Increased formation of distinct F2 isoprostanes in hypercholesterolemia

BACKGROUND: F2 isoprostanes are stable, free radical-catalyzed products of arachidonic acid that reflect lipid peroxidation in vivo. METHODS AND RESULTS: Specific assays were developed by use of mass spectrometry for the F2 isoprostanes iPF2alpha-III and iPF2alpha-VI and arachidonic acid (AA). Urinary excretion of the 2 F2 isoprostanes was significantly increased in hypercholesterolemic patients, whereas substrate AA in urine did not differ between the groups. iPF2alpha-III (pmol/mmol creatinine) was elevated (P<0.0005) in homozygous familial hypercholesterolemic (HFH) patients (85+/-5. 5; n=38) compared with age- and sex-matched normocholesterolemic control subjects (58+/-4.2; n=38), as were levels of iPF2alpha-VI (281+/-22 versus 175+/-13; P<0.0005). Serum cholesterol correlated with urinary iPF2alpha-III (r=0.41; P<0.02) and iPF2alpha-VI (r=0. 39; P<0.03) in HFH patients. Urinary excretion of iPF2alpha-III (81+/-10 versus 59+/-4; P<0.05) and iPF2alpha-VI (195+/-18 versus 149+/-20; P<0.05) was also increased in moderately hypercholesterolemic subjects (n=24) compared with their controls. Urinary excretion of iPF2alpha-III and iPF2alpha-VI was correlated (r=0.57; P<0.0001; n=106). LDL iPF2alpha-III levels (ng/mg arachidonate) were elevated (P<0.01) in HFH patients (0.32+/-0.08) compared with controls (0.09+/-0.02). The concentrations of iPF2-III in LDL and urine were significantly correlated (r=0.42; P<0.05) in HFH patients. CONCLUSIONS: Asymptomatic patients with moderate and severe hypercholesterolemia have evidence of oxidant stress in vivo.     

Arthrodesis of the shoulder for synovial osteochondromatosis

OBJECTIVES: To identify the reasons for non-compliance with fecal occultblood test in the screening programme for colorectal cancer. DESIGN AND SETTING: The people who had never participated in the screening programme for colorectal cancer served as the subjects of this study. A structured questionnaire which included the reasons for rejection was sent to each of non-compliers. They were requested to choose two major reasons which were described in a best way that why they did not participate in the programme. The frequency of the stated reasons were analysed from the viewpoint of both sex and age effects. MAIN RESULTS:A total of 439 people was identified as non-compliers, and 356 (81.1%) people completed the questionnaire. No significant difference was noted in response to the questionnaire between male and female as well as aged 40-59 and those 60-79. The most commonest reason was felt well (47.8%) in male, fear or shyness of further examination (40.2%) in female, and also felt well (48.5%) in aged 40-59, fear or shyness of further examination (40.1%) in aged 60-79. Significant differences were observed in the frequencies of felt well (p<0.01), fear or shyness of further examination (p<0. 01), busy for work (p<0.01) and fear of cancer (p<0.01) between male and female, and also felt well (p<0.01), fear or shyness of further examination (p<0.01), busy for work (p<0.01) and coexistent disease (p<0.01) between aged 40-59 and those 60-79. CONCLUSIONS: These results suggest that public education about the concept of asymptomatic illness, the benefits of early detection, the safety and painless colonoscopy, and the effective treatment should be emphasised to increase compliance with screening for fecal occult blood.     

Chromosomal duplication accompanies allelic loss in non-small cell lung carcinoma

Hemizygous deletion in the short (p) arm of chromosome 3 is a common finding in non-small cell lung carcinoma (NSCLC) and is postulated to be a crucial early change in lung tumorigenesis. Yet one of the most frequent nuclear abnormalities in both NSCLC and premalignant bronchial epithelium is increase in chromosomal copy number. Deletion and duplication have not been assessed in the same tumor set by both molecular and cytogenetic methods to determine whether allelic loss correlates with chromosomal duplication in the same tumor cell populations. It is also not established what biological mechanisms might lead to allelic deletion and chromosomal duplication. We have investigated changes in the copy number of chromosome 3 in touch preparations of 38 NSCLCs (19 adenocarcinomas and 19 squamous cell carcinomas) using dual-target, dual-color fluorescence in situ hybridization (FISH) assays. Chromosome 3 centromere probe was matched with a 3p14.2 probe [intron 4 of the fragile histidine triad (FHIT) gene] and a 3p21.31 probe (HSemaIV gene). We then correlated FISH results with results of molecular analyses for allelic losses at loci in the regions to which the FISH probes mapped in 20 of these cases. Although various combinations of FISH abnormalities were sometimes detected within the same specimens, individual cases could be classified according to the predominant FISH pattern, usually with one abnormality present in >60% of tumor cells. Chromosomal duplication, indicated by the presence of more than two centromeric signals, was the most frequent abnormality observed by FISH and was accompanied by loss of specific sequences on 3p in approximately one-half of the specimens in which it was observed. The most frequent abnormality observed by molecular analysis was loss of heterozygosity (LOH) in both of the chromosomal regions tested and was demonstrated in 83% of cases with chromosomal duplication. We conclude that LOH may occur in the presence of chromosomal duplication, suggesting that the duplicated chromosome is homozygous. Our findings imply that LOH occurs before chromosomal duplication during lung carcinogenesis.     

Effect of phenylglyoxal-modified alpha2-antiplasmin on urokinase-induced fibrinolysis

1. In this study the mechanisms of the acute vasodilator action of bacterial lipopolysaccharide (LPS) were investigated in the rat Langendorff perfused heart. 2. Infusion of LPS (5 microg ml(-1)) caused a rapid and sustained fall in coronary perfusion pressure (PP) of 59 +/- 4 mmHg (n = 12) and a biphasic increase in NO levels determined in the coronary effluent by chemiluminescent detection. Both the fall in PP and the increase in NO release were completely abolished (n = 3) by pretreatment of hearts with the NO synthase inhibitor L-NAME (50 microM). 3. LPS-induced vasodilatation was markedly attenuated to 5 +/- 4 mmHg (n 3) by pretreatment of hearts with the B2 kinin receptor antagonist Hoe-140 (100 nM). 4. Vasodilator responses to LPS were also blocked by brief pretreatment with mepacrine (0.5 microM, n = 3) or nordihydroguaiaretic acid (0.1 microM, n = 4) and markedly attenuated by WEB 2086 (3 microM, n = 4). 5. Thirty minutes pretreatment of hearts with dexamethasone (1 nM), but not progesterone (1 microM), significantly modified responses to LPS. The action of dexamethasone was time-dependent, having no effect when applied either simultaneously with or pre-perfused for 5 min before the administration of LPS but inhibiting the response to LPS by 91 +/- 1% (n = 4) when pre-perfused for 15 min. The inhibition caused by dexamethasone was blocked by 15 min pretreatment with the glucocorticoid receptor antagonist RU-486 (100 nM) or by 2 min pre-perfusion of a 1:200 dilution of LCPS1, a selective antilipocortin 1 (LC1) neutralizing antibody. 6. Treatment with the protein synthesis inhibitor, cycloheximide (10 microM, for 15 min) selectively blunted LPS-induced vasodilatation, reducing the latter to 3 +/- 5 mmHg (n = 3), while having no effect on vasodilator responses to either bradykinin or sodium nitroprusside. 7. These results indicate that LPS-induced vasodilatation in the rat heart is dependent on activation of kinin B2 receptors and synthesis of NO. In addition, phospholipase A2 (PLA2) is activated by LPS resulting in the release of platelet-activating factor (PAF) and lipoxygenase but not cyclo-oxygenase products. These effects are dependent on de novo synthesis of an intermediate protein which remains to be identified.     

Lagging-strand, early-labelling, and two-dimensional gel assays suggest multiple potential initiation sites in the Chinese hamster dihydrofolate reductase origin

5-Acetoxyacetylimino-4-methyl-delta2-1,3,4,-thiadiazoline -2-sulfonamide (compound (1)) is an ester prodrug that lowered intraocular pressure (IOP) in albino New Zealand rabbits, but was found to be inactive in pigmented Dutch Belt rabbits. In order to explain the differences in pharmacological activity for the two rabbit species, metabolism and melanin binding were studied. Depending on the initial concentration, the binding of compound (1) to natural melanin (Sepia officinalis) was 20-60%. The binding constant, K, at 37 degrees C was 4.32 x 10(5) M(-1) and the maximum moles bound to melanin, r(max), was 4.5 x 10(-7) mol/mg of melanin. From a determination of binding at temperatures between 25 degrees C and 47 degrees C, a van't Hoff plot was constructed to determine enthalpy and entropy changes accompanying the binding process, deltaH and deltaS, respectively. Values calculated from the plot were -12.7 and -15.4 kcal/(mol deg), respectively. Negative values for these parameters are consistent with charge transfer interactions and therefore suggest that this may be an operative mechanism between compound (1) and melanin. The in vitro incubation of compound (1) was also studied with various ocular tissues from both albino and pigmented rabbits which were iris-ciliary body, intact cornea, stroma/endothelium and aqueous humor. A major metabolite, MET 1, was identified and also observed from in vivo analyses of the same tissues following topical application. The metabolite was isolated and subjected to mass spectroscopy and proton nuclear magnetic resonance spectroscopy analysis. From these analyses, it was hypothesized that the formation of MET 1 involved a GSH conjugation mechanism which displaced the sufonamide (-SO2NH2) group. The metabolism was found to be less extensive in the pigmented rabbit than in the albino rabbit and suggested that the binding affinity of compound (1) for melanin was a better explanation for the lack of IOP activity in the pigmented rabbit than differences in metabolism.     

Intervention with PTCA and CABG following thrombolysis for acute myocardial infarction. Australian data from GUSTO 1 (1991-3) and International Study Group r-TPA-Streptokinase Mortality (1989) trials. Global Utilisation of Streptokinase and Tissue

Genotoxic stress triggers signalling pathways that either mediate cell killing or protection of affected cells. While induction of p53 is observed for most of the genotoxins, activation of MAPK/SAPK cascades is not a general response. The role of MAPK/SAPK activation on cell fate, seems to be dependent, in some systems, on the balanced response among both cascades. We have here examined the effect of cis and trans-DDP on the activation of ERK and JNK activities. While no significant induction of ERK was observed with the compounds, both of them are able to strongly activate JNK. Trans-DDP response is rapid and transient while the cis-DDP one is slow and persistent. In contrast with the observed nuclear translocation of JNK in response to U.V. light, none of the platinum compounds induces translocation, on the contrary, activation of JNK occurs in both the nuclear and cytoplasmic compartments. Inhibition of tyrosine phosphatases by orthovanadate pretreatment prolongs the time of JNK induction in response to both platinum compounds. The positive modulation of JNK activation correlates with an increase in toxicity that, for cis-DDP corresponds to a tenfold decrease in the IC50. A strong increase in MKP-1 levels was observed only in response to trans-DDP suggesting the involvement of this activity in the downregulation of JNK activity in response to this compound. Altogether the results suggest that the prolonged activation of JNK in response to cis-DDP contributes to cell death induction.     

Pathogenic mechanisms in the rheumatoid nodule: comparison of proinflammatory cytokine production and cell adhesion molecule expression in rheumatoid nodules and synovial membranes from the same patient

OBJECTIVE: To investigate the production of proinflammatory cytokines and expression of cell adhesion molecules in the rheumatoid nodule. METHODS: Cytokine content (tumor necrosis factor alpha [TNFalpha], interleukin-1beta [IL-1beta], and IL-1 receptor antagonist [IL-1Ra]), at the messenger RNA (mRNA) and protein levels, and cell adhesion molecule expression were studied in 16 rheumatoid nodules and 6 synovial membranes. RESULTS: Macrophages in the rheumatoid nodules contained TNFalpha, IL-1beta, and IL-1Ra mRNA and protein, particularly in perivascular cells of the stroma and in the palisading layer. All cell adhesion molecules studied were expressed in both the rheumatoid nodules and synovial membranes, with increased expression of E-selectin in the rheumatoid nodule compared with the synovial membrane, and with the absence of vascular cell adhesion molecule 1 expression on cells of the palisading layer in the rheumatoid nodule. CONCLUSION: The presence of similar proinflammatory cytokines and cell adhesion molecules in the rheumatoid nodule and synovial membrane suggests that similar pathogenic processes result in the chronic inflammation and tissue destruction in these lesions.     

Zoonoses and potential zoonoses transmitted by bats

PURPOSE: The purpose of this study was to develop an analytical method for the quantitative determination of the extent of neutralization of the carboxylic acid function in Carbopol 974P NF using Diffuse Reflectance Fourier Transform Infrared Spectroscopy (DRIFT) with Kubelka-Munk function analysis. METHODS: Carbopol 974P NF is a high molecular weight, chemically crosslinked polymer of acrylic acid, that has the C=O stretching band of the unionized carboxylic acid function at 1695 cm(-1). The quantitative determination of the extent of neutralization of the carboxylic acid function in Carbopol 974P NF is based upon the asymmetrical C=O stretching of the carboxylate anion at 1570 cm(-1) measured by DRIFT spectroscopy. RESULTS: To overcome spectral differences arising from sample preparation (powders, granules and tablets) and in an effort to increase the precision of the analytical method, the following approaches were used: (1) an internal standard, (2) first derivative of the spectrum to eliminate the effect of baseline drift and (3) the ratio of the first derivative of the C=O stretch of the carboxylate anion peak (1570 cm(-1)) in the neutralized Carbopol 974P NF to that of the peak of the internal standard (866 cm(-1)). The above data treatment techniques proved to be superior to the usual methods of peak height or peak area. The calibration curve of the ratio of the first derivative (1570 cm(-1)/866 cm(-1)) was a linear function of the mass of sodium carboxylate over the range from 0.0% to 100.0% neutralization of the carboxylic acid function in Carbopol 974P NF (Fig. 1a). No particle size or sample preparation effects were noted within the experimental error. CONCLUSIONS: DRIFT spectroscopy using the Kubelka-Munk function is a powerful tool for the routine determination of the extent of neutralization of the carboxylic acid function in Carbopol 974P NF in complex pharmaceutical formulations.     

Four practical and conceptual assessment issues that evaluators should address in capital case mental retardation evaluations.

What unique assessment issues do evaluators face when conducting mental retardation evaluations in capital cases? This article describes 4 assessment issues and reports how 20 evaluators in 1 state have approached them: (a) What methods are appropriate for evaluating adaptive functioning in this context? (b) Should information about criminal behavior be used as evidence of adaptive functioning? (c) Should correctional officers serve as informants regarding adaptive behavior? and (d) How should the Flynn effect influence the interpretation of intelligence test scores? Implications for practice are that practitioners should expect to be asked about the relation between criminal behavior and adaptive functioning, must think carefully about the validity of tests of adaptive functioning for inmates, and must be knowledgeable about the current state of Flynn effect research. (PsycINFO Database Record (c) 2010 APA, all rights reserved)