Predictive genetic test decisions for Huntington's disease: Elucidating the test/no-test dichotomy

Predictive genetic testing for serious, mature-onset genetic illness represents a unique context in health decision making. This article presents findings from an exploratory qualitative Australian-based study into the decision making of individuals at risk for Huntington's disease (HD) with regard to predictive genetic testing. Sixteen in-depth interviews were conducted with a range of at-risk individuals. Data analysis revealed four discrete decision-making positions rather than a 'to test' or not to test' dichotomy. A conceptual dimension of (non-)openness and (non-)engagement characterized the various decisions. Processes of decision making and a concept of 'test readiness' were identified. Findings from this research, while not generalizable, are discussed in relation to theoretical frameworks and stage models of health decision making, as well as possible clinical implications.

Animal production potential of some new Leucaena accessions in the Markham valley, Papua New Guinea

Signal grass pastures were oversown with four Leucaena spp. planted in hedgerows and evaluated for their agronomic productivity and ability to support steer liveweight gains. Each Leucaena sp. (L. leucocephala, L. pallida, L colli. nst. i., L. trichandra) was planted as seedlings into two I ha paddocks in rows 5 m apart, with I m spacing between trees. Cattle were rotationally grazed on the 2 replicates of each species, as well as on two I ha paddocks of a signal grass on y (Brachiaria decumbens) control, over a 243-day period at a stocking rate of 3 steers/ha. Mean presentation yield and herbage allowance of the Leucaena accessions over the grazing period were highest for L pallida (1100 kg/ha and 0.8 kg DM/kg LW, respectively), followed by L. leucocephala (700 kg/ha and 0.5 kg DM/kg LW), L. collinsii (700 kg/ha and 0.4 kg DM/kg LW) and L. trichandra (300 kg/ha and 0.2 kg DM/kg LW). Despite only moderate presentation yields and herbage allowances, steers grazing L. leucocephala and L. collinsii accessions produced the highest mean liveweight gains (LWG) of 0. and 0.56 kg/hd/d, respectively. While L. pallida produced the highest DM yields, it supported the lowest LWG of 0.36 kg/hd/d. The mean LWGs of steers grazing L. trichandra and the control (grass only) treatments were similar at 0.48 kg/ hd/d. The possible reasons for the differences in steer performance on the different Leucaena accessions are discussed.

Developmental expression of transcription factor genes in a demosponge: insights into the origin of metazoan multicellularity

Demosponges are considered part of the most basal evolutionary lineage in the animal kingdom. Although the sponge body plan fundamentally differs from that of other metazoans, their development includes many of the hallmarks of bilaterian and eumetazoan embryogenesis, namely fertilization followed by a period of cell division yielding distinct cell populations, which through a gastrulation-like process become allocated into different cell layers and patterned within these layers. These observations suggest that the last common ancestor (LCA) to all living animals was developmentally more sophisticated than is widely appreciated and used asymmetric cell division and morphogen gradients to establish localized populations of specified cells within the embryo. Here we demonstrate that members of a range of transcription factor gene classes, many of which appear to be metazoan-specific, are expressed during the development of the demosponge Reniera, including ANTP, Pax, POU, LIM-HD, Sox, nuclear receptor, Fox (forkhead), T-box, Mef2, and Ets genes. Phylogenetic analysis of these genes suggests that not only the origin but the diversification of some of the major developmental metazoan transcription factor classes took place before sponges diverged from the rest of the Metazoa. Their expression during demosponge development suggests that, as in today's sophisticated metazoans, these genes may have functioned in the regulatory network of the metazoan LCA to control cell specification and regionalized gene expression during embryogenesis.

Mapping the emergence of heart disease in a black, urban population in Africa: The Heart of Soweto Study

Background: There is increasing evidence that many populations in the developing world are in epidemiologic transition with the subsequent emergence of more affluent disease states. The Heart of Soweto Study will systematically investigate the emergence of heart disease (HD) in a large urban population in South Africa. Methods: Part of the conurbation of Johannesburg, South Africa, Soweto is a predominantly Black African community of I million individuals. During an initial two year period, all individuals presenting to the local Baragwanath Hospital (3500 beds) with any form of HD will be studied. Demographic and diagnostic coding data in those with pre-established HD will form an abbreviated clinical registry of > 12,000 prevalent cases. Similarly, socio-demographic, clinical and diagnostic data (e.g. echocardiography and ECG) in newly diagnosed patients will form a more detailed clinical registry of > 5000 incident cases. Sub-studies of the relationship between HIV status and H D and the optimal management of chronic heart failure will also be performed. Results: These data will provide a unique insight into the causes and consequences of a broad spectrum of HD-related conditions in a developing world community in epidemiologic transition. Initially documented Population rates, in addition to detailed examinations of the underlying risk factors and causes of HD-related morbidity/mortality will provide an important platform for future stages of the study: a community-based, population screening program and culturally specific primary and secondary programs of care. Conclusion: There is an urgent need to systematically track the emergence of HD in the developing world. Initially involving more than 15,000 individuals, the unique Heart of Soweto Study has the potential to provide a wealth of information in this regard. (c) 2006 Elsevier Ireland Ltd. All rights reserved.

The Las Campanas/Anglo-Australian Telescope Rich Cluster Survey - III. Spectroscopic studies of X-ray bright galaxy clusters at z similar to 0.1

We present the analysis of the spectroscopic and photometric catalogues of 11 X-ray luminous clusters at 0.07 < z < 0.16 from the Las Campanas/Anglo-Australian Telescope Rich Cluster Survey. Our spectroscopic data set consists of over 1600 galaxy cluster members, of which two-thirds are outside r(200). These spectra allow us to assign cluster membership using a detailed mass model and expand on our previous work on the cluster colour-magnitude relation ( CMR) where membership was inferred statistically. We confirm that the modal colours of galaxies on the CMR become progressively bluer with increasing radius d( B - R)/dr(p) = - 0.011 +/- 0.003 and with decreasing local galaxy density d( B - R)/dlog ( Sigma)= - 0.062 +/- 0.009. Interpreted as an age effect, we hypothesize that these trends in galaxy colour should be reflected in mean H delta equivalent width. We confirm that passive galaxies in the cluster increase in Hd line strength as dH delta/dr(p) = 0.35 +/- 0.06. Therefore, those galaxies in the cluster outskirts may have younger luminosity-weighted stellar populations; up to 3 Gyr younger than those in the cluster centre assuming d( B - R)/dt = 0.03 mag per Gyr. A variation of star formation rate, as measured by [ O II]lambda 3727 angstrom, with increasing local density of the environment is discernible and is shown to be in broad agreement with previous studies from the 2dF Galaxy Redshift Survey and the Sloan Digital Sky Survey. We divide our spectra into a variety of types based upon the MORPHs classification scheme. We find that clusters at z similar to 0.1 are less active than their higher-redshift analogues: about 60 per cent of the cluster galaxy population is non-star forming, with a further 20 per cent in the post-starburst class and 20 per cent in the currently active class, demonstrating that evolution is visible within the past 2 - 3 Gyr. We also investigate unusual populations of blue and very red non-star forming galaxies and we suggest that the former are likely to be the progenitors of galaxies which will lie on the CMR, while the colours of the latter possibly reflect dust reddening. We show that the cluster galaxies at large radii consist of both backsplash ones and those that are infalling to the cluster for the first time. We make a comparison to the field population at z similar to 0.1 and examine the broad differences between the two populations. Individually, the clusters show significant variation in their galaxy populations which we suggest reflects their recent infall histories.

A comparison of picture description abilities in individuals with vascular subcortical lesions and Huntington's Disease

The lexical-semantic and syntactic abilities of a group of individuals with chronic nonthalamic subcortical (NS) lesions following stroke (n = 6) were investigated using the Western Aphasia Battery (WAB) picture description task [Kertesz, A. (1982). The Western aphasia battery. New York: Grune and Stratton] and compared with those of a group of subjects with Huntington's Disease (HD) (n = 6) and a nonneurologically impaired control group (n = 6) matched for age, sex, and educational level. The performance of the NS and HD subjects did not differ significantly from the well controls on measures of lexical-semantic abilities. NS and HD subjects provided as much information about the target picture as control subjects, but produced fewer action information units. Analysis of syntactic abilities revealed that the HD subjects produced significantly more grammatical errors than both the NS and control subjects and that the NS group performed in a similar manner to control subjects. These findings are considered in terms of current theories of subcortical language function Learning outcomes: As a result of this activity, the reader will obtain information about the debate surrounding the role of subcortical language mechanisms and be provided with new information on the comparative picture description abilities of individuals with known vascular and degenerative subcortical pathologies and healthy control participants. (c) 2005 Elsevier Inc. All rights reserved.

Mutant huntingtin inhibits clathrin-independent endocytosis and causes accumulation of cholesterol in vitro and in vivo.

We show that the mutant Huntington's disease (HD) protein (mhtt) specifically inhibits endocytosis in primary striatal neurons. Unexpectedly, mhtt does not inhibit clathrin-dependent endocytosis as was anticipated based on known interacting partners. Instead, inhibition occurs through a non-clathrin, caveolar-related pathway. Expression of mhtt inhibited internalization of BODIPY-lactosylceramide (LacCer), which is internalized by a caveolar-related mechanism. In contrast, endocytosis of Alexa Fluor 594-transferrin (Tfn) and epidermal growth factor, internalized through clathrin pathway, was unaffected by mhtt expression. Caveolin-1 (cav1), the major structural protein of caveolae binds cholesterol and is responsible for its trafficking inside cells. Mhtt interacts with cav-1 and caused a striking accumulation of intracellular cholesterol. Cholesterol accumulated in cultured neurons expressing mhtt in vitro and in brains of mhtt-expressing animals in vivo, and was observed after induction of mhtt expression in PC-12 cell lines. The accumulation occurred only when mhtt and cav1 were simultaneously expressed in cells. Knockdown of cav1 in mhtt-expressing neurons blocked cholesterol accumulation and restored LacCer endocytosis. Thus, mhtt and cav1 functionally interact to cause both cellular defects. These data provide the first direct link between mhtt and caveolar-related endocytosis and also suggest a possible mechanism for HD neurotoxicity where cholesterol homeostasis is perturbed.

Studies of the drying of particulate slurries

The literature relating to the drying characteristics of pure liquid drops and particulate slurry drops has been reviewed. The experimental investigation was, therefore, divided into three parts: Pure water drops, Aqueous sodium sulphate decahydrate drops, and, Slurry drops from nine detergent formulations. The value of the constant,'Ψ, reported by Ranz and Marshall, was found to be temperature dependent. In the temperature range o 26.5≤T≤118.5°C,Ψ , for pure water drops, varied between 0.38 and 0.47. A revised correlation of the mass transfer coefficients is therefore proposed.  A mathematical model for estimating the variation of crust thickness, for aqueous sodium sulphate drops, with time is proposed: β = R _ {R3 - ( 1.5G/πCo ) ( ΔHD - ΔHU) Δ} 1/3 Experimental crust thickness evaluated from stereoscan micrographs showed good agreement with theoretical prediction. It has been shown that drying characteristics of detergent drops can be evaluated from the porosity:thickness ratio, {ε/\β}. Formulations having large {ε/β I-ratios dry better than those with smaller values. The agreement between the experimental and theoretical mass transfer coefficients shows, in addition to the above correlation, that the overall mass transfer coefficient can be predicted from the expression1/K = 1/K + β/DMε 1.5 The crust is the controlling resistance to transfer in particulate slurry drops. For aqueous sodium sulphate drops, the crust provides 64.2% of the total resistance while for detergents with thicker, but less porous crusts, the value is 97.5%.

Evaluating the potential neurotoxicity of hexanedione isomers:an in vitro approach

2,5-hexanedione (2,5HD) is the neurotoxic metabolite of the aliphatic hydrocarbon n-Hexane. The isomers, 2,3-hexanedione (2,3HD) and 3,4-hexanedione (3,4HD) are used as food additives. Although the neurotoxicity of 2,5HD is well established, there are no human data of the possible toxicity of the 2,3- and 3,4- isomers. MTT and flow cytometry were utilised to determine the cytotoxicity of hexanedione isomers in neuroblastoma cells. The neuroblastoma cell lines SK-N-SH and SH-SY5Y are sufficiently neuron-like to provide preliminary assessment of the neurotoxic potential of these isomers, in comparison with toxicity towards human non-neuronal cells. Initial studies showed that 2,5HD was the least toxic in all cell lines at all times (4, 24 and 48h). Although considerably lower than for 2,5HD, in general the IC50s for the α isomers were not significantly different from each other and, besides 4h exposure, the SH-SY5Y cells were significantly more sensitive to 2,3HD and 3,4HD than the SK-N-SH cells. All three isomers caused varying degrees of apoptosis in the neuroblastoma lines, with 3,4HD more potent than 2,3HD. Flow cytometry highlighted cell cycle arrest indicative of DNA damage with 2,3- and 3,4HD. The toxicity of the isomers towards 3 non-neuronal cell lines (MCF7, HepG2 and CaCo-2) was assessed by MTT assay. All 3 hexanedione isomers proved to be cytotoxic in all non-neuronal cell lines at all time points. These data suggest cytotoxicity of 2,3- and 3,4HD (mM range), but it is difficult to define this as specific neurotoxicity in the absence of specific neurotoxic endpoints. However, the neuroblastomas were significantly more susceptible to the cytotoxic effects of the α hexanedione isomers at exposures of 4 and 24 hours, compared to non-neuronal lines. Finally, a mechanism of toxicity is suggested for the α HD isomers whereby inhibition of the oxoglutarate carrier (OGC) releases apoptosis inducing factor (AIF), causing apoptosis-like cell death.

Apoptotic and necrotic effects of hexanedione derivatives on the human neuroblastoma line SK-N-SH

The potential cytotoxicity of two hexanedione food additives (2,3 and 3,4 isomers) was evaluated in comparison with the neurotoxic hexane metabolite 2,5-hexanedione in the human SK-N-SH neuroblastoma line using the MTT assay to indicate mitochondrial dehydrogenase activity and flow cytometry to monitor the cell cycle over 48 h. The IC50s of the 2,3-hexanedione (3.3 ± 0.1 mM) and 3,4-hexanedione (3.5 ± 0.1 mM), indicated that the sensitivity of the cells was approximately seven-fold greater to these toxins compared with the 2,5 derivative (IC50 of 22.4 ± 0.2 mM). Comparison between the respective IC50s of the 2,3-hexanedione and 3,4-hexanedione revealed no difference between the two isomers in terms of their effects on MTT turnover. With flow cytometry analysis, all three hexanediones showed increases in apoptosis within their respective concentration ranges of toxicity shown previously by MTT. In the presence of 2,5-hexanedione, between 8.5 and 17 mM concentrations, there was a significant increase in apoptotic nucleoids which was accompanied by a significant fall in the percentage of nucleoids in the G0/G1 phase (72.4 ± 0.3-45.3 ± 0.6%,), and a rise in the numbers of cells in the G2/M phase. This is likely to indicate growth arrest at cell cycle G2/M checkpoint in response to toxin damage. G2/M accumulation was also shown with 3,4 and 2,3 HD, which was maximal at much lower concentrations (approximately 4 and 3 mM, respectively). Arrest at G1 and G2/M phase is indicative of inhibition of the cell cycle at the stages of DNA replication and chromosome segregation, respectively. It was also apparent that flow cytometry, rather than the MTT assay, did distinguish between the effects of the α-diketones 2,3-hexanedione and 3,4-hexanedione on the cell cycle. At a concentration of 5.8 mM 3,4-hexanedione, the percentage of apoptotic nucleoids was 10.9 ± 0.8% whilst apoptosis induced by 3,4-hexanedione had already reached a maximal level of 60.4 ± 0.5%. In summary, flow cytometry indicated that the 3,4-hexanedione derivative was more toxic than its 2,3 isomer and that both food additives caused interruption in the neuroblastoma cell cycle and further investigation may be required to assess if these α-diketones present in diets pose any possible risks to human health. © 2006 Elsevier Ireland Ltd. All rights reserved.

Medicines management strategies to improve antibiotic prescribing

A systematic review was conducted to explicitly identify interventions that alone, or in combination, were effective in improving antibiotic prescribing. The citation search strategy used in the present review provided a database of 365077 studies, of which only twenty-five were included in the final review (“review studies”). Analysis of the interventions used within the review studies indicated that a combination of “guidelines” and “pharmacy” interventions have the greatest potential to improve antibiotic prescribing. Two types of qualitative research were conducted, semi-structured interviews and the collection of naturally occurring data. Semi-structured interviews were conducted in order to determine NHS managers? perceptions of current policies used to improve antibiotic prescribing within selected Primary Care Trusts and highlighted the importance of pharmacy intervention, formularies or guidelines and improved prescribing analysis (IT based intervention) on improving antibiotic prescribing. This was supported by the collection of naturally occurring data, which was used to provide further insight into interventions used to improve antibiotic prescribing. The Specialist Antibiotic Pharmacist (HD) produced and implemented an innovative electronic antibiotic prescribing analysis tool (the Antibiotic Database) to analyse and improve antibiotic prescribing in a consistent manner. The key advantage of the Antibiotic Database was the time and money saved on producing visual electronic outputs containing an inaccurate outcome measure or time period for analysis. The results concluded that an IT based intervention, such as the Antibiotic Database should be used, in addition to the use of antibiotic guidelines and pharmacy intervention, within all sectors of the NHS in order to improve antibiotic prescribing and its analysis.

The toxicity of hexanedione isomers in neural and astrocytic cell lines

The metabolite 2,5-hexanedione (HD) is the cause of neurotoxicity linked with chronic n-hexane exposure. Acute exposure to high levels of 2,5-HD, have also shown toxic effects in neuronal cells and non-neuronal cells. Isomers of 2,5-HD, 2,3- and 3,4-HD, added to foodstuffs, are reported to be non-toxic. The acute cytotoxic effects of 2,5-, 2,3- and 3,4-HD were evaluated in neural (NT2.N, SK-N-SH), astrocytic (CCF-STTG1) and non-neural (NT2.D1) cell lines. All the cell lines were highly resistant to 2,5-HD (34-426 mM) at 4-h exposure, although sensitivity was greatest with NT2.D1, then SK-N-SH, NT2.N and finally the CCF-STTG1 line. At 24-h exposure, cell vulnerability increased 5-10-fold. The NT2.D1 cells were again the most sensitive, followed by NT2.N, SK-N-SH and then the CCF-STTG1 cells. 2,3- and 3,4-HD (8-84 mM), were significantly more toxic towards all four cell lines compared with 2,5-HD, after 4-h exposure. After 24-h exposure there was a 12-fold increase in inhibition of MTT turnover in the SK-N-SH cells and a 4-fold increase in the CCF-STTG1 cells, compared with 2,5-HD exposure. 2,3- and 3,4-HD, were significantly less toxic to the NT2.N cells than the SK-N-SH cells after 24-h exposure to the compounds, demonstrating a differing toxin vulnerability between these neural and neuroblastoma cell lines. This study indicates that these non-neuronal and neuronal cells are acutely resistant to 2,5-HD cytotoxicity, whilst the previously unreported sensitivity of all four cell lines to the 2,3- and 3,4- isomers of HD to has been shown to be significantly greater than that of 2,5-HD. © 2006 Elsevier B.V. All rights reserved.

Hausdorff Distances for Searching in Binary Text Images

This work has been partially supported by Grant No. DO 02-275, 16.12.2008, Bulgarian NSF, Ministry of Education and Science.

Mélyszegénységből a felsőoktatásba (From deep poverty to higher education)

A társadalmi egyenlőtlenségek növekedése és a mobilitás csökkenése világszerte aggasztó tendenciákat mutat. Magyarországon a közoktatás szegényeket sújtó, feltűnően diszkriminatív jellege az elmúlt évtizedekben súlyos veszélybe sodorta a társadalmi mobilitást. A felsőoktatás-politika a belépést nehezítve (minimumpont- emelések, duális tandíjrendszer, tandíjemelések) és a teljesítményelvet túlhajszolva tovább súlyosbította a helyzetet, amit a Diákhitel–2 bevezetése sem tudott ellensúlyozni egy olyan környezetben, ahol az állam felsőoktatás-ellenes propagandát folytat, és közben drasztikusan csökkenti a finanszírozást. A hibás szabályozás miatt a többletpontok rendszere sem működik megfelelően. Mindezek miatt a halmozottan hátrányos helyzetű hallgatók felsőoktatás-beli részaránya felvételkor jelenleg fél százalék körül mozog, ami a gimnáziumi férőhelyek tervezett radikális szűkítése miatt várhatóan el fogja érni az abszolút nulla szintet. A tanulmányban bemutatunk egy általunk indított civil kezdeményezést, a Híd a felsőoktatásba elnevezésű programot, amelynek célja, hogy segítséget nyújtson a hátrányos helyzetű, főként roma középiskolásoknak a sikeres egyetemi felvételihez és a diploma megszerzéséhez. A fő tanulság: viszonylag kevés pénzből és rövid idő alatt még akkor is lehet eredményeket elérni, ha az általános társadalmi és politikai környezet egyáltalán nem támogató.

Emóció – Ráció: Tervezés – Vezetés: Designkommunikáció

Legyen az mérnöki tervezői folyamat, orvostudomány, üzlet, építészet vagy festészet nem azzal foglalkozik, hogy mi szükséges, hanem hogy mi lehetséges: röviden designnal (Simon, 1996). A design tehát alkotói magatartás, kreatív tervezés, tervezőművészet. Ehhez társul a kommunikáció, a tervezői, alkotói, kreatív kapcsolatteremtés, úgy az önreflexió, mint az interhumánus fenomén szintjén. Így hát a designkommunikáció egy olyan kapcsolatteremtési szemléletet képvisel, amely HÍD-ként jelenik meg a különböző diszciplínák, a társadalom és a gazdaság jelenségei között. Módszerével valósidejű kapcsolatot lehet teremteni oktatás, kutatás és vállalkozás között. Az élethosszig tartó tanulás a ma vezetője és tervezője számára egyaránt evidencia. A tanulás lehetőségét a saját területről, diszciplínából, komfort zónából való kilépés teremtheti meg: olyan helyzetekből, ahol a tervező tanul a menedzsertől, a vezető a művésztől, a közgazdász a mérnöktől és mindezt úgy, hogy az egyetemi évek a valódi karrier (identitás, inkubáció, akceleráció, start-up, vállalkozás, önálló vezérfonal stb.), azaz az életpálya-építés integráns részévé válnak. A szerzők interdiszciplináris megközelítésű cikkükben bemutatják, hogy a ma vállalatvezetője hogyan működhet designerként. Tanulmányuk szemlélete kettős: a tervezőművész és a közgazdász diaglógusa: ötvözi a rigorózus tudományos irodalomfeldolgozás retorikáját és a gyakorlati tervezői és vezetői párbeszéd érveléstechnikáját. A közvetlenül adaptálható elméleti keretek bemutatása mellett, felvázolják egy olyan képzési program koncepcióját, melynek célja vezető-tervezői/tervező-vezetői kompetenciák átadása.