bluuebunny/crossref_metadata_2025 huggingface dataset:
ExcisaninA, a diterpenoid compound purified from Isodon MacrocalyxinD, induces tumor cells apoptosis and suppresses tumor growth through inhibition of PKB/AKT kinase activity and blockade of its signal pathway
Authors: Deng Rong , Tang Jun , Xia Liang-Ping , Li Dan-Dan , Zhou Wen-Jun , Wang Lin-Lin , Feng Gong-Kan , Zeng Yi-Xin , Gao You-Heng , Zhu Xiao-Feng
Published: April 2009

Isodon diterpenoids have received considerable phytochemical and biological attention for their strong antitumor activity with low toxicity. In this study, ExcisaninA, a diterpenoid compound purified from Isodon MacrocalyxinD, was tested on human Hep3B and MDA-MB-453 cell lines and Hep3B xenograft models. The results showed ExcisaninA could inhibit the proliferation of Hep3B and MDA-MB-453 cells via induction of apoptosis, with the evidence of increasing AnnexinV–positive cells and characteristic morphologic changes of apoptosis in the nucleus. Also, ExcisaninA sensitized Hep3B cells to 5-fluorouracil treatment or MDA-MB-453 cells to ADM treatment in vitro. In Hep3B xenograft models, ExcisaninA at 20 mg/kg/d remarkably decreased the xenograft tumor size and induced tumor cells apoptosis using transferase-mediated FITC-12-dUTP nick-end labeling assay. More importantly, we found that ExcisaninA could inhibit AKT activity and block its signal pathway in vitro and in vivo. And treatment with ExcisaninA significantly reduced the number of viable cells in Hep3B/myr-AKT1 cells more than that in control cells. Together, ExcisaninA might be a potent inhibitor of AKT signaling pathway in tumor cells. These data provide validation for the development of ExcisaninA to treat cancers displaying elevated levels of AKT.[Mol Cancer Ther 2009;8(4):873–82]
Dual silencing of insulin-like growth factor-I receptor and epidermal growth factor receptor in colorectal cancer cells is associated with decreased proliferation and enhanced apoptosis
Authors: Kaulfuβ Silke , Burfeind Peter , Gaedcke Jochen , Scharf Jens-Gerd
Published: April 2009

Overexpression and activation of tyrosine kinase receptors are common features of colorectal cancer. Using the human colorectal cancer cell lines DLD-1 and Caco-2, we evaluated the role of the insulin-like growth factor-I (IGF-I) receptor (IGF-IR) and epidermal growth factor receptor (EGFR) in cellular functions of these cells. We used the small interfering RNA (siRNA) technology to specifically down-regulate IGF-IR and EGFR expression. Knockdown of IGF-IR and EGFR resulted in inhibition of cell proliferation of DLD-1 and Caco-2 cells. An increased rate of apoptosis was associated with siRNA-mediated silencing of IGF-IR and EGFR as assessed by activation of caspase-3/caspase-7. The combined knockdown of both EGFR and IGF-IR decreased cell proliferation and induced cell apoptosis more effectively than did silencing of either receptor alone. Comparable effects on cell proliferation and apoptosis were observed after single and combinational treatment of cells by the IGF-IR tyrosine kinase inhibitor NVP-AEW541 and/or the EGFR tyrosine kinase inhibitor erlotinib. Combined IGF-IR and EGFR silencing by either siRNAs or tyrosine kinase inhibitors diminished the phosphorylation of downstream signaling pathways AKT and extracellular signal–regulated kinase (ERK)-1/2 more effectively than did the single receptor knockdown. Single IGF-IR knockdown inhibited IGF-I–dependent phosphorylation of AKT but had no effect on IGF-I– or EGF-dependent phosphorylation of ERK1/2, indicating a role of EGFR in ligand-dependent ERK1/2 phosphorylation. The present data show that inhibition of the IGF-IR transduction cascade augments the antipoliferative and proapoptotic effects of EGFR inhibition in colorectal cancer cells. A clinical application of combination therapy targeting both EGFR and IGF-IR could be a promising therapeutic strategy.[Mol Cancer Ther 2009;8(4):821–33]
PRMT5, a Novel TRAIL Receptor-Binding Protein, Inhibits TRAIL-Induced Apoptosis via Nuclear Factor-κB Activation
Authors: Tanaka Hiroshi , Hoshikawa Yutaka , Oh-hara Tomoko , Koike Sumie , Naito Mikihiko , Noda Tetsuo , Arai Hiroyuki , Tsuruo Takashi , Fujita Naoya
Published: April 2009

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily and has selective antitumor activity. Although TNF-α-induced intracellular signaling pathways have been well studied, TRAIL signaling is not fully understood. Here, we identified a novel TRAIL receptor-binding protein, protein arginine methyltransferase 5 (PRMT5), as a result of proteomic screening. PRMT5 selectively interacted with death receptor 4 and death receptor 5 but not with TNF receptor 1 or Fas. PRMT5 gene silencing sensitized various cancer cells to TRAIL without affecting TRAIL resistance in nontransformed cells. PRMT5 contributed to TRAIL-induced activation of inhibitor of κB kinase (IKK) and nuclear factor-κB (NF-κB), leading to induction of several NF-κB target genes. Although IKK inhibition increased sensitivity to both TRAIL and TNF-α, PRMT5 knockdown potentiated TRAIL-mediated cytotoxicity alone. PRMT5 had no effect on TNF-α-mediated NF-κB signaling. These results show the selectivity of PRMT5 for TRAIL signaling. The PRMT5 small interfering RNA-mediated susceptibility to TRAIL was rescued by ectopic expression of active IKKβ, confirming the involvement of PRMT5 in TRAIL resistance by activating the NF-κB pathway. Collectively, our findings suggest the therapeutic potential of PRMT5 in TRAIL-based cancer treatments.(Mol Cancer Res 2009;7(4):557–69)
ErbB2-Mediated Src and Signal Transducer and Activator of Transcription 3 Activation Leads to Transcriptional Up-Regulation of p21Cip1 and Chemoresistance in Breast Cancer Cells
Authors: Hawthorne Valerie S. , Huang Wen-Chien , Neal Christopher L. , Tseng Ling-Min , Hung Mien-Chie , Yu Dihua
Published: April 2009

Overexpression of the ErbB2 receptor tyrosine kinase is prevalent in ∼30% of human breast cancers and confers Taxol resistance. Our previous work has shown that ErbB2 inhibits Taxol-induced apoptosis in breast cancer cells by transcriptionally up-regulating p21Cip1. However, the mechanism of ErbB2-mediated p21Cip1 up-regulation is unclear. Here, we show that ErbB2 up-regulates p21Cip1 transcription through increased Src activity in ErbB2-overexpressing cells. Src activation further activated signal transducer and activator of transcription 3 (STAT3) that recognizes a SIE binding site on the p21Cip1 promoter required for ErbB2-mediated p21Cip1 transcriptional up-regulation. Both Src and STAT3 inhibitors restored Taxol sensitivity in resistant ErbB2-overexpressing breast cancer cells. Our data suggest that ErbB2 overexpression can activate STAT3 through Src leading to transcriptional up-regulation of p21Cip1 that confers Taxol resistance of breast cancer cells. Our study suggests a potential clinical application of Src and STAT3 inhibitors in Taxol sensitization of ErbB2-overexpressing breast cancers. (Mol Cancer Res 2009;7(4):592–600)
Estradiol-Induced Regression in T47D:A18/PKCα Tumors Requires the Estrogen Receptor and Interaction with the Extracellular Matrix
Authors: Zhang Yiyun , Zhao Huiping , Asztalos Szilard , Chisamore Michael , Sitabkhan Yasmin , Tonetti Debra A.
Published: April 2009

Several breast cancer tumor models respond to estradiol (E2) by undergoing apoptosis, a phenomenon known to occur in clinical breast cancer. Before the application of tamoxifen as an endocrine therapy, high-dose E2 or diethystilbesterol treatment was successfully used, albeit with unfavorable side effects. It is now recognized that such an approach may be a potential endocrine therapy option. We have explored the mechanism of E2-induced tumor regression in our T47D:A18/PKCα tumor model that exhibits autonomous growth, tamoxifen resistance, and E2-induced tumor regression. Fulvestrant, a selective estrogen receptor (ER) down-regulator, prevents T47D:A18/PKCα E2-induced tumor growth inhibition and regression when given before or after tumor establishment, respectively. Interestingly, E2-induced growth inhibition is only observed in vivo or when cells are grown in Matrigel but not in two-dimensional tissue culture, suggesting the requirement of the extracellular matrix. Tumor regression is accompanied by increased expression of the proapoptotic FasL/FasL ligand proteins and down-regulation of the prosurvival Akt pathway. Inhibition of colony formation in Matrigel by E2 is accompanied by increased expression of FasL and short hairpin RNA knockdown partially reverses colony formation inhibition. Classic estrogen-responsive element-regulated transcription of pS2, PR, transforming growth factor-α, C3, and cathepsin D is independent of the inhibitory effects of E2. A membrane-impermeable E2-BSA conjugate is capable of mediating growth inhibition, suggesting the involvement of a plasma membrane ER. We conclude that E2-induced T47D:A18/PKCα tumor regression requires participation of ER-α, the extracellular matrix, FasL/FasL ligand, and Akt pathways, allowing the opportunity to explore new predictive markers and therapeutic targets. (Mol Cancer Res 2009;7(4):498–510)
The Ubiquitin Ligase Siah2 and the Hypoxia Response
Authors: Nakayama Koh , Qi Jianfei , Ronai Ze'ev
Published: April 2009

Growing evidence indicates that ubiquitin ligases play a critical role in the hypoxia response. Among them, Siah2, a RING finger ligase, is an important regulator of pathways activated under hypoxia. Siah2 regulates prolyl hydroxylases PHD3 and 1 under oxygen concentration of 2% to 5%, thereby allowing accumulation of hypoxia-inducible factor (HIF)-1α, a master regulator of the hypoxia response within the range of physiological normoxic to mild hypoxic conditions. Growing evidence also indicates an important function for Siah2 in tumor development and progression based on pancreatic cancer, mammary tumor, and melanoma mouse models. This review summarizes our current understanding of Siah2 regulation and function with emphasis on hypoxia and tumorigenesis. (Mol Cancer Res 2009;7(4):443–51)
Correlations between numerical chromosomal aberrations in the tumor and peripheral blood in canine lymphoma
Authors: Devitt J.J. , Maranon D.G. , Ehrhart E.J. , Bachand A.M. , Lana S.E. , LaRue S.M.
Published: April 2009

Lymphoma is the most frequently diagnosed hematopoietic malignancy in dogs. Untreated, the survival times are approximately one month. Chemotherapy is the current standard of care and can initiate and temporarily maintain remission, with average remission times of one year. Canine lymphoma is an established model of human non-Hodgkin’s lymphoma, and studying this disease in dogs can provide insight to both human and canine disease. Cytogenetic abnormalities can aid in diagnosing tumors as well as in giving a more accurate prognosis for the specific mutations present. Evaluating peripheral lymphocytes instead of tumor cells is less invasive for the affected dog and technically easier. This study was designed to investigate a correspondence between numerical aberrations detected in the tumor and the peripheral blood in dogs with lymphoma. Twenty-five dogs with lymphoma had one lymph node excised, a peripheral blood sample drawn, and a bone marrow aspirate performed. Portions of the lymph node were submitted for immunophenotyping and cytogenetic analysis. The peripheral blood sample was cultured for cytogenetic analysis and the bone marrow aspirate was used for staging purposes. A significant correspondence between the numerical aberrations in the tumor and the peripheral blood was found. The findings in this study pave the way toward an alternative method for evaluating lymphoma. When tumor analysis is not possible, the peripheral blood offers a viable option for cytogenetic assessment. Additionally, this may provide a method to evaluate the efficacy of the treatment protocol during the course of treatment.
Neo-XY body: an analysis of XY1Y2 meiotic behavior in Carollia (Chiroptera, Phyllostomidae) by chromosome painting
Authors: Noronha R.C.R. , Nagamachi C.Y. , O’Brien P.C.M. , Ferguson-Smith M.A. , Pieczarka J.C.
Published: April 2009

Classical and molecular cytogenetic analyses of mitotic and meiotic cells were performed on two species of Carollia from the family Phyllostomidae (Chiroptera), which have an XX/XY1Y2 sex determination system. Our results show that the species Carollia perspicillata and Carollia brevicauda have the same Xq-autosome translocation (neo-X). Using multicolor FISH we observed different levels of condensation of the original X and Y chromosomes when compared to the translocated autosomal segment, a likely consequence of the nucleolar organizer region blocking spreading of inactivation to the autosomal region of the neo-X. The use of chromosome painting showed the behavior of the sex chromosome trivalent – here called the ‘neo-XY body’ – in meiosis. We compared the variation between the condensation of the original X and Y and the autosome-sex chromosome axis and described the pairing between the original X-Y segments (pseudoautosomal region) and the XY2 homologous segments, suggesting genetic activity of the latter during meiosis.
Chromosomal study of native and hatchery trouts from Italy (Salmo trutta complex, Salmonidae): conventional and FISH analysis
Authors: Caputo V. , Giovannotti M. , Nisi Cerioni P. , Splendiani A. , Olmo E.
Published: April 2009

A cytogenetic analysis was carried out using conventional staining, banding techniques and fluorescence in situ hybridization (FISH) in Italian populations of brown trout (Salmo truttacomplex). All individuals analysed, belonging to the Atlantic (At), Marmoratus (Ma), Adriatic (Ad) and Mediterranean (Me) lineages, showed remarkable karyotype uniformity, with diploid complement of 2n = 80 chromosomes, arm number (NF) of 102 and invariable karyotype composition. Such uniformity was also observed with respect to the location of 5S rDNA and the active, i.e. silver-positive NOR sites. On the contrary, FISH with 28S ribosomal probe and fluorescent staining with CMA3 revealed that inactive NOR sites are more numerous in Ad and Me than in At and Ma lineages. A centromeric sequence was successfully isolated from Salmo trutta individuals by polymerase chain reaction (PCR)-based cloning, using primers designed from published Atlantic salmon (Salmo salar) satellite DNA sequences. This sequence had high AT content (65.3%) and short consensus motif (A/T)(G/C)AAA(T/C) similar to other centromeric satellite repeats. The isolated satellite DNA clones were localized with FISH in the centromeric regions of the brown trout chromosomes, showing lineage-specific patterns. Because it is well known that AT-rich sequences can induce a pronounced DNA curvature, which in turn would promote faster and higher chromatin spiralization, it may be hypothesised that the wide distribution of this satellite in the S. trutta genome may have played a role in its karyotype stability. The presence of this sequence in other salmonid species was also tested by Southern blot hybridization and used to analyze its evolution within salmonids.
A GC-rich satellite DNA and karyology of the bivalve mollusk Donax trunculus: a dominance of GC-rich heterochromatin
Authors: Petrović V. , Pérez-García C. , Pasantes J.J. , Šatović E. , Prats E. , Plohl M.
Published: April 2009

We characterized the DTF2 satellite DNA family of the clam Donaxtrunculus and compared its chromosomal localization with cytogenetic data revealed by fluorochrome banding, C-banding, and 28S rDNA FISH. In contrast to the other satellites detected previously in this species, DTF2 is an abundant (2%) GC-rich satellite that exhibits CpG methylation. Sequence characteristics of DTF2 indicate that its evolution is not affected by constraints that might indicate some functional interactions. Fluorescence in situ hybridization revealed subtelomeric location of this satellite on a subset of 14 out of 19 D. trunculus chromosome pairs. The chromomycin A3 (CMA) staining of GC-rich regions on D. trunculus chromosomes revealed a complex banding pattern that overlaps completely with C-bands. In total, only three bands show subtelomeric location, while 13 bands are located interstitially, one of them being coincident with the 28S rDNA hybridization signal. No bands, either CMA positive (GC-rich) or DAPI positive (AT-rich) were detected at centromeric chromosomal positions. Only two of the CMA-positive bands co-localize with the DTF2 satellite, showing a) the presence of small islands of GC-rich repetitive sequences that remained undetected by CMA/C-banding and b) the abundance of DTF2-divergent GC-rich sequences at interstitial chromosomal locations.
Karyotypes, heterochromatin, and physical mapping of 18S-26S rDNA in Cactaceae
Authors: Las Peñas M.L. , Urdampilleta J.D. , Bernardello G. , Forni-Martins E.R.
Published: April 2009

Karyotype analyses in members of the four Cactaceae subfamilies were performed. Numbers and karyotype formula obtained were: Pereskioideae = Pereskiaaculeata(2n = 22; 10 m + 1 sm), Maihuenioideae = Maihuenia patagonica (2n = 22, 9 m + 2 sm; 2n = 44, 18 m + 4 sm), Opuntioideae = Cumulopuntia recurvata(2n = 44; 20 m + 2 sm), Cactoideae = Acanthocalycium spiniflorum (2n = 22; 10 m + 1 sm),Echinopsis tubiflora (2n = 22; 10 m + 1 sm), Trichocereus candicans (2n = 22, 22 m). Chromosomes were small, the average chromosome length was 2.3 μm. Diploid species and the tetraploid C. recurvata had one terminal satellite, whereas the remaining tetraploid species showed four satellited chromosomes. Karyotypes were symmetrical. No CMA–/DAPI+ bands were detected, but CMA+/DAPI– bands associated with NOR were always found. Pericentromeric heterochromatin was found in C. recurvata, A. spiniflorum, and the tetraploid cytotype of M. patagonica. The locations of the 18S-26S rDNA sites in all species coincided with CMA+/DAPI– bands; the same occurred with the sizes and numbers of signals for each species. This technique was applied for the first time in metaphase chromosomes in cacti. NOR-bearing pair no.1 may be homeologous in all species examined. In Cactaceae, the 18S-26S loci seem to be highly conserved.
A 1q44 deletion, paternal UPD of chromosome 2 and a deletion due to a complex translocation detected in children with abnormal phenotypes using new SNP array technology
Authors: Talseth-Palmer B.A. , Bowden N.A. , Meldrum C. , Nicholl J. , Thompson E. , Friend K. , Liebelt J. , Bratkovic D. , Haan E. , Yu S. , Scott R.J.
Published: April 2009

Children with intellectual disability, dysmorphic features, malformations and/or growth abnormalities frequently display normal karyotypes. Recent studies have shown that genome-wide single nucleotide polymorphism (SNP) arrays can be effective in detecting abnormalities involving copy number variation (CNV), deletions, duplications and loss of heterozygosity (LOH) that routine cytogenetic tests fail to identify. Five patients with various degrees of intellectual disability and/or dysmorphic features and other malformations were whole-genome genotyped using the Human-1 Genotyping BeadChip – Exon-Centrix 100K SNP arrays (Illumina). All patients had undergone routine cytogenetic testing; four patients had normal karyotypes, while one patient had an apparently balanced complex translocation involving chromosomes 1q25, 1q32, 2q23, 7q22 and 16q24. We detected deletions on chromosome 1q44 and 13q31.1 in one patient, and LOH of the entire chromosome 2 in another patient, both with cytogenetically normal karyotypes. The patient with the complex translocation had a deletion on chromosome 7q22.2-22.3, which is in conjunction with one of the translocation breakpoints. Our findings provide further evidence of there being a critical region for the development of microcephaly and corpus callosum abnormalities in children with distal 1q deletions. We have also shown that apparently balanced complex translocations might not be balanced at the DNA level, and we report the fourth case of paternal uniparental disomy of chromosome 2. The results of this study suggest that it may be desirable to investigate idiopathic mental retardation using genome-wide SNP arrays, in conjunction with other cytogenetic and molecular techniques.
10p11.2 to 10q11.2 is a yet unreported region leading to unbalanced chromosomal abnormalities without phenotypic consequences
Authors: Liehr T. , Stumm M. , Wegner R.D. , Bhatt S. , Hickmann P. , Patsalis P.C. , Meins M. , Morlot S. , Klaschka V. , Ewers E. , Hinreiner S. , Mrasek K. , Kosyakova N. , Cai W.W. , Cheung S.W. , Weise A.
Published: April 2009

Directly transmitted unbalanced chromosomal abnormalities (UBCA) or euchromatic variants (EV) were recently reported for >50 euchromatic regions of almost all human autosomes. UBCA and EV are comprised of a few megabases of DNA, and carriers are in many cases clinically healthy. Here we report on partial trisomies of chromosome 10 within the pericentromeric region which were detected by standard G banding. Those were referred for further delineation of the size of these duplicated regions for molecular cytogenetics and/or array-CGH. Partial trisomies of chromosome 10 in the pericentromeric region were identified prenatally in seven cases. A maximum of three copies of the region from 10p12.1 to 10q11.22 was observed in all cases without apparent clinical abnormalities. The imbalances were either caused by a direct duplication in one familial case or by de novo small supernumerary marker chromosomes (sSMC). Thus, we report a yet unrecognized chromosomal region subject to UBCA detected in seven unrelated cases. To the best of our knowledge, this is the first report of a UBCA in the pericentromeric region of chromosome 10 that is not correlated with any clinical consequences.
Phytochemicals as Modulators of Neoplastic Phenotypes
Authors: Ding Heidrun , Tauzin Sébastien , Hoessli Daniel C.
Published: April 2009

It is generally accepted that nutritional behaviors constitute decisive components of human health. Phytochemicals (small, nonenergetic molecules of vegetal origin) are overall inhibitory on the expression of gene products promoting proliferation and resistance to apoptosis. On the contrary, phytochemicals stimulate the synthesis of adaptive proteins that favor resistance to cellular stress (detoxifying and antioxidant enzymes). They are effective modulators that act synergistically on membrane, cytoplasmic and nuclear enzymatic reactions to dampen cellular hyperproliferation and hyperactivity, reequilibrate metabolic activity and promote apoptosis of genetically unstable cells. Despite important gaps in our knowledge regarding how phytochemicals interfere with cellular function in vivo, effective chemopreventive measures have shown that phytochemicals can be utilized to prevent cancer, and possibly to treat cancer patients as well. We review how phytochemicals exert their beneficial effects at the cellular level.
Trends in Hormone Therapy and Breast Cancer Incidence – Results from the German Network of Cancer Registries
Authors: Katalinic Alexander , Lemmer Anna , Zawinell Anette , Rawal Rajesh , Waldmann Annika
Published: April 2009

Objective: Menopausal hormone therapy (HT) is a proven risk factor for breast cancer. Recent reports presented declining trends in breast cancer incidence, which were attributed to parallel declining trends in HT. Therefore, we analyzed recent data on hormone therapy and breast cancer incidence in Germany. Methods: We performed a population-based survey using breast cancer incidence (from cancer registries) and hormone prescription data (from health insurances) for the time period from 1997 to 2006. Age-standardized rates were calculated and joinpoint regression analyses for trends were performed. Results: Prescription of HT started to decline in 1999; about 2 years later, a parallel decline in breast cancer incidence was observed. HT prescription decreased by 69% up to 2006, and breast cancer incidence by 6.8% for all age groups (2002–2005) and 12.8% in the age group from 50 to 69 years. The reductions in HT prescription and breast cancer incidence were markedly correlated across the federal states in Germany. Conclusion: The recent decline in breast cancer incidence following decreasing HT prescription suggests a causal relationship between the risk of breast cancer and HT in Germany. Even after the ‘big HT drop’ in Germany, significant differences in HT prescription as well as breast cancer incidence persist at the federal state level. These results should be discussed in a public health context.
Ultrasound Contrast Agents in Ischemic Stroke
Authors: Seidel Günter , Meairs Stephen
Published: April 2009

The general indication for the use of ultrasound contrast agents in neurosonologic applications is an insufficient signal-to-noise ratio when investigating the cerebral macro- and microcirculation. Clinical problems that are often encountered in native sonography are ‘no flow, slow flow and low flow’ phenomena. In these cases, ultrasound contrast agents are used to differentiate between vessel occlusion and insufficient insonation conditions, as well as for the detection of very slow blood flow velocities and low flow volumes. Echo-contrast agents significantly increase the success rate of transcranial color duplex examinations of patients with acute cerebrovascular disease. Ultrasound contrast imaging also allows assessment of the cerebral microcirculation. There are a number of techniques available for performing perfusion studies. These generally utilize high mechanical index imaging, since until recently lower acoustic outputs were unable to detect microbubbles in the brain. New-generation microbubbles in combination with very sensitive contrast-specific ultrasound techniques now enable real-time visualization of stroke. Moreover, destruction sequences with assessment of microbubble replenishment using real-time, low mechanical index imaging are now available. This article reviews of state-of-the-art contrast-specific imaging techniques for ultrasound evaluation of acute stroke patients.
Imaging of Carotid Plaque Angiogenesis
Authors: Vicenzini Edoardo , Giannoni Maria Fabrizia , Benedetti-Valentini Fabrizio , Lenzi Gian Luigi
Published: April 2009

Currently, characterization of the vulnerable plaque is a hot research topic as a more adequate strategy for preventing cerebrovascular events is being sought. Histological studies have recognized that plaque inflammation and the presence of adventitial vasa vasorum, intimal angiogenesis and plaque neovascularization are strong predictors of instability in atheromatous lesions of cerebrovascular and cardiovascular patients. The in vivo study of these features has been the focus of development of several new radiological imaging methods. Carotid ultrasound, with ultrasound contrast agents, is not only able to provide an enhanced assessment of the arterial lumen and plaque morphology with an improved resolution of the carotid intima-media thickness, but also to directly visualize adventitial vasa vasorum and plaque neovascularization. This technique and its future clinical implications are discussed in the present review.
Microbubbles for Thrombolysis of Acute Ischemic Stroke
Authors: Meairs Stephen , Culp William
Published: April 2009

Improved treatment of acute ischemic stroke with ultrasound and microbubbles in combination with thrombolytic drugs shows great promise, but the optimal techniques, indications, and contraindications have not yet been well defined. Moreover, details such as microbubble dosage, delivery, required thrombolytic drug dosage, and optimal ultrasound characteristics all remain uncertain. Recent results suggest that ultrasound and microbubbles may be effective in clot lysis of ischemic stroke without additional thrombolytic drugs. Moreover, targeting thrombus with specific immunobubbles may improve the efficacy of sonothrombolysis. Safety remains a major concern in the further development of ultrasound-enhanced thrombolysis and extensive animal work is required to define the most promising methods to translate into human application.
Molecular Imaging with Targeted Contrast Ultrasound
Authors: Piedra Mark , Allroggen Achim , Lindner Jonathan R.
Published: April 2009

Molecular imaging with contrast-enhanced ultrasound uses targeted microbubbles that are retained in diseased tissue. The resonant properties of these microbubbles produce acoustic signals in an ultrasound field. The microbubbles are targeted to diseased tissue by using certain chemical constituents in the microbubble shell or by attaching disease-specific ligands such as antibodies to the microbubble. In this review, we discuss the applications of this technique to pathological states in the cerebrovascular system including atherosclerosis, tumor angiogenesis, ischemia, intravascular thrombus, and inflammation.
Lability of Neuronal Lineage Decisions Is Revealed by Acute Exposures to Ethanol
Authors: Miller Michael W. , Hu Huaiyu
Published: April 2009

On August 6, 2010, the Editor-in-Chief of Developmental Neuroscience, Steven W. Levison, was contacted by the legal counsel for SUNY Upstate Medical University and informed that an investigative committee at SUNY Upstate had determined that Dr. Michael Miller was guilty of multiple counts of research misconduct, and they requested that Developmental Neuroscience retract the 2009 article authored by Drs. Miller and Huaiyu Hu. The committee did not find Dr. Hu at fault for any scientific misconduct. After independently reviewing the reports of the investigative committee and the rebuttals provided by Dr. Miller, the Editor-in-Chief and the publisher concurred that there were errors in reporting sample sizes and in mathematical calculations. However, at that time it was our view that an erratum was more appropriate than a retraction of the article. Despite the flaws in the analyses of the data, it was our determination that those flaws could be corrected in a published erratum to produce a final product that would be more useful to the scientific community than a complete retraction of the work. On December 10, 2010, we requested that Dr. Miller provide a corrected figure with an explanation of the mistakes that had been previously published. However, that erratum was never published as we were provided with additional information and testimonies that convinced us that the collected data may also be unreliable. Accordingly, on October 18, 2011, we requested that a letter of retraction be provided that was co-authored and co-signed by both authors. It was our view that for an action as severe as an article retraction, both authors needed to sign the retraction letter. However, Drs. Miller and Hu were unable to agree upon a letter that could be jointly signed. Therefore, at the request of the President of SUNY Upstate, with this statement we formally retract the article by Drs. Miller and Hu, Developmental Neuroscience 2009;31:50–57. We have sent correspondence to both authors, to the President of SUNY Upstate and to Dr. Steven Goodman, Vice President for Research at SUNY Upstate, to inform them in advance that this action is being taken by the journal.
Juvenile Methylphenidate Exposure and Factors That Influence Incentive Processing
Authors: Brenhouse Heather C. , Napierata Lee , Kussmaul Lucinda , Leussis Melanie , Andersen Susan L.
Published: April 2009

Methylphenidate (MPH) is one of the few psychotropic agents approved for use in pediatric populations, underscoring the importance of elucidating any long-term consequences following exposure to this agent. Here, we examined the influence of several variables (i.e. age of assessment, age of exposure, sex, route of administration) on the effect of chronic low-dose MPH (2 mg/kg, twice daily) exposure on place conditioning to cocaine. Juvenile exposure to MPH, but not later exposure, resulted in aversions to cocaine-paired environments when assessed in young adult male rats, but not those entering adolescence. Juvenile MPH enhanced place preferences for cocaine-paired environments in female adolescent rats. The route of administration (i.p. injection or oral ingestion) did not produce enduring differential effects on behavior, and D-MPH was confirmed as the active enantiomer. These observations add to the growing literature on the enduring effects of MPH exposure, and highlight the need for more research in females.
Risk-Taking and the Feedback Negativity Response to Loss among At-Risk Adolescents
Authors: Crowley Michael J. , Wu Jia , Crutcher Clifford , Bailey Christopher A. , Lejuez C.W. , Mayes Linda C.
Published: April 2009

Event-related brain potentials were examined in 32 adolescents (50% female) from a high-risk sample, who were exposed to cocaine and other drugs prenatally. Adolescents were selected for extreme high- or low-risk behavior on the Balloon Analog Risk Task, a measure of real-world risk-taking propensity. The feedback error-related negativity (fERN), an event-related potential (ERP) that occurs when an expected reward does not occur, was examined in a game in which choices lead to monetary gains and losses with feedback delayed 1 or 2 s. The fERN was clearly visible in the fronto-central scalp region in this adolescent sample. Feedback type, feedback delay, risk status, and sex were all associated with fERN variability. Monetary feedback also elicited a P300-like component, moderated by delay and sex. Delaying reward feedback may provide a means for studying complementary functioning of dopamine and norepinephrine systems.
Prenatal Cocaine Exposure and Prolonged Focus Attention
Authors: Chiriboga Claudia A. , Starr Denise , Kuhn Louise , Wasserman Gail A.
Published: April 2009

In experimental models, prenatal cocaine exposure has been found to perturb monoaminergic development of systems implicated in modulating attention. To determine whether prenatal cocaine exposure affects infant attention, we assessed visual recognition memory and focused attention during free play. We enrolled at birth 380 infants, 113 cocaine exposed, using multiple biomarkers to assess drug exposure. Behavior was videotaped and coded off-line for sustained looking time (i.e. focused attention), banging and intrusion. Prenatal cocaine exposure was not associated with visual recognition memory, but was significantly associated with longer sustained looking times (average focused attention) at ages 6 months (p = 0.02) and 12 months (p = 0.04) in analyses that adjusted for variables, including maternal intelligence, education, depressive scores and other exposures (alcohol, tobacco and marijuana). Cocaine-exposed infants at age 12 months also spent significantly less time in banging activity (p = 0.02) after adjusting for confounding variables. This finding was not explained through cocaine effects on motor development, neurological findings or time spent in focused attention. Prenatal cocaine exposure was significantly associated with longer periods of sustained looking or focused attention in infancy, a finding that could interpreted as a measure of poor processing efficiency, or alternatively as precocious maturation of attentional systems. Either interpretation has implications for later cognitive development. Lower banging activity among cocaine exposed was not explained through cocaine effects on motor development or neurological findings, suggesting that activity level itself is diminished in these infants. Whether focused attention findings impact long term development awaits further study.
Functional MRI and Response Inhibition in Children Exposed to Cocaine in utero
Authors: Sheinkopf Stephen J. , Lester Barry M. , Sanes Jerome N. , Eliassen James C. , Hutchison Emmette R. , Seifer Ronald , LaGasse Linda L. , Durston Sarah , Casey B.J.
Published: April 2009

This study investigated the potential long-term effects of cocaine exposure on brain functioning using fMRI in school-aged children. The sample included 12 children with prenatal cocaine exposure and 12 non-exposed children (8–9 years old). Groups did not differ on IQ, socioeconomic status, or perinatal risk factors. A response inhibition task was administered during an fMRI scan using a 1.5-T MRI system. Task performance did not differentiate groups, but groups were differentiated by patterns of task-related brain activity. Cocaine-exposed children showed greater activation in the right inferior frontal cortex and caudate during response inhibition, whereas non-exposed children showed greater activations in temporal and occipital regions. These preliminary findings suggest that prenatal cocaine may affect the development of brain systems involved in the regulation of attention and response inhibition.
Rhythm as an Affordance for the Entrainment of Movement
Authors: Cummins Fred
Published: April 2009

A general account of rhythm in human behaviour is provided, according to which rhythm inheres in the affordance that a signal provides for the entrainment of movement on the part of a perceiver. This generic account is supported by an explication of the central concepts of affordance and entrainment. When viewed in this light, rhythm appears as the correct explanandum to account for coordinated behaviour in a wide variety of situations, including such core senses as dance and the production of music. Speech may appear to be only marginally rhythmical under such an account, but several experimental studies reveal that speech, too, has the potential to entrain movement.
Do Rhythm Measures Reflect Perceived Rhythm?
Authors: Barry William , Andreeva Bistra , Koreman Jacques
Published: April 2009

In a production study, Bulgarian, English and German verses with regular poetic metrical metres of different types and elicited prose utterances with varied accentual patterns are produced in textual and iterative (dada) form and measured at syllable level according to the pairwise variability index (PVI) principle. Systematic differences in PVI values show that the measure is sensitive to metrical differences. But variations for utterances with the same metrical structure and comparable measures for accentually different utterances show the measure to be insensitive to the temporal distribution of accents. A perceptual experiment with Bulgarian, English and German subjects confirms the hypothesis that the perceived strength of rhythmicity in a line of verse is determined not only by its temporal structure, but also by other acoustic properties, most clearly by F₀ change within the metrical foot.
The Concept of Ischemic Penumbra in Acute Stroke and Therapeutic Opportunities
Authors: Paciaroni Maurizio , Caso Valeria , Agnelli Giancarlo
Published: April 2009

Ischemic penumbra was first defined by Astrup in 1981 as perfused brain tissue at a level within the thresholds of functional impairment and morphological integrity, which has the capacity to recover if perfusion is improved. It exists, even for a short period of time in the center of ischemia, from which irreversible necrosis propagates to the neighboring tissues over time. Penumbra has become the focus of intense imaging research to differentiate it from infarction. Accurate detection of this ‘tissue at risk’ could be used to identify patients who would benefit most from acute treatment. Currently, recombinant tissue plasminogen activator (rtPA) is the only approved drug that has shown significant benefits in acute stroke patients when administered intravenously less than 4.5 h after stroke. However, its use is limited. Discrimination between infarct core and the surrounding potentially salvageable tissue is useful to better identify patients suitable for treatment. This can be achieved by positron emission tomography, single-photon-emission computed tomography, computed tomography perfusion scan and perfusion-weighted and diffusion-weighted magnetic resonance imaging. Identification of the penumbra might enable selective rtPA use in patients with large penumbras and small infarct cores, even beyond the 4.5-hour time window, where the penumbra may persist for more than 12 h. The purpose of this review was to describe neuroimaging modalities capable of identifying penumbra tissue so as to provide surrogate markers for new trials in acute ischemic stroke patients.
Cortical Infarction following Cardiosurgical Procedures – Air Embolism as a Probable Cause
Authors: Griese H. , Seifert D. , Koerfer R.
Published: April 2009

Background:Focal neurological deficits following cardiopulmonary bypass surgery are usually thought to be the result of embolic stroke. Computed tomography (CT) is sometimes negative although severe deficits persist. Objectives: To describe a syndrome consisting of reduced postoperative vigilance, frequent epileptic seizures and focal neurological deficits in the presence of an apparently normal CT scan and often isolated cortical infarction on magnetic resonance imaging (MRI). Methods: We retrospectively collected data on all patients fulfilling the above-mentioned criteria, seen for neurological examination by the consultant between 2002 and 2006 in our heart center. Results: We found 39 patients, nearly all of whom had cortical hyperintense lesions on diffusion-weighted MRI in the right hemisphere with corresponding left-sided hemiparesis. Early seizures occurred in 31 patients. Clinical outcome was heterogeneous. Conclusions: Predominance of right hemisphere involvement and lesion pattern in MRI make air embolism the most probable cause for this postoperative syndrome.
Mechanical Ventilation in Guillain-Barré Syndrome: Does Age Influence Functional Outcome?
Authors: Köhrmann Martin , Huttner Hagen B. , Nowe Tim , Schellinger Peter D. , Schwab Stefan
Published: April 2009

Purpose: To examine the effects of age on differences in the clinical course and functional outcome of mechanically ventilated Guillain-Barré syndrome (GBS) patients. Methods: 32 consecutive patients with GBS in need of mechanical ventilation were divided into two groups: (1) 15 patients <65 years, and (2) 17 patients ≥65 years. Length of ventilation, therapy, incidence of bulbar involvement, dysautonomia, preceding infections, need for tracheostomy, mortality, and functional outcome at 1-year follow-up using the Hughes outcome scale were analyzed. Results: The groups were comparable regarding treatment, lesion type, incidence of bulbar involvement, dysautonomia, preceding infections and duration of ventilation. The majority of patients (75%) received combination therapy (intravenous immunoglobulin and plasma exchange). Tracheostomy was performed in 91% of patients. Mortality was higher in older patients (41 vs. 7%; p = 0.02) and overall outcome worse (p = 0.05). Interestingly, once surviving the early, most critical period, older patients functionally recovered as well as younger patients (80% good outcome vs. 86%; p = 0.71). Conclusions: Despite all the advances in intensive care, mortality in older, ventilated GBS patients is still substantial. However, once they have survived the early, most critical period, older patients may recover as well as younger patients. Special care should therefore be taken to prevent and, if present, to vigorously treat complications commonly associated with intensive care treatment of severe GBS in elderly patients.
Association between Cerebral Arterial Calcification and Brachial-Ankle Pulse Wave Velocity in Patients with Acute Ischemic Stroke
Authors: Park Kwang-Yeol , Kim Yong Bum , Moon Heui-Soo , Suh Bum-Chun , Chung Pil-Wook
Published: April 2009

Background/Aims: Vascular calcification is known to be associated with cardiovascular mortality, and arterial stiffness measured by pulse wave velocity is associated with major cardiovascular risk factors. The aim of the present study was to elucidate the correlation between arterial stiffness and cerebral arterial calcification. Methods: Arterial stiffness, as measured by brachial-ankle pulse wave velocity (baPWV), and cerebral arterial calcification, as measured by CT angiography using a 40-multidetector scanner, were examined in patients with acute ischemic stroke. Sixty-seven subjects who were free of renal disease or peripheral arterial disease were included in the analysis. Results: Univariate analysis revealed that baPWV was significantly correlated with cerebral arterial calcification (r = 0.524, p < 0.001) and age (r = 0.452, p < 0.001), and multiple linear regression analysis indicated that age and cerebral arterial calcification were independent determinants of baPWV. Conclusion: We report that increased baPWV is closely associated with the degree of cerebral arterial calcification in patients with acute ischemic stroke. Our results suggest that the severity of cerebral arterial calcification is representative of the degree of systemic arterial stiffness.
The Effects of Intra-Aortic Balloon Pump Support on Macrocirculation and Tissue Microcirculation in Patients with Cardiogenic Shock
Authors: den Uil Corstiaan A. , Lagrand Wim K. , van der Ent Martin , Jewbali Lucia S.D. , Brugts Jasper J. , Spronk Peter E. , Simoons Maarten L.
Published: April 2009

Objectives: It was the aim of this study to evaluate the effects of intra-aortic balloon pump (IABP) counterpulsation on sublingual microcirculation as a model for tissue perfusion. Methods: In 13 patients with cardiogenic shock treated with IABP, the IABP assist ratio was reduced from 1:1 to 1:8 for 15 min. Using sidestream dark field imaging, 117 movie files of the sublingual microcirculation were obtained and quantified at different IABP assist ratios at 3 time points: 1:1 (T0), 1:8 (T1) and 1:1 (T2), respectively. Data are presented as the median and interquartile range. Results: The median age of the patients was 59 years (range 56–73), and 62% were males. Discontinuation of IABP decreased the mean arterial pressure [75 mm Hg (71–84) at T0 vs. 69 mm Hg (64–79) at T1; p < 0.001], cardiac index [2.9 l/min/m2 (1.6–3.3) at T0 vs. 2.4 l/min/m2 (1.5–2.8) at T1; p = 0.005] and cardiac power index [0.46 W/m2 (0.29–0.59) at T0 vs. 0.36 W/m2 (0.24–0.50) at T1; p = 0.006]. However, these modest changes in macrohemodynamics did not significantly influence sublingual perfused capillary density and capillary red blood cell velocity (p = 0.28 and 0.73, respectively). Conclusion: A temporary, modest decrease in microcirculatory driving force, induced by lowering the IABP assist ratio, does not impair sublingual microcirculatory perfusion as measured by a novel 2-dimensional imaging technique.
A Novel Method for the Diagnosis of Neurocardiogenic Syncope: Heart Rate Recovery Index
Authors: Kocabaş Uğur , Kaya Ergün Barış , Aytemir Kudret , Yorgun Hikmet , Kepez Alper , Aksoy Hakan , Ateş Ahmet Hakan , Tulumen Erol , Deveci Onur Sinan , Kabakcı Giray , Tokgözoğlu Lale , Nazlı Nasıh , Özkutlu Hilmi , Oto Ali
Published: April 2009

Objectives: Neurocardiogenic syncope is a common and challenging problem in clinical practice. Heart rate recovery after the first minute of exercise is mainly controlled by the parasympathetic nervous system. The aim of the present study was to evaluate heart rate recovery as an index of parasympathetic tonus for the diagnosis of neurocardiogenic syncope. Methods and Results: Ninety five patients (mean age 36.5 ± 11.8 years), who had vasovagal syncope episodes documented by tilt table testing and 70 healthy subjects (mean age 32.9 ± 9.1 years) were included in this study. Maximal exercise stress testing was performed in both groups and heart rate recovery values were calculated. Heart rate recovery was calculated by subtracting recovery heart rate in the first minute after exercise from peak heart rate. Heart rate recovery was significantly higher in the vasovagal syncope group than the control group during the first minute (42.1 vs. 30.9, p < 0.001). When the cutoff point for heart rate recovery was taken as 35, the sensitivity for the diagnosis of vasovagal syncope was 81% and the specificity was 78%. Conclusion: Results of our study show that heart rate recovery is greater in the first minute after exercise in vasovagal syncope patients and that it has a supportive role in the diagnosis of neurocardiogenic syncope.