bluuebunny/crossref_metadata_2025 huggingface dataset:
Microinjections of urocortin1 into the nucleus ambiguus of the rat elicit bradycardia
Authors: Chitravanshi Vineet C. , Sapru Hreday N.
Published: October 2010

Urocortins are members of the hypothalamic corticotropin-releasing factor (CRF) peptide family. Urocortin1 (UCN1) mRNA has been reported to be expressed in the brainstem neurons. The present investigation was carried out to test the hypothesis that microinjections of UCN1 into the nucleus ambiguus (nAmb) may elicit cardiac effects. Urethane-anesthetized, artificially ventilated, adult male Wistar rats, weighing between 300–350 g, were used. nAmb was identified by microinjections of l-glutamate (5 mM, 30 nl). Microinjections (30 nl) of different concentrations (0.062, 0.125, 0.25, and 0.5 mM) of UCN1 into the nAmb elicited bradycardic responses (26.5 ± 1, 30.1 ± 1.7, 46.9 ± 1.7, and 40.3 ± 2.6 beats/min, respectively). These heart rate responses were not accompanied by significant changes in mean arterial pressure. The bradycardic responses to maximally effective concentration of UCN1 (0.25 mM) were significantly ( P < 0.05) attenuated by prior microinjections of a selective antagonist (NBI 27914, 1.5 mM) for CRF type 1 receptor (CRF1R). Prior microinjections of ionotropic glutamate receptor (iGLUR) antagonists [d-(−)-2-amino-7-phosphono-heptanoic acid and 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo-(f)quinoxaline-7-sulfonamide disodium] also attenuated the bradycardia elicited by UCN1 microinjections into the nAmb. Microinjections of NBI 27914 (1.5 mM) into the nAmb did not alter baroreflex responses. Bilateral vagotomy abolished the bradycardic responses to microinjections of UCN1 into the nAmb. These results indicated that 1) microinjections of UCN1 into the nAmb elicited bradycardia, 2) the bradycardia was vagally mediated, 3) activation of CRF1Rs in the nAmb was responsible for the actions of UCN1, and 4) activation of iGLURs in the nAmb also participated in the bradycardia elicited by UCN1.
Linking lung function and inflammatory responses in ventilator-induced lung injury
Authors: Cannizzaro Vincenzo , Hantos Zoltan , Sly Peter D. , Zosky Graeme R.
Published: October 2010

Despite decades of research, the mechanisms of ventilator-induced lung injury are poorly understood. We used strain-dependent responses to mechanical ventilation in mice to identify associations between mechanical and inflammatory responses in the lung. BALB/c, C57BL/6, and 129/Sv mice were ventilated using a protective [low tidal volume and moderate positive end-expiratory pressure (PEEP) and recruitment maneuvers] or injurious (high tidal volume and zero PEEP) ventilation strategy. Lung mechanics and lung volume were monitored using the forced oscillation technique and plethysmography, respectively. Inflammation was assessed by measuring numbers of inflammatory cells, cytokine (IL-6, IL-1β, and TNF-α) levels, and protein content of the BAL. Principal components factor analysis was used to identify independent associations between lung function and inflammation. Mechanical and inflammatory responses in the lung were dependent on ventilation strategy and mouse strain. Three factors were identified linking 1) pulmonary edema, protein leak, and macrophages, 2) atelectasis, IL-6, and TNF-α, and 3) IL-1β and neutrophils, which were independent of responses in lung mechanics. This approach has allowed us to identify specific inflammatory responses that are independently associated with overstretch of the lung parenchyma and loss of lung volume. These data provide critical insight into the mechanical responses in the lung that drive local inflammation in ventilator-induced lung injury and the basis for future mechanistic studies in this field.
Muscle use during double poling evaluated by positron emission tomography
Authors: Bojsen-Møller Jens , Losnegard Thomas , Kemppainen Jukka , Viljanen Tapio , Kalliokoski Kari K. , Hallén Jostein
Published: October 2010

Due to the complexity of movement in cross-country skiing (XCS), the muscle activation patterns are not well elucidated. Previous studies have applied surface electromyography (SEMG); however, recent gains in three-dimensional (3D) imaging techniques such as positron emission tomography (PET) have rendered an alternative approach to investigate muscle activation. The purpose of the present study was to examine muscle use during double poling (DP) at two work intensities by use of PET. Eight male subjects performed two 20-min DP bouts on separate days. Work intensity was ∼53 and 74% of peak oxygen uptake (V̇o2peak), respectively. During exercise 188 ± 8 MBq of [18F]fluorodeoxyglucose ([18F]FDG) was injected, and subsequent to exercise a full-body PET scan was conducted. Regions of interest (ROI) were defined within 15 relevant muscles, and a glucose uptake index (GUI) was determined for all ROIs. The muscles that span the shoulder and elbow joints, the abdominal muscles, and hip flexors displayed the greatest GUI during DP. Glucose uptake did not increase significantly from low to high intensity in most upper body muscles; however, an increased GUI ( P < 0.05) was seen for the knee flexor (27%) and extensor muscles (16%), and for abdominal muscles (21%). The present data confirm previous findings that muscles of the upper limb are the primary working muscles in DP. The present data further suggest that when exercise intensity increases, the muscles that span the lumbar spine, hip, and knee joints contribute increasingly. Finally, PET provides a promising alternative or supplement to existing methods to assess muscle activation in complex human movements.
Recruitment and rate-coding strategies of the human genioglossus muscle
Authors: Saboisky Julian P. , Jordan Amy S. , Eckert Danny J. , White David P. , Trinder John A. , Nicholas Christian L. , Gautam Shiva , Malhotra Atul
Published: October 2010

Single motor unit (SMU) analysis provides a means to examine the motor control of a muscle. SMUs in the genioglossus show considerable complexity, with several different firing patterns. Two of the primary stimuli that contribute to genioglossal activation are carbon dioxide (CO2) and negative pressure, which act through chemoreceptor and mechanoreceptor activation, respectively. We sought to determine how these stimuli affect the behavior of genioglossus SMUs. We quantified genioglossus SMU discharge activity during periods of quiet breathing, elevated CO2 (facilitation), and continuous positive airway pressure (CPAP) administration (inhibition). CPAP was applied in 2-cmH2O increments until 10 cmH2O during hypercapnia. Five hundred ninety-one periods (each ∼3 breaths) of genioglossus SMU data were recorded using wire electrodes( n = 96 units) from 15 awake, supine subjects. Overall hypercapnic stimulation increased the discharge rate of genioglossus units (20.9 ± 1.0 vs. 22.7 ± 0.9 Hz). Inspiratory units were activated ∼13% earlier in the inspiratory cycle, and the units fired for a longer duration (80.6 ± 5.1 vs. 105.3 ± 4.2% inspiratory time; P < 0.05). Compared with baseline, an additional 32% of distinguishable SMUs within the selective electrode recording area were recruited with hypercapnia. CPAP led to progressive SMU inhibition; at ∼6 cmH2O, there were similar numbers of SMUs active compared with baseline, with peak frequencies of inspiratory units close to baseline, despite elevated CO2 levels. At 10 cmH2O, the number of units was 36% less than baseline. Genioglossus inspiratory phasic SMUs respond to hypercapnic stimulation with changes in recruitment and rate coding. The SMUs respond to CPAP with derecruitment as a homogeneous population, and inspiratory phasic units show slower discharge rates. Understanding upper airway muscle recruitment/derecruitment may yield therapeutic targets for maintenance of pharyngeal patency.
Hippo Pathway Effector Yap Is an Ovarian Cancer Oncogene
Authors: Hall Chad A. , Wang Runsheng , Miao Jiangyong , Oliva Esther , Shen Xiaoyun , Wheeler Thomas , Hilsenbeck Susan G. , Orsulic Sandra , Goode Scott
Published: October 2010

The Hippo pathway regulates organ size and tumorigenesis in Drosophila and mammals and is altered in a variety of human cancers, yet it remains unclear if the Hippo pathway is of prognostic significance to cancer patients. Here we show that the key targets of Hippo signaling, transcriptional coactivators Yki and Yap, play a conserved role in promoting ovarian cancer in flies and humans, respectively. Whereas studies linking Yap to cancer in other tissues have focused on overall Yap levels, we show for the first time that subcellular levels of Yap show an exceptionally strong association with poor patient survival. Specifically, high levels of nuclear Yap (nYap), or low levels of cytoplasmic phosphorylated Yap (cpYap), associated with poor survival from ovarian cancer. Patients with both high nYap and low cpYap had ∼50% lower 5-year survival, and this combination is an independent prognostic marker for survival, with an exceptionally high hazard ratio of 7.8. We find that Yap2 is the predominantly expressed Yap isoform in both the ovarian surface epithelium (OSE) and epithelial ovarian cancers. Overexpression of Yap2 and phosphorylation-defective Yap2-5SA in immortalized OSE cells resulted in increased cell proliferation, resistance to cisplatin-induced apoptosis, faster cell migration, and anchorage-independent growth, whereas Yap knockdown resulted in increased sensitivity to cisplatin-induced apoptosis. Findings argue that the Hippo signaling pathway defines an important pathway in progression of ovarian cancer. Cancer Res; 70(21); 8517–25. ©2010 AACR.
Androgen-Induced TMPRSS2:ERG Fusion in Nonmalignant Prostate Epithelial Cells
Authors: Bastus Nuria Coll , Boyd Lara K. , Mao Xueying , Stankiewicz Elzbieta , Kudahetti Sakunthala C. , Oliver R. Tim D. , Berney Daniel M. , Lu Yong-Jie
Published: October 2010

Fusion genes play important roles in tumorigenesis. The identification of the high-frequency TMPRSS2 fusion with ERG and other ETS family genes in prostate cancer highlights the importance of fusion genes in solid tumor development and progression. However, the mechanisms leading to these fusions are unclear. We investigated whether androgen, through stimulating its receptor, could promote spatial genome reorganization and contribute to the generation of the TMPRSS2:ERG fusion. We show that treatment with androgen can induce the TMPRSS2:ERG fusion in both malignant and nonmalignant prostate epithelial cells. Although the fusion could be detected in malignant cells following 24-hour treatment, prolonged exposure to androgen was required to detect the fusion transcript in nonmalignant cells. We associated the fusion incidence with genetic factors, including androgen-induced gene proximity, androgen receptor exon1 CAG repeat length and expression of the PIWIL1 gene. This study demonstrates that fusions can be induced prior to malignant transformation and generation of the fusion is associated with both gene proximity and loss of the ability to prevent double-strand breaks. Cancer Res; 70(23); 9544–8. ©2010 AACR.
IL-2 Costimulation Enables Statin-Mediated Activation of Human NK Cells, Preferentially through a Mechanism Involving CD56+ Dendritic Cells
Authors: Gruenbacher Georg , Gander Hubert , Nussbaumer Oliver , Nussbaumer Walter , Rahm Andrea , Thurnher Martin
Published: October 2010

Statins are inhibitors of cholesterol biosynthesis and protein prenylation that also have been studied in cancer therapy and chemoprevention. With regard to natural killer (NK) cells, only inhibitory effects of statins such as suppression of granule exocytosis have been reported so far. In this study, we show that statins can cooperate with IL-2 to potently induce the activation of CD56dim NK cells in a synergistic, time- and dose-dependent fashion. Supplementation experiments revealed that the statin effect was specific to inhibition of their target hydroxymethylglutaryl coenzyme A reductase and that downstream depletion of geranylgeranyl pyrophosphate was responsible for cooperating with IL-2 in NK cell activation. Mechanistic studies revealed that CD56+HLA-DR+CD14+ dendritic cell (DC)-like accessory cells mediated the ability of statin to activate NK cells. In contrast, BDCA-1+ (CD1c+) myeloid DCs, which partially expressed CD56, were somewhat less potent. Conventional blood monocytes, which lack CD56, exhibited the lowest accessory cell capacity. NK cell IFN-γ production was IL-12 independent but required endogenous IL-18, IL-1β, and caspase-1 activity. Statins directly induced apoptosis in human cancer cell lines and cooperated with NK cell–derived IFN-γ to generate potent cytotoxic antitumor effects in vitro even in the presence of statin-mediated inhibitory effects on granule exocytosis. Our work reveals novel and unexpected immunomodulatory properties of statins, which might be harnessed for the treatment of cancer. Cancer Res; 70(23); 9611–20. ©2010 AACR.
Inflammatory and MicroRNA Gene Expression as Prognostic Classifier of Barrett's-Associated Esophageal Adenocarcinoma
Authors: Nguyen Giang Huong , Schetter Aaron J. , Chou David B. , Bowman Elise D. , Zhao Ronghua , Hawkes Jason E. , Mathé Ewy A. , Kumamoto Kensuke , Zhao Yiqiang , Budhu Anuradha , Hagiwara Nobutoshi , Wang Xin Wei , Miyashita Masao , Casson Alan G. , Harris Curtis C.
Published: October 2010

Purpose: Esophageal cancer is one of the most aggressive and deadly forms of cancer; highlighting the need to identify biomarkers for early detection and prognostic classification. Our recent studies have identified inflammatory gene and microRNA signatures derived from tumor and nontumor tissues as prognostic biomarkers of hepatocellular, lung, and colorectal adenocarcinoma. Here, we examine the relationship between expression of these inflammatory genes and micro RNA (miRNA) expression in esophageal adenocarcinoma and patient survival.

Experimental Design: We measured the expression of 23 inflammation-associated genes in tumors and adjacent normal tissues from 93 patients (58 Barrett's and 35 Sporadic adenocarcinomas) by quantitative reverse transcription-polymerase chain reaction. These data were used to build an inflammatory risk model, based on multivariate Cox regression, to predict survival in a training cohort (n = 47). We then determined whether this model could predict survival in a cohort of 46 patients. Expression data for miRNA-375 were available for these patients and was combined with inflammatory gene expression.

Results: IFN-γ, IL-1α, IL-8, IL-21, IL-23, and proteoglycan expression in tumor and nontumor samples were each associated with poor prognosis based on Cox regression [(Z-score)>1.5] and therefore were used to generate an inflammatory risk score (IRS). Patients with a high IRS had poor prognosis compared with those with a low IRS in the training (P = 0.002) and test (P = 0.012) cohorts. This association was stronger in the group with Barrett's history. When combining with miRNA-375, the combined IRS/miR signature was an improved prognostic classifier than either one alone.

Conclusion: Transcriptional profiling of inflammation-associated genes and miRNA expression in resected esophageal Barrett's-associated adenocarcinoma tissues may have clinical utility as predictors of prognosis. Clin Cancer Res; 16(23); 5824–34. ©2010 AACR.
Comparison of Accumulation, Subcellular Location, and Sonodynamic Cytotoxicity between Hematoporphyrin and Protoporphyrin IX in L1210 Cells
Authors: Zhu Bo , Liu Quanhong , Wang Yuan , Wang Xiaobing , Wang Pan , Zhang Lina , Su Sheng
Published: October 2010

Background: Sonodynamic therapy (SDT) is a promising modality for cancer treatment which requires the synergistic effect of ultrasound and tumor-localized sonosensitizers. Sonodynamic efficacy can be improved through a better understanding of the accumulation and subcellular location of sonosensitizers. Here, a comparison of the accumulation, sublocation, and sonodynamic effect of hematoporphyrin (Hp) and protoporphyrin IX (PpIX) was studied in L1210 cells. Methods: The kinetics of intracellular Hp and PpIX accumulation were detected using a fluorescence spectrophotometer. The subcellular distributions of Hp and PpIX were monitored by laser scanning confocal microscopy. The cytotoxic effects of Hp-mediated SDT (Hp-SDT) and PpIX-mediated SDT (PpIX-SDT) were evaluated by MTT assay. Results: The accumulation of Hp and PpIX presented different kinetic changes depending on the time, and was also concentration- and temperature-dependent. The intracellular PpIX content was much higher than that of Hp under the same conditions; however, there were no obvious differences in terms of their subcellular locations, and both of them mainly accumulated on the mitochondria and the plasma membrane in L1210 cells. PpIX exhibited more potential cytotoxicity than did Hp when they were irradiated with ultrasound under the same experimental conditions. Conclusion: Our results indicate that there were significant differences regarding the intracellular accumulation features between Hp and PpIX. PpIX-SDT produced a more serious cytotoxic effect than did Hp-SDT, which may be due to the higher PpIX uptake in L1210 cells compared to that of Hp at the same concentrations. Additionally, the absorption of Hp and PpIX in L1210 cells might be energy dependent.
Antitumor Effects of Ginkgolic Acid in Human Cancer Cell Occur via Cell Cycle Arrest and Decrease the Bcl-2/Bax Ratio to Induce Apoptosis
Authors: Zhou Chenchen , Li Xiaoyu , Du Wei , Feng Yun , Kong Xiangli , Li Yan , Xiao Liying , Zhang Ping
Published: October 2010

Background: Ginkgolic acids (GAs), extracted from the seed coat of Ginkgo biloba L. Our previous study has shown that GA monomer could inhibit the growth of Hep-2 significantly and induce the fragmentation of the chromosomal DNA. To further assess the antitumor potential and turn it into a candidate new antitumor drug, the antitumor mechanism of GA was investigated. Method: The cytotoxicity and antitumor effect of GA monomer were assayed by MTT colorimetric assay with nontumorogenic MC-3T3-E1 as well as tumorogenic Hep-2 and Tac8113 cell lines. The effect of GA monomer on the proliferation of tumor cell lines was analyzed with MTT colorimetric and CFSE labeled assay. Cell cycle distribution and measurement of the percentage of apoptotic cells were performed by flow cytometry following stained with propidium iodide, annexin V-FITC. The expression of apoptotic proteins Bcl-2, Bax and caspase-3 was analyzed with Western blot. Result: GA only inhibited the growth of tumorogenic cell lines in a both dose- and time-dependent manner. Tumor cells were treated with GA for 72 h, 70.53 ± 4.54% Hep-2 and 63.5 ± 7.2% Tca8113 cells were retarded at GO/G1 phase, and the percentage of apoptosis was 40.4 ± 1.58 and 38.4 ± 1.7%, respectively. GA-treated activated caspase-3 downregulated the expression of anti-apoptotic Bcl-2 protein and upregulated the expression of pro-apoptotic Bax protein, eventually leading to a decrease in the Bcl-2/Bax ratio in tumor cells. Conclusions: The antitumor action of GA was due to inhibiting the proliferation in a manner of inhibiting division, retarding the progress of cell cycle and inducing apoptosis, making GA a candidate as new antitumor drug.
Comparative Activity of Telavancin and Other Antimicrobial Agents against Methicillin-Resistant Staphylococcus aureus Isolates Collected from 1991 to 2006
Authors: Shams Wael , Walker Elaine S. , Levy Foster , Reynolds Scott A. , Peterson Shalena M. , Sarubbi Felix A.
Published: October 2010

Background: Increasingly frequent reports of vancomycin treatment failures for serious methicillin-resistant Staphylococcus aureus (MRSA) infections provide impetus for comparative in vitro studies to assess the activity of newer antimicrobial agents against a range of MRSA isolates. Methods: A sample of 168 MRSA derived from a long-term MRSA collection was subjected to susceptibility testing to telavancin, daptomycin, linezolid, tigecycline and vancomycin by broth micro-dilution. Data were reviewed for sporadic occurrence of isolates with reduced susceptibility. Analyses were performed to test for temporal trends toward decreasing susceptibility and to compare susceptibility of isolates from different infection sites. Results: No MRSA isolate from any time period was resistant to test antibiotics. For daptomycin, linezolid and tigecycline, there were no susceptibility differences between the pre- and postclinical availability periods. All newer agents were active against MRSA isolates with minimum inhibitory concentrations (MICs) of vancomycin >1 mg/l, but there were significant correlations in susceptibility among several pairs of antibiotics. Conclusions: Telavancin and other newer antistaphylococcal agents were fully active against MRSA from various infection sites including isolates with vancomycin MIC >1 mg/l.
How Useful Are Bowel Sounds in Assessing the Abdomen?
Authors: Gu Yuqi , Lim Hyun Ja , Moser Michael A.J.
Published: October 2010

Background: The purpose of our study is to determine the accuracy of bowel sounds in the diagnosis of ileus and bowel obstruction. Methods: Healthy volunteers (n = 10) and patients with radiologically or laparotomy confirmed small bowel obstruction (n = 9) and ileus (n = 7) were enrolled. Two 30-second recordings from each subject were obtained using an electronic stethoscope. Study physicians (n = 20) were then presented with 43 recordings in blinded fashion and were asked whether each was from a normal subject or from a subject with bowel obstruction or ileus. Results: Physicians arrived at the correct diagnosis a median of 30 times out of 43 (69.8%). Intra-observer variation (ĸ = 0.72, agreement 81.3%) and intra-subject variation (ĸ = 0.63, agreement 78.7%) were very good. Bowel sounds from subjects with ileus and normal bowel sounds were correctly identified most of the time (84.5 and 78.1%, respectively). Bowel sounds from patients with obstruction were correctly identified only 42.1% of the time, but if a physician believed he or she was hearing a bowel obstruction, this had a strong positive predictive value (PPV, 72.7%). Conclusion: Our results suggest that the auscultation of bowel sounds is useful, especially in detecting ileus. The diagnosis of obstruction had a high PPV.
Dyspnea during Speech in Chronic Obstructive Pulmonary Disease Patients: Effects of Pulmonary Rehabilitation
Authors: Binazzi Barbara , Lanini Barbara , Romagnoli Isabella , Garuglieri Silvia , Stendardi Loredana , Bianchi Roberto , Gigliotti Francesco , Scano Giorgio
Published: October 2010

Background: For patients with limited physical activities who use oral communication for most social activities, the assessment of dyspnea during speech activities (DS) may provide relevant measurement criteria. Although speech production is altered by lung disease it has not been included in current dyspnea assessment tools. Objectives: We evaluated DS in patients with chronic obstructive pulmonary disease (COPD) with the aim of assessing: (i) the responsiveness to treatment of this newly developed evaluative dyspnea tool and (ii) whether DS is an independent measurement of other traditional outcomes. Methods: We assessed lung function, the 6-min walking test (6’WT), chronic exertional dyspnea (MRC and BDI/TDI), and DS using the speech section of the University of Cincinnati Dyspnea Questionnaire (UCDQ) before and after a pulmonary rehabilitation program in 31 patients with COPD. Results: The following items of the speech section of the UCDQ caused dyspnea: conversation, raising the voice, phoning, speaking to a group, talking in a noisy place, and singing. The mean overall DS score was 60 ± 23% of a maximal potential DS score. Pulmonary rehabilitation reduced each item of DS independently of change in lung function, chronic exertional dyspnea, and 6’WT. Conclusions: We concluded that DS is responsive to a respiratory rehabilitation program in patients with COPD. Evidence of independent objective measures supports the validity of a routine multivariable assessment including DS. We recommend assessment of DS particularly for patients who rely extensively on speech for communication.
Supramaximal Flows: Comparison between Asthmatics and Patients with Chronic Obstructive Pulmonary Disease
Authors: González Alejandra , Fernández Alejandra , Guardia Sergio , Sala Hernando
Published: October 2010

Background: The major motive that prompted this study was to investigate whether or not the differences in supramaximal flow (SF) behavior between patients suffering from asthma and patients suffering from chronic obstructive pulmonary disease (COPD) might aid in clarifying the differences in the physiopathology of the two diseases. Objectives: The aim of the present study was therefore to compare SFs in asthma and COPD patients with similar degrees of air-flow limitation. Methods: Twelve asthmatic patients were individually matched with 12 COPD patients by forced expiratory volume during the first second (FEV1) as a percent (±5%) of the reference value (ΔFEV1) and by age (±4 years). The subjects performed baseline maximal expiratory flow-volume curves (MEFV) and then repeated the same maneuvers through a valve that occluded the air flow 6 times per second with an open/closed time ratio of 4/1. We then plotted an envelope of the expiration-interrupted curve passing through the SF peaks, measured the increase in flow at 50% of the forced vital capacity between the baseline curve and the envelope curves (ΔVmax50), and compared the FEV1 of the interrupted curve to the FEV1 obtained from control MEFV curves (ΔFEV1). Results: We found significantly higher values for ΔVmax50 (p < 0.03) and ΔFEV1 (p < 0.01) in the asthmatics compared to the COPD patients. Conclusions: The differences reported here are best explained by a greater preservation of elastic recoil pressure at a similar degree of air-flow limitation in the asthmatics than in the COPD patients.
Surgical Outcome and Improvement in Quality of Life after Microvascular Decompression for Hemifacial Spasms: A Case Series Assessment Using a Validated Disease-Specific Scale
Authors: Ray Dibyendu K. , Bahgat Diaa , McCartney Shirley , Burchiel Kim J.
Published: October 2010

Background: Hemifacial spasm (HFS) is a movement disorder characterized by intermittent, involuntary clonic or tonic-clonic contractions of muscles innervated by the ipsilateral facial nerve. Recent studies have documented change in quality of life after HFS management with botulinum toxin injection. However, we failed to locate any study that documented change in quality of life after surgical management with retrosigmoid microvascular decompression (MVD). Methods: Our study objectives were 3-fold. Firstly, to use a disease-specific, validated quality of life assessment scale to document any change in quality of life after MVD for HFS. Secondly, to determine the time period in which the majority of patients undergoing MVD could be expected to benefit from surgery. Finally, to determine factors affecting the postoperative quality of life following MVD. A retrospective analysis of HFS patients treated with MVD at a single institution by a single surgeon (K.J.B.) between January 2000 and December 2007 was undertaken. A modification of a previously developed validated disease-specific quality of life assessment scale that included the addition of a parameter for difficulty in sleep was used to assess quality of life before and after surgery. Results: A total of 21 patients (14 female and 7 male) underwent treatment as specified. Eighty-five percent (17/20) of the patients reported prolonged remission of symptoms (mean follow-up period = 4.15 years). Five percent (1/20) reported occasional recurrence of twitches. The overall mean quality of life score improved from 11.1 preoperatively to 2.2 postoperatively. Conclusions: MVD offers significant and prolonged improvement in quality of life for the HFS patients we studied, as measured using a disease-specific, validated quality of life assessment scale. Postoperative quality of life, however, was strongly influenced by both the success of surgery in resolving the symptoms and the absence of any permanent complications of surgery.
Does External Counterpulsation Augment Mean Cerebral Blood Flow in the Healthy Brain? Effects of External Counterpulsation on Middle Cerebral Artery Flow Velocity and Cerebrovascular Regulatory Response in Healthy Subjects
Authors: Jungehuelsing G.J. , Liman T.G. , Brunecker P. , Ebel A. , Endres M. , Buschmann I. , Pagonas N. , Buschmann E.E. ,   on behalf of the Arteriogenesis Network and of the Center for Stroke Research Berlin
Published: October 2010

Background and Purpose:External counterpulsation (ECP) noninvasively improves myocardial and organ perfusion via diastolic augmentation. The effects on cerebral blood flow velocities (CBFV) and hemodynamics are controversial. In this study, the effect of active ECP treatment on CBF in healthy subjects was continuously measured. Methods: In 9 healthy volunteers (mean age 34.1 ± 11.1 years, 4 females), 20-min active ECP treatment was performed. CBFV in the middle cerebral artery were detected via transcranial Doppler. CBFV were registered continuously before, during and after ECP. The protocol was repeated twice. Results: At onset of ECP, immediate changes in CBFV were observed: peak diastolic blood flow velocities increased from baseline to treatment (63 vs. 76 cm/s; p < 0.001) and diastolic blood flow augmentation was maintained throughout ECP. Peak systolic (87 vs. 78 cm/s; p < 0.001) and end-diastolic velocities (40 vs. 28 cm/s; p < 0.001) decreased significantly, while mean CBFV maintained constant (59 vs. 58 cm/s; not significant). The pulsatility index and resistance index as indirect parameters for peripheral vascular resistance increased during ECP (pulsatility index 0.79 vs. 0.89, p < 0.001; resistance index 0.54 vs. 0.64; p < 0.001). Conclusions: ECP did not increase mean CBFV in healthy subjects even though peak diastolic CBFV were significantly augmented. Changes in CBFV and transcranial Doppler waveform characteristics suggest that the mean flow of the middle cerebral artery is maintained stable via cerebrovascular autoregulatory mechanisms.
Activation of NAD(P)H Oxidases by Thromboxane A
2
Receptor Uncouples Endothelial Nitric Oxide Synthase
Authors: Zhang Miao , Song Ping , Xu Jian , Zou Ming-Hui
Published: October 2010

Objective—

The thromboxane receptor (TPr) and multiple TPr ligands, including thromboxane A
2
(TxA
2
) and prostaglandin H
2
, are elevated during vascular and atherothrombotic diseases. How TPr stimulation causes vascular injury remains poorly defined. This study was conducted to investigate the mechanism by which TPr stimulation leads to vascular injury.

Methods and Results—

Exposure of bovine aortic endothelial cells to either [1
S
-(1α,2β(5
Z
),3α(1
E
,3
R
),4α]-7-[3-(3-hydroxy-4-(d′-iodophenoxy)-1-butenyl)-7-oxabicyclo-[2.2.1] heptan-2-yl]-5′-heptenoic acid (IBOP) or U46619, 2 structurally related TxA
2
mimetics, for 24 hours markedly increased the release of superoxide anions (O
2
·−
) and peroxynitrite (ONOO
−
) but reduced cyclic GMP, an index of nitric oxide bioactivity. IBOP also significantly suppressed activity of endothelial nitric oxide synthase (eNOS), increased enzyme-inactive eNOS monomers, and reduced levels of tetrahydrobiopterin, an essential eNOS cofactor. IBOP- and U46619-induced increases in O
2
·−
were accompanied by the membrane translocation of the p67
phox
subunit of NAD(P)H oxidase. Pharmacological or genetic inhibition of either NAD(P)H oxidase or TPr abolished IBOP-induced O
2
·−
formation. Furthermore, TPr activation significantly increased protein kinase C-ζ (PKC-ζ) in membrane fractions and PKC-ζ phosphorylation at Thr410. Consistently, PKC-ζ inhibition abolished TPr activation-induced membrane translocation of p67
phox
and O
2
·−
production. Finally, exposure of isolated mouse aortae to IBOP markedly increased O
2
·−
in wild-type but not in those from gp91
phox
knockout mice.

Conclusion—

We conclude that TPr activation via PKC-ζ-mediated NAD(P)H oxidase activation increases both O
2
·−
and ONOO
−
, resulting in eNOS uncoupling in endothelial cells.
Increased 12/15-Lipoxygenase Enhances Cell Growth, Fibronectin Deposition, and Neointimal Formation in Response to Carotid Injury
Authors: Deliri Hamid , Meller Nahum , Kadakkal Ajay , Malhotra Rohit , Brewster Jordan , Doran Amanda C. , Pei Hong , Oldham Stephanie N. , Skaflen Marcus D. , Garmey James C. , McNamara Coleen A.
Published: October 2010

Objective—

To determine whether increased 12/15-lipoxygenase (12/15LO) expression in vivo enhances neointimal formation in response to injury.

Methods and Results—

12/15LO expression in the vessel wall is increased in animal models of metabolic syndrome and diabetes mellitus. Increased expression of 12/15LO enhances cultured vascular smooth muscle cell (VSMC) proliferation, an effect mediated by the helix-loop-helix factor inhibitor of differentiation 3 (Id3). Carotid endothelial denudation was performed on apolipoprotein (Apo) E
−/−
, ApoE
−/−
/12/15LO
−/−
, C57BL/6, and 12/15LO-overexpressing transgenic mice. ApoE
−/−
/12/15LO
−/−
mice had attenuated and 12/15LO-overexpressing transgenic mice had enhanced neointimal formation compared with control mice. 12/15LO-overexpressing transgenic mice had greater postinjury carotid Id3 and Ki-67 expression, cell number, and fibronectin deposition compared with C57BL/6 mice. Loss of 12/15LO attenuated proliferation of cultured ApoE
−/−
VSMCs, whereas 12/15LO overexpression induced VSMC proliferation. Loss of Id3 enhanced immunoglobulin trascription factor (ITF)-2b binding to and activation of the p21
cip1
promoter and abrogated 12/15LO-induced VSMC proliferation.

Conclusion—

To our knowledge, these data are the first demonstration that increased expression of 12/15LO in the vessel wall enhances Id3-dependent cell proliferation, fibronectin deposition, and neointimal formation in response to injury. Results identify p21
cip1
as a potential target of the 12/15LO-Id3 pathway and suggest that modulation of this pathway may have therapeutic implications for targeting the increased risk of restenosis in patients with diabetes.
Sphingosine-1-Phosphate Receptor-2 Function in Myeloid Cells Regulates Vascular Inflammation and Atherosclerosis
Authors: Skoura Athanasia , Michaud Jason , Im Dong-Soon , Thangada Shobha , Xiong Yuquan , Smith Jonathan D. , Hla Timothy
Published: October 2010

Objective—

Sphingomyelin deposition and metabolism occurs in the atherosclerotic plaque, leading to the formation of sphingosine-1-phosphate (S1P), which activates G protein–coupled receptors to regulate vascular and immune cells. The role of S1P receptors in atherosclerosis has not been examined.

Methods and Results—

We tested the hypothesis that S1P receptor-2 (S1PR2) regulates atherosclerosis.
Apoe
−/−
S1pr2
−/−
mice showed greatly attenuated atherosclerosis compared with the
Apoe
−/−
mice. Bone marrow transplant experiments indicate that S1PR2 function in the hematopoietic compartment is critical. S1PR2 is expressed in bone marrow–derived macrophages and in macrophage-like foam cells in atherosclerotic plaques. Reduced macrophage-like foam cells were found in the atherosclerotic plaques of
Apoe
−/−
S1pr2
−/−
mice, suggesting that S1PR2 retains macrophages in atherosclerotic plaques. Lipoprotein profiles, plasma lipids, and oxidized low-density lipoprotein uptake by bone marrow–derived macrophages were not altered by the
S1pr2
genotype. In contrast, endotoxin-induced inflammatory cytokine (interleukin [IL]-1β, IL-18) levels in the serum of S1PR2 knockout mice were significantly reduced. Furthermore, treatment of wild-type mice with S1PR2 antagonist JTE-013 suppressed IL-1β and IL-18 levels in plasma.

Conclusion—

These data suggest that S1PR2 signaling in the plaque macrophage regulates macrophage retention and inflammatory cytokine secretion, thereby promoting atherosclerosis.
Differential Endothelial Transcriptomics Identifies Semaphorin 3G as a Vascular Class 3 Semaphorin
Authors: Kutschera Simone , Weber Holger , Weick Anja , De Smet Frederik , Genove Guillem , Takemoto Minoru , Prahst Claudia , Riedel Maria , Mikelis Constantinos , Baulande Sylvain , Champseix Catherine , Kummerer Petra , Conseiller Emmanuel , Multon Marie-Christine , Heroult Melanie , Bicknell Roy , Carmeliet Peter , Betsholtz Christer , Augustin Hellmut G.
Published: October 2010

Objective—

To characterize the role of a vascular-expressed class 3 semaphorin (semaphorin 3G [Sema3G]).

Methods and Results—

Semaphorins have been identified as axon guidance molecules. Yet, they have more recently also been characterized as attractive and repulsive regulators of angiogenesis. Through a transcriptomic screen, we identified Sema3G as a molecule of angiogenic endothelial cells. Sema3G-deficient mice are viable and exhibit no overt vascular phenotype. Yet, LacZ expression in the Sema3G locus revealed intense arterial vascular staining in the angiogenic vasculature, starting at E9.5, which was detectable throughout adolescence and downregulated in adult vasculature. Sema3G is expressed as a full-length 100-kDa secreted molecule that is processed by furin proteases to yield 95- and a 65-kDa Sema domain–containing subunits. Full-length Sema3G binds to NP2, whereas processed Sema3G binds to NP1 and NP2. Expression profiling and cellular experiments identified autocrine effects of Sema3G on endothelial cells and paracrine effects on smooth muscle cells.

Conclusion—

Although the mouse knockout phenotype suggests compensatory mechanisms, the experiments identify Sema3G as a primarily endothelial cell–expressed class 3 semaphorin that controls endothelial and smooth muscle cell functions in autocrine and paracrine manners, respectively.
Differential Effects of Rosiglitazone and Metformin on Postprandial Lipemia in Patients With HIV-Lipodystrophy
Authors: van Wijk Jeroen P.H. , Hoepelman Andy I.M. , de Koning Eelco J.P. , Dallinga-Thie Geesje , Rabelink Ton J. , Cabezas Manuel Castro
Published: October 2010

Objective—

To compare the effects of rosiglitazone (8 mg/d, n=19) and metformin (2 g/d, n=18) on postprandial lipemia in patients with HIV-lipodystrophy.

Methods and Results—

Lipodystrophy in HIV is associated with insulin resistance and disturbed postprandial triglyceride and free fatty acid (FFA) metabolism. We conducted an open randomized 6-month study with standardized 10-h oral fat-loading tests at baseline and after treatment. Rosiglitazone (−34%) and metformin (−37%) reduced homeostasis model assessment similarly (
P
<0.05). Rosiglitazone did not change the area under the curve for FFA and triglyceride; however, it did reduce the area under the curve for hydroxybutyric acid (a marker of hepatic FFA oxidation) by 25% (
P
<0.05). Rosiglitazone increased the area under the curve for remnantlike particle cholesterol by 40% (
P
<0.01) compared with baseline. Metformin did not change any of the postprandial measurements.

Conclusion—

Rosiglitazone improved insulin sensitivity and decreased postprandial hydroxybutyric acid levels in patients with HIV-lipodystrophy, suggesting improved FFA handling. Despite metabolic improvements, rosiglitazone caused a marked increase in postprandial remnantlike particle cholesterol, which may adversely affect cardiovascular risk. Metformin did not affect postprandial lipemia and could be used to treat insulin resistance in this population.
Annexin A5 Therapy Attenuates Vascular Inflammation and Remodeling and Improves Endothelial Function in Mice
Authors: Ewing Mark M. , de Vries Margreet R. , Nordzell Mariette , Pettersson Knut , de Boer Hetty C. , van Zonneveld Anton Jan , Frostegård Johan , Jukema J. Wouter , Quax Paul H.A.
Published: October 2010

Objective—

Annexin A5 (AnxA5) has antithrombotic, antiapoptotic, and antiinflammatory properties; we investigated its effectiveness against vascular inflammation, remodeling, and dysfunction in accelerated atherosclerosis.

Methods and Results—

AnxA5 (1 mg/kg per day or vehicle) was investigated in vascular injury models in hypercholesterolemic apolipoprotein E (ApoE)3*Leiden mice. AnxA5 treatment reduced adhesion and infiltration of leukocytes by 71% to 69% (
P
=0.015,
P
=0.031) and macrophages by 51% to 87% (
P
=0.014,
P
=0.018), as well as monocyte chemotactic protein-1 and tumor necrosis factor-α expression in a femoral artery inflammation model (perivascular cuff for 3 days), indicating reduced vascular inflammation. In a vein graft model, 28 days of AnxA5 treatment reduced vein graft thickening (48%;
P
=0.006) and leukocyte infiltration (46%;
P
=0.003). In these mice, reduced plasma concentrations of IFN-γ (−72%;
P
=0.040), granulocyte colony–stimulating factor (−41%;
P
=0.010), and macrophage inflammatory protein-1β (MIP-1β) (−66%;
P
=0.020) were measured, indicating reduced systemic inflammation. An in vitro endothelial cell model shows the importance of AnxA5's anticoagulant properties in reducing vascular inflammation. Endothelium-mediated dilatation in hypercholesterolemic ApoE
(−/−)
mice was improved by 3 days of AnxA5 treatment, shown by improved systolic and diastolic blood pressure reductions in response to metacholine, which could be abolished by
l
-Nitro-Arginine-Methyl Ester (
l
-NAME), indicating nitric oxide involvement.

Conclusion—

AnxA5 reduced local vascular and systemic inflammation and vascular remodeling and improved vascular function, indicating that it has a therapeutic potential against atherosclerotic cardiovascular diseases.
Clonal Analysis Reveals a Common Progenitor for Endothelial, Myeloid, and Lymphoid Precursors in Umbilical Cord Blood
Authors: Ramos Aline Lisie , Darabi Radbod , Akbarloo Nasrin , Borges Luciene , Catanese Jacquelyn , Dineen Sean P. , Brekken Rolf A. , Perlingeiro Rita C.R.
Published: October 2010

Rationale:

Several studies demonstrate that hematopoietic tissues are a source of endothelial progenitor cells, which contribute to newly formed blood vessels during tissue repair in adults. However, it is not clear which cell type in these hematopoietic tissues gives rise to endothelial progenitor cells.

Objective:

To identity the origin of endothelial progenitors within the hematopoietic hierarchy and to assess their in vivo revascularization potential.

Methods and Results:

Using a single-cell sorting approach and in vitro multilineage differentiation assays, here we show that individual CD34
+
CD45
+
CD133
+
CD38
+
cells from cord blood uniquely have the ability to differentiate into T- and B-lymphoid, myeloid, and endothelial cells. The latter were characterized by the expression of VE-cadherin, KDR, von Willebrand factor, endothelial nitric oxide synthase, the lack of CD45, CD133, and c-fms (colony stimulating factor-1 receptor). Unexpectedly when transplanted into hindlimb ischemic NOD-scid IL2Rγ
null
mice, freshly isolated CD34
+
CD45
+
CD133
+
CD38
+
cells maintained their hematopoietic identity and were rarely found to integrate into host blood vessels. Nevertheless, they significantly improved perfusion, most likely through a paracrine mechanism. On the other hand, CD34
+
CD45
+
CD133
+
CD38
+
cells differentiated in vitro into endothelial cells were able to form vessels in vivo in both Matrigel plug and hindlimb ischemia transplantation assays.

Conclusions:

These findings indicate that the CD34
+
CD45
+
CD133
+
CD38
+
cell fraction contains a common progenitor for the hematopoietic and vascular lineages and may represent a valuable cell source for therapeutic applications.
The Critical Role of Neutral Cholesterol Ester Hydrolase 1 in Cholesterol Removal From Human Macrophages
Authors: Igarashi Masaki , Osuga Jun-ichi , Uozaki Hiroshi , Sekiya Motohiro , Nagashima Shuichi , Takahashi Manabu , Takase Satoru , Takanashi Mikio , Li Yongxue , Ohta Keisuke , Kumagai Masayoshi , Nishi Makiko , Hosokawa Masakiyo , Fledelius Christian , Jacobsen Poul , Yagyu Hiroaki , Fukayama Masashi , Nagai Ryozo , Kadowaki Takashi , Ohashi Ken , Ishibashi Shun
Published: October 2010

Rationale:

Hydrolysis of intracellular cholesterol ester (CE) is the key step in the reverse cholesterol transport in macrophage foam cells. We have recently shown that neutral cholesterol ester hydrolase (Nceh)1 and hormone-sensitive lipase (Lipe) are key regulators of this process in mouse macrophages. However, it remains unknown which enzyme is critical in human macrophages and atherosclerosis.

Objective:

We aimed to identify the enzyme responsible for the CE hydrolysis in human macrophages and to determine its expression in human atherosclerosis.

Methods and Results:

We compared the expression of NCEH1, LIPE, and cholesterol ester hydrolase (CES1) in human monocyte-derived macrophages (HMMs) and examined the effects of inhibition or overexpression of each enzyme in the cholesterol trafficking. The pattern of expression of NCEH1 was similar to that of neutral CE hydrolase activity during the differentiation of HMMs. Overexpression of human NCEH1 increased the hydrolysis of CE, thereby stimulating cholesterol mobilization from THP-1 macrophages. Knockdown of NCEH1 specifically reduced the neutral CE hydrolase activity. Pharmacological inhibition of NCEH1 also increased the cellular CE in HMMs. In contrast, LIPE was barely detectable in HMMs, and its inhibition did not decrease neutral CE hydrolase activity. Neither overexpression nor knockdown of CES1 affected the neutral CE hydrolase activity. NCEH1 was expressed in CD68-positive macrophage foam cells of human atherosclerotic lesions.

Conclusions:

NCEH1 is expressed in human atheromatous lesions, where it plays a critical role in the hydrolysis of CE in human macrophage foam cells, thereby contributing to the initial part of reverse cholesterol transport in human atherosclerosis.
Safety of Intravenous Fibrinolysis in Imaging-Confirmed Single Penetrator Artery Infarcts
Authors: Lee Soo Joo , Saver Jeffrey L. , Liebeskind David S. , Ali Latisha , Ovbiagele Bruce , Kim Doojin , Vespa Paul , Froehler Michael , Tenser Matthew , Gadhia Jignesh , Starkman Sidney
Published: October 2010

Background and Purpose—

Hemorrhagic transformation (HT) after fibrinolytic therapy may be less common in patients with acute cerebral ischemia confined to single penetrator artery (SPA) territories than in patients with large artery ischemia. Previous investigations of HT diagnosed small vessel ischemia based on lacunar clinical syndromes, an approach known to yield misdiagnosis in one-third to one-half of cases.

Methods—

Consecutive intravenous tissue plasminogen activator-treated patients in a prospectively maintained hospital registry were analyzed. Patients were classified as having SPA ischemia if they had imaging evidence of: (1) deep location; (2) diameter ≤1.5 cm; and (3) distribution in a single penetrator territory, regardless of presenting clinical syndrome. Lacunar clinical syndrome was defined according to the Oxfordshire Community Stroke Project classification.

Results—

Among 93 intravenous tissue plasminogen activator-treated patients, mean age was 71.5, 62.4% were female, and median pretreatment National Institutes of Health Stroke Scale score was 14. Single penetrator artery ischemia was imaged in 13 (14.0%) and large artery ischemia was imaged in 75 (80.6%), with no visualized ischemic injury in 5 (5.4%). Lacunar clinical syndromes were present in 23 (24.7%), including 10 with SPA ischemia and 9 with large artery ischemia. No patient with imaging-confirmed SPA infarcts experienced any hemorrhagic transformation, whereas any radiological HT occurred in 29.3% of large artery infarcts (
P
=0.03). Symptomatic intracerebral hemorrhage occurred in 0% of SPA infarcts vs 4.0% of large artery infarcts.

Conclusion—

HT after lytic therapy in imaging-confirmed SPA infarcts is uncommon. Imaging demonstration of ischemia confined to SPA territory better-identifies this population at low risk for hemorrhagic complications than clinical lacunar syndromes.