Acceleration of atherogenesis by COX-1-dependent prostanoid formation in low density lipoprotein receptor knockout mice

The cyclooxygenase (COX) product, prostacyclin (PGI2), inhibits platelet activation and vascular smooth-muscle cell migration and proliferation. Biochemically selective inhibition of COX-2 reduces PGI2 biosynthesis substantially in humans. Because deletion of the PGI2 receptor accelerates atherogenesis in the fat-fed low density lipoprotein receptor knockout mouse, we wished to determine whether selective inhibition of COX-2 would accelerate atherogenesis in this model. To address this hypothesis, we used dosing with nimesulide, which inhibited COX-2 ex vivo, depressed urinary 2,3 dinor 6-keto PGF1α by approximately 60% but had no effect on thromboxane formation by platelets, which only express COX-1. By contrast, the isoform nonspecific inhibitor, indomethacin, suppressed platelet function and thromboxane formation ex vivo and in vivo, coincident with effects on PGI2 biosynthesis indistinguishable from nimesulide. Indomethacin reduced the extent of atherosclerosis by 55 ± 4%, whereas nimesulide failed to increase the rate of atherogenesis. Despite their divergent effects on atherogenesis, both drugs depressed two indices of systemic inflammation, soluble intracellular adhesion molecule-1, and monocyte chemoattractant protein-1 to a similar but incomplete degree. Neither drug altered serum lipids and the marked increase in vascular expression of COX-2 during atherogenesis. Accelerated progression of atherosclerosis is unlikely during chronic intake of specific COX-2 inhibitors. Furthermore, evidence that COX-1-derived prostanoids contribute to atherogenesis suggests that controlled evaluation of the effects of nonsteroidal anti-inflammatory drugs and/or aspirin on plaque progression in humans is timely.

Long term trends in the evolution of H(3) HA1 human influenza type A

We have studied the HA1 domain of 254 human influenza A(H3N2) virus genes for clues that might help identify characteristics of hemagglutinins (HAs) of circulating strains that are predictive of that strain’s epidemic potential. Our preliminary findings include the following. (i) The most parsimonious tree found requires 1,260 substitutions of which 712 are silent and 548 are replacement substitutions. (ii) The HA1 portion of the HA gene is evolving at a rate of 5.7 nucleotide substitutions/year or 5.7 × 10−3 substitutions/site per year. (iii) The replacement substitutions are distributed randomly across the three positions of the codon when allowance is made for the number of ways each codon can change the encoded amino acid. (iv) The replacement substitutions are not distributed randomly over the branches of the tree, there being 2.2 times more changes per tip branch than for non-tip branches. This result is independent of how the virus was amplified (egg grown or kidney cell grown) prior to sequencing or if sequencing was carried out directly on the original clinical specimen by PCR. (v) These excess changes on the tip branches are probably the result of a bias in the choice of strains to sequence and the detection of deleterious mutations that had not yet been removed by negative selection. (vi) There are six hypervariable codons accumulating replacement substitutions at an average rate that is 7.2 times that of the other varied codons. (vii) The number of variable codons in the trunk branches (the winners of the competitive race against the immune system) is 47 ± 5, significantly fewer than in the twigs (90 ± 7), which in turn is significantly fewer variable codons than in tip branches (175 ± 8). (viii) A minimum of one of every 12 branches has nodes at opposite ends representing viruses that reside on different continents. This is, however, no more than would be expected if one were to randomly reassign the continent of origin of the isolates. (ix) Of 99 codons with at least four mutations, 31 have ratios of non-silent to silent changes with probabilities less than 0.05 of occurring by chance, and 14 of those have probabilities <0.005. These observations strongly support positive Darwinian selection. We suggest that the small number of variable positions along the successful trunk lineage, together with knowledge of the codons that have shown positive selection, may provide clues that permit an improved prediction of which strains will cause epidemics and therefore should be used for vaccine production.

Construction of 17-19th century domes in the province of Alicante (Spain): the case of San Juan Bautista in Cox

From the late seventeenth to early nineteenth centuries, many religious temples have been built in the province of Alicante (south east of Spain) with brick domes as their main characteristic feature. Often, the limited data available about these remarkable constructions make rehabilitation interventions become into real research projects, with a high value for their historic conservation over time. The aim of this paper is to show a detailed refurbishment analysis of a religious temple built in 1778, showing the need of preservation of historic buildings as a part of the architectural heritage by establishing a common pattern of materials, geometry and constructive systems, specifically in their domes. In most cases, there was not an architectural project for the construction, that is why the analysis of any documentary and archival sources available is essential to find different ways to proceed on the use and maintenance of these religious buildings.

The Englishwoman in Egypt : letters from Cairo, written during residence there in 1842, 3 and 4, with E.W. Lane /

Disbound Original Held in Oak Street Library Facility.

Reports of deputations : who, in pursuance of resolutions of the Court of Assistants of the Drapers' Company, of Jan. 23, 1817; Aug. 3, 1818; Aug. 2, 1819; Aug. 7, 1820; April 7, 1827; July 12, 1832; & May 2, 1839; visited the estates of the company, in the County of Londonderry, in Ireland, in those years, and which were ordered by the Court to be printed for the use of its members..

Includes index.

Genomewide Linkage Scan of 409 European-ancestry and African American Families with Schizophrenia: Suggestive Evidence of Linkage at 8p23.3-p21.2 and 11p13.1-q14.1 in the Combined Sample

We report the clinical characteristics of a schizophrenia sample of 409 pedigrees-263 of European ancestry ( EA) and 146 of African American ancestry ( AA)-together with the results of a genome scan ( with a simple tandem repeat polymorphism interval of 9 cM) and follow-up fine mapping. A family was required to have a proband with schizophrenia ( SZ) and one or more siblings of the proband with SZ or schizoaffective disorder. Linkage analyses included 403 independent full-sibling affected sibling pairs ( ASPs) ( 279 EA and 124 AA) and 100 all-possible half-sibling ASPs ( 15 EA and 85 AA). Nonparametric multipoint linkage analysis of all families detected two regions with suggestive evidence of linkage at 8p23.3-q12 and 11p11.2-q22.3 ( empirical Z likelihood-ratio score [ Z(lr)] threshold >= 2.65) and, in exploratory analyses, two other regions at 4p16.1-p15.32 in AA families and at 5p14.3-q11.2 in EA families. The most significant linkage peak was in chromosome 8p; its signal was mainly driven by the EA families. Z(lr) scores >= 2.0 in 8p were observed from 30.7 cM to 61.7 cM ( Center for Inherited Disease Research map locations). The maximum evidence in the full sample was a multipoint Z(lr) of 3.25 ( equivalent Kong-Cox LOD of 2.30) near D8S1771 ( at 52 cM); there appeared to be two peaks, both telomeric to neuregulin 1 ( NRG1). There is a paracentric inversion common in EA individuals within this region, the effect of which on the linkage evidence remains unknown in this and in other previously analyzed samples. Fine mapping of 8p did not significantly alter the significance or length of the peak. We also performed fine mapping of 4p16.3-p15.2, 5p15.2-q13.3, 10p15.3-p14, 10q25.3-q26.3, and 11p13-q23.3. The highest increase in Z(lr) scores was observed for 5p14.1-q12.1, where the maximum Z(lr) increased from 2.77 initially to 3.80 after fine mapping in the EA families.

A combinatorial approach to the chemical synthesis and biological evaluation of 3,4,5-trisubstiituted furan-2(5H)-ones

Many important natural products contain the furan-2(5H)-one structure. The structure of this molecule lends itself to manipulation using combinatorial techniques due to the presence of more than one site for the attachment of different suhstituents. By developing different reaction schemes at the three sites available for attachment on the furan-2(5H)-one scaffold, combinatorial chemistry techniques can be employed to assemble libraries of novel furan 2(5H)-ones. These libraries can then be entered into various biological screening programmes. This approach will enable a vast diversity or compounds to be examined, in the hope or finding new biologically active Iead structures. The work in this thesis has investigated the potential that combinatorial chemistry has in the quest for new biologically active lead structures based on the furan-2(5H)-one structure. Different reactions were investigated with respect to their suitability for inclusion in a library. Once sets of reactions at the various sites had been established, the viability of these reactions in the assembly of combinatorial libraries was investigated. Purification methods were developed, and the purified products entered into suitable biological screening tests. Results from some of these tests were optimised using structure activity relationships, and the resulting products re-screened. The screening tests performed were for anticancer and antimicrobial activity, cholecystokinin (CCK-B) antagonism and anti-inflammatory activity (in the quest for novel cyclo-oxygenase (COX-2) selective non-steroidal anti-inflammatory drugs). It has been shown that many reactions undergone by the furan-2(5H)-one structure are suitable for the assembly of a combinatorial library. Investigation into the assembly of different libraries has been carried out with initial screening results included. From this work, further investigation into combinatorial library assembly and structure activity relationships of screened reaction products can be undertaken.

A diszkrét kiválasztási modell becslése Cox-regresszióval (Parameter estimation for multinomial discrete choice model using Cox-regression)

Considering the so-called "multinomial discrete choice" model the focus of this paper is on the estimation problem of the parameters. Especially, the basic question arises how to carry out the point and interval estimation of the parameters when the model is mixed i.e. includes both individual and choice-specific explanatory variables while a standard MDC computer program is not available for use. The basic idea behind the solution is the use of the Cox-proportional hazards method of survival analysis which is available in any standard statistical package and provided a data structure satisfying certain special requirements it yields the MDC solutions desired. The paper describes the features of the data set to be analysed.

Queilite actínica: expressão imuno-histoquímica da cox-2 e avaliação do diclofenaco sódico gel como uma terapia alternativa

Actinic cheilitis (AC) is a potentially malignant disorder which affects the lip vermilion and results from chronic exposure to sunlight. Currently, it is not possible to predict which cases of AC may progress to squamous cell carcinoma, and therefore, some biomolecular markers have been researched. Cyclooxygenase 2 (COX-2) is an enzyme associated with inflammatory response which is overexpressed in oral cancer; however, little is known about the role of this protein in actinic cheilitis. About the treatment of this lesion, currently available therapeutic modalities to AC may cause cytotoxic effects and deleterious results to patients. Therefore, the aim of this study was to evaluate the immunoexpression of COX-2 in AC of different risks of malignant transformation and analyse, through clinical follow-up, the efficacy of diclofenac sodium 3% gel in the treatment of this condition. Epithelial immunoexpression of COX-2 was analysed semi-quantitatively in 90 cases of AC classified as low risk (n = 55) and high risk (n = 35) of malignant transformation, in which the scores were assigned: (0) 0 to 5% of positive cells - Negative; (1) 6 to 30% of positive cells - Low expression; (2) 31 to 100% of positive cells - High expression. The chi-square test of Pearson was conducted to verify possible associations between immunoexpression of COX-2 and histologic grade of actinic cheilitis. The weighted kappa coefficient denoted a good interobserver agreement (0.677). Nineteen patients diagnosed with AC were instructed to perform topical application of the gel three times a day for a period of 90 days. In each biweekly visit, a follow-up record was accomplished through digital photographs and after treatment was completed, two researchers analysed all the images to assess clinical aspects of the lip. Furthermore, tolerability to the drug and patient satisfaction after treatment were evaluated. COX-2 was overexpressed in 74.4% of AC cases. Both low and high-risk groups revealed predominance of score 3, followed by scores 2 and 1. There was no significant association (p = 0.315) between COX-2 expression and histological grading. Among the total number of participants of this clinical study, ten showed total remission of all clinical features of the lesion and three had partial improvement of these characteristics. One participant presented worsening of the clinical condition. In five cases, the treatment was discontinued due to development of mild adverse effects at the site of gel application. Regarding analysis of satisfaction and tolerability to the drug, most patients were fully satisfied with the therapy (n = 11) and reported that the drug was not irritating to the lips (n = 9). Our study demonstrates that high expression of COX-2 is common in AC; however, this protein was not associated with malignant transformation risk of the analysed cases. Topical application of diclofenac sodium 3% gel provided a convenient and well tolerated approach in most cases, and may be a promising alternative for the treatment of actinic cheilitis.

Effets d'une diète riche en oméga-3 sur l'infarctus du myocarde chez le rat

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Effets d'une diète riche en oméga-3 sur l'infarctus du myocarde chez le rat

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Quantificação de riscos climáticos via modelos de regressão de Cox.

O gerenciamento de riscos climáticos requer informação sobre estados futuros de variáveis climáticas, geralmente representada por funções de distribuição de probabilidade acumulada (FDPA, P(Y?y) ou por sua funções complementares (P(Y>y)), ditas funções probabilidade de exceder (FPE). Uma variedade de métodos estatísticos tem sido utilizada para estimação de FPE, incluindo, modelos de regressão linear múltipla, regressão logística e métodos não paramétricos (MAIA et al, 2007; LO et al, 2008). Apesar de parecer intuitivo que a incerteza associada às estimativas das FPE é fundamental para os tomadores de decisão, esse tipo de informação raramente é fornecido. Modelos estatísticos de previsão baseados em séries históricas da variável de interesse (chuva, temperatura) e de preditores derivados de estados do oceano e da atmosfera (índices climáticos tais como: temperaturas da superfície do mar ? TSM, índice de oscilação sul, IOS, El Nino/Oscilação Sul - ENSO) se constituem em alternativas promissoras para auxílio às tomada de decisão, em escalas locais e regionais. O uso de tais indicadores permite incorporar mudanças de padrão derivadas de mudanças climáticas em modelos estatísticos que utilizam informação histórica. Neste trabalho, mostramos como o Modelo de Regressão de Cox (MRC; COX, 1972), tradicionalmente utilizado para modelagem de tempos de falha, em investigações na área médica e em ciências sociais, pode ser de grande utilidade para avaliação probabilística de riscos climáticos, mesmo para variáveis que não representam tempos de falha tais como chuva, produtividade de culturas, lucros, entre outras. O MRC pode ser utilizado para avaliar a influência de preditores (índices climáticos) sobre riscos de interesse (representados pelas FPE), estimar FPE para combinações específicas de preditores e incertezas associadas além de fornecer informação sobre riscos relativos, de grande valor para tomadores de decisão. Apresentamos dois estudos de caso nos quais o Modelo de Cox foi usado para investigar: a) o efeito do IOS e de um índice derivado de TSM do Pacífico sobre o início da estação chuvosa em Cairns (Austrália) e b) a influência o índice Nino 3.4, derivado de estados da TSM no Pacífico Equatorial sobre o chuva acumulada no período de Março a Junho em Limoeiro do Norte (Ceará, Brasil). O objetivo da apresentação desses estudos é meramente didático, para demonstrar o potencial do método proposto como ferramenta de auxílio à tomada de decisão.