Carbonic anhydrase IX expression and outcome after radiotherapy for muscle-invasive bladder cancer

Aims: Carbonic anhydrase IX (CA IX) expression has been described as an endogenous marker of hypoxia in solid neoplasms. Furthermore, CA IX expression has been associated with an aggressive phenotype and resistance to radiotherapy. We assessed the prognostic significance of CA IX expression in patients with muscle-invasive bladder cancer treated with radiotherapy. Materials and methods: A standard immunohistochemistry technique was used to show CA IX expression in 110 muscle-invasive bladder tumours treated with radiotherapy. Clinicopathological data were obtained from medical case notes. Results: CA IX immunostaining was detected in 89 (∼81%) patients. Staining was predominantly membranous, with areas of concurrent cytoplasmic and nuclear staining and was abundant in luminal and perinecrotic areas. No significant correlation was shown between the overall CA IX status and the initial response to radiotherapy, 5-year bladder cancer-specific survival or the time to local recurrence. Conclusions: The distribution of CA IX expression in paraffin-embedded tissue sections seen in this series is consistent with previous studies in bladder cancer, but does not provide significant prognostic information with respect to the response to radiotherapy at 3 months and disease-specific survival after radical radiotherapy. © 2007 The Royal College of Radiologists.

The highly abundant urinary metabolite urobilin interferes with the bicinchoninic acid assay

Estimation of total protein concentration is an essential step in any protein- or peptide-centric analysis pipeline. This study demonstrates that urobilin, a breakdown product of heme and a major constituent of urine, interferes considerably with the bicinchoninic acid (BCA) assay. This interference is probably due to the propensity of urobilin to reduce cupric ions (Cu2+) to cuprous ions (Cu1+), thus mimicking the reduction of copper by proteins, which the assay was designed to do. In addition, it is demonstrated that the Bradford assay is more resistant to the influence of urobilin and other small molecules. As such, urobilin has a strong confounding effect on the estimate of total protein concentrations obtained by BCA assay and thus this assay should not be used for urinary protein quantification. It is recommended that the Bradford assay be used instead.

Divergent outcomes following transcytosis of IgG targeting intracellular and extracellular chlamydial antigens

Antibodies can play a protective but non-essential role in natural chlamydial infections dependent on antigen specificity and antibody isotype. IgG is the dominant antibody in both male and female reproductive tract mucosal secretions, and is bi-directionally trafficked across epithelia by the neonatal Fc receptor (FcRn). Using physiologically relevant pH-polarized epididymal epithelia grown on Transwells®, IgG specifically targeting an extracellular chlamydial antigen; the Major Outer Membrane Protein (MOMP), enhanced uptake and translocation of infection at pH 6-6.5 but not at neutral pH. This was dependent on FcRn expression. Conversely, FcRn-mediated transport of IgG targeting the intracellular chlamydial inclusion membrane protein A (IncA), induced aberrant inclusion morphology, recruited autophagic proteins independent of lysosomes, and significantly reduced infection. Challenge of female mice with MOMP-specific IgG-opsonized C. muridarum delayed infection clearance but exacerbated oviduct occlusion. In male mice, MOMP-IgG elicited by immunization afforded no protection against testicular chlamydial infection, whereas; the transcytosis of IncA-IgG significantly reduced testicular chlamydial burden. Together these data show that the protective and pathological effects of IgG are dependent on FcRn-mediated transport as well as the specificity of IgG for intracellular or extracellular antigens.

Understanding the abnormal brain activity in epilepsy as a potential predictor of the onset of an epileptic seizure

The Brain Research Institute (BRI) uses various types of indirect measurements, including EEG and fMRI, to understand and assess brain activity and function. As well as the recovery of generic information about brain function, research also focuses on the utilisation of such data and understanding to study the initiation, dynamics, spread and suppression of epileptic seizures. To assist with the future focussing of this aspect of their research, the BRI asked the MISG 2010 participants to examine how the available EEG and fMRI data and current knowledge about epilepsy should be analysed and interpreted to yield an enhanced understanding about brain activity occurring before, at commencement of, during, and after a seizure. Though the deliberations of the study group were wide ranging in terms of the related matters considered and discussed, considerable progress was made with the following three aspects. (1) The science behind brain activity investigations depends crucially on the quality of the analysis and interpretation of, as well as the recovery of information from, EEG and fMRI measurements. A number of specific methodologies were discussed and formalised, including independent component analysis, principal component analysis, profile monitoring and change point analysis (hidden Markov modelling, time series analysis, discontinuity identification). (2) Even though EEG measurements accurately and very sensitively record the onset of an epileptic event or seizure, they are, from the perspective of understanding the internal initiation and localisation, of limited utility. They only record neuronal activity in the cortical (surface layer) neurons of the brain, which is a direct reflection of the type of electrical activity they have been designed to record. Because fMRI records, through the monitoring of blood flow activity, the location of localised brain activity within the brain, the possibility of combining fMRI measurements with EEG, as a joint inversion activity, was discussed and examined in detail. (3) A major goal for the BRI is to improve understanding about ``when'' (at what time) an epileptic seizure actually commenced before it is identified on an eeg recording, ``where'' the source of this initiation is located in the brain, and ``what'' is the initiator. Because of the general agreement in the literature that, in one way or another, epileptic events and seizures represent abnormal synchronisations of localised and/or global brain activity the modelling of synchronisations was examined in some detail. References C. M. Michel, G. Thut, S. Morand, A. Khateb, A. J. Pegna, R. Grave de Peralta, S. Gonzalez, M. Seeck and T. Landis, Electric source imaging of human brain functions, Brain Res. 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Photoelectron spectroscopy of HCCN- and HCNC- reveals the quasilinear triplet carbenes, HCCN and HCNC

Negative ion photoelectron spectroscopy has been used to study the HCCN- and HCNC- ions. The electron affinities (EA) of cyanocarbene have been measured to be EA(HCCN (X) over tilde (3)Sigma(-)=2.003+/-0.014 eV and EA(DCCN (X) over tilde (3)Sigma(-))=2.009+/-0.020 eV. Photodetachment of HCCN- to HCCN (X) over tilde (3)Sigma(-) shows a 0.4 eV long vibrational progression in nu(5), the H-CCN bending mode; the HCCN- photoelectron spectra reveal excitations up to 10 quanta in nu(5). The term energies for the excited singlet state are found to be T-0(HCCN (a) over tilde (1)A('))=0.515+/-0.016 eV and T-0(DCCN (a) over tilde (1)A('))=0.518+/-0.027 eV. For the isocyanocarbene, the two lowest states switch and HCNC has a singlet ground state and an excited triplet state. The electron affinities are EA(HCNC (X) over tilde (1)A('))=1.883+/-0.013 eV and EA((X) over tilde (1)A(') DCNC)=1.877+/-0.010 eV. The term energy for the excited triplet state is T-0(HCNC (a) over tilde (3)A("))=0.050+/-0.028 eV and T-0(DCNC (a) over tilde (3)A("))=0.063+/-0.030 eV. Proton transfer kinetics in a flowing afterglow apparatus were used to re-measure the enthalpy of deprotonation of CH3NC to be Delta(acid)H(298)(CH3NC)=383.6+/-0.6 kcal mol(-1). The acidity/EA thermodynamic cycle was used to deduce D-0(H-CHCN)=104+/-2 kcal mol(-1) [Delta(f)H(0)(HCCN)=110+/-4 kcal mol(-1)] and D-0(H-CHNC)=106+/-4 kcal mol(-1) [Delta(f)H(0)(HCNC)=133+/-5 kcal mol(-1)]. (C) 2002 American Institute of Physics.

Soluble laminin and arginine-glycine-aspartic acid containing peptides differentially regulate type IV collagenase messenger RNA, activation, and localization in testicular cell culture

Rat testicular cells in culture produce several metalloproteinases including type IV collagenases (Sang et al. Biol Reprod 1990; 43:946-955, 956-964). We have now investigated the regulation of testicular cell type IV collagenase and other metalloprotemases in vitro. Soluble laminin stimulated Sertoli cell type IV collagenase mRNA levels. However, three peptides corresponding to different domains of the laminin molecule (CSRAKQAASIKVASADR, FALRGDNP, CLQDGDVRV) did not influence type IV collagenase mENA levels. Zyniographic analysis of medium collected from these cultures revealed that neither soluble laminin nor any of the peptides influenced 72-Wa type IV collagenase protein levels. However, peptide FALRGDNP resulted in both, a selective increase in two higher molecular-weight metalloprotemnases (83 kDa and 110 Wa and in an activation of the 72-Wa rat type IV collagenase. Interleukin-1, phorbol ester, testosterone, and FSH did not affect collagenase activation, lmmunocytochemical studies demonstrated that the addition of soluble laminin resulted in a redistribution of type IV collagenase from intracellular vesicles to the cell-substrate region beneath the cells. Peptide FALRGDNP induced a change from a vesicular to peripheral plasma membrane type of staining pattern. Zymography of plasma membrane preparations demonstrated triton-soluble gelatinases of 76 Wa, 83 Wa, and 110 Wa and a triton-insoluble gelatinase of 225 Wa, These results indicate that testicular cell type IV collagenase mRNA levels, enzyme activation, and distribution are influenced by laminin and RGD-containing peptides.

Identyfikacja blednych podpisow w kolekcjach

Weryfikacja poprawnosci podpisów cyfrowych jest obliczeniowo kosztowna. Aby ja zwiekszyc, zamiast pojedynczych podpisów weryfikacji poddaje sie kolekcje. Jezeli wszystkie podpisy w kolekcji sa poprawne, to cała kolekcja jest akceptowana. Pojawienie sie błednych podpisów w kolekcji powoduje, ze weryfikacja jest błedna. Nie mozna odrzucic całej kolekcji, zachodzi wiec koniecznosc identyfikacji błednych podpisów w kolekcji. W artykule zdefiniowano metody identyfikacji błednych podpisów. W szczególnosci okreslono weryfikacje typu „dziel i rzadz”, w których wejsciowe kolekcje sa dzielone na podkolekcje tak długo, az koncowe błedne kolekcje zawieraja pojedyncze podpisy. Opisano równiez weryfikator Hamminga identyfikujacy jeden błedny podpis w kolekcji oraz uogólniono ten weryfikator do postaci dwupoziomowego weryfikatora, umozliwiajacego identyfikacje dwóch błednych podpisów. Podano tez definicje ogólnego weryfikatora zdolnego do identyfikacji dowolnej liczby błednych podpisów w kolekcjach.

Cultural relativity as exchange : J.W. Lindt’s bush character and Aboriginal from The Grafton Album (circa 1872)

J.W.Lindt’s Colonial man and Aborigine image from the GRAFTON ALBUM: “On chemistry and optics all does not depend, art must with these in triple union blend” (text from J.W. Lindt’s photographic backing card)...

A review of: "Wrong-Doing, Truth-Telling: The Function of Avowal in Justice. By Michel Foucault. Edited by Fabienne Brion and Bernard E. Harcourt. Translated by Stephen W. Sawyer"

Wrong-Doing, Truth-Telling: The Function of Avowal in Justice is a collection of seven lectures delivered by French philosopher and historian Michel Foucault at the Catholic University of Louvain in 1981. Compiled from audiovisual recordings and Foucault’s original manuscripts, these lectures explore the notion of avowal and its place within criminal justice processes. Accompanied by three contemporaneous interviews given by Foucault (only one of which has previously been available in English), and a preface and concluding essay by the editors contextualizing these lectures in Foucault’s oeuvre, this volume contributes much to Foucaultian scholarship, particularly when considered alongside the recently published volumes of Foucault’s lecture courses at the Collège de France. However, while the book promises to offer some insights of relevance to criminology, it is important to remember that this is not its key purpose, and criminologists should read it with this caveat in mind...

Genome-wide scan of healthy human connectome discovers SPON1 gene variant influencing dementia severity

Aberrant connectivity is implicated in many neurological and psychiatric disorders, including Alzheimer's disease and schizophrenia. However, other than a few disease-associated candidate genes, we know little about the degree to which genetics play a role in the brain networks; we know even less about specific genes that influence brain connections. Twin and family-based studies can generate estimates of overall genetic influences on a trait, but genome-wide association scans (GWASs) can screen the genome for specific variants influencing the brain or risk for disease. To identify the heritability of various brain connections, we scanned healthy young adult twins with high-field, highangular resolution diffusion MRI. We adapted GWASs to screen the brain's connectivity pattern, allowing us to discover genetic variants that affect the human brain's wiring. The association of connectivity with the SPON1 variant at rs2618516 on chromosome 11 (11p15.2) reached connectome-wide, genome-wide significance after stringent statistical corrections were enforced, and it was replicated in an independent subsample. rs2618516 was shown to affect brain structure in an elderly population with varying degrees of dementia. Older people who carried the connectivity variant had significantly milder clinical dementia scores and lower risk of Alzheimer's disease. As a posthoc analysis, we conducted GWASs on several organizational and topological network measures derived from the matrices to discover variants in and around genes associated with autism (MACROD2), development (NEDD4), and mental retardation (UBE2A) significantly associated with connectivity. Connectome-wide, genome-wide screening offers substantial promise to discover genes affecting brain connectivity and risk for brain diseases.

VFT performance of a 180/110 mm co-axial gap in SF6 up to 4 bar absolute

Disconnector switch operation in GIS generates VFT voltages in the system. It is important, for insulation co-ordination purposes, to obtain accurate VFT V-t data for typical gap geometries found in GIS. This paper presents experimentally obtained VFT V-t data for a 180/1 lOmm co-axial gap. The VFT has a time to first peak of 35 ns and a oscillation frequency of 13,6 MHz. Due to the location of the voltage divider in a compartment adjacent to the gap, a correction factor of 1.1 is used to relate the measured breakdown voltage to that in the gap. Positive polarity VFT V-t data is presented for 1, 2, 3 and 4 bar absolute and negative polarity VFT data for 3 and 4 bar absolute. Two methods of generating the VFT's are used. The first is to power up the test transformer at power frequency. The second is to generate a switching impulse by discharging a capacitor into the primary of the test transformer.

Association of variants at 1q32 and STAT3 with ankylosing spondylitis suggests genetic overlap with Crohn's disease

Ankylosing spondylitis (AS) is a common inflammatory arthritic condition. Overt inflammatory bowel disease (IBD) occurs in about 10% of AS patients, and in addition 70% of AS cases may have subclinical terminal ileitis. Spondyloarthritis is also common in IBD patients. We therefore tested Crohn's disease susceptibility genes for association with AS, aiming to identify pleiotropic genetic associations with both diseases. Genotyping was carried out using Sequenom and Applied Biosystems TaqMan and OpenArray technologies on 53 markers selected from 30 Crohn's disease associated genomic regions. We tested genotypes in a population of unrelated individual cases (n = 2,773) and controls (n = 2,215) of white European ancestry for association with AS. Statistical analysis was carried out using a Cochran-Armitage test for trend in PLINK. Strong association was detected at chr1q32 near KIF21B (rs11584383, P = 1.66 x 10-10, odds ratio (OR) = 0.74, 95% CI:0.68-0.82). Association with disease was also detected for 2 variants within STAT3 (rs6503695, P = 4.6×10-4. OR = 0.86 (95% CI:0.79-0.93); rs744166, P = 2.6×10-5, OR = 0.84 (95% CI:0.77-0.91)). Association was confirmed for IL23R (rs11465804, P = 1.2×10-5, OR = 0.65 (95% CI:0.54-0.79)), and further associations were detected for IL12B (rs10045431, P = 5.261025, OR = 0.83 (95% CI:0.76-0.91)), CDKAL1 (rs6908425, P = 1.1×10-4, OR = 0.82 (95% CI:0.74-0.91)), LRRK2/MUC19 (rs11175593, P = 9.9×10-5, OR = 1.92 (95% CI: 1.38-2.67)), and chr13q14 (rs3764147, P = 5.9×10-4, OR = 1.19 (95% CI: 1.08-1.31)). Excluding cases with clinical IBD did not significantly affect these findings. This study identifies chr1q32 and STAT3 as ankylosing spondylitis susceptibility loci. It also further confirms association for IL23R and detects suggestive association with another 4 loci. STAT3 is a key signaling molecule within the Th17 lymphocyte differentiation pathway and further enhances the case for a major role of this T-lymphocyte subset in ankylosing spondylitis. Finally these findings suggest common aetiopathogenic pathways for AS and Crohn's disease and further highlight the involvement of common risk variants across multiple diseases.

Evidence of genetic association between TNFRSF1A encoding the p55 tumour necrosis factor receptor, and ankylosing spondylitis in UK Caucasians

Objectives: To replicate the possible genetic association between ankylosing spondylitis (AS) and TNFRSF1A. Methods: TNFRSF1A was re-sequenced in 48 individuals with AS to identify novel polymorphisms. Nine single nucleotide polymorphisms (SNPs) in TNFRSF1A and 5 SNPs in the neighbouring gene SCNN1A were genotyped in 1604 UK Caucasian individuals with AS and 1019 matched controls. An extended study was implemented using additional genotype data on 8 of these SNPs from 1400 historical controls from the 1958 British Birth Cohort. A meta-analysis of previously published results was also undertaken. Results: One novel variant in intron 6 was identified but no new coding variants. No definite associations were seen in the initial study but in the extended study there were weak associations with rs4149576 (p=0.04) and rs4149577 (p=0.007). In the metaanalysis consistent, somewhat stronger associations were seen with rs4149577 (p=0.002) and rs4149578 (p=0.006). Conclusions: These studies confirm the weak genetic associations between AS and TNFRSF1A. In view of the previously reported associations of TNFRSF1A with AS, in Caucasians and Chinese, and the biological plausibility of this candidate gene, replication of this finding in well powered studies is clearly indicated.