bluuebunny/crossref_metadata_2025 huggingface dataset:
P-004 US Multicenter experience with the Wingspan stent system for the treatment of intracranial atherosclerosis: 1 year results
Authors: Turk A ,   for the US Wingspan Multicenter Group
Published: December 2010

Background and purpose

Symptomatic intracranial stenosis is a significant cause of stroke in the USA. No prospective data on long term outcomes have been reported in the literature.

Methods

All patients (n=158) undergoing angioplasty and stenting at five US centers with the Gateway balloon and Wingspan stent delivery system were prospectively tracked in a formalized central database. Primary end points were major ipsilateral stroke or major ipsilateral stroke and death. Secondary end points were restenosis, minor stroke or transient ischemic attacks.

Results

158 patients with 168 stenosis were treated over a 16 month period. Stents were successfully placed in 96% of cases. Periprocedural (within 30 days) were encountered in 5.7% of cases. Long term clinical follow-up was possible on 91% (143 of 158) of patients and angiographic follow-up on 84% (133 of 158) of patients. Further ipsilateral stroke or death was 9% at an average follow-up time of 14.2 months. In-stent restenosis was 31.6% (n=42) but only 9.7% (n=13) were symptomatic.

Conclusion

Intracranial angioplasty and stenting with the Wingspan system is safe and is effective at reducing the risk of stroke. This data reinforces the necessity of the ongoing randomized SAMMPRIS trial.
Diagnosis and management of coeliac disease in children
Authors: Steele Richard
Published: December 2010

Coeliac disease (CD) remains under diagnosed with only 10–20% of patients identified. Genes encoding HLA DQ2 or DQ8 are found in the vast majority of those with CD and testing for their presence can be useful to rule out the possibility CD. CD is more common in certain ethnic groups including those of North Indian origin. The classical presentation tends to occur in younger children, while atypical presentations occur at an older age. The number of children being diagnosed with CD is increasing; this may be due to greater recognition of the more atypical presentations, improved serologic tests, and the screening of asymptomatic groups at increased risk, but may also be due to an overall increased prevalence. Although serologic testing has become more reliable, there still remain significant problems around testing, particularly in those <18 months of age. All children should undergo a duodenal biopsy on a gluten containing diet in order to diagnose CD before recommending a gluten-free diet (GFD). A GFD should be offered to all children diagnosed with CD even when perceived as asymptomatic, as there is significant morbidity associated with CD later in life.
Tumour cryoablation combined with palliative bypass surgery in the treatment of unresectable pancreatic cancer: a retrospective study of 142 patients
Authors: Li Jingdong , Chen Xiaoli , Yang Hanfeng , Wang Xiaofei , Yuan Ding , Zeng Yong , Wen Tianfu , Yan Lunan , Li Bo
Published: December 2010

Background

Although cryosurgery has been proved to be an effective treatment to extend the survival time of unresectable liver cancer patients and improve their quality of life, few surgeons actually treat unresectable pancreatic cancer with this method because of its safety risks. This study aims to evaluate the safety and efficacy of cryosurgical ablation in the treatment for unresectable pancreatic cancer.

Methods

A retrospective study was conducted on 142 patients who underwent palliative bypass with cryoablation (PBC group: 68) or without cryoablation (PB group: 74) for unresectable pancreatic cancer from 1995 to 2002. The morbidity and 5 year survival rates of the two groups were compared. Carbohydrate antigen 19–9 (CA19-9) level and tumour size were evaluated in PBC group.

Results

There was no significant difference in the rate of overall complications between the two groups (p=0.809), except for a higher delayed gastric emptying rate observed in the PBC group (36.8% vs 16.2%, p=0.005). In the PBC group, the median preoperative CA19-9 concentration decreased from 690 U/ml to 56 U/ml (p=0.000). CT scan results of 55 patients indicated that tumour mass shrinkage occurred in 36 of them, from 4.3 cm to 2.4 cm (pre-ablation to 3 months after ablation). Kaplan–Meier analysis showed no significant difference in 5 year survival rates between the two groups (p=0.124).

Conclusions

Cryosurgery combined with palliative bypass surgery can be considered a safe and effective treatment for unresectable pancreatic cancer. Though this technique remains only palliative, it may be further employed to improve advanced stage pancreatic cancer.
Neurological and cognitive impairments detected in older people without a diagnosis of neurological or cognitive disease
Authors: Woodford Henry J , George James
Published: December 2010

Advanced age is associated with the finding of abnormalities on neurological and cognitive assessment. This review aims to identify studies that evaluated community samples of patients without a history of neurological disease and attempts to combine these data. While neurological signs were common, they were not universal and should not be considered an inevitable component of ageing. Additionally, they are associated with an increased risk of multiple adverse outcomes including functional decline and death. Therefore they should not be considered benign. Cognitive changes detected in studies that examined healthy older adults were only mild. More pronounced change suggests the development of dementia or mild cognitive impairment (a precursor to dementia). Changes in either neurological or cognitive examination in older adults should be considered abnormal and due to underlying disease. They should be investigated and treated in a similar way to abnormalities detected in younger individuals.
2D IMAGE TRANSMISSION USING BANDWIDTH EFFICIENT MAPPING TECHNIQUE
Authors: KULKARNI SHIVALI D. , NAIK AMEYA K. , NAGORI NITIN S.
Published: December 2010

Transmitting images over the wireless channel require that optimum compression ratio be maintained along with good image quality. This becomes a critical issue especially at higher values of bit error rate (BER). Joint photographic experts group (JPEG) standard and its successor JPEG 2000 provide excellent compression ratio but image reconstruction becomes highly difficult under extreme noise conditions. We present a mapping technique which gives better compression as compared to the existing techniques. Also, its performance is excellent even for higher bit error rates (BERs). This is supported by the results presented for JPEG, JPEG 2000, as well as mapping technique under fading channel conditions. Moreover, it is observed that the presence of high levels of noise has negligible effect on the reconstruction of images encoded using mapping technique.
ONLINE ANIMATION SYSTEM FOR PRACTICING CUED SPEECH
Authors: JOVANOVA BLAGICA , ARSOV IVICA , PREDA MARIUS , PRETEUX FRANÇOISE
Published: December 2010

This paper presents a set of information and communication technologies developed with the goal to improve the practice of cued speech. They are based on three-dimensional (3D) graphics and are covering the entire end-to-end content chain: production, transmission, and visualization. Starting from defining a set of potential applications, the requirements of the targeted system for cued speech are set. The research and development path takes into account high-quality animation, real-time constraints, personalization, user acceptability and, equally important, the easiness and feasibility of the deployment. The latter led to a strong orientation toward open standards. The original components of the system include 3D graphics and animation encoders, streaming servers, and visualization engines. The core technology is validated in two real-time applications: a web service for text to animation conversion and a chat service supporting two or more users.
SIMULATION OF THE RETINA: A TOOL FOR VISUAL PROSTHESES
Authors: DURETTE BARTHÉLÉMY , HÉRAULT JEANNY , ALLEYSSON DAVID
Published: December 2010

To extract high-level information from natural scenes, the visual system has to cope with a wide variety of ambient lights, reflection properties of objects, spatio-temporal contexts, and geometrical complexity. By pre-processing the visual information, the retina plays a key role in the functioning of the whole visual system. It is crucial to reproduce such a pre-processing in artificial devices aiming at replacing or substituting the damaged vision system by artificial means.

In this paper, we present a biologically plausible model of the retina at the cell level and its implementation as a real-time retinal simulation software. It features the non-uniform sampling of the visual information by the photoreceptor cells, the non-separable spatio-temporal properties of the retina, the subsequent generation of the Parvocellular and Magnocellular pathways, and the non-linear equalization of luminance and contrast at the local level. For each of these aspects, a description of the model is provided and illustrated. Their respective interest for the replacement or substitution of vision is discussed.
STAT subtype specificity and ischemic preconditioning in mice: is STAT-3 enough?
Authors: Goodman Michael D. , Koch Sheryl E. , Afzal Muhammad R. , Butler Karyn L.
Published: December 2010

The role of other STAT subtypes in conferring ischemic tolerance is unclear. We hypothesized that in STAT-3 deletion alternative STAT subtypes would protect myocardial function against ischemia-reperfusion injury. Wild-type (WT) male C57BL/6 mice or mice with cardiomyocyte STAT-3 knockout (KO) underwent baseline echocardiography. Langendorff-perfused hearts underwent ischemic preconditioning (IPC) or no IPC before ischemia-reperfusion. Following ex vivo perfusion, hearts were analyzed for STAT-5 and -6 phosphorylation by Western blot analysis of nuclear fractions. Echocardiography and postequilibration cardiac performance revealed no differences in cardiac function between WT and KO hearts. Phosphorylated STAT-5 and -6 expression was similar in WT and KO hearts before perfusion. Contractile function in WT and KO hearts was significantly impaired following ischemia-reperfusion in the absence of IPC. In WT hearts, IPC significantly improved the recovery of the maximum first derivative of developed pressure (+dP/d tmax) compared with that in hearts without IPC. IPC more effectively improved end-reperfusion dP/d tmax in WT hearts compared with KO hearts. Preconditioned and nonpreconditioned KO hearts exhibited increased phosphorylated STAT-5 and -6 expression compared with WT hearts. The increased subtype activation did not improve the efficacy of IPC in KO hearts. In conclusion, baseline cardiac performance is preserved in hearts with cardiac-restricted STAT-3 deletion. STAT-3 deletion attenuates preconditioning and is not associated with a compensatory upregulation of STAT-5 and -6 subtypes. The activation of STAT-5 and -6 in KO hearts following ischemic challenge does not provide functional compensation for the loss of STAT-3. JAK-STAT signaling via STAT-3 is essential for effective IPC.
Abnormal heart rate regulation in murine hearts with familial hypertrophic cardiomyopathy-related cardiac troponin T mutations
Authors: Jimenez Jesus , Tardiff Jil C.
Published: December 2010

Mutations in cardiac troponin T (cTnT), Δ160E and R92Q, have been linked to familial hypertrophic cardiomyopathy (FHC), and some studies have indicated that these mutations can lead to a high incidence of sudden cardiac death in the relative absence of significant ventricular hypertrophy. Alterations in autonomic function have been documented in patients with hypertrophic cardiomyopathy. We hypothesize that alterations in autonomic function may contribute to mutation-specific clinical phenotypes in cTnT-related FHC. Heart rate (HR) variability (HRV) has been used to assess autonomic function from an electrocardiograph. Nontransgenic, Δ160E, or R92Q mice were implanted with radiofrequency transmitters to obtain continuous electrocardiograph recordings during 24-h baseline and 30-min recordings after β-adrenergic receptor drug injections. Although Δ160E mice did not differ from nontransgenic mice for any 24-h HRV measurements, R92Q mice had impaired HR regulation, as measured by a decrease in the SD of the R-R interval, a decrease in the low frequency-to-high frequency ratio, a decrease in normalized low frequency, and an increase in normalized high frequency. β-Adrenergic receptor density measurements and HRV analysis after drug injections did not reveal any significant differences for Δ160E or R92Q mice versus nontransgenic mice. Arrhythmia analysis revealed both an increased incidence of heart block in R92Q mice at baseline and frequency of premature ventricular contractions after isoproterenol injections in Δ160E and R92Q mice. In addition, Δ160E and R92Q mice exhibited a prolonged P duration after drug injections. Therefore, between two independent and clinically severe cTnT mutations within the same functional domain, only R92Q mice exhibited altered autonomic function, whereas both mutations demonstrated abnormalities in conduction and ventricular ectopy.
Phorbol ester and endothelin-1 alter functional expression of Na+/Ca2+exchange, K+, and Ca2+currents in cultured neonatal rat myocytes
Authors: Puglisi José L. , Yuan Weilong , Timofeyev Valeriy , Myers Richard E. , Chiamvimonvat Nipavan , Samarel Allen M. , Bers Donald M.
Published: December 2010

Endothelin-1 (ET-1) and activation of protein kinase C (PKC) have been implicated in alterations of myocyte function in cardiac hypertrophy and heart failure. Changes in cellular Ca2+handling and electrophysiological properties also occur in these states and may contribute to mechanical dysfunction and arrhythmias. While ET-1 or PKC stimulation induces cellular hypertrophy in cultured neonatal rat ventricular myocytes (NRVMs), a system widely used in studies of hypertrophic signaling, there is little data about electrophysiological changes. Here we studied the effects of ET-1 (100 nM) or the PKC activator phorbol 12-myristate 13-acetate (PMA, 1 μM) on ionic currents in NRVMs. The acute effects of PMA or ET-1 (≤30 min) were small or insignificant. However, PMA or ET-1 exposure for 48–72 h increased cell capacitance by 100 or 25%, respectively, indicating cellular hypertrophy. ET-1 also slightly increased Ca2+current density (T and L type). Na+/Ca2+exchange current was increased by chronic pretreatment with either PMA or ET-1. In contrast, transient outward and delayed rectifier K+currents were strongly downregulated by PMA or ET-1 pretreatment. Inward rectifier K+current tended toward a decrease at larger negative potential, but time-independent outward K+current was unaltered by either treatment. The enhanced inward and reduced outward currents also result in action potential prolongation after PMA or ET-1 pretreatment. We conclude that chronic PMA or ET-1 exposure in cultured NRVMs causes altered functional expression of cardiac ion currents, which mimic electrophysiological changes seen in whole animal and human hypertrophy and heart failure.
Long-term preservation of myocardial energetic in chronic hibernating myocardium
Authors: Jameel Mohammad Nurulqadr , Li Qinglu , Mansoor Abdul , Xiong Qiang , Swingen Cory , Zhang Jianyi
Published: December 2010

We previously reported that the myocardial energetic state, as defined by the ratio of phosphocreatine to ATP (PCr/ATP), was preserved at baseline (BL) in a swine model of chronic myocardial ischemia with mild reduction of myocardial blood flow (MBF) 10 wk after the placement of an external constrictor on the left anterior descending coronary artery. It remains to be seen whether this stable energetic state is maintained at a longer-term follow-up. Hibernating myocardium (HB) was created in minipigs ( n = 7) by the placement of an external constrictor (1.25 mm internal diameter) on the left anterior descending coronary artery. Function was assessed with MRI at regular intervals until 6 mo. At 6 mo, myocardial energetic in the HB was assessed by31P-magnetic resonance spectrometry and myocardial oxygenation was examined from the deoxymyoglobin signal using1H-magnetic resonance spectrometry during BL, coronary vasodilation with adenosine, and high cardiac workload with dopamine and dobutamine (DpDb). MBF was measured with radiolabeled microspheres. At BL, systolic thickening fraction was significantly lower in the HB compared with remote region (34.4 ± 9.4 vs. 50.1 ± 10.7, P = 0.006). This was associated with a decreased MBF in the HB compared with the remote region (0.73 ± 0.08 vs. 0.97 ± 0.07 ml·min−1·g, P = 0.03). The HB PCr/ATP at BL was normal. DpDb resulted in a significant increase in rate pressure product, which caused a twofold increase in MBF in the HB and a threefold increase in the remote region. The systolic thickening fraction increased with DpDb, which was significantly higher in the remote region than HB ( P < 0.05). The high cardiac workload was associated with a significant reduction in the HB PCr/ATP ( P < 0.02), but this response was similar to normal myocardium. Thus HB has stable BL myocardial energetic despite the reduction MBF and regional left ventricular function. More importantly, HB has a reduced contractile reserve but has a similar energetic response to high cardiac workload like normal myocardium.
Quantification of calsequestrin 2 (CSQ2) in sheep cardiac muscle and Ca2+-binding protein changes in CSQ2 knockout mice
Authors: Murphy Robyn M. , Mollica Janelle P. , Beard Nicole A. , Knollmann Bjorn C. , Lamb Graham D.
Published: December 2010

Calsequestrin 2 (CSQ2) is generally regarded as the primary Ca2+-buffering molecule present inside the sarcoplasmic reticulum (SR) in cardiac cells, but findings from CSQ2 knockout experiments raise major questions about its role and necessity. This study determined the absolute amount of CSQ2 present in cardiac ventricular muscle to gauge its likely influence on SR free Ca2+concentration ([Ca2+]) and maximal Ca2+capacity. Ventricular tissue from hearts of freshly killed sheep was examined by SDS-PAGE without any fractionation, and CSQ2 was detected by Western blotting; this method avoided the >90% loss of CSQ2 occurring with usual fractionation procedures. Band intensities were compared against those for purified CSQ2 run on the same blots. Fidelity of quantification was verified by demonstrating that CSQ2 added to homogenates was detected with equal efficacy as purified CSQ2 alone. Ventricular tissue from sheep ( n = 8) contained 24 ± 2 μmol CSQ2/kg wet wt. Total Ca2+content of the ventricular tissue, measured by atomic absorption spectroscopy, was 430 ± 20 μmol/kg (with SR Ca2+likely <250 μmol/kg) and displayed a linear correlation with CSQ2 content, with gradient of ∼10 Ca2+per CSQ2. The large amount of CSQ2 bestows the SR with a high theoretical maximal Ca2+-binding capacity (∼1 mmol Ca2+/kg ventricular tissue, assuming a maximum of ∼40 Ca2+per CSQ2) and would keep free [Ca2+] within the SR relatively low, energetically favoring Ca2+uptake and reducing SR leak. In mice with CSQ2 ablated, histidine-rich Ca2+-binding protein was upregulated ∼35% in ventricular tissue, possibly in compensation.
Repeated increases in blood flow, independent of exercise, enhance conduit artery vasodilator function in humans
Authors: Naylor Louise H. , Carter Howard , FitzSimons Matthew G. , Cable N. Timothy , Thijssen Dick H. J. , Green Daniel J.
Published: December 2010

This study aimed to determine the importance of repeated increases in blood flow to conduit artery adaptation, using an exercise-independent repeated episodic stimulus. Recent studies suggest that exercise training improves vasodilator function of conduit arteries via shear stress-mediated mechanisms. However, exercise is a complex stimulus that may induce shear-independent adaptations. Nine healthy men immersed their forearms in water at 42°C for three 30-min sessions/wk across 8 wk. During each session, a pneumatic pressure cuff was inflated around one forearm to unilaterally modulate heating-induced increases in shear. Forearm heating was associated with an increase in brachial artery blood flow ( P < 0.001) and shear rate ( P < 0.001) in the uncuffed forearm; this response was attenuated in the cuffed limb ( P < 0.005). Repeated episodic exposure to bilateral heating induced an increase in endothelium-dependent vasodilation in response to 5-min ischemic ( P < 0.05) and ischemic handgrip exercise ( P < 0.005) stimuli in the uncuffed forearm, whereas the 8-wk heating intervention did not influence dilation to either stimulus in the cuffed limb. Endothelium-independent glyceryl trinitrate responses were not altered in either limb. Repeated heating increases blood flow to levels that enhance endothelium-mediated vasodilator function in humans. These findings reinforce the importance of the direct impacts of shear stress on the vascular endothelium in humans.
ZO-1 determines adherens and gap junction localization at intercalated disks
Authors: Palatinus Joseph A. , O'Quinn Michael P. , Barker Ralph J. , Harris Brett S. , Jourdan Jane , Gourdie Robert G.
Published: December 2010

The disruption of the spatial order of electromechanical junctions at myocyte-intercalated disks (ICDs) is a poorly understood characteristic of many cardiac disease states. Here, in vitro and in vivo evidence is provided that zonula occludens-1 (ZO-1) regulates the organization of gap junctions (GJs) and adherens junctions (AJs) at ICDs. We investigated the contribution of ZO-1 to cell-cell junction localization by expressing a dominant-negative ZO-1 construct (DN-ZO-1) in rat ventricular myocytes (VMs). The expression of DN-ZO-1 in cultured neonatal VMs for 72 h reduced the interaction of ZO-1 and N-cadherin, as assayed by colocalization and coimmunoprecipitation, prompting cytoplasmic internalization of AJ and GJ proteins. DN-ZO-1 expression in adult VMs in vivo also reduced N-cadherin colocalization with ZO-1, a phenomenon not observed when the connexin-43 (Cx43)-ZO-1 interaction was disrupted using a mimetic of the ZO-1-binding ligand from Cx43. DN-ZO-1-infected VMs demonstrated large GJs at the ICD periphery and showed a loss of focal ZO-1 concentrations along plaque edges facing the disk interior. Additionally, there was breakdown of the characteristic ICD pattern of small interior and large peripheral GJs. Continuous DN-ZO-1 expression in VMs over postnatal development reduced ICD-associated Cx43 GJs and increased lateralized and cytoplasmic Cx43. We conclude that ZO-1 regulation of GJ localization is via an association with the N-cadherin multiprotein complex and that this is a key determinant of stable localization of both AJs and GJs at the ICD.
Role of the Rho pathway in regulating valvular interstitial cell phenotype and nodule formation
Authors: Gu Xiaoxiao , Masters Kristyn S.
Published: December 2010

The differentiation of valvular interstitial cells (VICs) to a myofibroblastic or osteoblast-like phenotype is commonly found in calcific valvular stenosis, although the molecular-level mechanisms of this process remain poorly understood. Due to the role of the Rho pathway in various vascular diseases and in the expression of a myofibroblast phenotype, the present study was inspired by the hypothesis that Rho activation is involved in regulating cellular processes related to valve calcification. It was found that increased RhoA and Rho kinase (ROCK) activity was associated with increased nodule formation in VIC cultures in vitro, and intentional induction of RhoA activity led to a further increase in nodules and expression of α-smooth muscle actin. VICs treated with ROCK inhibitors were also examined for nodule formation, proliferation, apoptosis, and expression of myofibroblastic or osteoblastic markers. ROCK inhibition dramatically reduced myofibroblast-regulated nodule formation in VIC cultures, as evidenced by a decrease in nodule number, total nodule area, α-smooth muscle actin-positive stress fibers, apoptosis, and gene expression of myofibroblast-related phenotypic markers. Meanwhile, ROCK inhibition was less effective at reducing nodule formation associated with osteogenic activity. In fact, ROCK inhibition increased the expression of alkaline phosphatase and effected only a modest decrease in nodule number when applied to VIC cultures with higher osteogenic activity. Thus, the Rho pathway possesses a complex role in regulating the VIC phenotype and nodule formation, and it is hoped that further elucidation of these molecular-level events will lead to an improved understanding of valvular disease and identification of potential treatments.
Nicotinamide enhances apoptosis of G(M)-CSF-treated neutrophils and attenuates endotoxin-induced airway inflammation in mice
Authors: Fernandes Cláudia A. , Fievez Laurence , Ucakar Bernard , Neyrinck Audrey M. , Fillee Catherine , Huaux François , Delzenne Nathalie M. , Bureau Fabrice , Vanbever Rita
Published: December 2010

Neutrophils constitute the first line of host defense against invading microorganisms. Yet their removal from the inflammatory environment is fundamental for injury restraint and resolution of inflammation. Nicotinamide, a component of vitamin B3, is known to modulate cell survival. In this study, we assessed the influence of nicotinamide on neutrophil apoptosis, both in vitro and in vivo in a mouse model of endotoxin-induced lung inflammation. In vitro, nicotinamide promoted apoptosis of human blood neutrophils in a dose-dependent manner in the presence of the apoptosis inhibitors granulocyte colony-stimulating factor and granulocyte/macrophage colony-stimulating factor. The highest concentration of nicotinamide completely neutralized the pro-survival effect of granulocyte (macrophage) colony-stimulating factor. Nicotinamide proapoptotic effect was associated with enhanced caspase-3 activity. In addition, nicotinamide slightly reduced neutrophil chemotaxis in vitro. In vivo, pulmonary nicotinamide delivery decreased the levels of cellular and biochemical inflammation markers and increased the percentage of apoptotic neutrophils in bronchoalveolar lavages. Our findings suggest that nicotinamide is an apoptotic stimulus for neutrophils, thereby contributing to the resolution of neutrophilic inflammation in the lungs.
Postnatal episodic ozone results in persistent attenuation of pulmonary and peripheral blood responses to LPS challenge
Authors: Maniar-Hew Kinjal , Postlethwait Edward M. , Fanucchi Michelle V. , Ballinger Carol A. , Evans Michael J. , Harkema Jack R. , Carey Stephan A. , McDonald Ruth J. , Bartolucci Alfred A. , Miller Lisa A.
Published: December 2010

Early life is a dynamic period of growth for the lung and immune system. We hypothesized that ambient ozone exposure during postnatal development can affect the innate immune response to other environmental challenges in a persistent fashion. To test this hypothesis, we exposed infant rhesus macaque monkeys to a regimen of 11 ozone cycles between 30 days and 6 mo of age; each cycle consisted of ozone for 5 days (0.5 parts per million at 8 h/day) followed by 9 days of filtered air. Animals were subsequently housed in filtered air conditions and challenged with a single dose of inhaled LPS at 1 yr of age. After completion of the ozone exposure regimen at 6 mo of age, total peripheral blood leukocyte and polymorphonuclear leukocyte (PMN) numbers were reduced, whereas eosinophil counts increased. In lavage, total cell numbers at 6 mo were not affected by ozone, however, there was a significant reduction in lymphocytes and increased eosinophils. Following an additional 6 mo of filtered air housing, only monocytes were increased in blood and lavage in previously exposed animals. In response to LPS challenge, animals with a prior history of ozone showed an attenuated peripheral blood and lavage PMN response compared with controls. In vitro stimulation of peripheral blood mononuclear cells with LPS resulted in reduced secretion of IL-6 and IL-8 protein in association with prior ozone exposure. Collectively, our findings suggest that ozone exposure during infancy can result in a persistent effect on both pulmonary and systemic innate immune responses later in life.
Paradoxical attenuation of β2-AR function in airway smooth muscle by Gi-mediated counterregulation in transgenic mice overexpressing type 5 adenylyl cyclase
Authors: Wang Wayne C. H. , Schillinger Rachel M. , Malone Molly M. , Liggett Stephen B.
Published: December 2010

The limiting component within the receptor-G protein-effector complex in airway smooth muscle (ASM) for β2-adrenergic receptor (β2-AR)-mediated relaxation is unknown. In cardiomyocytes, adenylyl cyclase (AC) is considered the “bottleneck” for β-AR signaling, and gene therapy trials are underway to increase inotropy by increasing cardiac AC expression. We hypothesized that increasing AC in ASM would increase relaxation from β-agonists, thereby providing a strategy for asthma therapy. Transgenic (TG) mice were generated with approximately two- to threefold overexpression of type 5 AC (AC5) in ASM. cAMP and airway relaxation in response to direct activation of AC by forskolin were increased in AC5-TG. Counter to our hypothesis, isoproterenol-mediated airway relaxation was significantly attenuated (∼50%) in AC5-TG, as was cAMP production, suggesting compensatory regulatory events limiting β2-AR signaling when AC expression is increased. In contrast, acetylcholine-mediated contraction was preserved. Gαiexpression and ERK1/2 activation were markedly increased in AC5-TG (5- and 8-fold, respectively), and β-AR expression was decreased by ∼40%. Other G proteins, G protein-coupled receptor kinases, and β-arrestins were unaffected. β-agonist-mediated airway relaxation of AC5-TG was normalized to that of nontransgenic mice by pertussis toxin, implicating β2-AR coupling to the increased Gias a mechanism of depressed agonist-promoted relaxation in these mice. The decrease in β2-AR may account for additional relaxation impairment, given that there is no enhancement over nontransgenic after pertussis toxin, despite AC5 overexpression. ERK1/2 inhibition had no effect on the phenotype. Thus perturbing the ratio of β2-AR to AC in ASM by increasing AC fails to improve (and actually decreases) β-agonist efficacy due to counterregulatory events.
Inflammation and lung maturation from stretch injury in preterm fetal sheep
Authors: Hillman Noah H. , Polglase Graeme R. , Jane Pillow J. , Saito Masatoshi , Kallapur Suhas G. , Jobe Alan H.
Published: December 2010

Mechanical ventilation is a risk factor for the development of bronchopulmonary dysplasia in premature infants. Fifteen minutes of high tidal volume (Vt) ventilation induces inflammatory cytokine expression in small airways and lung parenchyma within 3 h. Our objective was to describe the temporal progression of cytokine and maturation responses to lung injury in fetal sheep exposed to a defined 15-min stretch injury. After maternal anesthesia and hysterotomy, 129-day gestation fetal lambs ( n = 7–8/group) had the head and chest exteriorized. Each fetus was intubated, and airway fluid was gently removed. While placental support was maintained, the fetus received ventilation with an escalating Vt to 15 ml/kg without positive end-expiratory pressure (PEEP) for 15 min using heated, humidified 100% nitrogen. The fetus was then returned to the uterus for 1, 6, or 24 h. Control lambs received a PEEP of 2 cmH2O for 15 min. Tissue samples from the lung and systemic organs were evaluated. Stretch injury increased the early response gene Egr-1 and increased expression of pro- and anti-inflammatory cytokines within 1 h. The injury induced granulocyte/macrophage colony-stimulating factor mRNA and matured monocytes to alveolar macrophages by 24 h. The mRNA for the surfactant proteins A, B, and C increased in the lungs by 24 h. The airway epithelium demonstrated dynamic changes in heat shock protein 70 (HSP70) over time. Serum cortisol levels did not increase, and induction of systemic inflammation was minimal. We conclude that a brief period of high Vt ventilation causes a proinflammatory cascade, a maturation of lung monocytic cells, and an induction of surfactant protein mRNA.
Properties of substance P-stimulated mucus secretion from porcine tracheal submucosal glands
Authors: Khansaheb Monal , Choi Jae Young , Joo Nam Soo , Yang Yu-Mi , Krouse Mauri , Wine Jeffrey J.
Published: December 2010

Human and pig airway submucosal glands secrete mucus in response to substance P (SubP), but in pig tracheal glands the response to SubP is >10-fold greater than in humans and shares features with cholinergically produced secretion. CFTR-deficient pigs provide a model for human cystic fibrosis (CF), and in newborn CF pigs the response of tracheal glands to SubP is significantly reduced (Joo et al. J Clin Invest 120: 3161–3166, 2010). To further define features of SubP-mediated gland secretion, we optically measured secretion rates from individual adult porcine glands in isolated tracheal tissues in response to mucosal capsaicin and serosal SubP. Mucosal capsaicin (EC50= 19 μM) stimulated low rates of secretion that were partially inhibited by tetrodotoxin and by inhibitors for muscarinic, VIP, and SubP receptors, suggesting reflex stimulation of secretion by multiple transmitters. Secretion in response to mucosal capsaicin was inhibited by CFTRinh-172, but not by niflumic acid. Serosal SubP (EC50= 230 nM) stimulated 10-fold more secretion than mucosal capsaicin, with a Vmaxsimilar to that of carbachol. Secretion rates peaked within 5 min and then declined to a lower sustained rate. SubP-stimulated secretion was inhibited 75% by bumetanide, 53% by removal of HCO3−, and 85% by bumetanide + removal of HCO3−; it was not inhibited by atropine but was inhibited by niflumic acid, clotrimazole, BAPTA-AM, nominally Ca2+-free bath solution, and the adenylate cyclase inhibitor MDL-12330A. Ratiometric measurements of fura 2 fluorescence in dissociated gland cells showed that SubP and carbachol increased intracellular Ca2+concentration by similar amounts. SubP produced rapid volume loss by serous and mucous cells, expansion of gland lumina, mucus flow, and exocytosis but little or no contraction of myoepithelial cells. These and prior results suggest that SubP stimulates pig gland secretion via CFTR- and Ca2+-activated Cl−channels.
Bone Marrow Stem Cell Derived Paracrine Factors for Regenerative Medicine: Current Perspectives and Therapeutic Potential
Authors: Burdon Tom J. , Paul Arghya , Noiseux Nicolas , Prakash Satya , Shum-Tim Dominique
Published: December 2010

During the past several years, there has been intense research in the field of bone marrow-derived stem cell (BMSC) therapy to facilitate its translation into clinical setting. Although a lot has been accomplished, plenty of challenges lie ahead. Furthermore, there is a growing body of evidence showing that administration of BMSC-derived conditioned media (BMSC-CM) can recapitulate the beneficial effects observed after stem cell therapy. BMSCs produce a wide range of cytokines and chemokines that have, until now, shown extensive therapeutic potential. These paracrine mechanisms could be as diverse as stimulating receptor-mediated survival pathways, inducing stem cell homing and differentiation or regulating the anti-inflammatory effects in wounded areas. The current review reflects the rapid shift of interest from BMSC to BMSC-CM to alleviate many logistical and technical issues regarding cell therapy and evaluates its future potential as an effective regenerative therapy.
Abstract A16: Dissemination and end-user evaluation of a culturally targeted brochure about hereditary breast and ovarian cancer for black women
Authors: Vadaparampil Susan T. , Fleming Patrice J. , Rivers Desiree , Harville Veronica , Tuya Pal. H
Published: December 2010

Background: Using a multistep iterative process, our community-academic team developed a culturally tailored brochure for black women to increase awareness about hereditary breast and ovarian cancer (HBOC).

Objective: To disseminate a culturally targeted brochure in the black community and collect feedback from the end users.

Methods: Upon finalization of the brochure, several strategies were used to disseminate the brochure. With respect to evaluation, a self-addressed postage-paid postcard was inserted within the brochure in order to collect demographic and clinical information, as well as feedback about the brochure, from its end users. As an incentive for participation, those who returned the postcard were eligible for a $100 gift card drawing.

Results: Dissemination channels included community partners and attendance at local community-based health education events. Since the brochure has been made available for general dissemination, approximately 3000 have been provided to 17 requestors. Of the 34 respondents who have returned the postcard, 27% were younger than age 50,12% reported a personal history, and 47% a family history of breast and/or ovarian cancer. The majority (67.6%) indicated that the brochure was very useful in helping them understand more about inherited breast cancer. Moreover, the majority (94.2%) indicated that after reading the brochure, they were likely to share the information with others and all indicated that they were likely to discuss their own personal and/or family history of cancer with their healthcare provider. Finally, the majority (57.1 %) were willing to be contacted by the study team to consider participation in future research opportunities.

Conclusion: Through an academic-community partnership, a culturally tailored brochure to improve awareness about HBOC is actively being disseminated to black women of varied sociodemographic characteristics and cancer histories. The majority of women who returned the postcard provided positive feedback about the brochure. The procedures implemented and information gathered through these efforts will inform future dissemination efforts related to the current brochure as well as that of other targeted and nontargeted educational materials.

Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):A16.
Abstract A20: Increasing pap testing with a community-based educational intervention in the Latina population
Authors: Barnack-Tavlaris Jessica L. , Navarro Ana , Murray Kate , McKennett Marianne , McNicholas Lori , Sanchez Olga
Published: December 2010

Introduction: Every year in the U.S., there are approximately 11,000 new cases of cervical cancer, and approximately 4000 deaths due to cervical cancer (Jemal, Siegel, Ward, Hao, Xu, & Thun, 2009). The Latino/a population is disproportionately affected by cervical cancer, in that Latinas have higher incidence rates (12.7 per 100,000) and mortality rates (3.1 per 100,000) due to cervical cancer than non-Latina white women (7.3 per 100,000 and 2.1 per 100,000, respectively) (American Cancer Society (ACS), 2009; Downs et al., 2008; Jemal et al., 2009; Saraiya et al, 2007). “Por la Vida” is a San Diego-based Latino/a program dedicated to increasing cancer education in the Latino/a community, through the involvement of consejeras (community health workers), since 1990. The purpose of this study is to examine the success of a “Women and Cancer” program in increasing pap testing in the Latina population. We examined self-reported changes in pap testing behaviors and beliefs about cervical cancer before and after participating in the “Women and Cancer” program, and compared the changes to women who participated in a “Nutrition and Cancer” program, which had no cervical cancer-specific information. Both programs were conducted by “Por la Vida” from the years 1997 through 2002.

Method: Participants were 260 Latinas from the “Women and Cancer” program, and 308 Latinas from the “Nutrition and Cancer” program. Participants completed a pre-test (before the program was initiated) and post-test (6 months after completion of the program) questionnaire that examined their health behaviors and health-related beliefs. McNemar tests were used to compare changes in behaviors and attitudes from pre-test to post-test for participants in each of the two programs.

Results: The number of women who reported they ever had a Pap test increased significantly from pre to post test for women in the “Women and Cancer” program. There was no change in pap testing over time for women in the “Nutrition and Cancer” program. Similarly, the number of women who had a Pap in the last year increased significantly for those in the “Women and Cancer” program, and stayed the same for women in the “Nutrition and Cancer” program. With regard to beliefs about cervical cancer, women who participated in the “Women and Cancer” program gained a significantly more positive outlook toward surviving early stage cervical cancer, while those who participated in the “Nutrition and Cancer” program did not.

Discussion: These results reinforce the importance of topic specific, and culturally appropriate education programs for increasing cancer screening behaviors. Such programs have the potential to reduce cancer disparities in underserved populations.

Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):A20.
Abstract A23: Psychometric development and validation of a Patient Satisfaction with Interpersonal Relationship with Navigator (PSN-I) measure: A multisite National Cancer Institute-sponsored Patient Navigation Research Program (PNRP) study
Authors: Jean-Pierre Pascal , Fiscella Kevin , Winters Paul C. , Wells Kristen , Battaglia Tracy , Post Douglas , Simon Melissa , Kilbourn Kristin
Published: December 2010

Background: Patient navigation (PN) is used increasingly to address racial, ethnic, and socioeconomic disparities in cancer care. Patient navigators provide logistic and emotional support to help patients successfully complete the cancer diagnostic and treatment care. Despite the importance of interpersonal relationships between patient and health care staff, there is no measure of patient satisfaction with the interpersonal relationship with his/her navigator.

Objective: To validate the PSN-I scale for patients undergoing diagnostic and therapeutic cancer care.

Methods: We administered the nine-item PSN-I to 783 participants recruited from the nine different sites of the National Cancer Institute-sponsored PNRP. We randomly divided the English language proficient sample into two subsamples (N1 = 391 and N2 = 392). We used the first subsample to test the latent structure of the PSN-I and the second subsample to replicate and confirm its stability. We evaluated the latent structure and internal consistency of the PSN using principal components analysis (PCA) and Cronbach coefficient alpha (α) respectively. We used correlation analyses to examine divergence and convergence of the PSN with the Patient Satisfaction with Cancer-Related Care (PSCC), the Rapid Estimate of Adult Literacy in Medicine-Long Form (REALM-LF), and patients’ demographic characteristics.

Results: The PCA revealed a coherent set of items that explicates 76% of the variance in PSN-I. Reliability assessment revealed high internal consistency (α ranging from 0.95 to 0.96). The PSN-I had good face validity, as well as convergent and divergent validities as indicated by moderate positive correlations with score on the PSCC (all ps < 0.0001) and nonsignificant correlations with primary language, marital status, and scores on the REALM-LF (all ps > 0.05).

Conclusion: The PSN-I is a nine-item scale that shows high internal consistency and construct validity for patient assessment of the interpersonal relationship with their navigator during cancer-related care.

Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):A23.
Abstract A26: Caseload for patient navigation: What is keeping navigators busy?
Authors: Howard Mary Beth , Freund Karen , Battaglia Tracy
Published: December 2010

Patient navigation is an innovative type of care management designed to reduce cancer disparities. As many sites adopt this model of care, a frequent query is how to assess appropriate caseload for these new positions. While data on the effectiveness of patient navigation interventions appears promising, there is a lack of methods to assess appropriate caseload for optimal effect of navigator intervention. Boston University and its affiliated Community Health Centers (CHCs) is one of nine sites participating in the NCI CRCHD National Cancer Institute Patient Navigation Research Program (PNRP), which aims to evaluate whether navigation improves cancer outcomes.

The purpose of this study is to develop and describe the caseload across six CHCs participating in the Boston PNRP. Navigators target female patients with abnormal breast or cervical cancer screening. Review of the literature identified several concepts to consider in assessing caseload. We examined the following four factors at each navigation site: (1) absolute number of cases navigated, (2) total patient days in navigation, (3) total time spent navigating, and (4) total documented patient-navigator encounters.

Eligible participants were women over 18 with an abnormal mammogram or Pap test at the participating CHCs from 7/1/2007 through 6/31/2008. Patients were navigated until their screening abnormality was resolved with a definitive diagnosis (cancer or noncancer) or until the end of cancer treatment.

Across the six CHCs, the median number of patients navigated was 145 (range: 19-216). The median number of encounters per patient at each of the CHCs was 5 (range: 3-11). The median time spent navigating per patient was 135 minutes (range: 77-240). The median number of days in navigation per patient was 56 (range: 73-142). The number of active patients a navigator was tracking, on average, ranged from 7 to 53 patients per day (median: 38).

We conclude that measuring caseload is more complex than counting heads. The four descriptions of caseload provide different representations of navigator workload that vary among the six CHCs. Patient characteristics (age, race/ethnicity, language, insurance) were not associated with these measures of caseload. Due to the different constructs assessed in each measure, a single caseload score may not adequately reflect navigator workload. Next research steps will involve assessing the predictive ability of these constructs on outcomes to help determine an appropriate navigator caseload.

Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):A26.
Abstract A3: Design and model for breast cancer literacy outcomes among medically underserved females in Michigan
Authors: Todem David , Williams Karen Patricia
Published: December 2010

Statistical theory requires that analysis of study outcomes be conducted conditional on the design process. Ignoring this process may result in severely biased estimates, leading to false inferences, especially when the outcome variable is associated with design variables. We propose in this paper a class of hierarchical models to investigate the dependence between the design process and the study outcomes of primary interest. We discuss a fully parametric and a semiparametric formulation of the hypothesized model and propose the EM algorithm to obtain maximum likelihood estimates. Our numerical results show that the semiparametric approach outperforms the fully parametric model with respect to some key features of the model. The methodology is used to gain insight into the mechanism that generates breast cancer literacy outcomes in a study conducted among medically underserved females in Michigan.

Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):A3.