bluuebunny/crossref_metadata_2025 huggingface dataset:
Amelioration of Severe TNBS Induced Colitis by Novel AP-1 and NF-κB Inhibitors in Rats
Authors: El-Salhy Magdy , Umezawa Kazuo , Gilja Odd Helge , Hatlebakk Jan G. , Gundersen Doris , Hausken Trygve
Published: January 2014

AP-1 and NF-κB inhibitors, namely, DTCM-G and DHMEQ, were investigated in male Wistar rats with severe colitis, induced by TNBS. The animals were randomized into 3 groups. The control group received 0.5 mL of 0.5% of the vehicle i.p., the DTCM-G group received 22.5 mg/kg body weight DTCM-G in 0.5% i.p., and the DHMEQ group received 15 mg/kg body weight DHMEQ i.p., all twice daily for 5 days. The body weight losses and mortality rates were significantly higher in the control group than those in DTCM-G-treated and DHMEQ-treated groups. The endoscopic inflammation scores in the control, DTCM-G-treated, and DHMEQ-treated groups were 6.3 ± 0.7, 1.0 ± 0.3, and 0.7 ± 0.3, respectively (P= 0.004 and 0.02, resp.). The inflammation scores as assessed by the macroscopic appearance were 4.3 ± 0.8, 0.7 ± 0.3, and 1.2 ± 0.4 in the control, DTCM-G-treated, and DHMEQ-treated groups, respectively (P= 0.01 and 0.009, resp.). The histopathological inflammation scores were 6.4 ± 0.7, 2.0 ± 1.0, and 2.2 ± 0.6 in the control, DTCM-G-treated, and DHMEQ-treated groups, respectively (P= 0.03 and 0.01, resp.). It was concluded that DTCM-G and DHMEQ exhibit strong anti-inflammatory and anticancer activities with no apparent toxicity, which make them excellent drug candidates for clinical use in inflammatory bowel diseases.
MicroRNAs in the DNA Damage/Repair Network and Cancer
Authors: Tessitore Alessandra , Cicciarelli Germana , Del Vecchio Filippo , Gaggiano Agata , Verzella Daniela , Fischietti Mariafausta , Vecchiotti Davide , Capece Daria , Zazzeroni Francesca , Alesse Edoardo
Published: January 2014

Cancer is a multistep process characterized by various and different genetic lesions which cause the transformation of normal cells into tumor cells. To preserve the genomic integrity, eukaryotic cells need a complex DNA damage/repair response network of signaling pathways, involving many proteins, able to induce cell cycle arrest, apoptosis, or DNA repair. Chemotherapy and/or radiation therapy are the most commonly used therapeutic approaches to manage cancer and act mainly through the induction of DNA damage. Impairment in the DNA repair proteins, which physiologically protect cells from persistent DNA injury, can affect the efficacy of cancer therapies. Recently, increasing evidence has suggested that microRNAs take actively part in the regulation of the DNA damage/repair network. MicroRNAs are endogenous short noncoding molecules able to regulate gene expression at the post-transcriptional level. Due to their activity, microRNAs play a role in many fundamental physiological and pathological processes. In this review we report and discuss the role of microRNAs in the DNA damage/repair and cancer.
Suicidal Ideation and Suicidal Behaviour in Delusional Disorder: A Clinical Overview
Authors: González-Rodríguez Alexandre , Molina-Andreu Oriol , Navarro Odriozola Víctor , Gastó Ferrer Cristóbal , Penadés Rafael , Catalán Rosa
Published: January 2014

Background. Most of the existing studies suggest that suicide is one of the leading causes of premature death in patients with chronic psychotic disorders. However, very few studies have specifically investigated suicidal behaviour in patients with delusional disorder. Thus, our objective was to review the literature regarding the percentage of lifetime ideation and suicidal behaviour in delusional disorder in order to provide suggestions for clinical practice.Methods. MEDLINE and PsycINFO were searched from January 1980 to September 2012 using the following keywords: delusional disorder, paranoia, suicidal ideation, and suicidal behaviour.Results. A total of 10 studies were identified and included in the review. The percentage of suicidal behaviour in delusional disorder was established between 8 and 21%, which is similar to schizophrenia. Suicidal ideation and suicide attempts were more frequent in patients showing persecutory and somatic delusions in the reviewed studies.Conclusions. To the best of our knowledge this is the first attempt to specifically review the suicide phenomenon in patients with delusional disorder. Interestingly, our results support the notion that percentages of both suicidal ideation and behaviour in delusional disorder are similar to patients with schizophrenia.
Green Route for Efficient Synthesis of Novel Amino Acid Schiff Bases as Potent Antibacterial and Antifungal Agents and Evaluation of Cytotoxic Effects
Authors: Sachdeva Harshita , Saroj Rekha , Khaturia Sarita , Dwivedi Diksha , Prakash Chauhan Om
Published: January 2014

Green chemical one-pot multicomponent condensation reaction of substituted 1H-indole-2,3-diones (1), various amino acids (2), and thiosemicarbazide (3) is found to be catalyzed by lemon juice as natural acid using water as a green solvent to give the corresponding Schiff bases (4) in good to excellent yields. This method is experimentally simple, clean, high yielding, and green, with reduced reaction times. The product is purified by simple filtration followed by washing with water and drying process. The synthesized compounds are characterized by FT-IR,13CNMR, and1HNMR spectroscopy and are screened for their antifungal activity againstAspergillus niger,Penicillium notatum,Fusarium oxysporum,Alternaria brassicicola,Chaetomium orium, andLycopodium sp.and antibacterial activity against Gram-positive bacteria,Bacillus licheniformis,Staphylococcus aureus, andMicrococcus luteus,and Gram-negative bacteria,Pseudomonas aeruginosaandEscherichia coli. Compounds have also been evaluated for cytotoxic effects against human colon cancer cell line Colo205.
Genetic Diversity ofEchinococcus granulosusin Southwest China Determined by the Mitochondrial NADH Dehydrogenase Subunit 2 Gene
Authors: Wang Jiahai , Wang Ning , Hu Dandan , Zhong Xiuqin , Wang Shuxian , Gu Xiaobin , Peng Xuerong , Yang Guangyou
Published: January 2014

We evaluated genetic diversity and structure ofEchinococcus granulosusby analyzing the complete mitochondrial NADH dehydrogenase subunit 2 (ND2) gene in 51 isolates ofE. granulosus sensu strictometacestodes collected at three locations in this region. We detected 19 haplotypes, which formed a distinct clade with the standard sheep strain (G1). Hence, all 51 isolates were identified asE. granulosus sensu stricto(G1–G3). Genetic relationships among haplotypes were not associated with geographical divisions, and fixation indices (Fst) among sampling localities were low. Hence, regional populations ofE. granulosusin the southwest China are not differentiated, as gene flow among them remains high. This information is important for formulating unified region-wide prevention and control measures. We found large negative Fu’s Fs and Tajima’sDvalues and a unimodal mismatch distribution, indicating that the population has undergone a demographic expansion. We observed high genetic diversity among theE. granulosus s. s.isolates, indicating that the parasite population in this important bioregion is genetically robust and likely to survive and spread. The data from this study will prove valuable for future studies focusing on improving diagnosis and prevention methods and developing robust control strategies.
Bit-Table Based Biclustering and Frequent Closed Itemset Mining in High-Dimensional Binary Data
Authors: Király András , Gyenesei Attila , Abonyi János
Published: January 2014

During the last decade various algorithms have been developed and proposed for discovering overlapping clusters in high-dimensional data. The two most prominent application fields in this research, proposed independently, are frequent itemset mining (developed for market basket data) and biclustering (applied to gene expression data analysis). The common limitation of both methodologies is the limited applicability for very large binary data sets. In this paper we propose a novel and efficient method to find both frequent closed itemsets and biclusters in high-dimensional binary data. The method is based on simple but very powerful matrix and vector multiplication approaches that ensure that all patterns can be discovered in a fast manner. The proposed algorithm has been implemented in the commonly used MATLAB environment and freely available for researchers.
Boundedness for some Schrödinger Type Operators on Weighted Morrey Spaces
Authors: Pan Guixia , Tang Lin
Published: January 2014

We establish the boundedness of some Schrödinger type operators on weighted Morrey spaces related to certain nonnegative potentials belonging to the reverse Hölder class.
Effectiveness and Safety of Concurrent Use of First-Line Antiretroviral and Antituberculous Drugs in Rwanda
Authors: Kadima Justin Ntokamunda , Mukanyangezi Marie Françoise , Uwizeye Claude Bernard
Published: January 2014

Background. Overlapping toxicity between drugs used for HIV and TB could complicate the management of HIV/TB coinfected patients, particularly those carrying multiple opportunistic infections. This study aimed to evaluate the clinical outcomes and adverse drug events in HIV patients managed with first-line antiretroviral and first-line anti-TB drugs.Methods. This is a retrospective study utilizing medical dossiers from single-HIV infected and HIV/TB coinfected patients already initiated on ART. Predictors of outcomes included changes in CD4 cells/mm3, body weight, physical improvement, death rate, and adverse drug reactions.Results. Records from 60 HIV patients and 60 HIV/TB patients aged between 20 and 58 years showed that all clinical indicators of effectiveness were better in single-HIV infected than in HIV/TB coinfected patients: higher CD4 cell counts, better physical improvement, and low prevalence of adverse drug events. The most frequently prescribed regimen was TDF/3TC/EFV+RHZE. The mortality rate was 20% in HIV/TB patients compared to 8.3% in the single-HIV group.Conclusion. Treatment regimens applied are efficient in controlling the progression of the infection. However, attention should be paid to adjust dosing when combining nonnucleoside antiretrovirals (EFV and NVR) with anti-TB drugs to minimize the risk of death by drug intoxication.
Kinetic Studies on Fermentative Production of Biofuel from Synthesis Gas UsingClostridium ljungdahlii
Authors: Mohammadi Maedeh , Mohamed Abdul Rahman , Najafpour Ghasem D. , Younesi Habibollah , Uzir Mohamad Hekarl
Published: January 2014

The intrinsic growth, substrate uptake, and product formation biokinetic parameters were obtained for the anaerobic bacterium,Clostridium ljungdahlii, grown on synthesis gas in various pressurized batch bioreactors. A dual-substrate growth kinetic model using Luong for CO and Monod for H2was used to describe the growth kinetics of the bacterium on these substrates. The maximum specific growth rate (μmax= 0.195 h−1) and Monod constants for CO (Ks,CO= 0.855 atm) and H2(Ks,H2= 0.412 atm) were obtained. This model also accommodated the CO inhibitory effects on cell growth at high CO partial pressures, where no growth was apparent at high dissolved CO tensions (PCO∗>0.743 atm). The Volterra model, Andrews, and modified Gompertz were, respectively, adopted to describe the cell growth, substrate uptake rate, and product formation. The maximum specific CO uptake rate (qmax= 34.364 mmol/gcell/h), CO inhibition constant (KI= 0.601 atm), and maximum rate of ethanol (Rmax= 0.172 mmol/L/h atPCO= 0.598 atm) and acetate (Rmax= 0.096 mmol/L/h atPCO= 0.539 atm) production were determined from the applied models.
Beta-Blockers in the Management of Hypertension and/or Chronic Kidney Disease
Authors: Tomiyama Hirofumi , Yamashina Akira
Published: January 2014

This minireview provides current summaries of beta-blocker use in the management of hypertension and/or chronic kidney disease. Accumulated evidence suggests that atenolol is not sufficiently effective as a primary tool to treat hypertension. The less-than-adequate effect of beta-blockers in lowering the blood pressure and on vascular protection, and the unfavorable effects of these drugs, as compared to other antihypertensive agents, on the metabolic profile have been pointed out. On the other hand, in patients with chronic kidney disease, renin-angiotensin system blockers are the drugs of first choice for achieving the goal of renal protection. Recent studies have reported that vasodilatory beta-blockers have adequate antihypertensive efficacy and less harmful effects on the metabolic profile, and also exert beneficial effects on endothelial function and renal protection. However, there is still not sufficient evidence on the beneficial effects of the new beta-blockers.
A New Approach in Regression Analysis for Modeling Adsorption Isotherms
Authors: Marković Dana D. , Lekić Branislava M. , Rajaković-Ognjanović Vladana N. , Onjia Antonije E. , Rajaković Ljubinka V.
Published: January 2014

Numerous regression approaches to isotherm parameters estimation appear in the literature. The real insight into the proper modeling pattern can be achieved only by testing methods on a very big number of cases. Experimentally, it cannot be done in a reasonable time, so the Monte Carlo simulation method was applied. The objective of this paper is to introduce and compare numerical approaches that involve different levels of knowledge about the noise structure of the analytical method used for initial and equilibrium concentration determination. Six levels of homoscedastic noise and five types of heteroscedastic noise precision models were considered. Performance of the methods was statistically evaluated based on median percentage error and mean absolute relative error in parameter estimates. The present study showed a clear distinction between two cases. When equilibrium experiments are performed only once, for the homoscedastic case, the winning error function is ordinary least squares, while for the case of heteroscedastic noise the use of orthogonal distance regression or Margart’s percent standard deviation is suggested. It was found that in case when experiments are repeated three times the simple method of weighted least squares performed as well as more complicated orthogonal distance regression method.
Metal (II) Complexes Derived from Naphthofuran-2-carbohydrazide and Diacetylmonoxime Schiff Base: Synthesis, Spectroscopic, Electrochemical, and Biological Investigation
Authors: Sumathi R. B. , Halli M. B.
Published: January 2014

A new Schiff base and a new series of Co(II), Ni(II), Cu(II), Cd(II), and Hg(II) complexes were synthesized by the condensation of naphthofuran-2-carbohydrazide and diacetylmonoxime. Metal complexes of the Schiff base were prepared from their chloride salts of Co(II), Ni(II), Cu(II), Cd(II), and Hg(II) in ethanol. The ligand along with its metal complexes have been characterized on the basis of analytical data, IR, electronic, mass,1HNMR, ESR spectral data, thermal studies, magnetic susceptibility, and molar conductance measurements. The nonelectrolytic behaviour of the complexes was assessed from the measured low conductance data. The elemental analysis of the complexes confirm the stoichiometry of the type CuL2Cl2and MLCl2where M = Ni(II), Co(II), Cd(II), and Hg(II) and L = Schiff base. The redox property of the Cu(II) complex was investigated by electrochemical method using cyclic voltammetry. In the light of these results, Co(II), Ni(II), and Cu(II) complexes are assigned octahedral geometry, Cd(II), and Hg(II) complexes tetrahedral geometry. In order to evaluate the effect of metal ions upon chelation, both the ligand and its metal complexes were screened for their antibacterial and antifungal activities by minimum inhibitory concentration (MIC) method. The DNA cleaving capacity of all the complexes was analysed by agarose gel electrophoresis method.
Smoke Exposure Has Transient Pulmonary and Systemic Effects in Wildland Firefighters
Authors: Dorman Sandra C. , Ritz Stacey A.
Published: January 2014

Respiratory exposure to air pollutants is associated with cardiovascular morbidity and mortality and firefighters have been shown to be at an increased risk of work-related cardiovascular events. Wildland firefighters experience intermittent, intense exposure to biomass smoke. The aim of this study was to characterize the respiratory and systemic effects of smoke exposure in wildland firefighters. Seventeen seasonal firefighters from a northeastern Ontario community were recruited at the beginning of the fire season and baseline measurements obtained; postexposure measurements were made at various times within 16 d of firefighting. Spirometric measurements showed a transient decline in forced vital capacity within 7 d of fire exposure, not evident by 8–16 d. Induced sputum showed a significant increase in macrophages and epithelial cells within 7 d, with evidence that macrophages had internalized particles; such changes were not evident in the second week following exposure. Likewise, peripheral blood analysis revealed significant increases in erythrocytes, hemoglobin, monocytes, and platelets within the first week after fire exposure, which were diminished 8–16 d in postexposure group. We conclude that acute exposure to forest-fire smoke elicits transient inflammatory responses, both in the airways and systemically. Whether these changes contribute to the observed increased risk of cardiovascular events requires further study.
Computing the Expected Cost of an Appointment Schedule for Statistically Identical Customers with Probabilistic Service Times
Authors: Dietz Dennis C.
Published: January 2014

A cogent method is presented for computing the expected cost of an appointment schedule where customers are statistically identical, the service time distribution has known mean and variance, and customer no-shows occur with time-dependent probability. The approach is computationally efficient and can be easily implemented to evaluate candidate schedules within a schedule optimization algorithm.
Circulating Oncometabolite 2-Hydroxyglutarate Is a Potential Surrogate Biomarker in Patients with Isocitrate Dehydrogenase-Mutant Intrahepatic Cholangiocarcinoma
Authors: Borger Darrell R. , Goyal Lipika , Yau Thomas , Poon Ronnie T. , Ancukiewicz Marek , Deshpande Vikram , Christiani David C. , Liebman Hannah M. , Yang Hua , Kim Hyeryun , Yen Katharine , Faris Jason E. , Iafrate A. John , Kwak Eunice L. , Clark Jeffrey W. , Allen Jill N. , Blaszkowsky Lawrence S. , Murphy Janet E. , Saha Supriya K. , Hong Theodore S. , Wo Jennifer Y. , Ferrone Cristina R. , Tanabe Kenneth K. , Bardeesy Nabeel , Straley Kimberly S. , Agresta Sam , Schenkein David P. , Ellisen Leif W. , Ryan David P. , Zhu Andrew X.
Published: January 2014

Purpose: Mutations in the IDH1 and IDH2 (IDH1/2) genes occur in approximately 20% of intrahepatic cholangiocarcinoma and lead to accumulation of 2-hydroxyglutarate (2HG) in the tumor tissue. However, it remains unknown whether IDH1/2 mutations can lead to high levels of 2HG circulating in the blood and whether serum 2HG can be used as a biomarker for IDH1/2 mutational status and tumor burden in intrahepatic cholangiocarcinoma.

Experimental Design: We initially measured serum 2HG concentration in blood samples collected from 31 patients with intrahepatic cholangiocarcinoma in a screening cohort. Findings were validated across 38 resected patients with intrahepatic cholangiocarcinoma from a second cohort with tumor volume measures. Circulating levels of 2HG were evaluated relative to IDH1/2 mutational status, tumor burden, and a number of clinical variables.

Results: Circulating levels of 2HG in the screening cohort were significantly elevated in patients with IDH1/2-mutant (median, 478 ng/mL) versus IDH1/2–wild-type (median, 118 ng/mL) tumors (P < 0.001). This significance was maintained in the validation cohort (343 ng/mL vs. 55 ng/mL, P < 0.0001) and levels of 2HG directly correlated with tumor burden in IDH1/2-mutant cases (P < 0.05). Serum 2HG levels ≥170 ng/mL could predict the presence of an IDH1/2 mutation with a sensitivity of 83% and a specificity of 90%. No differences were noted between the allelic variants IDH1 or IDH2 in regard to the levels of circulating 2HG.

Conclusions: This study indicates that circulating 2HG may be a surrogate biomarker of IDH1 or IDH2 mutation status in intrahepatic cholangiocarcinoma and that circulating 2HG levels may correlate directly with tumor burden. Clin Cancer Res; 20(7); 1884–90. ©2014 AACR.
Mutational Landscape of the Essential Autophagy Gene BECN1 in Human Cancers
Authors: Laddha Saurabh V. , Ganesan Shridar , Chan Chang S. , White Eileen
Published: January 2014

Evidence suggests that the catabolic process of macroautophagy (autophagy hereafter) can either suppress or promote cancer. The essential autophagy gene ATG6/BECN1 encoding the Beclin1 protein has been implicated as a haploinsufficient tumor suppressor in breast, ovarian, and prostate cancers. The proximity of BECN1 to the known breast and ovarian tumor suppressor breast cancer 1, early onset, BRCA1, on chromosome 17q21, has made this determination equivocal. Here, the mutational status of BECN1 was assessed in human tumor sequencing data from The Cancer Genome Atlas (TCGA) and other databases. Large deletions encompassing both BRCA1 and BECN1, and deletions of only BRCA1 but not BECN1, were found in breast and ovarian cancers, consistent with BRCA1 loss being a primary driver mutation in these cancers. Furthermore, there was no evidence for BECN1 mutation or loss in any other cancer, casting doubt on whether BECN1 is a tumor suppressor in most human cancers.

Implications: Contrary to previous reports, BECN1 is not significantly mutated in human cancer and not a tumor-suppressor gene, as originally thought.

Visual Overview: http://mcr.aacrjournals.org/content/early/2014/04/01/1541-7786.MCR-13-0614/F1.large.jpg. Mol Cancer Res; 12(4); 485–90. ©2014 AACR.
Health Economics and Surgical Treatment for Parkinson's Disease in a World Perspective: Results from an International Survey
Authors: Jourdain Vincent A. , Schechtmann Gastón
Published: January 2014

Background: Most studies in the field of neurosurgical treatment for movement disorders have been published by a small number of leading centers in developed countries. This study aimed to investigate the clinical practice of stereotactic neurosurgery for Parkinson's disease (PD) worldwide. Methods: Neurosurgeons were contacted via e-mail to participate in a worldwide survey. The results obtained are presented in order of the countries' economic development according to the World Bank, as well as by the source of financial support. Results: A total of 353 neurosurgeons from 51 countries who had operated on 13,200 patients in 2009 were surveyed. Surgical procedures performed in high-income countries were more commonly financed by a public health care system. In contrast, in lower-middle-income and upper-middle-income countries, patients frequently financed surgeries themselves, and ablative surgeries were most commonly performed. Unexpectedly, ablative surgery is still used by about 65% of neurosurgeons, regardless of their country's economic status. Conclusions: This study provides a previously unavailable picture of the surgical aspects of PD across the globe in relation to health economics and sociodemographic factors. Global educational and training programs are warranted to raise awareness of economically viable surgical options for PD that could be adopted by public health care systems in lower-income countries.
Speech in Alzheimer's Disease: Can Temporal and Acoustic Parameters Discriminate Dementia?
Authors: Meilán Juan José G. , Martínez-Sánchez Francisco , Carro Juan , López Dolores E. , Millian-Morell Lymarie , Arana José M.
Published: January 2014

Aims: The study explores how speech measures may be linked to language profiles in participants with Alzheimer's disease (AD) and how these profiles could distinguish AD from changes associated with normal aging. Methods: We analysed simple sentences spoken by older adults with and without AD. Spectrographic analysis of temporal and acoustic characteristics was carried out using the Praat software. Results: We found that measures of speech, such as variations in the percentage of voice breaks, number of periods of voice, number of voice breaks, shimmer (amplitude perturbation quotient), and noise-to-harmonics ratio, characterise people with AD with an accuracy of 84.8%. Discussion: These measures offer a sensitive method of assessing spontaneous speech output in AD, and they discriminate well between people with AD and healthy older adults. This method of evaluation is a promising tool for AD diagnosis and prognosis, and it could be used as a dependent measure in clinical trials.
Impact of Vancomycin or Linezolid Therapy on Development of Renal Dysfunction and Thrombocytopenia in Japanese Patients
Authors: Fujii Satoshi , Takahashi Satoshi , Makino Shinki , Kunimoto Yusuke , Nakata Hiromasa , Noda Norimasa , Sakurai Koichi , Miyamoto Atsushi
Published: January 2014

Background: Vancomycin and linezolid therapies are associated with renal dysfunction and thrombocytopenia, respectively. Methods: We retrospectively investigated Japanese patients with renal dysfunction or thrombocytopenia possibly associated with vancomycin and linezolid therapies, including 235 patients treated with parenteral vancomycin and 178 treated with parenteral linezolid. Results: Renal dysfunction occurred more frequently in patients receiving vancomycin (24%) than in those receiving linezolid (13%; p = 0.032), whereas thrombocytopenia occurred more frequently in linezolid-treated patients (41%) than in vancomycin-treated patients (17%; p < 0.001). Controlling trough vancomycin concentrations (<20 μg/ml) protects against renal dysfunction, but thrombocytopenia may occur after >7.5 days of linezolid treatment. Conclusion: Controlling trough vancomycin concentrations to <20 μg/ml protects Japanese patients against renal dysfunction. Linezolid is an appropriate initial therapy for severe infections in patients with acute renal dysfunction, but monitoring of platelet counts is essential after initiation of therapy.
Safety and Effectiveness of Endovascular Treatment of Stroke with Unknown Time of Onset
Authors: Millán M. , Aleu A. , Almendrote M. , Serena J. , Castaño C. , Roquer J. , Pérez de la Ossa N. , Gomis M. , Dorado L. , López-Cancio E. , García-Bermejo P. , Hernández-Pérez M. , Dávalos A.
Published: January 2014

Background: Currently, treatment options for patients with strokes with unknown time of onset (UKO) remain limited. With the advance of neuroimaging and endovascular treatment (EVT), selected patients might have a chance of a therapeutic option. We sought to compare clinical outcome after EVT in patients with known time of stroke onset (KO) and in those with UKO. Methods: We prospectively registered consecutive patients with acute large artery occlusion of the anterior territory who underwent EVT. Multimodal MR or Alberta Stroke Program early CT score (ASPECTS) and transcranial color-coded Duplex sonography were used to select patients for EVT. Recanalization, periprocedural complications, intracranial hemorrhage (ICH) and outcome were recorded. Symptomatic ICH (sICH) was defined as a worsening of ≥4 points in the National Institutes of Health Stroke Scale (NIHSS) score within 36 h in any bleeding. Favorable outcome was defined as a modified Rankin score ≤2 at 3 months. Results: A total of 141 patients were studied, 109 with KO and 32 with UKO. Mean age was 66.5 versus 64.7 years (p = 0.005) and median baseline NIHSS was 18 versus 17 (p = 0.095), respectively. Prior IV tPA was more frequently administered to KO patients (62.4 vs. 9.4%, p < 0.001), whereas patient selection using multimodal MR was more frequent in patients with UKO (78.1 vs. 45.4%, p < 0.001). Median time from stroke onset or from the last time the patient was seen well to groin puncture and to recanalization was significantly longer in patients with UKO, but no differences were found in the duration of the procedure. For KO/UKO patients recanalization was seen in 77.1 vs. 65.7% (p = 0.084), sICH occurred in 10 versus 0% (p = 0.061) and favorable outcome at 3 months was achieved in 41.3 versus 50% (p = 0.382), respectively. Conclusions: Clinical outcomes in this series of EVT in ischemic stroke patients due to large anterior arterial occlusion with salvageable brain are similar for patients treated with KO and UKO. These data support a randomized study of EVT in extended or uncertain time windows.
Early Time Course of FLAIR Signal Intensity Differs between Acute Ischemic Stroke Patients with and without Hyperintense Acute Reperfusion Marker
Authors: Ostwaldt Ann-Christin , Rozanski Michal , Schmidt Wolf U. , Nolte Christian H. , Hotter Benjamin , Jungehuelsing Gerhard J. , Villringer Kersten , Fiebach Jochen B.
Published: January 2014

Background: In animal models of stroke, the time course of blood-brain barrier (BBB) disruptions has been elaborately studied. In human patients, leakage of gadolinium into cerebrospinal fluid (CSF) space, visualized on MRI fluid attenuated inversion recovery (FLAIR) images, is considered a sign of BBB disruptions. It was termed ‘hyperintense acute reperfusion marker' (HARM) and was associated with hemorrhages. However, the time course of the leakage is unknown and difficult to study in human patients. Also, the association of HARM with signal intensities and enhancement in the parenchyma on FLAIR images has not been thoroughly researched. Methods: We analyzed imaging data of acute ischemic stroke patients who underwent repetitive MRI examinations within the first 36 h after the time of symptom onset. HARM was evaluated on FLAIR images. Regions of interest (ROI) of the hyperintensities on diffusion-weighted imaging (DWI) were determined for each time point and mirrored to the contralateral side. The ROI were furthermore corrected for CSF-filled space, using apparent diffusion coefficient (ADC) images. The corrected ROI were used to determine mean signal intensities of the lesions relative to the contralateral side on FLAIR, ADC and B₀ images for each time point. Results: The 18 included patients (5 females; median age: 69 years; median NIHSS score: 5) received 3-5 MRI examinations on the first day and 1-2 examinations on day 2 after stroke. Eight of the patients (44.4%) showed HARM on at least 1 examination. In 6 of these patients, HARM was already seen at the second examination, at the earliest 3.5 h after symptom onset. The HARM-positive patients had higher relative signal intensities (rSI) on FLAIR images in the parenchyma corresponding to the DWI-positive tissue compared with the HARM-negative patients. This difference between groups was statistically significant for the 2nd and 3rd examination (medians of 4.31 and 6.37 h from symptom onset, p < 0.001 and p = 0.005, respectively). No significant difference in rSI between groups was seen for ADC or B₀ images. Conclusion: HARM does not only represent a contrast medium leakage from the pial system into the CSF space. It is accompanied by a markedly increased rSI in the early ischemic lesion on FLAIR images, which is likely due to parenchymal enhancement. The lack of differences on B₀ images excludes a pure T2 effect.
Myocardial Infarction as a Complication in Acute Stroke: Results from the Austrian Stroke Unit Registry
Authors: Gattringer Thomas , Niederkorn Kurt , Seyfang Leonhard , Seifert-Held Thomas , Simmet Nicole , Ferrari Julia , Lang Wilfried , Brainin Michael , Willeit Johann , Fazekas Franz , Enzinger Christian
Published: January 2014

Background: Patients with transient ischemic attack (TIA) and stroke have an increased risk for subsequent cardiac events including myocardial infarction (MI), which might be associated with a worse clinical outcome. Rapid identification of stroke patients at higher risk for MI might foster intensified cardiac monitoring or certain therapeutic strategies. However, information regarding acute MI as a complication of stroke in the very acute phase is limited. Moreover, there are no systematic data on the occurrence of MI following intracerebral hematoma. We thus aimed to assess the frequency, clinical characteristics and short-term outcome of patients suffering from acute MI in the stroke unit setting. Methods: We analyzed 46,603 patients from 32 Austrian stroke units enrolled in the prospective Austrian Stroke Unit Registry because of TIA/acute stroke over a 6-year period (January 1, 2007 to January 13, 2013). A total of 41,619 patients (89.3%) had been treated for TIA/ischemic stroke and 4,984 (10.7%) for primary intracerebral hemorrhage (ICH). Acute MI was defined according to clinical evaluation, ECG findings and laboratory assessments. Patients with evidence for MI preceding the cerebrovascular event were not considered. Results: Overall, 421 patients (1%) with TIA/ischemic stroke and 17 patients (0.3%) with ICH suffered from MI during stroke unit treatment for a median duration of 3 days. Patients with TIA/ischemic stroke and MI were significantly older, clinically more severely affected and had more frequently vascular risk factors, atrial fibrillation and previous MI. Total anterior circulation and left hemispheric stroke syndromes were more often observed in MI patients. Patients with MI not only suffered from worse short-term outcome including a higher mortality (14.5 vs. 2%; p < 0.001) at stroke unit discharge, but also acquired more stroke complications like progressive stroke and pneumonia. Multivariate analyses identified previous MI and stroke severity at admission (according to the National Institutes of Health and Stroke Scale score) as factors independently associated with the occurrence of MI on the stroke unit. Conclusions: While quite rare in the acute phase after stroke, MI is associated with a poor short-term outcome including a higher mortality. Patients with previous MI and severe stroke syndromes appear to be at particular risk for MI as an early complication in the stroke unit setting. Further studies are needed to determine whether increased vigilance and prolonged (cardiac) monitoring or certain therapeutic approaches could improve the outcome in these high-risk patients.
A New Strategy of Minimally Invasive Surgery for Cholecystolithiasis: Calculi Removal and Gallbladder Preservation
Authors: Tan Yu-Yan , Zhao Gang , Wang Dong , Wang Jing-Min , Tang Jie-Rong , Ji Zhen-Ling
Published: January 2014

Background: Cholecystolithiasis is a common disease. Cholecystectomy is the main treatment method but is associated with various complications in some patients. This study explores a novel, minimally invasive surgery for the removal of calculi and the preservation of the gallbladder using a laparoscope combined with the soft choledochoscope. Method: A retrospective analysis was conducted between January 2010 and December 2012 in 65 patients with cholecystolithiasis who underwent the minimally invasive surgery for calculi removal and gallbladder preservation. Results: In 61 cases of gallstone removal, the gallbladder was preserved perfectly with no complications. The other 4 cases were switched to laparoscopic cholecystectomy because of tiny stones blocking the cystic duct or submucosal stones. The success rate was 93.8%. Follow-up included both clinical assessment and ultrasound examination every 6 months after the operation. The patients with preoperative symptoms were symptom-free, and gallbladder function was well preserved. The overall stone recurrence rate was 4.92% at a mean follow-up of 26 months (range 6-40). Conclusions: Using the laparoscope combined with the soft choledochoscope for gallbladder-preserving cholecystolithotomy can remove stones, preserve gallbladder function, and effectively avoid the various complications of cholecystectomy. In our follow-up, gallbladder function was not affected and the stone recurrence rate was quite low.
Platelet degranulation and glycoprotein IIbIIIa opening are not related to bleeding phenotype in severe haemophilia A patients
Authors: Schutgens Roger E. G. , Fischer Kathelijn , de Groot Philip G. , Roest Mark , van Bladel Esther R.
Published: January 2014

Recently we reported data suggesting that platelets could compensate for the bleeding phenotype in severe haemophilia A (HA). The aim of this study was to confirm these results in a larger population with a detailed characterisation of clinical phenotype. Patients with diagnostic severe HA (FVIII:C <1%) were scored for clinical phenotype by integrating data on age at first joint bleed, joint damage, bleeding frequency and FVIII consumption. Phenotype was defined as onset of joint bleeding-score + arthropathy-score + joint bleeding-score + (2* treatment intensity-score). After a washout period of three days, blood was collected for measurement of basal level of platelet activation, platelet reactivity, endothelial cell activation and presence of procoagulant phospholipids in plasma. Thirty-three patients with severe HA were included, 13 patients with a mild, 12 patients with an average and eight patients with a severe clinical phenotype. No relevant differences in basal level of platelet activation, platelet reactivity, endothelial cell activation and procoagulant phospholipids between all three groups were observed. The mean annual FVIII consumption per kg did not correlate with the platelet P-selectin expression and glycoprotein (GP)IIbIIIa activation on platelets. In conclusion, variability in clinical phenotype in patients with diagnostic severe HA is not related to platelet activation or reactivity, measured as platelet degranulation and platelet GPIIbIIIa opening.
A novel H-FABP assay and a fast prognostic score for risk assessment of normotensive pulmonary embolism
Authors: Tschepe Merle , Seeber Valerie , Zwiener Isabella , Kuhnert Katherina , Schäfer Katrin , Hasenfuß Gerd , Konstantinides Stavros , Lankeit Mareike , Dellas Claudia
Published: January 2014

We tested whether heart-type fatty acid binding protein (H-FABP) measured by a fully-automated immunoturbidimetric assay in comparison to ELISA provides additive prognostic value in patients with pulmonary embolism (PE), and validated a fast prognostic score in comparison to the ESC risk prediction model and the simplified Pulmonary Embolism Severity Index (sPESI). We prospectively examined 271 normotensive patients with PE; of those, 20 (7%) had an adverse 30-day outcome. H-FABP levels determined by immunoturbidimetry were higher (median, 5.2 [IQR; 2.7–9.8] ng/ml) than those by ELISA (2.9 [1.1–5.4] ng/ml), but Bland-Altman plot demonstrated a good agreement of both assays. The area under the curve for H-FABP was greater for immunoturbidimetry than for ELISA (0.82 [0.74–0.91] vs 0.78 [0.68–0.89]; P=0.039). H-FABP measured by immunoturbidimetry (but not by ELISA) provided additive prognostic information to other predictors of 30-day outcome (OR, 12.4 [95% CI, 1.6–97.6]; P=0.017). When H-FABP determined by immunoturbidimetry was integrated into a novel prognostic score (H-FABP, Syncope, and Tachycardia; FAST score), the score provided additive prognostic information by multivariable analysis (OR, 14.2 [3.9–51.4]; p<0.001; c-index, 0.86) which were superior to information obtained by the ESC model (c-index, 0.62; net reclassification improvement (NRI), 0.39 [0.21–0.56]; P<0.001) or the sPESI (c-index, 0.68; NRI, 0.24 [0.05–0.43]; P=0.012). In conclusion, determination of H-FABP by immunoturbidimetry provides prognostic information superior to that of ELISA and, if integrated in the FAST score, appears more suitable to identify patients with an adverse 30-day outcome compared to the ESC model and sPESI.
Fixed low-dose ultrasound-assisted catheter-directed thrombolysis followed by routine stenting of residual stenosis for acute ilio-femoral deep-vein thrombosis
Authors: Engelberger Rolf P. , Fahrni Jennifer , Willenberg Torsten , Baumann Frederic , Spirk David , Diehm Nicolas , Do Dai-Do , Baumgartner Iris , Kucher Nils
Published: January 2014

Patients with ilio-femoral deep-vein thrombosis (DVT) are at high risk of developing the postthrombotic syndrome (PTS). In comparison to anticoagulation therapy alone, extended venography-guided catheter-directed thrombolysis without routine stenting of venous stenosis in patients with ilio-femoral DVT is associated with an increased risk of bleeding and a moderate reduction of PTS. We performed a prospective single-centre study to investigate safety, patency and incidence of PTS in patients with acute iliofemoral DVT treated with fixed-dose ultrasound-assisted catheter-directed thrombolysis (USAT; 20 mg rt-PA during 15 hours) followed by routing stenting of venous stenosis, defined as residual luminal narrowing >50%, absent antegrade flow, or presence of collateral flow at the site of suspected stenosis. A total of 87 patients (age 46 ± 21 years, 60% women) were included. At 15 hours, thrombolysis success ≥50% was achieved in 67 (77%) patients. Venous stenting (mean 1.9 ± 1.3 stents) was performed in 70 (80%) patients, with the common iliac vein as the most frequent stenting site (83%). One major (1%; 95% CI, 0–6%) and 6 minor bleedings (7%; 95%CI, 3–14%) occurred. Primary and secondary patency rates at 1 year were 87% (95% CI, 74–94%) and 96% (95% CI, 88–99%), respectively. At three months, 88% (95% CI, 78–94%) of patients were free from PTS according to the Villalta scale, with a similar rate at one year (94%, 95% CI, 81–99%). In conclusion, a fixed-dose USAT regimen followed by routine stenting of underlying venous stenosis in patients with iliofemoral DVT was associated with a low bleeding rate, high patency rates, and a low incidence of PTS.
Angiogenesis and Cardiac Hypertrophy
Authors: Oka Toru , Akazawa Hiroshi , Naito Atsuhiko T. , Komuro Issei
Published: January 2014

Cardiac hypertrophy is an adaptive response to physiological and pathological overload. In response to the overload, individual cardiac myocytes become mechanically stretched and activate intracellular hypertrophic signaling pathways to re-use embryonic transcription factors and to increase the synthesis of various proteins, such as structural and contractile proteins. These hypertrophic responses increase oxygen demand and promote myocardial angiogenesis to dissolve the hypoxic situation and to maintain cardiac contractile function; thus, these responses suggest crosstalk between cardiac myocytes and microvasculature. However, sustained pathological overload induces maladaptation and cardiac remodeling, resulting in heart failure. In recent years, specific understanding has increased with regard to the molecular processes and cell–cell interactions that coordinate myocardial growth and angiogenesis. In this review, we summarize recent advances in understanding the regulatory mechanisms of coordinated myocardial growth and angiogenesis in the pathophysiology of cardiac hypertrophy and heart failure.
Linker of Nucleoskeleton and Cytoskeleton Complex Proteins in Cardiac Structure, Function, and Disease
Authors: Stroud Matthew J , Banerjee Indroneal , Veevers Jennifer , Chen Ju
Published: January 2014

The linker of nucleoskeleton and cytoskeleton (LINC) complex, composed of proteins within the inner and the outer nuclear membranes, connects the nuclear lamina to the cytoskeleton. The importance of this complex has been highlighted by the discovery of mutations in genes encoding LINC complex proteins, which cause skeletal or cardiac myopathies. Herein, this review summarizes structure, function, and interactions of major components of the LINC complex, highlights how mutations in these proteins may lead to cardiac disease, and outlines future challenges in the field.
Mammalian Target of Rapamycin Signaling in Cardiac Physiology and Disease
Authors: Sciarretta Sebastiano , Volpe Massimo , Sadoshima Junichi
Published: January 2014

The protein kinase mammalian or mechanistic target of rapamycin (mTOR) is an atypical serine/threonine kinase that exerts its main cellular functions by interacting with specific adaptor proteins to form 2 different multiprotein complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTORC1 regulates protein synthesis, cell growth and proliferation, autophagy, cell metabolism, and stress responses, whereas mTORC2 seems to regulate cell survival and polarity. The mTOR pathway plays a key regulatory function in cardiovascular physiology and pathology. However, the majority of information available about mTOR function in the cardiovascular system is related to the role of mTORC1 in the unstressed and stressed heart. mTORC1 is required for embryonic cardiovascular development and for postnatal maintenance of cardiac structure and function. In addition, mTORC1 is necessary for cardiac adaptation to pressure overload and development of compensatory hypertrophy. However, partial and selective pharmacological and genetic inhibition of mTORC1 was shown to extend life span in mammals, reduce pathological hypertrophy and heart failure caused by increased load or genetic cardiomyopathies, reduce myocardial damage after acute and chronic myocardial infarction, and reduce cardiac derangements caused by metabolic disorders. The optimal therapeutic strategy to target mTORC1 and increase cardioprotection is under intense investigation. This article reviews the information available regarding the effects exerted by mTOR signaling in cardiovascular physiology and pathological states.
Perspectives for Induced Pluripotent Stem Cell Technology
Authors: Nagata Naoki , Yamanaka Shinya
Published: January 2014

Induced pluripotent stem cell technology makes in vitro reprogramming of somatic cells from individuals with various genetic backgrounds possible. By applying this technology, it is possible to produce pluripotent stem cells from biopsy samples of arbitrarily selected individuals with various genetic backgrounds and to subsequently maintain, expand, and stock these cells. From these induced pluripotent stem cells, target cells and tissues can be generated after certain differentiation processes. These target cells/tissues are expected to be useful in regenerative medicine, disease modeling, drug screening, toxicology testing, and proof-of-concept studies in drug development. Therefore, the number of publications concerning induced pluripotent stem cells has recently been increasing rapidly, demonstrating that this technology has begun to infiltrate many aspects of stem cell biology and medical applications. In this review, we discuss the perspectives of induced pluripotent stem cell technology for modeling human diseases. In particular, we focus on the cloning event occurring through the reprogramming process and its ability to let us analyze the development of complex disease-harboring somatic mosaicism.
A Note on Bound Constraints Handling for the IEEE CEC’05 Benchmark Function Suite
Authors: Liao Tianjun , Molina Daniel , de Oca Marco A. Montes , Stützle Thomas
Published: January 2014

The benchmark functions and some of the algorithms proposed for the special session on real parameter optimization of the 2005 IEEE Congress on Evolutionary Computation (CEC’05) have played and still play an important role in the assessment of the state of the art in continuous optimization. In this article, we show that if bound constraints are not enforced for the final reported solutions, state-of-the-art algorithms produce infeasible best candidate solutions for the majority of functions of the IEEE CEC’05 benchmark function suite. This occurs even though the optima of the CEC’05 functions are within the specified bounds. This phenomenon has important implications on algorithm comparisons, and therefore on algorithm designs. This article's goal is to draw the attention of the community to the fact that some authors might have drawn wrong conclusions from experiments using the CEC’05 problems.