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In this (Nuffield Council on Bioethics 2002), the third in its series on ethics and related issues in genetics (see also Nuffield Council on Bioethics 1993 and Nuffield Council on Bioethics 1998), the Nuffield Council has focused on four'normal' behaviors; intelligence, personality, antisocial behavior and sexual orientation. This is a narrow range of behaviors and one where their discussion of the potential impact of predictive genetic testing is probably inappropriate. They also take an unduly narrow view of the purposes of behavior genetics in the 21st century. It is not simply to estimate heritability but to understand more about the structure of behavior and the processes which underlie it. Their narrow focus and their negative approach to the history and achievements of genetics is reflected in their less than positive support for future behavior genetic research. Behavior geneticists need to do more to publicize what their field has achieved in order to counter the very extensive antibehavior genetics initiatives which are almost unique in science. At the same time, organizations such as the Nuffield Council need to consider carefully the impact their deliberations may have on research funding.

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Previous genetic analyses of psychosis proneness have been limited by their small sample size. For the purposes of large-scale screening, a 12-item questionnaire was developed through a two-stage process of reduction from the full Chapman and Chapman scales. 3685 individuals (including 1438 complete twin pairs) aged 18-25 years and enrolled in the volunteer Australian Twin Registry returned a mail questionnaire which included this psychosis proneness scale and the Eysenck Personality Questionnaire. Despite the brevity of the questionnaire, item and factor analysis identified four unambiguous and essentially uncorrelated scales. There were (1) Perceptual Aberration--Magical Ideation; (2) Hypomania--Impulsivity/Nonconformity; (3) Social Anhedonia and (4) Physical Anhedonia. Model-fitting analyses showed additive genetic and specific environmental factors were sufficient for three of the four scales, with the Social Anhedonia scale requiring also a parameter for genetic dominance. There was no evidence for the previously hypothesised sex differences in the genetic determination of psychosis-proneness. The potential value of multivariate genetic analysis to examine the relationship between these four scales and dimensions of personality is discussed. The growing body of longitudinal evidence on psychosis-proneness suggests the value of incorporating this brief measure into developmental twin studies.

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We estimated genetic and environmental influences on mother-rated DSM-III-R separation anxiety disorder (SAD) symptoms in 2043 3 to 18-year-old male and female twin pairs and their siblings (348 pairs) recruited from the Australian NH&MRC Twin Registry. Using DeFries and Fulker's (1985) multiple regression analysis, we found that genetic and shared environmental influences both contributed appreciably to variation in SAD symptoms (h2 = .47, SE = .07; c2 = .21, SE = .05) and were significantly moderated by both sex and age. Genetic influences were greater for girls than boys (h2 = .50 and .14, respectively), whereas shared environmental influences were greater for boys than girls (c2 = .51 and .21, respectively). Genetic influences increased with age. whereas shared environmental influences decreased with age. Shared environmental influences were greater in magnitude for twins than for nontwin siblings (c2 = .28 versus .13, respectively). Implications of these findings for theories of the cause of separation anxiety are discussed.

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This article reports on the results of a multiple regression analysis of an adolescent multiple drug use index on 17 predictor variables from the PRIDE CANADA Drug survey with 18,685 Grades 9 through 12 students in two Western Canadian provinces in 1995-96. The predictor variables represent eight familial, five school and peer, and four individual level attributes and behaviours. The regression analysis is used to estimate the combined effects along with the relative importance of the predictor variables on the students' self-reported use of 11 drugs combined into a multiple drug use index. Separate analyses are conducted for the male and female students. The results indicate that two of the most important predictor variables are the frequency with which both the female and male students report getting into trouble at school and the frequency of the students' participation in worship. The relative importance of these two variables and other variables in relation to the students' multiple use of drugs differ to some extent for the two genders.

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AIM: To review the rate of retinal detachment after macular hole surgery in patients who received vitrectomy and scleral buckle versus those who had vitrectomy alone. METHODS: All patient charts and hospital records were examined for patients who underwent vitrectomy surgery for macular hole between September 1993 and June 1997. A total of 326 patients were identified and all were followed for a minimum of 6 months. Clinical records were examined for details of the surgical procedure, visual acuity, hole closure status, adjuvant therapies used, and postoperative retinal attachment status. Relative risks (the ratio of the incidence rate in the exposed to that in the unexposed) with 95% confidence intervals and chi(2) tests were calculated to determine which variables were associated with retinal detachment. The primary outcome measure in this review was retinal attachment status. RESULTS: Of 326 eyes which underwent surgery for macular hole during the study period, scleral buckles were utilised in 152 (46.6%) patients. Analysis revealed a detachment rate of 13.2% in patients who did not receive a scleral buckle compared with 5.9% detachment rate in those who did. Analysis of these results indicated a 2.42 times greater risk of developing a retinal detachment in patients without a scleral buckle. Complications related to the use of scleral buckles occurred in two of 152 cases (1.3%) CONCLUSIONS: A reduction in the rate of retinal detachment was noted in patients receiving prophylactic scleral buckles. Those finding suggest a possible beneficial effect of this adjunctive procedure in preventing postoperative retinal detachments. The authors are currently preparing a multicentred, prospective, clinical trial to further study this hypothesis

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In the current study, movement ability and underlying kinaesthetic processes of boys with attention deficit-hyperactivity disorder (ADHD) were compared with a group of control children. Two groups of 16 boys with either predominantly inattentive subtype ADHD (ADHD-PI) or combined subtype ADHD (ADHD-C) were compared with 16 control boys matched on age and verbal IQ. The findings demonstrated that the children with ADHD had significantly poorer movement ability than the control children. A high percentage of children with ADHD displayed movement difficulties consistent with developmental coordination disorder. In addition, the current study found that the type and degree of movement difficulty differed between subtypes. Children with ADHD-PI had significantly poorer fine motor skill while children with ADHD-C were found to experience significantly greater difficulty with gross motor skill. The severity of the children's inattentive symptomatology was found to be a significant predictor of motor coordination difficulties. Kinaesthetic sensitivity was not found to differ significantly between the groups.

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Analogs of the antitumor agents cryptophycins 1 and 8 with dialkyl substitution at C-6 (fragment C) were synthesized and evaluated for in vitro cytotoxicity against human leukemia cells (CCRF-CEM). The activity of these analogs decreased as the size of the substituents at C-6 increased. The C-6 spirocylopropyl compound (2g) was highly potent in vitro and showed excellent antitumor activity in animal models.

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BACKGROUND: Symptoms of attention-deficit/hyperactivity disorder (ADHD) have been associated with frontal lobe deficits. We used a novel brain electrical imaging method to investigate rapid and continuous changes in brain activity during the continuous performance task (CPT) in normal boys and in boys with ADHD. The amplitude and latency topography of the steady-state visually evoked potential (SSVEP) were examined while subjects performed the "X" version of the CPT (CPT-X; the reference task) and the "A-X" version of the CPT (CPT-AX). METHODS: Seventeen boys meeting DSM-III-R criteria for ADHD and 17 age-matched controls participated in the study. Brain electrical activity was recorded from 64 scalp sites. During the reference task, subjects pressed a microswitch on the unpredictable appearance of the letter X. During the CPT-AX, subjects were required to press the microswitch on the appearance of the letter X only if an A had preceded it. RESULTS: In the interval between the appearances of the A and the X of the correct trials of the CPT-AX, control boys showed transient reductions in SSVEP latency at right prefrontal sites. By contrast, boys with ADHD showed no change or an increase in prefrontal SSVEP latency at right prefrontal sites. CONCLUSION: Our results suggest increased speed of prefrontal neural processing in children without ADHD following a priming stimulus, and a deficit in such processes in children with ADHD.

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OBJECTIVE: Mental health registers contain diagnoses from serial contacts with mental health facilities over many years. This study examines the relationship between longitudinal diagnostic profiles and structured interview diagnoses. The aim is to improve the definition of diagnoses drawn from clinical case registers. METHOD: The Tasmanian Mental Health Case Register includes 1922 individuals, each with at least one diagnosis of schizophrenia between 1965 and 1990. A representative subsample of 29 individuals were assessed by the structured diagnostic interview for DSM-III-R (SCID). Diagnostic agreement between Register and SCID diagnoses was compared. RESULTS: Twenty-four subjects (82.8%) received a lifetime diagnosis of schizophrenia on the SCID. For each subject, 'schizophrenia diagnostic dominance', the percentage of register entries with schizophrenia diagnoses over total entries, was calculated. Agreement between register and SCID correlated positively with schizophrenia diagnostic dominance and negatively with register mood diagnoses. CONCLUSIONS: Longitudinal diagnostic profiles on databases may be superior to cross-sectional clinical diagnoses in predicting structured interview diagnoses, and may be useful in defining caseness in epidemiological studies using register diagnoses.

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OBJECTIVE: The aim of this study was to examine the rate of rehospitalisation for schizophrenia, bipolar disorder and depression over a 5-year period in Tasmania, and to identify predictors of the number and duration of readmissions. METHOD: The Tasmanian Mental Health Register was used to study the 5-year pattern of rehospitalisation for all patients admitted to a Tasmanian public psychiatric inpatient facility with a primary diagnosis of schizophrenia, bipolar disorder or depression, in 1983 or 1984. RESULTS: Seventy-one percent of patients receiving a diagnosis of schizophrenia were readmitted in the 5-year period, compared to 59% for bipolar disorder and 48% for depression. For all three diagnoses, the number of prior admissions was a predictor of the number of readmissions and the total number of days spent in hospital in the follow-up period. Age and sex also had significant effects, which varied across diagnostic groups. CONCLUSIONS: A substantial proportion of patients hospitalised for schizophrenia, bipolar disorder or schizophrenia were rehospitalised during the next 5 years. Patients with more previous admissions had more readmissions than those with fewer previous admissions.

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We studied twins to examine the genetics of epilepsy syndromes. We ascertained 358 twin pairs in whom one or both reported seizures. After evaluation, 253 of 358 (71%) had seizure disorders and 105 pairs were false positives. Among the monozygous (MZ) pairs, more were concordant for seizures (48 of 108; casewise concordance = 0.62 +/- 0.05) than among the dizygous (DZ) pairs (14 of 145; casewise concordance = 0.18 +/- 0.04). In 94% of concordant MZ pairs, and 71% of concordant DZ pairs, both twins had the same major epilepsy syndrome. When analyzed according to major epilepsy syndrome, the casewise concordances for generalized epilepsies (MZ = 0.82; DZ = 0.26), both idiopathic (MZ = 0.76; DZ = 0.33) and symptomatic (MZ = 0.83; DZ = 0), were greater than those for partial epilepsies (MZ = 0.36; DZ = 0.05), with intermediate values seen for febrile seizures (MZ = 0.58; DZ = 0.14) and unclassified epilepsies (MZ = 0.53; DZ = 0.18). We conclude that genetic factors are particularly important in the generalized epilepsies but also play a role in the partial epilepsies. The high frequency of concordant MZ pairs with the same major syndrome strongly suggests there are syndrome-specific genetic determinants rather than a broad genetic predisposition to seizures.

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OBJECTIVE: To investigate heritability and continuum versus categorical approaches to attention-deficit hyperactivity disorder (ADHD), using a large-scale twin sample. METHOD: A cohort of 1,938 families with twins and siblings aged 4 to 12 years, recruited from the Australian National Health and Medical Research Council Twin Registry, was assessed for ADHD using a DSM-III-R-based maternal rating scale. Probandwise concordance rates and correlations in monozygotic and dizygotic twins and siblings were calculated, and heritability was examined using the De Fries and Fulker regression technique. RESULTS: There was a narrow (additive) heritability of 0.75 to 0.91 which was robust across familial relationships (twin, sibling, and twin-sibling) and across definitions of ADHD as part of a continuum or as a disorder with various symptom cutoffs. There was no evidence for nonadditive genetic variation or for shared family environmental effects. CONCLUSIONS: These findings suggest that ADHD is best viewed as the extreme of a behavior that varies genetically throughout the entire population rather than as a disorder with discrete determinants. This has implications for the classification of ADHD and for the identification of genes for this behavior, as well as implications for diagnosis and treatment.

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OBJECTIVES: Seasonal affective disorder (SAD) is a variant of recurrent depression in which episodes are linked to a particular season, typically winter. SAD is understood as the extreme end of a continuum of seasonality in the general population. Photoperiod (the timing and duration of daylight) has been assumed to be aetiologically critical. The present research used a survey design to investigate the assumed centrality of photoperiod for SAD/seasonality in Australia. Two hypotheses were tested: that self-reported seasonality does not increase further from the equator and that seasonality does not stand alone from non-seasonal neurotic complaints. METHOD: The sampling frame used was adult females on the Australian Twin Registry roll. A sample of 526 women residing across the latitudes of Australia responded to a survey based around the Seasonal Pattern Assessment Questionnaire (SPAQ). The SPAQ asks respondents to retrospectively report on season-related changes in mood and behaviour. The survey also contained three questionnaire measures of neurotic symptoms of anxiety and depression: the General Health Questionnaire (GHQ), the Community Epidemiological Survey for Depression (CES-D) and the State-Trait Anxiety Inventory-Trait (STAI-T). RESULTS: Self-reported seasonality did not correlated with latitude (r = 0.01, NS). On the other hand, a substantial relationship was found between seasonality and each of the measures of non-seasonal complaints: GHQ (r = 0.35, p < 0.001); CES-D (r = 0.35, p < 0.001); and STAI-T (r = 0.30, p < 0.001). CONCLUSIONS: Within the limitations of a design based on retrospective self-report, the findings of the present study suggest that the diathesis for SAD/seasonality may not be photoperiod-specific. At least in Australia, there is provisional support for the proposal that human seasonality may have a broader psychological component. The findings are discussed in terms of established research into normal mood, trait personality and non-seasonal depression.

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OBJECTIVE: The purpose of the present study was to determine whether there was a significant seasonal variation in the birth dates of patients with schizophrenia born in Tasmania. METHOD: The season of birth in Tasmanian-born patients with schizophrenia (n = 1412), born between 1919-1970, was compared with general population data. RESULTS: No significant variation in month or quarter of birth was detected for the subjects with schizophrenia. Neither was there any significant seasonal excess when data from different decades were analysed separately, nor for subsidiary analyses of gender or paranoid/non paranoid subtype. CONCLUSION: These results are compared with those of six other published studies of Australasian-born subjects identified through registers in different States. While both positive and negative results are reported, no clear pattern emerges. The relevance of season of birth to the development of schizophrenia in Australia remains an open question.

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Changes in the rates of diagnosis of schizophrenia in Tasmania, Australia during the period of 1965-1990 were examined using records from the State mental health case register. Analyses were restricted to subjects with diagnoses recorded between the ages of 20 and 29 years in order to reduce possible errors caused by age-standardized methods. There was a significant decrease in the rate of non-paranoid subtypes of schizophrenia in female subjects, accompanied by a commensurate rise in the rate of bipolar diagnoses in that group. Differential changes in male and female subjects support explanations of phenotypic shifts in presentation of psychosis as well as changes in diagnostic practice.

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alpha-Phenyl-tert-butyl nitrone (PBN) is a nitrone spin trap, which has shown efficacy in animal models of oxidative stress, including stroke, aging, sepsis, and myocardial ischemia/reperfusion injury. We have prepared a series of novel cyclic variants of PBN and evaluated them for radical trapping activity in vitro. Specifically, their ability to inhibit iron-induced lipid peroxidation in liposomes was assessed, as well as superoxide anion (O2(-.)) and hydroxyl radical ((.)OH) trapping activity as determined biochemically and using electron spin resonance (ESR) spectroscopy. All cyclic nitrones tested were much more potent as inhibitors of lipid peroxidation than was PBN. The unsubstituted cyclic variant MDL 101,002 was approximately 8-fold more potent than PBN. An analysis of the analogs of MDL 101,002 revealed a direct correlation of activity with lipophilicity. However, lipophilicity does not solely account for the difference between MDL 101,002 and PBN, inasmuch as the calculated octanol/water partition coefficient for MDL 101,002 is 1.01 as compared to 1.23 for PBN. This indicated the cyclic nitrones are inherently more effective radical traps than PBN in a membrane system. The most active compound was a dichloro analog in the seven-membered ring series (MDL 104,342), which had an IC50 of 26 mum, which was 550-fold better than that of PBN. The cyclic nitrones were shown to trap (.)OH with MDL 101,002 being 20 25 times more active than PBN as assessed using 2-deoxyribose and p-nitrosodimethylaniline as substrates, respectively. Trapping of (.)OH by MDL 101,002 was also examined by using ESR spectroscopy. When Fenton's reagent was used, the (.)OH adduct of MDL 101,002 yielded a six-line spectrum with hyperfine coupling constants distinct from that of PBN. Importantly, the half-life of the adduct was nearly 5 min, while that of PBN is less than 1 min at physiologic pH. MDL 101,002 also trapped the O2(-.) radical to yield a six-line spectrum with coupling constants very distinct from that of the (.)OH adduct. In mice, the cyclic nitrones ameliorated the damaging effects of oxidative stress induced by ferrous iron injection into brain tissue. Similar protection was not afforded by the lipid peroxidation inhibitor U74006F, thus implicating radical trapping as a unique feature in the prevention of cell injury. Together, the in vivo activity, the stability of the nitroxide adducts, and the ability to distinguish between trapping of (.)OH and O2(-.) suggest the cyclic nitrones to be ideal reagents for the study of oxidative cell injury.

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Mental impairment and instability of the CCG repeat at FRAXE is described in six kindreds. Cosegregation of FRAXA and FRAXE was found within one of these kindreds. Cytogenetic expression of FRAXE was shown to skip a generation when associated with a reduction in size of the CCG expansion when transmitted through a male; however, in general, transmission occurred through females and a copy number increased from one generation to the next. In these respects the behaviour of FRAXE paralleled that of FRAXA. A relationship between FRAXE and non-specific mental impairment is strongly suggested by the occurrence in these families of more mentally impaired male and female carriers, after removal of index cases, than could reasonably be expected by chance.

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Many laboratory and clinical studies suggest that oxygen radical formation and resultant cell damage contribute to CNS injury following stroke and neurotrauma. Accordingly, antioxidants represent a viable therapeutic approach for management of CNS oxidative damage. Recently, several investigators have reported that the spin trap PBN protects against stroked-induced damage and reduces aging-associated neurological deficits. We have prepared and tested a cyclic analog of PBN, MDL 101,002, in a number of in vitro and in vivo assays designed to assess its neuroprotective properties. MDL 101,002 was found to be an effective .OH trap, to inhibit lipid peroxidation, and to decrease infarct size in a gerbil model of stroke. These results further indicate that oxidative damage arising from stroke contributes to infarct formation, and that spin traps are effective in ameliorating ischemia and reperfusion-induced CNS injury.

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The recent claims for a decline in intelligence test performance in males and females with fragile-X (fra(X)) syndrome have implications both clinically and in evaluating the underlying neurological basis. This commentary identifies three key issues in evaluating evidence for a decline and in planning future, more co-ordinated efforts. These are (1) problems in combining data across different intelligence tests and/or different ages with potentially incompatible norms, task demands, and models of the structure of intelligence; (2) limitations in applying to low ability persons tests designed to discriminate best around the population average; and (3) specific cognitive deficits and behavioral problems in fra(X) individuals which may be confounded with the task demands of particular IQ tests at particular ages. While the decline in ability may be a real phenomenon rather than an artifact, recommendations are made about the psychometric requirements for a larger and more definitive collaborative study.

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