bluuebunny/crossref_metadata_2025 huggingface dataset:
p14ARF Deletion and Methylation in Genetic Pathways to Glioblastomas
Authors: Nakamura Mitsutoshi , Watanabe Takao , Klangby Ulf , Asker Charlotte , Wiman Klas , Yonekawa Yasuhiro , Kleihues Paul , Ohgaki Hiroko
Published: July 2010

The CDKN2A locus on chromosome 9p21 contains the p14ARF and p16INK4a genes, and is frequently deleted in human neoplasms, including brain tumors. In this study, we screened 34 primary (de novo) glioblastomas and 16 secondary glioblastomas that had progressed from low‐grade diffuse astrocytomas for alterations of the p14ARF and p16INK4a genes, including homozygous deletion by differential PCR, promoter hypermethylation by methylation‐specific PCR, and protein expression by immunohistochemistry. A total of 29 glioblastomas (58%) had a p14ARF homozygous deletion or methylation, and 17 (34%) showed p16INK4a homozygous deletion or methylation. Thirteen glioblastomas showed both p14ARF and p16INK4a homozygous deletion, while nine showed only a p14ARF deletion. Immunohistochemistry revealed loss of p14ARF expression in the majority of glioblastomas (38/50, 76%), and this correlated with the gene status, i.e. homozygous deletion or promoter hypermethylation. There was no significant difference in the overall frequency of p14ARF and p16INK4a alterations between primary and secondary glioblastomas. The analysis of multiple biopsies from the same patients revealed hypermethylation of p14ARF (5/15 cases) and p16INK4a (1/15 cases) already at the stage of low‐grade diffuse astrocytoma but consistent absence of homozygous deletions. These results suggest that aberrant p14ARF expression due to homozygous deletion or promoter hypermethylation is associated with the evolution of both primary and secondary glioblastomas, and that p14ARF promoter methylation is an early event in subset of astrocytomas that undergo malignant progression to secondary glioblastoma.
Transcriptional Regulation of Caspases in Experimental Pneumococcal Meningitis
Authors: von Mering Matthias , Wellmer Andreas , Michel Uwe , Bunkowski Stephanie , Tłustochowska Anna , Brück Wolfgang , Kuhnt Ulrich , Nau Roland
Published: July 2010

Apoptosis and necrosis in brain account for neurological sequelae in survivors of bacterial meningitis. In meningitis, several mechanisms may trigger death pathways leading to activation of transcription factors regulating caspases mRNA synthesis. Therefore, we used a multiprobe RNA protection assay (RPA) to examine the expression of 9 caspase‐mRNA in the course of experimental Streptococcus pneumoniae meningitis in mouse brain. Caspase‐6, ‐7 and ‐11 mRNA were elevated 6 hours after infection. 12 hours after infection caspases‐1, ‐2, ‐8 and ‐12 mRNA rose. Caspase‐14 mRNA was elevated 18 h and caspase‐3 mRNA 24 h after infection. In situ hybridization detected caspases‐3, ‐8, ‐11 and ‐12 mRNA in neurons of the hippocampal formation and neocortex. Development of sepsis was paralleled by increased transcription of caspases mRNA in the spleen.

In TNFα‐deficient mice all caspases examined were less upregulated, in TNF‐receptor 1/2 knockout mice caspases‐1, ‐2, ‐7, ‐11 and ‐14 mRNA were increased compared to infected control animals. In caspase‐1 deficient mice, caspases‐11, and ‐12 mRNA levels did not rise in meningitis indicating the necessity of caspase‐1 activating these caspases. Hippocampal formations of newborn mice incubated with heat‐inactivated S. pneumoniae R6 showed upregulation of caspase‐1, ‐3, ‐11 and ‐12 mRNA.

These observations suggest a tightly regulated caspases network at the transcriptional level in addition to the known cascade at the protein level.
Insulin‐like Growth Factor Binding Protein 2: Gene Expression Microarrays and the Hypothesis‐generation Paradigm
Authors: Zhang; Wei , Wang; Hua , Song; Sonya W. , Fuller Gregory N.
Published: July 2010

A major goal of modern medicine is to identify key genes and their products that are altered in the diseased state and to elucidate the molecular mechanisms underlying disease development, progression, and resistance to therapy. This is a daunting task given the exceptionally high complexity of the human genome. The paradigm for research has historically been hypothesis‐driven despite the fact that the hypotheses under scrutiny often rest on tenuous subjective grounds or are derived from and dependent on chance observation. The imminent deciphering of the complete human genome, coupled with recent advances in high‐throughput bioanalytical technology, has made possible a new paradigm in which data‐based hypothesis‐generation is the initial step in the investigative process, followed by hypothesis‐testing. Genomics technologies are the primary source of the new hypothesis‐generating capabilities that are now empowering biomedical researchers. The synergistic interaction between contemporary genomics technologies and the hypothesis‐generation paradigm is well‐illustrated by the discovery and subsequent ongoing study of the role of insulin‐like growth factor binding protein 2 (IGFBP2) in human glioma biology. Using gene expression microarray technology, the IGFBP2 gene was recently found to be highly and differentially overexpressed in the most advanced grade of human glioma, glioblastoma. Based on this discovery, subsequent functional studies were initiated that suggest that IGFBP2 overexpression may contribute to the invasive nature of glioblastoma, and that IGFBP2 may exert its function via a newly identified novel binding protein. The IGFBP2 story is but one example of the power and potential of the new molecular methodologies that are transforming modern diagnostic and investigative neuropathology.
Mechanisms of Cell Death in Neurodegenerative Diseases: Fashion, Fiction, and Facts
Authors: Graeber Manuel B. , Moran Linda B.
Published: July 2010

Apoptosis has become a most popular concept of cell death. However, the term is now so widely used and employed in such general terms in relation to neurological diseases that its application is very problematic. In addition, with the exception of developmental conditions, there is essentially no evidence of apoptosis fulfilling the criteria of its classical definition in any of the important human neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's, Amyotrophic Lateral Sclerosis, and Creutzfeldt‐Jakob disease. Importantly, a number of new cell death forms have been described in the literature and there is good reason to pay attention to these emerging concepts as they may provide a rationale for the development of disease‐specific therapies.
Vitamin D and Its Analog EB1089 Induce p27 Accumulation and Diminish Association of p27 with Skp2 Independent of PTEN in Pituitary Corticotroph Cells
Authors: Liu Wei , Asa Sylvia L. , Ezzat Shereen
Published: July 2010

Disruption of the gene for the cyclin dependent kinase inhibitor (CDKI) p27/kip1 results in pituitary corticotroph hyperplasia while diminished expression of this protein has been described in aggressive human pituitary tumors. We have previously shown that 1,25‐vitamin D3 (VD) hypophosphorylates p27 and interferes with the degradation of this CDKI in thyroid carcinoma cells. In this study we investigated whether VD/EB1089 can induce p27 accumulation and cause growth arrest of pituitary corticotroph cells. VD and EB1089 exhibited a significant reduction in AtT20 corticotroph but not PRL235 Iactotroph cell growth. These changes were accompanied by selective accumulation of p27 in AtT20 but not in PRL235 cells. As p27 levels are highly dependent on protein degradation, we examined the effect of VD/EB1089 on p27 association with factors that target this CDKI to the proteasome. VD/EB1089 significantly restricted the association of p27 with Skp2 as well as with cyclin dependent kinase 2 (CDK2). As the tumor suppressor and phosphatase PTEN has been implicated in p27 regulation, we tested whether the effects of VD/EB1089 on p27 accumulation in corticotrophs could be mediated through this pathway. VD/EB1089 did not appreciably alter PTEN expression. Moreover, transfection of PTEN did not influence the effect of VD on p27 accumulation in corticotrophs. We conclude that VD/EB1089 can selectively arrest pituitary corticotroph growth and induce p27 accumulation. This effect is mediated at least partially through diminished p27 association with Skp2 and with CDK2. In contrast to other cell systems, PTEN does not participate in the regulation of corticotroph p27 and is not involved in mediating the effect of VD on p27 in these cells. Our findings highlight p27 and VD analogs as targets for manipulation and drug development respectively in the treatment of inoperable corticotroph adenomas.
Morphological Correlates of Acute and Permanent Hearing Loss During Experimental Pneumococcal Meningitis
Authors: Klein Matthias , Koedel Uwe , Pfister; Hans‐Walter , Kastenbauer Stefan
Published: July 2010

In patients with acute bacterial meningitis, hearing loss can be transient but is often permanent. The mechanisms underlying meningitis‐associated hearing loss are not fully understood. Therefore, we investigated the morphological correlates of hearing loss in a rat model of pneumococcal meningitis. Transcutaneous intracisternal injection of Streptococcus pneumoniae resulted in a dose‐dependent hearing loss (determined by auditory brainstem response audiometry), which was partially reversible during the acute stage. Nevertheless, a severe permanent hearing loss persisted until 2 weeks after infection. Suppurative labyrinthitis was accompanied by blood‐labyrinth barrier disruption (determined by cochlear Evans blue extravasation), which correlated closely with hearing loss during the acute stage but not after recovery. Two weeks after infection, spiral ganglion neuronal density was markedly decreased and correlated with the severity of permanent hearing loss. Neuronal loss can be explained by the new finding of meningitis‐associated spiral ganglion neuronal necrosis rather than apop‐tosis (determined by morphology, TUNEL staining, and immunohistochemistry).
Expression of Antioxidant Enzymes in Astrocytic Brain Tumors
Authors: Haapasalo Hannu , Kyläniemi Maarit , Paunu Niina , Kinnula Vuokko L. , Soini Ylermi
Published: July 2010

We studied the expression of antioxidant enzymes (AOEs) and related proteins manganese superoxide dismutase (MnSOD), thioredoxin (Trx), thioredoxin reductase (TrxR), and the catalytic (GLCL‐c) and regulatory (GLCL‐r) subunits of glutamate cysteine ligase (γ‐glutamylcysteinesynthetase) in 433 astrocytomas. Expression of MnSOD was found in 91%, Trx in 46%, TrxR in 66%, GLCL‐c 73% and GLCL‐r in 89% of the cases. Diffuse astro‐cytomas showed more intense staining for Trx (p= 0.002), TrxR (p=0.004), GLCL‐c (p=0.001), GLCL‐r (p=0.04) and MnSOD (p=0.01) than pilocytic astrocytomas. Within diffuse astrocytomas only Trx (p= 0.0001) and TrxR (p=0.04) significantly associated with increased malignancy grade. Necrotic tumors were more often immunopositive for Trx (p=0.001) and TrxR (p=0.02) and AOE expression was generally higher in mitotically active tumors. Expression of Trx and lack of MnSOD expression was associated with a worse prognosis in diffuse astrocytomas. None of the AOEs had any prognostic value in pilocytic grade I astrocytomas. Familial astrocytomas, which included 23 of the cases studied, did not differ in their expression of MnSOD from sporadic ones. The results show that MnSOD and Trx may influence the biological behaviour of astrocytomas, possibly by modulating cell proliferation and necrosis in these tumors.
Quantifying the Early Stages of Remyelination Following Cuprizone‐induced Demyelination
Authors: Stidworthy Mark F. , Genoud Stephane , Suter Ueli , Mantei Ned , Franklin Robin J. M.
Published: July 2010

The demyelinating toxin cuprizone is used increasingly in mouse studies of central nervous system remyelination. The value of this model for such studies depends on an accurate description of its quantifiable features. We therefore investigated histology and ultrastructure during the early oligodendrocyte differentiation phase of remyelination in mice given cuprizone and allowed to recover for 2 weeks. Limiting the dose of cuprizone to 0.2% overcame significant mouse morbidity and weight loss seen with a 0.4% dose, but the distribution of cuprizone‐induced demyelination was anatomically variable. The caudal corpus callosum and dorsal hippocampal commissure mostly demyelinated at this dose, but the rostral corpus callosum and rostral cerebellar peduncles did not. This variable response, together with small axon diameters and hence thin myelin sheaths, hindered analysis of the progress of early remyelination. The proportion of myelinated and unmyelinated axons in defined regions followed expected trends, but there was pronounced variation between animals. Furthermore, group mean G ratios did not change as expected during the early stages of remyelination, and regression analysis revealed a complex relationship between axon diameter and myelin sheath thickness during this period. We also noted axonal pathology that persisted for at least 2 weeks after cuprizone withdrawal.
Atypical Teratoid/Rhabdoid Tumors and Choroid Plexus Tumors: When Genetics “Surprise” Pathology
Authors: Gessi Marco , Giangaspero Felice , Pietsch Torsten
Published: July 2010

Atypical teratoid/rhabdoid tumor (ATRT) and choroid plexus tumors (CPT) represent, so far, 2 well defined types of CNS neoplasm on the basis of their histological features and clinical presentation (10). While CPTs are intraventricular epithelial tumors arising from choroid plexus epithelium, the cellular origin of ATRTs is still unknown. Inactivating mutations of the hSNF5/INI‐1 gene located in the chromosomal region 22q11.2 are regarded as a crucial step in the molecular pathogenesis of ATRTs; the genetic changes associated with CPTs are largely unknown. However, the recent finding of inactivation of hSNF5/INI‐1 in choroid plexus carcinomas and papillomas (9, 18) points to a closer relationship between these 2 entities. This is supported by the occurence of choroid plexus carcinomas (CPC) in the setting of families with rhabdoid predisposition syndrome (RPS), (19) caused by germ line inactivation of the INI1 gene.
Molecular Characterization of BCL6 Breakpoints in Primary Diffuse Large B‐cell Lymphomas of the Central Nervous System Identifies GAPD as Novel Translocation Partner
Authors: Montesinos‐Rongen Manuel , Akasaka Takashi , Zühlke‐Jenisch Reina , Schaller Carlo , van Roost Dirk , Wiestler Otmar D. , Siebert Reiner , Deckert Martina
Published: July 2010

Primary central nervous system lymphomas (PCNSL) constitute diffuse large B‐cell lymphomas arising in and remaining confined to the brain. Little information is available on cytogenetic changes in PCNSL, and recurrent chromosomal translocations have not yet been identified. Fluorescence in situ hybridization (FISH) of a series of 13 PCNSL from immunocompetent patients revealed 3 cases with signal patterns of a BCL6‐specific probe suggesting a breakpoint in this oncogene locus in chromosome band 3q27. Here, we describe cloning of the translocation breakpoints by long‐distance inverse polymerase chain reaction (LDI‐PCR) in 2 of these tumors. Both breakpoints affected the first intron of BCL6. In one PCNSL, the HSPCA (HSP90A) gene in 14q32.31 was identified as BCL6 partner. In the second lymphoma, the gene encoding glyceraldehyde‐3‐phosphate dehydrogenase (GAPD) on 12p13.31 was detected as a hitherto unknown partner of BCL6. Our results suggest translocation‐mediated BCL6 oncogene activation as a so far unknown pathogenetically relevant mechanism in PCNSL.
Gene Expression Profiling Reveals Unique Molecular Subtypes of Neurofibromatosis Type I‐associated and Sporadic Malignant Peripheral Nerve Sheath Tumors
Authors: Watson Mark A. , Perry Arie , Tihan Tarik , Prayson Richard A. , Guha Abhijit , Bridge Julia , Ferner Rosalie , Gutmann David H.
Published: July 2010

Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann cell neoplasms that are frequently associated with Type I Neurofibromatosis (NF1) and respond poorly to current therapeutic regimens. To better understand the molecular heterogeneity of these tumors, we performed gene expression profiling on 25 NF1‐associated and 17 sporadic MPNSTs using oligonucleotide microarrays representing approximately 8100 unique human gene transcripts. Using several previously reported statistical approaches, we were unable to identify a molecular signature that could reliably distinguish between NF1‐associated and sporadic MPNSTs in independent training and test sample sets. However, using an unsupervised clustering approach, we identified an extensive gene expression signature that distinguished 9 of the 42 tumors analyzed. This signature corresponded to relative overexpression of transcripts associated with neuroglial differentiation (NCAM, MBP, L1CAM, P1P) and relative down‐regulation of proliferation and growth factor associated transcripts (IGF2, FGFR1, MDK, Ki67). All tumors with this gene expression signature lacked expression of EGFR and all but one tumor were derived from patients with NF1. However, there were no other obvious associations with histological grade, tumor site, metastasis, recurrence, age, or patient survival. We conclude that distinct molecular classes of MPNST exist and that the ability to stratify these tumors based on unique and biologically relevant gene expression profiles may be important for future targeted therapeutics.
MARCH 2004: A 24‐YEAR‐OLD WOMAN WITH BIFRONTAL HEADACHES
Authors: Englund Chris , Silbergeld Daniel , Alvord Ellsworth C. , Small Randy , Hevner Robert F.
Published: July 2010

CASE OF THE MONTH: ABSTRACT

MARCH 2004 COM. A 24‐year‐old woman with bifrontal headaches was found to have a well‐circumscribed lesion in the frontal lobe subcortical white matter. Microscopic examination showed clusters of small round cells separated by hypocellular neuropil‐like areas, and a distinct border between tumor and surrounding white matter. Synaptophysin was diffusely positive in neuropil‐like areas, and many tumor cells expressed NeuN. Based on these findings, a diagnosis of “extraventricular neurocytoma” was made. A double‐label immunofluorescence stain was performed with NeuN and Ki‐67 antibodies to determine if NeuN+ cells remained in the mitotic cycle. No colocalization of these markers was found, thus supporting the hypothesis that neuronal differentiation (as marked by NeuN expression) is incompatible with continued proliferation of tumor cells, as well as normal neurons.
Selectivity and Types of Cell Death in the Neuronal Ceroid Lipofuscinoses (NCLs)
Authors: Mitchison Hannah M. , Lim Ming J. , Cooper Jonathan D.
Published: July 2010

Cloning of the individual genes that are mutated in neuronal cerold lipofuscinoses (NCLs), or Batten disease, has opened up new avenues of research into the pathogenesis of these fatal autosomal recessive storage disorders. Genetically accurate mouse models have now been generated for each major form of disorder, together with several variant forms. Ongoing analysis of these mice is revealing significant new data about the staging and progression of disease phenotypes. Combined with data from human autopsy tissues and large animal models, it is now clear that neurodegeneration is initially selective In the NCL CNS, targeting specific regions and particular cell populations. There is also evidence of selective glial activation that appears to precede obvious neurodegeneration, becoming more widesparead with disease progression. Currently, there is debate over the mechanisms of cell deat that operate in each form of NCL, with evidence of both apoptosis and autophagy. It is likely that these mechanisms may encompass a spectrum of cell death events, depending upon the specific context of each neuronal population. Taken together, these data have significant clinical implication for the development and targeting of appropriate therapeutic strategies, and for providing the landmarks to judge their efficacy.
Multiplex Ligation‐Dependent Probe Amplification for the Detection of 1p and 19q Chromosomal Loss in Oligodendroglial Tumors
Authors: Natté Remco , van Eijk Ronald , Eilers Paul , Cleton‐Jansen Anne‐Marie , Oosting Jan , Kouwenhove Mathilde , Kros Johan M. , van Duinen Sjoerd
Published: July 2010

Multiplex ligation‐dependent probe amplification (MLPA) is a new assay for the detection of multiple chromosomal deletions in tumor tissue in a single experiment. Since genotyping of gliomas with oligodendroglial features by the detection of 1p/19q chromosomal deletions became essential for treatment decisions, we developed and validated an MLPA‐ based assay to determine these losses in formalin fixed and paraffin embedded oligodendroglial tumors (OG). Nineteen OGs, and 10 control samples were analyzed by MLPA and the results were correlated with those obtained by fluorescent in situ hybridization (FISH). The MLPA results were reproducible in all samples in which repeated experiments were performed. In 18 of 19 OGs, MLPA and FISH were concordant for presence or absence of 1p deletion. In 3 OGs, MLPA detected a 19q deletion not shown by FISH. For the other 15 OGs, MLPA and FISH were concordant. In one sample with 50% to 75% of tumor, MLPA failed to detect the 1p/19q deletions revealed by FISH (though with borderline values of significance). We conclude that MLPA is a valid and reproducible method for the detection of 1p/19q chromosomal deletions in OGs stored on formalin fixed, paraffin embedded tissue.
High Pressure Inactivation Kinetics of a Thermomyces lanuginosus Xylanase Evaluated as a Process Indicator
Authors: Gogou Eleni , Katapodis Petros , Taoukis Petros S.
Published: July 2010

Abstract:  The potential use of Thermomyces lanuginosus xylanase to develop a pressure–temperature–time integrator (PTTI) for high pressure processing was investigated. The combined effect of pressure and temperature on the inactivation of xylanase was studied in the pressure range of 100 to 600 MPa and temperature range of 50 to 70 °C. A synergistic effect of pressure and temperature was observed. Xylanase inactivation at the studied processing conditions followed first‐order kinetics and was found to be very sensitive to changes in pressure and temperature. The values of activation energy and activation volume were estimated as 92.8 kJ/mol and −23.3 mL/mol at a reference pressure of 450 MPa and a reference temperature of 60 °C, respectively. A mathematical model of xylanase inactivation, having as variables time, pressure, and temperature allows the calculation of remaining enzyme activity at any combination of processing conditions within the studied domain.

Practical Application:  To ensure the optimization and control of high pressure processing, evaluation of the process impact on both safety and quality attributes of foods is essential. Enzymes can serve as effective tools in evaluating the impact of high pressure processes of foods.
Un commun dénominateur aux préoccupations des femmes et des hommes dans les musées allemands
Authors: Grab Titus
Published: July 2010

Peut‐on ouvrir les musées aux femmes sans reproduire des pratiques ayant cours de longue date, telles que l'inégalité sexuelle reflétée à la fois dans le recrutement et dans la conception des expositions? Le présent article étudie les multiples transformations introduites par le mouvement féministe dans les musées allemands et propose, pour l'avenir, des perspectives nouvelles. L'auteur, ethnographe, est titulaire d'un MA. sur les rôles des hommes et des femmes dans les musées de la République fédérale d'Allemagne, et prépare actuellement une thèse de doctorat sur le sexe masculin en Allemagne. On peut le joindre à l'adresse suivante: Langentalstrasse 13, D‐6500 Mainz 1 (Allemagne).
Jumelage algéro‐hongrois
Authors: Bentabet Mohamed
Published: July 2010

Le jumelage de musées, une idée à retenir pour ouvrir les musées d'art populaire à la diversité des cultures; Mohamed Bentabet, directeur du Musée national des arts et traditions populaires à Alger, en fournit un exemple convaincant.
Au Pérou, un site comme musée
Authors: Albini Marco
Published: July 2010

Les fouilles financées par la banque Wiese, à Lima, et menées sous le contrôle personnel de son propriétaire, Augusto Wiese, ont permis de mettre au jour un modèle extrêmement intéressant de monuments d'une époque relativement peu connue, la période Moche. Il y a là une série extraordinaire de reliefs peints sur divers niveaux qui témoignent de la vie sociale au cours de cette période. Encouragés par l'UNESCO, des architectes italiens, sous la conduite de Marco Albini, ont imaginé une solution inhabituelle — et d'une rare simplicité — pour transformer le site en un musée de plein air. L'auteur, professeur à la faculté d'architecture de l'Institut universitaire de technologie de Milan, a enseigné l'esthétique industrielle à l'Université internationale des arts de Venise. Il a été professeur invité à la Cornell University School of Architecture et à l'Université de Netv York, aux États‐Unis d'Amérique.
Unsuspected multiple myeloma presenting as Escherichia coli infectious spondylitis: a case report
Authors: YU Shan‐Fu , LUI Chun‐Chung , PEI Sung‐Nan , LIU Jien‐Wei , CHENG Tien‐Tsai
Published: July 2010

Multiple myeloma associated with infectious spondylitis at initial presentation is rare. We report a previously healthy woman with back pain for 3 weeks, initially diagnosed as Escherichia coli infectious spondylitis. Because magnetic resonance imaging revealed skip lesions other than infectious spondylitis, extensive work‐up disclosed monoclonal immunoglobulin G kappa and 30% plasma cells in bone marrow. The patient was treated with antibiotics for 8 weeks without recurrence in the subsequent 6 months. Although the panorama of infectious spondylitis was obvious and substantial, our case demonstrates that further investigations for underlying diseases are critical, especially when image findings are incompatible with common presentations of infectious spondylitis.
Is the 21st Century an “Asian Century”? Raising More Reservations than Hopes
Authors: Kim Myongsob , Hodges Horace Jeffery
Published: July 2010

Many are today arguing that the 21st century will be “the Asian Century,” and much ink has been spilled over the splendid achievements of Asia as evidence of such arguments. However, this paper suggests some reservations regarding that argument, though also some distant hopes. First of all, we do not know yet what Asia really is, as there are too many geographical Asias. More effort should be made to conceptualize the geographical, or geopolitical, boundaries of Asia, which are both too blurred and too intertwined among sub‐identities within Asia, and without. Second, Asia still has a lot of matters that need to be resolved by Asians themselves before the optimistic and audacious expression “Asian Century” can be legitimately used. In resolving those matters by themselves through international cooperation, the conceptual boundary of Asia could become clearer and a shared Asian geopolitical identity would have more possibility of emerging.
Barack Obama and North Korea: A Study in Presidential Transition
Authors: Martin Curtis H.
Published: July 2010

This study will examine the policy of the incoming administration of Barack Obama toward North Korea's nuclear program as a case‐study in presidential transitions. Obama did not give much prominence to North Korea during the campaign, but he clearly framed the talks on the DPRK nuclear question in the broader contexts of promoting international law, strengthening the nuclear nonproliferation regime, and pursuing broad multilateral diplomacy. Furthermore, he laid out simple but clear policy guidelines. The USA would engage the DPRK and remain open to positive incentives for denuclearization. On the other hand, the DPRK would receive no material incentives simply for returning to the Six‐Party Talks, would have to meet its existing obligations before new incentives could be offered, and could not expect bilateral talks outside the context of the Six‐Party Talks. The “two‐track” policy of diplomatic engagement and sanctions that had emerged by the end of the presidential transition closely conformed to the general guidelines that Obama had laid out in the campaign. The administration pressed successfully for new UN sanctions and resumed enforcement of the UN ban on weapons shipments that had been allowed to lapse under Bush. These actions were intended, however, to complement, not supplant, an engagement strategy. Throughout his first year in office, Obama continued actively to seek resumption of dialogue, culminating in the bilateral talks of December 2009. When judged against the lessons of the transition literature, the administration's success in formulating a coherent North Korea policy comes out reasonably well. The six months it took to complete assembling a full team was within normal bounds for a new administration. The appointment of a talented mix of loyalists, holdovers, worthies and all‐stars to the North Korea team provided a variety of experience and perspectives and positioned the administration well for either engagement or increased pressure. US policy reflected the diverse experiences and outlooks of the North Korea team. If the Six‐Party Talks resume, Obama's resolve to hold firm to his demands will be tested by the same problems that his recent predecessors confronted.
The Six‐Party Talks and North Korea's Denuclearization: Evaluation and Prospects
Authors: Kwak Tae‐Hwan
Published: July 2010

The six‐party process for North Korea's denuclearization has long been stalled since the Six‐Party Talks (SPT) failed to agree on a verification protocol in early December 2008. The DPRK officially stated on 10 February 2005 that it already possessed nuclear weapons. It now wants to be recognized as a nuclear power. The North Korean nuclear issue, a key obstacle to the Korean peace process, needs to be resolved peacefully through the six‐party process. The author has argued over the years that while the six‐party process is the best means to resolve the North's nuclear issue, bilateral US–DPRK talks are equally important to a peaceful and diplomatic resolution of the DPRK's issue. The peaceful resolution of the North's nuclear issue is prerequisite to building a peace regime on the Korean peninsula and regional peace in Northeast Asia. The author has two specific goals: (i) to evaluate the stalled SPT for denuclearizing the Korean peninsula since December 2008; and (ii) to make policy recommendations for continued denuclearization of the Korean peninsula in the framework of the SPT. The first part of this article examines DPRK's denuclearization process up to the point when the SPT failed to adopt a written verification protocol in December 2008. Since then, the six‐party process has been stalled. The second part discusses the impact of the DPRK's rocket launch in April 2009 and its second nuclear test in May on the SPT. The third part evaluates the DPRK's new proposal for peace treaty talks and its new conditions for returning to the SPT. Finally, this article proposes key issues on agenda to be negotiated at the next SPT and some policy recommendations for achieving denuclearization of the Korean peninsula.
Impact of
recA
on Levofloxacin Exposure-Related Resistance Development
Authors: Singh Renu , Ledesma Kimberly R. , Chang Kai-Tai , Tam Vincent H.
Published: July 2010

Genetic mutations are one of the major mechanisms by which bacteria acquire drug resistance. One of the known mechanisms for inducing mutations is the SOS response system. We investigated the effect of disrupting
recA
, an inducer of the SOS response, on resistance development using an
in vitro
hollow-fiber infection model. A clinical
Staphylococcus aureus
isolate and a laboratory wild-type strain of
Escherichia coli
were compared to their respective
recA
-deleted isogenic daughter isolates. Approximately 2 × 10
5
CFU/ml of bacteria were subjected to escalating levofloxacin exposures for up to 120 h. Serial samples were obtained to ascertain simulated drug exposures and total and resistant bacterial burdens. Quinolone resistance determining regions of
gyrA
and
grlA
(
parC
for
E. coli
) in levofloxacin-resistant isolates were sequenced to confirm the mechanism of resistance. The preexposure MICs of the
recA
-deleted isolates were 4-fold lower than those of their respective parents. In
S. aureus
, a lower area under the concentration-time curve over 24 h at steady state divided by the MIC (AUC/MIC) was required to suppress resistance development in the
recA
-deleted mutant (an AUC/MIC of >23 versus an AUC/MIC of >32 was necessary in the mutant versus the parent isolate, respectively), and a prominent difference in the total bacterial burden was observed at 72 h. Using an AUC/MIC of approximately 30,
E. coli
resistance emergence was delayed by 24 h in the
recA
-deleted mutant. Diverse mutations in
gyrA
were found in levofloxacin-resistant isolates recovered. Disruption of
recA
provided additional benefits apart from MIC reduction, attesting to its potential role for pharmacologic intervention. The clinical relevance of our findings warrants further investigations.
Comparative Effectiveness of Linezolid and Vancomycin among a National Cohort of Patients Infected with Methicillin-Resistant
Staphylococcus aureus
Authors: Caffrey Aisling R. , Quilliam Brian J. , LaPlante Kerry L.
Published: July 2010

While newer antibiotics play a key role in treating methicillin-resistant
Staphylococcus aureus
(MRSA) infections, knowledge of their real-world clinical impact is limited. We sought to quantify the effectiveness of linezolid compared to that of vancomycin among MRSA-infected patients. This national retrospective cohort study included adult patients admitted to all Veterans Affairs hospitals between January 2002 and June 2008, infected with MRSA, and treated with either linezolid (oral or intravenous [i.v.]) or vancomycin (i.v.). Patients were followed from their treatment initiation date until the event of interest, discharge, death, or December 2008. Utilizing propensity score methods, we estimated the treatment effects of linezolid primarily on time to discharge and secondarily on time to all-cause in-hospital mortality, therapy discontinuation, and all-cause 90-day readmission with Cox proportional-hazard models. We identified 20,107 patients treated with linezolid (3.2%) or vancomycin (96.8%). Baseline covariates were well balanced by treatment group within propensity score quintiles and between propensity score matched patients (626 pairs). The discharge rate was significantly higher among patients treated with linezolid, representing a decreased length of stay, in both the propensity score adjusted (hazard ratio [HR], 1.38; 95% confidence interval [95% CI], 1.27 to 1.50) and matched (HR, 1.70; 95% CI, 1.44 to 2.00) analyses. A significantly decreased rate of therapy discontinuation, indicating longer therapy duration, was observed in the linezolid group (adjusted HR, 0.64; 95% CI, 0.54 to 0.75; matched HR, 0.49; 95% CI, 0.36 to 0.65). In this clinical population of MRSA-infected patients, linezolid therapy was as effective as vancomycin therapy with respect to in-hospital survival and readmission.
Fluoroquinolone Efflux by the Plasmid-Mediated Multidrug Efflux Pump QacB Variant QacBIII in
Staphylococcus aureus
Authors: Nakaminami Hidemasa , Noguchi Norihisa , Sasatsu Masanori
Published: July 2010

Plasmids that carry the multidrug efflux genes
qacA
and
qacB
are widely distributed in methicillin-resistant
Staphylococcus aureus
(MRSA). Although the QacA and QacB proteins are similar to each other, their respective substrate specificities may differ. We investigated the variability and structure-function relationships of QacA and QacB in MRSA isolates. The amino acid sequences of 7 QacA and 25 QacB proteins showed that QacB was present in three variants, designated QacBII, QacBIII, and QacBIV, that were different from the prototypic QacB variant encoded by plasmid pSK23, which was named QacBI, while QacA was present in two variants. When cloned and expressed in
S. aureus
, the strain carrying
qacBIII
exhibited higher susceptibility to dyes and decreased susceptibility to norfloxacin and ciprofloxacin compared to strains carrying the other QacB variants. Site-directed mutagenesis experiments revealed that the residue at position 320 in QacB plays an important role in the resistance phenotypes to dyes and fluoroquinolones. Furthermore, the accumulation of norfloxacin and ciprofloxacin in the strain carrying
qacBIII
was significantly decreased. Our data demonstrate that the plasmid-mediated multidrug efflux pump QacB variant QacBIII confers the capability for fluoroquinolone efflux on
S. aureus
.
T-Cell Response to Human Papillomavirus Type 58 L1, E6, and E7 Peptides in Women with Cleared Infection, Cervical Intraepithelial Neoplasia, or Invasive Cancer
Authors: Chan Paul K. S. , Liu Shih-Jen , Cheung T. H. , Yeo Winnie , Ngai S. M. , Cheung Jo L. K. , Chong Pele , Man Stephen
Published: July 2010

Human papillomavirus type 58 (HPV-58) exists in a relatively high prevalence in certain parts of the world, including East Asia. This study examined the T-cell response to HPV-58 L1, E6, and E7 peptides among women with cleared infection, cervical intraepithelial neoplasia grade 2 (CIN2) or CIN3, or invasive cervical cancer (ICC). Peptides found to be reactive in thein vitropeptide binding assay or mouse-stimulating study were tested with a gamma interferon (IFN-γ) enzyme-linked immunospot (ELISPOT) assay to detect peptide-specific responses from the peripheral blood mononuclear cells (PBMC) collected from 91 HPV-58-infected women (32 with cleared infection, 16 CIN2, 15 CIN3, and 28 ICC). Four HLA-A11-restricted HPV-58 L1 peptides, located at amino acid positions 296 to 304, 327 to 335, 101 to 109, and 469 to 477, showed positive IFN-γ ELISPOT results and were mainly from women with cleared infection. Two HLA-A11-restricted E6 peptides (amino acid positions 64 to 72 and 94 to 102) and three HLA-A11-restricted E7 peptides (amino acid positions 78 to 86, 74 to 82, and 88 to 96) showed a positive response. A response to E6 and E7 peptides was mainly observed from subjects with CIN2 or above. One HLA-A2-restricted E6 peptide, located at amino acid position 99 to 107, elicited a positive response in two CIN2 subjects. One HLA-A24-restricted L1 peptide, located at amino acid position 468 to 476, also elicited a positive response in two CIN2 subjects. In summary, this study has identified a few immunogenic epitopes for HPV-58 E6 and E7 proteins. It is worthwhile to further investigate whether responses to these epitopes have a role in clearing an established cervical lesion.
A FRAMEWORK TO SIMULTANEOUSLY EXPLAIN TINY NEUTRINO MASS AND HUGE MISSING MASS PROBLEM OF THE UNIVERSE
Authors: FARZAN YASAMAN
Published: July 2010

A minimalistic scenario is developed to explain dark matter and tiny but nonzero neutrino masses. A new scalar called SLIM plays the role of the dark matter. Neutrinos achieve Majorana mass through a one-loop diagram. This scenario can be realized for both real and complex SLIM. Simultaneously explaining the neutrino mass and dark matter abundance constrains the scenario. In particular for real SLIM, an upper bound of a few MeV on the masses of the new particles and a lower bound on their coupling is obtained which make the scenario testable. The low energy scenario can be embedded within various SU (2)× U (1) symmetric models. A specific example is introduced and its phenomenological consequences are discussed.
In the Virtual Extension
Authors: CACM Staff
Published: July 2010

Communications
' Virtual Extension brings more quality articles to ACM members. These articles are now available in the ACM Digital Library.
The war against spam
Authors: Linden Greg , Bernstein Michael , Poole Erika Shehan
Published: July 2010

http://cacm.acm.org/blogs/blog-cacm

The
Communications
Web site, http://cacm.acm.org, features more than a dozen bloggers in the BLOG@CACM community. In each issue of
Communications
, we'll publish selected posts or excerpts.

twitter

Follow us on Twitter at http://twitter.com/blogCACM

Greg Linden asks if spammers have been defeated; Michael Bernstein discusses Clay Shirky's keynote speech at CSCW 2010; and Erika S. Poole writes about how the digital world can help parents cope with the death of a child.
Mechanism design meets computer science
Authors: Anthes Gary
Published: July 2010

A field emerging from economics is teaming up with computer science to improve auctions, supply chains, and communication protocols.
Remembrances of things pest
Authors: Spafford Eugene H.
Published: July 2010

Recalling malware milestones.
Rights for autonomous artificial agents?
Authors: Chopra Samir
Published: July 2010

The growing role of artificial agents necessitates modifying legal frameworks to better address human interests.
Moving to the edge
Authors: Creeger Mache
Published: July 2010

Leading experts debate how virtualization and clouds impact network service architectures.
Plat_Forms
Authors: Prechelt Lutz
Published: July 2010

Introduction

Software developers during their work face several fundamental choices with a multitude of options. There are methodological choices, where one selects among possible development processes, and technological choices regarding for instance development tools or base technologies for the software product.

While a number of solid research results are available on some methodological topics (such as review or testing techniques), there is hardly any high-quality information on how specific technologies influence development success. There are narrow benchmarking studies comparing the execution performance of, for example, dababase management systems or application servers, there are feature lists comparing the functionality of base technology products, but there are essentially no holistic studies that compare directly how competing technologies shape a realistic product and how that may influence the project. Those few such studies that exist are very small-scale in terms of the system considered, a good example being jccpprt, and despite their small scale some also lack the methodological rigor required for high credibility, a popular example being Kelly's entertaining, yet visibly biased video.
Using Data Mining Techniques to Discover Bias Patterns in Missing Data
Authors: Tremblay Monica Chiarini , Dutta Kaushik , Vandermeer Debra
Published: July 2010

In today’s data-rich environment, decision makers draw conclusions from data repositories that may contain data quality problems. In this context, missing data is an important and known problem, since it can seriously affect the accuracy of conclusions drawn. Researchers have described several approaches for dealing with missing data, primarily attempting to infer values or estimate the impact of missing data on conclusions. However, few have considered approaches to characterize patterns of bias in missing data, that is, to determine the specific attributes that predict the missingness of data values. Knowledge of the specific systematic bias patterns in the incidence of missing data can help analysts more accurately assess the quality of conclusions drawn from data sets with missing data. This research proposes a methodology to combine a number of Knowledge Discovery and Data Mining techniques, including association rule mining, to discover patterns in related attribute values that help characterize these bias patterns. We demonstrate the efficacy of our proposed approach by applying it on a demo census dataset seeded with biased missing data. The experimental results show that our approach was able to find seeded biases and filter out most seeded noise.
Service-Aware Retransmission Control in Cellular Networks
Authors: Ben Halima Nadhir , Kliazovich Dzmitry , Granelli Fabrizio
Published: July 2010

This paper proposes a service-aware cross-layer approach between application/transport layers on the mobile terminal and link layer on the wireless base station to enable dynamic control on the level of per-packet error protection for multimedia data streams. Specifically, in the context of cellular networks, the proposed scheme enables the mobile terminal to specify to the base station the desired level of Hybrid ARQ (HARQ) protection by using an in-band control feedback channel. Such protection is dynamically adapted on a per-packet basis and depends on the perceptual importance of different packets as well as on the reception history of the flow. Experimental results demonstrate the potential benefits deriving from the proposed strategy either for audio and video real-time streams as well as for TCP-based data transfers.
High-Speed Burring with and without the Use of Surgical Adjuvants in the Intralesional Management of Giant Cell Tumor of Bone: A Systematic Review and Meta-Analysis
Authors: Algawahmed H. , Turcotte Robert , Farrokhyar F. , Ghert M.
Published: July 2010

Local control rates for Giant Cell Tumor of Bone (GCT) have been reported in a large number of retrospective series. However, there remains a lack of consensus with respect to the need for a surgical adjuvant when intralesional curettage is performed. We have systematically reviewed the literature and identified six studies in which two groups from the same patient cohort were treated with intralesional curettage and high-speed burring with or without a chemical or thermal adjuvant. Studies were evaluated for quality and pooled data was analyzed using the fixed effects model. Data from 387 patients did not indicate improved local control with the use of surgical adjuvants. Given the available data, we conclude that surgical adjuvants are not required when meticulous tumor removal is performed.
Meaningful Share Generation for Increased Number of Secrets in Visual Secret‐Sharing Scheme
Authors: Ulutas Mustafa
Published: July 2010

This paper presents a new scheme for hiding two halftone secret images into two meaningful shares created from halftone cover images. Meaningful shares are more desirable than noise‐like (meaningless) shares in Visual Secret Sharing because they look natural and do not attract eavesdroppers′ attention. Previous works in the field focus on either increasing number of secrets or creating meaningful shares for one secret image. The method outlined in this paper both increases the number of secrets and creates meaningful shares at the same time. While the contrast ratio of shares is equal to that of Extended Visual Cryptography, two secrets are encoded into two shares as opposed to one secret in the Extended Visual Cryptography. Any two natural‐looking images can be used as cover unlike the Halftone Visual Cryptography method where one cover should be the negative of the other cover image and can only encode one secret. Effectiveness of the proposed method is verified by an experiment.