Influence of Deep Margin Elevation and preparation design on the fracture strength of indirectly restored molars.

The objectives of this in-vitro study were to investigate the influence of Deep Margin Elevation (DME) and the preparation design (cusp coverage) on the fracture strength and repairability of CAD/CAM manufactured lithium disilicate (LS2) restorations on molars. Sound extracted human molars (n = 60) were randomly divided into 4 groups (n = 15) (inlay without DME (InoD); inlay with DME (IWD); onlay without DME (OnoD); onlay with DME (OnWD)). All samples were aged (1.2 × 106 cycles of 50N, 8000 cycles of 5-55 °C) followed by oblique static loading until fracture. Fracture strength was measured in Newton and the fracture analysis was performed using a (scanning electron) microscope. Data was statistically analyzed using two-way ANOVA and contingency tables. DME did not affect the fracture strength of LS2 restorations to a statistically significant level (p = .15). Onlays were stronger compared to inlays (p = .00). DME and preparation design did not interact (p = .97). However, onlays with DME were significantly stronger than inlays without DME (p = .00). More repairable fractures were observed among inlays (p = .00). Catastrophic, crown-root fractures were more prevalent in onlays (p = .00). DME did not influence repairability of fractures or fracture types to a statistically significant level (p > .05). Within the limitations of this in-vitro study, DME did not statistical significantly affect the fracture strength, nor the fracture type or repairability of LS2 restorations in molars. Cusp coverage did increase the fracture strength. However, oblique forces necessary to fracture both inlays and onlays, either with or without DME, by far exceeded the bite forces that can be expected under physiological clinical conditions. Hence, both inlays and onlays are likely to be fracture resistant during clinical service.

Airborne concentrations and chemical considerations of radioactive ruthenium from an undeclared major nuclear release in 2017.

In October 2017, most European countries reported unique atmospheric detections of aerosol-bound radioruthenium (106Ru). The range of concentrations varied from some tenths of µBq·m-3 to more than 150 mBq·m-3 The widespread detection at such considerable (yet innocuous) levels suggested a considerable release. To compare activity reports of airborne 106Ru with different sampling periods, concentrations were reconstructed based on the most probable plume presence duration at each location. Based on airborne concentration spreading and chemical considerations, it is possible to assume that the release occurred in the Southern Urals region (Russian Federation). The 106Ru age was estimated to be about 2 years. It exhibited highly soluble and less soluble fractions in aqueous media, high radiopurity (lack of concomitant radionuclides), and volatility between 700 and 1,000 °C, thus suggesting a release at an advanced stage in the reprocessing of nuclear fuel. The amount and isotopic characteristics of the radioruthenium release may indicate a context with the production of a large 144Ce source for a neutrino experiment.

Uncertainties in calculated correction factors for true coincidence-summing (TCS).

The aim of this work was to estimate the uncertainties in Monte Carlo calculated correction factors for true coincidence summing (TCS). In this work TCS-factors and their uncertainties were calculated for 134Cs and then the corrected activities compared to empirical data. The study was carried out using a close-end coaxial p-type detector (Ø80mm×54.5mm, 80% relative efficiency) and a cylindrical glass fiber sample (Ø60mm×14mm). It was shown that the uncertainty in the calculated correction factor for the primary gamma ray was below 0.5%, which means it will not contribute significantly to the combined uncertainty in an activity measurement for e.g. environmental monitoring.

Tracking of airborne radionuclides from the damaged Fukushima Dai-ichi nuclear reactors by European networks.

Radioactive emissions into the atmosphere from the damaged reactors of the Fukushima Dai-ichi nuclear power plant (NPP) started on March 12th, 2011. Among the various radionuclides released, iodine-131 ((131)I) and cesium isotopes ((137)Cs and (134)Cs) were transported across the Pacific toward the North American continent and reached Europe despite dispersion and washout along the route of the contaminated air masses. In Europe, the first signs of the releases were detected 7 days later while the first peak of activity level was observed between March 28th and March 30th. Time variations over a 20-day period and spatial variations across more than 150 sampling locations in Europe made it possible to characterize the contaminated air masses. After the Chernobyl accident, only a few measurements of the gaseous (131)I fraction were conducted compared to the number of measurements for the particulate fraction. Several studies had already pointed out the importance of the gaseous (131)I and the large underestimation of the total (131)I airborne activity level, and subsequent calculations of inhalation dose, if neglected. The measurements made across Europe following the releases from the Fukushima NPP reactors have provided a significant amount of new data on the ratio of the gaseous (131)I fraction to total (131)I, both on a spatial scale and its temporal variation. It can be pointed out that during the Fukushima event, the (134)Cs to (137)Cs ratio proved to be different from that observed after the Chernobyl accident. The data set provided in this paper is the most comprehensive survey of the main relevant airborne radionuclides from the Fukushima reactors, measured across Europe. A rough estimate of the total (131)I inventory that has passed over Europe during this period was <1% of the released amount. According to the measurements, airborne activity levels remain of no concern for public health in Europe.

An intercomparison of Monte Carlo codes used in gamma-ray spectrometry.

In an intercomparison exercise, the Monte Carlo codes most commonly used in gamma-ray spectrometry today were compared with each other in order to gauge the differences between them in terms of typical applications. No reference was made to experimental data; instead, the aim was to confront the codes with each other, as they were applied to the calculation of full-energy-peak and total efficiencies. Surprising differences between the results of different codes were revealed.

Proficiency test for gamma spectroscopic analysis with a simulated fission product reference spectrum.

Within the proficiency test programme for the radionuclide laboratories supporting the verification of the Comprehensive Nuclear-Test-Ban Treaty, a simulated gamma spectrum with the characteristics of an atmospheric nuclear test was used as reference material. The spectrum was produced by the MCNP-based Virtual Gamma Spectroscopy Laboratory (VGSL), using analysis results of a historical measurement of nuclear weapons debris as input. The method was found suitable for a proficiency test assessing laboratories' gamma spectroscopic analysis.

Notes on radioxenon measurements for CTBT verification purposes.

The verification of the Comprehensive Nuclear-Test-Ban Treaty (CTBT) includes, beside three different waveform techniques, global monitoring of radioactive aerosols and noble gases. The noble gases are difficult to contain for the illicit tester and are therefore of particular importance to identify signals from underground or underwater nuclear tests. Several isotopes of xenon are sufficiently produced in fission and a few have suitable half-lives and radiations to be detected. These are (131m)Xe, (133m)Xe, (133)Xe and (135)Xe and they have been selected for continuous monitoring. Four different systems have been developed to sample and measure them. Three of them use cryogenic or room-temperature gas chromatography processes and one a membrane technology. One measures by gamma spectroscopy, two by beta-gamma coincidence spectroscopy and one by beta-gated gamma spectroscopy. These systems are now undergoing trials at worldwide locations in the so-called International Noble Gas Experiment (INGE). In parallel, specific analytical software is being developed to examine the spectra produced by these different systems. This paper presents results from data acquired both from regions having a high radioxenon background and from remote low background stations.

Comparative analysis of passive dosimetry and biomonitoring for assessing chlorpyrifos exposure in pesticide workers.

Under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), the US Environmental Protection Agency (EPA) has the authority to regulate the use of pesticides to prevent unreasonable adverse human health effects associated with pesticide exposure. Accordingly, the EPA requires pesticide registrants to perform studies evaluating the potential for pesticide handler exposure. Data from five such studies that included exposure measurements based on both external measurements and biological monitoring were used to examine methods of assessment, routes and determinants of exposure and dose to the pesticide chlorpyrifos. Eighty workers across four job classes were included: mixer/loaders (M/L, n = 24), mixer/loader/applicators (M/L/A, n = 37), applicators (A, n = 9) and re-entry scouts (RS, n = 10). Results showed that doses were highly variable and differed by job class (P < 0.05) with median total (inhalation and dermal combined) exposure-derived absorbed doses (EDADtot) of 129, 88, 85 and 45 microg/application for A, M/L/A, M/L and RS, respectively. Doses derived from the measurement of 3,5,6-trichloro- 2-pyridinol (3,5,6-TCP) in urine were similar in magnitude but differed in rank with median values of 275, 189, 122 and 97 microg/application for A, M/L, RS, and M/L/A, respectively. The relative contribution of dermal to inhalation exposure was examined by their ratio. The median ratios of exposure-derived absorbed dermal dose (EDADderm) (assuming 3% absorption) to exposure-derived absorbed inhalation dose (EDADinh) (assuming 100% absorption) across job classes were 1.7, 1.5, 0.44 and 0.18 for RS, M/L, A and M/L/A, respectively, with an overall median of 0.6. For 34 of 77 workers (44%), this ratio exceeded 1.0, indicating the significance of the dermal exposure pathway. Different dermal absorption factor (DAF) assumptions were examined by comparing EDADtot to the biomarker-derived absorbed dose (BDAD) as a ratio where EDADtot was calculated assuming a DAF of 1, 3 and 10%. Median ratios of 0.45, 0.71 and 1.28, respectively, were determined suggesting the DAF is within the range of 3-10%. A simple linear regression of urinary 3,5,6-TCP against EDADtot indicates a positive association explaining 29% of the variability in the 3,5,6-TCP derived estimate of dose. A multiple linear regression model including the variables EDADderm, EDADinh and application type explained 46% of the variability (R2 = 0.46) in the urinary dose estimate. EDADderm was marginally significant (P = 0.066) while EDADinh was not (P = 0.57). The EDADderm regression coefficient (0.0007) exceeded the coefficient for EDADinh (0.00002) by a factor of 35. This study demonstrates the value of the pesticide registrant database for the purpose of evaluating pesticide worker exposure. It highlights the significance of the dermal exposure pathway, and identifies the need for methods and research to close the gap between external and internal exposure measures.

Behavioral and learning problems in schoolchildren related to cognitive test data.

AIM: To assess cognitive functions in children who were reported by their teachers and parents to exhibit learning and/or behavioural problems, especially in the field of attention. METHOD: In connection with the scheduled school health examination in grade 4 in one municipality, 591 children were screened through questionnaires and interviews with the parents and teachers. Those with positive rating scores were subjected to further cognitive assessments, including the WISC III. A cluster analysis based on cognitive data was performed. RESULTS: One third (175 children) of the population obtained a positive rating score, indicating significant behavioural and/or learning problems. Of these, 144 children were assessed. Cluster analysis revealed six clusters. Within these clusters, two large groups were identified: one group displayed generally low cognitive abilities and one group was dominated by attention deficit symptoms. CONCLUSION: We found a surprisingly high number of positive rating scores in the cohort (30%). This could be explained, on the one hand, by known developmental disorders, such as mental retardation and learning disabilities, ADHD (Attention Deficit Hyperactivity Disorder) and pervasive developmental disorders, and, on the other hand, by prevalent milder cognitive dysfunctions that, in combination with inappropriate demands, seemed to lead to overt behavioural problems.

Mechanistic studies on the reversible metabolism of rofecoxib to 5-hydroxyrofecoxib in the rat: evidence for transient ring opening of a substituted 2-furanone derivative using stable isotope-labeling techniques.

Rofecoxib is a potent and highly selective cyclooxygenase-2 inhibitor used for the treatment of osteoarthritis and pain. Following administration of [4-(14)C]rofecoxib to intact rats, the plasma C(max) (at approximately 1 h) was followed by a secondary C(max) (at approximately 10 h), which was not observed in bile duct-cannulated rats. Following administration of [4-(14)C]5-hydroxyrofecoxib to intact or bile duct-cannulated rats, radiolabeled rofecoxib was detected in plasma, and once again a secondary C(max) for rofecoxib was observed (at approximately 10 h), which occurred only in the intact animals. These results indicate that reversible metabolism of rofecoxib to 5-hydroxyrofecoxib occurs in the rat and that the process is dependent upon an uninterrupted bile flow. Studies on the contents of the gastrointestinal tract of rats showed that conversion of 5-hydroxyrofecoxib to parent compound occurs largely in the lower intestine. Treatment of rats with [5-(18)O]5-hydroxyrofecoxib, followed by liquid chromatography-tandem mass spectrometry analyses of plasma samples, confirmed that 5-hydroxyrofecoxib undergoes metabolism to the parent drug, yielding [1-(18)O]rofecoxib, [2-(18)O]rofecoxib, and unlabeled rofecoxib. Similarly, treatment with [1,2-(18)O(2)]rofecoxib afforded the same three isotopic variants of rofecoxib. These findings are consistent with a metabolic sequence involving 5-hydroxylation of rofecoxib, biliary elimination of the corresponding glucuronide, and deconjugation of the glucuronide in the lower gastrointestinal tract. Reduction of the 5-hydroxyrofecoxib thus liberated yields a hydroxyacid that cyclizes spontaneously to regenerate rofecoxib, which is reabsorbed and enters the systemic circulation. This sequence represents a novel form of enterohepatic recycling and reflects the susceptibility of 5-hydroxyrofecoxib, as well as rofecoxib itself, to reversible 2-furanone ring opening under in vivo conditions.

Role of human liver cytochrome P4503A in the metabolism of etoricoxib, a novel cyclooxygenase-2 selective inhibitor.

Etoricoxib, a potent and selective cyclooxygenase-2 inhibitor, was shown to be metabolized via 6'-methylhydroxylation (M2 formation) when incubated with NADPH-fortified human liver microsomes. In agreement with in vivo data, 1'-N'-oxidation was a relatively minor pathway. Over the etoricoxib concentration range studied (1-1300 microM), the rate of hydroxylation conformed to saturable Michaelis-Menten kinetics (apparent K(m) = 186 +/- 84.3 microM; V(max) = 0.76 +/- 0.45 nmol/min/mg of protein; mean +/- S.D., n = 3 livers) and yielded a V(max)/K(m) ratio of 2.4 to 7.3 microl/min/mg. This in vitro V(max)/K(m) ratio was scaled, with respect to yield of liver microsomal protein and liver weight, to obtain estimates of M2 formation clearance (3.1-9.7 ml/min/kg of b.wt.) that agreed favorably with in vivo results (8.3 ml/min/kg of b.wt.) following i.v. administration of [(14)C]etoricoxib to healthy male subjects. Cytochrome P450 (P450) reaction phenotyping studies-using P450 form selective chemical inhibitors, immunoinhibitory antibodies, recombinant P450s, and correlation analysis with microsomes prepared from a bank of human livers-revealed that the 6'-methyl hydroxylation of etoricoxib was catalyzed largely (approximately 60%) by member(s) of the CYP3A subfamily. By comparison, CYP2C9 (approximately 10%), CYP2D6 (approximately 10%), CYP1A2 (approximately 10%), and possibly CYP2C19 played an ancillary role. Moreover, etoricoxib (0.1-100 microM) was found to be a relatively weak inhibitor (IC(50) > 100 microM) of multiple P450s (CYP1A2, CYP2D6, CYP3A, CYP2E1, CYP2C9, and CYP2C19) in human liver microsomes.

The absorption, distribution, metabolism and excretion of rofecoxib, a potent and selective cyclooxygenase-2 inhibitor, in rats and dogs.

Absorption, distribution, metabolism, and excretion studies were conducted in rats and dogs with rofecoxib (VIOXX, MK-0966), a potent and highly selective inhibitor of cyclooxygenase-2 (COX-2). In rats, the nonexponential decay during the terminal phase (4- to 10-h time interval) of rofecoxib plasma concentration versus time curves after i.v. or oral administration of [(14)C]rofecoxib precluded accurate determinations of half-life, AUC(0-infinity) (area under the plasma concentration versus time curve extrapolated to infinity), and hence, bioavailability. After i.v. administration of [(14)C]rofecoxib to dogs, plasma clearance, volume of distribution at steady state, and elimination half-life values of rofecoxib were 3.6 ml/min/kg, 1.0 l/kg, and 2.6 h, respectively. Oral absorption (5 mg/kg) was rapid in both species with C(max) occurring by 0.5 h (rats) and 1.5 h (dogs). Bioavailability in dogs was 26%. Systemic exposure increased with increasing dosage in rats and dogs after i.v. (1, 2, and 4 mg/kg), or oral (2, 5, and 10 mg/kg) administration, except in rats where no additional increase was observed between the 5 and 10 mg/kg doses. Radioactivity distributed rapidly to tissues, with the highest concentrations of the i.v. dose observed in most tissues by 5 min and by 30 min in liver, skin, fat, prostate, and bladder. Excretion occurred primarily by the biliary route in rats and dogs, except after i.v. administration of [(14)C]rofecoxib to dogs, where excretion was divided between biliary and renal routes. Metabolism of rofecoxib was extensive. 5-Hydroxyrofecoxib-O-beta-D-glucuronide was the major metabolite excreted by rats in urine and bile. 5-Hydroxyrofecoxib, rofecoxib-3',4'-dihydrodiol, and 4'-hydroxyrofecoxib sulfate were less abundant, whereas cis- and trans-3,4-dihydro-rofecoxib were minor. Major metabolites in dog were 5-hydroxyrofecoxib-O-beta-D-glucuronide (urine), trans-3, 4-dihydro-rofecoxib (urine), and 5-hydroxyrofecoxib (bile).

Disposition and pharmacokinetics of the antimigraine drug, rizatriptan, in humans.

The absorption and disposition of rizatriptan (MK-0462, Maxalt(TM)), a selective 5-HT(1B/1D) receptor agonist used in the treatment of migraine headaches, was investigated in humans. In a two-period, single i.v. (3 mg, 30-min infusion), and single oral (10 mg) dose study with [(14)C]rizatriptan in six healthy human males, total recovery of radioactivity was approximately 94%, with unchanged rizatriptan and its metabolites being excreted mainly in the urine (89% i.v. dose, 82% p.o. dose). Approximately 26 and 14% of i.v. and oral rizatriptan doses, respectively, were excreted in urine as intact parent drug. In a second, high-dose study (60 mg p.o.), five metabolites excreted into urine were identified using liquid chromatography-tandem mass spectrometry and NMR methods. They were triazolomethyl-indole-3-acetic acid, rizatriptan-N(10)-oxide, 6-hydroxy-rizatriptan, 6-hydroxy-rizatriptan sulfate, and N(10)-monodesmethyl-rizatriptan. Urinary excretion of triazolomethyl-indole-3-acetic acid after i.v. and oral administrations of rizatriptan accounted for 35 and 51% of the dose, respectively, whereas the corresponding values for rizatriptan-N(10)-oxide were 4 and 2% of the dose. Plasma clearance (CL) and renal clearance (CL(r)) were 1325 and 349 ml/min, respectively, after i.v. administration. A similar CL(r) value was obtained after oral administration (396 ml/min). The primary route of rizatriptan elimination occurred via nonrenal route(s) (i.e., metabolism) because the CL(r) of rizatriptan accounted for 25% of total CL. Furthermore, the CL(r) was higher than normal glomerular filtration rate ( approximately 130 ml/min), indicating that this compound was actively secreted by renal tubules. The absorption of rizatriptan was approximately 90%, but it experienced a moderate first-pass effect, resulting in a bioavailability estimate of 47%.

MMDB: 3D structure data in Entrez.

Three-dimensional structures are now known for roughly half of all protein families. It is thus quite likely, in searching sequence databases, that one will encounter a homolog with known structure and be able to use this information to infer structure-function properties. The goal of Entrez's 3D structure database is to make this information accessible and useful to molecular biologists. To this end, Entrez's search engine provides three powerful features: (i) Links between databases; one may search by term matching in Medline((R)), for example, and link to 3D structures reported in these articles. (ii) Sequence and structure neighbors; one may select all sequences similar to one of interest, for example, and link to any known 3D structures. (iii) Sequence and structure visualization; identifying a homolog with known structure, one may view a combined molecular-graphic and alignment display, to infer approximate 3D structure. Entrez's MMDB (Molecular Modeling DataBase) may be accessed at: http://www.ncbi.nlm.nih.gov/Entrez/structure.html

MMDB: Entrez's 3D structure database.

The three dimensional structures for representatives of nearly half of all protein families are now available in public databases. Thus, no matter which protein one investigates, it is increasingly likely that the 3D structure of a homolog will be known and may reveal unsuspected structure-function relationships. The goal of Entrez's 3D-structure database is to make this information accessible and usable by molecular biologists (http://www.ncbi.nlm.nih.gov/Entrez). To this end Entrez provides two major analysis tools, a search engine based on sequence and structure 'neighboring' and an integrated visualization system for sequence and structure alignments. From a protein's sequence 'neighbors' one may rapidly identify other members of a protein family, including those where 3D structure is known. By comparing aligned sequences and/or structures in detail, using the visualization system, one may identify conserved features and perhaps infer functional properties. Here we describe how these analysis tools may be used to investigate the structure and function of newly discovered proteins, using the PTEN gene product as an example.

Pharmaco-economic information and its effect on prescriptions.

Reports on a small-scale study of 30 general practitioners and 30 specialists in Greece where pharmaco-economic information was presented to these prescribers and an attempt made to observe changes in reported choice of treatment consequent on this exposure. Concludes with a credible level of statistical significance, that information which also takes into account economic performance criteria is likely to influence the prescription decision of the practitioners. Suggests, from a commercial point of view, that this offers the opportunity to pharmaceutical companies to complement their offerings so that they can be better targeted to those prescribers most likely to be influenced by this information. Notes that, from a general societal point of view, the question needs to be raised about the extent to which the independence of the prescriber might be eroded through the presence or absence of such information and thus the best interests of the patient safeguarded.

International sera exchange analyses in relation to DNA sequences: summary report from 1990 to 1994.

One hundred ninety-five sera were tested against over 7,000 cells originating from approximately 100 laboratories in the world during the past 5 years. This collaboration was useful to compare local data with data from other laboratories, although the local panel of cells varied from 30 to 200. In analyzing the reactions of the sera, it was noted that antibodies that react cleanly to well-defined antigens can usually be defined by a single unique amino acid residue. Antisera which appear to be definable by several amino acids (a motif) have reactivities which are more variable.

A method to analyze 2-dimensional daily radiotherapy portal images from an on-line fiber-optic imaging system.

On-line radiotherapy imaging systems allow convenient treatment verification and generate a wealth of data. Quantitative analysis of data will provide important information about the nature of treatment variations. Using an inhouse fiber-optic imaging system to acquire daily portal images for five patients, we have developed a method to analyze the cumulative positional variation of blocks in the 2-dimensional images. For each beam arrangement used to treat a particular patient, a reference portal image was established. All other images for that patient were registered with respect to the anatomical landmarks visible on the reference image. Two-dimensional frequency distributions describing the overlap of the blocks during the course of treatment were then calculated and superimposed on the reference image. Results of the analysis show positional and quantitative information about the daily variation in block placement, and appeared to be site-dependent. Long term verification studies using on-line imaging systems will be important in the understanding of treatment uncertainties.

Association of high sensitization to the structure of HLA class I alleles.

Some HLA Class I alleles or groups of alleles can be explained by exclusive residues which may explain their structural uniqueness. However, many sera are directed to alleles whose structural uniqueness is explained only by a combination of nonexclusive residues. A program implementing a combinatorial search algorithm was developed to analyze serological data by associating the primary structure of specific alleles to reaction patterns of broad multispecific sera. The method determines the residue or residues whose associated alleles best describe the serum specificity. The raw data reaction patterns direct the search, which utilizes known primary sequence information of HLA Class I alleles. Three-hundred highly positive sera from parous females were analyzed; 74 were highly correlated to the A locus and 125 to the B locus. Some of the remaining sera were associated with multiple loci. Reorganization methods were applied to the data. Clusters of residues associated with certain alleles focus attention on specific locations on the HLA Class I molecule. These regions may be included in, or in close proximity to, the serological determinant. Serological descriptions of certain broad specific sera have been termed "public epitopes." Specificities associated with distinct conserved regions of the Class I molecule offer a molecular basis for many public epitopes. Similar reaction patterns to 3 serologically allelic regions were found in pregnancy allosera, monoclonal antibodies, and transplant recipient sera. The correlated areas were: positions 166 and 167 of the alpha 2 domain alpha helix on the A locus, positions 79-83 of the alpha 1 domain alpha helix on the A locus, and positions 80-83 on the A and B loci.