bluuebunny/crossref_metadata_2025 huggingface dataset:
Hyperoxia attenuates muscle sympathetic nerve activity following isocapnic hypoxia in humans
Authors: Querido Jordan S. , Kennedy Paul M. , Sheel A. William
Published: February 2010

Hypoxia may sensitize the carotid chemoreceptors, resulting in a sustained elevation of muscle sympathetic nerve activity (MSNA) that outlasts the hypoxic stimulus. To test this hypothesis, we determined the effect of carotid body inhibition on the sustained elevation of MSNA following isocapnic hypoxia in humans. Seven healthy subjects (5 male, 2 female) breathed 100% O2 (hyperoxia) for 1 min before (2 interventions) and after (2–3 interventions) 20 min of isocapnic hypoxia (80% arterial oxyhemoglobin saturation). MSNA was continuously recorded from the common peroneal nerve with microneurography. There was no effect of hyperoxia on MSNA before exposure to isocapnic hypoxia. During the isocapnic hypoxia exposure, there was an increase in minute ventilation and heart rate that subsided once hypoxia was terminated. In contrast, there was an increase in MSNA burst frequency that persisted for ∼25 min after cessation of the stimulus. Hyperoxia resulted in a transient reduction in MSNA burst frequency of 28% ( P < 0.05), 15% ( P < 0.05), and 9% ( P > 0.05) in the three posthypoxia interventions, respectively. Our results suggest that input from the carotid chemoreceptors is obligatory for the sustained elevation of MSNA initiated by chemoreflex stimulation. We attribute the decrease in MSNA to a transient hyperoxia-induced attenuation of carotid chemoreceptor sensitivity.
Blood flow restriction exercise stimulates mTORC1 signaling and muscle protein synthesis in older men
Authors: Fry Christopher S. , Glynn Erin L. , Drummond Micah J. , Timmerman Kyle L. , Fujita Satoshi , Abe Takashi , Dhanani Shaheen , Volpi Elena , Rasmussen Blake B.
Published: February 2010

The loss of skeletal muscle mass during aging, sarcopenia, increases the risk for falls and dependence. Resistance exercise (RE) is an effective rehabilitation technique that can improve muscle mass and strength; however, older individuals are resistant to the stimulation of muscle protein synthesis (MPS) with traditional high-intensity RE. Recently, a novel rehabilitation exercise method, low-intensity RE, combined with blood flow restriction (BFR), has been shown to stimulate mammalian target of rapamycin complex 1 (mTORC1) signaling and MPS in young men. We hypothesized that low-intensity RE with BFR would be able to activate mTORC1 signaling and stimulate MPS in older men. We measured MPS and mTORC1-associated signaling proteins in seven older men (age 70 ± 2 yr) before and after exercise. Subjects were studied identically on two occasions: during BFR exercise [bilateral leg extension exercise at 20% of 1-repetition maximum (1-RM) with pressure cuff placed proximally on both thighs and inflated at 200 mmHg] and during exercise without the pressure cuff (Ctrl). MPS and phosphorylation of signaling proteins were determined on successive muscle biopsies by stable isotopic techniques and immunoblotting, respectively. MPS increased 56% from baseline after BFR exercise ( P < 0.05), while no change was observed in the Ctrl group ( P > 0.05). Downstream of mTORC1, ribosomal S6 kinase 1 (S6K1) phosphorylation and ribosomal protein S6 (rpS6) phosphorylation increased only in the BFR group after exercise ( P < 0.05). We conclude that low-intensity RE in combination with BFR enhances mTORC1 signaling and MPS in older men. BFR exercise is a novel intervention that may enhance muscle rehabilitation to counteract sarcopenia.
A Microdeletion at 12q24.31 Can Mimic Beckwith-Wiedemann Syndrome Neonatally
Authors: Baple E. , Palmer R. , Hennekam R.C.M.
Published: February 2010

We report on a patient who was initially suspected to have Beckwith-Wiedemann syndrome because of recurrent neonatal hypoglycaemias, macroglossia and overgrowth, but in whom no 11p15 abnormality could be found. Follow-up showed continued overgrowth and disturbed glucose homeostasis, a marked developmental delay, and severe behavioural problems especially caused by anxieties. Array comparative genomic hybridization analysis showed a de novo 12q24.31 interstitial deletion, which was confirmed by fluorescence in situ hybridization. The deleted region contains amongst others: HNF1 homeobox A (HNF1A) which is important for the regulation of gene expression in the liver and involved in maturity-onset diabetes of the young type 3 and insulin resistance; acyl-CoA dehydrogenase short chain (ACADS) which encodes an enzyme important in mitochondrial fatty acid beta-oxidation and can cause short-chain acyl-CoA dehydrogenese (SCAD) deficiency, and purinergic receptor P2X7 (P2RX7) which encodes a ligand-gated ion channel, and of which polymorphisms are found with increased frequency in patients with psychiatric disorders, especially anxieties. We conclude the present patient has a hitherto undescribed contiguous gene syndrome, which can initially resemble Beckwith-Wiedemann syndrome.
A Novel Familial BBS12 Mutation Associated with a Mild Phenotype: Implications for Clinical and Molecular Diagnostic Strategies
Authors: Pawlik B. , Mir A. , Iqbal H. , Li Y. , Nürnberg G. , Becker C. , Qamar R. , Nürnberg P. , Wollnik B.
Published: February 2010

Bardet-Biedl syndrome (BBS) is an autosomal recessively inherited ciliopathy mainly characterized by rod-cone dystrophy, postaxial polydactyly, obesity, renal tract anomalies, and hypogonadism. To date, 14 BBS genes, BBS1 to BBS14, have been identified, accounting for over 75% of mutations in BBS families. In this study, we present a consanguineous family from Pakistan with postaxial polydactyly and late-onset retinal dysfunction. Adult affected individuals did not show any renal or genital anomalies, obesity, mental retardation or learning difficulties and did thus not fulfill the proposed clinical diagnostic criteria for BBS. We mapped the disease in this family to the BBS12 locus on chromosome 4q27 and identified the novel homozygous p.S701X nonsense mutation in BBS12 in all three affected individuals of this family. We conclude that BBS12 mutations might cause a very mild phenotype, which is clinically not diagnosed by the current diagnostic criteria for BBS. Consequently, we suggest the use of less strict diagnostic criteria in familial BBS families with mild phenotypic expression.
Postnatal Hydrocortisone for Preventing or Treating Bronchopulmonary Dysplasia in Preterm Infants: A Systematic Review
Authors: Doyle Lex W. , Ehrenkranz Richard A. , Halliday Henry L.
Published: February 2010

Background: Corticosteroids have been used widely after birth in preterm infants with respiratory failure; hydrocortisone may be preferable to other corticosteroids for this purpose. Objectives: To determine if postnatal hydrocortisone is useful to prevent or treat bronchopulmonary dysplasia (BPD) in preterm infants. Methods: Randomised controlled trials (RCTs) of postnatal hydrocortisone therapy to prevent or treat BPD were sought. Data regarding clinical outcomes including mortality, BPD, death or BPD, complications during the primary hospitalisation, and long-term outcome were abstracted and analysed using RevMan 5. Results: Eight RCTs enrolling a total of 880 participants were eligible. In all trials treatment was started in the first week of life; there were no trials of treatment started in infants who were chronically ventilator-dependent after the first week of life with established or evolving BPD. A meta-analysis of the available trials demonstrated little evidence for a direct effect of hydrocortisone on the rates of BPD, mortality, or the combined outcome of BPD or mortality. Hydrocortisone in the doses used in these eight studies had few beneficial or harmful effects; the notable exception was an increase in gastrointestinal perforation. Conclusions: Postnatal hydrocortisone in the doses and regimens used in the reported trials has few beneficial or harmful effects and cannot be recommended for prevention of BPD. There are no randomised trials to substantiate the use of hydrocortisone in chronically ventilator-dependent infants with established or evolving BPD.
Severe Progressive Autism Associated with Two de novo Changes: A 2.6-Mb 2q31.1 Deletion and a Balanced t(14;21)(q21.1;p11.2) Translocation with Long-Range Epigenetic Silencing of LRFN5 Expression
Authors: de Bruijn D.R.H. , van Dijk A.H.A. , Pfundt R. , Hoischen A. , Merkx G.F.M. , Gradek G.A. , Lybæk H. , Stray-Pedersen A. , Brunner H.G. , Houge G.
Published: February 2010

In a 19-year-old severely autistic and mentally retarded girl, a balanced de novo t(14;21)(q21.1;p11.2) translocation was found in addition to a de novo 2.6-Mb 2q31.1 deletion containing 15 protein-encoding genes. To investigate if the translocation might contribute to developmental stagnation at the age of 2 years with later regression of skills, i.e. a more severe phenotype than expected from the 2q31.1 deletion, the epigenetic status and expression of genes proximal and distal to the 14q21.1 breakpoint were investigated in Ebstein Barr Virus-transformed lymphoblast and primary skin fibroblast cells. The 14q21.1 breakpoint was found to be located between a cluster of 7 genes 0.1 Mb upstream, starting with FBXO33, and the single and isolated LRFN5 gene 2.1 Mb downstream. Only expression of LRFN5 appeared to be affected by its novel genomic context. In patient fibroblasts, LRFN5 expression was 10-fold reduced compared to LRFN5 expressed in control fibroblasts. In addition, a relative increase in trimethylated histone H3 lysine 9 (H3K9M3)-associated DNA starting exactly at the translocation breakpoint and going 2.5 Mb beyond the LRFN5 gene was found. At the LRFN5 promoter, there was a distinct peak of trimethylated histone H3 lysine 27 (H3K27M3)-associated DNA in addition to a diminished trimethylated histone H3 lysine 4 (H3K4M3) level. We speculate that dysregulation of LRFN5, a postsynaptic density-associated gene, may contribute to the patient’s autism, even though 2 other patients with 14q13.2q21.3 deletions that included LRFN5 were not autistic. More significantly, we have shown that translocations may influence gene expression more than 2 Mb away from the translocation breakpoint.
Preferences for Hereditary Breast and Ovarian Cancer Information among Mexican, Cuban and Puerto Rican Women at Risk
Authors: Quinn Gwendolyn P. , McIntyre Jessica , Vadaparampil Susan T.
Published: February 2010

Background: Little is known about the preferences of at-risk Hispanic women to gain information on hereditary breast and ovarian cancer (HBOC). Aims: This study sought to qualitatively explore preferences for HBOC information among at-risk Mexican, Puerto Rican and Cuban women and to pilot a mock brochure aimed at Hispanic women. Methods: Hispanic women aged 18–65 years with a personal or family history of breast or ovarian cancer participated in a semistructured interview. Data were analyzed using a combination of open-coding and content analysis. Results: Fifty-three women participated in the study. For the majority of content areas, there were no major differences between the subethnicities. All women reported discussing cancer with a doctor after a family member had been diagnosed and discussing cancer within their families; however, the content of the discussion varied. Cuban and Puerto Rican women reported using the Internet routinely for health care information while Mexican women said they did not have access to computers and did not use them. All women liked the content and photos in the brochure but Mexican women thought the reading level was too high. Preferences for the spokesperson focused on the need for Spanish-speaking health care providers. Conclusions: While the data show some similarities, such as patterns of cancer discussion and appreciation of the mock brochure, there were differences between the groups on information preferences. In designing HBOC education information for Hispanic audiences, it is important to consider varied channels for dissemination and preferences for specific types of information across subethnicities.
Enhanced External Counterpulsation Attenuates Atherosclerosis Progression Through Modulation of Proinflammatory Signal Pathway
Authors: Zhang Yan , He Xiaohong , Liu Donghong , Wu Guifu , Chen Xiaolin , Ma Hong , Du Zhimin , Dong Yugang , Jin Yafei , He Wen , Wang Kuijian , Lawson William E. , Hui John C.K. , Zheng Zhensheng
Published: February 2010

Objective—

Shear stress may be the most crucial local factor affecting atherogenesis. The present study investigated the effect of exposure to increased shear stress promoted by enhanced external counterpulsation (EECP) on the progression of atherosclerosis and the underlying inflammation-related molecular mechanisms in a porcine model of hypercholesterolemia.

Methods and Results—

Hypercholesterolemic pigs were subjected to a 7-week EECP intervention while being fed a high-cholesterol diet. EECP resulted in a 34.38% increase of mean wall shear stress and a significantly lower pulsatility index in the brachial artery. The animals receiving EECP showed a marked reduction in atherosclerotic lesion size in the coronary artery and abdominal aorta compared with the hypercholesterolemic control group, associated with a decrease in macrophage accumulation. The expression of a set of genes involved in inflammation (including C-reactive protein [CRP], complement 3a, vascular cell adhesion molecule-1 [VCAM-1], and inducible nitric oxide synthase), mitogen-activated protein kinase (MAPK)-p38 phosphorylation, and nuclear factor-κB (NF-κB) activation, was attenuated.

Conclusion—

These findings suggested that long-term EECP exerts a retarding effect on atherosclerosis by downregulating proinflammatory gene expression. The underlying mechanisms are related to chronic exposure to increased pulsatile shear stress promoted by EECP; this exposure suppresses the overactivation of the MAPK-P38/NF-κB/VCAM-1 signaling pathway induced by hypercholesterolemia.
CREB Downregulation in Vascular Disease
Authors: Schauer Irene E. , Knaub Leslie A. , Lloyd Monique , Watson Peter A. , Gliwa Catherine , Lewis Katherine E. , Chait Alan , Klemm Dwight J. , Gunter Jody M. , Bouchard Ron , McDonald Thomas O. , O'Brien Kevin D. , Reusch Jane E.B.
Published: February 2010

Objective—

To examine the impact of low-density lipoprotein (LDL), an established mediator of atherosclerosis, on the transcription factor cAMP-response element-binding protein (CREB), which is a regulator of vascular smooth muscle cell (VSMC) quiescence.

Methods and Results—

VSMC CREB content is diminished in rodent models of diabetes and pulmonary hypertension. We examined aortic CREB content in rodent models of aging, hypertension, and insulin resistance, and we determined nuclear CREB protein in the medial VSMC of high-fat-fed LDL receptor-null mice. There was significant loss of CREB protein in all models. In vitro, primary culture rat aortic VSMC exposed to LDL and oxidized LDL exhibited a rapid, transient increase in CREB phosphorylation and transient phosphorylation/activation of Akt, ERK, JNK, ans p38 MAPK. Exposure to oxidized LDL, but not to LDL, for 24 to 48 hours decreased CREB protein in a dose-dependent fashion and led to nuclear exclusion of CREB. Pharmacological reactive oxygen species scavengers and inhibition of ERK activation blocked oxidized LDL-mediated CREB downregulation.

Conclusion—

These data support a model wherein loss of VSMC CREB protein, which renders these cells more susceptible to activation and apoptosis, is a common pathological response to vascular injury and potentially contributes to plaque progression.
Genome-Wide Association Study Identifies Variants at the
IL18
-BCO2
Locus Associated With Interleukin-18 Levels
Authors: He Meian , Cornelis Marilyn C. , Kraft Peter , van Dam Rob M. , Sun Qi , Laurie Cathy C. , Mirel Daniel B. , Chasman Daniel I. , Ridker Paul M , Hunter David J. , Hu Frank B. , Qi Lu
Published: February 2010

Objective—

Interleukin-18 (IL-18) is a proinflammatory cytokine involved in the processes of innate and acquired immunities and associated with cardiovascular disease and type 2 diabetes. We sought to identify the common genetic variants associated with IL-18 levels.

Methods and Results—

We performed a 2-stage genome-wide association study among women of European ancestry from the Nurses’ Health Study (NHS) and Women’s Genome Health Study (WGHS). IL-18 levels were measured by ELISA. In the discovery stage (NHS, n=1523), 7 single-nucleotide polymorphisms (SNPs) at the
IL18
-BCO2
locus were associated with IL-18 concentrations at the 1×10
−5
significance level. The strongest association was found for SNP rs2115763 in the
BCO2
gene (
P
=6.31×10
−8
). In silico replication in WGHS (435 women) confirmed these findings. The combined analysis of the 2 studies indicated that SNPs rs2115763, rs1834481, and rs7106524 reached a genome-wide significance level (
P
<5×10
−8
). Forward selection analysis indicated that SNPs rs2115763 and rs1834481 were independently associated with
IL-18
levels (
P
=0.0002 and 0.0006, respectively). The 2 SNPs together explained 2.9% of variation of plasma IL-18 levels.

Conclusion—

This study identified several novel variants at the
IL18
-BCO2
locus associated with IL-18 levels.
Macrophage LRP-1 Controls Plaque Cellularity by Regulating Efferocytosis and Akt Activation
Authors: Yancey Patricia G. , Blakemore John , Ding Lei , Fan Daping , Overton Cheryl D. , Zhang Youmin , Linton MacRae F. , Fazio Sergio
Published: February 2010

Objective—

The balance between apoptosis susceptibility and efferocytosis of macrophages is central to plaque remodeling and inflammation. LRP-1 and its ligand, apolipoprotein E, have been implicated in efferocytosis and apoptosis in some cell types. We investigated the involvement of the macrophage LRP-1/apolipoprotein E axis in controlling plaque apoptosis and efferocytosis.

Method and Results—

LRP-1
−/−
macrophages displayed nearly 2-fold more TUNEL positivity compared to wild-type cells in the presence of DMEM alone or with either lipopolysaccharide or oxidized low-density lipoprotein. The survival kinase, phosphorylated Akt, was barely detectable in LRP-1
−/−
cells, causing decreased phosphorylated Bad and increased cleaved caspase-3. Regardless of the apoptotic stimulation and degree of cell death, LRP-1
−/−
macrophages displayed enhanced inflammation with increased IL-1β, IL-6, and tumor necrosis factor-α expression. Efferocytosis of apoptotic macrophages was reduced by 60% in LRP-1
−/−
vs wild-type macrophages despite increased apolipoprotein E expression by both LRP-1
−/−
phagocytes and wild-type apoptotic cells. Compared to wild-type macrophage lesions, LRP-1
−/−
lesions had 5.7-fold more necrotic core with more dead cells not associated with macrophages.

Conclusion—

Macrophage LRP-1 deficiency increases cell death and inflammation by impairing phosphorylated Akt activation and efferocytosis. Increased apolipoprotein E expression in LRP-1
−/−
macrophages suggests that the LRP-1/apolipoprotein E axis regulates the balance between apoptosis and efferocytosis, thereby preventing necrotic core formation.
Nonalcoholic Fatty Liver Disease as the Transducer of Hepatic Oversecretion of Very-Low-Density Lipoprotein–Apolipoprotein B-100 in Obesity
Authors: Chan Dick C. , Watts Gerald F. , Gan SengKhee , Wong Annette T.Y. , Ooi Esther M.M. , Barrett P. Hugh R.
Published: February 2010

Objective—

To examine the association between liver fat content and very low-density lipoprotein (VLDL)–apolipoprotein (apo) B-100 kinetics and the corresponding responses to weight loss in obese subjects.

Methods and Results—

VLDL–apoB-100 kinetics were assessed using stable isotope tracers, and the fat content of the liver and abdomen was determined by magnetic resonance techniques in 25 obese subjects. In univariate analysis, liver fat content was significantly (
P
<0.05 in all) associated with body mass index (
r
=0.65), visceral fat area (
r
=0.45), triglycerides (
r
=0.40), homeostasis model assessment score (
r
=0.40), VLDL–apoB-100 concentrations (
r
=0.44), and secretion rate (
r
=0.45). However, liver fat content was not associated with plasma concentrations of retinol-binding protein 4, fetuin A, adiponectin, interleukin-6, and tumor necrosis factor-α. Of these 25 subjects, 9 diagnosed as having nonalcoholic fatty liver disease (which is highly prevalent in obese individuals and strongly associated with dyslipidemia) underwent a weight loss program. The low-fat diet achieved significant reduction in body weight, body mass index, liver fat, visceral and subcutaneous fat areas, homeostasis model assessment score, triglycerides, VLDL–apoB-100 concentrations, and VLDL–apoB-100 secretion rate. The percentage reduction of liver fat with weight loss was significantly associated with the corresponding decreases in VLDL–apoB-100 secretion (
r
=0.67) and visceral fat (
r
=0.84).

Conclusion—

In patients with obesity, hepatic steatosis increases VLDL–apoB-100 secretion. Weight loss can help reduce this abnormality.
TRAIL Promotes VSMC Proliferation and Neointima Formation in a FGF-2–, Sp1 Phosphorylation–, and NFκB-Dependent Manner
Authors: Chan Jeffrey , Prado-Lourenco Leonel , Khachigian Levon M. , Bennett Martin R. , Di Bartolo Belinda A. , Kavurma Mary M.
Published: February 2010

Rationale
:

TRAIL (tumor necrosis factor–related apoptosis-inducing ligand) is well reported as an inducer of apoptosis in tumor models; however, its role and function in vivo in atherosclerosis and vascular injury has not been established.

Objective
:

We sought to study the function of TRAIL in cardiovascular pathology and its regulation in vivo.

Methods and Results
:

Here, we show that TRAIL was upregulated in medial vascular smooth muscle cells (VSMCs) 24 hours following perivascular cuff placement around femoral arteries of mice. We also show that TRAIL mRNA and promoter activity was induced in VSMCs following in vitro mechanical injury. Intimal thickening 15 days after cuff placement was reduced 2- to 3-fold in TRAIL
−/−
compared to wild-type mice and was reversible by administration of recombinant TRAIL. Additionally, reduced VSMC proliferation was observed in injured arteries of TRAIL
−/−
mice. Fibroblast growth factor (FGF)-2, a potent growth factor released following vascular injury, was also reduced in arteries of TRAIL
−/−
mice, and VSMCs isolated from these animals did not respond to FGF-2 in vitro. Injury and FGF-2 regulated TRAIL transcriptional activity via 2 specificity protein (Sp)1 elements in the proximal TRAIL promoter, a binding site also shared by nuclear factor (NF)κB. Mutational studies confirmed a role for Sp1 in injury- and FGF-2–inducible TRAIL transcription. Furthermore, increased NFκB expression after injury transactivated the TRAIL promoter. Interestingly, following mechanical injury, Sp1 phosphorylation (Thr453) and an increase in the physical interaction of p-Sp1(Thr453) with NFκB was observed.

Conclusions
:

We conclude that TRAIL induction involves FGF-2, Sp1-phosphorylation and NFκB and that TRAIL promotes VSMC proliferation and neointima formation after arterial injury.
Low Levels of Antibodies Against Phosphorylcholine Predict Development of Stroke in a Population-Based Study From Northern Sweden
Authors: Fiskesund Roland , Stegmayr Birgitta , Hallmans Göran , Vikström Max , Weinehall Lars , de Faire Ulf , Frostegård Johan
Published: February 2010

Background and Purpose—

Natural immunoglobulin M antibodies specific for phosphorylcholine (anti-PC) have been implicated in atherosclerosis. We have shown previously that high levels of anti-PC predict a slower progression of atherosclerosis in humans and that low levels of anti-PC are associated with higher risk for cardiovascular disease. Here we determine the association between anti-PC and the incidence of stroke.

Methods—

Using a nested case control study design, we examined 227 incident cases (125 men and 102 women) of first-time stroke and 455 age- and sex-matched controls identified during a 13-year time period (1985 to 1999) within the population-based cohorts of the Västerbotten Intervention Project (VIP) and the World Health Organization Monitoring Trends and Determinants in Cardiovascular Disease (WHO MONICA) project in Northern Sweden. Odds ratios of stroke with 95% CIs with adjustments for age, gender, smoking, serum cholesterol, diabetes, body mass index, and blood pressure were determined. Anti-PC levels were measured using ELISA.

Results—

A significant association between low levels of anti-PC at baseline and incident stroke was seen for the whole group of anti-PC levels below the 30th percentile (multivariately adjusted odds ratio, 1.62; CI, 1.11 to 2.35). Analyses of gender-specific associations indicated fairly strong associations for females, especially at the lowest 30th percentile (multivariately adjusted odds ratio, 2.65; CI, 1.41 to 4.95). No associations were noted for men.

Conclusion—

Low anti-PC is a novel independent risk marker for development of stroke. Measurements of anti-PC could be used to identify immunodeficient subjects at an increased risk for stroke. The possibility that such subjects might be targets for novel modes of treatment such as immunotherapies deserves further investigation.
Differing Risk Factor Profiles of Ischemic Stroke Subtypes
Authors: Jackson Caroline A. , Hutchison Aidan , Dennis Martin S. , Wardlaw Joanna M. , Lindgren Arne , Norrving Bo , Anderson Craig S. , Hankey Graeme J. , Jamrozik Konrad , Appelros Peter , Sudlow Cathie L.M.
Published: February 2010

Background and Purpose—

Differences in risk factor profiles between lacunar and other ischemic stroke subtypes may provide evidence for a distinct lacunar arteriopathy, but existing studies have limitations. We overcame these by pooling individual data on 2875 patients with first-ever ischemic stroke from 5 collaborating prospective stroke registers that used similar, unbiased methods to define risk factors and classify stroke subtypes.

Methods—

We compared risk factors between lacunar and nonlacunar ischemic strokes, altering the comparison groups in sensitivity analyses, and incorporated these data into a meta-analysis of published studies.

Results—

Unadjusted and adjusted analyses gave similar results. We found a lower prevalence of cardioembolic source (adjusted odds ratio, 0.33; 95% CI, 0.24 to 0.46), ipsilateral carotid stenosis (odds ratio, 0.21; 95% CI, 0.14 to 0.30), and ischemic heart disease (odds ratio, 0.75; 95% CI, 0.58 to 0.97) in lacunar compared with nonlacunar patients but no difference for hypertension, diabetes, or any other risk factor studied. Results were robust to sensitivity analyses and largely confirmed in our meta-analysis.

Conclusions—

Hypertension and diabetes appear equally common in lacunar and nonlacunar ischemic stroke, but lacunar stroke is less likely to be caused by embolism from the heart or proximal arteries, and the lower prevalence of ischemic heart disease in lacunar stroke provides additional support for a nonatherosclerotic arteriopathy causing many lacunar ischemic strokes. Our findings have implications for how clinicians classify ischemic stroke subtypes and highlight the need for additional research into the specific causes of and treatments for lacunar stroke.
Recanalization of Vertebral Artery Dissection
Authors: Arauz Antonio , Márquez Juan Manuel , Artigas Carol , Balderrama Jorge , Orrego Hector
Published: February 2010

Background and Purpose—

We investigated the predictors and time course for recanalization after vertebral artery dissection.

Methods—

We prospectively studied 61 consecutive patients with confirmed diagnoses of vertebral artery dissection without intracerebral hemorrhage. Neuroimaging and clinical follow-up were performed at presentation and at 3, 6, and 12 months.

Results—

We included 61 patients with confirmed vertebral artery dissection; 19 were evaluated and followed up with conventional angiography, 24 with MR angiography, and 18 with CT angiography. Fifty-one patients had a stenotic dissection, 7 had an occlusive dissection, one had a double-lumen image, and 2 had a pseudoaneurysm. The estimated rate of complete recanalization after vertebral artery dissection was 45.9% at 3 months, 62.3% at 6 months, and 63.9% at 12 months. We found no association between outcome and complete or partial recanalization nor did we find any factors associated with recanalization.

Conclusions—

These results suggest that recanalization of vertebral artery dissection occurs mainly within the first 6 months after the onset of symptoms regardless of the location or pattern of the dissection.
Cystatin C and the Risk for Cardiovascular Events in Patients With Asymptomatic Carotid Atherosclerosis
Authors: Hoke Matthias , Amighi Jasmin , Mlekusch Wolfgang , Schlager Oliver , Exner Markus , Sabeti Schila , Dick Petra , Koppensteiner Renate , Minar Erich , Rumpold Helmut , Wagner Oswald , Schillinger Martin
Published: February 2010

Background and Purpose—

Renal dysfunction is a risk factor for cardiovascular events in patients with atherosclerosis. Unlike serum creatinine or estimated glomerular filtration rate, cystatin C reflects renal dysfunction independent of factors such as sex, weight, and race. We investigated whether baseline serum levels of cystatin C predict major cardiovascular events in patients with asymptomatic carotid atherosclerosis and compared the predictive value of cystatin C to these established markers of renal function.

Methods—

We prospectively studied 1004 of 1286 consecutive patients with carotid ultrasound scanning. Patients were followed for the occurrence of major cardiovascular events, a composite of myocardial infarction, percutaneous coronary intervention, coronary bypass graft, stroke, and death.

Results—

During a median of 3 years of follow-up, we recorded 346 major cardiovascular events in 311 patients. The risk for a first major cardiovascular event increased significantly with increasing quintiles of cystatin C; hazard ratios ranged from 1.18 to 1.94 for the highest versus the lowest quintile (
P
<0.001 for trend). Creatinine levels showed no significant association with major cardiovascular events, and for glomerular filtration rate, only the lowest quintile was moderately associated with adverse cardiovascular outcome.

Conclusions—

Cystatin C was significantly and gradually associated with future cardiovascular events in patients with carotid atherosclerosis. In contrast, neither serum creatinine nor estimated glomerular filtration rate were significant predictors of adverse cardiovascular outcomes.
Quality-Adjusted Life Expectancy (QALE) and Loss of QALE for Patients With Ischemic Stroke and Intracerebral Hemorrhage
Authors: Lee Hsin-Yi , Hwang Jing-Shiang , Jeng Jiann-Shing , Wang Jung-Der
Published: February 2010

Background and Purpose—

Few studies have evaluated the long-term health impact of stroke as categorized into different subtypes. The aim of this study is to quantify the loss of quality-adjusted life expectancy related to ischemic stroke and intracerebral hemorrhage.

Methods—

The hospital-based cohort, which consisted of 13 194 patients with first-ever stroke onset dates between 1995 and 2007, was classified into lacunar and nonlacunar infarctions and intracerebral hemorrhages. After linking with the National Mortality Registry, survival functions were determined and extrapolated over a 50-year period based on the survival ratio between the patients’ survival and age- and sex-matched reference population’s as calculated from the vital statistics of Taiwan. The survival functions were then multiplied by the quality of life assessed under the EuroQol 5-dimension (EQ-5D) questionnaire based on a sample of 486 patients with stroke.

Results—

The quality-adjusted life expectancy for a patient with ischemic stroke was 8.7 quality-adjusted life-years with an average loss of 8.3 quality-adjusted life-years, and there appeared to be no difference between lacunar and nonlacunar infarctions. Patients with intracerebral hemorrhage had a similar quality-adjusted life expectancy as those with ischemic stroke but with a significantly greater loss relative to the reference population (14.1 quality-adjusted life-years) because of younger ages.

Conclusion—

The lifelong health burden due to stroke was approximately 9.5 quality-adjusted life-years and should be considered in future cost-effectiveness analyses for prevention.
Embolus Trajectory Through a Physical Replica of the Major Cerebral Arteries
Authors: Chung Emma M.L. , Hague James P. , Chanrion Marie-Anne , Ramnarine Kumar V. , Katsogridakis Emmanuel , Evans David H.
Published: February 2010

Background and Purpose—

The observed distribution of cerebral infarcts varies markedly from expectations based on blood-flow volume or Doppler embolus detection. In this study, we used an in vitro model of the cerebral arteries to test whether embolus microspheres encountering the circle of Willis are carried proportionally to volume flow or express a preferred trajectory related to arterial morphology or embolus size.

Methods—

Our model consisted of a patient-specific silicone replica of the cerebral macrocirculation featuring physiologically realistic pulsatile flow of a blood-mimicking fluid at approximately 1000 mL/min and an input pressure of approximately 150/70 mm Hg. Particles of 200, 500, and 1000 μm diameter with equivalent density to thrombus were introduced to the carotid arteries and counted on exiting the model outlets.

Results—

The middle cerebral arteries (MCAs) of the replica attracted a disproportionate number of emboli compared with the anterior cerebral arteries; 98%±3% of 1000 μm and 93%±2% of 500 μm emboli entered the MCA compared with 82%±5% of the flow. The observed distribution of large emboli was consistent with the ratio of MCA:anterior cerebral artery infarcts, approximately 95% of which occur in territories supplied by the MCA. With decreasing embolus size, the distribution of emboli approaches that of the flow (approximately 89% of 200 μm emboli took the MCA).

Conclusions—

Embolus trajectory through the cerebral arteries is dependent on embolus size and strongly favors the MCA for large emboli. The 70:30 ratio of MCA:anterior cerebral artery emboli observed by Doppler ultrasound is consistent with the trajectories of small emboli that tend to be asymptomatic.
Precipitation Response to the Gulf Stream in an Atmospheric GCM*
Authors: Kuwano-Yoshida Akira , Minobe Shoshiro , Xie Shang-Ping
Published: February 2010

The precipitation response to sea surface temperature (SST) gradients associated with the Gulf Stream is investigated using an atmospheric general circulation model. Forced by observed SST, the model simulates a narrow band of precipitation, surface convergence, and evaporation that closely follows the Gulf Stream, much like satellite observations. Such a Gulf Stream rainband disappears in the model when the SST front is removed by horizontally smoothing SST. The analysis herein shows that it is convective precipitation that is sensitive to SST gradients. The Gulf Stream anchors a convective rainband by creating surface wind convergence and intensifying surface evaporation on the warmer flank. Deep convection develops near the Gulf Stream in summer when the atmosphere is conditionally unstable. As a result, a narrow band of upward velocity develops above the Gulf Stream throughout the troposphere in summer, while it is limited to the lower troposphere in other seasons.
On the Path of the Gulf Stream and the Atlantic Meridional Overturning Circulation
Authors: Joyce Terrence M. , Zhang Rong
Published: February 2010

The Atlantic meridional overturning circulation (AMOC) simulated in various ocean-only and coupled atmosphere–ocean numerical models often varies in time because of either forced or internal variability. The path of the Gulf Stream (GS) is one diagnostic variable that seems to be sensitive to the amplitude of the AMOC, yet previous modeling studies show a diametrically opposed relationship between the two variables. In this note this issue is revisited, bringing together ocean observations and comparisons with the GFDL Climate Model version 2.1 (CM2.1), both of which suggest a more southerly (northerly) GS path when the AMOC is relatively strong (weak). Also shown are some examples of possible diagnostics to compare various models and observations on the relationship between shifts in GS path and changes in AMOC strength in future studies.
The Impact of Stratospheric Model Configuration on Planetary-Scale Waves in Northern Hemisphere Winter
Authors: Shaw Tiffany A. , Perlwitz Judith
Published: February 2010

The impact of stratospheric model configuration on modeled planetary-scale waves in Northern Hemisphere winter is examined using the Canadian Middle Atmosphere Model (CMAM). The CMAM configurations include a high-lid (0.001 hPa) and a low-lid (10 hPa) configuration, which were each run with and without conservation of parameterized gravity wave momentum flux. The planetary wave structure, vertical propagation, and the basic state are found to be in good agreement with reanalysis data for the high-lid conservative configuration with the exception of the downward-propagating wave 1 signal. When the lid is lowered and momentum is conserved, the wave characteristics and basic state are not significantly altered, with the exception of the downward-propagating wave 1 signal, which is damped by the act of conservation. When momentum is not conserved, however, the wave amplitude increases significantly near the lid, and there is a large increase in both the upward- and downward-propagating wave 1 signals and a significant increase in the strength of the basic state. The impact of conserving parameterized gravity wave momentum flux is found to be much larger than that of the model lid height. The changes to the planetary waves and basic state significantly impact the stratosphere–troposphere coupling in the different configurations. In the low-lid configuration, there is an increase in wave-reflection-type coupling over zonal-mean-type coupling, a reduction in stratospheric sudden warming events, and an increase in the northern annular mode time scale. Conserving gravity wave momentum flux in the low-lid configuration significantly reduces these biases.
Sensitivity of Heavy Precipitation Forecasts to Small Modifications of Large-Scale Weather Patterns for the Elbe River
Authors: Schlüter Ingo , Schädler Gerd
Published: February 2010

Extreme flood events are caused by long-lasting and/or intensive precipitation. The detailed knowledge of the distribution, intensity, and spatiotemporal variability of precipitation is, therefore, a prerequisite for hydrological flood modeling and flood risk management. For hydrological modeling, temporal and spatial high-resolution precipitation data can be provided by meteorological models. This study deals with the question of how small changes in the synoptic situation affect the characteristics of extreme forecasts. For that purpose, two historic extreme precipitation events were hindcasted using the Consortium for Small Scale Modeling (COSMO) model of the German Weather Service (DWD) with different grid resolutions (28, 7, and 2.8 km), where the domains with finer resolutions were nested into the ones with coarser resolution. The results show that the model is capable of simulating such extreme precipitation events in a satisfactory way. To assess the impact of small changes in the synoptic situations on extreme precipitation events, the large-scale atmospheric fields were shifted to north, south, east, and west with respect to the orography by about 28 and 56 km, respectively, in one series of runs while in another series, the relative humidity and temperature were increased to modify the amount of precipitable water. Both series were performed for the Elbe flood events in August 2002 and January 2003, corresponding to two very different synoptic situations. The results show that the modeled precipitation can be quite sensitive to small changes of the synoptic situation with changes in the order of 20% for the maximum daily precipitation and that the types of synoptic situations play an important role. While van Bebber weather conditions, of Mediterranean origin, were quite sensitive to modifications, more homogeneous weather patterns were less sensitive.
Near-Inertial Wave Wake of Hurricanes Katrina and Rita over Mesoscale Oceanic Eddies
Authors: Jaimes Benjamin , Shay Lynn K.
Published: February 2010

Tropical cyclones (TCs) Katrina and Rita moved as major hurricanes over energetic geostrophic ocean features in the Gulf of Mexico. Increased and reduced oceanic mixed layer (OML) cooling was measured following the passage of both storms over cyclonic and anticyclonic geostrophic relative vorticity ζg, respectively. This contrasting thermal response is investigated here in terms of the evolution of the storms’ near-inertial wave wake in geostrophic eddies. Observational data and ray-tracing techniques in realistic geostrophic flow indicate that TC-forced OML near-inertial waves are trapped in regions of negative ζg, where they rapidly propagate into the thermocline. These anticyclonic-rotating regimes coincided with the distribution of reduced OML cooling because rapid downward dispersion of near-inertial energy reduced the amount of kinetic energy available to increase vertical shears at the OML base. By contrast, TC-forced OML near-inertial waves were stalled in upper layers of cyclonic circulations, which strengthened vertical shears and entrainment cooling. Upgoing near-inertial energy propagation dominated inside a geostrophic cyclone that interacted with Katrina; the salient characteristics of these upward-propagating waves were the following: (i) they were radiated from the ocean interior because of geostrophic adjustment following upwelling–downwelling processes; (ii) rather than with the buoyancy frequency, they amplified horizontally as they encountered increasing values of f + ζg/2 during upward propagation; and (iii) they produced episodic vertical mixing through shear instability at a critical layer underneath the OML. To improve the prediction of TC-induced OML cooling, models must capture geostrophic features and turbulence closures must represent near-inertial wave processes such as dispersion and breaking between the OML base and the thermocline.
Performance of an Eddy Diffusivity–Mass Flux Scheme for Shallow Cumulus Boundary Layers
Authors: Angevine Wayne M. , Jiang Hongli , Mauritsen Thorsten
Published: February 2010

Comparisons between single-column (SCM) simulations with the total energy–mass flux boundary layer scheme (TEMF) and large-eddy simulations (LES) are shown for four cases from the Gulf of Mexico Atmospheric Composition and Climate Study (GoMACCS) 2006 field experiment in the vicinity of Houston, Texas. The SCM simulations were run with initial soundings and surface forcing identical to those in the LES, providing a clean comparison with the boundary layer scheme isolated from any other influences. Good agreement is found in the simulated vertical transport and resulting moisture profiles. Notable differences are seen in the cloud base and in the distribution of moisture between the lower and upper cloud layer. By the end of the simulations, TEMF has dried the subcloud layer and moistened the lower cloud layer more than LES. TEMF gives more realistic profiles for shallow cumulus conditions than traditional boundary layer schemes, which have no transport above the dry convective boundary layer. Changes to the formulation and its parameters from previous publications are discussed.
The Role of Atmospheric Conditions in Determining Intensity of Crepuscular and Anticrepuscular Rays
Authors: Van Den Broeke Matthew S. , Beasley William H. , Richman Michael B.
Published: February 2010

During the summer of 2006, daily observations of crepuscular and anticrepuscular rays were made around sunset from central Oklahoma. A relative scale of ray intensity was developed and used to relate the rays to concurrent meteorological conditions. Evidence is presented suggesting that both topography and clouds can cast shadows leading to rays. Relationships are hypothesized between estimated ray intensity and atmospheric variables, and predictive equations are developed for ray intensity and assessed using data from the summer of 2008. Except for a few cases in which rays were traced back to topography east of the Rocky Mountains, the most intense rays were produced by towering cumulus (Cu) and cumulonimbus (Cb) clouds to the west after hot days with light winds.
Identifying the “Tipping Point” Age for Overweight Pediatric Patients
Authors: Harrington John W. , Nguyen Vu Q. , Paulson James F. , Garland Ruth , Pasquinelli Lawrence , Lewis Donald
Published: February 2010

According to the National Health and Nutrition Examination Survey in 2007, nearly half of all American children are either overweight or obese. Retrospective chart review identified patients with the diagnostic codes for overweight, obese, and/or excessive weight gain. Inclusion criteria were current age between 2 and 20 years, a minimum of 5 visits with weight and height measurements, and a body mass index (BMI) at or above the 85th percentile. A total of 184 patients met inclusion criteria. More than half the children became overweight before age 2, and all patients were obese or overweight by age 10. The rate of gain is approximately 1 excess BMI unit/year, therefore causing most children to be overweight by age 2 ( R2 = .53). This study indicates that the critical period for preventing childhood obesity in this subset of identified patients is during the first 2 years of life and for many by 3 months of age.
Kuhn and the Discovery of Paradigms
Authors: Brad Wray K.
Published: February 2010

I present a history of Kuhn’s discovery of paradigms, one that takes account of the complexity of the discovery process. Rather than emerging fully formed in Structure, the concept paradigm emerged through a series of phases. Early criticism of Structure revealed that the role of paradigms was unclear. It was only as Kuhn responded to criticism that he finally articulated a precise understanding of the concept paradigm. In a series of publications in the 1970s, he settled on a conception of a paradigm as a concrete exemplar that functions as a guide to future research.
Influence of Body Weight and Gender on the Pharmacokinetics, Pharmacodynamics, and Antihypertensive Efficacy of Aliskiren
Authors: Jarugula Venkateswar , Yeh Ching‐Ming , Howard Dan , Bush Christopher , Keefe Deborah L. , Dole William P.
Published: February 2010

Gender and body weight influence the pharmacokinetics and pharmacodynamics of many drugs. This pooled analysis of 17 clinical studies evaluated the effect of gender, body mass index (BMI), body weight, and lean body weight (LBW) on the pharmacokinetics of the direct renin inhibitor aliskiren in healthy volunteers (n = 392). A separate pooled analysis of 5 clinical studies in patients with hypertension (n = 2327) assessed the influence of gender and BMI on the effects of aliskiren on plasma renin activity and blood pressure. Area under the aliskiren plasma concentration‐time curve (AUCτ) was 22% lower and the peak aliskiren plasma concentration (Cmax) was 24% lower in men than women (P < .05). BMI was not significantly correlated with AUCτ (r = 0.005; P = .917); AUCτ was negatively correlated with body weight (r = −0.235; P < .0001) and LBW (r = −0.295; P < .0001). Results were similar for Cmax. Adjusting individual aliskiren AUCτ and Cmax values for overall mean body weight or LBW abolished gender differences. Based on r2 values, LBW variation accounted for 8.9% of aliskiren AUCτ variation. In patients with hypertension, gender and BMI did not significantly influence the effects of aliskiren on plasma renin activity or blood pressure. It was concluded that lower systemic exposure to aliskiren in men versus women relates to differences in body weight; neither gender nor body weight has clinically relevant effects on the pharmacokinetics or pharmacodynamics of aliskiren.