bluuebunny/crossref_metadata_2025_split huggingface dataset:
Matrix Metalloproteinase-13 Predominates Over Matrix Metalloproteinase-8 as the Functional Interstitial Collagenase in Mouse Atheromata
Authors: Quillard Thibaut , Araújo Haniel Alves , Franck Gregory , Tesmenitsky Yevgenia , Libby Peter 
Published: April 2014

Objective—
Substantial evidence implicates interstitial collagenases of the matrix metalloproteinase (MMP) family in plaque rupture and fatal thrombosis. Understanding the compensatory mechanisms that may influence the expression of these enzymes and their functions, therefore, has important clinical implications. This study assessed in mice the relative effect of the 2 principal mouse collagenases on collagen content and other plaque characteristics.

Approach and Results—

Apolipoprotein E–deficient (apoE
−/−
) mice, MMP-13
−/−
apoE
−/−
, MMP-8
−/−
apoE
−/−
double knockout mice, and MMP-13
−/−
MMP-8
−/−
apoE
−/−
triple knockout mice consumed a high-cholesterol diet for 10 and 24 weeks. Both double knockout and triple knockout mice showed comparable atherosclerotic lesion formation compared with apoE
−/−
controls. Analysis of aortic root sections indicated that lesions of MMP-8/MMP-13–deficient and MMP-13–deficient mice accumulate more fibrillar collagen than apoE
−/−
controls and MMP-8
−/−
apoE
−/−
double knockout. We further tested the relative effect of MMPs on plaque collagenolysis using in situ zymography. MMP-13 deletion alone abrogated collagenolytic activity in lesions, indicating a predominant role for MMP-13 in this process. MMP-13 and MMP-13/MMP-8 deficiency did not alter macrophage content but associated with reduced accumulation of smooth muscle cells.

Conclusions—
These results show that among MMP interstitial collagenases in mice, MMP-13 prevails over MMP-8 in collagen degradation in atheromata. These findings provide a rationale for the identification and selective targeting a predominant collagenase for modulating key aspects of plaque structure considered critical in clinical complications, although they do not translate directly to human lesions, which also contain MMP-1.
Four-Group Classification of Left Ventricular Hypertrophy Based on Ventricular Concentricity and Dilatation Identifies a Low-Risk Subset of Eccentric Hypertrophy in Hypertensive Patients
Authors: Bang Casper N. , Gerdts Eva , Aurigemma Gerard P. , Boman Kurt , de Simone Giovanni , Dahlöf Björn , Køber Lars , Wachtell Kristian , Devereux Richard B. 
Published: April 2014

Background—

Left ventricular hypertrophy (LVH; high LV mass [LVM]) is traditionally classified as concentric or eccentric based on LV relative wall thickness. We evaluated the prediction of subsequent adverse events in a new 4-group LVH classification based on LV dilatation (high LV end-diastolic volume [EDV] index) and concentricity (mass/end-diastolic volume [M/EDV]
2/3
) in hypertensive patients.

Methods and Results—

In the Losartan Intervention for Endpoint Reduction (LIFE) echocardiography substudy, 939 hypertensive patients with measurable LVM at baseline were randomized to a mean of 4.8 years of losartan- or atenolol-based treatment. Patients with LVH (LVM/body surface area ≥116 and ≥96 g/m
2
in men and woman, respectively) were divided into 4 groups—concentric nondilated (increased M/EDV, normal EDV), eccentric dilated (increased EDV, normal M/EDV), concentric dilated (increased M/EDV and EDV), and eccentric nondilated (normal M/EDV and EDV)—and compared with patients with normal LVM. Time-varying LVH classes were tested for association with all-cause and cardiovascular mortality and a composite end point of myocardial infarction, stroke, heart failure, and cardiovascular death in multivariable Cox analyses. At baseline, the LVs were categorized as eccentric nondilated in 12%, eccentric dilated in 20%, concentric nondilated in 29%, concentric dilated in 14%, and normal LVM in 25%. Treatment changed the prevalence of 4 LVH groups to 23%, 4%, 5%, and 7%; 62% had normal LVM after 4 years. In time-varying Cox analyses, compared with normal LVM, those with eccentric dilated and both concentric nondilated and dilated LVH had increased risks of all-cause or cardiovascular mortality or the composite end point, whereas the eccentric nondilated group did not.

Conclusions—
Hypertensive patients with relatively mild LVH without either increased LV volume or concentricity have similar risk of all-cause mortality or cardiovascular events because hypertensive patients with normal LVM seem to be a low-risk group.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00338260.
Exercise, Vascular Stiffness, and Tissue Transglutaminase
Authors: Steppan Jochen , Sikka Gautam , Jandu Simran , Barodka Viachaslau , Halushka Marc K. , Flavahan Nicholas A. , Belkin Alexey M. , Nyhan Daniel , Butlin Mark , Avolio Alberto , Berkowitz Dan E. , Santhanam Lakshmi 
Published: April 2014

Background

Vascular aging is closely associated with increased vascular stiffness. It has recently been demonstrated that decreased nitric oxide (
NO
)‐induced S‐nitrosylation of tissue transglutaminase (
TG
2) contributes to age‐related vascular stiffness. In the current study, we tested the hypothesis that exercise restores
NO
signaling and attenuates vascular stiffness by decreasing
TG
2 activity and cross‐linking in an aging rat model.

Methods and Results

Rats were subjected to 12 weeks of moderate aerobic exercise. Aging was associated with diminished phosphorylated endothelial nitric oxide synthase and phosphorylated vasodilator‐stimulated phosphoprotein abundance, suggesting reduced
NO
signaling.
TG
2 cross‐linking activity was significantly increased in old animals, whereas
TG
2 abundance remained unchanged. These alterations were attenuated in the exercise cohort. Simultaneous measurement of blood pressure and pulse wave velocity (
PWV
) demonstrated increased aortic stiffness in old rats, compared to young, at all values of mean arterial pressure (
MAP
). The
PWV
‐
MAP
correlation in the old sedentary and old exercise cohorts was similar. Tensile testing of the vessels showed increased stiffness of the aorta in the old phenotype with a modest restoration of mechanical properties toward the young phenotype with exercise.

Conclusions

Increased vascular stiffness during aging is associated with decreased
TG
2 S‐nitrosylation, increased
TG
2 cross‐linking activity, and increased vascular stiffness likely the result of decreased
NO
bioavailability. In this study, a brief period of moderate aerobic exercise enhanced
NO
signaling, attenuated
TG
cross‐linking activity, and reduced ex vivo tensile properties, but failed to reverse functional vascular stiffness in vivo, as measured by
PWV
.
The TLR9 Ligand, CpG‐ODN, Induces Protection against Cerebral Ischemia/Reperfusion Injury via Activation of PI3K/Akt Signaling
Authors: Lu Chen , Ha Tuanzhu , Wang Xiaohui , Liu Li , Zhang Xia , Kimbrough Erinmarie Olson , Sha Zhanxin , Guan Meijian , Schweitzer John , Kalbfleisch John , Williams David , Li Chuanfu 
Published: April 2014

Background

Toll‐like receptors (
TLR
s) have been shown to be involved in cerebral ischemia/reperfusion (I/R) injury.
TLR
9 is located in intracellular compartments and recognizes CpG‐
DNA
. This study examined the effect of CpG‐
ODN
on cerebral I/R injury.

Methods and Results

C57BL/6 mice were treated with CpG‐
ODN
by i.p. injection 1 hour before the mice were subjected to cerebral ischemia (60 minutes) followed by reperfusion (24 hours). Scrambled‐
ODN
served as control‐
ODN
. Untreated mice, subjected to cerebral I/R, served as I/R control. The effect of inhibitory CpG‐
ODN
(
iCpG
‐ODN) on cerebral I/R injury was also examined. In addition, we examined the therapeutic effect of CpG‐
ODN
on cerebral I/R injury by administration of CpG‐
ODN
15 minutes after cerebral ischemia. CpG‐
ODN
administration significantly decreased cerebral I/R‐induced infarct volume by 69.7% (6.4±1.80% vs 21.0±2.85%,
P
<0.05), improved neurological scores, and increased survival rate, when compared with the untreated I/R group. Therapeutic administration of CpG‐
ODN
also significantly reduced infarct volume by 44.7% (12.6±2.03% vs 22.8±2.54%,
P
<0.05) compared with untreated I/R mice. Neither control‐
ODN
, nor
iCpG
‐ODN altered I/R‐induced cerebral injury or neurological deficits. Nissl staining showed that CpG‐
ODN
treatment preserved neuronal morphology in the ischemic hippocampus. Immunoblot showed that CpG‐
ODN
administration increased Bcl‐2 levels by 41% and attenuated I/R‐increased levels of Bax and caspase‐3 activity in ischemic brain tissues. Importantly, CpG‐
ODN
treatment induced Akt and
GSK
‐3β phosphorylation in brain tissue and cultured microglial cells.
PI
3K inhibition with
LY
294002 abolished CpG‐
ODN
‐induced protection.

Conclusion

CpG‐
ODN
significantly reduces cerebral I/R injury via a
PI
3K/Akt‐dependent mechanism. Our data also indicate that CpG‐
ODN
may be useful in the therapy of cerebral I/R injury.
Postural Tachycardia Syndrome and Inappropriate Sinus Tachycardia: Role of Autonomic Modulation and Sinus Node Automaticity
Authors: Nwazue Victor C. , Paranjape Sachin Y. , Black Bonnie K. , Biaggioni Italo , Diedrich André , Dupont William D. , Robertson David , Raj Satish R. 
Published: April 2014

Background

Inappropriate sinus tachycardia (
IST
) and postural tachycardia syndrome (
POTS
) are 2 disorders characterized by sinus tachycardia. It is debated whether the pathophysiology of
IST
and
POTS
results from abnormal autonomic regulation or abnormal sinus node function. We hypothesized that intrinsic heart rate (
IHR
) after autonomic blockade would be increased in patients with
IST
but not
POTS
.

Methods and Results

We enrolled 48
POTS
patients, 8
IST
patients, and 17 healthy control (
HC
) subjects. Intravenous propranolol and atropine were given to block the sympathetic and parasympathetic limbs of the autonomic nervous system in order to determine the
IHR
. Patients with
IST
have a higher sympathetic contribution to heart rate when compared with
POTS
patients (31±13 bpm versus 12±7 bpm,
P
<0.001) and
HC
(8±4 bpm;
P
<0.001) and a trend to less parasympathetic contribution than
POTS
and
HC
(
IST
: 31±11 bpm versus
POTS
: 46±11 bpm versus
HC
: 48±11 bpm,
ANOVA
P
=0.108).
IHR
was not significantly different between
IST
and either
POTS
or
HC
(
IST
: 111±11 bpm versus
POTS
: 108±11 bpm versus
HC
: 106±12 bpm,
ANOVA
P
=0.237).

Conclusions

IST
patients have more sympathetic tone when compared with either
POTS
or
HC
, but
IST
patients do not have abnormal sinus node automaticity. These data suggest that the treatment of
IST
and
POTS
should focus on sympatholysis, reserving sinus node modification for patients with continued debilitating symptoms after beta‐blockade and possibly ivabradine.

Clinical Trial Registration

URL:
http://clinicaltrials.gov/
. Unique identifier: NCT00262470.
Relative Contributions of Sympathetic, Cholinergic, and Myogenic Mechanisms to Cerebral Autoregulation
Authors: Hamner J.W. , Tan Can Ozan 
Published: April 2014

Background and Purpose—
Prior work aimed at improving our understanding of human cerebral autoregulation has explored individual physiological mechanisms of autoregulation in isolation, but none has attempted to consolidate the individual roles of these mechanisms into a comprehensive model of the overall cerebral pressure–flow relationship.

Methods—
We retrospectively analyzed this relationship before and after pharmacological blockade of α-adrenergic–, muscarinic-, and calcium channel–mediated mechanisms in 43 healthy volunteers to determine the relative contributions of the sympathetic, cholinergic, and myogenic controllers to cerebral autoregulation. Projection pursuit regression was used to assess the effect of pharmacological blockade on the cerebral pressure–flow relationship. Subsequently, ANCOVA decomposition was used to determine the cumulative effect of these 3 mechanisms on cerebral autoregulation and whether they can fully explain it.

Results—

Sympathetic, cholinergic, and myogenic mechanisms together accounted for 62% of the cerebral pressure–flow relationship (
P
<0.05), with significant and distinct contributions from each of the 3 effectors. ANCOVA decomposition demonstrated that myogenic effectors were the largest determinant of the cerebral pressure–flow relationship, but their effect was outside of the autoregulatory region where neurogenic control appeared prepotent.

Conclusions—
Our results suggest that myogenic effects occur outside the active region of autoregulation, whereas neurogenic influences are largely responsible for cerebral blood flow control within it. However, our model of cerebral autoregulation left 38% of the cerebral pressure–flow relationship unexplained, suggesting that there are other physiological mechanisms that contribute to cerebral autoregulation.
The Ancestry of ‘Equitable Treatment’ in Trade
Authors: Pinchis Mona 
Published: April 2014

How the League of Nations applied the concept of ‘equitable treatment’ in fostering international economic co-operation throughout the inter-war period had practical consequences for both modern multilateral trade law and international investment law. The ‘equitable treatment’ clause constructed by a sub-Commission of the League’s Economic Committee in 1933 was later encapsulated in the non-violation nullification and impairment procedural remedy in multilateral trade law. Moreover, a number of scholars have noted that the ‘fair and equitable treatment’ (FET) clause found in the majority of international investment treaties may be connected to Article 23(e) of the Covenant of the League of Nations, emphasizing ‘equitable treatment for the commerce of other Members of the League’. In light of these connections, a historical contribution that examines the League’s understanding of ‘equitable treatment’ should resonate with scholars and policy-makers.
This article analyses the meaning and scope of the concept of ‘equitable treatment’ as it was elaborated by the League during the inter-war period. It finds that the flexible concept of ‘equitable treatment’ was a necessary ingredient in an inter-war multilateral framework that could adapt to rapidly changing economic circumstances. In addition to a brief historical background, the first part of this article explores how the concept of ‘equitable treatment’ was underlying the League’s efforts to build an ‘international community’ to promote economic co-operation, broaden policy-making perspectives, and to achieve economic stability and growth, all without imposing rigid rules upon its Members. The second part of this article examines how a sub-Commission established during the 1933 World Financial and Economic Conference directly applied the concept of ‘equitable treatment’ as a flexible tool to protect the reciprocally guaranteed benefits arising from international commercial treaties, which reinforced its ambitions for a multilateral framework for international economic ‘equilibrium.’ The third part of this article studies how the drafting of the ‘equitable treatment’ clause by the sub-Commission helped to clarify its purpose and function as a flexible remedy at the time. The final part summarizes key lessons and identifies future work.
Spatial Similarity and Transferability of Analog Dates for Precipitation Downscaling over France
Authors: Chardon Jeremy , Hingray Benoit , Favre Anne-Catherine , Autin Philemon , Gailhard Joël , Zin Isabella , Obled Charles 
Published: April 2014

High-resolution weather scenarios generated for climate change impact studies from the output of climate models must be spatially consistent. Analog models (AMs) offer a high potential for the generation of such scenarios. For each prediction day, the scenario they provide is the weather observed for days in a historical archive that are analogous according to different predictors. When the same “analog date” is chosen for a prediction at several sites, spatial consistency is automatically satisfied. The optimal predictors and consequently the optimal analog dates, however, are expected to depend on the location for which the prediction is to be made. In the present work, the predictor (1000- and 500-hPa geopotential heights) domain of a benchmark AM is optimized for the probabilistic daily prediction of 8981 local precipitation “stations” over France. The corresponding 8981 locally domain-optimized AMs are used to explore the spatial transferability and similarity of the optimal analog dates obtained for different locations. Whereas the similarity is very low even when the locations are close, the spatial transferability of the optimal analog dates for a given location is high. When they are used for the prediction at all other locations, the loss of prediction performance is therefore very low over large spatial domains (up to 500 km). Spatial transferability is lower in the presence of high mountains. It also depends on the parameters of the AM (e.g., its archive length, predictors, and number of analog dates used for the prediction). In the present case, AMs with higher prediction skill exhibit lower transferability.
Decoupling of the Agulhas Leakage from the Agulhas Current
Authors: Loveday Benjamin R. , Durgadoo Jonathan V. , Reason Chris J. C. , Biastoch Arne , Penven Pierrick 
Published: April 2014

Abstract
The relationship between the Agulhas Current and the Agulhas leakage is not well understood. Here, this is investigated using two basin-scale and two global ocean models of incrementally increasing resolution. The response of the Agulhas Current is evaluated under a series of sensitivity experiments, in which idealized anomalies, designed to geometrically modulate zonal trade wind stress, are applied across the Indian Ocean Basin. The imposed wind stress changes exceed plus or minus two standard deviations from the annual-mean trade winds and, in the case of intensification, are partially representative of recently observed trends. The Agulhas leakage is quantified using complimentary techniques based on Lagrangian virtual floats and Eulerian passive tracer flux. As resolution increases, model behavior converges and the sensitivity of the leakage to Agulhas Current transport anomalies is reduced. In the two eddy-resolving configurations tested, the leakage is insensitive to changes in Agulhas Current transport at 32°S, though substantial eddy kinetic energy anomalies are evident. Consistent with observations, the position of the retroflection remains stable. The decoupling of Agulhas Current variability from the Agulhas leakage suggests that while correlations between the two may exist, they may not have a clear dynamical basis. It is suggested that present and future Agulhas leakage proxies should be considered in the context of potentially transient forcing regimes.
Distinguishing the Cold Conveyor Belt and Sting Jet Airstreams in an Intense Extratropical Cyclone
Authors: Martínez-Alvarado Oscar , Baker Laura H. , Gray Suzanne L. , Methven John , Plant Robert S. 
Published: April 2014

Abstract
Strong winds equatorward and rearward of a cyclone core have often been associated with two phenomena: the cold conveyor belt (CCB) jet and sting jets. Here, detailed observations of the mesoscale structure in this region of an intense cyclone are analyzed. The in situ and dropsonde observations were obtained during two research flights through the cyclone during the Diabatic Influences on Mesoscale Structures in Extratropical Storms (DIAMET) field campaign. A numerical weather prediction model is used to link the strong wind regions with three types of “airstreams” or coherent ensembles of trajectories: two types are identified with the CCB, hooking around the cyclone center, while the third is identified with a sting jet, descending from the cloud head to the west of the cyclone. Chemical tracer observations show for the first time that the CCB and sting jet airstreams are distinct air masses even when the associated low-level wind maxima are not spatially distinct. In the model, the CCB experiences slow latent heating through weak-resolved ascent and convection, while the sting jet experiences weak cooling associated with microphysics during its subsaturated descent. Diagnosis of mesoscale instabilities in the model shows that the CCB passes through largely stable regions, while the sting jet spends relatively long periods in locations characterized by conditional symmetric instability (CSI). The relation of CSI to the observed mesoscale structure of the bent-back front and its possible role in the cloud banding is discussed.
Regionalizing Rainfall at Very High Resolution over La Réunion Island Using a Regional Climate Model
Authors: Morel Béatrice , Pohl Benjamin , Richard Yves , Bois Benjamin , Bessafi Miloud 
Published: April 2014

Abstract
Regional climate models (RCMs) should be evaluated with respect to their ability to downscale large-scale climate information to the local scales, which are sometimes strongly modulated by surface conditions. This is the case for La Réunion (southwest Indian Ocean) because of its island context and its complex topography. Large-scale atmospheric configurations such as tropical cyclones (TCs) may have an amplifying effect on local rainfall patterns that only a very high-resolution RCM, forced by the large scales and resolving finescale processes, may simulate properly.
This paper documents the capability of the Weather Research and Forecasting Model (WRF) RCM to regionalize rainfall variability at very high resolution (680 m) over La Réunion island for daily to seasonal time scales and year-to-year differences. Two contrasted wet seasons (November–April) are selected: 2000–01 (abnormally dry) and 2004–05 (abnormally wet). WRF rainfall is compared to a dense network of rain gauge records interpolated onto the WRF grid through the regression-kriging (RK) technique. RK avoids the point-to-grid comparison issue, but produces imperfect estimates due to sampling, so its quality also needs to be tested.
Seasonal rainfall amounts and contrasts produced by WRF are fairly realistic. At intraseasonal and daily time scales, differences to RK are more sizable. These differences are not easy to interpret in sectors where the rain gauge network is less dense and the quality of RK more uncertain, as over the eastern slopes of Piton de la Fournaise volcano where WRF seems to simulate more realistic rainfall than RK. Finally, the heavy rainfall associated with TC Ando on 6 January 2001, is documented. WRF shows weak disagreements with RK, indicating its capability to regionalize rainfall during extreme events.
Retinal profile: a clinical indicator of severity in dengue fever in a suburban Indian environment
Authors: Malhotra Rubii , Singh Luxmi , Bundela RK , Garg Pragati , Kant Diva , Garg Ankit , Lal BB 
Published: April 2014

Purpose To study the retinal changes in subjects suffering from dengue fever and check if these changes can be taken as sufficient indicator of severity and progression of the disease. Patients/Methods A detailed history was recorded of 118 patients on whom ocular examination, including direct ophthalmoscopy, indirect ophthalmoscopy and coloured fundus photography, was performed. Results Forty-seven percent of patients were found to have posterior segment abnormalities. Retinal vein dilatation or tortuosity was the most common finding followed by changes in the optic disc (8.4% of patients) and background haemorrhage (6.7% of patients). With increasing severity of thrombocytopenia, the proportion of patients with retinal abnormalities increased. In patients with grade I thrombocytopenia, no fundal abnormality was found. In those with grade II thrombocytopenia, fundal abnormality was found in 13.63% patients, whereas in the grade III category it was 27.90%. Conclusions Severity of thrombocytopenia had a significant association with retinal abnormalities. Occurrence of fundus changes increases with an increase in severity of thrombocytopenia. Fundus changes were found in all patients with grade IV thrombocytopenia.