Aryl hydrocarbon receptor interacting protein mutations seem not to associate with familial non-medullary thyroid cancer.

BACKGROUND: Over 95% of all thyroid malignancies are non-medullary thyroid carcinomas (NMTC). Familial NMTC are more aggressive and mortality is higher as compared with sporadic carcinomas. Known genetic factors do not explain all familial NMTC. Recently, thyroid disorders have been observed in families with germline mutations in aryl hydrocarbon receptor interacting protein (AIP) but, due to frequent occurrence of these conditions in the population, the significance of this co-occurrence is not clear. AIM, SUBJECTS AND METHODS: To examine whether AIP is involved in familial NMTC, we performed AIP mutation screening in 93 familial NMTC cases. In addition, the AIP status was studied in one follicular thyroid adenoma patient with a known AIP mutation from an additional cohort. RESULTS: No potentially pathogenic changes were identified, but two likely rare polymorphisms were detected. AIP mutation-positive patient's follicular thyroid adenoma showed no loss of heterozygosity or lack of immunohistochemical AIP staining. CONCLUSION: Our study indicates that germline AIP mutations are rare or do not exist in familial NMTC.

Characterisation of the chemical and biological properties of molecules with QSAR/QSPR and chemical grouping, and its application to a group of alkyl ethers.

This study presents a QSAR/QSPR modelling and chemical grouping (read-across) approach to provide information on the biological properties of a group of aliphatic ethers, with accurate biological predictions restricted to those physico-chemical and (eco)toxicological properties where the performance of QSAR/QSPR has been shown to be acceptable. The mathematical methods used ranged from multivariate regression models to PLS (partial least-squares), SVM (support vector machines) and Sammon's mapping. A novel grouping approach, based on a set of key descriptors, has been proposed to give a compact picture of the structural and biological properties of the compounds, and to provide a more mechanistic basis for the interpretations of chemical groups. Besides being a straightforward case study, the paper also exemplifies the capabilities and limitations of the methods in predictive toxicology on a more general level.

No evidence of somatic aryl hydrocarbon receptor interacting protein mutations in sporadic endocrine neoplasia.

Germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene were recently observed in patients with pituitary adenoma predisposition (PAP). Though AIP mutation-positive individuals with prolactin-, mixed growth hormone/prolactin-, and ACTH-producing pituitary adenomas as well as non-secreting pituitary adenomas have been reported, most mutation-positive patients have had growth hormone-producing adenomas diagnosed at relatively young age. Pituitary adenomas are also component tumors of some familial endocrine neoplasia syndromes such as multiple endocrine neoplasia type 1 (MEN1) and Carney complex (CNC). Genes underlying MEN1 and CNC are rarely mutated in sporadic pituitary adenomas, but more often in other lesions contributing to these two syndromes. Thus far, the occurrence of somatic AIP mutations has not been studied in endocrine tumors other than pituitary adenomas. Here, we have analyzed 32 pituitary adenomas and 79 other tumors of the endocrine system for somatic AIP mutations by direct sequencing. No somatic mutations were identified. However, two out of nine patients with prolactin-producing adenoma were shown to harbor a Finnish founder mutation (Q14X) with a complete loss of the wild-type allele in the tumors. These results are in agreement with previous studies in that prolactin-producing adenomas are component tumors in PAP. The data also support the previous finding that somatic AIP mutations are not common in pituitary adenomas and suggest that such mutations are rare in other endocrine tumors as well.

Serrated carcinomas form a subclass of colorectal cancer with distinct molecular basis.

Serrated colorectal carcinomas (CRCs) are morphologically different from conventional CRCs and have been proposed to follow a distinct pathway of CRC formation. Despite studies of single molecular events in this tumor type, the diagnosis of serrated CRC relies on morphology and the putative unique biological character of these tumors has not been established. Here we show that the gene expression profiling of 37 CRCs separated serrated and conventional CRCs into two distinct branches in unsupervised hierarchical clustering (P-value 7.8 x 10(-7)), and revealed 201 differentially expressed genes representing potential biomarkers for serrated CRC. Immunohistochemistry was utilized to verify the key findings in the 37 CRCs examined by expression profiling, and a separate validation set of 37 serrated and 86 conventional CRCs was examined to evaluate the candidate biomarkers in an extended sample material. Ephrin receptor B2, hypoxia-inducible factor 1-alpha and patched appeared as proteins important for genesis of serrated CRC. This study establishes serrated CRCs as a biologically distinct subclass of CRC and represents a step forward in the molecular classification of these cancers. The study also provides a platform to understand the molecular basis of serrated CRC and in long term may contribute to the development of specific treatment options for this tumor type.

Performance of multicomponent self-organizing regression (MCSOR) in QSAR, QSPR, and multivariate calibration: comparison with partial least-squares (PLS) and validation with large external data sets.

A novel method for underdetermined regression problems, multicomponent self-organizing regression (MCSOR), has been recently introduced. Here, its performance is compared with partial least-squares (PLS), which is perhaps the most widely adopted multivariate method in chemometrics. A potpourri of models is presented, and MCSOR appears to provide highly predictive models that are comparable with or better than the corresponding PLS models in large internal (leave-one-out, LOO) and pseudo-external (leave-many-out, LMO) validation tests. The "blind" external predictive ability of MCSOR and PLS is demonstrated employing large melting point, factor Xa, log P and log S data sets. In a nutshell, MCSOR is fast, conceptually simple (employing multiple linear regression, MLR, as a statistical tool), and applicable to all kinds of multivariate problems with single Y-variable.

Alternative QSAR models for selected estradiol and cytochrome P450 ligands: comparison between classical, spectroscopic, CoMFA and GRID/GOLPE methods.

The performance of the spectroscopic EVA (eigenvalue) and EEVA (electronic eigenvalue) methods was tested with data sets applying coumarin 7-hydroxylation inhibitors (28 compounds) for cytochrome P450 mouse CYP2A5 and human CYP2A6 enzymes and 11ss-, 16a-, and 17a-substituted estradiol derivatives (30 compounds) for the lamb uterine estrogen receptor, and compared with the performance of the classical Hansch-type, CoMFA and GRID/GOLPE methods. Besides the internal predictability, the external predictability of the models was tested with several randomized training and test sets to ensure the validity and reliability of the models. Partial least squares (PLS) regression was employed as a general statistical tool with the EVA and EEVA methods. Some supplementary models were also built using only one PLS component with McGowan's volumes (MgVol and MgVol(2)) as additional descriptors and employing multiple linear regression (MLR) as the modelling tool. In general, both the internal and external performance of the EVA model, and more especially the EEVA model, with one PLS component and MgVol parameters was satisfactory, being either as good as or clearly better than that of the Hansch-type, CoMFA and GRID/GOLPE models.

Improving the performance of SOMFA by use of standard multivariate methods.

Self-Organizing Molecular Field Analysis (SOMFA) comes with a built-in regression methodology, the Self-Organizing Regression (SOR), instead of relying on external methods such as PLS. In this article we present a proof of the equivalence between SOR and SIMPLS with one principal component. Thus, the modest performance of SOMFA on complex datasets can be primarily attributed to the low performance of the SOMFA regression methodology. A multi-component extension of the original SOR methodology (MCSOR) is introduced, and the performances of SOR, MCSOR and SIMPLS are compared using several datasets. The results indicate that in general the performance of SOMFA models is greatly improved if SOR is replaced with a more sophisticated regression method. The results obtained for the Cramer (CBG) dataset further underline the fact that it is a very poor benchmark dataset and should not be used to evaluate the performance of QSAR techniques.

Performance of (consensus) kNN QSAR for predicting estrogenic activity in a large diverse set of organic compounds.

A novel method (in the context of quantitative structure-activity relationship (QSAR)) based on the k nearest neighbour (kNN) principle, has recently been introduced for the derivation of predictive structure-activity relationships. Its performance has been tested for estimating the estrogen binding affinity of a diverse set of 142 organic molecules. Highly predictive models have been obtained. Moreover, it has been demonstrated that consensus-type kNN QSAR models, derived from the arithmetic mean of individual QSAR models were statistically robust and provided more accurate predictions than the great majority of the individual QSAR models. Finally, the consensus QSAR method was tested with 3D QSAR and log P data from a widely used steroid benchmark data set.

Sulphate-reducing laboratory-scale high-rate anaerobic reactors for treatment of metal- and sulphate-containing mine wastewater.

Upflow anaerobic sludge blanket (UASB) reactors were used in this study to evaluate the feasibility of the sulphate-reducing, anaerobic high-rate process to treat metal- and sulphate-containing mining wastewater (MWW). Four simultaneous reactors, inoculated with different inocula (mesophilic granular sludge from two UASB reactors, one treating sugar refinery wastewater and the other board mill wastewater) and operated with different loadings, were for 95 days fed with synthetic feed consisting of glucose and sulphate. In all reactors, 23-72% of sulphate and 12-93% of COD were removed. Subsequently, two reactors were fed with diluted MWW (zinc as the main metal) for 77 days with hydraulic retention times down to 8 hours. At the onset of the runs (until day 48), over 99.9% of zinc was removed in both reactors, after which removals fell to less than 30-80%. At the end of the runs, the highest zinc content (44 mg g(-1) TS) in the reactor sludges was 21 times higher than that in the inoculum. It cannot be concluded definitively that sulphide precipitation was the only mechanism of metal removal, for biosorption may have had a role to play in the process.

Effect of urea on fly ash PCDD/F concentrations in different particle sizes.

The effect of urea as an inhibitor for reducing polychlorinated dibenzo-p-dioxin and dibenzofuran (PCDD/F) concentrations in flue gases was studied in a pilot scale plant, together with the effect on the particle size distribution of these compounds. Total PCDD/F concentrations decreased by a maximum of 74%, the decrease being greatest for the most highly (octa-) chlorinated isomers. The PCDD/F reduction affected all the particle size classes when an adequate amount of urea was used (1% of the fuel input), which indicates that inhibition, unlike formation, is independent of the fly ash particle size distribution.

PCDD/F reduction in incinerator flue gas by adding urea to RDF feedstock.

The effect of urea on PCDD/F formation in a pilot incinerator was studied by incinerating urea with refuse-derived fuel (RDF) at three concentrations (0.1%, 0.5% and 1.0%, of the fuel feed). A distinct reduction in both PCDD/F and chlorophenol concentrations could be noticed when urea was introduced into the system. Partial-least-square (PLS) analysis of the data showed the importance of certain chlorophenol isomers as PCDD/F precursors, pointing to the possibility that the impact point of the urea inhibitor could be before the precursor molecules, i.e. chlorophenols, have been formed.

Urea as a PCDD/F inhibitor in municipal waste incineration.

Emissions of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) from municipal waste incineration have been widely studied because of their extensive toxicity, and many efforts have been made to restrict their emissions. Although a number of chemical compounds have been shown in laboratory-scale tests to inhibit the formation of PCDD/Fs, few have been tested in pilot- or full-scale plants. This work evaluates the effect of urea as a PCDD/F inhibitor in a pilot-scale incinerator that uses refuse-derived fuel (RDF). The decomposition of urea under the test conditions was also studied using detailed kinetic modeling. An aqueous solution of urea was injected into the flue gas stream after the furnace at approximately 730 degrees C, with varied urea concentrations and flue gas residence times used between the furnace and the sampling point. The results demonstrate that urea can successfully inhibit PCDD/F formation in waste incineration if concentrations and injection points are properly adjusted. The kinetic model showed that urea can be rapidly decomposed under appropriate flue gas conditions, indicating that in addition to the urea molecule itself, decomposition products of urea can also be responsible for the reduction of PCDD/F production during incineration.

Color vision defects after central serous chorioretinopathy.

PURPOSE: To reexamine patients diagnosed with central serous chorioretinopathy (CSC) during the 10-year period from 1987 to 1996 to identify remaining color vision defects in the eyes with normal visual acuity (VA). METHODS: Thirty-nine patients were found with normal VA of 20/20 (logMAR 0) or better 8 to 166 months (mean +/- SD, 58.8 +/- 41.2) after active CSC. Color vision was examined with the Standard Pseudoisochromatic Plates part 2, Farnsworth-Munsell 100 hue test, and Color Vision Meter 712 anomaloscope. RESULTS: Of the CSC eyes, 26 (67%) had a color vision defect, most of them in the blue area. There was no correlation between the time since the active disease and the results on the color vision tests. Of the contralateral eyes, 19 (49%) also had a color vision defect. CONCLUSION: In many patients some degree of color vision defect remains after CSC even if the VA has recovered to normal. The contralateral eye can also have a color vision defect. This has not been previously reported and might be due to earlier subclinical CSC.

Electronic eigenvalue (EEVA): a new QSAR/QSPR descriptor for electronic substituent effects based on molecular orbital energies. A QSAR approach to the Ah receptor binding affinity of polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs).

A new descriptor of molecular structure for use in the derivation of predictive QSAR and QSPR models, electronic eigenvalue (EEVA), is described. This is a modification of the recently proposed EVA approach, but is based on computationally-derived molecular orbital energies instead of vibrational frequencies. Like EVA, it is also invariant as to the alignment of the structures concerned. Its performance has been tested with respect to the Ah receptor binding of PCBs, PCDDs and PCDFs, and its predictive ability has been clearly demonstrated. In particular, it seems to be suitable for 'pure' electronic substituent effects. i.e., for cases in which both hydrophobic and steric factors are of minor importance.

Clinical features of Goldmann-Favre syndrome.

A 21-year-old woman complained of progressive loss of visual acuity. She had also had night blindness since she was ten years old. At the eye examination, the vitreous was found to be degenerated in both eyes. The fundus findings were a large retinoschisis in the right macula, edema resembling retinoschisis in the left macula and annular degenerative changes in the midperiphery. ERG and dark adaption were abnormal. This vitreoretinal degeneration was diagnosed as Goldmann-Favre syndrome.

Frontier orbital energies, hydrophobicity and steric factors as physical QSAR descriptors of molecular mutagenicity. A review with a case study: MX compounds.

A review on QSARs (Quantitative Structure-Activity Relationships) in modelling molecular mutagenicity is given. The importance of hydrophobicity, frontier orbital (HOMO and LUMO) energies and steric factors as physical descriptors of mutagenicity is emphasized. In addition, some possible connections between QSAR models and the general electrophilic theory of genotoxic activity are discussed. As a detailed example, QSARs for the Ames Salmonella typhimurium TA100 mutagenicity of halogenated hydroxyfuranones including MX, one of the most potent bacterial mutagens ever identified, are discussed and a plausible mechanism for their mutagenic activity is proposed.

Cataract in traffic.

BACKGROUND: To obtain a driver's licence to drive a private passenger car, the binocular visual acuity required is 0.5 or better, and the minimum horizontal width of the visual field is 120 degrees . Persons who fulfill these requirements can obtain a driver's licence even if they have an eye disease such as cataract. However, contrast sensitivity and visual acuity in glare can be considerably decreased in eyes with cataract, and this may create a risk factor in traffic. METHODS: Examinations of the eyes, visual fields, contrast sensitivity and glare sensitivity (visual acuity in glare and macular photostress test) were performed for 35 cataract patients aged 60 to 87 years (mean 70.1 years+/-6.1 SD). They had cataract in one or both eyes. In spite of the cataract, the visual acuity was > or =0.5 in 50 of the eyes. Twenty-two control eyes of persons within the same age range were similarly tested. RESULTS: The results in the contrast sensitivity test were significantly worse in the cataract eyes than in the control eyes. Contrast sensitivity decreased significantly as the visual acuity became worse. In the glare test, none of the control eyes lost any of the lines in the visual acuity chart. In the cataract eyes, the loss of lines with the highest glare varied from 0 to 6 lines (mean 1.4+/-1.5). The recovery time in the macular photostress test was longer, but not significantly, in cataract eyes than in normal eyes. There was no significant correlation between the loss of visual chart lines and visual acuity or between the recovery time in the macular photostress test and visual acuity. CONCLUSION: It would be advisable for traffic safety if simple tests for contrast and glare sensitivity were added to the requirements for a driver's licence, at least for older drivers. The age and test result limits should be defined.

Effect of liquid inhibitors on PCDD/F formation. Prediction of particle-phase PCDD/F concentrations using PLS modelling with gas-phase chlorophenol concentrations as independent variables.

Emissions of polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) from municipal waste incineration are currently a subject of considerable public concern because of their extreme toxicity. PCDD/F formation in incineration processes is being studied widely, but little work has been done on their inhibition. We studied the effect of two liquid inhibitors, sodium ammonium hydrogen phosphate (NAHF) and urea (H2NCONH2), on PCDD/F formation in the combustion of liquid fuel doped with copper and chlorine using a pilot-scale plant. The inhibitors were injected into the flue gas stream at a temperature of 725 degrees C, whereupon both the chlorophenol and PCDD/F concentrations decreased. Particle-phase PCDD/F concentrations in particular decreased by up to 90% with NAHF and 70% with urea, but gas phase reduction took place only with urea. The results suggest that the formation of PCDD/Fs is hindered in the particle phase at the early stages of the PCDD/F formation chain, probably even before precursors such as chlorophenols have been formed. As a consequence, particle-phase PCDD/F concentrations can be predicted by a PLS (partial least-squares) approach with the gas-phase chlorophenol concentrations as independent variables. The structure and partial charges of Cu(+)-urea complex were calculated by the HF/3-21G basis set.

Visual functions of drivers involved in traffic accidents.

Eye functions were studied in 56 drivers who had recently been involved in traffic accidents. There were 17 women and 39 men in the study group, aged 20-87 years. The traffic accidents had happened in intersections and city streets, in parking places and on highways. In seven drivers, a visual impairment was found: two drivers had strabismus and low visual acuities in one or both eyes, two had considerable hyperphoria, and three had a deutan color vision defect. However, comparing the type of accident to the defective eye functions showed no probable correlation.

Visual function in professional truck drivers.

OBJECTIVES: The purpose of this study was to examine the visual function of professional truck drivers at working age to find out whether older drivers had any defective function and should therefore be given less demanding duties at work. METHODS: Of the 100 drivers invited to the study, 77 came to the examination, including 74 men and 3 women aged from 30 to 66 years (mean 50.3+/-10.3 years). In addition to the basic eye examination, visual fields, dark adaptation, contrast sensitivity, color vision, and glare sensitivity were studied. RESULTS: Two drivers (2.6%) had an incipient cataract in one eye, four (5.2%) had slight fundus abnormalities, five (6.5%) had exo- or esotropia, and five (6.5%) had amblyopia. Visual acuity in the better eye varied from 0.4 to 1.2 (mean 1.06+/-0.17) and in the other eye from 0.1 to 1.2 (mean 0.96+/-0.23). Five drivers (6.5%) had inadequate visual acuity for a professional driver's license. Visual fields were interpreted as normal in all drivers. The results of the dark-adaptation, contrast-sensitivity, and glare testing showed values within normal ranges for all drivers. In the color-vision tests, five male drivers (6.8% of the men) had a slight congenital green defect, and two drivers had an acquired blue defect in one eye because of cataract and diabetes. CONCLUSIONS: According to the present study, there is no need to give older drivers less demanding duties because of their eyes. However, one serious finding in the present study needs attention: the visual acuity was lower than that required for a professional driver's license in five drivers. Evidently, more regular checkups of visual acuity are needed for a professional driver's license.