bluuebunny/crossref_metadata_2025_split huggingface dataset:
EFNS guidelines on the molecular diagnosis of mitochondrial disorders
Authors: Finsterer J. , Harbo H. F. , Baets J. , Van Broeckhoven C. , Di Donato S. , Fontaine B. , De Jonghe P. , Lossos A. , Lynch T. , Mariotti C. , Schöls L. , Spinazzola A. , Szolnoki Z. , Tabrizi S. J. , Tallaksen C. M. E. , Zeviani M. , Burgunder J.‐M. , Gasser T. 
Published: November 2009

Objectives:  These European Federation of Neurological Sciences (EFNS) guidelines are designed to provide practical help for the general neurologist to make appropriate use of molecular genetics for diagnosing mitochondrial disorders (MIDs), which gain increasing attention and are more frequently diagnosed due to improved diagnostic tools.Background:  Since the publication of the first EFNS guidelines on the molecular diagnosis of inherited neurological diseases in 2001, rapid progress has been made in this field, necessitating the creation of an updated version.Search strategy:  To collect data about the molecular diagnosis of MIDs search for literature in various electronic databases, such as Cochrane library, MEDLINE, OMIM, GENETEST or Embase, were carried out and original papers, meta‐analyses, review papers, and guideline recommendations were reviewed.Results:  The guidelines summarise the possibilities and limitations of molecular genetic diagnosis of MIDs and provide practical recommendations and diagnostic criteria in accordance with the EFNS Scientific Committee to guide the molecular diagnostic work‐up of MIDs.Recommendations:  The proposed guidelines suggest an approach to the molecular diagnosis of MIDs in a manner accessible to general neurologists.
Restenosis after carotid endarterectomy: significance of newly acquired risk factors
Authors: Fluri F. , Hatz F. , Voss B. , Lyrer P. A. , Engelter S. T. 
Published: November 2009

Background:  In patients who had carotid endarterectomy (CEA), the significance of newly acquired cerebrovascular risk factors (CRFs) is unknown. Newly acquired CRFs are defined as CRFs not present prior to CEA (baseline CRFs) but acquired during long‐term follow‐up.Objective:  We sought to determine the significance of newly acquired CRFs in CEA patients with regard to progressive ICA disease (≥50% restenosis; occurrence or progression of contralateral stenosis).Methods:  In a single‐center CEA‐registry, 361 CEA patients with annual follow‐up visits for 7 years were identified. Hazard ratios (HR) were calculated for (i) any baseline CRF (hypertension, diabetes, hypercholesterolemia, coronary heart disease (CHD), peripheral artery disease (PAD), smoking), (ii) any newly acquired CRF, and (iii) for the use of statins and antihypertensives.Results:  No baseline CRF was associated with progressive ICA disease (unadjusted analysis). After adjustment for age and gender, smoking (HR 1.52, 95%CI 1.02–2.26), diabetes (HR 1.64, 95%CI 1.00–2.68), and hypercholesterolemia (HR 1.61, 95%CI 1.03–2.52) were weakly related to progressive ICA disease. Newly acquired hypertension (HR 2.44, 95%CI 1.57‐3.79), CHD (HR 2.73, 95%CI 1.81–4.11), diabetes (HR 2.30, 95%CI 1.39‐3.80), and PAD (HR 3.94, 95%CI 2.69–5.76) were associated with progressive ICA disease; also, after adjustment for baseline CRFs. Acquisition of at least one new CRF was related to progressive ICA disease (HRadjusted 8.07, 95%CI 4.97–13.12). Neither statins nor antihypertensive drugs did alter the odds for progressive ICA disease.Conclusion:  CRFs acquired during long‐term follow‐up after CEA may independently contribute to progressive ICA stenosis after endarterectomy. Newly acquired CRFs might be more hazardous than CRFs present prior to CEA.
Therapeutic potential for novel drugs targeting the type 1 cholecystokinin receptor
Authors: Cawston Erin E , Miller Laurence J 
Published: November 2009

Cholecystokinin (CCK) is a physiologically important gastrointestinal and neuronal peptide hormone, with roles in stimulating gallbladder contraction, pancreatic secretion, gastrointestinal motility and satiety. CCK exerts its effects via interactions with two structurally related class I guanine nucleotide‐binding protein (G protein)‐coupled receptors (GPCRs), the CCK1receptor and the CCK2receptor. Here, we focus on the CCK1receptor, with particular relevance to the broad spectrum of signalling initiated by activation with the natural full agonist peptide ligand, CCK. Distinct ligand‐binding pockets have been defined for the natural peptide ligand and for some non‐peptidyl small molecule ligands. While many CCK1receptor ligands have been developed and have had their pharmacology well described, their clinical potential has not yet been fully explored. The case is built for the potential importance of developing more selective partial agonists and allosteric modulators of this receptor that could have important roles in the treatment of common clinical syndromes.This article is part of a themed section on Molecular Pharmacology of GPCR. To view the editorial for this themed section visithttp://dx.doi.org/10.1111/j.1476‐5381.2010.00695.x
Medieval Sicily and Southern Italy in Recent Historiographical Perspective
Authors: Davis‐Secord Sarah C. 
Published: November 2009

AbstractSicily and southern Italy during the Middle Ages have been a neglected area of study for many years, primarily due to the general belief that the area fell into decline after the ‘fall’ of Rome. Recently, however, there has been growing interest in the Muslims of medieval Sicily and Italy, as well as the Jewish and Greek populations that lived under Latin Christian rule for many centuries. There has also been a rise in scholarship on the medieval Mediterranean region as a whole, which has caused a re‐evaluation not only of the role and importance of the Mediterranean world, but also of how the medieval European system worked, how Latin Christendom related to the Muslim states on its southern borders, and what roles Muslim cultures and settlements played in the development of Italy’s society.
Limbic Encephalitis Investigated by 18FDG‐PET and 3D MRI
Authors: Kassubek Jan , Juengling Freimut D. , Nitzsche Egbert U. , Lücking Carl H. 
Published: November 2009

ABSTRACTTwo patients with clinically probable or possible limbic encephalitis (LE) are reported, both cases with typical findings in clinical symptoms (severe neuropsychological deficits and complex partial seizures) and in routine magnetic resonance imaging (MRI) (hyperintense mesiotemporal lesions). Underlying malignancy was identified (rectal carcinoma) in one case but could not be detected in the other patient. The 2 patients were investigated by cerebral 18F‐fluoro‐2‐deoxy‐D‐glucose—positron emission tomography (FDG‐PET) and 3‐dimensional (3D) MRI, and abnormalities in metabolic activity were mapped using coregistration of spatially normalized PET and MRI. Highly significant focal hypermetabolism in bilateral hippocampal areas was found in both cases. The authors' findings support FDG‐PET coregistered to 3D MRI as a potentially valuable additional tool in the imaging diagnostics of LE. Results are discussed with respect to the clinical symptoms and previously reported imaging findings in the disease.
The contribution of active medication to combined treatments of psychotherapy and pharmacotherapy for adult depression: a meta‐analysis
Authors: Cuijpers P. , Van Straten A. , Hollon S. D. , Andersson G. 
Published: November 2009

Cuijpers P, van Straten A, Hollon SD, Andersson G. The contribution of active medication to combined treatments of psychotherapy and pharmacotherapy for adult depression: a meta‐analysis.Objective:  Although there is sufficient evidence that combined treatments of psychotherapy and pharmacotherapy are more effective for depression in adults than each of the treatments alone, it remains unclear what the exact contribution of active medication is to the overall effects of combined treatments. This paper examines the contribution of active medication to combined psychotherapy and pharmacotherapy treatments.Method:  Meta‐analysis of randomised controlled trials comparing the combination of psychotherapy and pharmacotherapy with the combination of psychotherapy and placebo.Results:  Sixteen identified studies involving 852 patients met our inclusion criteria. The standardised mean difference indicating the differences between the combination of psychotherapy and pharmacotherapy and the combination of psychotherapy and placebo was 0.25 (95% CI: 0.03–0.46), which corresponds to a numbers‐needed‐to‐be‐treated of 7.14. No significant differences between subgroups of studies were found.Conclusion:  Active medication has a small but significant contribution to the overall efficacy of combined treatments.
Single‐port surgery: Current applications and limitations
Authors: Rao GV , Mansard MJ , Ravula PK , Rebala P , Dama RR , Reddy DN 
Published: November 2009

AbstractIntroduction: In an attempt to further enhance the benefits of cosmesis and reduced morbidity of minimally invasive surgery, single‐port (incision) laparoscopic surgery (SPS) has emerged as a bridge between conventional laparoscopy and natural orifice transluminal endoscopic surgery. As the expertise and instrumentation required are an extension of standard laparoscopic techniques, SPS has been adapted for a variety of procedures and specialties in a short span of time.Discussion: In this article, we discuss the various SPS techniques, as well as the new devices and instrumentation available for facilitating SPS. We also review current applications reported for SPS in various surgical specialties. We present a comprehensive review of the potential benefits, limitations and risks of these novel techniques.Conclusion: Initial reports have demonstrated the technical feasibility and safety of SPS for a wide range of surgical applications. With specialized instrumentation and refinement of technique, its role will increase in coming years. Future work is necessary to improve existing instrumentation, to increase clinical experience and to assess the benefits of this surgical approach.
Super paramagnetic iron oxide MRI shows defective Kupffer cell uptake function in non-alcoholic fatty liver disease
Authors: Asanuma Taketoshi , Ono Masafumi , Kubota Kei , Hirose Akira , Hayashi Yoshihiro , Saibara Toshiji , Inanami Osamu , Ogawa Yasuhiro , Enzan Hideaki , Onishi Saburo , Kuwabara Mikinori , Oben Jude A 
Published: November 2009

BackgroundThe pathogenesis of non-alcoholic fatty liver disease (NAFLD) is incompletely understood. Kupffer cells (KCs), phagocytic liver-resident macrophages, provide a protective barrier against egress of endotoxin from the portal to the systemic circulation. It is not known if KC phagocytic function is impaired in NAFLD. Super-paramagnetic iron oxide (SPIO) magnetic resonance imaging is a comparative technology dependent on KC phagocytic function.ObjectiveTo evaluate KC uptake function, in patients and experimental animals with NAFLD, using SPIO.MethodsAbdominal CT and histological examination of liver biopsy specimens were used to estimate the degree of steatosis in patients with NAFLD and controls with chronic hepatitis C. SPIO-MRI was then performed in all patients. Normal rats fed a methionine-choline-deficient diet to induce non-alcoholic steatohepatitis (NASH), the more severe stage of NAFLD, and obese, insulin resistant, Zucker fa/fa rats with steatohepatitis, were also studied with SPIO-MRI and analysed for hepatic uptake of fluorescent microbeads. Immunohistochemical analysis evaluated the numbers of KCs in patients and rat livers.ResultsRelative signal enhancement (RSE), inversely proportional to KC function, was higher in patients with NAFLD than in controls and with the degree of steatosis on CT. RSE also positively correlated with the degree of steatosis on histology and was similarly higher in rats with induced severe NAFLD (NASH). On immunohistochemistry, defective phagocytic function was the result of reduced phagocytic uptake and not due to reduced KC numbers in rats or patients with NAFLD.ConclusionsKC uptake function is significantly impaired in patients with NAFLD and experimental animals with NASH, worsens with the degree of steatosis and is not due to a reduction of KC numbers.
Human Bone Marrow–Derived Mesenchymal Stem Cells for Intravascular Delivery of Oncolytic Adenovirus Δ24-RGD to Human Gliomas
Authors: Yong Raymund L. , Shinojima Naoki , Fueyo Juan , Gumin Joy , Vecil Giacomo G. , Marini Frank C. , Bogler Oliver , Andreeff Michael , Lang Frederick F. 
Published: November 2009

Abstract
Δ24-RGD is an infectivity-augmented, conditionally replicative oncolytic adenovirus with significant antiglioma effects. Although intratumoral delivery of Δ24-RGD may be effective, intravascular delivery would improve successful application in humans. Due to their tumor tropic properties, we hypothesized that human mesenchymal stem cells (hMSC) could be harnessed as intravascular delivery vehicles of Δ24-RGD to human gliomas. To assess cellular events, green fluorescent protein–labeled hMSCs carrying Δ24-RGD (hMSC-Δ24) were injected into the carotid artery of mice harboring orthotopic U87MG or U251-V121 xenografts and brain sections were analyzed by immunofluorescence for green fluorescent protein and viral proteins (E1A and hexon) at increasing times. hMSC-Δ24 selectively localized to glioma xenografts and released Δ24-RGD, which subsequently infected glioma cells. To determine efficacy, mice were implanted with luciferase- labeled glioma xenografts, treated with hMSC-Δ24 or controls, and imaged weekly by bioluminescence imaging. Analysis of tumor size by bioluminescence imaging showed inhibition of glioma growth and eradication of tumors in hMSC-Δ24-treated animals compared with controls (P &lt; 0.0001). There was an increase in median survival from 42 days in controls to 75.5 days in hMSC-Δ24-treated animals (P &lt; 0.0001) and an increase in survival beyond 80 days from 0% to 37.5%, respectively. We conclude that intra-arterially delivered hMSC-Δ24 selectively localize to human gliomas and are capable of delivering and releasing Δ24-RGD into the tumor, resulting in improved survival and tumor eradication in subsets of mice. [Cancer Res 2009;69(23):8932–40]
Acyl-CoA Synthetase VL3 Knockdown Inhibits Human Glioma Cell Proliferation and Tumorigenicity
Authors: Pei Zhengtong , Sun Peng , Huang Ping , Lal Bachchu , Laterra John , Watkins Paul A. 
Published: November 2009

Abstract
The contribution of lipid metabolic pathways to malignancy is poorly understood. Expression of the fatty acyl-CoA synthetase ACSVL3 was found to be markedly elevated in clinical malignant glioma specimens but nearly undetectable in normal glia. ACSVL3 levels correlated with the malignant behavior of human glioma cell lines and glioma cells propagated as xenografts. ACSVL3 expression was induced by the activation of oncogenic receptor tyrosine kinases (RTK) c-Met and epidermal growth factor receptor. Inhibiting c-Met activation with neutralizing anti–hepatocyte growth factor monoclonal antibodies reduced ACSVL3 expression concurrent with tumor growth inhibition in vivo. ACSVL3 expression knockdown using RNA interference, which decreased long-chain fatty acid activation, inhibited anchorage-dependent and anchorage-independent glioma cell growth by ∼70% and ∼90%, respectively. ACSVL3-depleted cells were less tumorigenic than control cells, and subcutaneous xenografts grew ∼60% slower than control tumors. Orthotopic xenografts produced by ACSVL3-depleted cells were 82% to 86% smaller than control xenografts. ACSVL3 knockdown disrupted Akt function as evidenced by RTK-induced transient decreases in total and phosphorylated Akt, as well as glycogen synthase kinase 3β, via a caspase-dependent mechanism. Expressing constitutively active myr-Akt rescued cells from the anchorage-dependent and anchorage-independent growth inhibitory effects of ACSVL3 depletion. These studies show that ACSVL3 maintains oncogenic properties of malignant glioma cells via a mechanism that involves, in part, the regulation of Akt function. [Cancer Res 2009;69(24):9175–82]
Absence of Both CytochromeP450 3A and P-glycoprotein Dramatically Increases Docetaxel Oral Bioavailability and Risk of Intestinal Toxicity
Authors: van Waterschoot Robert A.B. , Lagas Jurjen S. , Wagenaar Els , van der Kruijssen Cornelia M.M. , van Herwaarden Antonius E. , Song Ji-Ying , Rooswinkel Rogier W. , van Tellingen Olaf , Rosing Hilde , Beijnen Jos H. , Schinkel Alfred H. 
Published: November 2009

AbstractDocetaxel is one of the most widely used anticancer drugs. A major problem with docetaxel treatment, however, is the considerable interpatient variability in docetaxel exposure. Another disadvantage of the drug is that it has a very low oral bioavailability and can therefore only be administered i.v. The drug-metabolizing enzyme cytochrome P450 3A (CYP3A) and the drug transporter P-glycoprotein (P-gp; MDR1) are considered to be major determinants of docetaxel pharmacokinetics. It has been hypothesized that CYP3A and P-gp work synergistically in limiting the systemic exposure to many orally ingested drugs. However, it has been difficult to examine this interplay in vivo. We therefore generated mice lacking all CYP3A and P-gp genes. Although missing two primary detoxification systems, Cyp3a/Mdr1a/1b−/− mice are viable, fertile, and without spontaneous abnormalities. When orally challenged with docetaxel, a disproportionate (&gt;70-fold) increase in systemic exposure was observed compared with the increases in single Cyp3a−/− (12-fold) or Mdr1a/1b−/− (3-fold) mice. Unexpectedly, although CYP3A and P-gp collaborated extremely efficiently in lowering docetaxel exposure, their individual efficacy was not dependent on activity of the other protein. On reflection, this absence of functional synergism makes biological sense, as synergism would conflict with a robust detoxification defense. Importantly, the disproportionate increase in docetaxel exposure in Cyp3a/Mdr1a/1b−/− mice resulted in dramatically altered and lethal toxicity, with severe intestinal lesions as a major cause of death. Simultaneous inhibition of CYP3A/P-gp might thus be a highly effective strategy to improve oral drug bioavailability but with serious risks when applied to drugs with narrow therapeutic windows. [Cancer Res 2009;69(23):8996–9002]
Gene Expression Profiles Classify Human Osteosarcoma Xenografts According to Sensitivity to Doxorubicin, Cisplatin, and Ifosfamide
Authors: Bruheim Skjalg , Xi Yaguang , Ju Jingfang , Fodstad Oystein 
Published: November 2009

AbstractPurpose: In osteosarcoma, aggressive preoperative and postoperative multidrug chemotherapy given to all patients has improved patient survival rate to the present level of ∼60%. However, no tumor marker is available that reliably can identify those patients who will or will not respond to chemotherapy.Experimental Design: In an attempt to find leads to such markers, we have obtained microarray gene expression profiles from a panel of 10 different human osteosarcoma xenografts and related the results to their sensitivity to ifosfamide, doxorubicin, and cisplatin.Results: The expression data identified genes with highly significant differential expression between poor and good responder xenografts to the three different drugs: 85 genes for doxorubicin, 74 genes for cisplatin, and 118 genes for ifosfamide. Technical validation with quantitative reverse transcription-PCR showed good correlation with the microarray expression data. Gene Ontology–guided analysis suggested that properties of the poorly responsive xenografts were resistance to undergo programmed cell death and, particularly for ifosfamide, a drive toward dedifferentiation and increased tumor aggressiveness. Leads toward metabolic alterations and involvement of mitochondrial pathways for apoptosis and stress response were more prominent for doxorubicin and cisplatin. Finally, small interfering RNA–mediated gene silencing of IER3 and S100A2 sensitized the human osteosarcoma cell line OHS to treatment with 4-hydroperoxyifosfamide.Conclusions: The expression profiles contained several novel biomarker candidates that may help predict the responsiveness of osteosarcoma to doxorubicin, cisplatin, and ifosfamide. The potential of selected candidates will be further validated on clinical specimens from osteosarcoma patients. (Clin Cancer Res 2009;15(23):7161–9)
Protein Kinase A Activation Confers Resistance to Trastuzumab in Human Breast Cancer Cell Lines
Authors: Gu Long , Lau Sean K. , Loera Sofia , Somlo George , Kane Susan E. 
Published: November 2009

AbstractPurpose: Trastuzumab is a monoclonal antibody targeted to the Her2 receptor and approved for treatment of Her2-positive breast cancer. Among patients who initially respond to trastuzumab therapy, resistance typically arises within 1 year. BT/HerR cells are trastuzumab-resistant variants of Her2-positive BT474 breast cancer cells. The salient feature of BT/HerR cells is failure to downregulate phosphoinositide 3-kinase/Akt signaling on trastuzumab binding. The current work addresses the mechanism of sustained signaling in BT/HerR cells, focusing on the protein kinase A (PKA) pathway.Experimental Design: We performed microarray analysis on BT/HerR and BT474 cell lines to identify genes that were upregulated or downregulated in trastuzumab-resistant cells. Specific genes in the PKA pathway were quantified using reverse transcription-PCR and Western hybridization. Small interfering RNA transfection was used to determine the effects of gene knockdown on cellular response to trastuzumab. Electrophoretic mobility shift assays were used to measure cyclic AMP–responsive element binding activity under defined conditions. Immunohistochemistry was used to analyze protein expression in clinical samples.Results: BT/HerR cells had elevated PKA signaling activity and several genes in the PKA regulatory network had altered expression in these cells. Downregulation of one such gene, the PKA-RIIα regulatory subunit, conferred partial trastuzumab resistance in Her2-positive BT474 and SK-Br-3 cell lines. Forskolin activation of PKA also produced significant protection against trastuzumab-mediated Akt dephosphorylation. In patient samples, PKA signaling appeared to be enhanced in residual disease remaining after trastuzumab-containing neoadjuvant therapy.Conclusions: Activation of PKA signaling may be one mechanism contributing to trastuzumab resistance in Her2-positive breast cancer. We propose a molecular model by which PKA confers its effects. (Clin Cancer Res 2009;15(23):7196–206)