay), standard ROTEM parameters were analysed. Scanning electron microscopy (SEM) was carried out to visualise the interactions of the beads, whole blood components and the ROTEM pin after clotting. SEM showed that the added microbeads were effectively incorporated into the final blood clot. In the presence of activated ECs, the clotting time (CT) of the blood was shortened fourfold compared to that in uncoated control beads. A significant reduction in CT was also observed in the presence of unstimulated ECs. Interestingly, CT was also reduced by the addition of purified EC culture supernatant. CT shortening was prevented by incubating the supernatant with an inhibiting antibody against tissue factor (TF). Our findings demonstrate that ECs can be incorporated into a ROTEM assay via coated microbeads, and whole blood clotting initiation is accelerated by non-activated and activated ECs.
Induced Pluripotent Stem Cell-Derived Cardiomyocytes
Authors: Sinnecker Daniel , Goedel Alexander , Laugwitz Karl-Ludwig , Moretti Alessandra
Published: March 2013

Induced pluripotent stem cells offer the possibility to generate patient-specific stem cell lines from individuals affected by inherited disorders. Cardiomyocytes differentiated from such patient-specific induced pluripotent stem cells lines have been used to study the pathophysiology of arrhythmogenic heart diseases, such as the long-QT syndrome or catecholaminergic polymorphic ventricular tachycardia. Testing for unwanted drug side effects or tailoring medical treatment to the specific needs of individual patients with arrhythmogenic disorders may become future applications of this emerging technology.
Induced Pluripotent Stem Cell–Derived Cardiomyocytes
Authors: Knollmann Björn C.
Published: March 2013

This article reviews the strengths and limitations of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) as models of cardiac arrhythmias. Specifically, the article attempts to answer the following questions: Which clinical arrhythmias can be modeled by iPSC-CM? How well can iPSC-CM model adult ventricular myocytes? What are the strengths and limitations of published iPSC-CM arrhythmia models? What new mechanistic insight has been gained? What is the evidence that would support using iPSC-CM to personalize antiarrhythmic drug therapy? The review also discusses the pros and cons of using the iPSC-CM technology for modeling specific genetic arrhythmia disorders, such as long QT syndrome, Brugada Syndrome, or Catecholaminergic Polymorphic Ventricular Tachycardia.