bluuebunny/crossref_metadata_2025 huggingface dataset:
Absolute Bioavailability of
cis
-Mirincamycin and
trans
-Mirincamycin in Healthy Rhesus Monkeys and
Ex Vivo
Antimalarial Activity against Plasmodium falciparum
Authors: Khemawoot Phisit , Saunders David , Rasameesoraj Maneerat , Melendez Victor , Imerbsin Rawiwan , Ohrt Colin , Fracisco Susan , Teja-isavadharm Paktiya
Published: September 2011

The pharmacokinetics, oral bioavailability, and
ex vivo
antimalarial activity of mirincamycin isomers in a healthy rhesus monkey model were assessed to support lead optimization of novel nonhemolytic drugs for radical cure and causal prophylaxis of malaria. Fourteen male rhesus monkeys were randomized to four groups, which included
cis
and
trans
isomers by the oral and intravenous routes, with vehicle-only controls for each dosing route. Concentration-time data were collected for 7 days and were analyzed by noncompartmental analysis.
cis
-Mirincamycin had an absolute oral bioavailability of 13.6%, which was slightly higher than that of
trans
-mirincamycin (11.7%), but this difference was not statistically significant. There was a statistically significant difference between the area under the concentration-time curve from zero to 48 h (AUC
0–48
) of
cis
-mirincamycin and that of
trans
-mirincamycin after oral dosing. When cultured
in vitro
with the W2 clone of
Plasmodium falciparum
, the 50% inhibitory concentrations for
cis
-mirincamycin,
trans
-mirincamycin, and dihydroartemisinin were 11,300, 12,300, and 2.30 nM, respectively. However, when dosed primate plasma was cultured
ex vivo
against the W2 clone, both isomers had much greater relative potencies than their
in vitro
activities relative to results for dihydroartemisinin, an increase of approximately 100-fold for the
cis
isomer and 150-fold for the
trans
isomer. Further, oral
ex vivo
activity was significantly higher than intravenous activity for both isomers, particularly during the first 90 min following dosing, suggesting the first-pass formation of one or more metabolites with blood-stage antimalarial activity. Identification of the metabolic pathways and metabolites may help to further delineate the properties of this class of drugs with previously demonstrated liver-stage antimalarial activity.
An Escherichia coli O157-Specific Engineered Pyocin Prevents and Ameliorates Infection by E. coli O157:H7 in an Animal Model of Diarrheal Disease
Authors: Ritchie Jennifer M. , Greenwich Jennifer L. , Davis Brigid M. , Bronson Roderick T. , Gebhart Dana , Williams Steven R. , Martin David , Scholl Dean , Waldor Matthew K.
Published: September 2011

AvR2-V10.3 is an engineered R-type pyocin that specifically kills
Escherichia coli
O157, an enteric pathogen that is a major cause of food-borne diarrheal disease. New therapeutics to counteract
E. coli
O157 are needed, as currently available antibiotics can exacerbate the consequences of infection. We show here that orogastric administration of AvR2-V10.3 can prevent or ameliorate
E. coli
O157:H7-induced diarrhea and intestinal inflammation in an infant rabbit model of infection when the compound is administered either in a postexposure prophylactic regimen or after the onset of symptoms. Notably, administration of AvR2-V10.3 also reduces bacterial carriage and fecal shedding of this pathogen. Our findings support the further development of pathogen-specific R-type pyocins as a way to treat enteric infections.
Digallate Dimers of (−)-Epigallocatechin Gallate Inactivate Herpes Simplex Virus
Authors: Isaacs Charles E. , Xu Weimin , Merz George , Hillier Sharon , Rohan Lisa , Wen Guang Y.
Published: September 2011

Topical microbicides are potentially an alternative method to vaccines for reducing the spread of herpes simplex virus (HSV). We have previously shown (S. Liu et al., Biochim. Biophys. Acta 1723:270–281, 2005) that the catechin (−)-epigallocatechin gallate (EGCG) inactivates HSV at neutral pH; however, to function in the female genital tract EGCG must also be effective at acidic pH. EGCG inactivated HSV-1 and HSV-2 at pH 8.0 by 3 log
10
to 4 log
10
but was ineffective at pH 5.7. The EGCG digallate dimers theasinensin A, P2, and theaflavin-3,3′-digallate (TF-3) inactivated both viruses by 3 log
10
to 4 log
10
at pH 5.7 and as much as 5 log
10
at pH 8.0. TF-3 inactivated HSV-1 and HSV-2 by 4 to 5 log
10
in the pH range of 4.0 to 5.7. Dimers with one gallate moiety had antiviral activity intermediate between the activities of EGCG and digallate dimers. Confocal and electron microscopy showed that theasinensin A did not damage Vero cells. All EGCG dimers inactivated enveloped viruses with class I, class II, and class III (HSV-1, HSV-2) fusion proteins more effectively than did monomeric EGCG. EGCG had no activity against the nonenveloped viruses tested, but TF-3 reduced the titer of 4 of 5 nonenveloped viruses by ≅2 to 3.5 log
10
. Results also showed that HSV-1 glycoprotein B (gB) was aggregated more rapidly by theasinensin A than EGCG, which, when taken together with the nonenveloped virus data, suggests that dimers may inhibit the function of viral proteins required for infectivity. Digallate dimers of EGCG appear to have excellent potential as microbicidal agents against HSV at acidic and neutral pHs.
The Type III System-Secreted Effector EspZ Localizes to Host Mitochondria and Interacts with the Translocase of Inner Mitochondrial Membrane 17b
Authors: Shames Stephanie R. , Croxen Matthew A. , Deng Wanyin , Finlay B. Brett
Published: September 2011

Enteropathogenic and enterohemorrhagic
Escherichia coli
(EPEC and EHEC, respectively) are attaching and effacing (A/E) bacterial pathogens that cause severe diarrheal disease worldwide. To cause disease, A/E pathogens require a type III secretion system, which facilitates transport of bacterial effector proteins directly into infected host cells. One of these effector proteins translocated by the type III secretion system, EspZ, is essential for A/E pathogen infection and functions to prevent rapid death of EPEC-infected cells. We further investigated the mechanism of EspZ-mediated protection of infected host cells and found that a severe decrease in host mitochondrial membrane potential (Δψ
m
) occurs concurrently with host cell lysis during infection with EPEC lacking EspZ (Δ
espZ
). It was also demonstrated that EspZ localizes to host cell mitochondria and interacts with the translocase of inner mitochondrial membrane 17b (TIM17b). In addition, host cell cytotoxicity was exacerbated in the absence of TIM17b during wild-type (WT) EPEC infection. The findings of this study together provide the first evidence that EspZ localizes to host mitochondria and that TIM17b contributes to protection against rapid cell death during EPEC infection.
The Iron-Repressed, AraC-Like Regulator MpeR Activates Expression of
fetA
in Neisseria gonorrhoeae
Authors: Hollander Aimee , Mercante Alexandra Dubon , Shafer William M. , Cornelissen Cynthia Nau
Published: September 2011

Neisseria gonorrhoeae
is an obligate human pathogen that causes the common sexually transmitted infection gonorrhea. Gonococcal infections cause significant morbidity, particularly among women, as the organism ascends to the upper reproductive tract, resulting in pelvic inflammatory disease, ectopic pregnancy, and infertility. In the last few years, antibiotic resistance rates have risen dramatically, leading to severe restriction of treatment options for gonococcal disease. Gonococcal infections do not elicit protective immunity, nor is there an effective vaccine to prevent the disease. Thus, further understanding of the expression, function, and regulation of surface antigens could lead to better treatment and prevention modalities in the future. In the current study, we determined that an iron-repressed regulator, MpeR, interacted specifically with the DNA sequence upstream of
fetA
and activated FetA expression. Interestingly, MpeR was previously shown to regulate the expression of gonococcal antimicrobial efflux systems. We confirmed that the outer membrane transporter FetA allows gonococcal strain FA1090 to utilize the xenosiderophore ferric enterobactin as an iron source. However, we further demonstrated that FetA has an extended range of substrates that encompasses other catecholate xenosiderophores, including ferric salmochelin and the dimers and trimers of dihydroxybenzoylserine. We demonstrated that
fetA
is part of an iron-repressed, MpeR-activated operon which putatively encodes other iron transport proteins. This is the first study to describe a regulatory linkage between antimicrobial efflux and iron transport in
N. gonorrhoeae
. The regulatory nidus that links these systems, MpeR, is expressed exclusively by pathogenic neisseriae and is therefore expected to be an important virulence factor.
Perceived barriers and facilitators to physical activity for children with disability: a systematic review
Authors: Shields Nora , Synnot Anneliese Jane , Barr Megan
Published: September 2011

Aim

The aim of this systematic review was to investigate the perceived barriers and facilitators to physical activity among children with disability.

Methods

10 electronic databases were searched from the earliest time available to September 2010 to identify relevant articles. Articles were included if they examined the barriers or facilitators to physical activity for children with disability and were written in English. Articles were excluded if they included children with an acute, transient or chronic medical condition, examined sedentary leisure activities, or societal participation in general. Two reviewers independently assessed the search yields, extracted the data and assessed trial quality. Data were analysed descriptively.

Results

14 articles met the inclusion criteria. Barriers included lack of knowledge and skills, the child's preferences, fear, parental behaviour, negative attitudes to disability, inadequate facilities, lack of transport, programmes and staff capacity, and cost. Facilitators included the child's desire to be active, practising skills, involvement of peers, family support, accessible facilities, proximity of location, better opportunities, skilled staff and information.

Conclusion

Personal, social, environmental, and policy and programme-related barriers and facilitators influence the amount of activity children with disability undertake. The barriers to physical activity have been studied more comprehensively than the facilitators.
Measurements and Consistent Families of Quantum Channels
Authors: Le Jan Yves , Rebolledo Rolando
Published: September 2011

This article introduces the notion of consistent families (Λ(n))n≥1of quantum channels. These families correspond to simultaneous observation of different copies of a given quantum system. Here, we are primarily interested in the analysis of measurements connected with them. As usual, the measurement of a quantum system requires the construction of a classical dilation of the corresponding quantum channel. In our case, the quantum systems represented by (Λ(n))n≥1are supposed to interact through the measurement instrument only. That is, we construct a classical probability space which allows to have a common dilation for all the Λ(n)' s . Doing this, we introduce and solve a quantum version of the moment problem.
Complex Time Evolution of Open Quantum Systems
Authors: Gagatsos C. N. , Karanikas A. I. , Kordas G. I.
Published: September 2011

We combine, in a single set-up, complex time parametrization in path integration, and closed time formalism of non-equilibrium field theories to produce a compact representation of time evolution of the reduced density matrix. In this framework we introduce a cluster-type expansion that facilitates perturbative and non-petrurbative calculations in the realm of open quantum systems. The technical details of some very simple examples are discussed.
Operational and Harmonic-Analytic Aspects of Quasi-Probability Distributions
Authors: Harada Ryo
Published: September 2011

Husimi distributions [11] and Wigner distributions [20] are well-known quasi-probability distributions which appear in several contexts. In this paper, we show some remarkable aspects of these distribution functions related to geometric structures of generalized coherent state systems [15,16] and operational quantum physics [7], and a scheme of formulating generalized version of quasi-probability distributions. Our scheme gives concrete formulae of quasi-probability distributions in more direct way from the theory of coherent state systems and clarify their operational meanings, especially of Husimi distributions and mutual relation between Husimi distributions and other classes of quasi-probability distributions.
Runtime Verification for LTL and TLTL
Authors: Bauer Andreas , Leucker Martin , Schallhart Christian
Published: September 2011

This article studies runtime verification of properties expressed either in lineartime temporal logic (LTL) or timed lineartime temporal logic (TLTL). It classifies runtime verification in identifying its distinguishing features to model checking and testing, respectively. It introduces a three-valued semantics (with truth values
true, false, inconclusive
) as an adequate interpretation as to whether a partial observation of a running system meets an LTL or TLTL property.

For LTL, a conceptually simple monitor generation procedure is given, which is
optimal
in two respects: First, the size of the generated deterministic monitor is
minimal
, and, second, the monitor identifies a continuously monitored trace as either satisfying or falsifying a property
as early as possible
. The feasibility of the developed methodology is demontrated using a collection of real-world temporal logic specifications. Moreover, the presented approach is related to the properties monitorable in general and is compared to existing concepts in the literature. It is shown that the set of
monitorable properties
does not only encompass the
safety
and
cosafety
properties but is strictly larger.

For TLTL, the same road map is followed by first defining a three-valued semantics. The corresponding construction of a timed monitor is more involved, yet, as shown, possible.
Gaia-PL
Authors: Dehlinger Josh , Lutz Robyn R.
Published: September 2011

Agent-oriented software engineering (AOSE) has provided powerful and natural, high-level abstractions in which software developers can understand, model and develop complex, distributed systems. Yet, the realization of AOSE partially depends on whether agent-based software systems can achieve reductions in development time and cost similar to other reuse-conscious development methods. Specifically, AOSE does not adequately address requirements specifications as reusable assets. Software product line engineering is a reuse technology that supports the systematic development of a set of similar software systems through understanding, controlling, and managing their common, core characteristics and their differing variation points. In this article, we present an extension to the Gaia AOSE methodology, named Gaia-PL (Gaia-Product Line), for agent-based distributed software systems that enables requirements specifications to be easily reused. We show how our methodology uses a product line perspective to promote reuse in agent-based software systems early in the development life cycle so that software assets can be reused throughout system development and evolution. We also present results from an application to show how Gaia-PL provided reuse that reduced the design and development effort for a large, multiagent system.
Depression among Asian Americans: Review and Recommendations
Authors: Kalibatseva Zornitsa , Leong Frederick T. L.
Published: September 2011

This article presents a review of the prevalence and manifestation of depression among Asian Americans and discusses some of the existing issues in the assessment and diagnosis of depression among Asian Americans. The authors point out the diversity and increasing numbers of Asian Americans and the need to provide better mental health services for this population. While the prevalence of depression among Asian Americans is lower than that among other ethnic/racial groups, Asian Americans receive treatment for depression less often and its quality is less adequate. In addition, the previous belief that Asians somatize depression may become obsolete as more evidence appears to support that Westerners may “psychologize” depression. The cultural validity of the current DSM-IV conceptualization of depression is questioned. In the course of the review, the theme of complexity emerges: the heterogeneity of ethnic Asian American groups, the multidimensionality of depression, and the intersectionality of multiple factors among depressed Asian Americans.
Propensity Score-Matched Analysis of Open Surgical and Endovascular Repair for Type B Aortic Dissection
Authors: Brunt Michael E. , Egorova Natalia N. , Moskowitz Alan J.
Published: September 2011

Objective. To identify national outcomes of thoracic endovascular aortic repair (TEVAR) for type B aortic dissections (TBADs).Methods. The Nationwide Inpatient Sample database was examined from 2005 to 2008 using ICD-9 codes to identify patients with TBAD who underwent TEVAR or open surgical repair. We constructed separate propensity models for emergently and electively admitted patients and calculated mortality and complication rates for propensity score-matched cohorts of TEVAR and open repair patients.Results. In-hospital mortality was significantly higher following open repair than TEVAR (17.5% versus 10.8%,P= .045) in emergently admitted TBAD. There was no in-hospital mortality difference between open repair and TEVAR (5.6% versus 3.3%,P= .464) for elective admissions. Hospitals performing thirty or more TEVAR procedures annually had lower mortality for emergent TBAD than hospitals with fewer than thirty procedures.Conclusions. TEVAR produces better in-hospital outcomes in emergent TBAD than open repair, but further longitudinal analysis is required.
Spontaneous Ag-Nanoparticle Growth at Single-Walled Carbon Nanotube Defect Sites: A Tool forIn SituGeneration of SERS Substrate
Authors: Maley Jason , Schatte Gabriele , Yang Jian , Sammynaiken R.
Published: September 2011

Silver nanoparticles were spontaneously formed on pristine and oxidized single-wall nanotubes. Nanoparticles were observed on carbon nanotubes with AFM, and the presence of Ag nanoparticles were confirmed by ESR experiments. Raman spectroscopy of the Ag-treated carbon nanotubes had a 4–10X enhancement of intensity compared to untreated carbon nanotubes. Ag nanoparticles formed at defect sites on the CNT surface, where free electrons located at the defect sites reduced Ag+to Ag. A mechanism for the propagation of the nanoparticles is through a continual negative charge generation on the nanoparticle by electron transfer from doublet oxygen (O2−).
The Oxidative State of Chylomicron Remnants Influences Their Modulation of Human Monocyte Activation
Authors: Armengol Lopez Sandra , Botham Kathleen M. , Lawson Charlotte
Published: September 2011

Chylomicron remnants (CMRs) contribute directly to human monocyte activationin vitro, by increasing reactive oxygen species (ROS) production and cell migration. In this study, the effects of the oxidative state of CMR on the degree of monocyte activation was investigated. CMR-like particles (CRLPs) were prepared in three different oxidative states, normal (CRLPs), protected from oxidation by incorporation of the antioxidant, probucol (pCRLPs), or oxidised with CuSO4(oxCRLPs). Lipid accumulation and ROS production were significantly increased in primary human monocytes incubated with CRLPs, whilst secretion on monocyte chemoattractant protein-1 was reduced, but oxCRLPs had no additional effect. In contrast, pCRLPs were taken up by monocytes to a lesser extent and had no significant effect on ROS or MCP-1 secretion. These studies suggest that the oxidative state of CMRs modulates their stimulation of the activation of peripheral blood human monocytes and that dietary antioxidants may provide some protection against these atherogenic effects.
Is It Downhill from Here? Eliminating Leukemic Stem Cells and Curing Chronic Myeloid Leukemia
Authors: Smith Catherine C. , Shah Neil P.
Published: September 2011

Patients with chronic phase chronic myeloid leukemia who respond to imatinib have a rapid initial decrease in BCR-ABL transcript levels (α), followed by a slow decline (β). The rate of β decrease is consistent with declining leukemic stem cells and may predict which patients may safely discontinue therapy. Clin Cancer Res; 17(21); 6605–7. ©2011 AACR.
What Does Built-In Software of Home Ventilators Tell Us? An Observational Study of 150 Patients on Home Ventilation
Authors: Pasquina Patrick , Adler Dan , Farr Pamela , Bourqui Pascale , Bridevaux Pierre Olivier , Janssens Jean-Paul
Published: September 2011

Background: Recent home ventilators are equipped with built-in software which provides data such as compliance, estimations of leaks, tidal volume, minute ventilation, respiratory rate, apnea and apnea-hypopnea indexes, and percentage of inspirations triggered by the patient (or ventilator). However, for many of these variables, there is neither consensus nor documentation as to what is to be expected in a population of stable patients under noninvasive ventilation (NIV). Objectives: To document the values and distribution of specific items downloaded from ventilator monitoring software, by diagnostic category. Methods: Analysis of data downloaded from home ventilators in clinically stable patients under long-term NIV, during elective home visits by specialized nurses. Results: Data were collected from home ventilators of 150 patients with chronic obstructive pulmonary disease (n = 32), overlap syndrome (n = 29), obesity-hypoventilation (n = 38), neuromuscular disorders (n = 19), restrictive disorders (n = 21), and central sleep apnea syndrome (n = 11). On average, leaks were low, being lowest in patients with facial masks (vs. nasal masks), and increased with older age. Compliance was excellent in all groups. Patients with neuromuscular diseases triggered their ventilators less and tended to be ‘captured’, while other groups triggered at least half of inspiratory cycles. Most patients had a respiratory rate just slightly above the back-up rate. Residual apneas and hypopneas were highest in patients with central apneas. Conclusions: Built-in software of home ventilators provides the clinician with new parameters, some of which are a useful adjunct to recommended tools for monitoring NIV and may contribute to a better understanding of residual hypoventilation and/or desaturations. However, an independent validation of the accuracy of this information is mandatory.
Effects of a Small Acute Subdural Hematoma following Traumatic Brain Injury on Neuromonitoring, Brain Swelling and Histology in Pigs
Authors: Meissner A. , Timaru-Kast R. , Heimann A. , Hoelper B. , Kempski O. , Alessandri B.
Published: September 2011

An acute subdural hematoma (ASDH) induces pathomechanisms which worsen outcome after traumatic brain injury, even after a small hemorrhage. Synergistic effects of a small ASDH on brain damage are poorly understood, and were studied here using neuromonitoring for 10 h in an injury model of controlled cortical impact (CCI) and ASDH. Pigs (n = 32) were assigned to 4 groups: sham, CCI (2.5 m/s), ASDH (2 ml) and CCI + ASDH. Intracranial pressure was significantly increased above sham levels by all injuries with no difference between groups. CCI and ASDH reduced ptiO2 by a maximum of 36 ± 9 and 26 ± 11%, respectively. The combination caused a 31 ± 11% drop. ASDH alone and in combination with CCI caused a significant elevation in extracellular glutamate, which remained increased longer for CCI + ASDH. The same two groups had significantly higher peak lactate levels compared to sham. Somatosensory evoked potential (SSEP) amplitude was persistently reduced by combined injury. These effects translated into significantly elevated brain water content and histological damage in all injury groups. Thus, combined injury had stronger effects on glutamate and SSEP when compared to CCI and ASDH, but no clear-cut synergistic effects of 2 ml ASDH on trauma were observed. We speculate that this was partially due to the CCI injury severity.
Association of HLA Alleles with Autoimmune Thyroid Disease in Korean Children
Authors: Cho Won Kyoung , Jung Min Ho , Choi Eun-Jeong , Choi Hee-Baeg , Kim Tai-Gyu , Suh Byung-Kyu
Published: September 2011

Backgrounds: Data regarding genetics of Hashimoto’s disease (HD) and Graves’ disease (GD) in Korean children are lacking. Methods: 73 patients with autoimmune thyroid disease (AITD; HD 32, GD 41) were recruited. We analyzed human leukocyte antigen (HLA) class I and HLA-DRB1 by PCR-SSP, and compared them with those of 159 controls. Results: In AITD, the allele frequencies of HLA-A*02, -B*46, -Cw*01 and -DRB1*08 were higher and those of HLA-A*30, -B*07, -Cw*07 and -DRB1*01 were lower than in controls. In HD, those of HLA-B*46 and -Cw*01 were higher and those of HLA-DRB1*01 and -Cw*07 were lower than in controls. In GD, those of HLA-A*02, -B*46, -Cw*01 and -DRB1*08 were higher and those of HLA-DRB1*07 and -Cw*07 were lower than in controls. Between HD and GD, there were no significant differences in allele frequencies. The risk of AITD in the presence of both HLA-B*46 and -Cw*01 is higher than in the presence of either allele alone. Conclusion: The susceptible and protectable alleles in HD are similar to those in GD. Coexistence of HLA-B*46 and -Cw*01 may be a genetic gene marker for early-onset AITD in Koreans.
Remote Ischemic Postconditioning: Does It Protect against Ischemic Damage in Percutaneous Coronary Revascularization? Justification and Design of a Randomized Placebo-Controlled Clinical Trial
Authors: Jiménez-Navarro M.F. , Carrasco-Chinchilla F. , Muñoz-García A.J. , Domínguez-Franco A. , Caballero-Borrego J. , Alonso-Briales J.H. , Hernández-García J.M. , de Teresa-Galván E.
Published: September 2011

Objective: Myocardial damage that is associated with percutaneous coronary intervention (PCI) partially affects the results of the procedure, and is related to medium-term cardiovascular death. Remote postischemic conditioning might reduce the myocardial lesions that are associated with PCI, but perhaps less so in diabetics. The aim of this study was to evaluate the protective effect of remote postischemic conditioning in patients undergoing elective PCI for stable angina or non-ST elevation acute coronary syndrome with troponin <1 ng/ml at the time of randomization. Methods: This randomized single-blinded single-center clinical trial involved 320 patients undergoing elective PCI who were randomized to either receive three 5-min cycles of ischemia by inflation of a cuff on the non-dominant arm to 200 mm Hg (remote postischemic conditioning) or to placebo (uninflated cuff). The primary outcome variable was the maximum increase in troponin in the first 24 h. The secondary outcome variable was readmission due to heart failure or cardiovascular mortality after 1 year of follow-up. In addition, a diabetic population was studied. Conclusions: This clinical trial evaluated the possible reduction in intervention-related myocardial damage that was attributable to remote postischemic conditioning.
Effect of Hypoxia-Inducible Factor-1α Gene Therapy on Walking Performance in Patients With Intermittent Claudication
Authors: Creager Mark A. , Olin Jeffrey W. , Belch Jill J.F. , Moneta Gregory L. , Henry Timothy D. , Rajagopalan Sanjay , Annex Brian H. , Hiatt William R.
Published: September 2011

Background—

Hypoxia-inducible factor-1α (HIF-1α) is a transcriptional regulatory factor that orchestrates cellular responses to hypoxia. It increases collateral vessel growth and blood flow in models of hind-limb ischemia. This study tested whether intramuscular administration of Ad2/HIF-1α/VP16, an engineered recombinant type 2 adenovirus vector encoding constitutively active HIF-1α, improves walking time in patients with peripheral artery disease and intermittent claudication.

Methods and Results—

Two hundred eighty-nine patients with claudication were randomized in a double-blind manner to 1 of 3 doses of Ad2/HIF-1α/VP16 (2×10
9
, 2×10
10
, or 2×10
11
viral particles) or placebo, administered by 20 intramuscular injections to each leg. Graded treadmill tests were performed at baseline and then 3, 6, and 12 months after treatment. The primary end point was the change in peak walking time from baseline to 6 months. The secondary end point was change in claudication onset time, and tertiary end points included changes in ankle-brachial index and quality-of-life assessments. Median peak walking time increased by 0.82 minutes (interquartile range, −0.05–1.93 minutes) in the placebo group and by 0.82 minutes (interquartile range, −0.07–2.12 minutes), 0.28 minutes (interquartile range, −0.37–1.70 minutes), and 0.78 minutes (interquartile range, −0.02–2.10 minutes) in the HIF-1α 2×10
9
, 2×10
10
, and 2×10
11
viral particle groups, respectively (
P
=NS between placebo and each HIF-1α treatment group). There were no significant differences in claudication onset time, ankle-brachial index, or quality-of-life measurements between the placebo and each HIF-1α group.

Conclusions—

Gene therapy with intramuscular administration of Ad2/HIF-1α/VP16 is not an effective treatment for patients with intermittent claudication.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00117650.
Disruption of Na
+
,HCO
3
−
Cotransporter NBCn1 (slc4a7) Inhibits NO-Mediated Vasorelaxation, Smooth Muscle Ca
2+
Sensitivity, and Hypertension Development in Mice
Authors: Boedtkjer Ebbe , Praetorius Jeppe , Matchkov Vladimir V. , Stankevicius Edgaras , Mogensen Susie , Füchtbauer Annette C. , Simonsen Ulf , Füchtbauer Ernst-Martin , Aalkjaer Christian
Published: September 2011

Background—

Disturbances in pH affect artery function, but the mechanistic background remains controversial. We investigated whether Na
+
,HCO
3
−
cotransporter NBCn1, by regulating intracellular pH (pH
i
), influences artery function and blood pressure regulation.

Methods and Results—

Knockout of NBCn1 in mice eliminated Na
+
,HCO
3
−
cotransport and caused a lower steady-state pH
i
in mesenteric artery smooth muscle and endothelial cells in situ evaluated by fluorescence microscopy. Using myography, arteries from NBCn1 knockout mice showed reduced acetylcholine-induced NO-mediated relaxations and lower rho-kinase-dependent norepinephrine-stimulated smooth muscle Ca
2+
sensitivity. Acetylcholine-stimulated NO levels (electrode measurements) and N-nitro-l-arginine methyl ester–sensitive l-arginine conversion (radioisotope measurements) were reduced in arteries from NBCn1 knockout mice, whereas relaxation to NO-donor S-nitroso-N-acetylpenicillamine, acetylcholine-induced endothelial Ca
2+
responses (fluorescence microscopy), and total and Ser-1177 phosphorylated endothelial NO-synthase expression (Western blot analyses) were unaffected. Reduced NO-mediated relaxations in arteries from NBCn1 knockout mice were not rescued by superoxide scavenging. Phosphorylation of myosin phosphatase targeting subunit at Thr-850 was reduced in arteries from NBCn1 knockout mice. Evaluated by an in vitro assay, rho-kinase activity was reduced at low pH. Without CO
2
/HCO
3
−
, no differences in pH
i
, contraction or relaxation were observed between arteries from NBCn1 knockout and wild-type mice. Based on radiotelemetry and tail-cuff measurements, NBCn1 knockout mice were mildly hypertensive at rest, displayed attenuated blood pressure responses to NO-synthase and rho-kinase inhibition and were resistant to developing hypertension during angiotensin-II infusion.

Conclusions—

Intracellular acidification of smooth muscle and endothelial cells after knockout of NBCn1 inhibits NO-mediated and rho-kinase–dependent signaling in isolated arteries and perturbs blood pressure regulation.
Pediatric Pulmonary Hypertension in the Netherlands
Authors: van Loon Rosa Laura E. , Roofthooft Marcus T.R. , Hillege Hans L. , ten Harkel Arend D.J. , van Osch-Gevers Magdalena , Delhaas Tammo , Kapusta Livia , Strengers Jan L.M. , Rammeloo Lukas , Clur Sally-Ann B. , Mulder Barbara J.M. , Berger Rolf M.F.
Published: September 2011

Background—

Incidence and prevalence rates for pediatric pulmonary hypertension (PH) and pulmonary arterial hypertension (PAH) are unknown. This study describes the nationwide epidemiological features of pediatric PH in the Netherlands during a 15-year period and the clinical course of pediatric PAH.

Methods and Results—

Two registries were used to retrospectively identify children (0–17 years) with PH. Overall, 3263 pediatric patients were identified with PH due to left heart disease (n=160; 5%), lung disease/hypoxemia (n=253; 8%), thromboembolic disease (n=5; <1%), and transient (n=2691; 82%) and progressive (n=154; 5%) PAH. Transient PAH included persistent PH of the newborn and children with congenital heart defects (CHD) and systemic-to-pulmonary shunt, in whom PAH resolved after successful shunt correction. Progressive PAH mainly included idiopathic PAH (n=36; iPAH) and PAH associated with CHD (n=111; PAH-CHD). Pulmonary arterial hypertension associated with CHD represented highly heterogeneous subgroups. Syndromes were frequently present, especially in progressive PAH (n=60; 39%). Survival for PAH-CHD varied depending on the subgroups, some showing better and others showing worse survival than for iPAH. Survival of children with Eisenmenger syndrome appeared worse than reported in adults. For iPAH and PAH-CHD, annual incidence and point prevalence averaged, respectively, 0.7 and 4.4 (iPAH) and 2.2 and 15.6 (PAH-CHD) cases per million children. Compared to studies in adults, iPAH occurred less whereas PAH-CHD occurred more frequently.

Conclusions—

Pediatric PH is characterized by various age-specific diagnoses, the majority of which comprise transient forms of PAH. Incidence of pediatric iPAH is lower whereas incidence of pediatric PAH-CHD is higher than reported in adults. Pediatric PAH-CHD represents a heterogeneous group with highly variable clinical courses.
Myocardial Structure, Function, and Scar in Patients With Type 1 Diabetes Mellitus
Authors: Turkbey Evrim B. , Backlund Jye-Yu C. , Genuth Saul , Jain Aditya , Miao Cuilian , Cleary Patricia A. , Lachin John M. , Nathan David M. , van der Geest Rob J. , Soliman Elsayed Z. , Liu Chia-Ying , Lima João A.C. , Bluemke David A. ,   the DCCT/EDIC Research Group
Published: September 2011

Background—

We report relationships between cardiovascular disease risk factors and myocardial structure, function, and scar in patients with type 1 diabetes mellitus in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study.

Methods and Results—

Cardiac magnetic resonance was obtained in 1017 patients with type 1 diabetes mellitus. Gadolinium cardiac magnetic resonance was also obtained in 741 patients. The mean age was 49±7 years; 52% were men; and mean duration of diabetes mellitus was 28±5 years. Associations of cardiovascular disease risk factors with cardiac magnetic resonance parameters were examined with linear and logistic regression models. History of macroalbuminuria was positively associated with left ventricular mass (by 14.8 g), leading to a significantly higher ratio of left ventricular mass to end-diastolic volume (by 8%). Mean hemoglobin A
1c
levels over the preceding 22 years were inversely associated with end-diastolic volume (−3.0 mL per unit mean hemoglobin A
1c
percent) and stroke volume (−2.3 mL per unit mean hemoglobin A
1c
percent) and positively related to the ratio of elevated left ventricular mass to end-diastolic volume (0.02 g/mL per unit). The overall prevalence of myocardial scar was 4.3% by cardiac magnetic resonance and 1.4% by clinical adjudication of myocardial infarction. Both mean hemoglobin A
1c
(odds ratio, 1.5 [95% confidence interval, 1.0–2.2] per unit) and macroalbuminuria (odds ratio, 3.5 [95% confidence interval, 1.2–9.9]) were significantly associated with myocardial scar and traditional cardiovascular disease risk factors.

Conclusions—

In addition to traditional cardiovascular disease risk factors, elevated mean hemoglobin A
1c
and macroalbuminuria were significantly associated with alterations in left ventricular structure and function. The prevalence of myocardial scar was 4.3% in this subcohort of DCCT/EDIC participants with relatively preserved renal function.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifiers: NCT00360893 and NCT00360815.
Endogenous Thrombospondin 1 Protects the Pressure-Overloaded Myocardium by Modulating Fibroblast Phenotype and Matrix Metabolism
Authors: Xia Ying , Dobaczewski Marcin , Gonzalez-Quesada Carlos , Chen Wei , Biernacka Anna , Li Na , Lee Dong-Wook , Frangogiannis Nikolaos G.
Published: September 2011

The matricellular protein thrombospondin (TSP) 1 is induced after tissue injury and may regulate reparative responses by activating transforming growth factor-β, by suppressing angiogenesis and by modulating inflammation and matrix metabolism. We hypothesized that endogenous TSP-1 may be involved in the pathogenesis of cardiac remodeling in the pressure-overloaded heart. Myocardial TSP-1 expression was increased in a mouse model of pressure overload because of transverse aortic constriction. TSP-1
−/−
mice exhibited increased early hypertrophy and enhanced late dilation in response to pressure overload. Pressure-overloaded TSP-1 null mice had intense degenerative cardiomyocyte changes, exhibiting more extensive sarcomeric loss and sarcolemmal disruption when compared with wild-type hearts. Accentuated hypertrophy and cardiomyocyte injury in TSP-1
−/−
hearts was accompanied by increased myofibroblast density. However, despite a 2-fold higher infiltration of the cardiac interstitium with myofibroblasts, pressure-overloaded TSP-1 null hearts did not exhibit significantly increased collagen content when compared with wild-type hearts. The disproportionately low collagen content in TSP-1 null hearts was attributed to infiltration with abundant, but functionally defective, fibroblasts that exhibited impaired myofibroblast differentiation and reduced collagen expression in comparison with wild-type fibroblasts. Impaired myofibroblast activation in TSP-1 null hearts was associated with reduced Smad2 phosphorylation reflecting defective transforming growth factor-β signaling. Moreover, TSP-1 null hearts had increased myocardial matrix metalloproteinase 3 expression and enhanced matrix metalloproteinase 9 activation after pressure overload. TSP-1 upregulation in the pressure-overloaded heart critically regulates fibroblast phenotype and matrix remodeling by activating transforming growth factor-β signaling and by promoting matrix preservation, thus preventing chamber dilation.
Mechanisms of Enhanced Vascular Reactivity in Preeclampsia
Authors: Mishra Nikita , Nugent William H. , Mahavadi Sunila , Walsh Scott W.
Published: September 2011

Preeclamptic women have enhanced blood pressure response to angiotensin II and extensive systemic vascular infiltration of neutrophils. Neutrophils release reactive oxygen species that might activate the RhoA kinase pathway to enhance vascular reactivity. We hypothesized that enhanced vascular reactivity in preeclampsia is attributed to neutrophil-mediated reactive oxygen species activation of the RhoA kinase pathway. Omental arteries were obtained at cesarean section and studied using a myograph system. We found that arteries of preeclamptic women had extensive infiltration of neutrophils and enhanced reactivity to angiotensin II. Treatment of arteries of normal pregnant women with reactive oxygen species or activated neutrophils enhanced vessel reactivity to angiotensin II mimicking preeclamptic vessels. Pretreatment with superoxide dismutase/catalase to quench reactive oxygen species or RhoA kinase inhibitor blocked enhanced responses in preeclamptic and normal vessels. Reactive oxygen species also enhanced vessel reactivity to norepinephrine, which was blocked by RhoA kinase inhibition. Treatment of arteries with reactive oxygen species increased RhoA kinase activity 3-fold, whereas culture of human vascular smooth muscle cells with angiotensin II and activated neutrophils or reactive oxygen species resulted in phosphorylation of key proteins in the RhoA kinase pathway. We conclude that enhanced vascular reactivity of omental arteries in preeclampsia is attributed to reactive oxygen species activation of the RhoA kinase pathway and that enhanced vascular reactivity is likely attributed to the infiltration of neutrophils. We speculate that neutrophil infiltration into systemic vasculature of preeclamptic women is an important mechanism for hypertension.
Isolated Diastolic Hypotension and Incident Heart Failure in Older Adults
Authors: Guichard Jason L. , Desai Ravi V. , Ahmed Mustafa I. , Mujib Marjan , Fonarow Gregg C. , Feller Margaret A. , Ekundayo O. James , Bittner Vera , Aban Inmaculada B. , White Michel , Aronow Wilbert S. , Love Thomas E. , Bakris George L. , Zieman Susan J. , Ahmed Ali
Published: September 2011

Aging is often associated with increased systolic blood pressure and decreased diastolic blood pressure. Isolated systolic hypertension or an elevated systolic blood pressure without an elevated diastolic blood pressure is a known risk factor for incident heart failure in older adults. In the current study, we examined whether isolated diastolic hypotension, defined as a diastolic blood pressure <60 mm Hg and a systolic blood pressure ≥100 mm Hg, is associated with incident heart failure. Of the 5795 Medicare-eligible community-dwelling adults age ≥65 years in the Cardiovascular Health Study, 5521 were free of prevalent heart failure at baseline. After excluding 145 individuals with baseline systolic blood pressure <100 mm Hg, the final sample included 5376 participants, of whom 751 (14%) had isolated diastolic hypotension. Propensity scores for isolated diastolic hypotension were calculated for each of the 5376 participants and used to match 545 and 2348 participants with and without isolated diastolic hypotension, respectively, who were balanced on 58 baseline characteristics. During >12 years of median follow-up, centrally adjudicated incident heart failure developed in 25% and 20% of matched participants with and without isolated diastolic hypotension, respectively (hazard ratio associated with isolated diastolic hypotension: 1.33 [95% CI: 1.10–1.61];
P
=0.004). Among the 5376 prematch individuals, multivariable-adjusted hazard ratio for incident heart failure associated with isolated diastolic hypotension was 1.29 (95% CI: 1.09–1.53;
P
=0.003). As in isolated systolic hypertension, among community-dwelling older adults without prevalent heart failure, isolated diastolic hypotension is also a significant independent risk factor for incident heart failure.
Assimilating Airborne Doppler Radar Observations with an Ensemble Kalman Filter for Convection-Permitting Hurricane Initialization and Prediction: Katrina (2005)
Authors: Weng Yonghui , Zhang Fuqing
Published: September 2011

Through a Weather Research and Forecasting model (WRF)-based ensemble Kalman filter (EnKF) data assimilation system, the impact of assimilating airborne radar observations for the convection-permitting analysis and prediction of Hurricane Katrina (2005) is examined in this study. A forecast initialized from EnKF analyses of airborne radar observations had substantially smaller hurricane track forecast errors than NOAA’s operational forecasts and a control forecast initialized from NCEP analysis data for lead times up to 120 h. Verifications against independent in situ and remotely sensed observations show that EnKF analyses successfully depict the inner-core structure of the hurricane vortex in terms of both dynamic (wind) and thermodynamic (temperature and moisture) fields. In addition to the improved analyses and deterministic forecast, an ensemble of forecasts initiated from the EnKF analyses also provided forecast uncertainty estimates for the hurricane track and intensity.

Also documented here are the details of a series of data thinning and quality control procedures that were developed to generate superobservations from large volumes of airborne radial velocity measurements. These procedures have since been implemented operationally on the NOAA hurricane reconnaissance aircraft that allows for more efficient real-time transmission of airborne radar observations to the ground.
In Situ Observations of Madden–Julian Oscillation Mixed Layer Dynamics in the Indian and Western Pacific Oceans
Authors: Drushka Kyla , Sprintall Janet , Gille Sarah T. , Wijffels Susan
Published: September 2011

The boreal winter response of the ocean mixed layer to the Madden–Julian oscillation (MJO) in the Indo-Pacific region is determined using in situ observations from the Argo profiling float dataset. Composite averages over numerous events reveal that the MJO forces systematic variations in mixed layer depth and temperature throughout the domain. Strong MJO mixed layer depth anomalies (>15 m peak to peak) are observed in the central Indian Ocean and in the far western Pacific Ocean. The strongest mixed layer temperature variations (>0.6°C peak to peak) are found in the central Indian Ocean and in the region between northwest Australia and Java. A heat budget analysis is used to evaluate which processes are responsible for mixed layer temperature variations at MJO time scales. Though uncertainties in the heat budget are on the same order as the temperature trend, the analysis nonetheless demonstrates that mixed layer temperature variations associated with the canonical MJO are driven largely by anomalous net surface heat flux. Net heat flux is dominated by anomalies in shortwave and latent heat fluxes, the relative importance of which varies between active and suppressed MJO conditions. Additionally, rapid deepening of the mixed layer in the central Indian Ocean during the onset of active MJO conditions induces significant basin-wide entrainment cooling. In the central equatorial Indian Ocean, MJO-induced variations in mixed layer depth can modulate net surface heat flux, and therefore mixed layer temperature variations, by up to ~40%. This highlights the importance of correctly representing intraseasonal mixed layer depth variations in climate models in order to accurately simulate mixed layer temperature, and thus air–sea interaction, associated with the MJO.
The Diabatic Pressure Difference: A New Diagnostic for the Analysis of Valley Winds
Authors: Schmidli Juerg
Published: September 2011

The purpose of this article is to introduce a new diagnostic measure of the time-integrated diabatic (thermal) forcing of a valley–plain system. This measure can be used to synchronize the evolution of thermally induced valley winds with respect to their forcing. Differences among numerical models or model configurations originating from diabatic forcing versus those originating from the model dynamics (e.g., turbulence scheme, dynamical core, etc.) can then be distinguished.