bluuebunny/crossref_metadata_2025 huggingface dataset:
Adding a radial dimension to the assessment of esophagogastric junction relaxation: validation studies of the 3D-eSleeve
Authors: Nicodème Frédéric , Pandolfino John E. , Lin Zhiyue , Xiao Yinglian , Escobar Gabriela , Kahrilas Peter J.
Published: May 2012

High-resolution manometry (HRM) with esophageal pressure topography (EPT) allowed for the establishment of an objective quantitative measurement of esophagogastric junction (EGJ) relaxation, the integrated relaxation pressure (IRP). This study assessed whether or not a novel 3D-HRM assembly could improve on this measurement. Twenty-five normal subjects were studied with both a standard HRM assembly and a novel hybrid assembly (3D-HRM), including a 9.0 cm 3D-HRM segment composed of 96 radially dispersed independent pressure sensors. The standard IRP was computed using each assembly and compared with a novel paradigm, the 3D-IRP, an analysis premised on finding the axial maximum and radial minimum pressure at each sensor ring along the sleeve segment. Fourteen additional subjects underwent barium swallows with 3D-HRM and concurrent videofluoroscopy to compare the electronic sleeve (eSleeve) paradigm (circumferential average) to the 3D eSleeve paradigm (radial minimum) as a predictor of transphincteric flow. The 3D-IRP was significantly less than all other calculations of IRP with the upper limit of normal being 12 mmHg vs. 17 mmHg for the standard IRP. The sensitivity (0.78) and the specificity (0.88) of the 3D-eSleeve were also better than the standard eSleeve (0.55 and 0.85, respectively) for predicting flow permissive time verified fluoroscopically. The 3D-IRP and 3D-eSleeve calculated using the radial pressure minimum lowered the normative range of EGJ relaxation (upper limit of normal 12 mmHg) and yielded intraluminal pressure gradients that better correlated with bolus flow than did analysis paradigms based on circumferentially averaged pressure.
Activation of the MyD88 signaling pathway inhibits ischemia-reperfusion injury in the small intestine
Authors: Watanabe Toshio , Kobata Atsushi , Tanigawa Tetsuya , Nadatani Yuji , Yamagami Hirokazu , Watanabe Kenji , Tominaga Kazunari , Fujiwara Yasuhiro , Takeuchi Koji , Arakawa Tetsuo
Published: May 2012

Toll-like receptors (TLRs) recognize microbial components and trigger the signaling cascade that activates innate and adaptive immunity. Recent studies have shown that the activation of TLR-dependent signaling pathways plays important roles in the pathogenesis of ischemia-reperfusion (I/R) injuries in many organs. All TLRs, except TLR3, use a common adaptor protein, MyD88, to transduce activation signals. We investigated the role of MyD88 in I/R injury of the small intestine. MyD88 and cyclooxygenase-2 (COX-2) knockout and wild-type mice were subjected to intestinal I/R injury. I/R-induced small intestinal injury was characterized by infiltration of inflammatory cells, disruption of the mucosal epithelium, destruction of villi, and increases in myeloperoxidase activity and mRNA levels of TNF-α and the IL-8 homolog KC. MyD88 deficiency worsened the severity of I/R injury, as assessed using the histological grading system, measuring luminal contents of hemoglobin (a marker of intestinal bleeding), and counting apoptotic epithelial cells, while it inhibited the increase in mRNA expression of TNF-α and KC. I/R significantly enhanced COX-2 expression and increased PGE2 concentration in the small intestine of wild-type mice, which were markedly inhibited by MyD88 deficiency. COX-2 knockout mice were also highly susceptible to intestinal I/R injury. Exogenous PGE2 reduced the severity of injury in both MyD88 and COX-2 knockout mice to the level of wild-type mice. These findings suggest that the MyD88 signaling pathway may inhibit I/R injury in the small intestine by inducing COX-2 expression.
Interventricular heterogeneity as a substrate for arrhythmogenesis of decoupled mitochondria during ischemia in the whole heart
Authors: Smith Rebecca M. , Velamakanni Saalini S. , Tolkacheva Elena G.
Published: May 2012

Myocardial ischemia results in metabolic changes, which collapse the mitochondrial network, that increase the vulnerability of the heart to ventricular fibrillation (VF). It has been demonstrated at the single cell level that uncoupling the mitochondria using carbonyl cyanide p-(tri-fluoromethoxy)phenyl-hydrazone (FCCP) at low concentrations can be cardioprotective. The aim of our study was to investigate the effect of FCCP on arrhythmogenesis during ischemia in the whole rabbit heart. We performed optical mapping of isolated rabbit hearts ( n = 33) during control and 20 min of global ischemia and reperfusion, both with and without pretreatment with the mitochondrial uncoupler FCCP at 100, 50, or 30 nM. No hearts went into VF during ischemia under the control condition, with or without the electromechanical uncoupler blebbistatin. We found that pretreatment with 100 ( n = 4) and 50 ( n = 6) nM FCCP, with or without blebbistatin, leads to VF during ischemia in all hearts, whereas pretreatment with 30 nM of FCCP led to three out of eight hearts going into VF during ischemia. We demonstrated that 30 nM of FCCP significantly increased interventricular (but not intraventricular) action potential duration and conduction velocity heterogeneity in the heart during ischemia, thus providing the substrate for VF. We showed that wavebreaks during VF occurred between the right and left ventricular junction. We also demonstrated that no VF occurred in the heart pretreated with 10 μM glibenclamide, which is known to abolish interventricular heterogeneity. Our results indicate that low concentrations of FCCP, although cardioprotective at the single cell level, are arrhythmogenic at the whole heart level. This is due to the fact that FCCP induces different electrophysiological changes to the right and left ventricle, thus increasing interventricular heterogeneity and providing the substrate for VF.
Protein kinase D increases maximal Ca2+-activated tension of cardiomyocyte contraction by phosphorylation of cMyBP-C-Ser315
Authors: Dirkx Ellen , Cazorla Olivier , Schwenk Robert W. , Lorenzen-Schmidt Ilka , Sadayappan Sakthivel , Van Lint Johan , Carrier Lucie , van Eys Guillaume J. J. M. , Glatz Jan F. C. , Luiken Joost J. F. P.
Published: May 2012

Cardiac myosin-binding protein C (cMyBP-C) is involved in the regulation of cardiac myofilament contraction. Recent evidence showed that protein kinase D (PKD) is one of the kinases that phosphorylate cMyBP-C. However, the mechanism by which PKD-induced cMyBP-C phosphorylation affects cardiac contractile responses is not known. Using immunoprecipitation, we showed that, in contracting cardiomyocytes, PKD binds to cMyBP-C and phosphorylates it at Ser315. The effect of PKD-mediated phosphorylation of cMyBP-C on cardiac myofilament function was investigated in permeabilized ventricular myocytes, isolated from wild-type (WT) and from cMyBP-C knockout (KO) mice, incubated in the presence of full-length active PKD. In WT myocytes, PKD increased both myofilament Ca2+sensitivity (pCa50) and maximal Ca2+-activated tension of contraction (Tmax). In cMyBP-C KO skinned myocytes, PKD increased pCa50but did not alter Tmax. This suggests that cMyBP-C is not involved in PKD-mediated sensitization of myofilaments to Ca2+but is essential for PKD-induced increase in Tmax. Furthermore, the phosphorylation of both PKD-Ser916and cMyBP-C-Ser315was contraction frequency-dependent, suggesting that PKD-mediated cMyBP-C phosphorylation is operational primarily during periods of increased contractile activity. Thus, during high contraction frequency, PKD facilitates contraction of cardiomyocytes by increasing Ca2+sensitivity and by an increased Tmaxthrough phosphorylation of cMyBP-C.
Prostaglandins but not leukotrienes alter extracellular matrix protein deposition and cytokine release in primary human airway smooth muscle cells and fibroblasts
Authors: Van Ly David , Burgess Janette K. , Brock Thomas G. , Lee Tak H. , Black Judith L. , Oliver Brian G. G.
Published: May 2012

Eicosanoids are lipid-signaling mediators released by many cells in response to various stimuli. Increasing evidence suggests that eicosanoids such as leukotrienes and prostaglandins (PGs) may directly mediate remodeling. In this study, we assessed whether these substances could alter extracellular matrix (ECM) proteins and the inflammatory profiles of primary human airway smooth muscle cells (ASM) and fibroblasts. PGE2decreased both fibronectin and tenascin C in fibroblasts but only fibronectin in ASM. PGD2decreased both fibronectin and tenascin C in both ASM and fibroblasts, whereas PGF2αhad no effect on ECM deposition. The selective PGI2analog, MRE-269, decreased fibronectin but not tenascin C in both cell types. All the PGs increased IL-6 and IL-8 release in a dose-dependent manner in ASM and fibroblasts. Changes in ECM deposition and cytokine release induced by prostaglandins in both ASM and fibroblasts were independent of an effect on cell number. Neither the acute nor repeated stimulation with leukotrienes had an effect on the deposition of ECM proteins or cytokine release from ASM or fibroblasts. We concluded that, collectively, these results provide evidence that PGs may contribute to ECM remodeling to a greater extent than leukotrienes in airway cells.
Transcriptional regulation of temperature-induced remodeling of muscle bioenergetics in goldfish
Authors: Bremer Katharina , Monk Christopher T. , Gurd Brendon J. , Moyes Christopher D.
Published: May 2012

Central to mammalian mitochondrial biogenesis is the transcriptional master regulator peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1α (PGC-1α), and a network of DNA-binding proteins it coactivates. We explored the role of this pathway in muscle mitochondrial biogenesis in response to thermal acclimation in goldfish ( Carassius auratus ). We investigated the transcriptional response of PGC-1α, PGC-1β, and their antagonist the nuclear receptor interacting protein 1 ( RIP140), as well as the mRNA and protein patterns of DNA-binding proteins that bind PGC-1, including nuclear respiratory factors (NRF) 1 and 2, retinoid X receptor α (RXRα), estrogen-related receptor α (ERRα), thyroid receptor α-1 (TRα-1), PPARα, and PPARβ/δ, and the host cell factor 1 (HCF1), which links PGC-1 and NRF-2. Cold-acclimated (4°C) fish had higher COX activities (4.5-fold) and COX4-1 mRNA levels (3.5-fold per total RNA; 6.5-fold per gram tissue) than warm-acclimated (32°C) fish. The transcription factor patterns were profoundly influenced by changes in RNA per gram tissue (2-fold higher in cold fish) and nuclear protein content (2-fold higher in warm fish). In cold-acclimated fish, mRNA per gram tissue was elevated for PGC-1β, RIP140, NRF-1, HCF1, NRF-2α, NRF-2β-2, ERRα, PPAR β/δ, and RXRα, but other transcriptional regulators either did not change ( PGC-1α, PPARα) or even decreased ( TRα-1). Nuclear protein levels in cold-acclimated fish were higher only for NRF-1; other proteins were either unaffected (NRF-2α, ERRα) or decreased (NRF-2β1/2, TRα, RXRα). Collectively, these data support the role for NRF-1 in regulating cold-induced mitochondrial biogenesis in goldfish, with effects mediated by PGC-1β, rather than PGC-1α.
Estrogen protects renal endothelial barrier function from ischemia-reperfusion in vitro and in vivo
Authors: Hutchens Michael P. , Fujiyoshi Tetsuhiro , Komers Radko , Herson Paco S. , Anderson Sharon
Published: May 2012

Emerging evidence suggests that renal endothelial function may be altered in ischemia-reperfusion injury. Acute kidney injury is sexually dimorphic, and estrogen protects renal tubular function after experimental ischemic injury. This study tested the hypothesis that during ischemia-reperfusion, estrogen alters glomerular endothelial function to prevent hyperpermeability. Glomerular endothelial cells were exposed to 8-h oxygen-glucose deprivation (OGD) followed by 4- and 8-h reoxygenation-glucose repletion. After 4-h reoxygenation-glucose repletion, transendothelial permeability to Ficoll-70 was reduced, and transendothelial resistance increased, by 17β-estradiol vs. vehicle treatment during OGD (OGD-vehicle: 91.0 ± 11.8%, OGD-estrogen: 102.6 ± 10.8%, P < 0.05). This effect was reversed by coadministration of G protein-coupled receptor 30 (GPR30) antagonist G15 with 17β-estradiol (OGD-estrogen-G15: 89.5 ± 6.9, P < 0.05 compared with 17β-estradiol). To provide preliminary confirmation of this result in vivo, Ficoll-70 was administered to mice 24 h after cardiac arrest and cardiopulmonary resuscitation (CA/CPR). Blood urea nitrogen (BUN) and serum creatinine (SCr) in these mice were elevated within 12 h following CA/CPR and reduced at 24 h by pretreatment with 17β-estradiol (BUN/SCr 17β-estradiol: 34 ± 19/0.2 ± 0.1 vehicle: 92 ± 49/0.5 ± 0.3, n = 8–12, P < 0.05). Glomerular sieving of Ficoll 70 was increased by CA/CPR within 2 h of injury and 17β-estradiol treatment (θ; 17β-estradiol: 0.74 ± 0.26 vs. vehicle: 1.05 ± 0.53, n = 14–15, P < 0.05). These results suggest that estrogen reduces postischemic glomerular endothelial hyperpermeability at least in part through GPR30 and that estrogen may regulate post CA/CPR glomerular permeability in a similar fashion in vivo.
Fine-grained analysis of shared neural circuits between perceived and observed pain: implications for the study of empathy for pain
Authors: Valentini Elia , Koch Katharina
Published: May 2012

Feeling pain and seeing it in others activates largely overlapping neural substrates. A recent study (Corradi-Dell'Acqua C, Hofstetter C, Vuilleumier P. J Neurosci 31: 17996–18006, 2011) for the first time raises the question of whether shared neural activations specifically code pain-related contents or merely their negative-aversive implication. The authors conclude that mid-insula and mid-cingulate share information specific to the presence of pain, whereas anterior insula shares information about its aversive content. We suggest that, together with valence and arousal, the control of saliency and threat may have an important heuristic potential in the study of empathy for pain.
Perturbation of Rb, p53, and Brca1 or Brca2 Cooperate in Inducing Metastatic Serous Epithelial Ovarian Cancer
Authors: Szabova Ludmila , Yin Chaoying , Bupp Sujata , Guerin Theresa M. , Schlomer Jerome J. , Householder Deborah B. , Baran Maureen L. , Yi Ming , Song Yurong , Sun Wenping , McDunn Jonathan E. , Martin Philip L. , Van Dyke Terry , Difilippantonio Simone
Published: May 2012

The majority of human high-grade serous epithelial ovarian cancer (SEOC) is characterized by frequent mutations in p53 and alterations in the RB and FOXM1 pathways. A subset of human SEOC harbors a combination of germline and somatic mutations as well as epigenetic dysfunction for BRCA1/2. Using Cre-conditional alleles and intrabursal induction by Cre-expressing adenovirus in genetically engineered mice, we analyzed the roles of pathway perturbations in epithelial ovarian cancer initiation and progression. Inactivation of RB-mediated tumor suppression induced surface epithelial proliferation with progression to stage I carcinoma. Additional biallelic inactivation and/or missense p53 mutation in the presence or absence of Brca1/2 caused progression to stage IV disease. As in human SEOC, mice developed peritoneal carcinomatosis, ascites, and distant metastases. Unbiased gene expression and metabolomic profiling confirmed that Rb, p53, and Brca1/2-triple mutant tumors aligned with human SEOC, and not with other intraperitoneal cancers. Together, our findings provide a novel resource for evaluating disease etiology and biomarkers, therapeutic evaluation, and improved imaging strategies in epithelial ovarian cancer. Cancer Res; 72(16); 4141–53. ©2012 AACR.
Integrative Genomic Analysis Implicates Gain ofPIK3CAat 3q26 andMYCat 8q24 in Chronic Lymphocytic Leukemia
Authors: Brown Jennifer R. , Hanna Megan , Tesar Bethany , Werner Lillian , Pochet Nathalie , Asara John M. , Wang Yaoyu E. , dal Cin Paola , Fernandes Stacey M. , Thompson Christina , MacConaill Laura , Wu Catherine J. , Van de Peer Yves , Correll Mick , Regev Aviv , Neuberg Donna , Freedman Arnold S.
Published: May 2012

Purpose: The disease course of chronic lymphocytic leukemia (CLL) varies significantly within cytogenetic groups. We hypothesized that high-resolution genomic analysis of CLL would identify additional recurrent abnormalities associated with short time-to-first therapy (TTFT).

Experimental Design: We undertook high-resolution genomic analysis of 161 prospectively enrolled CLLs using Affymetrix 6.0 SNP arrays, and integrated analysis of this data set with gene expression profiles.

Results: Copy number analysis (CNA) of nonprogressive CLL reveals a stable genotype, with a median of only 1 somatic CNA per sample. Progressive CLL with 13q deletion was associated with additional somatic CNAs, and a greater number of CNAs was predictive of TTFT. We identified other recurrent CNAs associated with short TTFT: 8q24 amplification focused on the cancer susceptibility locus near MYC in 3.7%; 3q26 amplifications focused on PIK3CA in 5.6%; and 8p deletions in 5% of patients. Sequencing of MYC further identified somatic mutations in two CLLs. We determined which catalytic subunits of phosphoinositide 3-kinase (PI3K) were in active complex with the p85 regulatory subunit and showed enrichment for the α subunit in three CLLs carrying PIK3CA amplification.

Conclusions: Our findings implicate amplifications of 3q26 focused on PIK3CA and 8q24 focused on MYC in CLL. Clin Cancer Res; 18(14); 3791–802. ©2012 AACR.
Elevation of c-FLIP in Castrate-Resistant Prostate Cancer Antagonizes Therapeutic Response to Androgen Receptor–Targeted Therapy
Authors: McCourt Clare , Maxwell Pamela , Mazzucchelli Roberta , Montironi Rodolfo , Scarpelli Marina , Salto-Tellez Manuel , O'Sullivan Joe M. , Longley Daniel B. , Waugh David J.J.
Published: May 2012

Purpose: To characterize the importance of cellular Fas-associated death domain (FADD)–like interleukin 1β-converting enzyme (FLICE) inhibitory protein (c-FLIP), a key regulator of caspase-8 (FLICE)–promoted apoptosis, in modulating the response of prostate cancer cells to androgen receptor (AR)–targeted therapy.

Experimental Design: c-FLIP expression was characterized by immunohistochemical analysis of prostatectomy tissue. The functional importance of c-FLIP to survival and modulating response to bicalutamide was studied by molecular and pharmacologic interventions.

Results: c-FLIP expression was increased in high-grade prostatic intraepithelial neoplasia and prostate cancer tissue relative to normal prostate epithelium (P < 0.001). Maximal c-FLIP expression was detected in castrate-resistant prostate cancer (CRPC; P < 0.001). In vitro, silencing of c-FLIP induced spontaneous apoptosis and increased 22Rv1 and LNCaP cell sensitivity to bicalutamide, determined by flow cytometry, PARP cleavage, and caspase activity assays. The histone deacetylase inhibitors (HDACi), droxinostat and SAHA, also downregulated c-FLIP expression, induced caspase-8- and caspase-3/7–mediated apoptosis, and increased apoptosis in bicalutamide-treated cells. Conversely, the elevated expression of c-FLIP detected in the CRPC cell line VCaP underpinned their insensitivity to bicalutamide and SAHA in vitro. However, knockdown of c-FLIP induced spontaneous apoptosis in VCaP cells, indicating its relevance to cell survival and therapeutic resistance.

Conclusion: c-FLIP reduces the efficacy of AR-targeted therapy and maintains the viability of prostate cancer cells. A combination of HDACi with androgen deprivation therapy may be effective in early-stage disease, using c-FLIP expression as a predictive biomarker of sensitivity. Direct targeting of c-FLIP, however, may be relevant to enhance the response of existing and novel therapeutics in CRPC. Clin Cancer Res; 18(14); 3822–33. ©2012 AACR.
Alpha-Melanocyte–Stimulating Hormone Suppresses Oxidative Stress through a p53-Mediated Signaling Pathway in Human Melanocytes
Authors: Kadekaro Ana Luisa , Chen Juping , Yang Jennifer , Chen Shuna , Jameson Joshua , Swope Viki B. , Cheng Tan , Kadakia Madhavi , Abdel-Malek Zalfa
Published: May 2012

Epidermal melanocytes are skin cells specialized in melanin production. Activation of the melanocortin 1 receptor (MC1R) on melanocytes by α-melanocyte–stimulating hormone (α-MSH) induces synthesis of the brown/black pigment eumelanin that confers photoprotection from solar UV radiation (UVR). Contrary to keratinocytes, melanocytes are slow proliferating cells that persist in the skin for decades, in an environment with high levels of UVR-induced reactive oxygen species (ROS). We previously reported that in addition to its role in pigmentation, α-MSH also reduces oxidative stress and enhances the repair of DNA photoproducts in melanocytes, independent of melanin synthesis. Given the significance of ROS in carcinogenesis, here we investigated the mechanisms by which α-MSH exerts antioxidant effects in melanocytes. We show that activation of the MC1R by α-MSH contributes to phosphorylation of p53 on serine 15, a known requirement for stabilization and activation of p53, a major sensor of DNA damage. This effect is mediated by the cAMP/PKA pathway and by the activation of phosphoinositide 3-kinase (PI3K) ATR and DNA protein kinase (DNA-PK). α-MSH increases the levels of 8-oxoguanine DNA glycosylase (OGG1) and apurinic apyrimidinic endonuclease 1 (APE-1/Ref-1), enzymes essential for base excision repair. Nutlin-3, an HDM2 inhibitor, mimicked the effects of α-MSH resulting in reduced phosphorylation of H2AX (γ-H2AX), a marker of DNA damage. Conversely, the p53 inhibitor pifithrin-α or silencing of p53 abolished the effects of α-MSH and augmented oxidative stress. These results show that p53 is an important target of the downstream MC1R signaling that reduces oxidative stress and possibly malignant transformation of melanocytes. Mol Cancer Res; 10(6); 778–86. ©2012 AACR.
Assessment of Fetal Myocardial Deformation Using Speckle Tracking Techniques
Authors: Germanakis Ioannis , Gardiner Helena
Published: May 2012

Objective: To report the current status of speckle tracking techniques in evaluation of fetal myocardial deformation. Methods: A variety of non-Doppler ultrasound methods are available using offline analysis of standard four-chamber and short axis views of the heart. Results: Most reports have used techniques developed for the measurement of strain and strain rate in the adult heart and produced conflicting descriptions of gestational changes in strain. Myocardial velocities usually reflect mean modal velocities and are lower than the peak velocities obtained using Doppler techniques. Conclusions: In the fetus, most current methods of acquisition result in frame rates that are too low, and the fetal heart size is too small to achieve reliable measures of fetal myocardial deformation.
Adeno-Associated Virus Type 2 Vector-Mediated Glial Cell Line-Derived Neurotrophic Factor Gene Transfer Induces Neuroprotection and Neuroregeneration in a Ubiquitin-Proteasome System Impairment Animal Model of Parkinson’s Disease
Authors: Du Yunlan , Zhang Xiaojie , Tao Qingqing , Chen Sheng , Le Weidong
Published: May 2012

Background: The impairment of the ubiquitin-proteasome system (UPS) is a cellular mechanism underlying the neurodegenerative process in Parkinson’s disease (PD). A mouse model induced by the selective proteasome inhibitor lactacystin targeting on substantia nigra has been demonstrated to be valuable in investigating etiopathogenesis and neuroprotection for PD. Objective: In the present study, we used adeno-associated virus type 2 vector (AAV2) encoding glial cell line-derived neurotrophic factor (GDNF) injected into the striatum of this animal model to test the effectiveness and possible mechanisms of GDNF gene therapy. Results: Our results showed that AAV2-mediated GDNF gene therapy significantly attenuated lactacystin-induced loss of nigral dopamine (DA) neurons and striatal DA levels. Furthermore, we found that GDNF protein is mostly expressed in astrocytes in the subventricular zone (SVZ) and dentate gyrus (DG). AAV2-mediated GDNF therapy can induce neurogenesis in the SVZ and DG, and increase the number of nigral newborn DA neurons. Conclusion: These data indicate that AAV2-mediated GDNF gene therapy can protect the nigral DA neurons from the UPS impairment-induced degeneration, which may partly result from the nigral DA neuron regeneration in the brain, and such experimental results may have implications for the treatment of PD.
Sleep Disorders and Multiple Sclerosis: A Clinical and Polysomnography Study
Authors: Neau Jean-Philippe , Paquereau Joël , Auche Vanessa , Mathis Stéphane , Godeneche Gaëlle , Ciron Jonathan , Moinot Nathalie , Bouche Gautier ,   Groupe des Neurologues Poitou-Charentes (GNPC)
Published: May 2012

Background: Patients with multiple sclerosis (MS) report sleep disturbances (SD) and excessive daytime sleepiness (EDS) more frequently than the general population. Our objectives were to evaluate SD and EDS in MS patients and to test the reliability of subjective sleep questionnaires. Methods: Demographic and clinical characteristics of unselected consecutive patients with MS were collected. Different questionnaires were used to assess quality of sleep, daytime sleepiness, fatigue, anxiety, depression and quality of life (QoL). Nocturnal polysomnography and Multiple Sleep Latency Test (MSLT) were performed in 25 selected MS patients with fatigue and with or without EDS. Results: 205 MS patients were enrolled. More than half of the MS patients were classified as ‘poor sleepers’. In multivariate analysis, SD were correlated with disability, fatigue, depression, QoL, and pain, but not with EDS. Subjective sleepiness evaluated with the Epworth Sleepiness Scale and SD with the Pittsburgh Sleep Quality Index were not correlated with the results of the objective assessments of vigilance (MSLT) and sleep. Conclusions: SD and EDS are frequent among MS patients. Objective assessment of vigilance and sleep can be challenging but MS patients who are poor sleepers should receive immediate assessment and treatment in order to improve QoL.
Mitochondrial Inhibitor Models of Huntington’s Disease and Parkinson’s Disease Induce Zinc Accumulation and Are Attenuated by Inhibition of Zinc Neurotoxicity in vitro or in vivo
Authors: Sheline Christian T. , Zhu Julia , Zhang Wendy , Shi Chunxiao , Cai Ai-Li
Published: May 2012

Background: Inhibition of mitochondrial function occurs in many neurodegenerative diseases, and inhibitors of mitochondrial complexes I and II are used to model them. The complex II inhibitor, 3-nitroproprionic acid (3-NPA), kills the striatal neurons susceptible in Huntington’s disease. The complex I inhibitor N-methyl-4-phenylpyridium (MPP+) and 6-hydroxydopamine (6-OHDA) are used to model Parkinson’s disease. Zinc (Zn2+) accumulates after 3-NPA, 6-OHDA and MPP+ in situ or in vivo. Objective: We will investigate the role of Zn2+ neurotoxicity in 3-NPA, 6-OHDA and MPP+. Methods: Murine striatal/midbrain tyrosine hydroxylase positive, or near-pure cortical neuronal cultures, or animals were exposed to 3-NPA or MPP+ and 6-OHDA with or without neuroprotective compounds. Intracellular zinc ([Zn2+]i), nicotinamide adenine dinucleotide (NAD+), NADH, glycolytic intermediates and neurotoxicity were measured. Results: We showed that compounds or genetics which restore NAD+ and attenuate Zn2+ neurotoxicity (pyruvate, nicotinamide, NAD+, increased NAD+ synthesis, sirtuin inhibition or Zn2+ chelation) attenuated the neuronal death induced by these toxins. The increase in [Zn2+]i preceded a reduction in the NAD+/NADH ratio that caused a reversible glycolytic inhibition. Pyruvate, nicotinamide and NAD+ reversed the reductions in the NAD+/NADH ratio, glycolysis and neuronal death after challenge with 3-NPA, 6-OHDA or MPP+, as was previously shown for exogenous Zn2+. To test efficacy in vivo, we injected 3-NPA into the striatum of rats and systemically into mice, with or without pyruvate. We observed early striatal Zn2+ fluorescence, and pyruvate significantly attenuated the 3-NPA-induced lesion and restored behavioral scores. Conclusions: Together, these studies suggest that Zn2+ accumulation caused by MPP+ and 3-NPA is a novel preventable mechanism of the resultant neurotoxicity.
Sensory and Motor Characterization in the Postnatal Valproate Rat Model of Autism
Authors: Reynolds Stacey , Millette Alexandre , Devine Darragh P.
Published: May 2012

Although autism is diagnosed according to three core features of social deficits, communication impairments, and repetitive or stereotyped behaviors, other behavioral features such as sensory and motor impairments are present in more than 70% of individuals with autism spectrum disorders (ASD). Exposure of rat pups to the teratogen valproate during sensitive periods of brain development has been shown to elicit behavioral features associated with autism diagnosis and has been proposed as a valid animal model of the disorder. The purpose of this study was to characterize sensory and motor performance in rats postnatally treated with valproate. Thirty-four rat pups were injected with either valproate (150 mg/kg) or saline on postnatal days 6–12. Auditory and tactile startle as well as auditory sensory gating was assessed during both the juvenile and adolescent stages of development; motor testing was conducted during late adolescence and included a sunflower seed eating task and a vermicelli handling task. Valproate-treated rats were underresponsive to auditory stimuli, showed deficits in auditory sensory gating, and demonstrated impairments in motor speed and performance. These findings suggest that postnatal valproate treatment elicits sensory and motor features often seen in individuals with ASD. Further, the hyposensitivity seen in postnatally valproate-treated rats contrasted with hypersensitivity previously reported in prenatally valproate-exposed rats. This suggests that timing of teratogenic exposure during early brain development may be important to consider when investigating the neurobiological basis of sensorimotor impairments in ASD.
Endothelin-1 Stimulates Small Artery VCAM-1 Expression through p38MAPK-Dependent Neutral Sphingomyelinase
Authors: Ohanian Jacqueline , Forman Simon P. , Katzenberg Gideon , Ohanian Vasken
Published: May 2012

Endothelin-1 (ET-1) stimulates vascular cell adhesion molecule (VCAM-1) expression, a process associated with arterial remodelling. However, the pathways activated by ET-1 that lead to VCAM-1 expression are not fully understood. It is reported that sphingomyelinases are necessary for VCAM-1 expression in response to cytokines. Our aim was to investigate the role of sphingomyelinases in ET-1-induced VCAM-1 expression. Acid and neutral sphingomyelinase activities were measured in extracts from rat mesenteric small arteries (RMSA). ET-1 (1–100 nmol/l) stimulated neutral but not acid sphingomyelinase. The activation was rapid, peaking within 5 min and transient, returning towards baseline by 10 min and inhibited by BQ-788, GW4869 and SB203580, which are inhibitors of ETB receptor, neutral sphingomyelinase and p38MAPK, respectively. Both GW4869 and SB203580 are reported to inhibit activation of neutral sphingomyelinase 2 implicating it in the response to ET-1. Accordingly we investigated the expression of this isoform and found it was present in RMSA, predominantly in endothelial cells. Treatment of RMSA with ET-1 (1–100 nmol/l) for 16 h increased VCAM-1 expression, which was inhibited by GW4869 and SB203580. These results indicate that ET-1 stimulates arterial VCAM-1 expression through p38MAPK-dependent activation of neutral sphingomyelinases. This suggests a role for sphingolipids in ET-1-induced vascular inflammation in cardiovascular disease.
Effect of Obesity on Serum Prostate-Specific Antigen in Nigerian Men
Authors: Ikuerowo S.O. , Omisanjo O.A. , Bioku M.J. , Ajala M.O. , Esho J.O.
Published: May 2012

Objective: Lower serum total prostate-specific antigen (PSA) levels (tPSA) have been reported in obese men. It has not been confirmed if this association truly exists in all ethnic groups. Thus, we evaluated the relationship between tPSA and obesity among Nigerian men. Methods: Men aged ≥40 years with tPSA <20 ng/ml and no known prostatic disease were involved. Obesity was defined using the body mass index (BMI) and waist to hip ratio (WHR). Multivariate linear regression was used to investigate the relationship between tPSA and either BMI or WHR. The odds of having abnormal tPSA were estimated using logistic regression. Results: A total of 3,191 men participated, and 3,049 (95.6%) were eligible for analysis. A BMI ≥25.0 and a WHR ≥0.9 were found in 47.7 and 64.6%, respectively. tPSA was significantly associated with age (p < 0.001) and digital rectal examination status (p < 0.001). Multivariate linear regression analysis showed no relationship between tPSA and obesity (BMI, p = 0.581; WHR, p = 0.160). Adjusting for age and digital rectal examination status, logistic regression showed no significantly observable trend of having a tPSA level greater than thresholds for men with a BMI ≥25 or a WHR ≥0.9 when compared with normal BMI or WHR, respectively. Conclusion: Although overweight and obesity were common among healthy Nigerian men, there was no associated tendency towards lower serum tPSA.
Climacteric Lowers Plasma Levels of Platelet-Derived Microparticles: A Pilot Study in Pre- versus Postmenopausal Women
Authors: Rank Andreas , Nieuwland Rienk , Roesner Sabine , Nikolajek Katharina , Hiller Erhard , Toth Bettina
Published: May 2012

Background: Climacteric increases the risk of thrombotic events by alteration of plasmatic coagulation. Up to now, less is known about changes in platelet- (PMP) and endothelial cell-derived microparticles (EMP). Methods: In this prospective study, plasma levels of microparticles (MP) were compared in 21 premenopausal and 19 postmenopausal women. Results: No altered numbers of total MP or EMP were measured within the study groups. However, the plasma values of CD61-exposing MP from platelets/megakaryocytes were higher in premenopausal women (5,364 × 106/l, range 4,384–17,167) as compared to postmenopausal women (3,808 × 106/l, range 2,009–8,850; p = 0.020). This differentiation was also significant for the subgroup of premenopausal women without hormonal contraceptives (5,364 × 106/l, range 4,223–15,916; p = 0.047; n = 15). Furthermore, in premenopausal women, higher plasma levels of PMP exposing CD62P were also present as compared to postmenopausal women (288 × 106/l, range 139–462, vs. 121 × 106/l, range 74–284; p = 0.024). This difference was also true for CD63+ PMP levels (281 × 106/l, range 182–551, vs. 137 × 106/l, range 64–432; p = 0.015). Conclusion: Climacteric lowers the level of PMP but has no impact on the number of EMP in women. These data suggest that PMP and EMP do not play a significant role in enhancing the risk of thrombotic events in healthy, postmenopausal women.
Morphological Changes on the Intestinal Mucosa in Orthotopic Neobladder
Authors: Di Tonno F. , Siracusano S. , Ciciliato S. , Visalli F. , Lampropoulou N. , Lavelli D.
Published: May 2012

Introduction: The intestinal mucosa undergoes significant atrophic changes when it is used to reconstruct the urinary tract. We analyzed the ultrastructural changes of intestinal mucosa in the orthotopic neobladder on the basis of our clinical experience. Patients and Methods: Fifteen male patients with an ileal neobladder underwent endoscopic biopsy at different postoperative intervals. Results: No significant changes were observed 3 months after surgery. After 6 and 12 months, the structure of the microvilli was modified significantly. No other substantial changes after 24 months were observed. Conclusions: Progressive modifications occur in the cytoplasmic structures involved in the absorptive process. They do not seem to begin before 3 months and are almost totally completed after 1 year.
The Use of the Finasteride-Adjusted Prostate Cancer Prevention Trial Prostate Cancer Risk Calculator in a Mexican Referral Population: A Validation Study
Authors: Liang Yuanyuan , Ketchum Norma S. , Louden Christopher , Jimenez-Rios Miguel A. , Thompson Ian M. , Camarena-Reynoso Hector R.
Published: May 2012

Objectives: To perform the first validation study of the finasteride-adjusted Prostate Cancer Prevention Trial Prostate Cancer Risk Calculator (finPCPTRC) in a contemporary referral population in Mexico. Methods: 837 patients referred to the Instituto Nacional de Cancerología, Mexico City, Mexico, between 2005 and 2009 were used to validate the finPCPTRC by examining various measures of discrimination and calibration. Net benefit curve analysis was used to gain insight into the use of the finPCPTRC for clinical decisions. Results: Prostate cancer (PCa) incidence (72.8%) was high in this Mexican referral cohort and 45.7% of men who were diagnosed with PCa had high-grade lesions (HGPCa, Gleason score >6). 1.3% of the patients were taking finasteride. The finPCPTRC was a superior diagnostic tool compared to prostate-specific antigen alone when discriminating patients with PCa from those without PCa (AUC = 0.784 vs. AUC = 0.687, p < 0.001) and when discriminating patients with HGPCa from those without HGPCa (AUC = 0.768 vs. AUC = 0.739, p < 0.001). The finPCPTRC underestimated the risk of PCa but overestimated the risk of HGPCa (both p < 0.001). Compared with other strategies to opt for biopsy, the net benefit would be larger with utilization of the finPCPTRC for patients accepting higher risks of HGPCa. Conclusions: Rates of biopsy-detectable PCa and HGPCa were high and 1.3% of this referral cohort in Mexico was taking finasteride. The risks of PCa or HGPCa calculated by the finPCPTRC were not well calibrated for this referral Mexican population and new clinical diagnostic tools are needed.
Preservation of Myocardial Structure Is Enhanced by Pim-1 Engineering of Bone Marrow Cells
Authors: Quijada Pearl , Toko Haruhiro , Fischer Kimberlee M. , Bailey Brandi , Reilly Patrick , Hunt Kristin D. , Gude Natalie A. , Avitabile Daniele , Sussman Mark A.
Published: May 2012

Rationale:

Bone marrow–derived cells to treat myocardial injury improve cardiac function and support beneficial cardiac remodeling. However, survival of stem cells is limited due to low proliferation of transferred cells.

Objective:

To demonstrate long-term potential of c-kit
+
bone marrow stem cells (BMCs) enhanced with Pim-1 kinase to promote positive cardiac remodeling.

Methods and Results:

Lentiviral modification of c-kit
+
BMCs to express Pim-1 (BMCeP) increases proliferation and expression of prosurvival proteins relative to BMCs expressing green fluorescent protein (BMCe). Intramyocardial delivery of BMCeP at time of infarction supports improvements in anterior wall dimensions and prevents left ventricle dilation compared with hearts treated with vehicle alone. Reduction of the akinetic left ventricular wall was observed in BMCeP-treated hearts at 4 and 12 weeks after infarction. Early recovery of cardiac function in BMCeP-injected hearts facilitated modest improvements in hemodynamic function up to 12 weeks after infarction between cell-treated groups. Persistence of BMCeP is improved relative to BMCe within the infarct together with increased recruitment of endogenous c-kit
+
cells. Delivery of BMC populations promotes cellular hypertrophy in the border and infarcted regions coupled with an upregulation of hypertrophic genes. Thus, BMCeP treatment yields improved structural remodeling of infarcted myocardium compared with control BMCs.

Conclusions:

Genetic modification of BMCs with Pim-1 may serve as a therapeutic approach to promote recovery of myocardial structure. Future approaches may take advantage of salutary BMC actions in conjunction with other stem cell types to increase efficacy of cellular therapy and improve myocardial performance in the injured myocardium.
Relationship Between Chest Compression Rates and Outcomes From Cardiac Arrest
Authors: Idris Ahamed H. , Guffey Danielle , Aufderheide Tom P. , Brown Siobhan , Morrison Laurie J. , Nichols Patrick , Powell Judy , Daya Mohamud , Bigham Blair L. , Atkins Dianne L. , Berg Robert , Davis Dan , Stiell Ian , Sopko George , Nichol Graham
Published: May 2012

Background—

Guidelines for cardiopulmonary resuscitation recommend a chest compression rate of at least 100 compressions per minute. Animal and human studies have reported that blood flow is greatest with chest compression rates near 120/min, but few have reported rates used during out-of-hospital (OOH) cardiopulmonary resuscitation or the relationship between rate and outcome. The purpose of this study was to describe chest compression rates used by emergency medical services providers to resuscitate patients with OOH cardiac arrest and to determine the relationship between chest compression rate and outcome.

Methods and Results—

Included were patients aged ≥20 years with OOH cardiac arrest treated by emergency medical services providers participating in the Resuscitation Outcomes Consortium. Data were abstracted from monitor-defibrillator recordings during cardiopulmonary resuscitation. Multiple logistic regression analysis assessed the association between chest compression rate and outcome. From December 2005 to May 2007, 3098 patients with OOH cardiac arrest were included in this study. Mean age was 67±16 years, and 8.6% survived to hospital discharge. Mean compression rate was 112±19/min. A curvilinear association between chest compression rate and return of spontaneous circulation was found in cubic spline models after multivariable adjustment (
P
=0.012). Return of spontaneous circulation rates peaked at a compression rate of ≈125/min and then declined. Chest compression rate was not significantly associated with survival to hospital discharge in multivariable categorical or cubic spline models.

Conclusions—

Chest compression rate was associated with return of spontaneous circulation but not with survival to hospital discharge in OOH cardiac arrest.
Axonal Outgrowth and Dendritic Plasticity in the Cortical Peri-Infarct Area After Experimental Stroke
Authors: Ueno Yuji , Chopp Michael , Zhang Li , Buller Benjamin , Liu Zhongwu , Lehman Norman L. , Liu Xian Shuang , Zhang Yi , Roberts Cynthia , Zhang Zheng Gang
Published: May 2012

Background and Purpose—

Axonal remodeling is critical to brain repair after stroke. The present study investigated axonal outgrowth after stroke and the signaling pathways mediating axonal outgrowth in cortical neurons.

Methods—

Using a rodent model of middle cerebral artery occlusion, we examined high-molecular weight neurofilament (NFH) immunoreactive axons and myelin basic protein-positive oligodendrocytes in the peri-infarct area. In vitro, using cultured cortical neurons in a microfluidic chamber challenged by oxygen-glucose deprivation (OGD), we investigated mechanisms selectively regulating axonal outgrowth after OGD.

Results—

NFH
+
axons and MBP
+
oligodendrocytes substantially increased in the peri-infarct area during stroke recovery, concomitantly with an increase in dendrites and spines identified by Golgi-Cox staining. In vitro, cortical neurons subjected to OGD exhibited significant increases in axonal outgrowth and in phosphorylated NFH protein levels, concurrently with downregulation of phosphatase tensin homolog deleted on chromosome 10, activation of Akt, and inactivation of glycogen synthase kinase-3β in regenerated axons. Blockage of phosphoinositide 3-kinase with pharmacological inhibitors suppressed Akt activation and attenuated phosphorylation of glycogen synthase kinase-3β, which resulted in suppression of phosphorylated NFH and axonal outgrowth after OGD; whereas GSK-3 inhibitors augmented axonal regeneration and elevated phosphorylated NFH levels after OGD.

Conclusions—

Stroke induces axonal outgrowth and myelination in rodent ischemic brain during stroke recovery, and the phosphoinositide 3-kinase/Akt/glycogen synthase kinase-3β signaling pathway mediates axonal regeneration of cortical neurons after OGD.
Apolipoprotein E Genotype Is Associated With CT Angiography Spot Sign in Lobar Intracerebral Hemorrhage
Authors: Brouwers H. Bart , Biffi Alessandro , McNamara Kristen A. , Ayres Alison M. , Valant Valerie , Schwab Kristin , Romero Javier M. , Viswanathan Anand , Greenberg Steven M. , Rosand Jonathan , Goldstein Joshua N.
Published: May 2012

Background and Purpose—

The CT angiography (CTA) spot sign predicts hematoma expansion and poor outcome in patients with primary intracerebral hemorrhage (ICH). The biological underpinnings of the spot sign remain poorly understood; it may be that the underlying vasculopathy influences its presence. Therefore, we conducted a study to identify genetic predictors of the spot sign.

Methods—

In an ongoing prospective cohort study, we analyzed 371 patients with CTA and genetic data available. CTAs were reviewed for the spot sign by 2 experienced readers, blinded to clinical data, according to validated criteria. Analyses were stratified by ICH location.

Results—

In multivariate analysis, patients on warfarin were more likely to have a spot sign regardless of ICH location (OR, 3.85; 95% CI, 1.33–11.13 in deep ICH and OR, 2.86; 95% CI, 1.33–6.13 in lobar ICH). Apolipoprotein E ϵ2, but not ϵ4, was associated with the presence of a spot sign in lobar ICH (OR, 2.09; 95% CI, 1.05–4.19). There was no effect for ϵ2 or ϵ4 in deep ICH.

Conclusions—

Patients with ICH on warfarin are more likely to present with a spot sign regardless of ICH location. Among patients with lobar ICH, those who possess the apolipoprotein E ϵ2 allele are more likely to have a spot sign. Given the established relationship between apolipoprotein E ϵ2 and vasculopathic changes in cerebral amyloid angiopathy, our findings suggest that both hemostatic factors and vessel pathology influence spot sign presence.
Clinical Significance of Impaired Cerebrovascular Autoregulation After Severe Aneurysmal Subarachnoid Hemorrhage
Authors: Jaeger Matthias , Soehle Martin , Schuhmann Martin U. , Meixensberger Jürgen
Published: May 2012

Background and Purpose—

The purpose of this study was to investigate the relationship between cerebrovascular autoregulation and outcome after aneurysmal subarachnoid hemorrhage.

Methods—

In a prospective observational study, 80 patients after severe subarachnoid hemorrhage were continuously monitored for cerebral perfusion pressure and partial pressure of brain tissue oxygen for an average of 7.9 days (range, 1.9–14.9 days). Autoregulation was assessed using the index of brain tissue oxygen pressure reactivity (ORx), a moving correlation coefficient between cerebral perfusion pressure and partial pressure of brain tissue oxygen. High ORx indicates impaired autoregulation; low ORx signifies intact autoregulation. Outcome was determined at 6 months and dichotomized into favorable (Glasgow Outcome Scale 4–5) and unfavorable outcome (Glasgow Outcome Scale 1–3).

Results—

Twenty-four patients had a favorable and 56 an unfavorable outcome. In a univariate analysis, there were significant differences in autoregulation (ORx 0.19±0.10 versus 0.37±0.11,
P
<0.001, for favorable versus unfavorable outcome, respectively), age (44.1±11.0 years versus 54.2±12.1 years,
P
=0.001), occurrence of delayed cerebral infarction (8% versus 46%,
P
<0.001), use of coiling (25% versus 54%,
P
=0.02), partial pressure of brain tissue oxygen (24.9±6.6 mm Hg versus 21.8±6.3 mm Hg,
P
=0.048), and Fisher grade (
P
=0.03). In a multivariate analysis, ORx (
P
<0.001) and age (
P
=0.003) retained an independent predictive value for outcome. ORx correlated with Glasgow Outcome Scale (
r
=−0.70,
P
<0.001).

Conclusions—

The status of cerebrovascular autoregulation might be an important pathophysiological factor in the disease process after subarachnoid hemorrhage, because impaired autoregulation was independently associated with an unfavorable outcome.