bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantitative evaluation of ontogenetic change in heart rate and its autonomic regulation in newborn mice with the use of a noninvasive piezoelectric sensor
Authors: Sato Shinichi
Published: February 2008

A reliable basal heart rate (HR) measurement in freely moving newborn mice was accomplished for the first time by using a novel noninvasive piezoelectric transducer (PZT) sensor. The basal HR was ∼320 beats/min at postnatal day (P)0 and increased with age to ∼690 beats/min at P14. Contribution of autonomic control to HR was then assessed. Sympathetic blockade with metoprolol significantly reduced basal HR at both P6 (−236 ± 23 beats/min; mean ± SE) and P12 (−105 ± 8 beats/min), but atropine was without effect, indicating the predominant tonic adrenergic stimulation and absence of vagal control for basal HR in newborn mice. In contrast to stable basal HR during 5-min recording, HR measured by ECG (ECG-HR) was markedly decreased because of the restraint stress of attaching ECG electrodes, with accompanying freezing behavior. ECG-HR lowered and further decreased gradually during 5 min (slow cardiodeceleration) at P0–P3 and rapidly decreased and gradually recovered within 5 min (transient bradycardia) at P9–P14. The response was not uniform in P4–P8 mice: they showed either of these two patterns or sustained bradycardia (9–29%), and the number of mice that showed transient bradycardia increased with age (30–100%) during the period. Studies with autonomic blockade suggest that the slow cardiodeceleration and transient bradycardia are mediated mainly by withdrawal of adrenergic stimulation and phasic vagal activation, respectively, and the autonomic control of HR response to restraint stress is likely to change from the withdrawal of adrenergic stimulation to the phasic vagal activation at different stages during P4–P8 in individual mice. The PZT sensor may offer excellent opportunities to monitor basal HR of small animals noninvasively.
Functional resolution of fibrosis in mdx mouse dystrophic heart and skeletal muscle by halofuginone
Authors: Huebner Kyla D. , Jassal Davinder S. , Halevy Orna , Pines Mark , Anderson Judy E.
Published: February 2008

The effect of halofuginone (Halo) on established fibrosis in older mdx dystrophic muscle was investigated. Mice (8 to 9 mo) treated with Halo (or saline in controls) for 5, 10, or 12 wk were assessed weekly for grip strength and voluntary running. Echocardiography was performed at 0, 5, and 10 wk. Respiratory function and exercise-induced muscle damage were tested. Heart, quadriceps, diaphragm, and tibialis anterior muscles were collected to study fibrosis, collagen I and III expression, collagen content using a novel collagenase-digestion method, and cell proliferation. Hepatocyte growth factor and α-smooth muscle actin proteins were assayed in quadriceps. Halo decreased fibrosis (diaphragm and quadriceps), collagen I and III expression, collagen protein, and smooth muscle actin content after 10 wk treatment. Muscle-cell proliferation increased at 5 wk, and hepatocyte growth factor increased by 10 wk treatment. Halo markedly improved both cardiac and respiratory function and reduced damage and improved recovery from exercise. The overall impact of established dystrophy and dysfunction in cardiac and skeletal muscles was reduced by Halo treatment. Marked improvements in vital-organ functions implicate Halo as a strong candidate drug to reduce morbidity and mortality in Duchenne muscular dystrophy.
Shifting sources of functional limitation following extensive (70%) lung resection
Authors: Hsia Connie C. W. , Dane D. Merrill , Estrera Aaron S. , Wagner Harrieth E. , Wagner Peter D. , Johnson Robert L.
Published: February 2008

We previously found that, following surgical resection of ∼58% of lung units by right pneumonectomy (PNX) in adult canines, oxygen-diffusing capacity (DlO2) fell sufficiently to become a major factor limiting exercise capacity, although the decline was mitigated by recruitment, remodeling, and growth of the remaining lung units. To determine whether an upper limit of compensation is reached following the loss of even more lung units, we measured pulmonary gas exchange, hemodynamics, and ventilatory power requirements in adult canines during treadmill exercise following two-stage resection of ∼70% of lung units in the presence or absence of mediastinal distortion. Results were compared with that in control animals following right PNX or thoracotomy without resection (Sham). Following 70% lung resection, peak O2 uptake was 45% below normal. Ventilation-perfusion mismatch developed, and pulmonary arterial pressure and ventilatory power requirements became markedly elevated. In contrast, the relationship of DlO2 to cardiac output remained normal, indicating preservation of DlO2-to-cardiac output ratio and alveolar-capillary recruitment up to peak exercise. The impairment in airway and vascular function exceeded the impairment in gas exchange and imposed the major limitation to exercise following 70% resection. Mediastinal distortion further reduced air and blood flow conductance, resulting in CO2 retention. Results suggest that adaptation of extra-acinar airways and blood vessels lagged behind that of acinar tissue. As more lung units were lost, functional compensation became limited by the disproportionately reduced convective conductance rather than by alveolar diffusion disequilibrium.
Acute MRI Changes in Progressive Ischemic Stroke
Authors: Kalowska E. , Rostrup E. , Rosenbaum S. , Petersen P. , Paulson O.B.
Published: February 2008

Background and Purpose: Neurological deterioration following acute stroke is common and associated with increased morbidity and mortality. The underlying pathophysiological mechanisms are not fully understood, and it is difficult to predict which patients are at risk of deterioration. Our study aimed to assess if acute MRI findings could be used for the prediction of stroke in progression (SIP). Methods: Prospectively 41 patients, 13 with lacunar infarcts and 28 with territorial infarcts, were admitted to an acute stroke unit within 24 h of stroke onset (median 11 h, range 3– 22). Diffusion-weighted imaging (DWI), perfusion-weighted imaging and magnetic resonance angiography were performed 3 times, immediately after clinical evaluation, on day 7 and after 3 months. Clinical neurological assessments were performed every 2 h during the first 24 h and once daily from day 2 to 7. SIP was defined as a permanent decrease of ≧3 Scandinavian Stroke Scale (SSS) points for speech or ≧2 SSS points for consciousness or ≧2 SSS points for limb strength, when assessed at baseline compared to the day after admission and daily during the following week. Patients were followed up on day 90 and assessed using the modified Rankin Scale, Barthel Index and SSS score. Patients with and without SIP were compared using both clinical and MRI data obtained on admission, on day 7 and after 3 months. Results: Fifteen patients (37%) developed SIP. Increased DWI lesion volume on day 7 in all strokes was associated with SIP (χ2, p = 0.005). All lacunar infarcts with a DWI volume >1.5 cm3 at baseline (4 patients) developed SIP (p < 0.005). Patients with territorial infarcts and SIP had lower baseline SSS scores with severer symptoms than non-SIP patients (p ≤ 0.05). Despite trends in MRI differences at baseline, only the baseline SSS score in patients with territorial infarcts remained an independent predictor of SIP, when using a logistic regression model (p < 0.05). Conclusions: These findings suggest that SIP is due to growth of the lesion volume from baseline to day 7. In patients with lacunar infarcts, there was an association between initial lesion size and risk of developing SIP. However, for territorial infarcts, baseline SSS was found to be the best individual predictor of SIP and clinical outcome.
Prognostic Modelling in Ischaemic Stroke Study, Additional Value of Genetic Characteristics
Authors: Achterberg S. , Kappelle L.J. , Algra A.
Published: February 2008

Background and Aim: The prediction of prognosis after cerebral infarction might be improved by genetic information. The aim of the Prognostic Modelling in Ischaemic Stroke study is to develop 2 different prognostic models on the basis of traditional vascular risk factors and genetic information in patients who have suffered from cerebral ischaemia of arterial origin, 1 concerning new ischaemic and the other new haemorrhagic events. Methods: Polymorphisms and haplotypes describing the haemostatic system and those that influence antithrombotic drug activity will be identified in a cohort of 1,200 patients with cerebral ischaemia of arterial origin who will be followed up for a mean of 6.5 years. In total, 312 ischaemic and 78 haemorrhagic events are anticipated. With a prevalence of a genetic characteristic of 10% a relative risk of 1.4 (95% confidence interval = 1.1–1.8) for ischaemic events and of 1.8 (95% confidence interval = 1.0–3.2) for haemorrhagic events can be estimated with sufficient precision. To determine the additional prognostic value of genetic characteristics the area under the ROC curves of 2 separate models will be compared: 1 based on non-genetic risk factors only, the other also including genetic data.
Obesity and Carpal Tunnel Syndrome: Is There a Causal Relationship?
Authors: Kurt Semiha , Kisacik Bunyamin , Kaplan Yuksel , Yildirim Beytullah , Etikan Ilker , Karaer Hatice
Published: February 2008

Objectives: Obesity is defined as a risk factor for carpal tunnel syndrome (CTS). In this study, the presence or absence of recovery in median nerve conduction velocities after weight loss in obese patients was assessed in order to determine whether excess weight or other factors influence the higher prevalence of CTS in obese patients. Methods: Patients with body mass indexes (BMIs) ≧30 were included in the study. CTS symptoms, age, gender, height, body weight, and concomitant diseases were evaluated. Nerve conduction studies (NCS) were obtained on one upper extremity. All patients were included in dietetic programs. Three months later, NCS were repeated and compared with the first NCS. Results: BMIs were statistically significantly lower on the second visits 3 months later (p = 0.0001). No statistically significant difference was observed in the second NCS of electromyographically diagnosed cases with CTS (p > 0.05). Conclusion: We expected a recovery in median nerve conduction velocities in patients with CTS after weight loss. In the literature, even in untreated cases with CTS, spontaneous improvements in second NCS have been reported. This finding suggests that factors other than excess body weight may be influential in the higher prevalence of CTS in obese patients. A more detailed, genetic-factor-targeted investigation may prove more beneficial to clarify this issue.
Diagnostic Value of 123I-Ioflupane and 123I-Iodobenzamide SPECT Scans in 248 Patients with Parkinsonian Syndromes
Authors: Vlaar Annemarie M.M. , de Nijs Tjerk , Kessels Alfons G.H. , Vreeling Fred W. , Winogrodzka Ania , Mess Werner H. , Tromp Selma C. , van Kroonenburgh Marinus J.P.G. , Weber Wim E.J.
Published: February 2008

Background: SPECT is one of the most employed techniques in the diagnostic workup of idiopathic Parkinson’s disease (IPD). Despite its widespread use, the exact diagnostic accuracy of this technique in parkinsonian syndromes remains controversial. Methods: In this study, we investigated the diagnostic accuracy of an initial 123I-ioflupane (FP-CIT) and/or 123I-iodobenzamide (IBZM) SPECT to differentiate between IPD and other parkinsonian disorders. 248 patients underwent a SPECT scan because of an as yet unclassified parkinsonian syndrome in our clinic between 2001 and 2006. Gold standard was the clinical diagnosis derived from the latest available clinical record, or, when this was not possible, a new complete physical and neurological examination by a blinded movement disorder specialist neurologist. Mean follow-up between SPECT and the latest clinical information was 18 months (range 3 months to 5 years). Results: 223 of the 248 patients were clinically definitely diagnosed after follow-up: IPD 127, atypical parkinsonian syndromes (APS) 27, essential tremor (ET) 22, vascular parkinsonism (VP) 16, drug-induced parkinsonism (DIP) 5, doubt between PD and APS 2, other diseases without dopaminergic involvement 24. The mean odds ratio (95% CI) for FP-CIT SPECT’s ability to distinguish between IPD and ET was 82 (11–674); between IPD and VP 61 (8–490); between IPD and DIP 36 (2–697) and between IPD and APS was 1 (0–4). The odds ratio for the IBZM SPECT tracer to differentiate between IPD and APS was 7 (2–17). Conclusions: FP-CIT SPECT is accurate to differentiate patients with IPD from those with ET, and IPD from VP and DIP. The accuracy of both FP-CIT and IBZM SPECT scans to differentiate between IPD and APS is low.
Timing of Clinical Improvement and Symptom Resolution in the Treatment of Major Depressive Disorder
Authors: Papakostas George I. , Crawford Christine M. , Scalia Margaret J. , Fava Maurizio
Published: February 2008

Background: Our objective was to assess for the relationship between timing of clinical improvement and resolution of depressive symptoms during the treatment of major depressive disorder (MDD). Thirty-nine MDD outpatients who responded following a 12-week, double-blind study comparing Hypericum perforatum, fluoxetine or placebo were included in the analysis. Methods: Onset of clinical improvement was defined as a 25% decrease in 17-item Hamilton Depression Scale (HDRS-17) scores that was not followed by a subsequent worsening of symptoms. Controlling for baseline symptom severity, we then assessed for the relationship between timing of clinical improvement and depressive symptom severity at endpoint. Results: Among responders, earlier clinical improvement predicted lower HDRS-17 scores at week 12 (p = 0013). This was also true of responders who received active treatment (n = 29, p = 0.0113) but not placebo responders (n = 10; p > 0.05). Finally, patients with an early onset of clinical improvement (occurring during the first 2 weeks) had lower week 12 HDRS-17 scores than patients with a late onset of clinical improvement (p = 0.0404). Conclusion: In the present work, earlier as well as early clinical improvement during treatment is predictive of greater symptom resolution at endpoint among responders. This was replicated among patients who received active treatment (either hypericum or fluoxetine) but not placebo.
Platelet Monoamine Oxidase Kinetics, Alcoholism Subtypes and Cigarette Smoking
Authors: Cicin-Sain Lipa , Matosic Ana , Mokrovic Gordana , Balija Melita , Marusic Srdjan , Jernej Branimir
Published: February 2008

In trying to dissociate the effect of alcohol and tobacco use on platelet monoamine oxidase-B (MAO-B) activity, we compared the enzyme kinetics in controls (n = 66) and alcohol-dependent patients (n = 81), subdivided according to the severity of both, alcohol and tobacco use. Platelet MAO-B kinetics was measured spectrophotofluorimetrically in chronic alcohol intoxication and after 3 weeks abstinence. In alcoholic patients, an increased Michaelis-Menten constant (16%, p < 0.01) was shown, notwithstanding smoking status. Maximal velocity did not differ between patients and controls when adjusted for smoking. In cigarette smokers, a highly significant dose-dependent reduction of platelet MAO velocity (40%, p < 0.001) was demonstrated, with a similar degree of reduction in patients and controls. Tobacco use itself had no influence on MAO affinity. No differences were shown between subtype 1 and 2 alcoholics, or between the day of admission and the 21st day of abstinence. In conclusion, it seems that both, alcohol and tobacco consumption, may contribute to the lowering of overall platelet MAO-B activity. The effect of alcohol is small, due to interference with substrate binding, and not alteration of catalytic activity. In contrast, the effect of cigarette smoking is pronounced and relates to the dose-dependent reduction of platelet MAO velocity, with no influence on its affinity.
Plasma Lipid Levels in the Elderly Are Not Associated with the Risk of Mild Cognitive Impairment
Authors: Reitz Christiane , Tang Ming-Xin , Manly Jennifer , Schupf Nicole , Mayeux Richard , Luchsinger José A.
Published: February 2008

Background: There are conflicting data relating plasma lipids to the risk of Alzheimer‘s disease (AD). We explored the association of plasma lipids to mild cognitive impairment (MCI), a transitional stage between normal cognition and dementia, in a prospective community-based cohort study among randomly sampled Medicare recipients ≧65 years. Baseline data were collected from 1992 to 1994, follow-up data were collected at 18-month intervals. Methods: Multivariate proportional hazards regression was used to relate plasma lipid levels to incident total MCI, amnestic MCI and nonamnestic MCI in 854 persons without MCI or dementia at baseline. Results: There were 324 cases of incident MCI, 153 cases of amnestic MCI and 171 cases of nonamnestic MCI during 4,189 person-years of follow-up. Higher levels of total cholesterol and LDL were associated with a decreased risk of total MCI in models adjusting for age and sex. However, these associations were attenuated after adjusting for ethnicity, education, APOEΕ4 and vascular risk factors. There was no association between lipids and the risk of amnestic or nonamnestic MCI, and there was no effect of lipid-lowering treatment on MCI risk. Conclusions: Plasma lipid levels or lipid-lowering treatment in the elderly are not associated with the risk of MCI.
Cognitive Impairment No Dementia – Neuropsychological and Neuroimaging Characterization of an Amnestic Subgroup
Authors: Jacova Claudia , Peters Kevin R. , Beattie B. Lynn , Wong Erick , Riddehough Andrew , Foti Dean , Scheltens Philip , Li David K.B. , Feldman Howard H.
Published: February 2008

Background/Aims: Cognitive impairment no dementia (CIND) describes individuals whose cognitive functioning falls below normal but who do not meet dementia criteria. An important goal within CIND is to identify subgroups that will predictably progress to Alzheimer disease. CIND with amnestic deficits has been associated with high risk of Alzheimer disease but has until now been investigated on a retrospective basis. In this study a prospectively defined amnestic CIND group was characterized on a detailed neuropsychological test battery and on structural magnetic resonance imaging (MRI) measures. Methods: Amnestic CIND was defined as meeting at least 1 but not all DSM-IV-TR criteria for dementia, scoring ≧1 SD below norms on Rey Auditory Verbal Learning Test delayed recall, having a Clinical Dementia Rating score of 0.5 and a Mini-Mental State Exam score ≧24. This cross-sectional study compared subjects meeting these criteria (n = 25) to age- and education-matched controls (n = 26). The neuropsychological battery included memory and nonmemory measures that were analyzed as continuous variables and dichotomized into impaired (≧1 SD below controls) versus nonimpaired. MRI scans were evaluated with a global-brain volumetric measure [brain fractional ratio (BFR)] and with visually based medial temporal lobe atrophy (MTA) ratings. Results: Amnestic CIND had neuropsychological impairment in the episodic memory domain and also in nonmemory domains. There were 80% of CIND subjects with multidomain impairment. The most clear-cut nonmemory impairment was in the verbal ability domain, with 64% of subjects affected and a moderate effect size (d = 0.7). On MRI, BFR was lower (74.5 ± 4.6 vs. 75.5 ± 4.4) and MTA higher (72 vs. 38% with MTA ≧1) in CIND than in control subjects. BFR correlated with MTA (r = –0.45) and with a composite memory score (r = 0.296). Conclusion: A prospective amnestic CIND grouping appears to identify individuals with a multidomain pattern of neuropsychological impairment and with both medial temporal lobe and global brain atrophy.
Maternal Betamethasone and Chorioamnionitis Induce Different Collagenases during Lung Maturation in Fetal Sheep
Authors: Sweet David G. , Huggett Matthew T. , Warner Jane A. , Moss Timothy J.M. , Kloosterboer Nico , Halliday Henry L. , Newnham John P. , Kallapur Suhas G. , Jobe Alan H. , Kramer Boris W.
Published: February 2008

Background: Fetal lung maturation occurs after both maternal corticosteroid administration and chorioamnionitis. The effectors of this antenatally-induced lung maturation are not understood. Matrix metalloproteinases (MMPs) 2 and 9 are type-IV collagenases that can degrade alveolar basement membranes. Objectives: We hypothesized that the structural changes of lung maturation by both antenatal corticosteroid treatment and chorioamnionitis would be associated with increases in these MMPs. Methods: 64 pregnant ewes were randomly assigned to one of four treatment groups: intra-amniotic injection of 10 mg endotoxin, maternal intramuscular injection of 0.5 mg/kg betamethasone, both treatments combined or saline-treated controls. We quantified MMP-2 which is derived from connective tissue and MMP-9 which is predominantly derived from neutrophils in fetal lung fluid of lambs after maternal corticosteroid therapy and induction of chorioamnionitis and the combination of both therapies given at 109–111 days’ gestational age with delivery 1, 5 or 15 days later. Results: Betamethasone, endotoxin and the combined treatments increased both surfactant pool size, lung gas volume and reduced alveolar wall thickness at 15 days. MMP-2 concentration was increased after betamethasone. MMP-9 concentration increased after endotoxin-induced chorioamnionitis but decreased by the combined treatments. Conclusion: Lung maturation via different pathways may use different forms of collagenases for remodelling lung structure.
Religious Delusions: Finding Meanings in Psychosis
Authors: Bhavsar Vishal , Bhugra Dinesh
Published: February 2008

Background: Religious delusions have been reported with varying prevalence from cultures around the world. Their contents, context and significance vary according to cultural and economic mores. In this review we discuss the potential relationship between religious delusions and aspects of culture, in particular religious symbols. We suggest that religious rituals and expectations of the family play a major role in the genesis and maintenance of delusions. We consider the roles of religious signifiers in the formation and maintenance of these important phenomena. Sampling and Methods: Evidence relating to the clinical significance of religious delusions is reviewed. The real clinical significance of religious delusions varies from violence to others to self-harm. The implications of these issues are discussed in relation to their management. Results and Conclusions: It is argued that there should be a reassessment of the importance of religious delusions in the light of new ethnographic and clinical evidence.
Traces of Freud – The Unconscious Conflict as a Cause of Mental Disorders in the Eyes of the General Public
Authors: Schomerus Georg , Matschinger Herbert , Angermeyer Matthias C.
Published: February 2008

Background: We aim to elicit how far the public has incorporated Freudian theory in its understanding of mental illness in different countries, focussing on the unconscious conflict as a possible cause of mental disorders. Sampling and Methods: We conducted representative population surveys with identical sampling procedures and face-to-face interviews in Germany (1990, n = 3,078; 2001, n = 5,025), Novosibirsk (Russia, 2002, n = 745), and Bratislava (Slovakia, 2003, n = 1,000) and a representative telephone survey in Germany in 2006. Results: Two thirds of respondents in Germany endorsed an unconscious conflict as a cause of mental disorder. Endorsement was stronger for depression than for schizophrenia, increased with duration of schooling, and was less prevalent in Bratislava and Novosibirsk and in East compared to West Germany. Endorsement in Germany increased between 1990 and 2001. However, only 5% of respondents could offer a definition of unconscious conflict that resembled Freud’s initial theory. Discussion: The observed West-East gradient is likely to mirror the past political undesirability of psychoanalysis in former communist countries. The popularity of psychoanalytical concepts seems to lag behind their actually declining influence within psychiatry in Germany. Public conception of unconscious conflict however hardly resembles Freud’s original ideas. Conclusions: Although psychoanalytical concepts warrant consideration when exploring patients’ causal beliefs about mental illness, psychiatrists should focus on the subjective meaning of seemingly psychoanalytic phrases.
Evaluation of Matrix Metalloproteinases in Atherosclerosis Using a Novel Noninvasive Imaging Approach
Authors: Lancelot Eric , Amirbekian Vardan , Brigger Irène , Raynaud Jean-Sébastien , Ballet Sébastien , David Christelle , Rousseaux Olivier , Le Greneur Soizic , Port Marc , Lijnen Henri R. , Bruneval Patrick , Michel Jean-Baptiste , Ouimet Tanja , Roques Bernard , Amirbekian Smbat , Hyafil Fabien , Vucic Esad , Aguinaldo Juan Gilberto S. , Corot Claire , Fayad Zahi A.
Published: February 2008

Objective—

Despite great advances in our knowledge, atherosclerosis continues to kill more people than any other disease in the Western world. This is because our means of identifying truly vulnerable patients is limited. Prediction of atherosclerotic plaque rupture may be addressed by MRI of activated matrix metalloproteinases (MMPs), a family of enzymes that have been implicated in the vulnerability of plaques prone to rupture. This study evaluated the ability of the novel gadolinium-based MRI contrast agent P947 to target MMPs in atherosclerotic plaques.

Methods and Results—

The affinity of P947 toward activated MMPs was demonstrated in vitro. The affinity and specificity of P947 toward matrix metalloproteinase (MMP)-rich plaques was evaluated both in vivo using ApoE
−/−
mice and ex vivo in hyperlipidemic rabbits. Gadolinium content quantification and MRI showed a preferential accumulation of P947 in atherosclerotic lesions compared with the nontargeted reference compound, Gd-DOTA. The ex vivo assay on rabbit plaques revealed a higher uptake of P947. Moreover, using human carotid artery endarterectomy specimens, P947 facilitated discrimination between histologically defined MMP-rich and MMP-poor plaques. An in vivo MRI investigation in mice revealed that P947 greatly improved the ability to visualize and delineate atherosclerotic plaques.

Conclusions—

P947 may be a useful tool for the detection and characterization of the MMP-rich atherosclerotic plaques.
In Vivo Arterial Lipoprotein Lipase Expression Augments Inflammatory Responses and Impairs Vascular Dilatation
Authors: Takahashi Mayumi , Hiyama Yaeko , Yokoyama Masayoshi , Yu Shuiqing , Hu Yunying , Melford Kristan , Bensadoun André , Goldberg Ira J.
Published: February 2008

Objective—

Although epidemiologic data suggest that hypertriglyceridemia and elevated plasma levels of fatty acids are toxic to arteries, in vitro correlates have been inconsistent. To investigate whether increased endothelial cell expression of lipoprotein lipase (LpL), the primary enzyme creating free fatty acids from circulating triglycerides (TG), affects vascular function, we created transgenic mice that express human LpL (hLpL) driven by the promoter and enhancer of the Tie2 receptor.

Methods and Results—

Mice expressing this transgene, denoted EC-hLpL and L for low and H for high expression, had decreased plasma TG levels compared with wild-type mice (WT): 106±31 in WT, 37±17 (line H), and 63±31 mg/dL (line L) because of a reduction in VLDL TG; plasma cholesterol and HDL levels were unaltered. Crossing a high expressing EC-hLpL transgene onto the LpL knockout background allowed for survival of the pups; TG in these mice was approximately equal to that of heterozygous LpL knockout mice. Surprisingly, under control conditions the EC-hLpL transgene did not alter arterial function or endothelial cell gene expression; however, after tumor necrosis factor (TNF)-α treatment, arterial vascular cell adhesion molecule-1 (VCAM-1), E-selectin, and endogenous TNF-α mRNA levels were increased and arteries had impaired endothelium-dependent vasodilatation. This was associated with reduced eNOS dimers.

Conclusions—

Therefore, we hypothesize that excess vascular wall LpL augments vascular dysfunction in the setting of inflammation.
Evidence for the Involvement of miRNA in Redox Regulated Angiogenic Response of Human Microvascular Endothelial Cells
Authors: Shilo Shani , Roy Sashwati , Khanna Savita , Sen Chandan K.
Published: February 2008

Objective—

A Dicer knockdown approach was used to test the significance of miRNA in regulating the redox state and angiogenic response of human microvascular endothelial cells (HMECs).

Methods and Results—

Lowering of miRNA content by Dicer knockdown induced vascular endothelial growth factor expression but diminished the angiogenic response of HMECs as determined by cell migration and Matrigel tube formation. Such impairment of angiogenic response in the Matrigel was rescued by exogenous low micromolar H
2
O
2
. Dicer knockdown HMECs demonstrated lower inducible production of reactive oxygen species (ROS) when activated with either phorbol ester, tumor necrosis factor-α, or vascular endothelial growth factor. Limiting the production of ROS by antioxidant treatment or NADPH oxidase knockdown approaches impaired angiogenic responses. Experiments to identify how ROS production is limited by Dicer knockdown identified lower expression of p47phox protein in these cells. This lowering of cellular miRNA content induced expression of the transcription factor HBP1, a suppressor transcription factor that negatively regulates p47phox expression. Knockdown of HBP1 restored the angiogenic response of miRNA-deficient HMECs.

Conclusion—

This study provides the first evidence that redox signaling in cells is subject to regulation by miRNA. Specifically, p47phox of the NADPH oxidase complex has been identified as one target that regulates the angiogenic properties of endothelial cells.
Targeting the Calpain/Calpastatin System as a New Strategy to Prevent Cardiovascular Remodeling in Angiotensin II–Induced Hypertension
Authors: Letavernier Emmanuel , Perez Joëlle , Bellocq Agnès , Mesnard Laurent , de Castro Keller Alexandre , Haymann Jean-Philippe , Baud Laurent
Published: February 2008

In hypertension, angiotensin (Ang) II is a critical mediator of cardiovascular remodeling, whose prominent features include myocardial and vascular media hypertrophy, perivascular inflammation, and fibrosis. The signaling pathways responsible for these alterations are not completely understood. Here, we investigated the importance of calpains, calcium-dependent cysteine proteases. We generated transgenic mice constitutively expressing high levels of calpastatin, a calpain-specific inhibitor. Chronic infusion of Ang II led to similar increases in systolic blood pressure in wild-type and transgenic mice. In contrast, compared with wild-type mice, transgenic mice displayed a marked blunting of Ang II–induced hypertrophy of left ventricle. Ang II–dependent vascular remodeling, ie, media hypertrophy and perivascular inflammation and fibrosis, was also limited in both large arteries (aorta) and small kidney arteries from transgenic mice as compared with wild type. In vitro experiments using vascular smooth muscle cells showed that calpastatin transgene expression blunted calpain activation by Ang II through epidermal growth factor receptor transactivation. In vivo and in vitro models of inflammation showed that impaired recruitment of mononuclear cells in transgenic mice was attributable to a decrease in both the release of and the chemotactic response to monocyte chemoattractant protein-1. Finally, results from collagen synthesis assay and zymography suggested that limited fibrogenesis was attributable to a decrease in collagen deposition rather than an increase in collagen degradation. These results indicate a critical role for calpains as downstream mediators in Ang II–induced cardiovascular remodeling and, thus, highlight an attractive therapeutic target.
The Hydrodynamically Relevant Endothelial Cell Glycocalyx Observed In Vivo Is Absent In Vitro
Authors: Potter Daniel R. , Damiano Edward R.
Published: February 2008

In recent years, the endothelial cell surface glycocalyx has emerged as a structure of fundamental importance to a broad range of phenomena that determine cardiovascular health and disease. This new understanding of the functional significance of the glycocalyx has been made possible through recently developed experimental techniques using intravital microscopy that are capable of directly probing the glycocalyx in vivo. Using fluorescent microparticle image velocimetry in venules and endothelialized cylindrical collagen microchannels, we show that the hydrodynamically relevant endothelial cell glycocalyx surface layer observed in microvessels in vivo (0.52±0.28 μm thickness), which is a fundamental determinant of the hydrodynamic and mechanical environment at the endothelial cell surface, is absent from human umbilical vein (0.03±0.04 μm thickness) and bovine aortic (0.02±0.04 μm thickness) endothelial cells grown and maintained under standard cell culture conditions in vitro. An endothelial surface–bound glycosaminoglycan layer, not necessarily indicative of but having similar hydrodynamic properties to the endothelial glycocalyx observed in vivo, was detected (0.21±0.27 μm thickness) only after hyaluronan and chondroitin sulfate were added to the cell culture media at hyperphysiological concentrations (0.2 mg/mL perfused for 75 minutes). The implications of this glycocalyx deficiency under standard cell culture conditions in these pervasive in vitro models broadly impact a myriad of studies involving endothelial cell monolayers in which inferences are made that may depend on endothelial cell surface chemistry. In light of these findings, conclusions drawn from such studies in the areas of microvascular permeability, inflammation, mechanotransduction, and atherosclerosis must be carefully reconsidered.
c-kit Is Required for Cardiomyocyte Terminal Differentiation
Authors: Li Ming , Naqvi Nawazish , Yahiro Eiji , Liu Ke , Powell Pamela C. , Bradley Wayne E. , Martin David I.K. , Graham Robert M. , Dell’Italia Louis J. , Husain Ahsan
Published: February 2008

c-kit, the transmembrane tyrosine kinase receptor for stem cell factor, is required for melanocyte and mast cell development, hematopoiesis, and differentiation of spermatogonial stem cells. We show here that in the heart, c-kit is expressed not only by cardiac stem cells but also by cardiomyocytes, commencing immediately after birth and terminating a few days later, coincident with the onset of cardiomyocyte terminal differentiation. To examine the function of c-kit in cardiomyocyte terminal differentiation, we used compound heterozygous mice carrying the
W
(null) and
W

v

(dominant negative) mutations of c-kit. In vivo, adult
W
/
W

v

cardiomyocytes are phenotypically indistinguishable from their wild-type counterparts. After acute pressure overload adult
W
/
W

v

cardiomyocytes reenter the cell cycle and proliferate, leading to left ventricular growth; furthermore in transgenic mice with cardiomyocyte-restricted overexpression of the dominant negative
W

v

mutant, pressure overload causes cardiomyocytes to reenter the cell cycle. In contrast, in wild-type mice left ventricular growth after pressure overload results mainly from cardiomyocyte hypertrophy. Importantly,
W/W

v

mice with pressure overload–induced cardiomyocyte hyperplasia had improved left ventricular function and survival. In
W
/
W

v

mice, c-kit dysfunction also resulted in an ≈14-fold decrease (
P
<0.01) in the number of c-kit
+
/GATA4
+
cardiac progenitors. These findings identify novel functions for c-kit: promotion of cardiac stem cell differentiation and regulation of cardiomyocyte terminal differentiation.
History of Fetal Growth Restriction Is More Strongly Associated With Severe Rather Than Milder Pregnancy-Induced Hypertension
Authors: Rasmussen Svein , Irgens Lorentz M.
Published: February 2008

We assessed whether fetal growth restriction without pregnancy-induced hypertension (PIH) is associated with the different clinical subgroups of PIH in the subsequent pregnancy. We also assessed the maternal and paternal contributions to this effect. Pairs of first and second, second and third, third and fourth, and fourth and fifth births were identified among all of the births in Norway: 137 375 pairs with same mother and father, 18 376 pairs with same mother and different fathers, and 18 916 pairs with same father and different mothers. Second births in each pair were restricted to those that occurred in 1998–2005. Odds ratios to predict early onset, severe, and mild preeclampsia and transient hypertension in the second birth from birth weight <1500 g in the first compared with 3500 to 3999 g were 13.8, 7.1, 3.5, and 2.2, respectively. Odds ratios to predict early onset, severe, and mild preeclampsia and transient hypertension from birth weight below the 2.5th percentile compared with percentiles 10.0 to 89.9 were 4.2, 2.5, 2.1, and 1.7, respectively. Men who fathered a child with low birth weight in 1 woman were not more likely to later father a PIH pregnancy in another woman. The results indicate that placental dysfunction and PIH share a genetic factor that can be expressed as fetal growth restriction in 1 pregnancy and PIH in a subsequent pregnancy. Future genetic study is needed to confirm whether the association is caused by delayed genetic expression of endothelial dysfunction and whether the clinical subgroups of PIH have different genetic backgrounds.
Pregnancy Reverses Hypertensive Remodeling of Cerebral Arteries
Authors: Cipolla Marilyn J. , Smith Jeremiah , Bishop Nicole , Bullinger Lisa V. , Godfrey Julie A.
Published: February 2008

Previous studies have shown that pregnancy prevents hypertensive remodeling of cerebral arteries. In the present study, we sought to determine whether pregnancy could reverse preexisting remodeling. Nonpregnant virgin Sprague-Dawley rats were treated with the NO synthase inhibitor nitro-
l
-arginine (0.5 g/L in drinking water) for 2 weeks before mating, after which treatment continued until late gestation for a total of 5 weeks. Pregnant animals with preexisting hypertension (n=6) were compared with nonpregnant animals that were treated with nitro-
l
-arginine for either 2 (n=8) or 5 (n=9) weeks and compared with nontreated controls (n=8). Blood pressure, passive and active diameters, wall thickness, media thickness, and passive distensibility of cerebral arteries were compared between groups. Treatment with nitro-
l
-arginine caused a significant increase in mean arterial pressure in all of the groups compared with controls that was sustained for the entire study: 103±3 versus 137±2, 141±4, and 140±7 mm Hg (
P
<0.01). Both 2 and 5 weeks of hypertension caused inward eutrophic remodeling in nonpregnant animals, characterized by decreased inner and outer lumen diameters and no change in media thickness. Pregnancy reversed this remodeling, because late-pregnant animals with preexisting hypertension had inner and outer diameters similar to controls. Passive distensibility was significantly less, and active myogenic tone increased in all of the hypertensive animals, independent of pregnancy. These results demonstrate that pregnancy reverses preexisting hypertensive remodeling of cerebral arteries without a decrease in blood pressure. This reversal of protective remodeling during hypertension in pregnancy may be detrimental by lowering the upper limit of autoregulation, whereas blood pressure remains elevated.
Imbalance in Sex Hormone Levels Exacerbates Diabetic Renal Disease
Authors: Xu Qin , Wells Corinne C. , Garman Joseph H. , Asico Laureano , Escano Crisanto S. , Maric Christine
Published: February 2008

Studies suggest that the presence of testosterone exacerbates, whereas the absence of testosterone attenuates, the development of nondiabetic renal disease. However, the effects of the absence of testosterone in diabetic renal disease have not been studied. The study was performed in male Sprague-Dawley nondiabetic, streptozotocin-induced diabetic, and streptozotocin-induced castrated rats (n=10 to 11 per group) for 14 weeks. Diabetes was associated with the following increases: 3.2-fold in urine albumin excretion, 6.3-fold in glomerulosclerosis, 6.0-fold in tubulointerstitial fibrosis, 1.6-fold in collagen type I, 1.2-fold in collagen type IV, 1.3-fold in transforming growth factor-β protein expression, and 32.7-fold in CD68-positive cell abundance. Diabetes was also associated with a 1.3-fold decrease in matrix metalloproteinase protein expression and activity. Castration further exacerbated all of these parameters. Diabetes was also associated with a 4.7-fold decrease in plasma testosterone, 2.9-fold increase in estradiol, and 2.1-fold decrease in plasma progesterone levels. Castration further decreased plasma testosterone levels but had no additional effects on plasma estradiol and progesterone. These data suggest that diabetes is associated with abnormal sex hormone levels that correlate with the progression of diabetic renal disease. Most importantly, our results suggest an important role for sex hormones in the pathophysiology of diabetic renal complications.
Age- and Sodium-Sensitive Hypertension and Sex-Dependent Renal Changes in Rats With a Reduced Nephron Number
Authors: Salazar Francisco , Reverte Virginia , Saez Fara , Loria Analia , Llinas M. Teresa , Salazar F. Javier
Published: February 2008

We have demonstrated that the reduction of angiotensin II effects during the nephrogenic period reduces the nephron number and induces the development of hypertension. The hypotheses examined are that this reduction of angiotensin effects leads to the development of an age-dependent sodium sensitive hypertension and that the hypertension is angiotensin II dependent. Newborn rats were treated with an angiotensin II type 1 receptor antagonist during the first 2 weeks of age. At 3 to 4 and 11 to 12 months of age, changes in systolic blood pressure, proteinuria, and renal function in response to a prolonged high sodium intake were examined. The basal blood pressure response to the administration of the angiotensin II receptor antagonist was also evaluated at both ages. Basal blood pressure was similarly elevated (
P
<0.05) in male and female treated rats, and the increment was age dependent. High sodium intake only elicited a blood pressure elevation (136±1 to 154±3 mm Hg;
P
<0.05) and a decrease in glomerular filtration rate (28%;
P
<0.05) at 11 to 12 months in treated rats. Blockade of angiotensin II receptors during renal development induced an increase (
P
<0.05) in proteinuria that was age and sex dependent, but high sodium intake only induced an elevation in proteinuria in the younger rats (50%;
P
<0.05). Hypertension was maintained by angiotensin II at both ages because blood pressure decreased to normal levels after treatment with an angiotensin II type 1 receptor antagonist. This study shows that the reduction of angiotensin II effects during the nephrogenic period modifies renal function and induces the development of an angiotensin II–dependent hypertension that becomes sodium sensitive during aging.
Systematic, Genome-Wide, Sex-Specific Linkage of Cardiovascular Traits in French Canadians
Authors: Šeda Ondrej , Tremblay Johanne , Gaudet Daniel , Brunelle Pierre-Luc , Gurau Alexandru , Merlo Ettore , Pilote Louise , Orlov Sergei N. , Boulva Francis , Petrovich Milan , Kotchen Theodore A. , Cowley Allen W. , Hamet Pavel
Published: February 2008

The sexual dimorphism of cardiovascular traits, as well as susceptibility to a variety of related diseases, has long been recognized, yet their sex-specific genomic determinants are largely unknown. We systematically assessed the sex-specific heritability and linkage of 539 hemodynamic, metabolic, anthropometric, and humoral traits in 120 French-Canadian families from the Saguenay-Lac-St-Jean region of Quebec, Canada. We performed multipoint linkage analysis using microsatellite markers followed by peak-wide linkage scan based on Affymetrix Human Mapping 50K Array
Xba240
single nucleotide polymorphism genotypes in 3 settings, including the entire sample and then separately in men and women. Nearly one half of the traits were age and sex independent, one quarter were both age and sex dependent, and one eighth were exclusively age or sex dependent. Sex-specific phenotypes are most frequent in heart rate and blood pressure categories, whereas sex- and age-independent determinants are predominant among humoral and biochemical parameters. Twenty sex-specific loci passing multiple testing criteria were corroborated by 2-point single nucleotide polymorphism linkage. Several resting systolic blood pressure measurements showed significant genotype-by-sex interaction, eg, male-specific locus at chromosome 12 (male-female logarithm of odds difference: 4.16; interaction
P
=0.0002), which was undetectable in the entire population, even after adjustment for sex. Detailed interrogation of this locus revealed a 220-kb block overlapping parts of TAO-kinase 3 and SUDS3 genes. In summary, a large number of complex cardiovascular traits display significant sexual dimorphism, for which we have demonstrated genomic determinants at the haplotype level. Many of these would have been missed in a traditional, sex-adjusted setting.
Effects of Losartan in Women With Hypertension and Left Ventricular Hypertrophy
Authors: Os Ingrid , Franco Veronica , Kjeldsen Sverre E. , Manhem Karin , Devereux Richard B. , Gerdts Eva , Hille Darcy A. , Lyle Paulette A. , Okin Peter M. , Dahlöf Björn , Oparil Suzanne
Published: February 2008

Hypertension is a risk factor for cardiovascular disease and outcomes in women. These posthoc analyses from the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study evaluated losartan- versus atenolol-based therapy on the primary composite end point of cardiovascular death, stroke, and myocardial infarction and other end points in 4963 women. Fewer events occurred in women versus men. Women in the losartan group had significant reductions in the primary end point (215 [18.2 per 1000 patient-years] versus 261 [22.5 per 1000 patient-years]; hazard ratio [HR]: 0.82 [95% CI: 0.68 to 0.98];
P
=0.031), stroke (109 versus 154; HR: 0.71 [95% CI: 0.55 to 0.90];
P
=0.005), total mortality (HR: 0.77 [95% CI: 0.63 to 0.95];
P
=0.014), and new-onset diabetes (HR: 0.75 [95% CI: 0.59 to 0.94];
P
=0.015) versus the atenolol group, with no between-treatment difference for myocardial infarction (HR: 1.02 [95% CI: 0.74 to 1.39];
P
=0.925), cardiovascular mortality (HR: 0.86 [95% CI: 0.64 to 1.14];
P
=0.282), or hospitalization for heart failure (HR: 0.94 [95% CI: 0.68 to 1.28];
P
=0.677). More women in the losartan group required hospitalization for angina (HR: 1.70 [95% CI: 1.16 to 2.51];
P
=0.007). Risk reductions for the primary composite end point, stroke, total mortality, and new-onset diabetes were significantly greater with losartan- versus atenolol-based treatment in women with hypertension and left ventricular hypertrophy in the LIFE study. The risk reductions for losartan, along with the tests for the interaction of treatment and gender, indicated that the treatment effect was consistent in men and women for all of the end points tested, with the exception of hospitalization for angina.