bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of esophageal acid exposure on the cortical swallowing network in healthy human subjects
Authors: Kern Mark , Chai Krisna , Lawal Adeyemi , Shaker Reza
Published: May 2009

Recent studies have demonstrated common cortical activity regions associated with esophageal acidification and swallowing. The effect of sensory signals imparted on these regions by esophageal acidification on swallow-related brain activity has physiological and clinical ramifications. Our aim in this study was to determine the effect of prior, unperceived esophageal acid exposure on cortical activity associated with swallowing. Functional magnetic resonance imaging (fMRI) techniques monitored brain activity associated with volitional swallowing before and after subliminal esophageal acid stimulation. Studies were carried out in two phases. In phase I (15 healthy, right-handed subjects, age 21–49 yr, 7 female) using whole brain imaging, we documented the potentiating effects of esophageal acidification alone on swallow-related cortical activity. In phase II (10 healthy, right-handed subjects, age 20–54 yr, 5 female) using high-resolution fMRI, we measured swallow-induced regional brain activity within the cortical swallowing network before and after esophageal acidification. Unlike the phase I studies, we also tested the effect of saline perfusion alone on the cortical swallowing network in the phase II studies. Because of constraints imposed by high-resolution MRI for region-of-interest (ROI) analysis, we studied only the left hemisphere in this phase. None of the subjects developed heartburn during acid perfusion. In phase I, the number of swallow-induced activated voxels increased by 43% following esophageal acid stimulation (preacid, 44 ± 3 voxels; postacid, 63 ± 6 voxels; means ± SE, P < 0.05) In phase II, contrary to saline perfusion, ROI analysis showed significantly increased regional swallow-related fMRI activity volumes as well as percent maximum signal change after esophageal acid perfusion in cingulate, prefrontal, insula, and sensory/motor regions ( P < 0.05). The precuneus showed no significant change. We concluded that subliminal esophageal acid stimulation has a potentiating effect on the cortical swallowing network in healthy individuals.
Electrical stimulation of the mucosa evokes slow EPSPs mediated by NK1 tachykinin receptors and by P2Y1purinoceptors in different myenteric neurons
Authors: Gwynne Rachel M. , Bornstein Joel C.
Published: May 2009

Slow excitatory postsynaptic potentials (EPSPs) in enteric neurons arise from diverse sources, but which neurotransmitters mediate specific types of slow EPSPs is unclear. We investigated transmitters and receptors mediating slow EPSPs in myenteric neurons evoked by electrical stimulation of the mucosa in guinea pig small intestine. Segments of ileum or jejunum were dissected to allow access to the myenteric plexus adjacent to intact mucosa, in vitro. AH and S neurons were impaled with conventional intracellular electrodes. Trains of stimuli delivered to the mucosa evoked slow EPSPs in AH neurons that were blocked or depressed by the neurokinin-1 (NK1) tachykinin antagonist SR140333 (100 nM) in 10 of 11 neurons; the NK3 tachykinin receptor antagonist SR142801 (100 nM) had no effect on slow EPSPs in seven of nine AH neurons. Single pulses to the mucosa evoked fast EPSPs and slow depolarizations in S neurons. The depolarizations were divided into intermediate (durations 300–900 ms) or slow (durations 1.3–9 s) EPSPs. The slow EPSPs were blocked by pyridoxal phosphate-6-axophenyl-2–4-disulfonic acid (30 μM, N = 3) or the specific P2Y1antagonist MRS 2179 (10 μM, N = 6) and were predominantly in anally projecting S neurons that were immunoreactive for nitric oxide synthase (NOS). In contrast, intermediate EPSPs were predominantly evoked in NOS-negative neurons; these were abolished by MRS 2179 ( N = 8). Thus activation of pathways running from the mucosa excites three different types of slow EPSP in myenteric neurons, which are mediated by either a tachykinin (NK1, AH neurons) or a purine nucleotide (P2Y1, S neurons).
Heart failure therapy mediated by the trophic activities of bone marrow mesenchymal stem cells: a noninvasive therapeutic regimen
Authors: Shabbir Arsalan , Zisa David , Suzuki Gen , Lee Techung
Published: April 2009

Heart failure carries a poor prognosis with few treatment options. While myocardial stem cell therapeutic trials have traditionally relied on intracoronary infusion or intramyocardial injection routes, these cell delivery methods are invasive and can introduce harmful scar tissue, arrhythmia, calcification, or microinfarction in the heart. Given that patients with heart failure are at an increased surgical risk, the development of a noninvasive stem cell therapeutic approach is logistically appealing. Taking advantage of the trophic effects of bone marrow mesenchymal stem cells (MSCs) and using a hamster heart failure model, the present study demonstrates a novel noninvasive therapeutic regimen via the direct delivery of MSCs into the skeletal muscle bed. Intramuscularly injected MSCs and MSC-conditioned medium each significantly improved ventricular function 1 mo after MSC administration. MSCs at 4 million cells/animal increased fractional shortening by ∼40%, enhanced capillary and myocyte nuclear density by ∼30% and ∼80%, attenuated apoptosis by ∼60%, and reduced fibrosis by ∼50%. Myocyte regeneration was evidenced by an approximately twofold increase in the expression of cell cycle markers (Ki67 and phosphohistone H3) and an ∼13% reduction in mean myocyte diameter. Increased circulating levels of hepatocyte growth factor (HGF), leukemia inhibitory factor, and macrophage colony-stimulating factor were associated with the mobilization of c-Kit-positive, CD31-positive, and CD133-positive progenitor cells and a subsequent increase in myocardial c-Kit-positive cells. Trophic effects of MSCs further activated the expression of HGF, IGF-II, and VEGF in the myocardium. The work highlights a cardiac repair mechanism mediated by trophic cross-talks among the injected MSCs, bone marrow, and heart that can be explored for noninvasive stem cell therapy.
ERM protein moesin is phosphorylated by advanced glycation end products and modulates endothelial permeability
Authors: Guo Xiaohua , Wang Lingjun , Chen Bo , Li Qiang , Wang Jiping , Zhao Ming , Wu Wei , Zhu Ping , Huang Xuliang , Huang Qiaobing
Published: April 2009

Advanced glycation end products (AGEs) accumulated in different pathological conditions have the potent capacity to alter cellular properties that include endothelial structural and functional regulations. The disruption of endothelial barrier integrity may contribute to AGE-induced microangiopathy and macrovasculopathy. Previous studies have shown that AGEs induced the rearrangement of actin and subsequent hyperpermeability in endothelial cells (ECs). However, the mechanisms involved in this AGE-evoked EC malfunction are not well understood. This study directly evaluated the involvement of moesin phosphorylation in AGE-induced alterations and the effects of the RhoA and p38 MAPK pathways on this process. Using immortalized human dermal microvascular ECs (HMVECs), we first confirmed that the ezrin/radixin/moesin (ERM) protein moesin is required in AGE-induced F-actin rearrangement and hyperpermeability responses in ECs by knockdown of moesin protein expression with small interfering RNA. We then detected AGE-induced moesin phosphorylation by Western blot analysis. The mechanisms involved in moesin phosphorylation were analyzed by blocking AGE receptor binding and inhibiting Rho and MAPK pathways. AGE-treated HMVECs exhibited time- and dose-dependent increases in the Thr558phosphorylation of moesin. The increased moesin phosphorylation was attenuated by preadministrations of AGE receptor antibody, Rho kinase (ROCK), or p38 inhibitor. Suppression of p38 activation via the expression of dominant negative mutants with Ad.MKK6b or Ad.p38α also decreased moesin phosphorylation. The activation of the p38 pathway by transfection of HMVECs with an adenoviral construct of dominant active MKK6b resulted in moesin phosphorylation. These results suggest a critical role of moesin phosphorylation in AGE-induced EC functional and morphological regulations. Activation of the ROCK and p38 pathways is required in moesin phosphorylation.
Role of oxidative stress and AT1 receptors in cerebral vascular dysfunction with aging
Authors: Modrick Mary L. , Didion Sean P. , Sigmund Curt D. , Faraci Frank M.
Published: April 2009

Vascular dysfunction occurs with aging. We hypothesized that oxidative stress and ANG II [acting via ANG II type 1 (AT1) receptors] promotes cerebral vascular dysfunction with aging. We studied young (5–6 mo), old (17–19 mo), and very old (23 ± 1 mo) mice. In basilar arteries in vitro, acetylcholine (an endothelium-dependent agonist) produced dilation in young wild-type mice that was reduced by ∼60 and 90% ( P < 0.05) in old and very old mice, respectively. Similar effects were seen using A23187, a second endothelium-dependent agonist. The vascular response to acetylcholine in very old mice was almost completely restored with tempol (a scavenger of superoxide) and partly restored by PJ34, an inhibitor of poly(ADP-ribose) polymerase (PARP). We used mice deficient in Mn-SOD (Mn-SOD+/−) to test whether this form of SOD protected during aging but found that age-induced endothelial dysfunction was not altered by Mn-SOD deficiency. Cerebral vascular responses were similar in young mice lacking AT1 receptors (AT1−/−) and wild-type mice. Vascular responses to acetylcholine and A23187 were reduced by ∼50% in old wild-type mice ( P < 0.05) but were normal in old AT1-deficient mice. Thus, aging produces marked endothelial dysfunction in the cerebral artery that is mediated by ROS, may involve the activation of PARP, but was not enhanced by Mn-SOD deficiency. Our findings suggest a novel and fundamental role for ANG II and AT1 receptors in age-induced vascular dysfunction.
Genetic influence on electrocardiogram time intervals and heart rate in aging mice
Authors: Xing Shuqin , Tsaih Shirng-Wreng , Yuan Rong , Svenson Karen L. , Jorgenson Linda M. , So Milly , Paigen Beverly J. , Korstanje Ron
Published: April 2009

Understanding the genetic influence on ECG time intervals and heart rate (HR) is important for identifying the genes underlying susceptibility to cardiac arrhythmias. The objective of this study was to determine the genetic influence on ECG parameters and their age-related changes in mice. ECGs were recorded in lead I on 8 males and 8 females from each of 28 inbred strains at the ages of 6, 12, and 18 mo. Significant interstrain differences in the P-R interval, QRS complex duration, and HR were found. Age-related changes in the P-R interval, QRS complex duration, and HR differed among strains. The P-R interval increased with age in 129S1/SvlmJ females. The QRS complex duration decreased with age in C57BR/J males and DBA2/J females but increased in NON/ShiLtJ females. HR decreased in C57L/J females and SM/J and P/J males but increased in BALB/cByJ males. Differences between males and females were found for HR in SJL/J mice and in the P-R interval in 129S1/SvlmJ mice. Broad-sense heritability estimates of ECG time intervals and HR ranged from 0.31 for the QRS complex duration to 0.52 for the P-R interval. Heritability estimates decreased with age for the P-R interval. Our study revealed that genetic factors play a significant role on cardiac conduction activity and age-related changes in ECG time intervals and HR.
Reductions in mitochondrial O2consumption and preservation of high-energy phosphate levels after simulated ischemia in chronic hibernating myocardium
Authors: Hu Qingsong , Suzuki Gen , Young Rebeccah F. , Page Brian J. , Fallavollita James A. , Canty John M.
Published: April 2009

We performed the present study to determine whether hibernating myocardium is chronically protected from ischemia. Myocardial tissue was rapidly excised from hibernating left anterior descending coronary regions (systolic wall thickening = 2.8 ± 0.2 vs. 5.4 ± 0.3 mm in remote myocardium), and high-energy phosphates were quantified by HPLC during simulated ischemia in vitro (37°C). At baseline, ATP (20.1 ± 1.0 vs. 26.7 ± 2.1 μmol/g dry wt, P < 0.05), ADP (8.1 ± 0.4 vs. 10.3 ± 0.8 μmol/g, P < 0.05), and total adenine nucleotides (31.2 ± 1.3 vs. 40.1 ± 2.9 μmol/g, P < 0.05) were depressed compared with normal myocardium, whereas total creatine, creatine phosphate, and ATP-to-ADP ratios were unchanged. During simulated ischemia, there was a marked attenuation of ATP depletion (5.6 ± 0.9 vs. 13.7 ± 1.7 μmol/g at 20 min in control, P < 0.05) and mitochondrial respiration [145 ± 13 vs. 187 ± 11 ng atoms O2·mg protein−1·min−1in control (state 3), P < 0.05], whereas lactate accumulation was unaffected. These in vitro changes were accompanied by protection of the hibernating heart from acute stunning during demand-induced ischemia. Thus, despite contractile dysfunction at rest, hibernating myocardium is ischemia tolerant, with reduced mitochondrial respiration and slowing of ATP depletion during simulated ischemia, which may maintain myocyte viability.
Recombinant human activated protein C improves endotoxemia-induced endothelial dysfunction: a blood-free model in isolated mouse arteries
Authors: Sennoun Nacira , Baron-Menguy Celine , Burban Mélanie , Lecompte Thomas , Andriantsitohaina Ramaroson , Henrion Daniel , Mercat Alain , Asfar Pierre , Levy Bruno , Meziani Ferhat
Published: April 2009

Recombinant human activated protein C (rhAPC) is one of the treatment panels for improving vascular dysfunction in septic patients. In a previous study, we reported that rhAPC treatment in rat endotoxemia improved vascular reactivity, although the mechanisms involved are still under debate. In the present study, we hypothesized that rhAPC may improve arterial dysfunction through its nonanticoagulant properties. Ten hours after injection of LPS in mice (50 mg/kg ip), aortic rings and mesenteric arteries were isolated and incubated with or without rhAPC for 12 h. Aortic rings were mounted in a myograph, after which arterial contractility and endothelium-dependent relaxation were measured in the presence or absence of nitric oxide synthase or cyclooxygenase inhibitors. Flow (shear stress)-mediated dilation with or without the above inhibitors was also measured in mesenteric resistance arteries. Protein expression was assessed by Western blotting. Lipopolysaccharide (LPS) reduced aortic contractility to KCl and phenylephrine as well as dilation to acetylcholine. LPS also reduced flow-mediated dilation in mesenteric arteries. In rhAPC-treated aorta and mesenteric arteries, contractility and endothelial responsiveness to vasodilator drug and shear stress were improved. rhAPC treatment also improved LPS-induced endothelial dysfunction; this effect was associated with an increase in the phosphorylated form of endothelial nitric oxide synthase and protein kinase B as well as cyclooxygenase vasodilatory pathways, thus suggesting that these pathways, together with the decrease in nuclear factor-κB activation and inducible nitric oxide synthase expression in the vascular wall, are implicated in the endothelial effect of rhAPC. In conclusion, ex vivo application of rhAPC improves arterial contractility and endothelial dysfunction resulting from endotoxemia in mice. This finding provides important insights into the mechanism underlying rhAPC-induced improvements on arterial dysfunction during septic shock.
Effect of proinflammatory cytokines on regulation of sarcoplasmic reticulum Ca2+reuptake in human airway smooth muscle
Authors: Sathish Venkatachalem , Thompson Michael A. , Bailey Jeffrey P. , Pabelick Christina M. , Prakash Y. S. , Sieck Gary C.
Published: April 2009

Airway inflammation leads to increased intracellular Ca2+([Ca2+]i) levels in airway smooth muscle (ASM) cells. Sarcoplasmic reticulum Ca2+release and reuptake are key components of ASM [Ca2+]iregulation. Ca2+reuptake occurs via sarcoendoplasmic reticulum Ca2+ATPase (SERCA) and is regulated by the inhibitory protein phospholamban (PLB) in many cell types. In human ASM, we tested the hypothesis that inflammation increases PLB, thus inhibiting SERCA function, and leading to maintained [Ca2+]ilevels. Surprisingly, we found that human ASM does not express PLB protein (although mRNA is detectable). Overnight exposure to the proinflammatory cytokines TNFα and IL-13 did not induce PLB expression, raising the issue of how SERCA is regulated. We then found that direct SERCA phosphorylation (via CaMKII) occurs in human ASM. In fura-2-loaded human ASM cells, we found that the CaMKII antagonist KN-93 significantly slowed the rate of fall of [Ca2+]itransients induced by ACh or bradykinin (in zero extracellular Ca2+), suggesting a role for CaMKII-mediated SERCA regulation. SERCA expression was decreased by cytokine exposure, and the rate of fall of [Ca2+]itransients was slowed in cells exposed to TNFα and IL-13. Cytokine effects on Ca2+reuptake were unaffected by additional exposure to KN-93. These data indicate that in human ASM, SERCA is regulated by mechanisms such as CaMKII and that airway inflammation maintains [Ca2+]ilevels by decreasing SERCA expression and slowing Ca2+reuptake.
Neutral sphingomyelinase 2 is activated by cigarette smoke to augment ceramide-induced apoptosis in lung cell death
Authors: Levy Michal , Khan Elaine , Careaga Milo , Goldkorn Tzipora
Published: April 2009

Cigarette smoke (CS) induces a rapid, sustained upregulation of ceramide production in human bronchial epithelial cells, leading to increased apoptosis. Using loss-of-function and overexpression analyses, we show that neutral sphingomyelinase 2 (nSMase2) is required for CS-mediated ceramide generation and apoptosis. Glutathione (GSH), a crucial antioxidant in lung defense, blocks nSMase2 activity and thus inhibits apoptosis triggered by CS. We found that the exposure to CS, as with exposure to H2O2, results in increased nSMase2 activation leading to ceramide generation and therefore increased apoptosis. Interestingly, exposure of cells to GSH abolishes nSMase2 activation caused by CS and leads to a decrease in CS-induced apoptosis. This suggests that the effects of CS oxidants on nSMase2 are counteracted by GSH. Our data support a model where CS induces nSMase2 activation thereby increasing membrane-sphingomyelin hydrolysis to ceramide. In turn, elevated ceramide enhances airway epithelial cell death, which causes bronchial and alveolar destruction and lung injury in pulmonary diseases.
Knockdown of stromal interaction molecule 1 attenuates store-operated Ca2+ entry and Ca2+ responses to acute hypoxia in pulmonary arterial smooth muscle
Authors: Lu Wenju , Wang Jian , Peng Gongyong , Shimoda Larissa A. , Sylvester J. T.
Published: April 2009

Stromal interaction molecule 1 (STIM1) is a recently discovered membrane-spanning protein thought to sense lumenal Ca2+ in sarco(endo)plasmic reticulum (SR/ER) and transduce activation of Ca2+-permeable store-operated channels (SOC) in plasmalemma in response to SR/ER Ca2+ depletion. To evaluate the role of STIM1 and a closely related protein, STIM2, in Ca2+ signaling of rat distal pulmonary arterial smooth muscle cells (PASMC) during hypoxia, we used fluorescent microscopy and the Ca2+-sensitive dye, fura 2, to measure basal intracellular Ca2+ concentration ([Ca2+]i), store-operated Ca2+ entry (SOCE), and increases in [Ca2+]i caused by acute hypoxia (4% O2) or depolarization (60 mmol/l KCl) in cells treated with small interfering RNA targeted to STIM1 (siSTIM1) or STIM2 (siSTIM2). As determined by real-time quantitative PCR analysis (qPCR), STIM1 mRNA was 200-fold more abundant than STIM2 in untreated control PASMC. siSTIM1 and siSTIM2 caused specific and significant knockdown of both mRNA measured by qPCR and protein measured by Western blotting. siSTIM1 markedly inhibited SOCE and abolished the sustained [Ca2+]i response to hypoxia but did not alter the initial transient [Ca2+]i response to hypoxia, the [Ca2+]i response to depolarization, or basal [Ca2+]i. The only effect of siSTIM2 was a smaller inhibition of SOCE. We conclude that STIM1 was quantitatively more important than STIM2 in activation of SOC in rat distal PASMC and that the increase in [Ca2+]i induced by acute hypoxia in these cells required SR Ca2+ release and STIM1-dependent activation of SOC.
Pulmonary ozone exposure induces vascular dysfunction, mitochondrial damage, and atherogenesis
Authors: Chuang Gin C. , Yang Zhen , Westbrook David G. , Pompilius Melissa , Ballinger Carol A. , White C. Roger , Krzywanski David M. , Postlethwait Edward M. , Ballinger Scott W.
Published: April 2009

More than 100 million people in the United States live in areas that exceed current ozone air quality standards. In addition to its known pulmonary effects, environmental ozone exposures have been associated with increased hospital admissions related to cardiovascular events, but to date, no studies have elucidated the potential molecular mechanisms that may account for exposure-related vascular impacts. Because of the known pulmonary redox and immune biology stemming from ozone exposure, we hypothesized that ozone inhalation would initiate oxidant stress, mitochondrial damage, and dysfunction within the vasculature. Accordingly, these factors were quantified in mice consequent to a cyclic, intermittent pattern of ozone or filtered air control exposure. Ozone significantly modulated vascular tone regulation and increased oxidant stress and mitochondrial DNA damage (mtDNA), which was accompanied by significantly decreased vascular endothelial nitric oxide synthase protein and indices of nitric oxide production. To examine influences on atherosclerotic lesion formation, apoE−/− mice were exposed as above, and aortic plaques were quantified. Exposure resulted in significantly increased atherogenesis compared with filtered air controls. Vascular mitochondrial damage was additionally quantified in ozone- and filtered air-exposed infant macaque monkeys. These studies revealed that ozone increased vascular mtDNA damage in nonhuman primates in a fashion consistent with known atherosclerotic lesion susceptibility in humans. Consequently, inhaled ozone, in the absence of other environmental toxicants, promotes increased vascular dysfunction, oxidative stress, mitochondrial damage, and atherogenesis.
l-2-Oxothiazolidine-4-carboxylate reverses glutathione oxidation and delays fatigue of skeletal muscle in vitro
Authors: Ferreira Leonardo F. , Gilliam Laura A. A. , Reid Michael B.
Published: May 2009

Fatiguing exercise promotes oxidation of intracellular thiols, notably glutathione. Interventions that oppose or reverse thiol oxidation can inhibit fatigue. The reduced cysteine donor l-2-oxothiazolidine-4-carboxylate (OTC) supports glutathione synthesis and is approved for use in humans but has not been evaluated for effects on skeletal muscle. We tested the hypotheses that OTC would 1) increase reduced glutathione (GSH) levels and decrease oxidized glutathione, and 2) inhibit functional indexes of fatigue. Diaphragm fiber bundles from adult male ICR mice were incubated for 1 or 2 h at 37°C with buffer (control, C) or OTC (10 mM). N-acetylcysteine (NAC; 10 mM) was used as a positive control. We measured GSH metabolites and fatigue characteristics. We found that muscle GSH content was increased after 1-h incubation with OTC or NAC but was not altered after 2-h incubation. One-hour treatment with OTC or NAC slowed the decline in force with repetitive stimulation [mean (SD) fatigue index at 300 s: OTC = 34 ± 6% vs. C = 50 ± 8%, P < 0.05; NAC = 55 ± 4% vs. C = 65 ± 8%, P < 0.05] as did the 2-h OTC treatment (OTC = 38 ± 9% vs. C = 51 ± 9%, P < 0.05). These results demonstrate that OTC modulates the muscle GSH pool and opposes fatigue under the current experimental conditions.
Fibronectin Is an Important Regulator of Flow-Induced Vascular Remodeling
Authors: Chiang Hou-Yu , Korshunov Vyacheslav A. , Serour Andrew , Shi Feng , Sottile Jane
Published: May 2009

Objective—

Fibronectin is an important regulator of cell migration, differentiation, growth, and survival. Our data show that fibronectin also plays an important role in regulating extracellular matrix (ECM) remodeling. Fibronectin circulates in the plasma and is also deposited into the ECM by a cell dependent process. To determine whether fibronectin affects vascular remodeling in vivo, we asked whether the fibronectin polymerization inhibitor, pUR4, inhibits intima-media thickening, and prevents excess ECM deposition in arteries using a mouse model of vascular remodeling.

Methods and Results—

To induce vascular remodeling, partial ligation of the left external and internal carotid arteries was performed in mice. pUR4 and the control peptide were applied periadventitially in pluronic gel immediately after surgery. Animals were euthanized 7 or 14 days after surgery. Morphometric analysis demonstrated that the pUR4 fibronectin inhibitor reduced carotid intima (63%), media (27%), and adventitial thickening (40%) compared to the control peptide (III-11C). Treatment with pUR4 also resulted in a dramatic decrease in leukocyte infiltration into the vessel wall (80%), decreased ICAM-1 and VCAM-1 levels, inhibited cell proliferation (60% to 70%), and reduced fibronectin and collagen I accumulation in the vessel wall. In addition, the fibronectin inhibitor prevented SMC phenotypic modulation, as evidenced by the maintenance of smooth muscle (SM) α-actin and SM myosin heavy chain levels in medial cells.

Conclusions—

These data are the first to demonstrate that fibronectin plays an important role in regulating the vascular remodeling response. Collectively, these data suggest a therapeutic benefit of periadventitial pUR4 in reducing pathological vascular remodeling.
An Acute Experimental Model Demonstrating 2 Different Forms of Sustained Atrial Tachyarrhythmias
Authors: Niu Guodong , Scherlag Benjamin J. , Lu Zhibing , Ghias Muhammad , Zhang Yuan , Patterson Eugene , Dasari Tarun W. , Zacharias Soni , Lazzara Ralph , Jackman Warren M. , Po Sunny S.
Published: April 2009

Background—

The objective of this study was to develop an acute experimental model showing both focal and macroreentrant sustained atrial fibrillation (AF).

Methods and Results—

In 31 anesthetized dogs, bilateral thoracotomies allowed the attachment of electrode catheters at the right and left superior pulmonary veins, atrial free walls, and atrial appendages. Acetylcholine, 100 mmol/L, was applied topically to either appendage. Sequential radiofrequency ablation was achieved for the ganglionated plexi (GP), found adjacent to the 4 pulmonary veins. In 12 separate studies, a propafenone bolus, 2 mg/kg, was given before and after GP ablations at the start of acetylcholine-induced AF.

Acetylcholine caused abrupt onset of AF (n=22) or induced AF by burst pacing (n=9) that lasted ≥10 minutes. Rapid, regular, or fractionated atrial electrograms were consistently seen (average cycle length, 37�7 ms) at the appendages versus cycle lengths of 114�23 ms at other atrial sites. After ablations of GP, AF abruptly terminated (n=25). In 6 dogs, sustained atrial tachyarrhythmias continued. Pacing at specific atrial sites organized electrograms of one atrium or also captured the other atrium. The latter resulted in termination when pacing was stopped in 4 of these 6 experiments. Propafenone did not change the duration of focal AF before GP ablation (17�9 versus 14�8 minutes; control,
P
=0.6) but terminated reentrant atrial tachyarrhythmias (12�3 versus 2�1 minutes,
P
=0.0009).

Conclusions—

Before GP ablation, acetylcholine (100 mmol/L) induced sustained AF characterized by rapid, focal firing. GP ablations were associated with loss of focal firing and regularization of electrograms in both atria before termination. Propafenone failed to terminate focal AF but rapidly terminated entrainable macroreentrant atrial tachyarrhythmias.
New-Onset Postoperative Atrial Fibrillation After Isolated Coronary Artery Bypass Graft Surgery and Long-Term Survival
Authors: Filardo Giovanni , Hamilton Cody , Hebeler Robert F. , Hamman Baron , Grayburn Paul
Published: April 2009

Background—

The advancing age and generally increasing risk profile of patients receiving isolated coronary artery bypass graft (CABG) surgery is expected to raise incidence of new-onset postoperative atrial fibrillation (AFIB) resulting in potentially higher risk of adverse outcomes. In the early postoperative course, new-onset post-CABG AFIB is considered relatively easy to treat and is believed to have little impact on patients’ long-term outcome. However, little has been done to determine the effect of new-onset post-CABG AFIB on long-term survival, and this relationship is unclear.

Methods and Results—

Survival was assessed in a cohort of 6899 consecutive patients without preoperative AFIB who underwent isolated CABG at Baylor University Medical Center, Dallas, Tex, between January 1, 1997 and December 31, 2006; patients who died during CABG were excluded. Ten-year unadjusted survival was 52.3% (48.4%, 56.0%) for patients with new-onset postoperative AFIB and 69.4% (67.3%, 71.4%) for patients without it. A propensity-adjusted model controlling for risk factors identified by the Society of Thoracic Surgeons and other clinical/nonclinical details was used to investigate the association between new-onset AFIB post-CABG and long-term survival. After adjustment, new-onset AFIB post-CABG was significantly associated (hazard ratio, 1.29; 95% CI, 1.16, 1.45) with increased risk of death.

Conclusions—

This study provides evidence that new-onset post-CABG AFIB is significantly associated with increased long-term risk of mortality independent of patient preoperative severity. After controlling for a comprehensive array of risk factors associated with post-CABG adverse outcomes, risk of long-term mortality in patients that developed new-onset post-CABG AFIB was 29% higher than in patients without it.
Medication Underuse During Long-Term Follow-Up in Patients With Peripheral Arterial Disease
Authors: Hoeks Sanne E. , Scholte op Reimer Wilma J.M. , van Gestel Yvette R.B.M. , Schouten Olaf , Lenzen Mattie J. , Flu Willem-Jan , van Kuijk Jan-Peter , Latour Corine , Bax Jeroen J. , van Urk Hero , Poldermans Don
Published: April 2009

Background—

Patients with peripheral arterial disease constitute a high-risk population. Guideline-recommended medical therapy use is therefore of utmost importance. The aims of our study were to establish the patterns of guideline-recommended medication use in patients with PAD at the time of vascular surgery and after 3 years of follow up, and to evaluate the effect of these therapies on long-term mortality in this patient group.

Methods and Results—

Data on 711 consecutive patients with peripheral arterial disease undergoing vascular surgery were collected from 11 hospitals in the Netherlands (enrollment between May and December 2004). After 3.1±0.1 years of follow-up, information on medication use was obtained by a questionnaire (n=465; 84% response rate among survivors). Guideline-recommended medical therapy use for the combination of aspirin and statins in all patients and β-blockers in patients with ischemic heart disease was 41% in the perioperative period. The use of perioperative evidence-based medication was associated with a reduction of 3-year mortality after adjustment for clinical characteristics (hazard ratio, 0.65; 95% CI, 0.45 to 0.94). After 3 years of follow-up, aspirin was used in 74%, statins in 69%, and β-blockers in 54% of the patients respectively. Guideline-recommended medical therapy use for the combination of aspirin, statins, and β-blockers was 50%.

Conclusions—

The use of guideline recommended therapies in the perioperative period was associated with reduction in long-term mortality in patients with peripheral arterial disease. However, the proportion of patients receiving these evidence-based treatments—both at baseline and 3 years after vascular surgery—was lower than expected based on the current guidelines. These data highlight a clear opportunity to improve the quality of care in this high-risk group of patients.
Acute Blood Pressure Levels and Neurological Deterioration in Different Subtypes of Ischemic Stroke
Authors: Toyoda Kazunori , Fujimoto Shigeru , Kamouchi Masahiro , Iida Mitsuo , Okada Yasushi
Published: May 2009

Background and Purpose—

The purpose of this study was to determine at which time points acute blood pressure (BP) was associated with neurological deterioration at 3 weeks in patients with ischemic stroke as a whole and in patients with different subtypes.

Methods—

BP was measured every 6 hours for the first 36 hours of emergent hospitalization in 565 consecutive patients (347 men, 70±11 years in age) presenting within 24 hours of an acute ischemic stroke. Neurological deterioration was defined as a ≥2-point increase in the National Institutes of Health stroke scale (NIHSS) score at 3 weeks compared to the admission score.

Results—

At 3 weeks, 64 patients (11.3%) had deteriorated neurologically. For the group as a whole, high systolic BP (SBP) values measured at 12, 18, 24, and 36 hours postadmission were independently related to neurological deterioration after adjustment for age, sex, and known predictors, including admission NIHSS score, admission blood glucose level, and large infarct size. At 24 hours, the odds of neurological deterioration increased by 20% per 10-mm Hg increase in SBP. For cardioembolic stroke patients, high SBP values measured at 12 through 36 hours were independently related to neurological deterioration after multivariate adjustment. For patients having stroke other than cardioembolism, no SBP values at any time point were related to neurological deterioration.

Conclusions—

Acute SBP values between 12 and 36 hours postadmission, but not those on admission or at 6 hours, were predictive of neurological deterioration within the initial 3 weeks of ischemic stroke, particularly for cardioembolic stroke patients.
Problems and Benefits Reported by Stroke Family Caregivers
Authors: Haley William E. , Allen Jessica Y. , Grant Joan S. , Clay Olivio J. , Perkins Martinique , Roth David L.
Published: May 2009

Background and Purpose—

Stroke symptoms can be very stressful for family caregivers, but most knowledge about the prevalence and stressfulness of stroke-related patient problems is derived from convenience samples. In addition, little is known about perceived benefits of the stroke caregiving experience. The purpose of this study was to determine the prevalence and stressfulness of stroke-related problems, and perceived benefits of caregiving, as reported by an epidemiologically derived sample of caregivers of stroke survivors.

Methods—

Stroke survivors (N=75) from a prospective epidemiological study of stroke, the REasons for Geographic and Racial Differences in Stroke (REGARDS) study, and their family caregivers were followed. Caregivers were given a comprehensive telephone interview 8 to 12 months after the stroke, using measures of stroke patient problems, caregiver appraisals of the stressfulness of these problems, and perceived benefits of caregiving.

Results—

Caregivers rated patient problems with mood (depression, loneliness and anxiety), memory, and physical care (bowel control), as the most stressful, but reported prevalence of these problems was lower than those reported previously in studies using clinical samples. Caregivers also reported many benefits from caregiving, with over 90% reporting that caregiving enabled them to appreciate life more.

Conclusions—

Epidemiologically based studies of stroke caregiving provide a unique picture of caregiver strains and benefits compared with clinical studies, which tend to over-represent more impaired patients. Support for caregivers should include interventions to aid their coping with highly stressful mood, physical care, and cognitive problems of stroke patients, but should also attend to perceived benefits of caregiving.
Rapid Diagnosis of Sepsis and Bacterial Meningitis in Children with Real-Time Fluorescent Quantitative Polymerase Chain Reaction Amplification in the Bacterial 16S rRNA Gene
Authors: Chen Li-Hua , Duan Qun-Jun , Cai Mei-Ting , Wu Yi-Dong , Shang Shi-Qiang
Published: May 2009

A method for the detection of bacterial pathogens in sepsis and bacterial meningitis with 16S rRNA gene— based real-time fluorescent quantitative polymerase chain reaction (FQ-PCR) is developed. A total of 190 blood specimens and 5 cerebrospinal fluid specimens from neonates with suspected sepsis or bacterial meningitis were evaluated with 16S rRNA gene—based real-time FQ-PCR assay. The positive rate of the real-time FQ-PCR assay was significantly higher (25/195, 12.82%) than that of bacterial culture (15/195, 7.69%; P = .002). When bacterial culture was used as a control, the sensitivity of the real-time FQ-PCR was 100%, the specificity was 94.4%, and Youden's index was 0.944. This study suggests that 16S rRNA gene—based real-time FQ-PCR assay is an important and accurate method in the detection of bacterial pathogens of sepsis and bacterial meningitis and should have a promising usage in the diagnosis of sepsis and bacterial meningitis.
Among Prelates and Primates
Authors: Thomas Paul
Published: April 2009

Darwin's understanding of evolution as involving his original concept of natural selection involves discussions of development, progress, human pride, the construct o `primitivism,' and slavery. These discussions have to a remarkable extent been ignored by political theorists. This omission is all the more surprising in that these same discussions also call to mind Rousseau's often misunderstood concept of perfectibility.
Population Pharmacokinetics of Telbivudine and Determination of Dose Adjustment for Patients With Renal Impairment
Authors: Zhou Xiao‐Jian , Ke June , Sallas William M. , Farrell Colm , Mayers Douglas L. , Pentikis Helen S.
Published: April 2009

Telbivudine is a new nucleoside analog indicated for the treatment of chronic hepatitis B infection. A population pharmacokinetic model was developed based on data pooled from 16 early phase studies in 363 healthy participants and patients. Telbivudine was administered as single and/or multiple doses of 25 to 1800 mg daily for up to 28 days. A 2‐compartment model with first‐order input and lag time provided the best fit to the data. A final model was built with identified covariates, including creatinine clearance on plasma clearance, dose and race on bioavailability fraction, and body weight on central volume of distribution. The final model was applied to simulate steady‐state exposure for patients with impaired renal function for various dosing regimens. Results from these simulation analyses support that in patients with moderate to severe renal impairment or end‐stage renal disease, reduced daily doses of telbivudine could be an alternative to interval adjustment to achieve exposure comparable to patients with normal renal function or mild renal impairment treated with the full clinical dose.
Stressful Experiences, Coping Strategies, and Predictors of Health-related Outcomes among Wives of Deployed Military Servicemen
Authors: Dimiceli Erin E. , Steinhardt Mary A. , Smith Shanna E.
Published: May 2009

A survey of military wives ( N = 77) identifies their most stressful experiences, self-appraised control over these stressors, and coping strategies used. The authors examine two competing hypotheses: the goodness-of-fit hypothesis that the effects of problem-focused coping (PFC) and emotion-focused coping (EFC) strategies on distress are moderated by the appraised controllability of the stressor, and the main-effects hypothesis that PFC strategies are more effective than EFC strategies in reducing distress regardless of appraisal of controllability. Wives identified deployment of soldiers as their most stressful experience, and reported using PFC strategies more frequently than EFC strategies. EFC strategies were predictive of greater physical symptoms of illness, while PFC strategies were related to reduced physical symptoms of illness only when military wives’ perceived control of the situation was low. PFC strategies and controllability were significantly related to decreased depressive symptoms; EFC was marginally related to increased depressive symptoms, lending greater support to the main-effects hypothesis.
Community-Based Peer-Led Diabetes Self-management
Authors: Lorig Kate , Ritter Philip L. , Villa Frank J. , Armas Jean
Published: May 2009

Purpose

The purpose of this study is to determine the effectiveness of a community-based diabetes self-management program comparing treatment participants to a randomized usual-care control group at 6 months.

Methods

A total of 345 adults with type 2 diabetes but no criteria for high A1C were randomized to a usual-care control group or 6-week community-based, peer-led diabetes self-management program (DSMP). Randomized participants were compared at 6 months. The DSMP intervention participants were followed for an additional 6 months (12 months total). A1C and body mass index were measured at baseline, 6 months, and 12 months. All other data were collected by self-administered questionnaires.

Results

At 6 months, DSMP participants did not demonstrate improvements in A1C as compared with controls. Baseline A1C was much lower than in similar trials. Participants did have significant improvements in depression, symptoms of hypoglycemia, communication with physicians, healthy eating, and reading food labels (P < .01). They also had significant improvements in patient activation and self-efficacy. At 12 months, DSMP intervention participants continued to demonstrate improvements in depression, communication with physicians, healthy eating, patient activation, and self-efficacy (P < .01). There were no significant changes in utilization measures.

Conclusions

These findings suggest that people with diabetes without elevated A1C can benefit from a community-based, peer-led diabetes program. Given the large number of people with diabetes and lack of low-cost diabetes education, the DSMP deserves consideration for implementation.
Model Selection Indices for Polytomous Items
Authors: Kang Taehoon , Cohen Allan S. , Sung Hyun-Jung
Published: April 2009

This study examines the utility of four indices for use in model selection with nested and nonnested polytomous item response theory (IRT) models: a cross-validation index and three information-based indices. Four commonly used polytomous IRT models are considered: the graded response model, the generalized partial credit model, the partial credit model, and the rating scale model. In a simulation study, comparisons among the four indices suggest that model selection is dependent to some extent on the particular conditions simulated. Overall, the Bayesian information criterion index appears to be most accurate in selecting the correct polytomous IRT model. Results are presented from analysis of a real data set to illustrate the use of the four indices for selecting an appropriate model.
Gene Expression Studies Reveal That DNA Damage, Vascular Perturbation, and Inflammation Contribute to the Pathogenesis of Carbonyl Sulfide Neurotoxicity
Authors: Morrison James P. , Ton Thai-Vu , Collins Jennifer B. , Switzer Robert C. , Little Peter B. , Morgan Daniel L. , Sills Robert C.
Published: April 2009

Carbonyl sulfide (COS) is an odorless gas that produces highly reproducible lesions in the central nervous system. In the present study, the time course for the development of the neurotoxicological lesions was defined and the gene expression changes occurring in the posterior colliculus upon exposure to COS were characterized. Fischer 344 rats were exposed to 0 or 500 ppm COS for one, two, three, four, five, eight, or ten days, six hours per day. On days 1 and 2, no morphological changes were detected; on day 3, 10/10 (100%) rats had necrosis in the posterior colliculi; and on day 4 and later, necrosis was observed in numerous areas of the brain. Important gene expression changes occurring in the posterior colliculi after one or two days of COS exposure that were predictive of the subsequent morphological findings included up-regulation of genes associated with DNA damage and G1/S checkpoint regulation (KLF4, BTG2, GADD45g), apoptosis (TGM2, GADD45g, RIPK3), and vascular mediators (ADAMTS, CTGF, CYR61, VEGFC). Proinflammatory mediators (CCL2, CEBPD) were up-regulated prior to increases in expression of the astrocytic marker GFAP and macrophage marker CSF2rb1. These gene expression findings were predictive of later CNS lesions caused by COS exposure and serve as a model for future investigations into the mechanisms of disease in the central nervous system.
Neutralization of IL-10 Exacerbates Cycloheximide-Induced Hepatocellular Apoptosis and Necrosis
Authors: Kumagai Kazuyoshi , Ito Kazumi , Ando Yosuke , Hakamata Shinobu , Teranishi Munehiro , Nakayama Hiroyuki , Manabe Sunao
Published: April 2009

Cycloheximide (CHX)-induced liver injury in rats has been characterized by hepatocellular apoptosis and necrosis. We previously reported that Kupffer cell inactivation causes a reduction of IL-10 production, resulting in the exacerbation of CHX-induced liver injury. In this study, we directly evaluate the role of IL-10 in liver injury by a pretreatment with anti-IL-10 neutralizing antibody (IL-10Ab). Rats were given goat IgG or IL-10Ab before being treated with CHX (CHX group or IL-10Ab/CHX group). In the CHX group, the CHX treatment markedly induced hepatic mRNA and serum protein levels of IL-10. The up-regulation of IL-10 was significantly suppressed in the IL-10Ab/CHX group. Blocking IL-10 in the IL-10Ab/ CHX group led to greater increases in hepatic mRNA and serum levels of proinflammatory cytokines, such as TNF-α and IL-6. The IL-10Ab/CHX group developed more severe hepatocellular apoptosis, neutrophil transmigration, and necrotic change of hepatocytes compared with the CHX group. The caspase activities and mRNA levels of Cc120, LOX-1, and E-selectin in the livers were significantly higher in the IL-10Ab/CHX group than the CHX group. These results demonstrate that IL-10 plays an important role in counteracting the effect of proinflammatory cytokines, such as a TNF signaling cascade, and in attenuating the CHX-induced liver injury.
Dissection of placebo analgesia in mice: the conditions for activation of opioid and non-opioid systems
Authors: Guo J-Y. , Wang J-Y. , Luo F.
Published: April 2009

Amanzio and Benedetti (J Neurosci 1999; 19: 484—494) first addressed the conditions necessary for the activation of opioid and non-opioid placebo responses in human. Here, we investigated whether placebo analgesia is subdivided into opioid and non-opioid components in mice by using the model of hot-plate test. Drug conditioning was performed by the combination of the conditioned cue stimulus with the unconditioned drug stimulus, either opioid agonist morphine hydrochloride or non-opioid aspirin. Placebo analgesic responses were evoked by an exposure to a conditioned cue previously paired with drug conditioning. Morphine conditioning produced placebo responses that were completely antagonised by naloxone. By contrast, the conditioned cue after aspirin conditioning elicited a placebo effect that was not blocked by naloxone. Therefore, we first evoked opioid and non-opioid placebo responses in mice that were either naloxone-reversible or naloxone-insensitive, depending on the drug used in conditioning procedure. These findings support that the mechanisms underlying placebo analgesia may depend on the drug conditioning that was originally performed. The present procedure of mice may serve as a model for further understanding of the opioid and non-opioid mechanisms underlying placebo responses.