bluuebunny/crossref_metadata_2025 huggingface dataset:
Interatrial shunt for chronic pulmonary hypertension: differential impact of low-flow vs. high-flow shunting
Authors: Zierer Andreas , Melby Spencer J. , Voeller Rochus K. , Moon Marc R.
Published: January 2009

The purpose of the present study was to determine for the first time the qualitative and quantitative impact of varying degrees of interatrial shunting on right heart dynamics and systemic perfusion in subjects with chronic pulmonary hypertension (CPH). Eight dogs underwent 3 mo of progressive pulmonary artery banding, following which right atrial and ventricular end-systolic and end-diastolic pressure-volume relations were calculated using conductance catheters. An 8-mm shunt prosthesis was inserted between the superior vena cava and left atrium, yielding a controlled model of atrial septostomy. Data were obtained 1) preshunt or “CPH”; 2) “Low-Flow” shunt; and 3) “High-Flow” shunt (occluding superior vena cava forcing all flow through the shunt). With progressive shunting, right ventricular pressure fell from 72 ± 19 mmHg (CPH) to 54 ± 17 mmHg (Low-Flow) and 47 ± 17 mmHg (High-Flow) ( P < 0.001). Cardiac output increased from 1.5 ± 0.3 l/min at CPH to 1.8 ± 0.4 l/min at Low-Flow (286 ± 105 ml/min, 15% of cardiac output; P < 0.001), but returned to 1.6 ± 0.3 l/min at High-Flow (466 ± 172 ml/min, 29% of cardiac output; P = 0.008 vs. Low-Flow, P = 0.21 vs. CPH). There was a modest rise in systemic oxygen delivery from 252 ± 46 ml/min at CPH to 276 ± 50 ml/min at Low-Flow ( P = 0.07), but substantial fall to 222 ± 50 ml/min at High-Flow ( P = 0.005 vs. CPH, P < 0.001 vs. Low-Flow). With progressive shunting, bichamber contractility did not change ( P = 0.98), but the slope of the right atrial end-diastolic pressure volume relation decreased ( P < 0.04), consistent with improved compliance. This study demonstrated that Low-Flow interatrial shunting consistently improved right atrial mechanics and systemic perfusion in subjects with CPH, while High-Flow exceeded an “ideal shunt fraction”.
The hexosamine biosynthesis inhibitor azaserine prevents endothelial inflammation and dysfunction under hyperglycemic condition through antioxidant effects
Authors: Rajapakse Angana Gupta , Ming Xiu-Fen , Carvas João M. , Yang Zhihong
Published: January 2009

Hexosamine biosynthetic pathway (HBP) accounts for some cardiovascular adverse effects of hyperglycemia. We investigated whether the HBP inhibitor azaserine protects against hyperglycemia-induced endothelial damage dependently of HBP. Human endothelial cells isolated from umbilical veins were exposed either to a high (30.5 mmol/l) or low concentration of glucose (5.5 mmol/l) for 4 days, followed by a stimulation with TNF-α (1 ng/ml, 24 h). The blockade of the rate-limiting enzyme glutamine:fructose-6-phosphate amidotransferase inhibited HBP flux and oxidative stress (generation of superoxide and peroxynitrite) under the hyperglycemic condition and prevented the synergistic stimulation of VCAM-1 and ICAM-1 expression by hyperglycemia and TNF-α. In the cells cultured under a low-glucose condition when no increased HBP flux occurred, azaserine enhanced the manganese-superoxide dismutase (MnSOD) protein level and also inhibited the oxidative stress and the expression of VCAM-1 and ICAM-1 in response to TNF-α. Moreover, the polyphenol resveratrol inhibited the oxidative stress and adhesion molecule expression and did not decrease the HBP flux under the hyperglycemia condition. In addition, in isolated rat aortas exposed to hyperglycemic buffer for 5 h when no significant HBP flux occurred, azaserine upregulated the MnSOD protein level and prevented decreased endothelium-dependent relaxations to acetylcholine. In conclusion, hyperglycemia independently increases oxidative stress and HBP flux, amplifies endothelial inflammation, and impairs endothelial function mainly through oxidative stress and not the HBP pathway. Azaserine protects against hyperglycemic endothelial damage through its antioxidant effect independently of inhibiting HBP pathway.
Granulocyte colony-stimulating factor protects cardiac mitochondria in the early phase of cardiac injury
Authors: Hiraumi Yoshimi , Iwai-Kanai Eri , Baba Shiro , Yui Yoshihiro , Kamitsuji Yuri , Mizushima Yasuhiro , Matsubara Hiroshi , Watanabe Motonobu , Watanabe Ken-ichirou , Toyokuni Shinya , Matsubara Hiroaki , Nakahata Tatsutoshi , Adachi Souichi
Published: January 2009

Although granulocyte colony-stimulating factor (G-CSF) reportedly plays a cardioprotective role in several models of cardiac injury, clinical use of this drug in cardiac patients has been controversial. Here, we tested, in vivo and in vitro, the effect of G-CSF on cardiac mitochondria, which play a key role in determining cardiac cellular fate and function. Mild stimulation of C57/BL6 mice with doxorubicin (Dox) did not induce cardiac apoptosis or fibrosis but did induce damage to mitochondrial organization of the myocardium as observed through an electron microscope. Cardiac catheterization and echocardiography revealed that Dox did not alter cardiac systolic function or left ventricular size but did reduce diastolic function, an early sign of cardiac damage. Treatment with G-CSF attenuated significantly the damage to mitochondrial organization and rescued diastolic function. In an in vitro model for rat neonatal cardiomyocytes, a subapoptotic dose of Dox induced severe mitochondrial damage, including marked swelling of the cardiac mitochondria and/or decreased mitochondrial membrane potential. These mitochondrial changes were completely blocked by pretreatment with G-CSF. In addition, G-CSF dramatically improved ATP generation, which rescued Dox-impaired mitochondrial electron transport and oxygen consumption mainly through complex IV. These findings clearly indicate that G-CSF protects cardiac mitochondria, which are key organelles in the determination of cardiac cellular fate, in the early phase of cardiac injury.
Cardiomyocytes from postinfarction failing rat hearts have improved ischemia tolerance
Authors: Sharikabad Mohammad Nouri , Aronsen Jan Magnus , Haugen Espen , Pedersen Janne , Møller Anne-Sophie W. , Mørk Halvor Kjeang , Aass Hans C. D. , Sejersted Ole M. , Sjaastad Ivar , Brørs Odd
Published: January 2009

Altered myocardial Ca2+ and Na+ handling in congestive heart failure (CHF) may be expected to decrease the tolerance to ischemia by augmenting reperfusion Ca2+ overload. The aim of the present study was to investigate tolerance to hypoxia-reoxygenation by measuring enzyme release, cell death, ATP level, and cell Ca2+ and Na+ in cardiomyocytes from failing rat hearts. CHF was induced in Wistar rats by ligation of the left coronary artery during isoflurane anesthesia, after which cardiac failure developed within 6 wk. Isolated cardiomyocytes were cultured for 24 h and subsequently exposed to 4 h of hypoxia and 2 h of reoxygenation. Cell damage was measured as lactate dehydrogenase (LD) release, cell death as propidium iodide uptake, and ATP by firefly luciferase assay. Cell Ca2+ and Na+ were determined with radioactive isotopes, and free intracellular Ca2+ concentration ([Ca2+]i) with fluo-3 AM. CHF cells showed less increase in LD release and cell death after hypoxia-reoxygenation and had less relative reduction in ATP level after hypoxia than sham cells. CHF cells accumulated less Na+ than sham cells during hypoxia (117 vs. 267 nmol/mg protein). CHF cells maintained much lower [Ca2+]i than sham cells during hypoxia (423 vs. 1,766 arbitrary units at 4 h of hypoxia), and exchangeable Ca2+ increased much less in CHF than in sham cells (1.4 vs. 6.7 nmol/mg protein) after 120 min of reoxygenation. Ranolazine, an inhibitor of late Na+ current, significantly attenuated both the increase in exchangeable Ca2+ and the increase in LD release in sham cells after reoxygenation. This supports the suggestion that differences in Na+ accumulation during hypoxia cause the observed differences in Ca2+ accumulation during reoxygenation. Tolerance to hypoxia and reoxygenation was surprisingly higher in CHF than in sham cardiomyocytes, probably explained by lower hypoxia-mediated Na+ accumulation and subsequent lower Ca2+ accumulation in CHF after reoxygenation.
Respiratory modulation of heart sound morphology
Authors: Amit Guy , Shukha Khuloud , Gavriely Noam , Intrator Nathan
Published: January 2009

Heart sounds, the acoustic vibrations produced by the mechanical processes of the cardiac cycle, are modulated by respiratory activity. We have used computational techniques of cluster analysis and classification to study the effects of the respiratory phase and the respiratory resistive load on the temporal and morphological properties of the first (S1) and second heart sounds (S2), acquired from 12 healthy volunteers. Heart sounds exhibited strong morphological variability during normal respiration and nearly no variability during apnea. The variability was shown to be periodic, with its estimated period in good agreement with the measured duration of the respiratory cycle. Significant differences were observed between properties of S1 and S2 occurring during inspiration and expiration. S1 was commonly attenuated and slightly delayed during inspiration, whereas S2 was accentuated and its aortic component occurred earlier at late inspiration and early expiration. Typical split morphology was observed for S1 and S2 during inspiration. At high-breathing load, these changes became more prominent and occurred earlier in the respiratory cycle. Unsupervised cluster analysis was able to automatically identify the distinct morphologies associated with different respiratory phases and load. Classification of the respiration phase (inspiration or expiration) from the morphology of S1 achieved an average accuracy of 87 ± 7%, and classification of the breathing load was accurate in 82 ± 7%. These results suggest that quantitative heart sound analysis can shed light on the relation between respiration and cardiovascular mechanics and may be applied to continuous cardiopulmonary monitoring.
Synergism of coupled subsarcolemmal Ca2+clocks and sarcolemmal voltage clocks confers robust and flexible pacemaker function in a novel pacemaker cell model
Authors: Maltsev Victor A. , Lakatta Edward G.
Published: January 2009

Recent experimental studies have demonstrated that sinoatrial node cells (SANC) generate spontaneous, rhythmic, local subsarcolemmal Ca2+releases (Ca2+clock), which occur during late diastolic depolarization (DD) and interact with the classic sarcolemmal voltage oscillator (membrane clock) by activating Na+-Ca2+exchanger current ( INCX). This and other interactions between clocks, however, are not captured by existing essentially membrane-delimited cardiac pacemaker cell numerical models. Using wide-scale parametric analysis of classic formulations of membrane clock and Ca2+cycling, we have constructed and initially explored a prototype rabbit SANC model featuring both clocks. Our coupled oscillator system exhibits greater robustness and flexibility than membrane clock operating alone. Rhythmic spontaneous Ca2+releases of sarcoplasmic reticulum (SR)-based Ca2+clock ignite rhythmic action potentials via late DD INCXover much broader ranges of membrane clock parameters [e.g., L-type Ca2+current ( ICaL) and/or hyperpolarization-activated (“funny”) current ( If) conductances]. The system Ca2+clock includes SR and sarcolemmal Ca2+fluxes, which optimize cell Ca2+balance to increase amplitudes of both SR Ca2+release and late DD INCXas SR Ca2+pumping rate increases, resulting in a broad pacemaker rate modulation (1.8–4.6 Hz). In contrast, the rate modulation range via membrane clock parameters is substantially smaller when Ca2+clock is unchanged or lacking. When Ca2+clock is disabled, the system parametric space for fail-safe SANC operation considerably shrinks: without rhythmic late DD INCXignition signals membrane clock substantially slows, becomes dysrhythmic, or halts. In conclusion, the Ca2+clock is a new critical dimension in SANC function. A synergism of the coupled function of Ca2+and membrane clocks confers fail-safe SANC operation at greatly varying rates.
Surface expression of CD74 by type II alveolar epithelial cells: a potential mechanism for macrophage migration inhibitory factor-induced epithelial repair
Authors: Marsh Leigh M. , Cakarova Lidija , Kwapiszewska Grazyna , von Wulffen Werner , Herold Susanne , Seeger Werner , Lohmeyer Juergen
Published: January 2009

Macrophage migration inhibitory factor (MIF) is a pleiotropic proinflammatory cytokine involved in acute lung injury and other processes such as wound repair and tumor growth. MIF exerts pro-proliferative effects on a variety of cell types including monocytes/macrophages, B cells, and gastric epithelial cell lines through binding to the major histocompatibility complex type II-associated invariant chain, CD74. In acute lung injury, inflammatory damage of the alveolar epithelium leads to loss of type I alveolar epithelial cells (AEC-I), which are replaced by proliferation and differentiation of type II alveolar epithelial cells (AEC-II). In this study we have investigated the potential of MIF to contribute to alveolar repair by stimulating alveolar epithelial cell proliferation. We show that murine AEC-II, but not AEC-I, express high surface levels of CD74 in vivo. Culture of AEC-II in vitro resulted in decreased mRNA levels for CD74 and loss of surface CD74 expression, which correlated with a transition of AEC-II to an AEC-I-like phenotype. MIF stimulation of AEC-II induced rapid and prolonged phosphorylation of ERK1/2 and Akt, increased expression of cyclins D1 and E, as well as AEC-II proliferation. Corresponding MIF signaling and enhanced thymidine incorporation was observed after MIF stimulation of MLE-12 cells transfected to overexpress CD74. In contrast, MIF did not induce MAPK activation, gene transcription, or increased proliferation in differentiated AEC-I-like cells that lack CD74. These data suggest a previously unidentified role of MIF-CD74 interaction by inducing proliferation of AEC-II, which may contribute to alveolar repair.
Long-term effects of prenatal hypoxia on endothelium-dependent relaxation responses in pulmonary arteries of adult sheep
Authors: Liu Jie , Gao Yuansheng , Negash Sewite , Longo Lawrence D. , Raj J. Usha
Published: January 2009

Chronic hypoxia during the course of pregnancy is a common insult to the fetus. However, its long-term effect on the pulmonary vasculature in adulthood has not been described. In this study, the vasorelaxation responses of conduit pulmonary arteries in adult female sheep that were chronically hypoxic as fetuses and raised postnatally at sea level were investigated. Vessel tension studies revealed that endothelium-dependent relaxation responses were attenuated in pulmonary arteries from adult sheep that experienced prenatal hypoxia. Endothelial nitric oxide synthase (eNOS) protein expression was unchanged, but eNOS activity was significantly decreased in pulmonary arteries from prenatally hypoxic sheep. Protein expression of eNOS partners, caveolin-1, calmodulin, and heat shock protein 90 (Hsp90) did not change following prenatal hypoxia. However, the association between eNOS and caveolin-1, its inhibitory binding partner, was significantly increased, whereas association between eNOS and its stimulatory partners calmodulin and Hsp90 was greatly decreased. Furthermore, phosphorylation of Ser1177in eNOS decreased, whereas phosphorylation of Thr495increased, in the prenatally hypoxic pulmonary arteries, events that are related to eNOS activity. These data demonstrate that prenatal hypoxia results in persistent abnormalities in endothelium-dependent relaxation responses of pulmonary arteries in adult sheep due to decreased eNOS activity resulting from altered posttranslational regulation.
Role of clathrin-mediated endocytosis of surfactant protein A by alveolar macrophages in intracellular signaling
Authors: Moulakakis Christina , Stamme Cordula
Published: January 2009

We recently provided evidence that anti-inflammatory macrophage activation, i.e., the inhibition of constitutive and signal-induced NF-κB activity by the pulmonary collectin surfactant protein (SP)-A, critically involves a promoted stabilization of IκB-α, the predominant inhibitor of NF-κB, via posttranscriptional mechanisms comprising the activation of atypical (a)PKCζ. SP-A uptake and degradation by alveolar macrophages (AMφ) occur in a receptor-mediated, clathrin-dependent manner. However, a mutual link between endocytosis of and signaling by SP-A remains elusive. The aim of this study was to investigate whether clathrin-mediated endocytosis (CME) of SP-A by AMφ is a prerequisite for its modulation of the IκB-α/NF-κB pathway. The inhibition of clathrin-coated pit (CCP) formation and clathrin-coated vesicle (CCV) formation/budding abrogates SP-A-mediated IκB-α stabilization and SP-A-mediated inhibition of LPS-induced NF-κB activation in freshly isolated rat AMφ, as determined by Western analysis, fluorescence-activated cell sorting, confocal microscopy, and EMSA. Actin depolymerization and inhibition of CCP formation further abolished SP-A-mediated inhibition of LPS-induced TNF-α release, as determined by ELISA. In addition, SP-A-induced atypical PKCζ activation was abolished by pretreatment of AMφ with CCV inhibitors as determined by in vitro immunocomplex kinase assay. Although CME is classically considered as a means to terminate signaling, our results demonstrate that SP-A uptake via CME by AMφ has to precede the initiation of SP-A signaling.
Mechanisms of eosinophil major basic protein-induced hyperexcitability of vagal pulmonary chemosensitive neurons
Authors: Gu Qihai , Lim Michelle E. , Gleich Gerald J. , Lee Lu-Yuan
Published: January 2009

We have reported recently that eosinophil-derived basic proteins directly enhance the capsaicin- and electrical stimulation-evoked whole cell responses in rat pulmonary sensory neurons ( 19 ). Our present study further elucidates the mechanisms underlying the sensitization of pulmonary afferent nerves induced by these cationic proteins. Our results show that pretreatment with eosinophil major basic protein (MBP; 2 μM, 60 s) significantly enhanced the excitability of isolated rat vagal pulmonary chemosensitive neurons to acid and ATP in the current-clamp mode, but this potentiating effect was absent in the voltage-clamp recordings. The hyperexcitability induced by MBP was not prevented by the blockade of either transient receptor potential vanilloid type-1 receptor (TRPV1) selectively (inhibitor: AMG 9810; 1 μM, 2 min) or all TRPV1–4 channels (inhibitor: ruthenium red; 5 μM, 2 min). In addition, MBP also markedly potentiated the excitability of mouse pulmonary chemosensitive neurons, and no detectable difference was found between those isolated from wild-type and TRPV1 knockout mice. Furthermore, MBP pretreatment affected the decay time and recovery phase of the action potentials evoked by current injections and significantly inhibited both the sustained delayed-rectifier voltage-gated K+ current ( IKdr) and the A-type, fast-inactivating K+ current ( IKa) in these sensory neurons. In conclusion, our results indicate that the inhibition of IKdr and IKa should, at least in part, account for the hyperexcitability of pulmonary chemosensitive neurons induced by eosinophil-derived cationic proteins, whereas an interaction with TRPV1 channels does not seem to be required for the sensitizing effect of these proteins.
Neutrophil elastase cleaves VEGF to generate a VEGF fragment with altered activity
Authors: Kurtagic Elma , Jedrychowski Mark P. , Nugent Matthew A.
Published: January 2009

Excessive neutrophil elastase (NE) activity and altered vascular endothelial growth factor (VEGF) signaling have independently been implicated in the development and progression of pulmonary emphysema. In the present study, we investigated the potential link between NE and VEGF. We noted that VEGF165is a substrate for NE. Digestion of purified VEGF165with NE generated a partially degraded disulfide-linked fragment of VEGF. Mass spectrometric analysis revealed that NE likely cleaves VEGF165at both the NH2and COOH termini to produce VEGF fragment chains ∼5 kDa reduced in size. NE treatment of VEGF-laden endothelial cell cultures and smooth muscle cells endogenously expressing VEGF generated VEGF fragments similar to those observed with purified VEGF165. NE-generated VEGF fragment showed significantly reduced binding to VEGF receptor 2 and heparin yet retained the ability to bind to VEGF receptor 1. Interestingly, VEGF fragment showed altered signaling in pulmonary artery endothelial cells compared with intact VEGF165. Specifically, treatment with VEGF fragment did not activate extracellular-regulated kinases 1 and 2 (ERK1/2), yet resulted in enhanced activation of protein kinase B (Akt). Treatment of monocyte/macrophage RAW 264.7 cells with VEGF fragment, on the other hand, led to both Akt and ERK1/2 activation, increased VEGFR1 expression, and stimulated chemotaxis. These findings suggest that the tissue response to NE-mediated injury might involve the generation of diffusible VEGF fragments that stimulate inflammatory cell recruitment and activation via VEGF receptor 1.
Hypoxia-induced mitogenic factor (HIMF/FIZZ1/RELMα) induces the vascular and hemodynamic changes of pulmonary hypertension
Authors: Angelini Daniel J. , Su Qingning , Yamaji-Kegan Kazuyo , Fan Chunling , Skinner John T. , Champion Hunter C. , Crow Michael T. , Johns Roger A.
Published: January 2009

Pulmonary hypertension (PH) is a serious disease of multiple etiologies mediated by hypoxia, immune stimuli, and elevated pulmonary pressure that leads to vascular thickening and eventual right heart failure. In a chronic hypoxia model of PH, we previously reported the induction of a novel pleiotropic cytokine, hypoxia-induced mitogenic factor (HIMF), that exhibits mitogenic, vasculogenic, contractile, and chemokine properties during PH-associated vascular remodeling. To examine the role of HIMF in hypoxia-induced vascular remodeling, we performed in vivo knockdown of HIMF using short hairpin RNA directed at rat HIMF in the chronic hypoxia model of PH. Knockdown of HIMF partially blocked increases in mean pulmonary artery pressure, pulmonary vascular resistance, right heart hypertrophy, and vascular remodeling caused by chronic hypoxia. To demonstrate a direct role for HIMF in the mechanism of PH development, we performed HIMF-gene transfer into the lungs of rats using a HIMF-expressing adeno-associated virus (AAV). AAV-HIMF alone caused development of PH similar to that of chronic hypoxia with increased mean pulmonary artery pressure and pulmonary vascular resistance, right heart hypertrophy, and neomuscularization and thickening of small pulmonary arterioles. The findings suggest that HIMF represents a critical cytokine-like growth factor in the development of PH.
An Educational Program in a Pediatric Hospice Setting
Authors: Wood Isabel
Published: January 2009

Canuck Place Children's Hospice, a family-centered pediatric hospice in Vancouver, Canada, provides family support and respite, pain and symptom management, and end-of-life care. One of the goals of pediatric hospice palliative care is to create an environment that supports a normal way of life and enhances quality of life. At Canuck Place, a unique school program for children with progressive life-threatening illnesses has been set up to meet this goal. This article describes the Canuck Place educational program, gives insights into the importance and challenges of providing a complete school experience, and discusses the expanded role of the teacher in the pediatric hospice setting.
Beyond Polarization, Public Preferences Suggest Policy Opportunities to Address Aging, Dying, and Family Caregiving
Authors: Byock Ira R. , Corbeil Yvonne J. , Goodrich Martha E.
Published: January 2009

Despite well-documented deficiencies and widespread suffering experienced by millions of elderly or ill Americans and their families, politicians rarely address end-of-life issues. Citizen Forums in New Hampshire surveyed 463 people regarding aging, serious illness, and caregiving. More than 80% indicated it was very or extremely important to have their dignity respected, preferences honored, pain controlled, and to not leave family with debt. Less than half strongly endorsed being kept alive as long as possible, prayed with or for, or having assisted-suicide available. Over 80% strongly endorsed palliative care requirements clinical licensure and reimbursement, expansion of family caregiver leave, respite care, and bereavement support. By avoiding actions which elicit strong divergence of opinion and focusing on actions on which consensus exists, public officials and candidates can respond to problems and improve care and experience for frail elders, dying Americans, and their families.
Daclizumab in treatment of multiple sclerosis patients
Authors: Ali EN , Healy BC , Stazzone LA , Brown BA , Weiner HL , Khoury SJ
Published: January 2009

Background

Daclizumab is a humanized monoclonal antibody (mAb) that blocks the interleukin-2 receptor alpha subunit (IL-2R-alpha chain; CD25) expressed on activated T cells leading to the inhibition of T-cell expansion, thus strongly reduces brain inflammation in patients with multiple sclerosis (MS). Another mechanism is significant expansion of CD56 (bright) natural killer (NK) cells that in turn inhibit T-cell survival.

Objective

At the Partners MS center, we have been using Daclizumab in an open-label fashion in patients who fail first line therapy or non-standard immunosuppressive treatment. Our aim was to assess its safety and tolerability in our patient population.
Angiotensin-converting enzyme (ACE) and ACE2 levels in the cerebrospinal fluid of patients with multiple sclerosis
Authors: Kawajiri M , Mogi M , Higaki N , Matsuoka T , Ohyagi Y , Tsukuda K , Kohara K , Horiuchi M , Miki T , Kira JI
Published: January 2009

Background

We reported a reduction in the levels of angiotensin II in cerebrospinal fluid (CSF) from patients with multiple sclerosis (MS).

Objective and methods

To clarify the mechanism underlying this reduction, we assayed angiotensin-converting enzyme (ACE) and ACE2 concentrations along with angiotensin II concentrations in CSF samples from 20 patients with MS and 17 controls with non-neurological diseases.

Results

ACE levels were significantly elevated in patients with MS compared with controls (48.42 ± 4.84 vs 44.71 ± 3.9 pg/mL), whereas ACE2 levels were significantly reduced (2.56 ± 0.26 vs 2.78 ± 0.24 pg/mL), acting toward a normalization of angiotensin II levels.

Conclusion

These results further indicate an alteration of the intrathecal renin-angiotensin system in patients with MS.
Complement-dependent T-cell lymphopenia caused by thymocyte deletion of the membrane complement regulator Crry
Authors: Miwa Takashi , Zhou Lin , Kimura Yuko , Kim David , Bhandoola Avinash , Song Wen-Chao
Published: January 2009

Although complement lysis is frequently used for the purification of lymphocyte subpopulations in vitro, how lymphocytes escape complement attack in vivo has not been clearly delineated. Here, we show that conditional gene targeting of a murine membrane complement regulator Crry on thymocytes led to complement-dependent peripheral T-cell lymphopenia. Notably, despite evidence of hypersensitivity to complement attack, Crry-deficient T cells escaped complement injury and developed normally in the thymus, because of low intrathymic complement activity. Crry-deficient T cells were eliminated in the periphery by a C3- and macrophage-mediated but C5-independent mechanism. Thus, Crry is essential for mature T-cell survival in the periphery but not for lymphogenesis in the thymus. The observation that the thymus is a complement-privileged site may have implications for complement-based antitumor therapies.
Self-renewal and chemotherapy resistance of p75NTR positive cells in esophageal squamous cell carcinomas
Authors: Huang Sheng-Dong , Yuan Yang , Liu Xiao-Hong , Gong De-Jun , Bai Chen-Guang , Wang Feng , Luo Jun-Hui , Xu Zhi-Yun
Published: January 2009

Background

p75NTR has been used to isolate esophageal and corneal epithelial stem cells. In the present study, we investigated the expression of p75NTR in esophageal squamous cell carcinoma (ESCC) and explored the biological properties of p75NTR+ cells.

Methods

p75NTR expression in ESCC was assessed by immunohistochemistry. p75NTR+ and p75NTR- cells of 4 ESCC cell lines were separated by fluorescence-activated cell sorting. Differentially expressed genes between p75NTR+ and p75NTR- cells were determined by real-time quantitative reverse transcription-PCR. Sphere formation assay, DDP sensitivity assay, 64copper accumulation assay and tumorigenicity analysis were performed to determine the capacity of self-renewal, chemotherapy resistance and tumorigenicity of p75NTR+ cells.

Results

In ESCC specimens, p75NTR was found mainly confined to immature cells and absent in cells undergoing terminal differentiation. The percentage of p75NTR+ cells was 1.6%–3.7% in Eca109 and 3 newly established ESCC cell lines. The expression of Bmi-1, which is associated with self-renewal of stem cells, was significantly higher in p75NTR+ cells. p63, a marker identified in keratinocyte stem cells, was confined mainly to p75NTR+ cells. The expression of CTR1, which is associated with cisplatin (DDP)-resistance, was significantly decreased in p75NTR+ cells. Expression levels of differentiation markers, such as involucrin, cytokeratin 13, β1-integrin and β4-integrin, were lower in p75NTR+ cells. In addition, p75NTR+ cells generated both p75NTR+ and p75NTR- cells, and formed nonadherent spherical clusters in serum-free medium supplemented with growth factors. Furthermore, p75NTR+ cells were found to be more resistant to DDP and exhibited lower 64copper accumulation than p75NTR- cells.

Conclusion

Our results demonstrated that p75NTR+ cells possess some characteristics of CSCs, namely, self-renewal and chemotherapy resistance. Chemotherapy resistance of p75NTR+ cells may probably be attributable to decreased expression of CTR1.
Body aches, tender bones and rapid loss of weight: a case report
Authors: Vijay Hadda , Navil Vikram Kishore , Vaibhav Jain , Chopra Anita , Goel Ashish , Sood Rita
Published: January 2009

Introduction

Bone metastases presenting with pain and body-ache may be the first presentation of carcinoma in about a fourth of patients with cancer. Radiologically majority of the metastases are osteolytic and multiple. Sometimes these may be confused with infective or inflammatory conditions, particularly in young individuals, and degenerative conditions of the spine and hip in elderly, which may delay the diagnosis and treatment leading to poor outcomes.

Case presentation

A 30 year old non-smoking male teetotaller presented with intermittent, high-grade nocturnal fever with night sweats of one year. He also had low back ache over his right hip. We found him febrile, pale and his long bones, ribs and pelvis were tender. He had a 3 × 4 cm tender and hard swelling over the upper part of his sternum. Another firm, non-tender swelling about 4 × 5 cm was seen in the right iliac region. Radiographs of the skull, spine and pelvis revealed multiple variable sized lytic lesions. A metastatic malignancy or disseminated tuberculosis was considered. His anti-tubercular therapy was intensified Fine needle aspiration from sternal lesion showed inflammatory cells. A bone marrow biopsy showed infiltration by tumor cells suggestive of metastatic adenocarcinoma. Patient's condition continued to deteriorate and he died within a fortnight of his hospitalization.

Conclusion

Although masquerading as tuberculosis lytic lesions might be an evidence of malignant metastatic. Although, treatment is ineffective in this stage palliative efforts to improve quality of life should be made.
Concomitant dislocation of the tarsometatarsal and metatarsophalangeal joints of the second toe (floating second metatarsal): a case report
Authors: Mobarake Mahmood Karimi , Saied Alireza , Baron Elisabeth
Published: January 2009

When examining patients with injuries of the tarsometatarsal joint, the physician must pay attention to the foot as a whole.

An extremely rare foot injury has been described in which axial and compressive forces cause simultaneous dislocation of the tarsometatarsal joint and the metatarsophalangeal joint of the same or adjacent ray. The following is a report of one of these rare injuries.

We will also discuss probable mechanism and diagnosis of this rare traumatic injury.
International legal and regulatory developments for carbon dioxide capture and storage: From the London Convention to the Clean Development Mechanism
Authors: Dixon T
Published: January 2009

Several major international legal and regulatory instruments have seriously considered carbon dioxide capture and storage (CCS). This article describes the processes they underwent to consider CCS and produce ‘evidence-based policy-change’ on CCS, drawing upon scientific, technical, and engineering evidence from CCS, geological, and environmental sciences. The specific examples used will be the London Convention, OSPAR, the European Union Emissions Trading Scheme, and the Clean Development Mechanism. In particular, the work undertaken within the London Convention and OSPAR has provided the world with useful risk assessment and management guidelines for CCS, with wider applicability than those conventions. Lessons can be learnt from these instruments for the development of regulatory frameworks for CCS.
Numerical study and experimental validation of the performance of two different volutes with the same compressor impeller
Authors: Dai Y , Engeda A , Cave M , Di Liberti J-L
Published: January 2009

Volute scroll, conic diffuser, and sudden expansion discharge losses account for 4–6 points of efficiency decrement in a typical centrifugal compressor stage. The flow in a volute is highly complex. It is strongly believed that an understanding of the detailed flow structure in a volute will provide insights on minimizing the losses by isolating the mechanisms that contribute to entropy generation. The result will be a more efficient centrifugal compressor product for customers.

This article presents the experimental and numerical investigation on the matching of two different overhung volutes with the same centrifugal compressor impeller. The experimental data were measured from flange to flange initially, and then three Kiel probes were installed at different circumferential pinch locations. At the same time, a detailed numerical simulation of the performance of the two volutes has been carried out. A computational model, using the k-ε turbulence model and wall function, has been used to predict the internal flows of both volutes. Good agreement between experimental data and numerical simulation results is found, except at high mass flowrate. The overall performance of the two volutes was also compared thoroughly.
Impact of the tip vortex on the passage flow structures of a jet fan with symmetric blades
Authors: Fernández Oro J M , Argüelles Díaz K M , Santolaria Morros C , Ballesteros-Tajadura R
Published: January 2009

The goal of this study is the simulation of the flow inside a rotor with elliptic airfoils, where the Kutta condition cannot be satisfied. This work develops a three-dimensional numerical modelling of a monoplane axial jet fan with symmetric blades. The three-dimensional model includes tip clearance gridding and turbulence modelling based on high-order Reynolds-averaged Navier—Stokes (RANS) schemes. The flow patterns inside the blade passage and the wake-core structure will be studied at design operating conditions. Also, the interaction of the tip leakage flow with blade-to-blade structures will be analysed in detail. The investigation shows how the tip leakage vortex modifies the blade loading on the suction surface. The leakage flow rolls up in a vortical structure at the suction side, establishing a mixing mechanism that produces a low-axial velocity region. As a result, the adverse pressure gradient is enhanced and a major flow separation overcomes. This feature is especially critical in the case of a rotor with symmetric blades, where the flow is always detached at the trailing edge. The simulation is carried out using a commercial code, FLUENT, which resolves the Navier—Stokes set of equations. A high dense mesh is introduced in the model, so tip leakage is expected to be well captured. Different turbulence models have been tested in order to determine the most accurate choice. It is shown that a linear Reynolds stress model provides velocity distributions more adjusted to experimental data. This suitable prediction for rotating flow passages is a consequence of the characteristics of the model: consideration of anisotropic turbulence and direct inclusion of curvature and rotation effects in the transport equations. Therefore, swirl effects of the tip vortex can be modelled correctly. The numerical results are compared with previous experimental data of velocity fields to validate the simulation. In particular, the instantaneous wake flow structure was measured with a two hot-wire anemometer. Axial and tangential velocity profiles were obtained after pitch averaging the time-resolved flow patterns.
Effects of FSH on testicular mRNA transcript levels in the hypogonadal mouse
Authors: Abel M H , Baban D , Lee S , Charlton H M , O'Shaughnessy P J
Published: January 2009

FSH acts through the Sertoli cell to ensure normal testicular development and function. To identify transcriptional mechanisms through which FSH acts in the testis, we have treated gonadotrophin-deficient hypogonadal (hpg) mice with recombinant FSH and measured changes in testicular transcript levels using microarrays and real-time PCR 12, 24 and 72 h after the start of treatment. Approximately 400 transcripts were significantly altered at each time point by FSH treatment. At 12 h, there was a clear increase in the levels of a number of known Sertoli cell transcripts (e.g. Fabp5, Lgals1, Tesc, Scara5, Aqp5). Additionally, levels of Leydig cell transcripts were also markedly increased (e.g. Ren1, Cyp17a1, Akr1b7, Star, Nr4a1). This was associated with a small but significant rise in testosterone at 24 and 72 h. At 24 h, androgen-dependent Sertoli cell transcripts were up-regulated (e.g. Rhox5, Drd4, Spinlw1, Tubb3 and Tsx) and this trend continued up to 72 h. By contrast with the somatic cells, only five germ cell transcripts (Dkkl1, Hdc, Pou5f1, Zfp541 and 1700021K02Rik) were altered by FSH within the time-course of the experiment. Analysis of canonical pathways showed that FSH induced a general decline in transcripts related to formation and regulation of tight junctions. Results show that FSH acts directly and indirectly to induce rapid changes in Sertoli cell and Leydig cell transcript levels in the hpg mouse but that effects on germ cell development must occur over a longer time-span.
A long-acting glucagon-like peptide-1 analogue attenuates induction of plasminogen activator inhibitor type-1 and vascular adhesion molecules
Authors: Liu Hongbin , Dear Anthony E , Knudsen Lotte B , Simpson Richard W
Published: January 2009

Glucagon-like peptide-1 (GLP-1) administration attenuates endothelial cell dysfunction in diabetic patients and inhibits tumour necrosis factor α (TNF)-mediated plasminogen activator inhibitor type-1 (PAI-1) induction in human vascular endothelial cells. The short half-life of GLP-1 mediated via degradation by the enzyme dipeptidyl peptidase 4 mandates the clinical use of long-acting GLP-1 analogues. The effects of a long-acting GLP-1 analogue on PAI-1 and vascular adhesion molecule expression in vascular endothelial cells are unknown. In this report, we demonstrate for the first time that the treatment with liraglutide, a long-acting GLP-1 analogue, inhibited TNF or hyperglycaemia-mediated induction of PAI-1, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 mRNA and protein expression in a human vascular endothelial cell line. In addition, treatment attenuated TNF- or hyperglycaemia-mediated induction of the orphan nuclear receptor Nur77 mRNA expression. Taken together, these observations indicate that liraglutide inhibits TNF- or glucose-mediated induction of PAI-1 and vascular adhesion molecule expression, and this effect may involve the modulation of NUR77. These effects suggest that liraglutide may potentially improve the endothelial cell dysfunction associated with premature atherosclerosis identified in type 2 diabetic patients.
Genome-wide identification of DNA–protein interactions using chromatin immunoprecipitation coupled with flow cell sequencing
Authors: Hoffman Brad G , Jones Steven J M
Published: January 2009

The transcriptional networks underlying mammalian cell development and function are largely unknown. The recently described use of flow cell sequencing devices in combination with chromatin immunoprecipitation (ChIP-seq) stands to revolutionize the identification of DNA–protein interactions. As such, ChIP-seq is rapidly becoming the method of choice for the genome-wide localization of histone modifications and transcription factor binding sites. As further studies are performed, the information generated by ChIP-seq is expected to allow the development of a framework for networks describing the transcriptional regulation of cellular development and function. However, to date, this technology has been applied only to a small number of cell types, and even fewer tissues, suggesting a huge potential for novel discovery in this field.
A New Mathematics Model and Theory for Heavy-Oil Reservoir Heating by Huff 'n' Puff
Authors: Dou Hong'en , Chang Yuwen , Yu Jun , Wang Xiaolin , Chen Changchun , Ma Yingwei
Published: January 2009

This paper presents a new mathematic model to calculate heated reservoir area based on the heat balance principle in order to determine the well spacing for thermal recovery. The calculation result of the new model was compared with the classical models of J.W Marx and R. H. Langenheim (Petroleum Transactions, AIME Vol. 216, pp. 312-315, 1959), B. T Willman (JPT, July 1961, pp. 681-696), and Farouq. Ali (1970), using data from Liaohe heavy crude oilfield, China. The results showed that the new model is more accordable with oilfield actual condition than the three classical models. Also, this research reveals a new theory on huff ‘n’ puff, which is that the heated radius of the heated region is expanded from the first cycle to the fourth cycle of huff ‘n’ puff; in this case, the heated front was expanded with the increase of cycle. However, subsequent cycles (from fifth cycle to tenth cycle of huff ‘n’ puff) repeat the heating of the previous heated areas, and the expanding heated area of the next cycle is smaller than the last cycle, and the new heating region should hardly be expanded after the 10th cycle. The authors point out the development results of heavy oil, extra heavy oil and super heavy oil deteriorate due to this reason. In addition, the authors emphasize that the traditional huff ‘n’ puff for producing heavy oil, especially for extra-heavy oil and super-heavy oil has to be changed using new technique methods after the fourth cycle. Finally, a suitable well spacing for thermal recovery with huff ‘n’ puff was obtained. The new theory was proved by heavy crude/extra heavy oilfield development.
The Nomination and the Election: Clearing Away Underbrush
Authors: Shafer Byron E. , Wichowsky Amber
Published: January 2009

The politics of presidential selection in 2008 reinvigorated an old argument from democratic theory about the relationship between nominating politics and the general election. Now that the latter is over, it is possible to return to these debates and ask how candidate fortunes at the nominating stage were linked to performances in November. For 2008, the strongest of these relationships proved to be perverse, with nominees performing best in states that they would cede to their opponent in the general election. Other relationships, however, as with improving or impairing results in individual states, achieved a more straightforward character, especially when institutional structure and temporal order were taken into account.
Foreign Affairs and the 2008 Election
Authors: Saldin Robert P
Published: January 2009

Much of the commentary in the wake of last month's presidential election has focused on the magnitude and historic aspects of Barack Obama's victory and the deteriorating economic environment in which it played out. Little thought has been given to the influence of foreign affairs in the election. Yet even in this year's contest, which appears to lend considerable support to economic-based theories of elections, international events clearly played an important role by shaping the nomination process for both major parties and in Obama's selection of Joseph Biden as his running mate.
The Return of the Voter: Voter Turnout in the 2008 Presidential Election
Authors: McDonald Michael P.
Published: January 2009

The presidential turnout rate for those eligible to vote was 61.6% in 2008, which marks the third consecutive increase in presidential turnout rates since the modern low point of 51.7% in 1996. Turnout is no longer declining  if it ever was  and has reverted to the 'high' levels experienced during the 1950s and 1960s. This challenges many theories posited to explain turnout declines. I explore election trends among the states in hopes to provide clues as to why civic engagement has been restored.
The Magnitude of the 2008 Democratic Victory: By the Numbers
Authors: Ceaser James W. , DiSalvo Daniel
Published: January 2009

This essay explores the scope of the Democratic Party's victory in the 2008 elections by comparing it to other U.S. elections since 1896. Three conclusions are drawn from the analysis: (1) that Obama's personal victory, though significant, was far from being massive, or even unusual, by historical standards; (2) that the Democratic congressional victory of 2008, relative to the midterm election of 2006, falls in the upper range of congressional victories in a presidential year; (3) that the Democrats' victory becomes more impressive in light of its reversal of the 2004 election, which represented the high-water mark for Republicans since 1928. The essay also briefly considers whether and in what sense the Democrats' victory might have inaugurated a party realignment.
β-Cell Hyperplasia Induced by Hepatic Insulin Resistance
Authors: Escribano Oscar , Guillén Carlos , Nevado Carmen , Gómez-Hernández Almudena , Kahn C. Ronald , Benito Manuel
Published: January 2009

OBJECTIVE

Type 2 diabetes results from a combination of insulin resistance and impaired insulin secretion. To directly address the effects of hepatic insulin resistance in adult animals, we developed an inducible liver-specific insulin receptor knockout mouse (iLIRKO).

RESEARCH DESIGN AND METHODS

Using this approach, we were able to induce variable insulin receptor (IR) deficiency in a tissue-specific manner (liver mosaicism).

RESULTS

iLIRKO mice presented progressive hepatic and extrahepatic insulin resistance without liver dysfunction. Initially, iLIRKO mice displayed hyperinsulinemia and increased β-cell mass, the extent of which was proportional to the deletion of hepatic IR. Our studies of iLIRKO suggest a cause-and-effect relationship between progressive insulin resistance and the fold increase of plasma insulin levels and β-cell mass. Ultimately, the β-cells failed to secrete sufficient insulin, leading to uncontrolled diabetes. We observed that hepatic IGF-1 expression was enhanced in iLIRKO mice, resulting in an increase of circulating IGF-1. Concurrently, the IR-A isoform was upregulated in hyperplastic β-cells of iLIRKO mice and IGF-1–induced proliferation was higher than in the controls. In mouse β-cell lines, IR-A, but not IR-B, conferred a proliferative capacity in response to insulin or IGF-1, providing a potential explanation for the β-cell hyperplasia induced by liver insulin resistance in iLIRKO mice.

CONCLUSIONS

Our studies of iLIRKO mice suggest a liver-pancreas endocrine axis in which IGF-1 functions as a liver-derived growth factor to promote compensatory pancreatic islet hyperplasia through IR-A.