bluuebunny/crossref_metadata_2025 huggingface dataset:
Cartilage Collagen Fibril Network in Newborn Transgenic Mice Analyzed by Electron Microscopic Stereology
Authors: Långsjö Teemu K. , Arita Machiko , Helminen Heikki J.
Published: March 2009

The objective was to investigate by electron microscopic stereology the properties of the cartilage collagen fibril network in newborn transgenic mice. The mice harbored transgenes targeted to affect the structure or assembly of the collagen fibrils. The mouse lines investigated here harbored either (i) one or (ii) two human COL2A1 genes with Arg519Cys mutation in addition to one or (iii) no active allele(s) of the murine Col2a1 gene, (iv) two inactive alleles of the procollagen N-proteinase genes, or (v) a human COL2A1 gene with deleted exons 16–27. In all newborn mice carrying the COL2A1 transgene with Arg519Cys mutation, the growth plate collagen fibrils were thinner than in the wild-type (wt) mice and showed clearly reduced volume fraction of the fibril network. In mice with the inactive procollagen N-proteinase genes, the fibril thickness and the volume fraction of collagen did not differ from the wt mice. In mice harboring the transgene of human COL2A1 gene with internally deleted exons 16–27, the collagen fibril diameter remained the same, but the volume density of collagen network was reduced. Using the indirect stereology, the differences in the collagen fibril stereological estimates could be reliably detected in newborn mice harboring mutations that affect the structure and assembly of collagen fibrils. The EM stereology permitted early detection of altered phenotype of the collagen fibril network in newborn transgenic mice. It is recommended that the indirect model-based stereological technique is utilized instead of the direct design-based technique for the estimation of collagen volume, surface, and length densities.
Efferent Projections of the Anterior and Posterodorsal Regions of the Medial Nucleus of the Amygdala in the Mouse
Authors: Usunoff Kamen G. , Schmitt Oliver , Itzev Dimitar E. , Haas Stefan Jean-Pierre , Lazarov Nikolai E. , Rolfs Arndt , Wree Andreas
Published: March 2009

The efferent projections of the anterior and posterodorsal part of the medial nucleus (MePD) in the mouse were studied by means of anterograde axonal tracing using biotinylated dextran amine. The MePD axons ran mainly via the stria terminalis and to a lesser extent via the ventral amygdalofugal pathway. The projections to the forebrain were broadly distributed and varied from very strong to scant. The most significant connections were destined to the bed nucleus of the stria terminalis in which all parts of the medial division were innervated by MePD neurons. Moderate projections reached the limbic striatum (nucleus accumbens), olfactory tubercle and the lateral septal nucleus. The substantia innominata was also innervated by the MePD, and especially the projection to its ventral portion was substantial. The profuse innervation of the medial preoptic nucleus and medial preoptic area indicated significant involvement of the MePD in sexual behavior. Many hypothalamic nuclei were innervated but to a different extent. The very strong innervation of the ventral premammillary nucleus further indicated the involvement of the MePD in the neuronal circuitry for sexual behavior. Substantial projections also reached the anterior hypothalamus and tuber cinereum, while the connections to the lateral hypothalamus were widespread but showed moderate density. MePD strongly innervated the ventrolateral part of the ventromedial hypothalamic nucleus and moderately its remaining parts. The neurosecretory hypothalamic nuclei and the arcuate nucleus contained only a few MePD terminals. The thalamic innervation was very scant and reached the lateral habenular nucleus and the nuclei of the midline. The mesencephalic connections were moderate to sparse and projected to the mesolimbic dopaminergic groups in the ventral tegmental area, the pars lateralis and the dorsal tier of the substantia nigra pars compacta, the periaqueductal gray and the dorsal raphe nucleus. The present results principally resembled data known in other rodent species; however, the efferents of the MePD often differed in extent and/or topical distribution.
The Psoriasis Family Index: Preliminary Results of Validation of a Quality of Life Instrument for Family Members of Patients with Psoriasis
Authors: Eghlileb A.M. , Basra M.K.A. , Finlay A.Y.
Published: March 2009

Background: Psoriasis can have a major impact on the lives of patients, the members of their families and their partners. Objectives: To develop and validate a disease-specific instrument to measure the secondary impact of psoriasis on the health-related quality of life (HRQoL) of family members of psoriasis patients. Methods: The development of the new questionnaire involved a number of different stages: qualitative interviews with family members/partners, formulation of the first draft, refinement, initial validation, further refinement and finally revalidation of the questionnaire. Results: Items for the measure were generated from the content analysis of interview transcripts. The psychometric evaluation of the final draft of the Psoriasis Family Index (PFI-15) was carried out in a new cohort of participants. The PFI-15 demonstrated high internal consistency (Cronbach’s α = 0.86) and high test-retest reliability (intraclass correlation coefficient = 0.93). The construct validity was assessed by testing a number of a priori hypotheses about its construct; a moderate to strong correlation was seen between families’ PFI scores and patients’ Dermatology Life Quality Index scores (r = 0.54, p < 0.01) and Psoriasis Disability Index scores (r = 0.59, p < 0.01), and between families’ PFI scores and patients’ Psoriasis Area and Severity Index scores (r = 0.43, p < 0.01). Conclusions: The PFI is a simple and practical measure to assess the HRQoL of family members/partners of patients with psoriasis.
Effect of Severe Aortic Stenosis on the Outcome in Elderly Patients Undergoing Repair of Hip Fracture
Authors: Leibowitz David , Rivkin Gurion , Schiffman Jochanan , Rott David , Weiss A. Teddy , Mattan Yoav , Kandel Leonid
Published: March 2009

Background: The perioperative assessment and management of elderly patients with hip fracture and significant aortic stenosis (AS) is an increasingly common clinical problem with little data available to guide perioperative management. Objectives: It was the aim of this study to examine the incidence of perioperative events in an elderly population of patients with severe AS undergoing repair of hip fracture as compared with controls without severe AS. Methods: Patients over the age of 70 with an echocardiographic diagnosis of severe AS defined as an aortic valve area ≤1.0 cm2 who underwent surgery for hip fracture repair were retrospectively identified. An age-matched group of patients without a history of AS who underwent surgical repair of hip fracture was the control group. The primary outcome of the incidence of postoperative cardiac events defined as death, acute coronary syndrome or pulmonary edema within 30 days was compared. Results: Thirty-two patients with AS (median age 84.5 years, range 72–94; 27 females and 5 males) and 88 controls (median age 86 years, range 80–95; 67 females and 21 males) were entered into the study. There were no significant differences between the AS group and controls for 30-day mortality (6.2 vs. 6.8%) or for the total cardiac event rate (18.7 vs. 11.8%). Conclusions: Our results demonstrate that elderly patients with severe AS can safely undergo repair of hip fractures with a mortality and morbidity comparable with a control population. These patients should not be denied surgery on the basis of their aortic valve disease.
Decision Analysis Supports the Paradigm That Indiscriminate Supplementation of Vitamin E Does More Harm than Good
Authors: Dotan Yedidya , Pinchuk Ilya , Lichtenberg Dov , Leshno Moshe
Published: March 2009

Objectives—

For many years, the prevailing concept was that LDL oxidation plays a central role in atherogenesis. As a consequence, supplementation of antioxidants, particularly vitamin E, became very popular. Unfortunately, however, the major randomized clinical trials have yielded disappointing results on the effects of vitamin E on both mortality and morbidity. Moreover, recent meta-analyses have concluded that vitamin E supplementation increases mortality. This conclusion has raised much criticism, most of it relating to three issues: (1) the choice of clinical trials to be included in the meta-analyses; (2) the end point of these meta-analyses (only mortality); and (3) the heterogeneity of the analyzed clinical trials with respect to both population and treatment. Our goal was to bring this controversy to an end by using a Markov-model approach, which is free of most of the limitations involved in using meta-analyses.

Methods and Results—

We used a Markov model to compare the vitamin E supplemented virtual cohorts with nonsupplemented cohorts derived from published randomized clinical trials that were included in at least one of the major meta-analyses. The difference between the virtual supplemented and nonsupplemented cohorts is given in terms of a composite end point denoted quality-adjusted life year (QALY). The vitamin E supplemented virtual cohort had 0.30 QALY (95%CI 0.21 to 0.39) less than the nontreated virtual cohort.

Conclusions—

Our study demonstrates that in terms of QALY, indiscriminate supplementation of high doses of vitamin E is not beneficial in preventing CVD. Selective supplementation of vitamin E to individuals under oxidative stress requires further investigation.
Apolipoprotein A-I and Its Role in Lymphocyte Cholesterol Homeostasis and Autoimmunity
Authors: Wilhelm Ashley J. , Zabalawi Manal , Grayson Jason M. , Weant Ashley E. , Major Amy S. , Owen John , Bharadwaj Manish , Walzem Rosemary , Chan Lawrence , Oka Kazuhiro , Thomas Michael J. , Sorci-Thomas Mary G.
Published: March 2009

Objective—

The purpose of this study was to determine the effects of an atherogenic diet on immune function in LDLr
−/−
, ApoA-I
−/−
mice.

Methods and Results—

When LDLr
−/−
, ApoA-I
−/−
(DKO), and LDLr
−/−
(SKO) mice were fed an atherogenic diet, DKO had larger peripheral lymph nodes (LNs) and spleens compared to SKO mice. LNs were enriched in cholesterol and contain expanded populations of T, B, dendritic cells, and macrophages. Expansion of all classes of LN cells was accompanied by a ≈1.5-fold increase in T cell proliferation and activation. Plasma antibodies to dsDNA, β2-glycoprotein I, and oxidized LDL were increased in DKO, similar to levels in diet-fed Fas
lpr/lpr
mice, suggesting the development of an autoimmune phenotype. Both LN enlargement and cellular cholesterol expansion were “prevented” when diet-fed DKO mice were treated with helper dependent adenovirus expressing apoA-I. Independent of the amount of dietary cholesterol, DKO mice consistently showed lower plasma cholesterol than SKO mice, yet greater aortic cholesterol deposition and inflammation.

Conclusions—

ApoA-I prevented cholesterol-associated lymphocyte activation and proliferation in peripheral LN of diet-fed DKO mice. A ≈1.5-fold increase in T cell activation and proliferation was associated with a ≈3-fold increase in concentrations of circulating autoantibodies and ≈2-fold increase in the severity of atherosclerosis suggesting a common link between plasma apoA-I, inflammation, and atherosclerosis.
Effects of Aspirin on Clot Structure and Fibrinolysis Using a Novel In Vitro Cellular System
Authors: Ajjan R.A. , Standeven K.F. , Khanbhai M. , Phoenix F. , Gersh K.C. , Weisel J.W. , Kearney M.T. , Ariëns R.A.S. , Grant P.J.
Published: March 2009

Objectives—The purpose of this study was to investigate the direct effects of aspirin on fibrin structure/function.

Methods and Results—Chinese Hamster Ovary cell lines stably transfected with fibrinogen were grown in the absence (0) and presence of increasing concentrations of aspirin. Fibrinogen was purified from the media using affinity chromatography, and clots were made from recombinant protein. Mean final turbidity [OD(±SEM)] was 0.083(±0.03), 0.093(±0.002), 0.101(±0.005), and 0.125(±0.003) in clots made from 0, 1, 10, and 100 mg/L aspirin-treated fibrinogen, respectively (P<0.05). Permeability coefficient (Ks cm2×10−8) was 1.68(±0.29) and 4.13(±0.33) comparing fibrinogen produced from cells grown with 0 mg/L and 100 mg/L aspirin respectively (P<0.05). Scanning electron microscopy confirmed a looser clot structure and increased fiber thickness of clots made from aspirin-treated fibrinogen, whereas rheometer studies showed a significant 30% reduction in clot rigidity. Fibrinolysis was quicker in clots made from aspirin-treated fibrinogen. Ex vivo studies in 3 normal volunteers given 150 mg aspirin daily for 1 week demonstrated similar changes in clot structure/function.

Conclusion—Aspirin directly altered clot structure resulting in the formation of clots with thicker fibers and bigger pores, which are easier to lyse. This study clearly demonstrates an alternative mode of action for aspirin, which should be considered in studies evaluating the biochemical efficacy of this agent.
Role of the Low-Affinity Leukotriene B
4
Receptor BLT2 in VEGF-Induced Angiogenesis
Authors: Kim Geun-Young , Lee Jin-Wook , Cho Sung-Hoon , Seo Ji-Min , Kim Jae-Hong
Published: March 2009

Objective—

The leukotriene B
4
(LTB
4
) receptor BLT2 is expressed in endothelium, but no clear physiological function for it has yet been identified, especially in vascular angiogenesis. The purpose of this study is to characterize the potential function of BLT2 in vascular endothelial growth factor (VEGF)-induced angiogenesis.

Methods and Results—

VEGF significantly upregulates BLT2 expression in human umbilical vein endothelial cells (HUVECs), and BLT2 knockdown by siRNA or inhibition of BLT2 by a specific BLT2 antagonist LY255283 attenuates VEGF-induced angiogenesis, which was determined by its effect on the formation of tube-like structures and on transmigration. The role of BLT2 in VEGF-induced angiogenesis was more evident in vivo, where BLT2 inhibition by LY255283 almost completely blocked VEGF-induced vessel formation in Matrigel-plug assays. In addition, we found that VEGF upregulates synthesis of the BLT2 ligand, 12(S)-hydroxyeicosatetraenoic acid (HETE). siRNA knockdown of 12-lipoxygenase (12-LO) expression attenuates VEGF-induced angiogenesis in HUVECs, and the addition of 12(S)-HETE to the 12-LO knockdown-HUVECs restores VEGF-induced angiogenesis. The activation of BLT2 itself by either 12(S)-HETE or LTB
4
evoked significant angiogenic phenotypes, both in vitro and in vivo.

Conclusion—

Our findings indicate that BLT2 plays an essential role in mediating VEGF-induced angiogenesis.
Periventricular White Matter Lucencies Relate to Low Vitamin B12 Levels in Patients With Small Vessel Stroke
Authors: Pieters Barbe , Staals Julie , Knottnerus Iris , Rouhl Rob , Menheere Paul , Kessels AlFons , Lodder Jan
Published: March 2009

Background and Purpose—

Blood–brain barrier dysfunction may be an early phenomenon in the development of the small vessel disease, which underlies white matter lesions. Because vitamin B12 plays a role in maintaining the integrity of the blood–brain barrier, we studied serum vitamin B12 level in relation to such lesions.

Methods—

In 124 patients with first lacunar stroke, we measured serum vitamin B12 level and rated the degree of white matter lesions on MRI.

Results—

Mean vitamin B12 level was 202 pmol/L (SD, 68.9). Thirty-nine patients (31.5%) had a vitamin B12 level less than the lower reference value of 150 pmol/L. Lower vitamin B12 level was (statistically significant) associated with more severe periventricular white matter lesions (odds ratio/100 pmol/L decrease, 1.773; 95% CI, 1.001–3.003), but not with deep white matter lesions (odds ratio/100 pmol/L decrease, 1.441; 95% CI, 0.881–2.358; ordered multivariate regression analysis).

Conclusions—

More severe periventricular white matter lesions in lacunar stroke patients relate to lower vitamin B12 levels. A possible causal relationship should now be studied prospectively.
A Method to Determine Stroke Trial Success Using Multidimensional Pooled Control Functions
Authors: Mandava Pitchaiah , Kent Thomas A.
Published: March 2009

Background and Purpose—

Many early phase trials in stroke have not been subsequently confirmed. Randomization balance in baseline factors that influence outcome are difficult to achieve and may be partly responsible for misleading early results. We hypothesized that comparison with an outcome function derived from a large number of pooled control arms would mitigate these randomization problems and provide a reliable predictor for decision-making before proceeding to later phase trials. We developed such a model and added a novel feature of generation of multidimensional 95% prediction surfaces by which individual studies could be compared. We performed a proof-of-principle study with published clinical trials, determining whether our method correctly identified known outcomes.

Methods—

The control arms from all randomized, controlled trials for acute stroke with ≥10 subjects, including baseline National Institute of Health Stroke Scale, age, and 3-month outcomes published between 1994 and May 2008, were identified. A Matlab program (PPREDICTS) was written to generate outcome functions based on these parameters. Published treatment trials were compared with these 95% intervals to determine whether it successfully identified positive and negative trials.

Results—

Models of mortality and functional outcome were successfully generated (mortality:
R
2
=0.69; functional outcome, modified Rankin Scale 0 to 2:
R
2
=0.81; both
P
<0.0001). The National Institute of Neurological Diseases and Stroke intravenous recombinant tissue plasminogen activator trial and 3 studies yet to be subjected to Phase III study had modified Rankin Scale 0 to 2 outcomes above the 95% prediction interval. Sixteen treatment arm outcomes fell within prediction surface bounds. This group included 2 major trials, Stroke-Acute Ischemic NXY Treatment and Abciximab Emergent Stroke Treatment Trial, that initially appeared promising but went on to negative Phase III results.

Conclusion—

This proof-of-principle analysis confirmed all positive and negative clinical stroke trial results and identified some promising therapies. The use of a pooled standard treatment group function combined with statistical bounds may improve selection of early studies for further study. This method may be applicable to any condition in which baseline factors influence outcome and at any stage of the development process.
Flow-Induced Dilation Is Mediated by Akt-Dependent Activation of Endothelial Nitric Oxide Synthase-Derived Hydrogen Peroxide in Mouse Cerebral Arteries
Authors: Drouin Annick , Thorin Eric
Published: March 2009

Background and Purpose—

Endothelial nitric oxide synthase produces superoxide under physiological conditions leading to hydrogen peroxide (H
2
O
2
) -dependent dilations to acetylcholine in isolated mouse cerebral arteries. The purpose of this study was to investigate whether H
2
O
2
was involved in flow-mediated dilation (FMD).

Methods—

Cerebral arteries were isolated from 12±2-week-old C57Bl/6 male mice. FMD (0 to 10 μL/min, 2-μL step increase at constant internal pressure) was induced in vessels preconstricted with phenylephrine (30 μmol/L). Simultaneously to diameter acquisition, H
2
O
2
or nitric oxide production was detected by the fluorescent dyes CMH
2
CFDA or 4,5-diaminofluorescein diacetate, respectively. Results are expressed as mean±SEM of 6 to 8 mice.

Results—

FMD (at 10 μL/min, 25±3% of maximal diameter) was prevented (
P
<0.05) by endothelium removal (6±1%) or endothelial nitric oxide synthase inhibition with N-nitro-
l
-arginine (11±1%) but not by the specific nitric oxide scavenger 2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl3-oxide (24±3%). Addition of PEG-catalase and silver diethyl dithio-carbamate (superoxide dismutase inhibitor) reduced (
P
<0.05) FMD to 10±2% and 15±1%, respectively. Simultaneously to FMD, H
2
O
2
-associated rise in fluorescence (+133±19 a.u.) was prevented by N-nitro-
l
-arginine, PEG-catalase, and silver diethyl dithio-carbamate (+55±10, +64±4, and +50±10 a.u., respectively;
P
<0.05). Inhibition of FMD by PEG-catalase was fully restored by the addition of tetrahydrobiopterin, a cofactor of endothelial nitric oxide synthase (23±3%); this functional reversal in dilation was associated with the simultaneous increase in nitric oxide-associated fluorescence (+418±58 a.u.,
P
<0.05), which was prevented by 2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl3-oxide (+93±26 a.u.). Akt inhibition with triciribine prevented FMD and H
2
O
2
-associated rise in fluorescence (3±1% and +23±4% a.u., respectively;
P
<0.05), but not acetylcholine-induced dilation.

Conclusion—

In healthy C57Bl/6 mouse cerebral arteries, Akt-dependent activation of endothelial nitric oxide synthase-derived H
2
O
2
mediates flow-dependent dilation.
Density and Shape as CT Predictors of Intracerebral Hemorrhage Growth
Authors: Barras Christen D. , Tress Brian M. , Christensen Soren , MacGregor Lachlan , Collins Marnie , Desmond Patricia M. , Skolnick Brett E. , Mayer Stephan A. , Broderick Joseph P. , Diringer Michael N. , Steiner Thorsten , Davis Stephen M.
Published: March 2009

Background and Purpose—

Intracerebral hemorrhage (ICH) growth predicts mortality and functional outcome. We hypothesized that irregular hematoma shape and density heterogeneity, reflecting active, multifocal bleeding or a variable bleeding time course, would predict ICH growth.

Methods—

Three raters examined baseline sub-3-hour CT brain scans of 90 patients in the placebo arm of a Phase IIb trial of recombinant activated Factor VII in ICH. Each rater, blinded to growth data, independently applied novel 5-point categorical scales of density and shape to randomly presented baseline CT images of ICH. Density and shape were defined as either homogeneous/regular (Category 1 to 2) or heterogeneous/irregular (Category 3 to 5). Within- and between-rater reliability was determined for these scales. Growth was assessed as a continuous variable and using 3 binary definitions: (1) any ICH growth; (2) ≥33% or ≥12.5 mL ICH growth; and (3) radial growth >1 mm between baseline and 24-hour CT scan. Patients were divided into tertiles of baseline ICH volume: “small” (0 to 10 mL), “medium” (10 to 25 mL), and “large” (25 to 106 mL).

Results—

Inter- and intrarater agreements for the novel scales exceeded 85% (±1 category). Median growth was significantly higher in the large-volume group compared with the small group (
P
<0.001) and in heterogeneous compared with homogeneous ICH (
P
=0.008). Median growth trended higher in irregular ICHs compared with regular ICHs (
P
=0.084). Small ICHs were more regularly shaped (43%) than medium (17%) and large (3%) ICHs (
P
<0.001). Small ICHs were more homogeneous (73%) compared with medium (37%) and large (17%) ICHs (
P
<0.001). Adjusting for baseline ICH volume and time to scan, density heterogeneity, but not shape irregularity, independently predicted ICH growth (
P
=0.046) on a continuous growth scale.

Conclusions—

Large ICHs were significantly more irregular in shape, heterogeneous in density, and had greater growth. Density heterogeneity independently predicted ICH growth using some definitions.
The Challenge of Designing a Treatment Trial for Warfarin-Associated Intracerebral Hemorrhage
Authors: Flaherty Matthew L. , Adeoye Opeolu , Sekar Padmini , Haverbusch Mary , Moomaw Charles J. , Tao Haiyang , Broderick Joseph P. , Woo Daniel
Published: March 2009

Background and Purpose—

Warfarin-associated intracerebral hemorrhage (WICH) became more frequent in the past 2 decades. Interest in potential WICH treatment trials has grown, but the practicality of such trials has received less attention. We determined the number of patients that would be eligible for enrollment in hypothetical treatment trials for WICH using a population-based study.

Methods—

We identified all patients aged 18 years or older from the Greater Cincinnati/Northern Kentucky region with nontraumatic intracerebral hemorrhage in 2005. Three hypothetical WICH treatment trial criteria sets were used to determine eligibility for enrollment, varying from relatively strict to broadly inclusive. For the hypothetical trials, we assumed the comparison of a standard therapy to an alternative therapy. Sample size calculations assumed different rates of poor outcome depending on the criteria set, various effect sizes, a 2-sided alpha of 0.05, and 80% power. Given 5 years of trial enrollment, the population base needed to enroll the required subjects was then calculated.

Results—

Warfarin-associated intracerebral hemorrhage accounted for 54 of 286 (19%) cases of intracerebral hemorrhage within the Greater Cincinnati/Northern Kentucky region in 2005. Eligibility rates ranged from 2 of 54 WICH patients (4% of cases, strictest set) to 11 of 54 WICH patients (20% of cases, most inclusive set). Given these rates, a population base of at least 67 million persons would be required to conduct a 5-year trial for WICH with a 10% effect size using a moderately strict criteria set.

Conclusions—

Any planned treatment trial for WICH should anticipate significant challenges in successfully enrolling adequate numbers of patients.
Immune Response in Human Cerebral Cavernous Malformations
Authors: Shi Changbin , Shenkar Robert , Du Hongyan , Duckworth Edward , Raja Harish , Batjer H. Hunt , Awad Issam A.
Published: March 2009

Background and Purpose—

Preliminary observations suggesting the presence of B and plasma cells and oligoclonality of immunoglobulin (Ig) G in cerebral cavernous malformations (CCM) have motivated a systematic study correlating the infiltration of the immune cells with clinical activity and antigen-triggered immune response in surgically excised lesions.

Methods—

Infiltration of plasma, B, T, and human leukocyte antigen-DR–expressing cells and macrophages within 23 excised CCM was related to clinical activity. Relative amounts of Ig isotypes were determined. IgG clonality of mRNA from CCM was assessed by spectratyping, cloning, and sequencing.

Results—

Infiltration of the immune cells ranged widely within CCM lesions, and cells were generally coexpressed with each other. Immune cell infiltration did not associate with recent bleeding and lesion growth. Significantly more B lymphocytes in CCM lesions were associated with venous anomaly. More T cells were present in solitary lesions. More T cells and less macrophages were present in CCM from younger subjects. IgG isotype was present in all CCM lesions. Most lesions also expressed IgM and IgA, with IgM predominance over IgA correlating with recent CCM growth. Oligoclonality was shown in IgG mRNA from CCM, but not from peripheral blood lymphocytes, with only 8 complementary-determining region 3 sequences observed among 134 clones from 2 CCM lesions.

Conclusions—

An antigen-directed oligoclonal IgG immune response is present within CCM lesions regardless of recent clinical activity. Apparent differences in immune response in younger patients and in lesions with recent growth will need confirmation in other series. The pathogenicity of oligoclonal immune response will require systematic hypothesis testing in recently available CCM murine models.
Low Level of Low-Density Lipoprotein Cholesterol Increases Hemorrhagic Transformation in Large Artery Atherothrombosis but Not in Cardioembolism
Authors: Kim Beom Joon , Lee Seung-Hoon , Ryu Wi-Sun , Kang Bong Su , Kim Chi Kyung , Yoon Byung-Woo
Published: March 2009

Background and Purpose—

Low cholesterol level is known to be associated with increased cerebral hemorrhage. However, the associations of hemorrhagic transformation (HTf) after acute ischemic stroke and the low levels of total cholesterol (TC) or low-density lipoprotein cholesterol (LDLC) are largely undiscovered.

Methods—

Of the 1034 patients with acute ischemic stroke who were consecutively admitted to our hospital, 377 patients with stroke attributable to large artery atherothrombosis (LAA; n=210) or cardioembolism (n=167) were selected for this study. Demographic and clinical information was collected and HTf was evaluated through follow-up T2*-weighted gradient-echo MRI performed usually within 1 week after stroke. Measurement of lipid parameters included TC, LDLC, high-density lipoprotein cholesterol, and triglyceride.

Results—

Of the 377 patients, HTf was noted in 74 patients (19.6%). When patients were divided into 4 groups according to their TC and LDLC levels, the incidence of HTf was significantly elevated in the lowest quartile of each TC (
P
<0.01) and LDLC (
P
<0.01) level in LAA subgroup, but not in cardioembolism. After adjusting covariates, a low level of LDLC (OR, 0.46 per 1 mmol/L-increase; 95% CI, 0.22–0.98) was independently associated with HTf in LAA, but not in cardioembolism. There was no significant association between low levels of TC (OR, 0.63 per 1 mmol/L-increase; 95% CI, 0.35–1.15) and HTf in LAA.

Conclusions—

Low levels of LDLC, and possibly TC, are associated with greater risk of hemorrhagic transformation after acute ischemic stroke attributable to LAA.
Effects of Combined Peripheral Nerve Stimulation and Brain Polarization on Performance of a Motor Sequence Task After Chronic Stroke
Authors: Celnik Pablo , Paik Nam-Jong , Vandermeeren Yves , Dimyan Michael , Cohen Leonardo G.
Published: March 2009

Background and Purpose—

Recent work demonstrated that application of peripheral nerve and cortical stimulation independently can induce modest improvements in motor performance in patients with stroke. The purpose of this study was to test the hypothesis that combining peripheral nerve stimulation (PNS) to the paretic hand with anodal direct current stimulation (tDCS) to the ipsilesional primary motor cortex (M1) would facilitate beneficial effects of motor training more than each intervention alone or sham (tDCS
Sham
and PNS
Sham
).

Methods—

Nine chronic stroke patients completed a blinded crossover designed study. In separate sessions, we investigated the effects of single applications of PNS+tDCS, PNS+tDCS
Sham
, tDCS+PNS
Sham
, and PNS
Sham
+tDCS
Sham
before motor training on the ability to perform finger motor sequences with the paretic hand.

Results—

PNS+tDCS resulted in a 41.3% improvement in the number of correct key presses relative to PNS
Sham
+tDCS
Sham
, 15.4% relative to PNS+tDCS
Sham
, and 22.7% relative to tDCS+PNS
Sham
. These performance differences were maintained 1 and 6 days after the end of the training.

Conclusions—

These results indicate that combining PNS with tDCS can facilitate the beneficial effects of training on motor performance beyond levels reached with each intervention alone, a finding of relevance for the neurorehabilitation of motor impairments after stroke.
Intracerebral Hemorrhage Volume Predicts Poor Neurologic Outcome in Children
Authors: Jordan Lori C. , Kleinman Jonathan T. , Hillis Argye E.
Published: March 2009

Background and Purpose—

Although intracerebral hemorrhage (ICH) volume and location are important predictors of outcome in adults, few data exist in children.

Methods—

A consecutive cohort of children, including full-term newborns to those younger than 18 years of age with nontraumatic, acute ICH and head CT available for analysis were studied. Clinical information was abstracted via chart review. Hemorrhage volume was expressed as percentage of total brain volume (TBV) with large hemorrhage defined as ≥4% of TBV. Hemorrhages were manually traced on each head CT slice and volumes were calculated by multiplying by slice thickness. Location was classified as supratentorial or infratentorial. Logistic regression was used to identify predictors of poor neurological outcome, defined as a Glasgow outcome scale ≤2 (death or persistent vegetative state).

Results—

Thirty children were included, median age 6 years. Median ICH volume was 20.4 cm
3
and median ICH size as a percentage of TBV was 1.9%. Only 4 of 22 children with ICH <4% of TBV had poor outcomes, vs 5 of 8 children with ICH ≥4% of TBV (
P
=0.03). In multivariate analysis, hemorrhage ≥4% of TBV (OR, 22.5; 95% CI, 1.4–354;
P
=0.03) independently predicted poor outcome 30 days after ICH. In this small sample, infratentorial hemorrhage location and the presence of intraventricular hemorrhage did not predict poor outcome.

Conclusions—

ICH volume predicts neurological outcome at 30 days in children, with worst outcome when hemorrhage is ≥4% of TBV. Location and ICH etiology may also be important. These findings identify children with ICH who are candidates for aggressive management and may influence counseling regarding prognosis.
An Analytic Scaling Law for the Depositional Growth of Snow in Thin Mixed-Phase Layer Clouds
Authors: Larson Vincent E. , Smith Adam J.
Published: March 2009

In various practical problems, such as assessing the threat of aircraft icing or calculating radiative transfer, it is important to know whether mixed-phase clouds contain significant liquid water content. Some mixed-phase clouds remain predominantly liquid for an extended time, whereas others glaciate quickly.

The glaciation rate of mixed-phase layer clouds is thought to depend on various factors, including number concentration of snow crystals, terminal velocity of snow crystals, and crystal habit type. This paper attempts to quantify some of these factors by deriving scaling laws (i.e., power laws) for the mixing ratio and sedimentation flux of snow at cloud base. The scaling laws are derived from the governing equation for snow mixing ratio. They neglect aggregation of snow crystals and accretion of supercooled liquid by snow crystals. The scaling laws permit arbitrary exponents and prefactors of the mass–diameter and fall speed–diameter power laws, allowing flexibility in crystal habit properties.

The scaling laws are tested using idealized large-eddy simulation (LES) of three thin, midlevel layer clouds. The scaling laws agree adequately with the LES over one order of magnitude for snow flux and over two orders of magnitude for snow mixing ratio. They indicate, for instance, that in the present LES, cloud-base snow flux and snow mixing ratio increase faster than linearly with increasing cloud thickness and supersaturation with respect to ice.

By varying the exponents and prefactors of the scaling laws, one may explore the sensitivity of glaciation rate to habit type. The relationship is complex, but, for the cloud cases examined, dendrites tend to glaciate cloud more rapidly than plates.
Axial Wind Effects on Stratification and Longitudinal Salt Transport in an Idealized, Partially Mixed Estuary*
Authors: Chen Shih-Nan , Sanford Lawrence P.
Published: March 2009

A 3D hydrodynamic model [Regional Ocean Model System (ROMS)] is used to investigate how axial wind influences stratification and to explore the associated longitudinal salt transport in partially mixed estuaries. The model is configured to represent a straight estuarine channel connecting to a shelf sea. The results confirm that wind straining of the along-channel salinity gradient exerts an important control on stratification. Two governing parameters are identified: the Wedderburn number (W) defined as the ratio of wind stress to axial baroclinic pressure gradient force, and the ratio of an entrainment depth to water depth (hs/H). Here W controls the effectiveness of wind straining, which promotes increases (decreases) in stratification during down-estuary (up-estuary) wind. The ratio hs/H determines the portion of the water column affected by direct wind mixing. While stratification is always reduced by up-estuary wind, stratification shows an increase-then-decrease transition when down-estuary wind stress increases. Such transition is a result of the competition between wind straining and direct wind mixing. A horizontal Richardson number modified to include wind straining/mixing is shown to reasonably represent the transition, and a regime diagram is proposed to classify the wind’s role on stratification. Mechanisms driving salt flux during axial wind events are also explored. At the onset and end of the wind events, barotropic adjustment drives strong transient salt fluxes. Net salt flux is controlled by the responses of subtidal shear dispersion to wind forcing. Moderate down-estuary winds enhance subtidal shear dispersion, whereas up-estuary winds always reduce it. Supporting observations from upper Chesapeake Bay are presented.
Demonstration of Aerosol Property Profiling by Multiwavelength Lidar under Varying Relative Humidity Conditions
Authors: Veselovskii I. , Whiteman D. N. , Kolgotin A. , Andrews E. , Korenskii M.
Published: March 2009

The feasibility of using a multiwavelength Mie–Raman lidar based on a tripled Nd:YAG laser for profiling aerosol physical parameters in the planetary boundary layer (PBL) under varying conditions of relative humidity (RH) is studied. The lidar quantifies three aerosol backscattering and two extinction coefficients and from these optical data the particle parameters such as concentration, size, and complex refractive index are retrieved through inversion with regularization. The column-integrated, lidar-derived parameters are compared with results from the AERONET sun photometer. The lidar and sun photometer agree well in the characterization of the fine-mode parameters, however the lidar shows less sensitivity to coarse mode. The lidar results reveal a strong dependence of particle properties on RH. The height regions with enhanced RH are characterized by an increase of backscattering and extinction coefficient and a decrease in the Ångström exponent coinciding with an increase in the particle size. The hygroscopic growth factor calculated for a select case is consistent with previous literature results despite the lack of collocated radiosonde data. These results demonstrate the potential of the multiwavelength Raman lidar technique for the study of aerosol humidification process.
Multimodel Ensemble ENSO Prediction with CCSM and CFS
Authors: Kirtman Ben P. , Min Dughong
Published: March 2009

Results are described from a large sample of coupled ocean–atmosphere retrospective forecasts during 1982–98. The prediction system is based on the National Center for Atmospheric Research (NCAR) Community Climate System Model, version 3 (CCSM3.0), and a state-of-the-art ocean data assimilation system made available by the National Oceanic and Atmospheric Administration (NOAA) Geophysical Fluid Dynamics Laboratory (GFDL). The retrospective forecasts are initialized in January, April, July, and November of each year, and ensembles of 6 forecasts are run for each initial month, yielding a total of 408 1-yr predictions. In generating the ensemble members, perturbations are added to the atmospheric initial state only. The skill of the prediction system is analyzed from both a deterministic and a probabilistic perspective, it is then compared to the operational NOAA Climate Forecast System (CFS), and the forecasts are combined with CFS to produce a multimodel prediction system. While the skill scores for each model are highly dependent on lead time and initialization month, the overall level of skill of the individual models is quite comparable. The multimodel combination (i.e., the unweighted average of the forecast), while not always the most skillful, is generally as skillful as the best model, using either deterministic or probabilistic skill metrics.
Building Communication Between Professionals at Children's Specialty Hospitals and the Medical Home
Authors: Stille Christopher J. , Frantz Jennifer , Vogel Lawrence C. , Lighter Donald
Published: March 2009

Objective. Build a quality improvement (QI) intervention to improve communication between a children's specialty hospital and referring primary care providers (PCPs). Methods. A network of charitable children's hospitals identified improving communication as a systemwide goal. At one model hospital, we used qualitative telephone interviewing of hospital specialists and staff, and referring PCPs, to characterize the communication system and identify potential improvements. We identified potential high-impact areas through content analysis and developed a QI change package with hospital leadership. Results. Participants described inconsistent communication, with no systematic identification of PCPs. Families were the typical means of inter-physician communication. Multiple non-PCP referral sources were a major contributor to communication breakdowns. Respondents identified a system for identification and communication with PCPs as an essential first step. Conclusions. Systems for communication with PCPs are underdeveloped at a children's charitable specialty hospital. Straightforward changes could build an effective system that is generalizable to other hospitals.
Ludwig's Angina in the Pediatric Population
Authors: Lin Harrison W. , O'Neill Allison , Cunningham Michael J.
Published: March 2009

As many as 1 in 3 of cases of Ludwig's angina occur in children and adolescents, and pediatricians are therefore ideally situated to detect these individuals at an early stage of their potentially life-threatening disease. The early identification and referral of children afflicted with Ludwig's angina to tertiary care centers allows for the rapid initiation of medical therapy and the consultation of those emergency services critical to providing such patients with optimal diagnostic and therapeutic interventions. This review provides an overview of the anatomical and pathophysiological considerations in Ludwig's angina and describes practical management principles to assist pediatricians in the diagnosis and treatment of this disease. Included in this review is an evidence-based algorithm for airway management.
A Longitudinal Model for Predicting Performance of Police Officers Using Personality and Behavioral Data
Authors: Forero Carlos G. , Gallardo-Pujol David , Maydeu-Olivares Alberto , Andrés-Pueyo Antonio
Published: March 2009

A growing body of evidence suggests that the performance of police officers depends on individual dispositions. Although predictive studies of police performance using personality measures often focus on academy training, in this study the authors fitted a longitudinal structural equation model to examine the predictive validity of the training process for actual performance after graduation. To do so, the authors used behavioral and self-reported personality measures as predictors in a sample of 2,010 police candidates enrolled at the Catalan Institute for Public Safety. While academic qualifications alone predicted 27.3% of performance variance, the predictive power was greatly improved when training was included as a mediator of personal dispositions. The full final model accounted for 60% of performance variance. Results suggest that actual job performance is indeed influenced by personality, but that this influence is mediated by training.
If They Knew, They Would Change
Authors: Militello Matthew , Schimmel David , Eberwein H. Jake
Published: March 2009

The purpose of this national survey is to determine secondary school principals' knowledge of the rights of students and teachers, how often principals are legally threatened and sued, how they adjust their behaviors in response, and how they obtain and disseminate legal information. Survey results show that a majority of principals are uninformed or misinformed about school law issues and that 85% of the principals said they would change their behavior if they knew the answers to our law survey questions.
Involvement of PLC-β3 in the effect of morphine on memory retrieval in passive avoidance task
Authors: Bianchi E. , Lehmann D. , Vivoli E. , Norcini M. , Ghelardini C.
Published: March 2009

Phospholipase C (PLC) is one signalling effector enzyme whose activity is directly modulated by opioids. Several physiological studies have implicated PLC-linked pathways in in-vivo pain regulation and opioid tolerance. Co-administration of PLC-β 2/3 activity blocker M119 with morphine resulted in a dramatic increase in morphine-induced amnesic effect in mice, proving a role for β subunit of PLC enzyme in these processes. Administration of morphine to mice at amnesic dose increased PLC-β3 activity, with respect to basal value, in the membrane-soluble material from anterior cortex and hippocampal formation in brain areas. PLC-β3 appears to be simultaneously implicated in both analgesic and amnesic effects induced by administration of morphine to mice suggesting a commonality in the molecular mechanisms of morphine-induced analgesia and memory impairment.
Agmatine disrupts prepulse inhibition of acoustic startle reflex in rats
Authors: Uzbay T. , Kayir H. , Goktalay G. , Yildirim M.
Published: March 2009

Agmatine is a guanidine-amine formed by the enzymatic decarboxylation of arginine. Agmatine has been proposed to be a neuromodulator and its downstream derivatives, the polyamines, have been suggested to be responsible for sensory gating deficits seen in schizophrenia. In this study, male Wistar rats underwent treatments with agmatine, vehicle or other agents known to alter sensory gating in an experimental paradigm of prepulse inhibition (PPI) of the acoustic startle response. Apomorphine (1 mg/kg s.c.), a nonselective dopamine agonist known to disrupt PPI responses, was injected as the positive reference. Neither apomorphine nor agmatine (40—160 mg/kg i.p.) induced effects on the intensity of startle reflex without a prepulse. However, apomorphine or agmatine (160 mg/kg i.p.) disrupted the PPI of acoustic startle reflex. Furthermore, when given 30 min prior, agmatine acted additively with apomorphine’s effect on PPI. In an attempt to gain more insight, haloperidol (1 and 2 mg/kg i.p.), clozapine (2.5—7.5 mg/kg i.p.) or quetiapine (2.5 and 7.5 mg/kg i.p.) was also injected prior to agmatine (160 mg/kg i.p.). Haloperidol (1 mg/kg) and clozapine (2.5 and 5 mg/kg) were able to prevent the PPI-disrupting effects of apomorphine. However, none of these antipsychotics prevent the PPI-disrupting effects of agmatine. These results suggest that agmatine disrupts the PPI of acoustic startle reflex of rats in a fundamentally different manner than apomorphine does. It may also have a critical role in the pathogenesis of sensorimotor gating-related dysfunctions.
Risperidone long-acting injection: factors associated with changes in bed stay and hospitalisation in a 3-year naturalistic follow-up
Authors: Taylor D. , Cornelius V.
Published: March 2009

We examined factors associated with hospital admissions and bed stay for 211 patients prescribed risperidone long-acting injection (RLAI) in clinical practice. Hospital bed days increased by a median of 74 days in the 3 years after RLAI initiation compared with the 3 years before initiation ( P < 0.0001). Only subjects starting RLAI as outpatients showed no increase in bed days after RLAI initiation. A greater than expected number of bed days was observed in women (36% increase), patients prescribed >25 mg/2 weeks (70% increase) and patients previously treated with clozapine (118% increase). Overall, number of hospital admissions did not increase, although those previously prescribed clozapine saw a 31% increase in admissions compared with patients not previously exposed to clozapine. This and other analyses of the same patient cohort indicate that RLAI produces most favourable outcomes in outpatients and those not previously treated with clozapine.