bluuebunny/crossref_metadata_2025 huggingface dataset:
Epigenetics and the Environmental Regulation of the Genome and Its Function
Authors: Zhang Tie-Yuan , Meaney Michael J.
Published: December 2009

There are numerous examples in psychology and other disciplines of the enduring effects of early experience on neural function. In this article, we review the emerging evidence for epigenetics as a candidate mechanism for these effects. Epigenetics refers to functionally relevant modifications to the genome that do not involve a change in nucleotide sequence. Such modifications include chemical marks that regulate the transcription of the genome. There is now evidence that environmental events can directly modify the epigenetic state of the genome. Thus studies with rodent models suggest that during both early development and in adult life, environmental signals can activate intracellular pathways that directly remodel the “epigenome,” leading to changes in gene expression and neural function. These studies define a biological basis for the interplay between environmental signals and the genome in the regulation of individual differences in behavior, cognition, and physiology.
An Odor is Not Worth a Thousand Words: From Multidimensional Odors to Unidimensional Odor Objects
Authors: Yeshurun Yaara , Sobel Noam
Published: December 2009

Olfaction is often referred to as a multidimensional sense. It is multidimensional in that ∼1000 different receptor types, each tuned to particular odor aspects, together contribute to the olfactory percept. In humans, however, this percept is nearly unidimensional. Humans can detect and discriminate countless odorants, but can identify few by name. The one thing humans can and do invariably say about an odor is whether it is pleasant or not. We argue that this hedonic determination is the key function of olfaction. Thus, the boundaries of an odor object are determined by its pleasantness, which—unlike something material and more like an emotion—remains poorly delineated with words.
EFFICIENT VALIDATION OF TEACHING AND LEARNING USING MULTIPLE-CHOICE EXAMS
Authors: DeSantis Mark , McKean Thomas A.
Published: December 2009

One purpose of this study was to quantify, by means of single-format, multiple-choice questions at the beginning and end of the course, the extent to which first-year medical students learn neuroscience material from an introductory course in their curriculum. Compared with their precourse test performance (mean = 41.8%), collectively, the students nearly doubled their grade by the end of the course (mean = 81.4%). Their scores in subcategories of the material improved in inverse proportion to what they knew initially. A second goal was to evaluate a two-dimensional, computer-generated matrix as a way to assess test question validity and value. The evaluation of individual test questions as assessed from the matrix often, but not always, was similar to the classical pedagogical analysis that uses difficulty and discrimination indexes. Strengths of the matrix are its ability to render data as a gestalt, as well as flexibility and intuitive ease of use.
HOW DO LEARNING ISSUES RELATE WITH CONTENT IN A PROBLEM-BASED LEARNING PATHOPHYSIOLOGY COURSE?
Authors: Corrêa B. Barahona , Pinto P. Rosado , Rendas A. B.
Published: December 2009

The relation between learning process and content coverage is becoming increasingly important for the understanding of the effects of problem-based learning (PBL) on students’ learning. In our medical school, PBL is used as a major educational strategy in the discipline of pathophysiology. A computer program was developed allowing students to register learning issues identified as needed during tutorial sessions and learning issues stated as covered during the individual study periods. In our study, we compared “planned” (learning issues identified during PBL sessions) and “accomplished” learning issues (covered after the independent study periods) identified by pathophysiology students from three consecutive years. We found that the planned learning issues raised during tutorial sessions related to the issues effectively accomplished during the independent study and that their number grew stepwise from basic to preclinical to clinical sciences. Pathophysiology was, globally, the most mentioned discipline. Moreover, the most mentioned disciplines from the basic, preclinical, and clinical areas were physiology, histopathology, and internal medicine, respectively. The single-discipline approach did not limit the student’s capacity to identify and cover learning issues beyond the objectives of pathophysiology.
Pressure-Volume Curve and Compliance of a Balloon: a Simulation
Authors: Weissenberg Sarah , Lavy Revital
Published: December 2009

As educators, we are continually designing new methods and procedures to enhance learning. During this process, good ideas are frequently generated and tested, but the extent of such activities may not be adequate for a full manuscript. Nonetheless, the ideas may be quite beneficial in improving the teaching and learning of physiology. Illuminations is a column designed to facilitate the sharing of these ideas (illuminations). The format of submissions is quite simple: a succinct description of about one or two double-spaced pages (less title and authorship) of something you have used for the classroom, teaching, lab, conference room, etc. You may include one or two simple figures or references. Submit ideas for inclusion in Illuminations directly to the Associate Editor in charge, Stephen DiCarlo (sdicarlo@med.wayne.edu).
OXYGEN TRANSPORT AND UTILIZATION: AN INTEGRATION OF THE MUSCLE SYSTEMS
Authors: Richardson R. S.
Published: December 2009

Exercise offers a unique stage from which to study and teach the integration of physiological systems. In this article, the process of matching O2 transport from air to its ultimate consumption in the contracting cell is utilized to integrate the workings of the cardiac, smooth, and skeletal muscle systems. Specifically, the physiology of exercise and the maximal oxygen consumption (V˙o2 max) achieved through the precise linking of these three muscle systems are utilized to highlight the complexity and importance of this integration. Smooth muscle plays a vital “middleman” role in the distribution of blood-borne O2 to the appropriate area of demand. Cardiac muscle instigates the convective movement of this O2, whereas skeletal muscle acts as the recipient and ultimate consumer of O2 in the synthesis of ATP and performance of work. In combination, these muscle systems facilitate the remarkable 15- to 30-fold increase in metabolic rate from rest to maximal effort in endurance-type exercise.
Expression of transient receptor potential channels and two-pore potassium channels in subtypes of vagal afferent neurons in rat
Authors: Zhao Huan , Sprunger Leslie K. , Simasko Steven M.
Published: December 2009

Vagal afferent neurons relay important information regarding the control of the gastrointestinal system. However, the ionic mechanisms that underlie vagal activation induced by sensory inputs are not completely understood. We postulate that transient receptor potential (TRP) channels and/or two-pore potassium (K2p) channels are targets for activating vagal afferents. In this study we explored the distribution of these channels in vagal afferents by quantitative PCR after a capsaicin treatment to eliminate capsaicin-sensitive neurons, and by single-cell PCR measurements in vagal afferent neurons cultured after retrograde labeling from the stomach or duodenum. We found that TRPC1/3/5/6, TRPV1-4, TRPM8, TRPA1, TWIK2, TRAAK, TREK1, and TASK1/2 were all present in rat nodose ganglia. Both lesion results and single-cell PCR results suggested that TRPA1 and TRPC1 were preferentially expressed in neurons that were either capsaicin sensitive or TRPV1 positive. Expression of TRPM8 varied dynamically after various manipulations, which perhaps explains the disparate results obtained by different investigators. Last, we also examined ion channel distribution with the A-type CCK receptor (CCK-RA) and found there was a significant preference for neurons that express TRAAK to also express CCK-RA, especially in gut-innervating neurons. These findings, combined with findings from prior studies, demonstrated that background conductances such as TRPC1, TRPA1, and TRAAK are indeed differentially distributed in the nodose ganglia, and not only do they segregate with specific markers, but the degree of overlap is also dependent on the innervation target.
Oxidative stress and endothelial dysfunction in pulmonary arteries of aged rats
Authors: Podlutsky Andrej , Ballabh Praveen , Csiszar Anna
Published: December 2009

Aging in the systemic circulation is associated with generalized endothelial dysfunction and increased oxidative stress, which are thought to contribute to the increased morbidity and mortality of cardiovascular diseases in the elderly. Previous studies have shown that pulmonary artery pressure and vascular resistance increase with normal aging in humans, yet age-related functional and phenotypic changes in the pulmonary arteries have not been characterized. To determine whether in the pulmonary circulation aging elicits endothelial dysfunction and oxidative stress, isolated pulmonary arteries of young (3 mo old) and aged (28 mo old) F344 rats were compared. We found that aging in rat pulmonary arteries is associated with impaired acetylcholine-induced relaxation and vascular oxidative stress [assessed by dihydroethidine and 5 (and 6)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate-acetyl ester fluorescence assays]. Endothelial dysfunction in the aged pulmonary vessels is reversed by the inhibition of NAD(P)H oxidase. The expressions of gp91 phox (both mRNA and protein), NAD(P)H oxidase isoform type 1 (Nox-1; mRNA), and Nox-4 (mRNA) tend to increase in aged vessels; however, only changes in Nox-4 reached statistical significance. In pulmonary arteries of aged rats, the protein expression of endothelial nitric oxide synthase, Cu,Zn-SOD, Mn-SOD, and glutathione peroxidase is unaltered, whereas the expression of catalase is significantly decreased. Our results suggest that aging is associated with oxidative stress and endothelial dysfunction in the pulmonary arteries, which may contribute to the age-related functional alterations in the pulmonary circulation.
The Roles of CaMKII and F-Actin in the Structural Plasticity of Dendritic Spines: A Potential Molecular Identity of a Synaptic Tag?
Authors: Okamoto Kenichi , Bosch Miquel , Hayashi Yasunori
Published: December 2009

Ca2+/calmodulin-dependent protein kinase II (CaMKII) and actin are two crucial molecules involved in long-term potentiation (LTP). In addition to its signaling function, CaMKII plays a structural role via direct interaction with actin filaments, thus coupling functional and structural plasticity in dendritic spines. The status of F-actin, regulated by CaMKII, determines the postsynaptic protein binding capacity and thus may act as a synaptic tag that consolidates LTP.
Serologic Investigations in Children with Inflammatory Bowel Disease and Food Allergy
Authors: Grzybowska-Chlebowczyk Urszula , Woś Halina , Sieroń Aleksander L. , Więcek Sabina , Auguściak-Duma Aleksandra , Koryciak-Komarska Halina , Kasznia-Kocot Joanna
Published: December 2009

The aim of the study was the evaluation of frequency and titre of IgA ASCA and IgG ASCA and p-ANCA, c-ANCA in children with IBD and occurrence of ASCA antibodies in relation to coexistence of FA. Patients and methods. The study comprised 95 children at the ages of 2 to 18 years. The diagnosis of IBD was established on the basis of Porto criteria. Tests of blood serum were performed in all children: IgA and IgG ASCA, p-ANCA, c-ANCA using ELISA method. Results. IgE-dependent FA was found in 32.5% children with UC and in 21% with CD. We did not observe any relation between the occurrence of FA and the frequency and ASCA titre. p-ANCA were significantly more frequent in the group of children with UC. The occurrence of ASCA antibodies was observed in 73.7% of children with CD, 17.5% with UC and almost 30% with allergic colitis. Conclusions. Patients with CD and the presence of ASCA revealed a significantly more frequent localization of lesions within the small bowel and a tendency towards older age. We observed a connection between the occurrence of antibodies and the examined mutations of gene NOD2/CARD15.
Studies on Development of Polymeric Materials Using Gamma Irradiation for Contact and Intraocular Lenses
Authors: Chhabra Pranshu , Gupta Ruchi , Suri Gunjan , Tyagi Mukti , Seshadri Geetha , Sabharwal S. , Niyogi U. K. , Khandal R. K.
Published: December 2009

For the development of materials for contact lenses and intraocular lenses, the selection criteria is based on the (i) capacity to absorb and retain water, (ii) hydrophilicity and hydrophobicity, (iii) refractive index and (iv) hardness besides the other essential properties. Various monomers are being studied to develop suitable materials for such applications. Selection of suitable monomers that can be converted into optical materials of desired characteristics is the most essential step. In the present paper, an attempt has been made to develop suitable optical polymers based on 2-hydroxy ethyl methacrylate (HEMA), N-vinyl pyrrolidone (NVP), methyl methacrylate (MMA), methacrylic acid (MAA), and styrene. Compositions were prepared in such a way that polymers of varying hydrophilicity or hydrophobicity could be obtained keeping HEMA as the base (main) monomer. For polymerization, gamma irradiation (Co-60 as a source) was used. The results of the study showed that: (i) an increase in NVP and MAA content brought in an increase in hydrophilicity of polymerized HEMA (pHEMA), while the addition of styrene and MMA decreased hydrophilicity of polymerized HEMA (pHEMA), (ii) polymers for contact lenses with water retention capacity as high as >50 wt.% and as low as <10 wt% with varying content of suitable comonomers can be designed, (iii) polymeric materials for contact lenses can be made by using radiation processing such as Co-60 and (iv) a dose of 40 kGy was found to be ideal for purpose.
Vascular Endothelial Growth Factor Plus Epidermal Growth Factor Receptor Dual Targeted Therapy in Metastatic Colorectal Cancer: Synergy or Antagonism?
Authors: Marshall John L.
Published: December 2009

There has been an intensive effort to develop novel therapies for the treatment of metastatic colorectal cancer (mCRC). The anti-epidermal growth factor receptor (EGFR) antibodies panitumumab and cetuximab and the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab have demonstrated clinical efficacy and acceptable toxicity in the treatment of mCRC as single agents or in combination with chemotherapy. Recent clinical trials have explored the efficacy and safety of treatment regimens incorporating chemotherapy in combination with bevacizumab and either panitumumab or cetuximab in patients with mCRC. Results from the BOND-2 trial, which investigated cetuximab, bevacizumab, and chemotherapy in mCRC, provided support for this therapeutic approach. Two large randomized phase 3 trials were initiated to evaluate firstline treatment of mCRC. The Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) study investigated the efficacy and safety of oxaliplatin- or irinotecan-based chemotherapy and bevacizumab with or without panitumumab; CAIRO2 assessed the efficacy and safety of capecitabine/oxaliplatin and bevacizumab with or without cetuximab. In both trials, the combination of bevacizumab, an EGFR-specific antibody, and chemotherapy in first-line treatment of mCRC was associated with increased toxicity and no improvement in patient outcome. These results suggest that these specific combinations should not be used in first-line mCRC outside investigational studies.
Evaluation of Approaches to Identify Associated SNPs That Explain the Linkage Evidence in Nuclear Families with Affected Siblings
Authors: Chen Ming-Huei , Van Eerdewegh Paul , Vincent Quentin B. , Alcais Alexandre , Abel Laurent , Dupuis Josée
Published: December 2009

Linkage analysis is often followed by association mapping to localize disease variants. In this paper, we evaluate approaches to determine how much of the observed linkage evidence, namely the identity-by-descent (IBD) sharing at the linkage peak, is explained by associated SNPs. We study several methods: Homozygote Sharing Tests (HST), Genotype Identity-by-Descent Sharing Test (GIST), and a permutation approach. We also propose a new approach, HSTMLB, combining HST and the Maximum Likelihood Binomial (MLB) linkage statistic. These methods can identify SNPs partially explaining the linkage peak, but only HST and HSTMLB can identify SNPs that do not fully explain the linkage evidence and be applied to multiple-SNPs. We contrast these methods with the association tests implemented in the software LAMP. In our simulations, GIST is more powerful at finding SNPs that partially explain the linkage peak, while HST and HSTMLB are equally powerful at identifying SNPs that do not fully explain the linkage peak. When applied to the North American Rheumatoid Arthritis Consortium data, HST and HSTMLB identify marker pairs that may fully explain the linkage peak on chromosome 6. In conclusion, HST and HSTMLB provide simple and flexible tools to identify SNPs that explain the IBD sharing at the linkage peak.
Exceptional Bone Metastasis of Basal Cell Carcinoma in Gorlin-Goltz Syndrome
Authors: Lamon Tatiana , Gerard Stephane , Meyer Nicolas , Losfeld Benjamin , Abellan van Kan Gabor , Balardy Laurent , Vellas Bruno
Published: December 2009

Background: Basal cell carcinoma (BCC), the most prevalent form of cancer worldwide, is a malignant skin neoplasm. It is locally invasive, with an exceptional incidence of reported metastasis. It can also be part of the Gorlin-Goltz syndrome, an autosomal dominant genetic disorder with high penetrance and variable expressivity, which is principally characterized by cutaneous BCC, odontogenic keratocysts, palmar and/or plantar pits, and falx cerebri calcification. Observation: We report the exceptional clinical observation of a 54-year-old man presenting bone metastasis from BCC in Gorlin-Goltz syndrome. Conclusion: Less than 300 cases of metastatic BCC have been reported in the literature. The present case is the second associated with Gorlin-Goltz syndrome.
Adult Xanthogranuloma Mimicking Basal Cell Carcinoma: Dermoscopy, Reflectance Confocal Microscopy and Pathological Correlation
Authors: Lovato Louise , Salerni Gabriel , Puig Susana , Carrera Cristina , Palou Josep , Malvehy Josep
Published: December 2009

Juvenile xanthogranuloma in adulthood is an infrequent non-Langerhans cell histiocytosis, which may simulate malignant tumors such as basal cell carcinoma (BCC) or amelanotic melanoma. Dermoscopy has been described as a useful tool in the preoperative diagnosis of xanthogranuloma. We report a xanthogranuloma on the suprapubic area of a 48-year-old female, which clinically and dermoscopically mimicked a BCC with a yellowish hue and arborizing vessels. Reflectance confocal microscopy exhibited large highly refractive atypical cells in the dermis, some of them with pleomorphic nuclei, corresponding to Touton cells in the histopathological study. To our knowledge this is the first description of the clinical, dermoscopic and confocal microscopy correlations of a xanthogranuloma.
Protective Effect of the Nuclear Factor Kappa B Inhibitor Pyrrolidine Dithiocarbamate in Lung Injury in Rats with Streptozotocin-Induced Diabetes
Authors: Eren Gulay , Cukurova Zafer , Hergunsel Oya , Demir Guray , Kucur Mine , Uslu Ezel , Dalo Enis , Uhri Mehmet , Tugcu Volkan
Published: December 2009

Background: Diabetes mellitus (DM) causes debilitating complications and, as a result, diabetics frequently require intensive care. Although lungs are not thought to be affected primarily by DM, an increasing number of studies indicate physiological and structural abnormalities in diabetic lungs. Objectives: Pyrrolidine dithiocarbamate (PDTC) is a metal chelator and a potent inhibitor of NF-ĸB. Keeping in mind that NF-ĸB activation may be crucial in end-organ injury due to DM, we studied the role of PDTC on the inhibition of NF-ĸB activation and its effects on possible lung injury in rats with streptozotocin-induced DM. Methods: 36 Sprague-Dawley rats were allocated into 4 groups: diabetes, diabetes + PDTC, control and control + PDTC. At the end of 10 weeks, rats were sacrificed and their lungs were taken for histopathological and immunohistochemical evaluation [for NF-ĸB (p65) and endothelial nitric oxide (eNOS) immunoreactivities]. Protein carbonyl content (PCC), superoxide dismutase (SOD) and reduced glutathione (GSH) activities were measured. Results: Histopathologically, basal membranes were thickened and there was intense inflammatory reaction in diabetic lungs. However, the PDTC group, in which there were poor positive expressions of eNOS and p65 activity compared to diabetes group, revealed fewer inflammatory changes. PCC levels in diabetic lungs were higher, but SOD and GSH activities were lower. However, measurements of these parameters in the PDTC group and controls gave similar results. Conclusion: Lungs are exposed to changes induced by oxidative stress in diabetes through NF-ĸB activation and PDTC seems to be useful to prevent diabetic lung injury.
RANTES in Exhaled Breath Condensate of Allergic Asthma Patients with Exercise-Induced Bronchoconstriction
Authors: Zietkowski Z. , Skiepko R. , Tomasiak-Lozowska M.M. , Mroczko B. , Szmitkowski M. , Bodzenta-Lukaszyk A.
Published: December 2009

Background: The response of asthmatics to exercise differs from that of healthy subjects, and the mechanisms responsible for exercise-induced bronchoconstriction (EIB) remain to be elucidated. Objectives: The aim of this study was to evaluate changes in RANTES levels in exhaled breath condensate (EBC) following intensive exercise in allergic asthmatics. Methods: The study was conducted in a group of 19 asthmatics (11 with EIB and 8 without EIB) and 7 healthy volunteers. Changes in the concentrations of RANTES in EBC induced during the 24 h after intensive exercise were determined. Moreover, these measurements were tested for possible correlations with the results of other tests commonly associated with asthma as well as with changes in airway inflammation after exercise. Results: In contrast to asthmatic patients without EIB and healthy controls, in asthmatics with EIB RANTES concentrations were statistically significantly increased in EBC collected during the first 24 h after an exercise test. There was a statistically significant correlation between the maximum increase in RANTES concentrations in EBC after exercise and either baseline exhaled nitric oxide (FENO) or bronchial hyperreactivity to histamine and an increase in serum eosinophil cationic protein or FENO 24 h after exercise in the EIB asthmatics. Conclusions: The increase in RANTES in asthmatic airways, promoting the migration and activation of inflammatory cells including eosinophils, may play an important role in the upregulation of airway inflammation after EIB in asthmatic patients.
Peroxisome Proliferator-Activated Receptor-γ Coactivator 1-α Overexpression Prevents Endothelial Apoptosis by Increasing ATP/ADP Translocase Activity
Authors: Won Jong Chul , Park Joong-Yeol , Kim Yun Mi , Koh Eun Hee , Seol Somi , Jeon Byeong Hwan , Han Jin , Kim Jung Ran , Park Tae-Sik , Choi Cheol Soo , Lee Woo Je , Kim Min-Seon , Lee In-Kyu , Youn Jang Hyun , Lee Ki-Up
Published: December 2009

Objective—

Fatty acids increase reactive oxygen species generation and cell apoptosis in endothelial cells. The peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC-1α) is a transcriptional coactivator that increases mitochondrial biogenesis and fatty acid oxidation in various cells. This study was undertaken to investigate the possible preventive effect of PGC-1α on endothelial apoptosis and its molecular mechanism.

Methods and Results—

Treatment with linoleic acid in cultured human aortic endothelial cells increased reactive oxygen species generation and cell apoptosis. These effects appeared to be mediated by increases in cytosolic fat metabolites, ie, fatty acyl CoA, diacylglycerol, and ceramide, and consequent decreases in ATP/ADP translocase activity of adenine nucleotide translocator. Adenoviral overexpression of PGC-1α prevented linoleic acid-induced increases in reactive oxygen species generation and cell apoptosis in human aortic endothelial cells by increasing fatty acid oxidation, decreasing diacylglycerol and ceramide, and increasing ATP/ADP translocase activity. In isolated aorta, PGC-1α overexpression prevented linoleic acid-induced decrease in endothelium-dependent vasorelaxation, and this effect was abolished by adenine nucleotide translocator1 shRNA.

Conclusions—

PGC-1α regulates reactive oxygen species generation and apoptosis in endothelial cells by increasing fatty acid oxidation and enhancing ATP/ADP translocase activity. Measures to increase PGC-1α expression or ATP/ADP translocase activity in vascular cells may aid in the prevention or treatment of atherosclerosis.
The Relationship of Right- and Left-Sided Filling Pressures in Patients With Heart Failure and a Preserved Ejection Fraction
Authors: Drazner Mark H. , Prasad Anand , Ayers Colby , Markham David W. , Hastings Jeffrey , Bhella Paul S. , Shibata Shigeki , Levine Benjamin D.
Published: December 2009

Background—

Although right-sided filling pressures often mirror left-sided filling pressures in systolic heart failure, it is not known whether a similar relationship exists in heart failure with preserved ejection fraction.

Methods and Results—

Eleven subjects with heart failure with preserved ejection fraction underwent right heart catheterization at rest and under loading conditions manipulated by lower body negative pressure and saline infusion. Right atrial pressure (RAP) was classified as elevated when ≥10 mm Hg and pulmonary capillary wedge pressure (PCWP) when ≥22 mm Hg. If both the RAP and the PCWP were elevated or both not elevated, they were classified as concordant; otherwise, they were classified as discordant. Correlation of RAP and PCWP was determined by a repeated measures model. Among 66 paired measurements of RAP and PCWP, 44 (67%) had a low RAP and PCWP and 8 (12%) a high RAP and PCWP, yielding a concordance rate of 79%. In a sensitivity analysis performed by varying the definition of elevated RAP (from 8 to 12 mm Hg) and PCWP (from 15 to 25 mm Hg), the mean±SD concordance of RAP and PCWP was 76±10%. The correlation coefficient of RAP and PCWP for the overall cohort was
r
=0.86 (
P
<0.0001).

Conclusions—

Right-sided filling pressures often reflect left-sided filling pressures in heart failure with preserved ejection fraction, supporting the role of estimation of jugular venous pressure to assess volume status in this condition.
Phospholamban Ablation Rescues Sarcoplasmic Reticulum Ca
2+
Handling but Exacerbates Cardiac Dysfunction in CaMKIIδ
C
Transgenic Mice
Authors: Zhang Tong , Guo Tao , Mishra Shikha , Dalton Nancy D. , Kranias Evangelia G. , Peterson Kirk L. , Bers Donald M. , Brown Joan Heller
Published: December 2009

Rationale
:

We previously showed that transgenic mice expressing Ca
2+
/calmodulin-dependent protein kinase II δ
C
(CaMKII-TG) develop dilated cardiomyopathy associated with increased ryanodine receptors (RyR2) phosphorylation, enhanced sarcoplasmic reticulum (SR) Ca
2+
leak and lowering of SR Ca
2+
load. We hypothesized that phospholamban (PLN) ablation would restore SR Ca
2+
load and prevent the decreased ventricular contractility, dilation and mortality seen in CaMKII-TG.

Objective
:

Our objectives were to generate CaMKII-TG mice lacking PLN, determine whether the maladaptive effects of cardiac CaMKIIδ
C
expression were corrected, and establish the mechanistic basis for these changes.

Methods and Results
:

CaMKII-TG were crossed with PLN knockout (PLN-KO) mice to generate KO/TG mice. Myocytes from wild type (WT), CaMKII-TG, PLN-KO and KO/TG were compared. The decreased SR Ca
2+
load and twitch Ca
2+
transients seen in CaMKII-TG were normalized in KO/TG. Surprisingly the heart failure phenotype was exacerbated, as indicated by increased left ventricular dilation, decreased ventricular function, increased apoptosis and greater mortality. In KO/TG myocytes SR Ca
2+
sparks and leak were significantly increased, presumably because of the combined effects of restored SR Ca
2+
load and RyR2 phosphorylation. Mitochondrial Ca
2+
loading was increased in cardiomyocytes from KO/TG versus WT or CaMKII-TG mice and this was dependent on elevated SR Ca
2+
sparks. Cardiomyocytes from KO/TG showed poor viability, improved by inhibiting SR Ca
2+
release and mitochondrial Ca
2+
loading.

Conclusions
:

Normalizing cardiomyocyte SR Ca
2+
loading in the face of elevated CaMKII and RyR2 phosphorylation leads to enhanced SR Ca
2+
leak and mitochondrial Ca
2+
elevation, associated with exacerbated cell death, heart failure and mortality.
Functional Recapitulation of Smooth Muscle Cells Via Induced Pluripotent Stem Cells From Human Aortic Smooth Muscle Cells
Authors: Lee Tae-Hee , Song Sun-Hwa , Kim Koung Li , Yi Ji-Yeun , Shin Ga-Hee , Kim Ji Yeon , Kim Jihoon , Han Yong-Mahn , Lee Sang Hun , Lee Suk-Ho , Shim Sung Han , Suh Wonhee
Published: December 2009

Rationale
:

Generation of induced pluripotent stem (iPS) cells has been intensively studied by a variety of reprogramming methods, but the molecular and functional properties of the cells differentiated from iPS cells have not been well characterized.

Objective
:

To address this issue, we generated iPS cells from human aortic vascular smooth muscle cells (HASMCs) using lentiviral transduction of defined transcription factors and differentiated these iPS cells back into smooth muscle cells (SMCs).

Methods and Results
:

Established iPS cells were shown to possess properties equivalent to human embryonic stem cells, in terms of the cell surface markers, global mRNA and microRNA expression patterns, epigenetic status of OCT4, REX1, and NANOG promoters, and in vitro/in vivo pluripotency. The cells were differentiated into SMCs to enable a direct, comparative analysis with HASMCs, from which the iPS cells originated. We observed that iPS cell–derived SMCs were very similar to parental HASMCs in gene expression patterns, epigenetic modifications of pluripotency-related genes, and in vitro functional properties. However, the iPS cells still expressed a significant amount of lentiviral transgenes (OCT4 and LIN28) because of partial gene silencing.

Conclusions
:

Our study reports, for the first time, the generation of iPS cells from HASMCs and their differentiation into SMCs. Moreover, a parallel comparative analysis of human iPS cell–derived SMCs and parental HASMCs revealed that iPS-derived cells possessed representative molecular and in vitro functional characteristics of parental HASMCs, suggesting that iPS cells hold great promise as an autologous cell source for patient-specific cell therapy.
Cardiac Fibroblast
Authors: Souders Colby A. , Bowers Stephanie L.K. , Baudino Troy A.
Published: December 2009

The permanent cellular constituents of the heart include cardiac fibroblasts, myocytes, endothelial cells, and vascular smooth muscle cells. Previous studies have demonstrated that there are undulating changes in cardiac cell populations during embryonic development, through neonatal development and into the adult. Transient cell populations include lymphocytes, mast cells, and macrophages, which can interact with these permanent cell types to affect cardiac function. It has also been observed that there are marked differences in the makeup of the cardiac cell populations depending on the species, which may be important when examining myocardial remodeling. Current dogma states that the fibroblast makes up the largest cell population of the heart; however, this appears to vary for different species, especially mice. Cardiac fibroblasts play a critical role in maintaining normal cardiac function, as well as in cardiac remodeling during pathological conditions such as myocardial infarct and hypertension. These cells have numerous functions, including synthesis and deposition of extracellular matrix, cell–cell communication with myocytes, cell–cell signaling with other fibroblasts, as well as with endothelial cells. These contacts affect the electrophysiological properties, secretion of growth factors and cytokines, as well as potentiating blood vessel formation. Although a plethora of information is known about several of these processes, relatively little is understood about fibroblasts and their role in angiogenesis during development or cardiac remodeling. In this review, we provide insight into the various properties of cardiac fibroblasts that helps illustrate their importance in maintaining proper cardiac function, as well as their critical role in the remodeling heart.
Angiotensin Receptor Agonistic Autoantibody Is Highly Prevalent in Preeclampsia
Authors: Siddiqui Athar H. , Irani Roxanna A. , Blackwell Sean C. , Ramin Susan M. , Kellems Rodney E. , Xia Yang
Published: December 2009

Preeclampsia (PE), a syndrome affecting 5% of pregnancies, characterized by hypertension and proteinuria, is a leading cause of maternal and fetal morbidity and mortality. The condition is often accompanied by the presence of a circulating maternal autoantibody, the angiotensin II type I receptor agonistic autoantibody (AT
1
-AA). However, the prevalence of AT
1
-AA in PE remains unknown, and the correlation of AT
1
-AA titers with the severity of the disease remains undetermined. We used a sensitive and high-throughput luciferase bioassay to detect AT
1
-AA levels in the serum of 30 normal, 37 preeclamptic (10 mild and 27 severe), and 23 gestational hypertensive individuals. Here we report that AT
1
-AA is highly prevalent in PE (≈95%). Next, by comparing the levels of AT
1
-AA among women with mild and severe PE, we found that the titer of AT
1
-AA is proportional to the severity of the disease. Intriguingly, among severe preeclamptic patients, we discovered that the titer of AT
1
-AA is significantly correlated with the clinical features of PE: systolic blood pressure (
r
=0.56), proteinuria (
r
=0.70), and soluble fms-like tyrosine kinase-1 level (
r
=0.71), respectively. Notably, only AT
1
-AA, and not soluble fms-like tyrosine kinase-1, levels are elevated in gestational hypertensive patients. These data serve as compelling clinical evidence that AT
1
-AA is highly prevalent in PE, and its titer is strongly correlated to the severity of the disease.
Stent-Assisted Coiling of Intracranial Aneurysms
Authors: Piotin Michel , Blanc Raphaël , Spelle Laurent , Mounayer Charbel , Piantino Rhelen , Schmidt Paul J. , Moret Jacques
Published: December 2009

Background and Purpose—

Stent-assisted coiling has expanded the treatment of intracranial aneurysms, but the rates of procedure-related neurological complications and the incidence of angiographic aneurysm recurrence of this novel treatment are not yet well known. We present our experience with stent-assisted coiling with special emphasis on procedure-related neurological complications and incidence of angiographic recurrence.

Methods—

Clinical and angiographic outcomes of 1137 consecutive patients (1325 aneurysms) coiled with and without stent-assisted coiling technique from January 2002 to January 2009 were retrospectively analyzed.

Results—

There were 1109 aneurysms (83.5%) treated without and 216 (16.5%) treated with stents (15 of 216; 6.9% balloon-expandable versus 201 of 216; 93.1% self-expandable stents). Stents were delivered after coiling in 55.1% (119 of 216) and before coiling in 44.9% (97 of 216) of the cases. Permanent neurological procedure-related complications occurred in 7.4% (16 of 216) of the procedures with stents versus 3.8% (42 of 1109) in the procedures without stents (logistic regression
P
=0.644; OR: 1.289; 95% CI: 0.439 to 3.779). Procedure-induced mortality occurred in 4.6% (10 of 216) of the procedures with stents versus 1.2% (13 of 1109) in the procedures without stents (logistic regression
P
=0.006; OR: 0.116; 95% CI: 0.025 to 0.531). A total of 52.7% (114 of 216) of aneurysms treated with stents have been followed so far versus 69.8% (774 of 1109) of aneurysms treated without stents, disclosing angiographic recurrence in 14.9% (17 of 114) versus 33.5% (259 of 774), respectively (Fisher exact test
P
<0.0001; OR: 0.3485; 95% CI: 0.2038 to 0.5960).

Conclusions—

Stents were associated with a significant decrease of angiographic recurrences, but they were associated with more lethal complications compared with coiling without stents.
Reliable Perfusion Maps in Stroke MRI Using Arterial Input Functions Derived From Distal Middle Cerebral Artery Branches
Authors: Ebinger Martin , Brunecker Peter , Jungehülsing Gerhard J. , Malzahn Uwe , Kunze Claudia , Endres Matthias , Fiebach Jochen B.
Published: December 2009

Background and Purpose—

Perfusion imaging is widely used in stroke, but there are uncertainties with regard to the choice of arterial input function (AIF). Two important aspects of AIFs are signal-to-noise ratio and bolus-related signal drop, ideally close to 63%. We hypothesized that distal branches of the middle cerebral artery (MCA) provide higher quality of AIF compared with proximal branches.

Methods—

Over a period of 3 months, consecutive patients with suspected stroke were examined in a 3-T MRI scanner within 24 hours of symptom onset. AIFs were selected manually in M1, M2, and M3 branches of the MCA contralateral to the suspected ischemia. Signal-to-noise ratio and bolus-related signal drop were analyzed. Perfusion maps were created for every patient and mean values at the insular level as well as relative ranges were compared.

Results—

Mean age of 132 included patients (53 females) was 67.3 years (SD, 14.9) and median National Institutes of Health Stroke Scale was 3 (interquartile range [IQR] 0 to 6). For further analyses, 4 patients were excluded due to discontinuation of scanning or insufficient bolus arrival (signal drop <15%). Median signal-to-noise ratio was highest in M3 branches (36.41; IQR, 29.29 to 43.58). Median signal-to-noise ratio in M2 branches was intermediate (27.54; IQR, 20.78 to 34.00) and median signal-to-noise ratio in M1 was low (12.40; IQR, 9.11 to 17.15). Using AIFs derived from M1 and M2 branches of the MCA median signal drop was 77% (IQR, 72% to 82%) and 78% (IQR, 73% to 83%), respectively. Signal drop was significantly reduced when AIF was selected in M3 branches with a median of 72% (IQR, 63% to 77%;
P
<0.01). Highest variability of 3456 perfusion maps was found in those derived from M1.

Conclusion—

The level of AIF selection in the MCA has a major impact on reliability and even quantitative parameters of perfusion maps. For better comparison of perfusion maps, the AIF should be defined by selection of distal branches of the MCA contralateral to the suspected ischemia. In future trials involving perfusion imaging, the MCA segment used for the AIF should be specified.
Thromboembolic Events With Recombinant Activated Factor VII in Spontaneous Intracerebral Hemorrhage
Authors: Diringer Michael N. , Skolnick Brett E. , Mayer Stephan A. , Steiner Thorsten , Davis Stephen M. , Brun Nikolai C. , Broderick Joseph P.
Published: December 2009

Background and Purpose—

Patients with intracerebral hemorrhage have a high risk of thromboembolic events (TEs) due to advanced age, hypertension, atherosclerosis, diabetes, and immobility. Use of recombinant activated factor VII (rFVIIa) could increase TEs in high-risk patients. Factor Seven for Acute Hemorrhagic Stroke (FAST) trial data were reviewed to define the frequency of and risk factors for TE with rFVIIa.

Methods—

Eight hundred forty-one patients presenting <3 hours after spontaneous intracerebral hemorrhage were randomized to 20 or 80 μg/kg of rFVIIa or placebo. Those with Glasgow Coma Scale score <5, planned early surgery, coagulopathy, or recent TE were excluded. Myocardial, cerebral, or venous TEs were subject to detailed reporting and expedited local review. Additionally, a blinded Data Monitoring Committee reviewed all electrocardiograms, centrally analyzed troponin I values, and CT scans.

Results—

There were 178 arterial and 47 venous TEs. Venous events were similar across groups. There were 49 (27%) arterial events in the placebo group, 47 (26%) in the 20-μg/kg group, and 82 (46%) in the 80 μg/kg group (
P
=0.04). Of the myocardial events, 38 were investigator-reported and 103 identified by the Data Monitoring Committee. They occurred in 17 (6.3%) placebo and 57 (9.9%) rFVIIa patients (
P
=0.09). Arterial TEs were associated with: receiving 80 μg/kg rFVIIa (OR=2.14;
P
=0.031), signs of cardiac or cerebral ischemia at presentation (OR=4.19;
P
=0.010), age (OR=1.14/5 years;
P
=0.0123), and prior use of antiplatelet agents (OR=1.83;
P
=0.035). Ischemic strokes possibly related to study drug occurred in 7, 5, and 8 patients in the placebo, 20 μg/kg, and 80-μg/kg groups, respectively.

Conclusions—

Higher doses of rFVIIa in a high-risk population are associated with a small increased risk of what are usually minor cardiac events. Demonstration of the ability of rFVIIa to improve outcome in future studies should be driven by its effectiveness in slowing bleeding outweighting the risk of a small increase in arterial TEs.
Women before the Qādī under the Abbasids
Authors: Tillier Mathieu
Published: December 2009

In this article, I examine the appearance of Muslim women before the judge during the Abbasid period (132-334/750-945), both in theory and practice. The cases involving women found in law books suggest that they came freely to the court, especially for familial or marital purposes, and that the judges employed some women as court auxiliaries. However, a comparison of judicial manuals and the biographical literature shows that a woman's appearance before the judge could create a social disturbance and that not all women were allowed to appear in court. I argue that the social distinction between those who could leave their houses—and thus come before the judge—and those who could not correlated with the social hierarchy.
The Global Atmospheric Circulation in Moist Isentropic Coordinates
Authors: Pauluis Olivier , Czaja Arnaud , Korty Robert
Published: December 2009

Differential heating of the earth’s atmosphere drives a global circulation that transports energy from the tropical regions to higher latitudes. Because of the turbulent nature of the flow, any description of a “mean circulation” or “mean parcel trajectories” is tied to the specific averaging method and coordinate system. In this paper, the NCEP–NCAR reanalysis data spanning 1970–2004 are used to compare the mean circulation obtained by averaging the flow on surfaces of constant liquid water potential temperature, or dry isentropes, and on surfaces of constant equivalent potential temperature, or moist isentropes. While the two circulations are qualitatively similar, they differ in intensity. In the tropics, the total mass transport on dry isentropes is larger than the circulation on moist isentropes. In contrast, in midlatitudes, the total mass transport on moist isentropes is between 1.5 and 3 times larger than the mass transport on dry isentropes.

It is shown here that the differences between the two circulations can be explained by the atmospheric transport of water vapor. In particular, the enhanced mass transport on moist isentropes corresponds to a poleward flow of warm moist air near the earth’s surface in midlatitudes. This low-level poleward flow does not appear in the zonally averaged circulation on dry isentropes, as it is hidden by the presence of a larger equatorward flow of drier air at same potential temperature. However, as the equivalent potential temperature in this low-level poleward flow is close to the potential temperature of the air near the tropopause, it is included in the total circulation on moist isentropes. In the tropics, the situation is reversed: the Hadley circulation transports warm moist air toward the equator, and in the opposite direction to the flow at upper levels, and the circulation on dry isentropes is larger than that on moist isentropes.

The relationship between circulation and entropy transport is also analyzed. A gross stratification is defined as the ratio of the entropy transport to the net transport on isentropic surfaces. It is found that in midlatitudes the gross stability for moist entropy is approximately the same as that for dry entropy. The gross stratification in the midlatitude circulation differs from what one would expect for either an overturning circulation or horizontal mixing; rather, it confirms that warm moist subtropical air ascends into the upper troposphere within the storm tracks.
Assessing the Differential Effects of Race and Ethnicity on Sentence Outcomes Under Different Sentencing Systems
Authors: Wang Xia , Mears Daniel P. , Spohn Cassia , Dario Lisa
Published: December 2009

Although many states have adopted sentencing guidelines, questions remain about whether guidelines achieve one of their primary goals—reducing disparities that arise from such extralegal factors as race and ethnicity. To date, research has not taken a cross-state approach to testing for racial or ethnic disparity in sentences imposed in guideline and nonguideline states or to examining whether less disparity exists in states with voluntary or presumptive guidelines. To address this research gap and inform sentencing scholarship, data from the State Court Processing Statistics program are used to determine whether offenders’ race or ethnicity affects incarceration and sentence length decisions in jurisdictions with different types of sentencing systems. Implications of the findings for theory, research, and policy are discussed.
Communication and Cooperation in Social Dilemmas: A Meta-Analytic Review
Authors: Balliet Daniel
Published: December 2009

Among the most researched solutions to social dilemmas is communication. Since the late 1950s, it has been well known that communication enhances cooperation in social dilemmas. This article reports a meta-analysis of this literature (forty-five effect sizes) and finds a large positive effect of communication on cooperation in social dilemmas ( d = 1.01). This effect is moderated by the type of communication, with a stronger effect of face-to-face discussion ( d = 1.21) compared to written messages ( d = 0.46). The communication-cooperation relationship is also stronger in larger, compared to smaller, group social dilemmas. Whether communication occurred before or during iterated dilemmas did not statistically affect the communication-cooperation effect size. Results are discussed according to theory and research on communication in social dilemmas.
Measuring Residents’ Attitudes toward Sustainable Tourism: A Reexamination of the Sustainable Tourism Attitude Scale
Authors: Yu Chia-Pin (Simon) , Chancellor H. Charles , Shu Tian Cole
Published: December 2009

This project examined the Sustainable Tourism Attitude Scale (SUS-TAS), which measures residents’ attitudes toward sustainable tourism. This study has two major purposes: (1) to reassess reliability and construct validity of the 44-item SUS-TAS using confirmatory factor analysis and (2) to identify a shorter version of the SUS-TAS that would not compromise the scale’s psychometric properties. To accomplish these purposes, an empirical study was conducted in rural Orange County, Indiana. Findings support a seven-dimension SUS-TAS model using 27 items that maintained construct validity and internal consistency.