Genetic influence on ERP slow wave measures of working memory

Individual differences in the variance of event-related potential (ERP) slow wave (SW) measures were examined. SW was recorded at prefrontal and parietal sites during memory and sensory trials of a delayed-response task in 391 adolescent twin pairs. Familial resemblance was identified and there was a strong suggestion of genetic influence. A common genetic factor influencing memory and sensory SW was identified at the prefrontal site (accounting for an estimated 35%-37% of the reliable variance) and at the parietal site (51%-52% of the reliable variance). Remaining reliable variance was influenced by unique environmental factors. Measurement error accounted for 24% to 30% of the total variance of each variable. The results show genetic independence for recording site, but not trial type, and suggest that the genetic factors identified relate more directly to brain structures, as defined by the cognitive functions they support, than to the cognitive networks that link them.

Genetic covariance among measures of information processing speed, working memory, and IQ

The genetic relationship between lower (information processing speed), intermediate (working memory), and higher levels (complex cognitive processes as indexed by IQ) of mental ability was studied in a classical twin design comprising 166 monozygotic and 190 dizygotic twin pairs. Processing speed was measured by a choice reaction time (RT) task (2-, 4-, and 8-choice), working memory by a visual-spatial delayed response task, and IQ by the Multidimensional Aptitude Battery. Multivariate analysis, adjusted for test-retest reliability, showed the presence of a genetic factor influencing all variables and a genetic factor influencing 4- and 8-choice RTs, working memory, and IQ. There were also genetic factors specific to 8-choice RT, working memory, and IQ. The results confirmed a strong relationship between choice RT and IQ (phenotypic correlations: -0.31 to -0.53 in females, -0.32 to -0.56 in males; genotypic correlations: -0.45 to -0.70) and a weaker but significant association between working memory and IQ (phenotypic: 0.26 in females, 0.13 in males; genotypic: 0.34). A significant part of the genetic variance (43%) in IQ was not related to either choice RT or delayed response performance, and may represent higher order cognitive processes.

Optical encoding of microbeads for gene screening: alternatives to microarrays

Rapid access to genetic information is central to the revolution presently occurring in the pharmaceutical industry, particularly In relation to novel drug target identification and drug development. Genetic variation, gene expression, gene function and gene structure are just some of the important research areas requiring efficient methods of DNA screening. Here, we highlight state-of-the-art techniques and devices for gene screening that promise cheaper and higher-throughput yields than currently achieved with DNA microarrays. We include an overview of existing and proposed bead-based strategies designed to dramatically increase the number of probes that can be interrogated in one assay. We focus, in particular, on the issue of encoding and/or decoding (bar-coding) large bead-based libraries for HTS.

Hydromorphone-3-glucuronide - A more potent neuro-excitant than its structural analogue, morphine-3-glucuronide

In humans, hydromorphone (HMOR) is metabolised principally by conjugation with glucuronic acid to form hydromorphone-3-glucuronide (H3G), a close structural analogue of morphine-3-glucuronide (M3G), the major metabolite of morphine. In a previous study we described the biochemical synthesis of H3G together with a preliminary evaluation of its pharmacology which revealed that it is a neuro-excitant in rats in a manner analogous to M3G. Thus the aims of the current study were to quantify the neuro-excitatory behaviours evoked by intracerebroventricular (icv) H3G in the rat and to define its potency relative to M3G. Groups of adult male Sprague-Dawley rats received icy injections (1 muL) of H3G (1 - 3 mug), M3G (2 - 7 mug) or vehicle via a stainless steel guide cannula that had been implanted stereotaxically seven days prior to drug administration. Behavioural excitation was monitored by scoring fifteen different behaviours (myoclonic jerks, chewing, wet-dog-shakes, rearing, tonic-clonic-convulsions, explosive motor behaviour, grooming, exploring, general activity, eating, staring, ataxia, righting reflex, body posture, touch evoked agitation) immediately prior to icy injection and at the following post-dosing times: 5, 15, 25, 35, 50, 65 and 80 min. H3G produced dose-dependent behavioural excitation in a manner analogous to that reported previously for M3G by our laboratory and reproduced herein. H3G was found to be approximately 2.5-fold more potent than M3G, such that the mean (+/- S.D.) ED50 values were 2.3 (+/- 0.1) mug and 6.1 (+/- 0.6) mug respectively. Thus, our data clearly imply that if H3G crosses the BBB with equivalent efficiency to M3G, then the myoclonus, allodynia and seizures observed in some patients dosed chronically with large systemic doses of HMOR, are almost certainly due to the accumulation of sufficient H3G in the central nervous system, to evoke behavioural excitation. (C) 2001 Elsevier Science Inc. All rights reserved.

Corneal endothelial response to induced myopia in the chicken

Purpose: To investigate the role of corneal endothelial surface enlargement in the chicken myopia model in inducing corneal endothelial changes. Methods: Lid suture was performed on one eye of 1-day-old cockerels. Five chickens were killed at 1 week, and four chickens killed at each of 3 weeks, 6 weeks, and 10 weeks postnatal. The endothelial morphology was obtained by flat mounting the endothelial surface and the subsequent digitisation. Comparisons were undertaken between the control unsutured eye and the lid-sutured eye endothelium, and between the central endothelial areas compared to the peripheral endothelial areas in both the myopic and the normal corneas. Calculation of the contribution to the endothelial change by hypertrophy and mitosis were calculated using Bahn's formula. Results: Total endothelial surface area increased significantly over time in the myopic model compared to control eyes but the mean cell area of endothelial cells remained the same for both the enlarged myopic endothelial surface area and in the normal controls. Sampling from the central and the peripheral corneal endothelial surface also disclosed no difference. The mean cell area did increase steadily with age but was the same for both normal and myopic corneas. Conclusions: It would appear that there are equal contributions from hypertrophy and mitosis in the myopic group and the normal corneal group with a slightly increasing trend towards mitotic activity in the myopic corneal endothelial layer.

Review of treatment of pterygium in Queensland: 10 years after a primary survey

Purpose: To assess the practices in pterygium removal as a follow-up study to a similar project 10 years ago, in order to compare the current trends with those noted a decade ago. Methods: A survey was sent to all practising ophthalmologists in Queensland (100). Results: Eighty-seven of the 100 ophthalmologists undertook pterygium surgery with no change in indications for removal, grading or anaesthesia compared to 10 years ago. Nearly half of the ophthalmologists varied their surgical technique from eight commonly used methods according to the individual patient. More than half the respondents used a swinging conjunctival flap and 29% used simple excision leaving the area bare for primary pterygia, although nearly one-quarter of the ophthalmologists added adjunctive therapies such as beta irradiation or mitomycin. For recurrent pterygia, one-third of ophthalmologists preferred adjunctive therapies, and 57% used an autoconjunctival transplant. Conclusion: There has been no consistent trend in surgical removal of pterygia with a significant number of primary pterygia still removed using bare scleral closure.

Conversion of glucosamine to galactosamine and allosamine derivatives: Control of inversions of stereochemistry at C-3 and C-4

The reactions of sodium benzoate with a series of trimesylates derived from glucosamine have been examined in an attempt to gain facile access to galactosamine analogues. Trimesylate 17, in which the amino group was protected as a phthalimide, underwent double displacement at positions 4 and 6 to give the dibenzoate 18 with the desired galactosamine configuration. In contrast, trimesylates 21 and 27, in which the amino groups were protected as acetamides, unexpectedly underwent double displacement at positions 3 and 6, giving products 22 and 28, respectively, with allosamine configurations.

Genetics of brain function and cognition

There is overwhelming evidence for the existence of substantial genetic influences on individual differences in general and specific cognitive abilities, especially in adults. The actual localization and identification of genes underlying variation in cognitive abilities and intelligence has only just started, however. Successes are currently limited to neurological mutations with rather severe cognitive effects. The current approaches to trace genes responsible for variation in the normal ranges of cognitive ability consist of large scale linkage and association studies. These are hampered by the usual problems of low statistical power to detect quantitative trait loci (QTLs) of small effect. One strategy to boost the power of genomic searches is to employ endophenotypes of cognition derived from the booming field of cognitive neuroscience This special issue of Behavior Genetics reports on one of the first genome-wide association studies for general IQ. A second paper summarizes candidate genes for cognition, based on animal studies. A series of papers then introduces two additional levels of analysis in the ldquoblack boxrdquo between genes and cognitive ability: (1) behavioral measures of information-processing speed (inspection time, reaction time, rapid naming) and working memory capacity (performance on on single or dual tasks of verbal and spatio-visual working memory), and (2) electrophyiosological derived measures of brain function (e.g., event-related potentials). The obvious way to assess the reliability and validity of these endophenotypes and their usefulness in the search for cognitive ability genes is through the examination of their genetic architecture in twin family studies. Papers in this special issue show that much of the association between intelligence and speed-of-information processing/brain function is due to a common gene or set of genes, and thereby demonstrate the usefulness of considering these measures in gene-hunting studies for IQ.

Genetics of cognition: Outline of a collaborative twin study

Amultidisciplinary collaborative study examining cognition in a large sample of twins is outlined. A common experimental protocol and design is used in The Netherlands, Australia and Japan to measure cognitive ability using traditional IQ measures (i.e., psychometric IQ), processing speed (e.g., reaction time [RT] and inspection time [IT]), and working memory (e.g., spatial span, delayed response [DR] performance). The main aim is to investigate the genetic covariation among these cognitive phenotypes in order to use the correlated biological markers in future linkage and association analyses to detect quantitativetrait loci (QTLs). We outline the study and methodology, and report results from our preliminary analyses that examines the heritability of processing speed and working memory indices, and their phenotypic correlation with IQ. Heritability of Full Scale IQ was 87% in the Netherlands, 83% in Australia, and 71% in Japan. Heritability estimates for processing speed and working memory indices ranged from 33–64%. Associations of IQ with RT and IT (−0.28 to −0.36) replicated previous findings with those of higher cognitive ability showing faster speed of processing. Similarly, significant correlations were indicated between IQ and the spatial span working memory task (storage [0.31], executive processing [0.37]) and the DR working memory task (0.25), with those of higher cognitive ability showing better memory performance. These analyses establish the heritability of the processing speed and working memory measures to be used in our collaborative twin study of cognition, and support the findings that individual differences in processing speed and working memory may underlie individual differences in psychometric IQ.

The reliability of immunohistochemistry as a prescreening method for the diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC) - Results of an international collaborative study

Hereditary nonpolyposis colorectal cancer syndrome (HNPCC) is an autosomal dominant condition accounting for 2–5% of all colorectal carcinomas as well as a small subset of endometrial, upper urinary tract and other gastrointestinal cancers. An assay to detect the underlying defect in HNPCC, inactivation of a DNA mismatch repair enzyme, would be useful in identifying HNPCC probands. Monoclonal antibodies against hMLH1 and hMSH2, two DNA mismatch repair proteins which account for most HNPCC cancers, are commercially available. This study sought to investigate the potential utility of these antibodies in determining the expression status of these proteins in paraffin-embedded formalin-fixed tissue and to identify key technical protocol components associated with successful staining. A set of 20 colorectal carcinoma cases of known hMLH1 and hMSH2 mutation and expression status underwent immunoperoxidase staining at multiple institutions, each of which used their own technical protocol. Staining for hMSH2 was successful in most laboratories while staining for hMLH1 proved problematic in multiple labs. However, a significant minority of laboratories demonstrated excellent results including high discriminatory power with both monoclonal antibodies. These laboratories appropriately identified hMLH1 or hMSH2 inactivation with high sensitivity and specificity. The key protocol point associated with successful staining was an antigen retrieval step involving heat treatment and either EDTA or citrate buffer. This study demonstrates the potential utility of immunohistochemistry in detecting HNPCC probands and identifies key technical components for successful staining.