Variation and genetic control of individual recombination rates in Norwegian Red dairy cattle.

Meiotic recombination is an important evolutionary mechanism that breaks up linkages between loci and creates novel haplotypes for selection to act upon. Understanding the genetic control of variation in recombination rates is therefore of great interest in both natural and domestic breeding populations. In this study, we used pedigree information and medium-density (∼50K) genotyped data in a large cattle (Bos taurus) breeding population in Norway (Norwegian Red cattle) to investigate recombination rate variation between sexes and individual animals. Sex-specific linkage mapping showed higher rates in males than in females (total genetic length of autosomes = 2,492.9 cM in males and 2,308.9 cM in females). However, distribution of recombination along the genome showed little variation between males and females compared with that in other species. The heritability of autosomal crossover count was low but significant in both sexes (h2 = 0.04 and 0.09 in males and females, respectively). We identified 2 loci associated with variation in individual crossover counts in female, one close to the candidate gene CEP55 and one close to both MLH3 and NEK9. All 3 genes have been associated with recombination rates in other cattle breeds. Our study contributes to the understanding of how recombination rates are controlled and how they may vary between closely related breeds as well as between species.

Using genomic prediction to detect microevolutionary change of a quantitative trait.

Detecting microevolutionary responses to natural selection by observing temporal changes in individual breeding values is challenging. The collection of suitable datasets can take many years and disentangling the contributions of the environment and genetics to phenotypic change is not trivial. Furthermore, pedigree-based methods of obtaining individual breeding values have known biases. Here, we apply a genomic prediction approach to estimate breeding values of adult weight in a 35-year dataset of Soay sheep (Ovis aries). Comparisons are made with a traditional pedigree-based approach. During the study period, adult body weight decreased, but the underlying genetic component of body weight increased, at a rate that is unlikely to be attributable to genetic drift. Thus cryptic microevolution of greater adult body weight has probably occurred. Genomic and pedigree-based approaches gave largely consistent results. Thus, using genomic prediction to study microevolution in wild populations can remove the requirement for pedigree data, potentially opening up new study systems for similar research.

Genetic architecture and lifetime dynamics of inbreeding depression in a wild mammal.

Inbreeding depression is ubiquitous, but we still know little about its genetic architecture and precise effects in wild populations. Here, we combine long-term life-history data with 417 K imputed SNP genotypes for 5952 wild Soay sheep to explore inbreeding depression on a key fitness component, annual survival. Inbreeding manifests in long runs of homozygosity (ROH), which make up nearly half of the genome in the most inbred individuals. The ROH landscape varies widely across the genome, with islands where up to 87% and deserts where only 4% of individuals have ROH. The fitness consequences of inbreeding are severe; a 10% increase in individual inbreeding FROH is associated with a 60% reduction in the odds of survival in lambs, though inbreeding depression decreases with age. Finally, a genome-wide association scan on ROH shows that many loci with small effects and five loci with larger effects contribute to inbreeding depression in survival.

Angle closure glaucoma in the Northern Ireland Diabetic Retinopathy Screening Programme.

PurposeTo ascertain the risk of angle closure glaucoma associated with mydriasis in the Northern Ireland Diabetic Retinopathy Screening Programme.MethodsA retrospective case note review was carried out, cross referencing hospital records with those of the screening programme, to identify episodes of angle closure glaucoma, which occurred within 14 days of a retinopathy screening episode involving pharmacological mydriasis.ResultsThree cases of angle closure following mydriasis for screening were identified. The incidence of angle closure within the screening programme was calculated to be 1 in 31 755 patients dilated or 0.75 patients per year.ConclusionAngle closure is a rare complication of mydriasis used in photographic screening for diabetic retinopathy. We advocate the provision of clear instructions to patients in screening programmes on when and how to access emergency ophthalmic care following dilation to prevent loss of vision in this rare event.

Horn type and horn length genes map to the same chromosomal region in Soay sheep.

The evolution of male weaponry in animals is driven by sexual selection, which is predicted to reduce the genetic variability underlying such traits. Soay sheep have an inherited polymorphism for horn type in both sexes, with males presenting with either large, normal horns or small, deformed horns (scurs). In addition, there is additive genetic variation in horn length among males with normal horns. Given that scurred males cannot win conflicts with normal-horned males, it is unusual that genes conferring scurs should persist in the population. Identifying the genetic basis of these traits should help us in understanding their evolution. We developed microsatellite markers in a targeted region of the Soay sheep genome and refined the location of the Horns locus (Ho) to a approximately 7.4 cM interval on chromosome 10 (LOD=8.78). We then located quantitative trait loci spanning a 34 cM interval with a peak centred close to Ho, which explained the majority of the genetic variation for horn length and base circumference in normal-horned males (LOD=2.51 and LOD=1.04, respectively). Therefore, the genetic variation in both horn type and horn length is attributable to the same chromosomal region. Understanding the maintenance of horn type and length variation will require an investigation of selection on genotypes that (co)determine both traits.

Butterfly speciation and the distribution of gene effect sizes fixed during adaptation.

Mimicry has had a significant historical influence as a tractable system for studying adaptation and is known to play a role in speciation. Here, we discuss recent theoretical treatment of adaptive walks to local adaptive peaks and contrast this with the adaptive landscape of mimicry. Evolution of novel Müllerian mimicry patterns almost certainly involves substitution of a major mutation to provide an initial similarity to the model, such that major gene effects are expected to an even greater degree than for other adaptive traits. The likelihood of large adaptive peak shifts in mimicry evolution may therefore promote speciation. In addition, mimicry adaptive peaks are determined by the local abundance of particular patterns and may be more fluid than the case for other traits. It will therefore be of considerable interest to test empirically the distribution of effect sizes fixed during mimicry evolution. Here, we show the feasibility of this by presenting a preliminary quantitative trait locus (QTL) analysis of Heliconius colour patterns. This shows that a number of modifier loci of different effect sizes influence forewing band morphology. We also show multiple pleiotropic effects of major Heliconius patterning loci and discuss the likelihood of multiple substitutions at the same loci in pattern evolution, which would inflate the importance of major loci in QTL analysis of the gene effect sizes. Analyses such as these have the potential to uncover the genetic architecture of both within and between species adaptive differences.

Preventing alcohol-related harm in college students: Alcohol-related Harm Prevention program effects on hypothesized mediating variables.

The Alcohol-related Harm Prevention (AHP) program is a normative education and skill-acquisition program designed to reduce serious, long-term alcohol-related harm in college students. Without admonishing students not to drink, which is likely to fail in many student populations, the AHP program attempts to give students the necessary perceptions, motivation and skills to intervene within their peer group, and to make proactive harm-avoidance plans with friends prior to social occasions that involve using alcohol. The AHP program is a two-session, in-class intervention that corrects misperceived norms regarding levels of alcohol use, caring about friends, acceptability of risky behaviors and willingness to intervene. The program also makes use of interactive discussions with students and a graded, peer interview assignment to identify and promote harm-prevention strategies. The AHP program was implemented during fall 1999 at a large northeastern university. The program was received very well by students and showed significant effects on the proximal outcomes hypothesized to mediate more distal health-relevant outcomes.

Capillary electrophoretic analysis of alkaline phosphatase inhibition by theophylline.

An analytical method for studying enzyme inhibition has been developed using capillary electrophoresis with laser-induced fluorescence detection. This technique is based on electrophoretic mixing of zones of enzyme and inhibitor in substrate-filled capillaries. Enzyme catalytic activity is measured by detecting the fluorescent reaction product as it migrates past the detector. Reversible enzyme inhibition is indicated by a transient decrease in product formation. The enzyme, alkaline phosphatase, has been studied using the fluorogenic substrate AttoPhos ([2,2'-bibenzothiazol]-6-hydroxy-benzthiazole phosphate). This assay has been used to quantify theophylline, a noncompetitive, reversible inhibitor of alkaline phosphatase. The detection limit for theophylline is estimated at 3 microM, and 8.6 amole of alkaline phosphatase are required for each assay. The calculated K(i) for theophylline is 90 microM for the capillary electrophoretic enzyme-inhibitor assays.

Renewing professionalism: an opportunity for medicine.

In recent decades, both the concept and the performance of professionals have been widely questioned. Professionalism and the idea of service have been placed under intense pressure, but they have survived. Medicine may now have an opportunity to reestablish itself as a respected, influential, and useful profession in Western society. The authors believe this could occur (1) because of the strength of the democratic process and the place of organized medicine within it; (2) because medicine's role as a source of relatively impartial expertise is being reestablished (because medicine no longer controls the health care system); and (3), most important, because of the importance of the individual physician as healer in both society's view of medicine and medicine's view of itself. To take advantage of this opportunity, the authors offer several recommendations, including (1) that medicine must continue current efforts to place first the doctor-patient relationship (the role of the healer) and the idea of service in redefining and fulfilling its obligations to society; (2) that there be a comprehensive education campaign to help physicians understand professionalism and its obligations (which the authors define); and (3) that physicians should assume responsibility for their local and national associations. If the individual medical professional and all the institutions connected with the practice and teaching of medicine truly understand and seek to fulfill their contracts with society and the obligations derived from these, the morality inherent in medical professionalism can be a dominant force, and better health care will result.

Using a computerized scheduling system to predict procedure lengths.

To determine the effectiveness of our computerized OR scheduling system and database, we compared scheduled surgical procedure lengths to actual procedure lengths for a large, multispecialty sample (1,103 procedures in 14 surgical subspecialties). We were able to accurately predict procedure lengths, within 15 minutes, 65% of the time. The estimated procedure lengths were more accurate in some surgical subspecialties than others, and four specific factors accounted for a large percentage (ie, 84%) of all delayed start times.

Bayesian inference for model-based segmentation of computed radiographs of the hand.

We present a method for medical image understanding by computer that uses model-based, hierarchical Bayesian inference to accurately segment imaged anatomy. A first application is a prototype system that automatically segments and measures symptoms of arthridities in hand radiographs. This is potentially useful in radiological diagnosis and tracking of arthridities. Key steps of the model-based, Bayesian inference approach are: (1) prediction of imagery features from 3D models of anatomy, parameterized by population statistics, (2) local image feature extraction in predicted sub-regions, and (3) the use of a probabilistic calculus to accrue results of image processing and image feature matching procedures in support or denial of hypotheses about the imaged anatomy. The prototype system for hand radiograph analysis accurately segments normal and somewhat degenerated hand anatomy. Results are shown of the ability of the automated system to 'fail soft', recognizing when segmentation is inadequate for accurate measurement. This self evaluation capability improves reliability of measurements for potential clinical use.

Serious unintentional injuries associated with architectural glass.

Injuries associated with architectural glass have become a matter of considerable concern in recent years. Despite this concern there has been no attempt to document either the extent of the problem in New Zealand or the circumstances under which these events occur. In this study, national injury mortality data for the period 1977-86 were examined and cases selected if the cause of death was attributable to an event involving architectural glass. A total of nine deaths were identified. All discharges from New Zealand public hospitals during 1986 were examined to identify victims who had been treated for injuries associated with architectural glass. Descriptive information contained on each patient record was coded to provide more specific information on the circumstances of injury. A total of 501 first admissions to hospital were identified, giving an incidence rate of 15 per 100,000 persons per year. The highest rate of 60 per 100,000 per year, was found for males in the age group 15-24 years. Seventy-eight percent of the events involved males, 62% occurred at home, 64% involved windows, and 32% involved doors. Ninety-three percent of the injuries were open wounds. Seventy-nine percent of the injuries were to the upper limbs, 13% were to lower limbs and 5% were to the head. The mean length of stay in hospital was 3.3 days. Opportunities for injury prevention are discussed including visual and physical barriers, mandatory glazing standards and public education. Specific areas requiring further research are identified.

Purposely self-inflicted injury resulting in death and hospitalisation in New Zealand.

Purposely self-inflicted injury is the second most common cause of injury death in New Zealand and is also a major cause of hospitalisation. Despite the significance of the problem there has been relatively little research undertaken in New Zealand. Injury mortality and morbidity data files for 1984 were examined and upgraded to provide as comprehensive an overview of this injury problem as the data would permit. The results show that the fatality rate was highest amongst the elderly, and males had higher death rates than females for all ages. In contrast to this, hospitalisation rates peaked among the 15-20 year olds and females had higher rates than males for all ages. Whereas Maori had a significantly lower fatality rate than non-Maori the converse was the case for hospitalisation. A more consistent effect occurred for marital status, the married group had significantly lower fatality and hospitalisation rates than the non-married group. The major occupational group "production, transport and labourers" had the highest mortality rate, whereas service workers, in particular house staff, had the highest rate of morbidity. Whereas hanging was the most common method (33%) used in fatal injury events, poisoning was the most common method (91%) used for those events which resulted in hospitalisation. In the latter case, psychotropic agents, in particular tranquillisers, accounted for 50 per cent of all poisoning. These data show that mortality experience is not a reliable guide to injury morbidity experience. Prevention is discussed in the context of limiting the availability and lethality of agents.

Tizanidine (DS103-282), a centrally acting muscle relaxant, selectively depresses excitation of feline dorsal horn neurones to noxious peripheral stimuli by an action at alpha 2-adrenoceptors.

The effects of microiontophoretic ejection of tizanidine were compared with those of adrenoceptor agonists on responses of single laminae IV and V neurones to noxious and innocuous cutaneous stimuli. Tizanidine, noradrenaline and clonidine depressed neuronal responses to noxious but not innocuous stimuli. Spontaneous activity was also depressed by these three substances. By contrast, beta- and alpha 1-adrenoceptor agonists had no consistent effect on neuronal responses to cutaneous stimuli. The selective actions of tizanidine, noradrenaline and clonidine were reversibly antagonized by the alpha 2-adrenoceptor antagonist RX781094 but not by WB4101 (alpha 1 antagonist). The binding of an alpha 2-adrenoceptor ligand to rat brain membranes was preferentially displaced by tizanidine. These results indicate an interaction of tizanidine with central alpha 2-adrenoceptors.

Selective antinociceptive effects of tizanidine (DS 103-282), a centrally acting muscle relaxant, on dorsal horn neurones in the feline spinal cord.

The effects of the centrally acting muscle relaxant tizanidine (DS 103-282) have been examined on the responses of laminae IV and V dorsal horn neurones to peripheral noxious and non-noxious stimuli in cats spinalized at L1. Iontophoretic ejection of tizanidine near the cell bodies of the recorded neurones or more dorsally into laminae II-III resulted in a marked and prolonged depression of excitation of laminae IV and V neurones evoked by noxious stimuli. Spontaneous firing was also depressed in many neurons but responses to innocuous stimuli were unaffected. Intravenous administration of tizanidine also produced a long lasting and selective reduction in responses of laminae IV and V neurones to noxious stimuli and depressed the long latency excitation of these neurones evoked by electrical stimulation of small diameter unmyelinated primary afferents. In contrast to the selective antinociceptive effect of tizanidine, ejection of gamma-aminobutyric acid (GABA) near laminae IV and V neurones or isoguvacine into laminae II-III produced parallel reductions in responses to noxious and non-noxious stimuli. Furthermore, ejections of the excitant amino acid kainate into laminae II-III produced parallel enhancement of responses induced by both types of stimuli. The site and mechanism of the antinociceptive action of tizanidine is not known but does not appear to involve an interaction with opiate receptors as it was not antagonized by naloxone. The possibility is discussed that tizanidine acts at synapses formed between excitatory interneurones in lamina II or III and laminae IV and V neurones, either interfering with transmitter release or its postsynaptic action. The effects of iontophoretically administered tizanidine are quite distinct from those of baclofen, which produced non-selective depression of responses to both noxious and innocuous stimuli, but were similar to those of noradrenaline. This raises the possibility that noradrenaline and tizanidine may act at a common site in the spinal cord.

Descending inhibitions from the nucleus raphe magnus and adjacent reticular formation to the dorsal horn of the rat are not antagonized by bicuculline or strychnine.

The effects of iontophoretically applied bicuculline and strychnine on brainstem-and segmental-evoked inhibitions of dorsal horn cells have been examined in the rat. Both antagonists failed to reduce the descending inhibitory influences at concentrations which selectively blocked responses to GABA or glycine and segmentally-derived inhibitions of the same neurones. These results suggest that neither GABA nor glycine is involved in brainstem inhibition of rat dorsal horn cells.