bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantitative analysis of Kerr nonlinearity and Kerr-like nonlinearity induced via terahertz generation in ZnTe
Authors: Tian Zhen , Wang Changlei , Xing Qirong , Gu Jianqiang , Li Yanfeng , He Mingxia , Chai Lu , Wang Qingyue , Zhang Weili
Published: January 2008

Kerr nonlinearity and Kerr-like nonlinearity induced via terahertz generation and the electro-optical effect in ZnTe crystal are investigated. In general, these nonlinear effects are concomitant and difficult to quantitatively analyze in the time domain. Even Z-scan technique, which is a simple and sensitive single-beam method to determine both the sign and magnitude of the nonlinear refractive index as well as the nonlinear absorption coefficient of a given material, cannot quantitatively analyze the contribution of each nonlinear effect directly. A method is proposed in the spectral domain to distinguish between Kerr nonlinearity and Kerr-like nonlinearity. Experimental results agree with theoretical analysis.
TheO-fucose glycan in the ligand-binding domain of Notch1 regulates embryogenesis and T cell development
Authors: Ge Changhui , Stanley Pamela
Published: January 2008

Mechanisms by which the extracellular domain of Notch1 controls Notch1 signaling are not well defined. Here, we show that theO-fucose glycan in the Notch1 ligand-binding domain regulates the strength of Notch1 signaling during embryogenesis, postweaning growth, and T cell development in the mouse. Heterozygotes carrying aNotch112fallele and an inactiveNotch1allele die at approximately embryonic day (E)12 with a typicalNotch1null phenotype. HomozygousNotch112f/12fmice are viable and fertile but grow somewhat more slowly than littermates after weaning.Notch112f/12fthymocytes bind less Delta1 and exhibit reduced Notch1 signaling. The number of double-positive (DP) and single-positive (SP) T cells are decreased inNotch112f/12fthymus, and DP T cells are more apoptotic. By contrast, proportionately more SP cells have matured, and SP-to-DP ratios are increased in mutant thymus. Thus, theO-fucose glycan in EGF12 of mouse Notch1 is required for optimal Notch1 signaling and T cell development in mammals.
Abrupt climate change and collapse of deep-sea ecosystems
Authors: Yasuhara Moriaki , Cronin Thomas M. , deMenocal Peter B. , Okahashi Hisayo , Linsley Braddock K.
Published: January 2008

We investigated the deep-sea fossil record of benthic ostracodes during periods of rapid climate and oceanographic change over the past 20,000 years in a core from intermediate depth in the northwestern Atlantic. Results show that deep-sea benthic community “collapses” occur with faunal turnover of up to 50% during major climatically driven oceanographic changes. Species diversity as measured by the Shannon–Wiener index falls from 3 to as low as 1.6 during these events. Major disruptions in the benthic communities commenced with Heinrich Event 1, the Inter-Allerød Cold Period (IACP: 13.1 ka), the Younger Dryas (YD: 12.9–11.5 ka), and several Holocene Bond events when changes in deep-water circulation occurred. The largest collapse is associated with the YD/IACP and is characterized by an abrupt two-step decrease in both the upper North Atlantic Deep Water assemblage and species diversity at 13.1 ka and at 12.2 ka. The ostracode fauna at this site did not fully recover until ≈8 ka, with the establishment of Labrador Sea Water ventilation. Ecologically opportunistic slope species prospered during this community collapse. Other abrupt community collapses during the past 20 ka generally correspond to millennial climate events. These results indicate that deep-sea ecosystems are not immune to the effects of rapid climate changes occurring over centuries or less.
Leaf palmate venation and vascular redundancy confer tolerance of hydraulic disruption
Authors: Sack Lawren , Dietrich Elisabeth M. , Streeter Christopher M. , Sánchez-Gómez David , Holbrook N. Michele
Published: January 2008

Leaf venation is a showcase of plant diversity, ranging from the grid-like network in grasses, to a wide variety of dendritic systems in other angiosperms. A principal function of the venation is to deliver water; however, a hydraulic significance has never been demonstrated for contrasting major venation architectures, including the most basic dichotomy, “pinnate” and “palmate” systems. We hypothesized that vascular redundancy confers tolerance of vein breakage such as would occur during mechanical or insect damage. We subjected leaves of woody angiosperms of contrasting venation architecture to severing treatmentsin vivo, and, after wounds healed, made detailed measurements of physiological performance relative to control leaves. When the midrib was severed near the leaf base, the pinnately veined leaves declined strongly in leaf hydraulic conductance, stomatal conductance, and photosynthetic rate, whereas palmately veined leaves were minimally affected. Across all of the species examined, a higher density of primary veins predicted tolerance of midrib damage. This benefit for palmate venation is consistent with its repeated evolution and its biogeographic and habitat distribution. All leaves tested showed complete tolerance of damage to second- and higher-order veins, demonstrating that the parallel flow paths provided by the redundant, reticulate minor vein network protect the leaf from the impact of hydraulic disruption. These findings point to a hydraulic explanation for the diversification of low-order vein architecture and the commonness of reticulate, hierarchical leaf venation. These structures suggest roles for both economic constraints and risk tolerance in shaping leaf morphology during 130 million years of flowering plant evolution.
The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP
Authors: Yun Cai-Hong , Mengwasser Kristen E. , Toms Angela V. , Woo Michele S. , Greulich Heidi , Wong Kwok-Kin , Meyerson Matthew , Eck Michael J.
Published: January 2008

Lung cancers caused by activating mutations in the epidermal growth factor receptor (EGFR) are initially responsive to small molecule tyrosine kinase inhibitors (TKIs), but the efficacy of these agents is often limited because of the emergence of drug resistance conferred by a second mutation, T790M. Threonine 790 is the “gatekeeper” residue, an important determinant of inhibitor specificity in the ATP binding pocket. The T790M mutation has been thought to cause resistance by sterically blocking binding of TKIs such as gefitinib and erlotinib, but this explanation is difficult to reconcile with the fact that it remains sensitive to structurally similar irreversible inhibitors. Here, we show by using a direct binding assay that T790M mutants retain low-nanomolar affinity for gefitinib. Furthermore, we show that the T790M mutation activates WT EGFR and that introduction of the T790M mutation increases the ATP affinity of the oncogenic L858R mutant by more than an order of magnitude. The increased ATP affinity is the primary mechanism by which the T790M mutation confers drug resistance. Crystallographic analysis of the T790M mutant shows how it can adapt to accommodate tight binding of diverse inhibitors, including the irreversible inhibitor HKI-272, and also suggests a structural mechanism for catalytic activation. We conclude that the T790M mutation is a “generic” resistance mutation that will reduce the potency of any ATP-competitive kinase inhibitor and that irreversible inhibitors overcome this resistance simply through covalent binding, not as a result of an alternative binding mode.
Interaction ruling animal collective behavior depends on topological rather than metric distance: Evidence from a field study
Authors: Ballerini M. , Cabibbo N. , Candelier R. , Cavagna A. , Cisbani E. , Giardina I. , Lecomte V. , Orlandi A. , Parisi G. , Procaccini A. , Viale M. , Zdravkovic V.
Published: January 2008

Numerical models indicate that collective animal behavior may emerge from simple local rules of interaction among the individuals. However, very little is known about the nature of such interaction, so that models and theories mostly rely on aprioristic assumptions. By reconstructing the three-dimensional positions of individual birds in airborne flocks of a few thousand members, we show that the interaction does not depend on the metric distance, as most current models and theories assume, but rather on the topological distance. In fact, we discovered that each bird interacts on average with a fixed number of neighbors (six to seven), rather than with all neighbors within a fixed metric distance. We argue that a topological interaction is indispensable to maintain a flock's cohesion against the large density changes caused by external perturbations, typically predation. We support this hypothesis by numerical simulations, showing that a topological interaction grants significantly higher cohesion of the aggregation compared with a standard metric one.
Induction of labour for post‐term pregnancy and risk estimates for intrauterine and perinatal death
Authors: HEIMSTAD RUNA , ROMUNDSTAD PÅL R. , SALVESEN KJELL Å.
Published: January 2008

Background. Beyond term there is increased risk of intrauterine fetal death (IUFD) and perinatal death, and we aimed to assess this risk beyond 41 weeks and estimate numbers needed to treat to avoid 1 fetal or neonatal death. Design and methods. All singletons births beyond 41 weeks from 1999–2005 registered in the Norwegian Medical Birth Registry were assessed concerning IUFD and perinatal death day by day, and numbers needed to induce to avoid 1 death was estimated. Results. The perinatal death rate increased with increasing gestational age. NNT for perinatal death was 527 at day 287, and 195 at day 302+ (p‐value = 0.02). Routine induction of labour at 41 weeks implicates >14,000 inductions per year. Conclusions. NNT to avoid 1 fetal or neonatal death is high (671–195), but decreases constantly with gestational age beyond 41 weeks.
Maternal body mass index at delivery and risk of caesarean due to dystocia in low risk pregnancies
Authors: ROMAN HORACE , GOFFINET FRANCOIS , HULSEY TARA F. , NEWMAN ROGER , YVES ROBILLARD PIERRE , HULSEY THOMAS C.
Published: January 2008

Background. To investigate the association between maternal body mass index (BMI) at delivery and the risk of caesarean section due to dystocia during the first stage of labour in low risk pregnancies. Methods. Historical cohort study that included 6,949 low risk women who delivered at the Medical University of South Carolina from 1994 to 2004, presenting a singleton birth at term, and a vaginal delivery attempt by spontaneous labour. Women presenting large for gestational age newborns were excluded. Adjusted odds ratios (ORs) for caesarean section due to dystocia and for caesarean section due to other reasons were estimated using a multinomial regression logistic model and compared using the Wald's test. Results. Women with a BMI > = 30 kg/m2, of maternal age > = 30 years and nulliparas had an increased rate of caesarean section delivery either due to dystocia or for other reasons. Newborn weight > = 3,500 g, races other than Caucasian, age between 25 and 29 years, BMI between 25 and 29.9 kg/m2, and fetal membranes rupture more than 24 h before the onset of the labour were associated with an increased rate of caesarean section due to dystocia only. On the contrary, newborn weight between 2,500 and 2,999 g was associated with a significant decrease in the rate of caesarean section due to dystocia. Newborn weight <3,000 g was associated with a risk for caesarean section due to other reasons. The population risk for caesarean section due to dystocia, attributable to BMI > = 35 kg/m2 in low risk pregnancies, was 13.3%. Conclusions. An increased maternal BMI was associated with the risk of caesarean section due to dystocia. This information should be made available to women who are overweight or obese at antenatal booking or at the first trimester visit.
Early postpartum changes in circulating pro‐ and anti‐angiogenic factors in early‐onset and late‐onset pre‐eclampsia
Authors: WIKSTRÖM ANNA‐KARIN , LARSSON ANDERS , ERIKSSON ULF J. , NASH PEPPI , OLOVSSON MATTS
Published: January 2008

Background. Pre‐eclampsia is associated with altered plasma concentrations of the pro‐ and anti‐angiogenic factors placental growth factor (PlGF), vascular endothelial growth factor‐A (VEGF‐A) and soluble fms‐like tyrosine kinase 1 (sFlt1). However, there is insufficient knowledge about how these concentrations change after delivery, and whether the changes differ between early‐onset and late‐onset pre‐eclampsia. Methods. Plasma concentrations of sFlt1, PlGF and VEGF‐A were measured before delivery and on days 1, 3 and 7 postpartum in women with early‐onset (24–32 weeks’ gestation) (n = 18) and late‐onset pre‐eclampsia (35–42 weeks’ gestation) (n = 20) and in control groups delivered in corresponding weeks of gestation. Results. All groups showed a rapid decrease in median sFlt1 concentration postpartum. Women with late‐onset pre‐eclampsia did not differ in sFlt1 concentration from controls on day 1 postpartum, whereas women with early‐onset pre‐eclampsia displayed a persistently elevated sFlt1 concentration on day 7 postpartum compared with controls. PlGF concentrations did not change from before delivery to any time point postpartum in the pre‐eclampsia groups. VEGF‐A concentrations were slightly increased on day 7 postpartum in both pre‐eclampsia and control groups compared to concentrations prior to delivery. Conclusion. Median sFlt1 concentrations decreased rapidly postpartum in all groups, but remained higher in early‐onset pre‐eclampsia than controls on day 7. Postpartum, the median PlGF concentrations were similar to the concentrations measured before delivery in women with pre‐eclampsia.
Trans‐obturator suburethral tape for female stress incontinence: a cohort of 254 women with 1‐year to 2‐year follow‐up
Authors: POZA JOSÉ L. , PLA FRANCESC , SABADELL JORDI , SÁNCHEZ‐IGLESIAS JOSÉ L. , MARTÍNEZ‐GÓMEZ XAVIER , XERCAVINS JORDI
Published: January 2008

Background. A clinical cohort study of 254 women undergoing trans‐obturator surgery for stress urinary incontinence was conducted to assess the efficacy of the trans‐obturator suburethral tape (TOT) after a follow‐up of 1 year (251 evaluable patients) and 2 years (62 patients). Results. Seventy‐five patients had previous gynaecologic surgery. Overall cure and improvement rates were 82% at 6 and 12 months, and 90% at 24 months. The most favourable results were obtained in patients with occult incontinence and urethral hypermobility. The relative risk (RR) for failure in patients with a history of gynaecologic surgery was 3.3 (95% CI: 1.1–14.7). There were 8 cases of bladder perforation (3.1%) during the learning phase with the TOT procedure, 20 of urinary retention (7.9%) – in 1 patient the tape was released after 12 days of insertion – and 3 of tape erosion (1.2%). Conclusion. Results are encouraging but should be substantiated on a larger series over a longer follow‐up.
Successful conservative treatment of endocervical adenocarcinoma stage Ib1 diagnosed early in pregnancy
Authors: VAN CALSTEREN KRISTEL , HANSSENS MYRIAM , MOERMAN PHILIPPE , ORYE GUY , BIELEN DIDIER , VERGOTE IGNACE , AMANT FREDERIC
Published: January 2008

Traditionally when cervical cancer is diagnosed during the first trimester of pregnancy, oncological treatment is given priority despite the pregnant state. A 32‐year‐old primigravida was diagnosed with invasive endocervical adenocarcinoma stage Ib1 at 8 weeks’ gestation. As the patient wanted to preserve the pregnancy, an amputation of the anterior cervix and retroperitoneal pelvic lymphadenectomy were performed. Based on favourable prognostic markers, we decided to maintain the pregnancy with careful cytological and histological follow‐up. The patient gave birth at term to a healthy boy, and 18 months after the delivery there is no evidence of recurrent disease. In the absence of poor prognostic markers, we decided to adopt a conservative approach for cervical adenocarcinoma in a pregnant patient at 8 weeks’ gestation.
The macrosomic fetus: a challenge in current obstetrics
Authors: HENRIKSEN TORE
Published: January 2008

Background. There has been a rise in the prevalence of large newborns over a few decades in many parts of the world. There is ample evidence that fetal macrosomia is associated with increased risk of complications both for the mother and the newborn. In current obstetrics, the macrosomic fetus represents a frequent clinical challenge. Evidence is emerging that being born macrosomic is also associated with future health risks. Objective. To provide a review of causes and risks, prevention, prediction and clinical management of suspected large fetus/fetal macrosomia, primarily aimed at clinical obstetricians. Methods. Medline and EMBASE were searched between 1980 and 2007 by combining either ‘fetal macrosomia’ or ‘large for gestational age’ with other relevant terms. The Cochrane Database of Systematic Reviews was searched for the term ‘fetal macrosomia’. Results and conclusions. Although the causes of high birthweight include both genetic and environmental factors, the rapid increase in the prevalence of large newborns has environmental causes. The evidence is extensive that maternal overweight and associated metabolic changes, including type 2 and gestational diabetes, play a central role. There is a paucity of studies of the effect of intervention before and/or during pregnancy on the risk of having an ‘overweight newborn’. It appears rational, however, that preventive measures should primarily be implemented before pregnancy and should include guidance about nutrition and physical activity in order to reduce the prevalence of overweight. In pregnancy, limited weight gain, especially in obese women, seems to reduce the risk of macrosomia, as do good control of plasma glucose among those with diabetes. Prediction of fetal macrosomia remains an inaccurate task even with modern ultrasound equipment. There is little evidence that routine elective delivery (induction or caesarean section) for the mere reason of suspected macrosomia should be employed in a general population. Vaginal delivery of a macrosomic fetus requires considered attention by an experienced obstetrician and preparedness for operative delivery, shoulder dystocia and newborn asphyxia.
Sustained desensitization to bacterial Toll-like receptor ligands after resolutionof respiratory influenza infection
Authors: Didierlaurent Arnaud , Goulding John , Patel Seema , Snelgrove Robert , Low Lionel , Bebien Magali , Lawrence Toby , van Rijt Leonie S. , Lambrecht Bart N. , Sirard Jean-Claude , Hussell Tracy
Published: January 2008

The World Health Organization estimates that lower respiratory tract infections (excluding tuberculosis) account for ∼35% of all deaths caused by infectious diseases. In many cases, the cause of death may be caused by multiple pathogens, e.g., the life-threatening bacterial pneumonia observed in patients infected with influenza virus. The ability to evolve more efficient immunity on each successive encounter with antigen is the hallmark of the adaptive immune response. However, in the absence of cross-reactive T and B cell epitopes, one lung infection can modify immunity and pathology to the next for extended periods of time. We now report for the first time that this phenomenon is mediated by a sustained desensitization of lung sentinel cells to Toll-like receptor (TLR) ligands; this is an effect that lasts for several months after resolution of influenza or respiratory syncytial virus infection and is associated with reduced chemokine production and NF-κB activation in alveolar macrophages. Although such desensitization may be beneficial in alleviating overall immunopathology, the reduced neutrophil recruitment correlates with heightened bacterial load during secondary respiratory infection. Our data therefore suggests that post-viral desensitization to TLR signals may be one possible contributor to the common secondary bacterial pneumonia associated with pandemic and seasonal influenza infection.
Giambelli formulae for the equivariant quantum cohomology of the Grassmannian
Authors: Mihalcea Leonardo
Published: January 2008

We find presentations by generators and relations for the equivariant quantum cohomology of the Grassmannian. For these presentations, we also find determinantal formulae for the equivariant quantum Schubert classes. To prove this, we use the theory of factorial Schur functions and a characterization of the equivariant quantum cohomology ring.
Geometric characterizations of finite Chevalley groups of type B₂
Authors: Thas Koen , Van Maldeghem Hendrik
Published: January 2008

Finite Moufang generalized quadrangles were classified in 1974 as a corollary to the classification of finite groups with a split BN-pair of rank

2
2

, by P. Fong and G. M. Seitz (1973), (1974). Later on, work of S. E. Payne and J. A. Thas culminated in an almost complete, elementary proof of that classification; see Finite Generalized Quadrangles, 1984. Using slightly more group theory, first W. M. Kantor (1991), then the first author (2001), and finally, essentially without group theory, J. A. Thas (preprint), completed this geometric approach. Recently, J. Tits and R. Weiss classified all (finite and infinite) Moufang polygons (2002), and this provides a third independent proof for the classification of finite Moufang quadrangles. In the present paper, we start with a much weaker condition on a BN-pair of Type

B

2

\mathbf {B}_2

and show that it must correspond to a Moufang quadrangle, proving that the BN-pair arises from a finite Chevalley group of (relative) Type

B

2

\mathbf {B}_2

. Our methods consist of a mixture of combinatorial, geometric and group theoretic arguments, but we do not use the classification of finite simple groups. The condition on the BN-pair translates to the generalized quadrangle as follows: for each point

x
x

, the stabilizer of all lines through that point acts transitively on the points opposite

x
x

.
On asymptotic stability in 3D of kinks for the 𝜙⁴ model
Authors: Cuccagna Scipio
Published: January 2008

We add to a kink, which is a 1 dimensional structure, two transversal directions. We then check its asymptotic stability with respect to compactly supported perturbations in 3D and a time evolution under a Nonlinear Wave Equation (NLW). The problem is inspired by work by Jack Xin on asymptotic stability in dimension larger than 1 of fronts for reaction diffusion equations. The proof involves a separation of variables. The transversal variables are treated as in work on Nonlinear Klein Gordon Equation (NLKG) originating from Klainerman and from Shatah in a particular elaboration due to Delort et al. The longitudinal variable is treated by means of a result by Weder on dispersion for Schrödinger operators in 1D.
General logical metatheorems for functional analysis
Authors: Gerhardy Philipp , Kohlenbach Ulrich
Published: January 2008

In this paper we prove general logical metatheorems which state that for large classes of theorems and proofs in (nonlinear) functional analysis it is possible to extract from the proofs effective bounds which depend only on very sparse local bounds on certain parameters. This means that the bounds are uniform for all parameters meeting these weak local boundedness conditions. The results vastly generalize related theorems due to the second author where the global boundedness of the underlying metric space (resp. a convex subset of a normed space) was assumed. Our results treat general classes of spaces such as metric, hyperbolic, CAT(0), normed, uniformly convex and inner product spaces and classes of functions such as nonexpansive, Hölder-Lipschitz, uniformly continuous, bounded and weakly quasi-nonexpansive ones. We give several applications in the area of metric fixed point theory. In particular, we show that the uniformities observed in a number of recently found effective bounds (by proof theoretic analysis) can be seen as instances of our general logical results.
Pseudocycles and integral homology
Authors: Zinger Aleksey
Published: January 2008

We describe a natural isomorphism between the set of equivalence classes of pseudocycles and the integral homology groups of a smooth manifold. Our arguments generalize to settings well-suited for applications in enumerative algebraic geometry and for construction of the virtual fundamental class in the Gromov-Witten theory.
SOAP: short oligonucleotide alignment program
Authors: Li Ruiqiang , Li Yingrui , Kristiansen Karsten , Wang Jun
Published: January 2008

Summary: We have developed a program SOAP for efficient gapped and ungapped alignment of short oligonucleotides onto reference sequences. The program is designed to handle the huge amounts of short reads generated by parallel sequencing using the new generation Illumina-Solexa sequencing technology. SOAP is compatible with numerous applications, including single-read or pair-end resequencing, small RNA discovery and mRNA tag sequence mapping. SOAP is a command-driven program, which supports multi-threaded parallel computing, and has a batch module for multiple query sets.

Availability:  http://soap.genomics.org.cn

Contact:  soap@genomics.org.cn
On distance and similarity in fold space
Authors: Sippl Manfred J.
Published: January 2008

Summary: Metric information on similarities and distances in fold space is essential for quantitative work in structural bioinformatics and structural biology. Here we derive a suitable metric for protein structures from the fundamental axioms of similarity. Derivation of the metric also clarifies the relationship between the interrelated concepts of distance and similarity.

Contact:  sippl@came.sbg.ac.at
Philosophy, Psychology, Physics and Practice of Ki
Authors: Ohnishi S. Tsuyoshi , Ohnishi Tomoko
Published: January 2008

Ki (in Japanese) or Qi (in Chinese) is the key concept in Eastern medicine, Eastern philosophy, as well as in martial arts. We explain the philosophical and psychological background of Ki. We emphasize that the unique aspects of Eastern philosophy are ‘non‐linearity’ and ‘holistic’ approach. We then present physics aspect of Ki. Our experiments demonstrated that a ‘Ki‐beam’ carries ‘entropy’ (or information), which is different from ‘energy’. We introduce our experience of having taught Ki to 37 beginners in the United States through the Nishino Breathing Method. If beginners had martial arts training or a strong background in music or dance, about half of them could sense Ki within 10 weeks (1 h class per week) of practice.
James Clerk Maxwell's Scottish chair
Authors: Reid John S
Published: January 2008

This account of Maxwell as professor of natural philosophy at Marischal College, Aberdeen, fills in many details that have been left out of Maxwell's biographies. It discusses the degree programme that Maxwell taught on, the nature of his colleagues, the type of student he had in his classes and the range of activities involved in his teaching. Evidence is cited that Maxwell was an enthusiastic and effective teacher, contrary to the often repeated but thinly supported view to the contrary. Following a brief summary of Maxwell's research interests while at Aberdeen, the myth that Maxwell was sacked from the University of Aberdeen is exploded and the detail of why he moved on is spelt out.
Microglia: Immune Network in the CNS
Authors: Graeber Manuel B. , Stre'rt Wolfgang J.
Published: January 2008

In recent years much progress has been made toward a better understanding of the nature and function of microglial cells. This review summarizes new developments and attempts to provide a perspective for future avenues to take in microglial research. Microglia are considered to play an active role in a variety of neurological diseases. Their function in forming a network of immune competent cells within the CNS is discussed.
Neurotropic Herpesviruses, Neural Mechanisms and Arteritis
Authors: Martin John R. , Mitchell William J. , Henken Deborah B.
Published: January 2008

Cumulative evidence suggests that varicella‐zoster virus (VZV) can infect walls of CNS arteries, causing stroke in man. We review observations relating infection with this neurotropic virus to the development of arteritis in the CNS and note evidence supporting the hypothesis that VZV spreads from ganglionic reactivation sites to the arterial wall by neural pathways. Problems relating to the pathogenesis of arteritis and experimental approaches to their solution are suggested.
The Molecular Genetics of Meningiomas
Authors: Collins V. Peter , Nordenskjold Magnus , Dumanski Jan P.
Published: January 2008

There are many findings which suggest that an individual may inherit a predisposition for developing a meningioma. The cytogenetics of meningiomas has been well known for some time with monosomy of chromosome 22 as the most characteristic finding. We have confirmed the cytogenetic findings in cultured cells, using molecular genetic techniques on primary tumour tissue. The only difference found between the results of the two techniques was the greater proportion of terminal deletions of the long arm of chromosome 22 detected by the molecular method. The minimal deletion common to 81 meningiomas, and thus the position of the tentative meningioma tumour suppressor gene (TSG), has been determined to lie distal to the myoglobin locus on the long arm of chromosome 22, corresponding to the region 22q12.3‐qter. All common histological types of meningioma show the same genetic abnormalities. Study of one tumour with areas of both meningothelial and anaplastic meningioma demonstrated the tumour to be clonal and a partial deletion of 22q to have occurred prior to the development of anaplasia. In order to map in more detail the position of, and finally identify, the TSG involved, a new series of 195 chromosome 22 genomic DNA fragments have been cloned. Current evidence suggests that the genes involved in neurofibromatosis type 2 and meningioma are located at different points on the long arm of chromosome 22 and thus are separate entities.
Molecular Genetics in the Pathology and Diagnosis of Retinoblastoma
Authors: Gennett Irene N. , Cavenee Webster K.
Published: January 2008

Retinoblastoma, the most common intraocular malignancy of children, has served as an important paradigm for understanding the events involved in neoplastic transformation. Much of the contemporary molecular description of human cancers stems directly from experimental approaches first developed to study this childhood tumour. This analytical methodology has demonstrated a major role for heritable predisposition in tumourigenesis, provided evidence for tissue pleiotropy of cancer genes, and revealed a more precise estimation of the number, activity, and location of other tumour suppressor loci.
Amplification of the MYCN oncogene and deletion of putative tumour suppressor gene in human neuroblastomas
Authors: Schwab Manfred
Published: January 2008

Human neuroblastoma cells often carry non‐random chromosomal abnormalities signalling genetic alterations. Quite frequent are ‘double minutes’ (DMs) and homogeneously staining regions (HSRs), both cytogenetic manifestations of amplified DNA, and chromosome Ip‐deletions indicating loss of genetic information. With the identification of amplified MYCN and the demonstration of a consensus deletion spanning the chromosome 1p36.1–2 region it appears now likely that both amplification of a cellular oncogene and loss of a tumour‐suppressor gene play an important role in neuroblastoma. Amplification of MYCN is an indicator for poor prognosis, even when classical morphological criteria would suggest a better outcome. Consequently, patients with amplification are subjected to more intensive therapeutic regimens. Amplification of MYCN is a paradigm for the clinical use of an oncogene alteration.
Neuroblastoma ‐Clinical Applications of Molecular Parameters
Authors: Brodeur Garrett M.
Published: January 2008

At least two genetic events have been identified which are characteristic of certain neuroblastomas. These are loss of a critical region on the short arm of chromosome 1, and amplification of the MYCN proto‐oncogene. Our studies suggest that the two genetic events may be related, and that loss of heterozygosity (LOH) for chromosome 1p may precede the development of amplification. RAS gene mutations appear to be rare, and no other oncogene has been shown to be consistently activated by amplification or other mechanism. LOH for chromosome 14q has been identified recently, but its frequency and significance is not clear. Based on flow cytometric analysis of DNA content, tumour cytogenetics and molecular studies, three distinct genetic subsets of neuroblastomas are emerging. The first is characterized by a hyperdiploid or near‐triploid modal karyotype, with few if any cytogenetic rearrangements. These patients are generally less than one year of age with localized disease and a good prognosis. The second group is characterized by a near‐diploid or near‐tetraploid karyotype, with no consistent rearrangement identified to date. They are generally older patients with more advanced stages of disease that progress slowly and are ultimately fatal. The third group is characterized by a neardiploid or tetraploid karyotype, with deletions or LOH for chromosome 1p, amplification of MYCN, or both. These patients are generally older with advanced stages of disease which is rapidly progressive. Thus, genetic analysis of neuroblastoma cells by karyotype, flow cytometry and determination of MYCN copy number provides information that has prognostic significance and can more appropriately direct the choice of treatment. A better understanding of these genetic abnormalities and the biochemical pathways that they effect may provide insights into malignant transformation and progression, as well as provide targets for future therapeutic approaches.
The Art of Brain Tumour Classification ‐A Tribute to Lucien J. Rubinstein (1925–1990)
Authors: Davis Richard L. , Kepes John J. , Rorke Lucy B. , VandenBerg Scott R. , Kleihues Paul
Published: January 2008

On the occasion of a WHO Meeting on Brain Tumour Classification which was held in Zurich during March 29–31, several friends and colleagues shared their memories of Dr Lucien J. Rubinstein who died on January 22, 1990. The following is the transcript of a video recording.
Migration of Hematogenous Cells Through the Blood‐Brain Barrier and the Initiation of CNS Inflammation
Authors: Hickey William F.
Published: January 2008

The central nervous system has long been considered an immunologically privileged site. Nevertheless, cells derived from the bone marrow can and do enter the CNS in a number of circumstances. Derivatives of the monocyte/macrophage lineage appear to enter and take up residence in various structures of the CNS as part of normal ontogeny and physiology. Immunocompetent cells, such as T‐lymphocytes of both CD4 and CD8 positive groups, enter the nervous system in what appears to be a random fashion when they are activated by antigenic stimulation. These lymphocytes perform the required immunological surveillance of the CNS, and initiate inflammation therein during infectious and autoimmune reactions. In this review, the evidence supporting the above observations is examined, and a hypothesis for the pathogenesis of CNS inflammatory reactions is presented.
Interaction of T Lymphocytes with Cerebral Endothelial Cells in vitro
Authors: Wekerle Hartmut , Engelhardt Britta , Risau Werner , Meyermann Richard
Published: January 2008

As a prerequisite of inflammatory lesion formation in (auto‐)immune disease of the central nervous system, lymphocytes have to interact with brain endo‐thelia. In recent years much progress has been made towards a better understanding of mechanisms and factors involved in organ specific homing of lymphocytes. Many lines of evidence indicate that T lymphocytes recognizing antigens which are exclusively beyond the blood‐brain barrier cross this barrier only when they are in an activated state, irrespective of their antigen specificity. Antigen presentation by blood‐brain barrier endothelia, however, may play a role in later stages of florid inflammation.
Tau Proteins and Neurofibrillary Degeneration
Authors: Goedert M. , Spillantini M. G. , Crowther R. A.
Published: January 2008

The paired helical filament is the major fibrous component of neurofibrillary pathology in Alzheimer's disease. Over the last three years evidence has accumulated that the microtubule‐associated protein tau forms an important, if not the sole, constituent of the paired helical filament. Tau protein in normal brain is bound to axonal microtubules by a tandem repeat region. In Alzheimer's disease a proportion of tau protein becomes abnormally phos‐phorylated and is no longer associated with axonal microtubules but instead accumulates in paired helical filaments throughout affected nerve cells. The tandem repeat region contributes substantially to the structural core of the paired helical filament, around which the amino‐terminal half of the molecule forms a disordered coat.
Aged Non‐Human Primates: An Animal Model of Age‐Associated Neurodegenerative Disease
Authors: Price Donald L. , Martin Lee J. , Sisodia Sangram S. , Wagster Molly V. , Koo Edward H. , Walker Lary C. , Koliatsos Vassilis E. , Cork Linda C.
Published: January 2008

Aged non‐human primates develop age‐associated behavioral and brain abnormalities similar to those that occur in aged humans and, to a greater extent, in individuals with Alzheimer's disease. Declines in performance on cognitive and memory tasks begin at the monkey equivalent of late‐middle life. As occurs in elderly humans, significant differences have been demonstrated in levels of performance between animals within older age groups. The brains of old monkeys show degenerative changes in neurons, abnormal axons and neurites (particularly in telencephalic areas), and deposits of amyloid in senile plaques and around blood vessels. Moreover, in some older animals, decrements occur in markers of specific neurotransmitter circuits, including the basal forebrain cholinergic system. It has been suggested that alterations in these cholinergic neurons contribute to the memory deficits that occur in older individuals. Because axotomy‐induced retrograde degeneration of these neurons can be prevented by the administration of nerve growth factor, we have begun studies to determine whether administration of nerve growth factor improves performance of aged animals on memory tasks. This review describes the complementary nature of studies of non‐human primates and human subjects, illustrating how these investigations can clarify factors that influence behavior and brain biology in age‐associated diseases.
Molecular Biology and Pathology of Scrapie and the Prion Diseases of Humans
Authors: Prusiner Stanley B. , DeArmond Stephen J.
Published: January 2008

Scrapie and bovine spongiform encephalopathy of animals and Creutzfeldt‐Jakob and Gerstmann‐Sträussler‐Scheinker diseases of humans are transmissible and genetic neurodegenerative diseases caused by prions. Infectious prion particles are composed largely, if not entirely, of an abnormal isoform of the prion protein which is encoded by a chromosomal gene. An as yet unidentified post‐transla‐tional process converts the cellular prion protein into an abnormal isoform. Scrapie neuropathology, incubation times, and prion synthesis in transgenic mice are controlled by the prion protein gene. Point mutations in the prion protein genes of animals and humans are genetically linked to development of neurodegeneration. Transgenic mice expressing mutant prion proteins spontaneously develop neurologic dysfunction and spongiform neuropathology. Studies of prion diseases may advance investigations of other neurodegenerative disorders and of how neurons differentiate, function for decades and grow senescent.
MEETING REPORT
Authors: Budka Herbert , Wiestler Otmar D. , Herriich Peter
Published: January 2008

East‐West Danube Symposium on Human and Zoonotic Spongiform Encephalopathies, in Bratislava, Czechoslovakia, May 22–23, 1991

Zülch Symposium on Growth Control and Neoplastic Transformation in the Brain, Goslar, Germany, April 28, 1991 ‐ May 1, 1991
Primary Central Nervous System Lymphoma
Authors: Grant John W. , Isaacson Peter G.
Published: January 2008

Primary central nervous system lymphomas (PCNSL) are uncommon neoplasms accounting for less than 2% of brain tumours. Their incidence appears to be increasing across a wide age range, in both immunocompetent and immunosuppressed populations. Particular risk groups include those with congenital and acquired immunodeficiencies and transplant recipients. The spread of the AIDS epidemic has seen large numbers of complicating PCNSL develop. Epstein‐Barr virus infection appears to play a role in the development of these lymphomas in the immunosuppressed population. The aetiology of these tumours in the immunocompetent is uncertain. Their tendency to remain within the nervous system is not well understood but may be a function of CMS binding molecules carried by lymphocytes. Clinically PCNSL may present with a wide variety of signs and symptoms and has a capacity to mimic many other neurological conditions. Radiologically they appear as hyperdense homogenous deposits in subcortical white matter. Although most lesions are intermediate or high grade B cell lymphomas, T cell lymphomas are being recognised with increasing frequency. Immunohistochemistry and genotypic analysis have an important role in accurately characterising PCNSL, particularly in stereotactic biopsies. Involvement of multiple areas of the neuraxis, the eye and multiple intracranial sites can occur in the absence of obvious systemic lymphoma. The role of surgery in their treatment is uncertain. A combination of radiotherapy and chemotherapy can increase the length of survival. The prognosis, however, remains poor in comparison with nodal lymphomas, and particularly so in those with AIDS.
New Morphological Approaches to the Study of Mitochondrial Encephalomyopathies
Authors: Bonilla Eduardo , Sciacco Monica , Tanji Kuranai , Sparaco Marco , Petruzzella Vittoria , Moraes Carlos T.
Published: January 2008

Molecular genetics, biochemistry, immunology and morphology, are being applied in a coordinated fashion to unveil the molecular basis of the mitochondrial encephalomyopathies. Mutations of mitochondrial DNA (mtDNA) have been found in well characterized clinical groups of these disorders. New and old morphologic methods have been applied to investigate muscle biopsies from patients with mtDNA mutations. Important observations have been made on the cellular localization of normal and mutated mtDNA and on the expression of mtDNA‐encoded polypeptides. These observations have provided insight into the pathogenesis of respiratory chain enzyme deficiency at the level of individual muscle fibers. Application of immunocytochemical and in situ hybridization techniques at the electron microscopic level will extend these studies to the level of individual mitochondria.
Disorders Associated with Multiple Deletions of Mitochondrial DNA
Authors: Haltia Matti , Suomalainen Anu , Majander Anna , Somer Hannu
Published: January 2008

Multiple deletions of mitochondrial DNA (mtDNA) have recently been described in a number of patients with neurological disorders. Most cases have been clinically characterized by autosomal dominant inheritance, adult onset, and a slowly progressive course with external ophthalmoplegia and muscle weakness. Some patients have had evidence of central or peripheral nervous system involvement or episodes of myoglobinuria. Muscle biopsy findings include ragged‐red fibres (RRF), muscle fibres with absent COX‐activity and abundant abnormal mitochondria with paracrystalline inclusions. Biochemically, a generalized reduction in the activities of mtDNA‐encoded enzymes is observed in skeletal muscle. Southern blotting or PCR analysis reveal multiple populations of deleted mtDNA. The deletions occur at multiple sites between the replication initiation sites, involving a large portion of mtDNA, and most deletions seem to be flanked by direct sequence repeats, shown to be “hot spots” in the case of single large deletions. Apparently, a defect in a nuclear gene results in multiple deletions of mtDNA. Both clinical, genetic and molecular genetic observations indicate heterogeneity of this new disease category, apparently based on a disturbance in the “cross‐talk” between the nuclear and the mitochondrial genomes.
Neuropathology of Immunosuppression
Authors: Smith Thomas W. , Girolami Umberto De , Hickey William F.
Published: January 2008

Traditionally, the brain has been considered an “immunologically privileged” organ. Under normal conditions, the blood‐brain barrier (BBB) is highly effective in preventing both cellular and humoral constituents of the blood from entering the brain parenchyma. In certain pathological conditions, such as viral infections and demyelinating disorders, the BBB may become altered, activated T cells and monocytes may gain access to the brain parenchyma, and microglia may assume the functions of antigen‐presenting cells and macrophages. Naturally‐occurring or clinically‐induced immunosuppression may dramatically alter various cellular and/or humoral aspects of the immune system. Consequently, the brain may become susceptible to disorders that would otherwise be excluded or may develop more severe manifestations of diseases, such as certain infections. This review considers the neuropathologic aspects of various conditions that may be encountered in the setting of both acquired and inherited immunosuppression. The major categories include infectious, neoplastic, vascular, and metabolic disorders. The review also briefly addresses the neuropathology of complications of chemo‐therapeutic agents, radiotherapy, and organ transplantation inasmuch as they often occur in the clinical setting of acquired immunosuppression.
Anatomical Features of the Developing Brain Implicated in Pathogenesis of Hypoxic‐Ischemic Injury
Authors: Rorke Lucy B.
Published: January 2008

The developing nervous system is subject to damage from lack of vital substances necessary for normal maturation and function as well as from trauma or a variety of toxins and infectious agents. By far, the most important of these is inadequate oxygen delivery to the fetus in utero, and/or during the intrapartum and/or early neonatal period. Many types of lesions have been described under the rubric of hypoxic‐ischemic encephalopathy, a major proportion of which are found only in the immature nervous system and essentially are never seen later in life. Moreover, a large number are primarily hemorrhagic rather than ischemic in character. The unique character and distribution of these lesions results from a collision of the changing anatomy of the developing nervous system and pathophysiological factors afflicting the immature organism. Whereas the majority of hypoxic‐ischemic lesions in the fetus/neonate fall into this group, abnormalities characteristically found in the mature nervous system are also seen. Recognition of the anatomic and physiological features peculiar to the developing nervous system will assist in diagnosis of hypoxic‐ischemic damage peculiar to the fetus and neonate.