bluuebunny/crossref_metadata_2025 huggingface dataset:
Improvement in Sensory Impairment and Social Interaction in Young Children with Autism Following Treatment with an Original Qigong Massage Methodology
Authors: Silva Louisa M. T. , Cignolini Anita , Warren Roxanne , Budden Sarojini , Skowron-Gooch Annette
Published: June 2007

In clinical research, sensory impairment is considered one of the core deficits in autism and is associated with impaired socialization, behavioral disturbances and bowel and sleep problems. The effectiveness of the Cignolini methodology, an original Qigong massage methodology, in treating sensory impairment in young children with autism was evaluated in a small, controlled study. Thirteen children with autism between the ages of three and six received daily treatment according to the methodology for 5 months. Compared with untreated children, treated children experienced significant improvement of their sensory impairment ( p < 0.01), and demonstrated increased social skills ( p < 0.04) and basic living skills ( p < 0.02) on standardized measures. In addition, all of the children with bowel and sleep abnormalities demonstrated improvement after treatment.
Safety and Tolerability of Ganoderma lucidum in Healthy Subjects: A Double-Blind Randomized Placebo-Controlled Trial
Authors: Wicks Sheila M. , Tong Robin , Wang Chong-Zhi , O'Connor Michael , Karrison Theodore , Li Shang , Moss Jonathan , Yuan Chun-Su
Published: June 2007

Ganoderma lucidum is a herbal medicine commonly used in oriental countries as a remedy for treating various medical conditions. In this controlled study, we evaluated the safety and tolerance of oral administration of Ganoderma lucidum in 16 human volunteers who received 2 grams of the extract or placebo twice daily for 10 consecutive days. During the study, information from subjective questionnaires were obtained, electrocardiograms, complete blood counts, blood chemistry analysis and urinalysis were performed. In addition, blood tests reflecting immunity were done. Our data showed that compared to placebo group, no adverse effects were observed after the extract intake. Although there were no obvious changes in CD4, CD8, and CD19 levels after the extract, CD56 cell count increased during the study and returned to baseline 10 days after the herbal intake. However, due to relatively high variability and small sample size, this CD56 increase did not achieve statistical significance, and remains to be re-evaluated in the future. It appears that an additional long-term safety and tolerance trial with herbal dose-escalating design is warranted.
Inhibitory Effect of Dauricine on Inflammatory Process Following Focal Cerebral Ischemia/Reperfusion in Rats
Authors: Yang Xiao-Yan , Jiang Shi-Qin , Zhang Li , Liu Qiang-Ni , Gong Pei-Li
Published: June 2007

Our previous experimental studies showed that dauricine could protect the brain from ischemic damage, but the underlying mechanisms were unknown. In this study, we investigated the effect of dauricine on the changes of the inflammation process induced by ischemia/reperfusion (I/R). After I/R, the enzyme activity of MPO, the expression of ICAM-1 and the transcription of IL-1β and TNF-α mRNA were all significantly increased (p < 0.01). And after treatment with dauricine, they were all significantly reduced compared to the vehicle-treated I/R group (p < 0.05 or p < 0.01). These results suggest that dauricin attenuates the inflammation process induced by I/R. The neuroprotective effect of dauricine may partly due to the inhibition acute inflammation induced by I/R.
ON SOME NCP-FUNCTIONS BASED ON THE GENERALIZED FISCHER–BURMEISTER FUNCTION
Authors: CHEN JEIN-SHAN
Published: June 2007

In this paper, we study several NCP-functions for the nonlinear complementarity problem (NCP) which are indeed based on the generalized Fischer–Burmeister function, ϕp(a, b) = ||(a, b)||p - (a + b). It is well known that the NCP can be reformulated as an equivalent unconstrained minimization by means of merit functions involving NCP-functions. Thus, we aim to investigate some important properties of these NCP-functions that will be used in solving and analyzing the reformulation of the NCP.
A BMAP/PH/N SYSTEM WITH IMPATIENT REPEATED CALLS
Authors: KLIMENOK VALENTINA I. , ORLOVSKY DMITRY S. , DUDIN ALEXANDER N.
Published: June 2007

A multi-server queueing model with a Batch Markovian Arrival Process, phase-type service time distribution and impatient repeated customers is analyzed. After any unsuccessful attempt, the repeated customer leaves the system with the fixed probability. The behavior of the system is described in terms of continuous time multi-dimensional Markov chain. Stability condition and an algorithm for calculating the stationary state distribution of this Markov chain are obtained. Main performance measures of the system are calculated. Numerical results are presented.
EARLY HOMOGENEOUS UNIVERSE WITH VARIABLE COSMOLOGICAL CONSTANT: KINEMATICS TESTS
Authors: SINGH C. P.
Published: June 2007

A spatially homogeneous cosmological model with flat geometry filled with perfect fluid is studied in the presence of a variable cosmological "constant." Einstein's field equations are solved by using the "gamma-law" equation of state p = (γ-1)ρ, where the adiabatic parameter γ, varies with cosmic time. The functional form of γ, which is assumed to be the function of scale factor R as proposed by Carvalho, is used to describe the early evolution of universe with variable cosmological "constant." A unified description of early universe is given in which an inflationary phase is followed by radiation-dominated phase. It has been observed that the solutions are compatible with the result of recent observations. Exact expressions for the look-back time, proper distance, luminosity distance and angular diameter distance versus redshift are derived and their meaning are discussed in detail. The various physical aspects of the models are also discussed.
FRACTAL WAVEFIELD ANALYSIS TO CHARACTERIZE GEOMETRIC PROPERTIES OF FRACTURED MEDIA
Authors: DROUJININE ALEXANDER , ROK VLADIMIR
Published: June 2007

We have investigated wave scattering by chaotic fractured systems of fractal geometry with random spatial variation that causes energy loss of the directly propagated field. We have examined simple analytic solutions in fractal poroelastic media. These solutions may be characterized by their frequency-power-law (FPL) signature caused by wave dispersion and attenuation. It has been proved that medium memory effects cause smoothing of the wavefield in the vicinity of the wavefront and rapid amplitude decay far from the wavefront. It appears that finite-bandwidth signals are delayed with respect to the wavefront in comparable elastic media. To examine the FPL dependence of direct body waves propagating in a homogeneous medium containing fractal inhomogeneities, we compute acoustic finite-difference snapshots in the frequency range f = 20 - 200 Hz. Numerical results show that the fractal dimension can be estimated from the FPL dependence of the scattered wavefield. Applications to fracture characterization are considered. Results are important for multi-scale depth imaging, inverse Q filtering, fracture detection, and integrated geophysical reservoir monitoring.
APPLYING BUCKET RANDOM PERMUTATIONS TO STATIONARY SEQUENCES WITH LONG-RANGE DEPENDENCE
Authors: ZHOU YINGCHUN , TAQQU MURAD S.
Published: June 2007

Bucket random permutations (shuffling) are used to modify the dependence structure of a time series, and this may destroy long-range dependence, when it is present. Three types of bucket permutations are considered here: external, internal and two-level permutations. It is commonly believed that (1) an external random permutation destroys the long-range dependence and keeps the short-range dependence, (2) an internal permutation destroys the short-range dependence and keeps the long-range dependence, and (3) a two-level permutation distorts the medium-range dependence while keeping both the long-range and short-range dependence. This paper provides a theoretical basis for investigating these claims. It extends the study started in Ref. 1 and analyze the effects that these random permutations have on a long-range dependent finite variance stationary sequence both in the time domain and in the frequency domain.
RECONSTRUCTING TUMOR PHYLOGENIES FROM HETEROGENEOUS SINGLE-CELL DATA
Authors: PENNINGTON GREGORY , SMITH CHARLES A. , SHACKNEY STANLEY , SCHWARTZ RUSSELL
Published: June 2007

Studies of gene expression in cancerous tumors have revealed that tumors presenting indistinguishable symptoms in the clinic can be substantially different entities at the molecular level. The ability to distinguish between these genetically distinct cancers will make possible more accurate prognoses and more finely targeted therapeutics, provided we can characterize commonly occurring cancer sub-types and the specific molecular abnormalities that produce them. We develop a new method for identifying these common tumor progression pathways by applying phylogeny inference algorithms to single-cell assays, taking advantage of information on tumor heterogeneity lost to prior microarray-based approaches. We combine this approach with expectation maximization to infer unknown parameters used in the phylogeny construction. We further develop new algorithms to merge inferred trees across different assays. We validate the expectation maximization method on simulated data and demonstrate the combined approach on a set of fluorescent in situ hybridization (FISH) data measuring cell-by-cell gene and chromosome copy numbers in a large sample of breast cancers. The results further validate the proposed computational methods by showing consistency with several previous findings on these cancers and provide novel insights into the mechanisms of tumor progression in these patients.
Food-induced expression of orexin receptors in rat duodenal mucosa regulates the bicarbonate secretory response to orexin-A
Authors: Bengtsson Magnus W. , Mäkelä Kari , Sjöblom Markus , Uotila Sanna , Åkerman Karl E. O. , Herzig Karl-Heinz , Flemström Gunnar
Published: June 2007

Presence of appetite-regulating peptides orexin-A and orexin-B in mucosal endocrine cells suggests a role in physiological control of the intestine. Our aim was to characterize orexin-induced stimulation of duodenal bicarbonate secretion and modulation of secretory responses and mucosal orexin receptors by overnight food deprivation. Lewis × Dark Agouti rats were anesthetized and proximal duodenum cannulated in situ. Mucosal bicarbonate secretion (pH stat) and mean arterial blood pressure were continuously recorded. Orexin-A was administered intra-arterially close to the duodenum, intraluminally, or into the brain ventricles. Total RNA was extracted from mucosal specimens, reverse transcribed to cDNA and expression of orexin receptors 1 and 2 (OX1 and OX2) measured by quantitative real-time PCR. OX1 protein was measured by Western blot. Intra-arterial orexin-A (60–600 nmol·h−1·kg−1) increased ( P < 0.01) the duodenal secretion in fed but not in fasted animals. The OX1 receptor antagonist SB-334867, which was also found to have a partial agonist action, abolished the orexin-induced secretory response but did not affect secretion induced by the muscarinic agonist bethanechol. Atropine, in contrast, inhibited bethanechol but not orexin-induced secretion. Orexin-A infused into the brain ventricles (2–20 nmol·kg−1·h−1) or added to luminal perfusate (1.0–100 nM) did not affect secretion, indicating that orexin-A acts peripherally and at basolateral receptors. Overnight fasting decreased mucosal OX1 and OX2 mRNA expression ( P < 0.01) as well as OX1 protein expression ( P < 0.05). We conclude that stimulation of secretion by orexin-A may involve both receptor types and is independent of cholinergic pathways. Intestinal OX receptors and secretory responses are markedly related to food intake.
Role of spatial dispersion of repolarization in inherited and acquired sudden cardiac death syndromes
Authors: Antzelevitch Charles
Published: June 2007

This review examines the role of spatial electrical heterogeneity within the ventricular myocardium on the function of the heart in health and disease. The cellular basis for transmural dispersion of repolarization (TDR) is reviewed, and the hypothesis that amplification of spatial dispersion of repolarization underlies the development of life-threatening ventricular arrhythmias associated with inherited ion channelopathies is evaluated. The role of TDR in long QT, short QT, and Brugada syndromes, as well as catecholaminergic polymorphic ventricular tachycardia (VT), is critically examined. In long QT syndrome, amplification of TDR is often secondary to preferential prolongation of the action potential duration (APD) of M cells; in Brugada syndrome, however, it is thought to be due to selective abbreviation of the APD of the right ventricular epicardium. Preferential abbreviation of APD of the endocardium or epicardium appears to be responsible for the amplification of TDR in short QT syndrome. In catecholaminergic polymorphic VT, reversal of the direction of activation of the ventricular wall is responsible for the increase in TDR. In conclusion, long QT, short QT, Brugada, and catecholaminergic polymorphic VT syndromes are pathologies with very different phenotypes and etiologies, but they share a common final pathway in causing sudden cardiac death.
Simulations of propagated mouse ventricular action potentials: effects of molecular heterogeneity
Authors: Bondarenko Vladimir E. , Rasmusson Randall L.
Published: June 2007

The molecular heterogeneity of repolarizing currents produces significant spatial heterogeneity and/or dispersion of repolarization in many mammalian cardiac tissues. Transgenic mice are prominent experimental models for the study of the molecular basis of repolarization and arrhythmias. However, it is debated whether the small mouse heart can sustain physiologically relevant heterogeneity of repolarization. We used a comprehensive model of the mouse action potential (AP) to predict how small a region of the cardiac tissue can maintain spatial gradients of repolarization due to differential expression of channels. Our simulations of a one-dimensional multicellular ring or cable predict that substantial gradients in repolarization and intracellular Ca2+ concentration transients can be maintained through heterogeneity of expression of K+ channels in distances of ∼10 cells that are sufficient to block propagation. The abruptness of expression gradients and the site of stimulation can cause Ca2+ transient oscillations and affect the stability of Ca2+ dynamics and AP propagation. Two different mechanisms of instability of AP propagation in one-dimensional cable occur at fast pacing rates. Transitions from periodic activity to alternans or to irregular behavior were observed. Abrupt gradients of channel expression can cause alternans at slower pacing rates than gradual changes. Our simulations demonstrate the importance of incorporating realistic Ca2+ dynamics and current densities into models of propagated AP. They also emphasize that microscopic aspects of tissue organization are important for predicting large-scale propagation phenomena. Finally, our results predict that the mouse heart should be able to sustain substantial molecularly based heterogeneity of repolarization.
Plexiform-like lesions and increased tissue factor expression in a rat model of severe pulmonary arterial hypertension
Authors: White R. James , Meoli David F. , Swarthout Robert F. , Kallop Dara Y. , Galaria Irfan I. , Harvey Jennifer L. , Miller Christine M. , Blaxall Burns C. , Hall Carla M. , Pierce Richard A. , Cool Carlyne D. , Taubman Mark B.
Published: June 2007

Severe pulmonary arterial hypertension (PAH) occurs in idiopathic form and in association with diverse diseases. The pathological hallmarks are distal smooth muscle hypertrophy, obliteration of small pulmonary arteriole lumens, and disorganized cellular proliferation in plexiform lesions. In situ thrombosis is also observed. A detailed understanding of the disease progression has been hampered by the absence of an animal model bearing all the pathological features of human disease. To create a model with these characteristics, we gave young (200-g) rats monocrotaline 1 wk following left pneumonectomy; controls with vehicle treatment or sham operation were also studied. In experimental rats, pulmonary arteries had distal smooth muscle hypertrophy and proliferative perivascular lesions. The lesions had a plexiform appearance, occurred early in disease development, and were composed of cells expressing endothelial antigens. Three-dimensional microangiography revealed severe vascular pruning and disorganized vascular networks. We found that expression of tissue factor (TF), the membrane glycoprotein that initiates coagulation, facilitates angiogenesis, and mediates arterial injury in the systemic circulation, was increased in the pulmonary arterioles and plexiform-like lesions of the rats. TF was also heavily expressed in the vessels and plexiform lesions of humans with pulmonary arterial hypertension. We conclude that plexiform-like lesions can be reproduced in rats, and this model will facilitate experiments to address controversies about the role of these lesions in PAH. Increased TF expression may contribute to the prothrombotic diathesis and vascular cell proliferation typical of human disease.
Active Export Proteins Mediating Drug Resistance in Staphylococci
Authors: Hassan Karl A. , Skurray Ronald A. , Brown Melissa H.
Published: June 2007

Drug resistance mediated by integral membrane transporters is an important mode of cellular resistance to cytotoxic agents across all classes of living organisms. Gram-positive bacteria, such as staphylococcal species, are not encapsulated by a selective outer membrane permeability barrier. Therefore, these organisms often employ integral membrane drug transport systems to maintain cellular concentrations of antimicrobials at subtoxic levels. Staphylococcal species, including the opportunistic human pathogen Staphylococcus aureus, encode a multitude of drug exporters, encompassing transporters from each of the five currently recognized families of bacterial drug resistance transporters. A number of these transporters are chromosomally encoded and allow the host cell to realize clinically significant levels of drug resistance after minor mutations to regulatory regions. Others are plasmid-encoded and can be easily passed between staphylococcal strains and species, or acquired from other Gram-positive genera. In combination, staphylococcal drug transporters potentiate resistance to a vast array of antimicrobial compounds, including macrolide, quinolone, tetracycline and streptogramin antibiotics, as well as a broad range of biocides, such as quaternary ammonium compounds, biguanidines and diamidines. An understanding of the genetic and molecular properties of drug transporters will lead to effective treatments of staphylococcal infections. Here we provide a detailed review of the active drug transporters of the staphylococci.
A Phylogenetic Analysis of the Sugar Porters in Hemiascomycetous Yeasts
Authors: Palma Margarida , Goffeau André , Spencer-Martins Isabel , Baret Philippe V.
Published: June 2007

A total of 214 members of the sugar porter (SP) family (TC 2.A.1.1) from eight hemiascomycetous yeasts: Saccharomyces cerevisiae, Candida glabrata, Kluyveromyces lactis, Ashbya (Eremothecium) gossypii, Debaryomyces hansenii, Yarrowia lipolytica, Candida albicans and Pichia stipitis, were identified. The yeast SPs were classified in 13 different phylogenetic clusters. Specific sugar substrates could be allocated to nine phylogenetic clusters, including two novel TC clusters that are specific to fungi, i.e. the glycerol:H+ symporter (2.A.1.1.38) and the high-affinity glucose transporter (2.A.1.1.39). Four phylogenetic clusters are identified by the preliminary fifth number Z23, Z24, Z25 and Z26 and the substrates of their members remain undetermined. The amplification of the SP clusters across the Hemiascomycetes reflects adaptation to specific carbon and energy sources available in the habitat of each yeast species.
Sodium Channel Auxiliary Subunits
Authors: Tseng Tsai-Tien , McMahon Allison M. , Johnson Victoria T. , Mangubat Erwin Z. , Zahm Robert J. , Pacold Mary E. , Jakobsson Eric
Published: June 2007

Voltage-gated ion channels are well known for their functional roles in excitable tissues. Excitable tissues rely on voltage-gated ion channels and their auxiliary subunits to achieve concerted electrical activity in living cells. Auxiliary subunits are also known to provide functional diversity towards the transport and biogenesis properties of the principal subunits. Recent interests in pharmacological properties of these auxiliary subunits have prompted significant amounts of efforts in understanding their physiological roles. Some auxiliary subunits can potentially serve as drug targets for novel analgesics. Three families of sodium channel auxiliary subunits are described here: β1 and β3, β2 and β4, and temperature-induced paralytic E (TipE). While sodium channel β-subunits are encoded in many animal genomes, TipE has only been found exclusively in insects. In this review, we present phylogenetic analyses, discuss potential evolutionary origins and functional data available for each of these subunits. For each family, we also correlate the functional specificity with the history of evolution for the individual auxiliary subunits.
Myelofibrosis – What’s in a Name?
Authors: Thiele Jürgen , Kvasnicka Hans M.
Published: June 2007

Objective: Myelofibrosis (MF) implies an increase in the bone marrow (BM) fiber content without referring to quantity or quality (reticulin vs. collagen). Methods: This review on chronic myeloproliferative disorders is based on initial and sequential BM biopsies, clinical data and follow-up examinations. A semiquantitative grading system for MF approved by a panel of experts was applied. Results: In chronic myelogenous leukemia, minimal reticulin to advanced collagen MF is detectable at presentation in about 30% of patients. Significant correlations between BM and clinical features, but especially prognosis, are evident. Chronic idiopathic MF includes a prodromal stage showing no or little reticulin and no relevant MF with myeloid metaplasia (MMM). A stepwise evolution is demonstrable and associated with corresponding clinical data. Usually MMM is the diagnostic guideline for this disorder and consequently early stages with accompanying thrombocytosis may clinically mimic essential thrombocythemia. MF of various degrees may be observed in polycythemia vera depending on the progress of disease. Terminal stages (spent phase) reveal overt collagen corresponding with MMM. If diagnosis of essential thrombocythemia regards characteristic BM features, no relevant MF is seen at presentation and transformation into MMM is neglectable for many years. Conclusion: To recognize dynamics of the disease process in chronic myeloproliferative disorders, an easily to reproduce scoring system for MF has been proposed. The clinical diagnosis of MMM does not include initial-early reticulin MF and therefore fails to detect prodromal stages.
Mastocytosis: State of the Art
Authors: Horny Hans-Peter , Sotlar Karl , Valent Peter
Published: June 2007

Mastocytosis is a neoplastic disease involving mast cells (MC) and their CD34+ progenitors. Symptoms in mastocytosis are caused by biological mediators released from MC and/or the infiltration of neoplastic MC in various organs, the skin and the bone marrow being predominantly involved. A WHO consensus classification for mastocytosis exists, which is widely accepted and includes three major categories: (1) Cutaneous mastocytosis (CM), a benign disease in which MC infiltration is confined to the skin, is preferentially seen in young children and exhibits a marked tendency to regress spontaneously. (2) Systemic mastocytosis (SM) which is commonly diagnosed in adults and includes four major subtypes: (i) indolent SM (ISM, the most common form involving mainly skin and bone marrow); (ii) a unique subcategory termed SM with an associated non-mast cell clonal hematological disease (SM-AHNMD); (iii) aggressive SM usually presenting without skin lesions, and (iv) MC leukemia, probably representing the rarest variant of human leukemias. (3) The extremely rare localized extracutaneous MC neoplasms, either presenting as malignancy (MC sarcoma) or as benign tumor termed extracutaneous mastocytoma. Diagnostic criteria for mastocytosis are available and are widely accepted. SM criteria include one major criterion (multifocal compact tissue infiltration by MC) and four minor criteria: (1) prominent spindling of MC; (2) atypical immunophenotype of MC with coexpression of CD2 and/or CD25 (antigens which have not been found to be expressed on normal/reactive MC); (3) activating (somatic) point mutations of the c-kit proto-oncogene usually involving exon 17, with the imatinib-resistant type D816V being most frequent, and (4) persistently elevated serum tryptase level (>20 ng/ml). To establish the diagnosis of SM, at least one major and one minor criterion, or at least three minor criteria, have to be fulfilled. The natural clinical course of mastocytosis is variable. Most patients, in particular those with CM and ISM, remain in an indolent stage over many years or even decades, while others, in particular those with aggressive SM, SM-AHNMD, or mast cell leukemia, show a progressive course, usually with a fatal outcome.
Predictive Clinical Features of Eczema Craquelé Associated with Internal Malignancy
Authors: Sparsa Agnès , Boulinguez Serge , Liozon Eric , Roux Cyril , Peyrot Itzia , Doffoel-Hantz Valérie , Labrousse François , Vidal Elisabeth , Bordessoule Dominique , Bonnetblanc Jean-Marie , Bédane Christophe
Published: June 2007

Objective: To describe a series of hospitalized patients with eczema craquelé (EC) and the possible correlations between clinical features of EC and cancer in an open prospective observational study. Patients and Interventions: The study population comprised 68 consecutive patients included between January 1, 1999 and December 31, 2000 who were followed up through December 2004. All patients who had localized or generalized EC were included. Patients underwent complete clinical examinations, routine laboratory tests, chest x-rays, abdominal ultrasound, and cutaneous biopsies performed on EC. Main Outcome Measures and Results: Rates of EC associated with cancer, clinical features of eczema, rate of recalcitrant eczema, relationship to other clinical prognostic factors, and paraneoplastic evolution were evaluated. Cancer was diagnosed in 32 patients (47%). We observed a significant difference in the presenting clinical signs of EC between patients with malignant tumors and patients without cancer. In patients with malignancies, EC was widespread on the trunk and we noted deep red and inflammatory fissures. In all cases, EC led to the discovery of malignancy or recurrence of cancer. Conclusion: Widespread EC, topical corticosteroid resistance, and deep red and inflammatory fissures were significantly correlated with neoplasia.
Eruptive Pseudoangiomatosis: Report of an Adult Case and Unifying Hypothesis of the Pathogenesis of Paediatric and Adult Cases
Authors: Chaniotakis I. , Nomikos K. , Gamvroulia C. , Zioga A. , Stergiopoulou C. , Bassukas I.D.
Published: June 2007

One month after the onset of immunosuppressive treatment with corticosteroids and mycophenolate mofetil for a newly diagnosed pemphigus vulgaris, a 50-year-old female patient developed a new eruption clinically and histomorphologically consistent with eruptive pseudoangiomatosis (EP). Its self-limited course further confirmed this diagnosis. Although initially described as a paediatric eruption, meanwhile more adult cases of EP (30 out of a total of 53 cases identified by a Medline search) are reported in the literature. The review of adult cases of EP disclosed some common clinical and epidemiological characteristics: adult EP cases tend to cluster in the Mediterranean region of Europe, develop during the summer months, sometimes in the form of limited micro-epidemics, affect immunocompromised individuals and have lesions confined to the exposed skin sites. These characteristics, together with the exanthematic nature of the disease in children, point to some vector-transmitted infectious agent as the cause of this probably underdiagnosed disease.
The Interposed Nasalis Myocutaneous Island Flap for Lesions of the Ala and Lateral Tip of the Nose
Authors: Skaria A.M.
Published: June 2007

Background: Skin cancer of the ala of the nose is observed frequently. The local defects after Mohs surgery in this localization are difficult to repair by a 1-step procedure. Objective: The purpose of this paper is to present a new flap for lesions of the nasal ala. Methods: The design and positioning of the flap is demonstrated with photographs. Results: The interposed nasalis myocutaneous island flap is a new flap with a good viability and clinical results. Conclusion: The interposed nasalis myocutaneous island flap is a reliable flap for the reconstruction of ala defects and defects of the lateral tip of the nose.
The Transdifferentiation of Bone-Marrow-Derived Cells in Colonic Mucosal Regeneration after Dextran-Sulfate-Sodium-Induced Colitis in Mice
Authors: Hayashi Yujiro , Tsuji Shingo , Tsujii Masahiko , Nishida Tsutomu , Ishii Shuji , Nakamura Tohru , Eguchi Hiroshi , Kawano Sunao
Published: June 2007

Bone-marrow-derived cells (BMDCs) transdifferentiate into various types of gastrointestinal cells. The precise transdifferentiation of BMDCs in gut regeneration, however, is controversial. In this study, we examined the transdifferentiation of BMDCs in the regeneration of damaged colonic epithelia. Lethally irradiated wild-type female mice (C57BL/6) were rescued by bone marrow transplantation from male green fluorescent protein transgenic mouse donors. Chronic colitis was induced by administering 3% dextran sulfate sodium (DSS) in the drinking water for 5 days on day 28 after the bone marrow transplantation. The mice were killed on day 25 after DSS administration. BMDC phenotypes were examined by confocal microscopy and fluorescence immunohistochemistry. BMDCs were frequently observed in the vimentin-positive colonic interstitial cells, which also expressed α-smooth muscle actin and had a spindle-like morphology, but did not express leukocyte common antigen. Green-fluorescent-protein-positive cells were rarely or less frequently found in Ki-67-positive proliferating cells, cytokeratin-positive epithelial cells, or CD31-positive endothelial cells. BMDCs frequently transdifferentiated into subepithelial myofibroblasts and fibroblasts, and often continued to reside in the colonic subepithelia after the experimental colitis had healed. In conclusion, our data indicate the fate of BMDCs, which might be involved in the healing process of the colon after DSS-induced colitis. Our data show that BMDCs contribute to colonic interstitial cells after the colitis has healed. Understanding the fate of BMDCs may be important for stem cell therapy by BMDCs.
Modulation of Gap Junction-Dependent Arterial Relaxation by Ascorbic Acid
Authors: Edwards David H. , Chaytor Andrew T. , Bakker Linda M. , Griffith Tudor M.
Published: June 2007

Aims: To investigate whether ascorbic acid (AA) can influence endothelium-dependent relaxation by modulating the spread of endothelial hyperpolarization through the arterial wall via gap junctions. Methods: Force development and membrane potential were monitored by myography and sharp electrode techniques in isolated rabbit iliac arteries. Results: AA prevented the ability of the gap junction blocker 2-aminoethoxydiphenyl borate to inhibit endothelium-dependent relaxations and subintimal smooth muscle hyperpolarizations evoked by cyclopiazonic acid in the presence of nitric oxide (NO) synthase and cyclooxygenase blockade. AA also prevented the ability of a connexin-mimetic peptide targeted against Cx37 and Cx40 (37,40Gap 26) to attenuate the transmission of endothelial hyperpolarization to subintimal smooth muscle, and a peptide targeted against Cx43 (43Gap 26) to attenuate the spread of subintimal hyperpolarization to subadventitial smooth muscle and the associated mechanical relaxation. Parallel studies with endothelium-denuded preparations demonstrated that AA and cyclopiazonic acid both depressed relaxation evoked by the NO donor MAHMA NONOate. Conclusions: The data suggest that AA can modulate arterial function through a previously unrecognized ability to preserve electrotonic signalling via myoendothelial and homocellular smooth muscle gap junctions under conditions where cell coupling is depressed. Underlying mechanisms do not involve amplification of ‘residual’ NO activity by AA.
Development of an in vitro Skin Permeation Model Simulating Atopic Dermatitis Skin for the Evaluation of Dermatological Products
Authors: Simonsen L. , Fullerton A.
Published: June 2007

Atopic dermatitis (AD) skin has a defective barrier function as indicated by increased transepidermal water loss (TEWL). In order to test potential new formulations for AD, it was our aim to develop a skin permeation model simulating AD skin by inducing barrier impairment to otherwise healthy skin simulating the barrier properties of AD skin as evaluated by TEWL measurements. Pig ear skin was mounted to Franz-type diffusion cells. Skin barrier impairment was induced by tape strippings. As the number of strips increased, higher TEWL values were obtained. By performing 25 tape strippings, the TEWL value within the range reported for involved skin of AD patients was reached. The in vitro skin permeation of fusidic acid and betamethasone-17-valerate was found to correlate with the number of tape strippings used to remove stratum corneum cell layers. A comparison of the permeability of fusidic acid and betamethasone-17-valerate from Fucicort® cream to a new Fucicort® Lipid formulation was studied with intact (0 strippings) and barrier-impaired skin simulating involved AD skin (25 strippings). As opposed to intact skin, no statistically significant difference through barrier-impaired skin was found for fusidic acid and betamethasone-17-valerate for the two formulations. This is in accordance with the clinical results of an international multicentre study and thus confirms the predictability of the model.
Pulmonary Hypertension and Erythropoietin
Authors: Buemi M. , Senatore M. , Gallo G.C. , Crascì E. , Campo S. , Sturiale A. , Coppolino G. , Bolignano D. , Frisina N.
Published: June 2007

Numerous uremic patients on hemodialysis have pulmonary hypertension attributable to the presence of arteriovenous fistulas, vascular calcification, and endothelial dysfunction due to alterations in the balance between vasoconstrictive and vasodilatory substances. For these reasons, the effects of recombinant human erythropoietin, a drug widely used in patients on dialysis, on the pulmonary circulation were studied. Some authors maintain that recombinant human erythropoietin has an antihypertensive effect, while others have observed that this hormone induces a reduction in pulmonary arterial pressure due to its vasoactive and stimulatory effects on endothelial and smooth muscle cell precursors.
Sildenafil Promotes Ischemia-Induced Angiogenesis Through a PKG-Dependent Pathway
Authors: Senthilkumar Annamalai , Smith Ray D. , Khitha Jayant , Arora Neeraj , Veerareddy Srikar , Langston Will , Chidlow John H. , Barlow Shayne C. , Teng Xinjun , Patel Rakesh P. , Lefer David J. , Kevil Christopher G.
Published: June 2007

Background—

Peripheral artery disease (PAD) is a prevalent cardiovascular disorder that results in tissue ischemia which can progress to critical limb ischemia. Restoration of tissue perfusion in the setting of chronic ischemia through stimulation of arteriogenesis and angiogenesis remains a key therapeutic target for PAD. However, experimental therapeutics, including growth factor and gene therapy, have had little clinical success indicating the need for a better understanding of molecular pathways required for therapeutic angiogenesis.

Methods and Results—

Here we report that phosphodiesterase-5 inhibition by sildenafil significantly increases vascular perfusion, tissue blood flow, and vascular density during chronic ischemia of the mouse hind limb. Importantly, sildenafil therapy did not alter any of these parameters in nonischemic limbs. Sildenafil increased tissue cGMP levels independently of increases in nitric oxide production, and sildenafil therapy stimulated angiogenesis in ischemic limbs of eNOS
−/−
and iNOS
−/−
mice. Lastly, sildenafil-mediated angiogenic activity was blocked by inhibition of protein kinase G using the PKG antagonist DT-3.

Conclusions—

These data demonstrate that sildenafil therapy results in increased angiogenic activity through a PKG-dependent pathway that is independent of nitric oxide production or NOS activity and identify the angiogenic therapeutic potential of sildenafil for critical limb ischemia.
Kininostatin Associates With Membrane Rafts and Inhibits αvβ3 Integrin Activation in Human Umbilical Vein Endothelial Cells
Authors: Wu Yi , Rizzo Victor , Liu Yuchuan , Sainz Irma M. , Schmuckler Noah G. , Colman Robert W.
Published: June 2007

Objective—

The cleaved form of high molecular weight kininogen (HKa) is a potent inhibitor of angiogenesis and tumor growth in vivo; the functional domain has been identified as domain 5 (D5, named as kininostatin). We now identify the subcellular targeting site for D5 on endothelial cells (ECs), and investigate D5 inhibition of integrin functions.

Methods and Results—

Endothelial membrane rafts were isolated using sucrose density gradient centrifugation. D5, bound to ECs, was predominantly associated with membrane rafts, in which uPAR, a HKa receptor, was also localized. In contrast, other HKa receptors, cytokeratin-1 and gC1q receptor, were not detected in membrane rafts. Colocalization of D5 with caveolin-1 was demonstrated on ECs by confocal microscopy. Disruption of membrane rafts by cholesterol removal decreased D5 binding to ECs. On stimulation with vascular endothelial growth factor, αvβ3 integrin formed a complex with uPAR and caveolin-1, which was accompanied by an increase in ligand binding affinity of αvβ3 integrin. These events were inhibited by D5. Consistently, D5 suppressed specific αvβ3 integrin-mediated EC adhesion and spreading as well as small guanosine triphosphatase Rac1 activation.

Conclusions—

D5 binds to ECs via membrane rafts and downregulates αvβ3 integrin bidirectional signaling and the downstream Rac1 activation pathway.
Hypoxia-Dependent Regulation of Nonphagocytic NADPH Oxidase Subunit NOX4 in the Pulmonary Vasculature
Authors: Mittal Manish , Roth Markus , König Peter , Hofmann Simone , Dony Eva , Goyal Parag , Selbitz Anne-Christin , Schermuly Ralph Theo , Ghofrani Hossein Ardeschir , Kwapiszewska Grazyna , Kummer Wolfgang , Klepetko Walter , Hoda Mir Ali Reza , Fink Ludger , Hänze Jörg , Seeger Werner , Grimminger Friedrich , Schmidt Harald H.H.W. , Weissmann Norbert
Published: June 2007

Nonphagocytic NADPH oxidases have recently been suggested to play a major role in the regulation of physiological and pathophysiological processes, in particular, hypertrophy, remodeling, and angiogenesis in the systemic circulation. Moreover, NADPH oxidases have been suggested to serve as oxygen sensors in the lung. Chronic hypoxia induces vascular remodeling with medial hypertrophy leading to the development of pulmonary hypertension. We screened lung tissue for the expression of NADPH oxidase subunits. NOX1, NOXA1, NOXO1, p22phox, p47phox, p40phox, p67phox, NOX2, and NOX4 were present in mouse lung tissue. Comparing mice maintained for 21 days under hypoxic (10% O
2
) or normoxic (21% O
2
) conditions, an upregulation exclusively of NOX4 mRNA was observed under hypoxia in homogenized lung tissue, concomitant with increased levels in microdissected pulmonary arterial vessels. In situ hybridization and immunohistological staining for NOX4 in mouse lungs revealed a localization of NOX4 mRNA and protein predominantly in the media of small pulmonary arteries, with increased labeling intensities after chronic exposure to hypoxia. In isolated pulmonary arterial smooth muscle cells (PASMCs), NOX4 was localized primarily to the perinuclear space and its expression levels were increased after exposure to hypoxia. Treatment of PASMCs with siRNA directed against NOX4 decreased NOX4 mRNA levels and reduced PASMC proliferation as well as generation of reactive oxygen species. In lungs from patients with idiopathic pulmonary arterial hypertension (IPAH), expression levels of NOX4, which was localized in the vessel media, were 2.5-fold upregulated. These results support an important role for NOX4 in the vascular remodeling associated with development of pulmonary hypertension.
Therapeutic Arteriogenesis by Ultrasound-Mediated VEGF
165
Plasmid Gene Delivery to Chronically Ischemic Skeletal Muscle
Authors: Leong-Poi Howard , Kuliszewski Michael A. , Lekas Michael , Sibbald Matthew , Teichert-Kuliszewska Krystyna , Klibanov Alexander L. , Stewart Duncan J. , Lindner Jonathan R.
Published: June 2007

Current methods of gene delivery for therapeutic angiogenesis are invasive, requiring either intraarterial or intramuscular administration. A noninvasive method of gene delivery has been developed using ultrasound-mediated destruction of intravenously administered DNA-bearing carrier microbubbles during their microcirculatory transit. Here we show that chronic ischemia could be markedly improved by ultrasound-mediated destruction of microbubbles bearing vascular endothelial growth factor-165 (VEGF
165
) plasmid DNA. Using a model of severe chronic hindlimb ischemia in rats, we demonstrated that ultrasound mediated VEGF
165
/green fluorescent protein (GFP) plasmid delivery resulted in a significant improvement in microvascular blood flow by contrast-enhanced ultrasound, and an increased vessel density by fluorescent microangiography, with minimal changes in control groups. The improvement in tissue perfusion was attributed predominantly to increases in noncapillary blood volume or arteriogenesis, with perfusion peaking at 14 days after delivery, followed by a partial regression of neovascularization at 6 weeks. Transfection was localized predominantly to the vascular endothelium of arterioles in treated ischemic muscle. RT-PCR confirmed the presence of VEGF
165
/GFP mRNA within treated ischemic muscle, being highest at day 3 postdelivery, and subsequently decreasing, becoming almost undetectable by 6 weeks. We found a modulation of endogenous growth factor expression in VEGF-treated ischemic muscle, consistent with a biologic effect of ultrasound mediated gene delivery. The results of our study demonstrate the utility of ultrasonic destruction of plasmid-bearing microbubbles to induce therapeutic arteriogenesis in the setting of severe chronic ischemia.
Acutely and Retrospectively Diagnosed Perinatal Stroke
Authors: Laugesaar Rael , Kolk Anneli , Tomberg Tiiu , Metsvaht Tuuli , Lintrop Mare , Varendi Heili , Talvik Tiina
Published: June 2007

Background and Purpose—

There are not very many epidemiological studies on perinatal stroke, and many authors suggest that this may be an underdiagnosed condition. The aim of the study was to estimate the incidence of perinatal arterial ischemic and hemorrhagic stroke in Estonia, to study the first clinical signs and to identify possible differences in predisposing factors and outcome between acutely and retrospectively diagnosed cases of perinatal stroke.

Methods—

A retro- and prospective study of acutely (within the first month) and retrospectively diagnosed ischemic and hemorrhagic cases of perinatal stroke was conducted in a children population born in the eastern and southern regions of Estonia during the years 1994 to 2003. Patients were identified from a pilot study, hospital records, and an inquiry of child neurologists and general practitioners. The diagnosis was confirmed in 38 (12 were diagnosed acutely and 26 retrospectively) cases by neuroradiology (MRI or CT).

Results—

The incidence rate of perinatal stroke in Estonia is 63 per 100 000 live births. Main clinical findings in the neonatal period were seizures, abnormalities of muscular tone, and disturbed level of alertness. Previously identified risk factors occurred in 32% of cases. Children with early diagnosis had more often adverse events during pregnancy and delivery (
P
<0.05) and developed more severe stage of hemiparesis compared with children with late diagnosis (
P
<0.05).

Conclusions—

The incidence rate of 63 per 100 000 live birth is higher than previously reported. Detailed analysis of the first signs of perinatal stroke may improve the early diagnostics of perinatal stroke.
The contrOL of dYslipideMia in outPatIent clinics in GreeCe (Olympic) Study
Authors: Diamantopoulos E. J. , Athyros V. G. , Yfanti G. K. , Migdalis E. N. , Elisaf M. , Vardas P. E. , Manolis A. S. , Karamitsos D. T. , Ganotakis E. S. , Hatseras D. ,   OLYMPIC Study Group
Published: June 2007

The objective of this study was to determine the proportion of Greek patients referred to outpatient clinics for dyslipidemia who achieved the low-density lipoprotein cholesterol (LDL C) goal defined by the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) guidelines, using lifestyle changes, lipid-lowering drug treatment (LLDT), or both. Adult patients with dyslipidemia, who had been receiving a hypolipidemic diet and/or LLDT for at least 3 months were assessed in a multicenter study performed at 66 sites across Greece. Patients were followed up for an additional 3-month treatment period. Lipid levels were recorded at baseline and at the end of the study. The primary endpoint was the proportion of patients achieving their individual LDL-C target at the end of the study, according to their coronary heart disease (CHD) risk status or its equivalents, as defined by the NCEP-ATP III guidelines. Multivariate logistic models were used to identify determinants of undertreatment. The study included 2,660 adults (20-75 years) from 7 regions of Greece. Of the evaluable sample (n=2,211; men 51%; mean age 62 ±9 years) 81% were receiving LLDT (96% with statins and 3% with fibrates), 44% had a history of CHD, 61% arterial hypertension, 36% diabetes, and 26% a family history of premature CHD. Overall, 6% were at low CHD risk, 30% at medium CHD risk, and 63% at high CHD risk. At the end of the study, 26% of all patients and 30% of those receiving LLDT achieved the NCEP-specified LDL-C target levels. The percentage of patients at LDL-C goal according to CHD risk status was: low risk 67% (95% CI=59-75), medium risk 29% (95% CI=26-33), and high risk 20% (95% CI=18-22). Statins proved to be more effective than fibrates (p<0.0001). Atorvastatin-treated subjects (n=1,222, mean dose 19 mg/day) attained the LDL-C target (31% of the cases) at a higher rate than those receiving other LLDT (n=574, 26% at target, p<0.01) or not receiving drug treatment (n=415, 8%, p<0.001). This outcome was more evident in the high-CHD risk group (n=1,402, 26% with atorvastatin vs 16% with other LLDT and 3% not receiving LLDT attained the LDL-C goal, ANOVA, p<0.001). The majority of dyslipidemic patients receiving LLDT, mainly those with high-CHD risk, are not achieving the NCEP LDL-C target. This is mainly explained by inadequate dose titration to ensure target goals are met. Promoting healthy lifestyle and appropriate LLDT (potent statins with sufficient dose titration) must be implemented to ensure that patients attain LDL-C treatment goals and thus benefit from the reduction in individual CHD risk.