Domain-structured N1,N2-derivatized hydrazines as inhibitors of ribonucleoside diphosphate reductase: redox-cycling considerations

Eight analogues of 1-[5-halogenosalicylidene]-2-[2'-pyridinoyl]hydrazine and -[2'-pyridyl]hydrazine, four of 1-[pyridoxylidene]-2-[2'-pyridinoyl]hydrazine, seven of 1-[pyridoxylidene]-2-[2'-pyridyl]hydrazine, and one each of 1, 2-bis[pyridoxylidene]diaminoethane and bis[pyridoxylidenehydrazino]phthalazine were synthesized. Their solutions in DMF were assayed for activity against the metalloenzyme ribonucleoside diphosphate reductase (RdR), prepared from a subcutaneously growing murine tumor (sarcoma 180) implanted in B6D2F3 male mice. The 14C-labeled CDP reductase was assayed by the modified method of Takeda and Weber, in which [14C]cytidine was separated from deoxycytidine by thin-layer chromatography (TLC) on cellulose foil. Distribution of radioactivity was assessed with an automatic TLC linear analyzer. Of the 31 compounds tested, 13 were essentially inactive, 7 were highly active against RdR, and the remaining 20 were slightly more active than hydroxyurea (used as a reference compound). The mechanism of inhibition is discussed in terms of three alternative pathways, initiated by sequestration of iron embedded in the R1 subunit of the metalloenzyme to form a C-centered chelate radical (via redox cycling). Alternatively, the latter could either reduce the tyrosyl radical or intercept radicals generated in the reduction process.     

Update on antitumor pharmacology: reality and perspectives in 1998]

Tubulointerstitial changes, characterized by the accumulation of extracellular matrix proteins (ECM) and fibrosis, are often associated with primary glomerular injury. Furthermore, these changes may be better prognostic indicators for decline in renal function than the anatomical changes seen within the glomerulus itself. Although hyperlipidemia and the increased renal accumulation of atherogenic lipoproteins are commonly seen in both human and experimental models of renal disease, the possible role that atherogenic lipoproteins may play in the cellular and molecular events associated with the development of tubulointerstitial injury remains unclear. Since atherogenic lipoproteins have been shown to be mediators of renal injury, we examined the effects of native LDL and oxidatively-modified LDL (ox-LDL, a more atherogenic form of LDL) on fibronectin protein synthesis and gene expression in proximal tubular epithelial cells (TEC). Human LDL was freshly isolated and ox-LDL prepared by incubation of LDL with 100 microM CuS04. Incubation of TEC with LDL or ox-LDL (25-50 micrograms/ml) for 24 h increased the steady-state mRNA expression of fibronectin by 16-135% over control as measured by Northern blot analysis and the effect was greater with ox-LDL than native LDL. Additional studies were done to examine whether the increased fibronectin message in response to lipoprotein activation was translated into TEC protein synthesis. The activation of TEC by LDL or ox-LDL stimulated the synthesis and secretion of fibronectin (52-150%, over control) as measured by Western blot analysis. The data show that LDL and ox-LDL stimulate TEC fibronectin gene message and protein synthesis supporting a pathobiological role for these atherogenic lipoproteins in tubulointerstitial fibrosis.     

The control of protein release from poly(DL-lactide co-glycolide) microparticles by variation of the external aqueous phase surfactant in the water-in oil-in water method

A unique feature of p21 that distinguishes it from the other cyclin-dependent kinase (CDK) inhibitors is its ability to associate with the proliferating cell nuclear antigen (PCNA), an auxiliary factor for DNA polymerases delta and epsilon. While it is now well established that inhibition of cyclin/CDK complexes by p21 can result in G1 cell cycle arrest, the consequences of p21/PCNA interaction on cell cycle progression have not yet been determined. Here, we show, using a tetracycline-regulated system, that expression of wild-type p21 in p53-deficient DLD1 human colon cancer cells inhibits DNA synthesis and causes G1 and G2 cell cycle arrest. Similar effects are observed in cells expressing p21CDK-, a mutant impaired in the interaction with CDKs, but not in cells expressing p21PCNA-, a mutant deficient for the interaction with PCNA. Analysis of cells treated with a p21-derived PCNA-binding peptide provides additional evidence that the growth inhibitory effects of p21 and p21CDK result from their ability to bind to PCNA. Our results suggest that p21 might inhibit cell cycle progression by two independent mechanisms, inhibition of cyclin/CDK complexes, and inhibition of PCNA function resulting in both G1 and G2 arrest.     

Caroli's disease with intrahepatic gall-stones and salmonella infection

At operation for small bowel intussusception, a 26-year-old man was found to have an enlarged liver and spleen. Subsequent investigations suggested bile passage infection associated with numerous intrahepatic gall-stones but symptomatic cholangitis did not present until 5 months later. Retrograde cholangiography showed cavernous ectasia of the bile ducts which contained gall-stones.     

Physician's working diagnosis compared to the Euricterus Real Life Data Diagnostic Tool Trial in three jaundice databases: Euricterus Dutch, independent prospective and independent retrospective

BACKGROUND/AIMS: In the European Union Euricterus Project on (sub)Icterus proforma, the history and physical examination items were to be used for the physician's working diagnosis (PWD) and 'among others, for the development of the real life data electronic diagnostic tool, Trial. Trial delivers diagnosis probabilities based on Bayes' Theorem (B), completed by Trial Algorithm (TA). We wanted to compare the diagnostic accuracies (PWD and Trial probabilities as a percentage of the final diagnosis (FD) in a patient population) in 3 Dutch databases. METHODOLOGY: The inclusion criteria for both Euricterus and Trial were age > or = 16 and bilirubin > or = 20 mmol/l. Euricterus data gathering took place at the bedside on a proforma with (among other questions) 79 questions on history and physical examination as well as the diagnosis levels for the PWD (1 alternative possible) and FD (17 disease categories, dc). Trial was developed on the data of 7,104 Euricterus patients and its data-entry Demo has the same questions. It calculates the probability of each diagnosis of the 17 dc as a percentage, as each significant finding is encountered (BO, Bayesian Overall). It can simultaneously calculate the resemblance of the patient's signs and symptoms to each disease concomitantly (BV, Bayesian Vertical), and to any subset of a disease. Any probability is further tested for compatibility using TA, a subset of BV, delivering TA-PWD, TA-BO and TA-BV. The Trial test patients came from 3 databases: a Euricterus Dutch Patients Random Sample EDRS (n = 184, internal database) and 2 independent databases: prospective P (n = 80) and retrospective R (n = 152), totalling 416 patients. RESULTS: The accuracies of PWD and Trial showed no differences between the databases, and the results are therefore pooled (n = 416). With testing on the highest probability found, the PWD accuracy was 78%, TA-PWD 81%, TA-BO 74% and TA-BV 72%. The true FD's were mentioned (at any probability) in the PWD in 86%, TA-PWD in 92%, TA-BO in 94% and TA-BV in 91% of the patients. Testing only patients whose FD was "certain" or whose data were without omissions did not improve accuracy. Testing on probability > 95% improved BO and BV accuracy, but not TA-BO or TA-BV. CONCLUSIONS: The Physician's Working Diagnosis accuracy was approximately 80% and did not greatly improve after TA. The Trial TA-BO and TA-BV accuracies were only slightly less than the PWD. For well-trained physicians, Trial strengthens the physician's judgment, and for those less trained (or those to be trained), it delivers a (sub)icterus diagnostic disease probability at nearly consultant level.     

Mechanical and elastic properties of transparent nanocrystalline TeO2-based glass-ceramics

Mechanical and elastic properties of transparent TeO₂-based glass-ceramics (15K₂O · 15Nb₂O₅ · 70TeO₂) consisting of nanocrystalline particles (each particle size: 40–50 nm) and showing optical second harmonic generation were evaluated by means of usual Vickers indentation and nanoindentation tests. The precursor glass has Vickers hardness H _v of 2.9 GPa, Young's modulus E of 54.7 GPa, the fracture toughness K _c of 0.25 MPam^1/2 and Poisson's ratio of 0.24. The transparent nanocrystalline glass-ceramic heat-treated at 420°C for 1 h has H _v = 3.8 GPa, E = 75.9 GPa and K _c = 0.34 MPam^1/2, and the opaque glass-ceramic heat-treated at 475°C for 1 h has H _v = 4.5 GPa, E = 82.9 GPa and K _c = 0.68 MPam^1/2, demonstrating that poor mechanical and elastic properties of the precursor TeO₂-based glass are improved through sufficient crystallization. The fracture surface energy, brittleness and elastic recoveries (about 44%) after unloading (the maximum load: 30 mN) of transparent nanocrystalline glass-ceramics are almost the same as those of the precursor glass, implying that the interaction among nanocrystalline particles is not so strong.     

Primary biliary cirrhosis: an electronic diagnostic tool trial based on symptoms, (past) history and signs only, using the European database euricterus. The Euricterus PMG

BACKGROUND/AIMS: Primary Biliary Cirrhosis (PBC) is a relatively rare chronic progressive disease in which a working diagnosis of PBC easily leads to a final diagnosis by testing for anti-mitochondrial antibodies. Liver transplantation is the only effective treatment. The aim of this study was to test an electronic diagnostic tool (tool) for it's ability to include PBC in the working differential diagnosis. METHODOLOGY: In the European Union Euricterus project a large number of (sub)icteric patients in 17 discrete disease categories, PBC being one of them, were gathered prospectively. A tool was developed-using Bayes (B) and Trial Algorithm (TA) pattern-recognition and based on items related to the history, symptoms and signs of all Euricterus patients. We have tested the diagnostic tool on 143 PBC Euricterus patients. RESULTS: PBC was mentioned by the tool in 86% (B) and 91% (TA) of the 143 patients. These figures were higher for patients under 60 and (TA only) females. Females under 60 (n = 89) scored 92% B and 96% TA. A sole diagnosis of PBC was made in 31% (B) and 66% (TA). In the other patients with a PBC probability, 7 other (first) diagnoses were presented by the tool of which non-alcoholic active liver disease and pancreatic or biliary carcinoma were the leaders. These 7 diseases appeared evenly distributed along the percentual probabilities of PBC given by the tool (B) and also along Pugh and Mayo scores (B and TA). PBC was mentioned by the tool in all patients with a Pugh score 10 or higher (advanced disease, class C). In the patients in whom the tool did not mention PBC, the primary diagnoses came from 9 other disease categories. CONCLUSION: This electronic tool has been able to identify PBC as one of the differential diagnostic modalities in the large majority of a present population of PBC patients.     

A method for the incorporation of parametric uncertainty in the weighted evaluation multi-attribute decision analysis model

We develop an extension of the classic Weighted Evaluation (WE) Multi-Attribute Decision Analysis (MADA) model that allows for uncertainty in the parameters of the model. Uncertainties in attribute importance weights and alternative evaluation ratings are represented by independent uniform, triangular or beta random variables; and an iterative multi-variate integration scheme is used to evaluate the mean, variance and skewness of the resulting Probabilistic Weighted Evaluation (PWE). These moments are used to compute two-term Edgeworth and normal approximations to the distribution of: (a) the PWE for each of several alternatives that are to be analysed separately; or (b) the difference between PWEs for selected alternatives that are to be analysed on a pairwise basis. The proposed methodology is used to compare probabilistically three alternative solutions to the Mexico City Airport Siting Problem of Keeney and Raiffa (Keeney, R. L. and Raiffa, H., Decisions with Multiple Objectives. Wiley, New York, 1976).     

Domestic cooking and food skills: A review

Domestic cooking skills (CS) and food skills (FS) encompass multiple components, yet there is a lack of consensus on their constituent parts, inter-relatedness, or measurement, leading to limited empirical support for their role in influencing dietary quality. This review assessed the measurement of CS and FS in adults (>16 years); critically examining study designs, psychometric properties of measures, theoretical basis, and associations of CS/FS with diet. Electronic databases (PsychInfo), published reports, and systematic reviews on cooking and home food preparation interventions provided 834 articles of which 26 met the inclusion criteria. Multiple CS/FS measures were identified across three study designs—qualitative, cross-sectional, and dietary interventions—conducted from 1998 to 2013. Most measures were not theory-based, limited psychometric data were available, with little consistency of items or scales used for CS/FS measurements. Some positive associations between CS/FS and fruit and vegetables intake were reported, though lasting dietary changes were uncommon. The role of psycho-social (e.g., gender, attitudes) and external factors (e.g., food availability) on CS/FS is discussed. A conceptual framework of CS/FS components is presented for future measurement facilitation, which highlights the role for CS/FS on food-related behavior and dietary quality. This will aid future dietary intervention design.