Association of preterm birth with ADHD-like cognitive impairments and additional subtle impairments in attention and arousal malleability.

BACKGROUND: Whilst preterm-born individuals have an increased risk of developing attention-deficit/hyperactivity disorder (ADHD), and are reported to have ADHD-like attention and arousal impairments, direct group comparisons are scarce. METHODS: We directly compared preterm-born adolescents (n = 186) to term-born adolescents with ADHD (n = 69), and term-born controls (n = 135), aged 11-23, on cognitive-performance, event-related potential and skin conductance level (SCL) measures associated with attention and arousal. The measures are from baseline and fast-incentive conditions of a four-choice reaction time task, previously shown to discriminate between the individuals with ADHD and controls. We aimed to establish whether preterm-born adolescents show: (a) identical cognitive-neurophysiological impairments to term-born adolescents with ADHD (b) possible additional impairments, and whether (c) the observed impairments correlate with ADHD symptom scores. RESULTS: The preterm group, like the term-born ADHD group, showed increased mean reaction time (MRT) and reaction time variability (RTV) in the baseline condition, and attenuated contingent negative variation (CNV) amplitude (response preparation) in the fast-incentive condition. The preterm group, only, did not show significant within-group adjustments in P3 amplitude (attention allocation) and SCL (peripheral arousal). Dimensional analyses showed that ADHD symptoms scores correlated significantly with MRT, RTV and CNV amplitude only. CONCLUSIONS: We find impairments in cognition and brain function in preterm-born adolescents that are linked to increased ADHD symptoms, as well as further impairments, in lack of malleability in neurophysiological processes. Our findings indicate that such impairments extend at least to adolescence. Future studies should extend these investigations into adulthood.

EEG Source Imaging Indices of Cognitive Control Show Associations with Dopamine System Genes.

Cognitive or executive control is a critical mental ability, an important marker of mental illness, and among the most heritable of neurocognitive traits. Two candidate genes, catechol-O-methyltransferase (COMT) and DRD4, which both have a roles in the regulation of cortical dopamine, have been consistently associated with cognitive control. Here, we predicted that individuals with the COMT Met/Met allele would show improved response execution and inhibition as indexed by event-related potentials in a Go/NoGo task, while individuals with the DRD4 7-repeat allele would show impaired brain activity. We used independent component analysis (ICA) to separate brain source processes contributing to high-density EEG scalp signals recorded during the task. As expected, individuals with the DRD4 7-repeat polymorphism had reduced parietal P3 source and scalp responses to response (Go) compared to those without the 7-repeat. Contrary to our expectation, the COMT homozygous Met allele was associated with a smaller frontal P3 source and scalp response to response-inhibition (NoGo) stimuli, suggesting that while more dopamine in frontal cortical areas has advantages in some tasks, it may also compromise response inhibition function. An interaction effect emerged for P3 source responses to Go stimuli. These were reduced in those with both the 7-repeat DRD4 allele and either the COMT Val/Val or the Met/Met homozygous polymorphisms but not in those with the heterozygous Val/Met polymorphism. This epistatic interaction between DRD4 and COMT replicates findings that too little or too much dopamine impairs cognitive control. The anatomic and functional separated maximally independent cortical EEG sources proved more informative than scalp channel measures for genetic studies of brain function and thus better elucidate the complex mechanisms in psychiatric illness.

Disorder-specific and shared neurophysiological impairments of attention and inhibition in women with attention-deficit/hyperactivity disorder and women with bipolar disorder.

BACKGROUND: In adults, attention-deficit/hyperactivity disorder (ADHD) and bipolar disorder (BD) have certain overlapping symptoms, which can lead to uncertainty regarding the boundaries of the two disorders. Despite evidence of cognitive impairments in both disorders separately, such as in attentional and inhibitory processes, data on direct comparisons across ADHD and BD on cognitive-neurophysiological measures are as yet limited. METHOD: We directly compared cognitive performance and event-related potential measures from a cued continuous performance test in 20 women with ADHD, 20 women with BD (currently euthymic) and 20 control women. RESULTS: The NoGo-N2 was attenuated in women with BD, reflecting reduced conflict monitoring, compared with women with ADHD and controls (both p < 0.05). Both ADHD and BD groups showed a reduced NoGo-P3, reflecting inhibitory control, compared with controls (both p < 0.05). In addition, the contingent negative variation was significantly reduced in the ADHD group (p = 0.05), with a trend in the BD group (p = 0.07), compared with controls. CONCLUSIONS: These findings indicate potential disorder-specific (conflict monitoring) and overlapping (inhibitory control, and potentially response preparation) neurophysiological impairments in women with ADHD and women with BD. The identified neurophysiological parameters further our understanding of neurophysiological impairments in women with ADHD and BD, and are candidate biomarkers that may aid in the identification of the diagnostic boundaries of the two disorders.

Attention and inhibition in children with ASD, ADHD and co-morbid ASD + ADHD: an event-related potential study.

BACKGROUND: Substantial overlap has been reported between attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Deficits in executive function (EF) are characteristic of both disorders but these impairments have not been compared directly across pure and co-morbid cases using event-related potentials (ERPs). METHOD: Behavioural parameters and ERPs were recorded during a flankered cued-continuous performance test (CPT-OX) administered to 8-13-year-old boys with ASD (n = 19), ADHD (n = 18), co-morbid ASD + ADHD (n = 29) and typically developing controls (TD; n = 26). Preparatory processing (contingent negative variation, CNV) and attentional orienting (Cue-P3) at cues, response execution at targets (Go-P3), inhibitory processing at non-targets (NoGo-P3) and conflict monitoring between target and non-target trials (Go-N2 v. NoGo-N2) were examined. RESULTS: Categorical diagnoses and quantitative trait measures indicated that participants with ADHD (ADHD/ASD + ADHD) made more omission errors and exhibited increased reaction-time (RT) variability and reduced amplitude of the Cue-P3 and NoGo-P3 compared to TD/ASD participants. Participants with ASD (ASD/ ASD + ADHD) demonstrated reduced N2 enhancement from Go to NoGo trials compared to TD/ADHD participants. Participants with ASD-only displayed enhanced CNV amplitude compared to ASD + ADHD and TD participants. CONCLUSIONS: Children with ADHD show deficits in attentional orienting and inhibitory control whereas children with ASD show abnormalities in conflict monitoring and response preparation. Children with co-morbid ASD + ADHD present as an additive co-occurrence with deficits of both disorders, although non-additive effects are suggested for response preparation. Measuring ERPs that index attention and inhibition is useful in disentangling cognitive markers of ASD and ADHD and elucidating the basis of co-occurring ASD + ADHD to guide clinical assessment.

Different heritabilities but shared etiological influences for parent, teacher and self-ratings of ADHD symptoms: an adolescent twin study.

BACKGROUND: Parent and teacher ratings of attention deficit hyperactivity disorder (ADHD) symptoms yield high estimates of heritability whereas self-ratings typically yield lower estimates. To understand why, the present study examined the etiological overlap between parent, teacher and self-ratings of ADHD symptoms in a population-based sample of 11-12-year-old twins. Method Participants were from the Twins Early Development Study (TEDS). ADHD symptoms were assessed using the Strengths and Difficulties Questionnaire (SDQ) hyperactivity scale completed by parents, teachers and children. Structural equation modeling was used to examine genetic and environmental contributions to phenotypic variance/covariance. RESULTS: The broad-sense heritability of ADHD symptoms was 82% for parent ratings, 60% for teacher ratings and 48% for self-ratings. Post-hoc analyses revealed significantly higher heritability for same-teacher than different-teacher ratings of ADHD (76% v. 49%). A common pathway model best explained the relationship between different informant ratings, with common genetic influences accounting for 84% of the covariance between parent, teacher and self-rated ADHD symptoms. The remaining variance was explained by rater-specific genetic and non-shared environmental influences. CONCLUSIONS: Despite different heritabilities, there were shared genetic influences for parent, teacher and self-ratings of ADHD symptoms, indicating that different informants rated some of the same aspects of behavior. The low heritability estimated for self-ratings and different-teacher ratings may reflect increased measurement error when different informants rate each twin from a pair, and/or greater non-shared environmental influences. Future studies into the genetic influences on ADHD should incorporate informant data in addition to self-ratings to capture a pervasive, heritable component of ADHD symptomatology.

The relationship between ADHD and key cognitive phenotypes is not mediated by shared familial effects with IQ.

BACKGROUND: Twin and sibling studies have identified specific cognitive phenotypes that may mediate the association between genes and the clinical symptoms of attention deficit hyperactivity disorder (ADHD). ADHD is also associated with lower IQ scores. We aimed to investigate whether the familial association between measures of cognitive performance and the clinical diagnosis of ADHD is mediated through shared familial influences with IQ. METHOD: Multivariate familial models were run on data from 1265 individuals aged 6-18 years, comprising 920 participants from ADHD sibling pairs and 345 control participants. Cognitive assessments included a four-choice reaction time (RT) task, a go/no-go task, a choice-delay task and an IQ assessment. The analyses focused on the cognitive variables of mean RT (MRT), RT variability (RTV), commission errors (CE), omission errors (OE) and choice impulsivity (CI). RESULTS: Significant familial association (rF) was confirmed between cognitive performance and both ADHD (rF=0.41-0.71) and IQ (rF=-0.25 to -0.49). The association between ADHD and cognitive performance was largely independent (80-87%) of any contribution from etiological factors shared with IQ. The exception was for CI, where 49% of the overlap could be accounted for by the familial variance underlying IQ. CONCLUSIONS: The aetiological factors underlying lower IQ in ADHD seem to be distinct from those between ADHD and RT/error measures. This suggests that lower IQ does not account for the key cognitive impairments observed in ADHD. The results have implications for molecular genetic studies designed to identify genes involved in ADHD.

Metabonomic analysis identifies molecular changes associated with the pathophysiology and drug treatment of bipolar disorder.

Bipolar affective disorder is a severe and debilitating psychiatric condition characterized by the alternating mood states of mania and depression. Both the molecular pathophysiology of the disorder and the mechanism of action of the mainstays of its treatment remain largely unknown. Here, (1)H NMR spectroscopy-based metabonomic analysis was performed to identify molecular changes in post-mortem brain tissue (dorsolateral prefrontal cortex) of patients with a history of bipolar disorder. The observed changes were then compared to metabolic alterations identified in rat brain following chronic oral treatment with either lithium or valproate. This is the first study to use (1)H NMR spectroscopy to study post-mortem bipolar human brain tissue, and it is the first to compare changes in disease brain with changes induced in rat brain following mood stabilizer treatment. Several metabolites were found to be concordantly altered in both the animal and human tissues. Glutamate levels were increased in post-mortem bipolar brain, while the glutamate/glutamine ratio was decreased following valproate treatment, and gamma-aminobutyric acid levels were increased after lithium treatment, suggesting that the balance of excitatory/inhibitory neurotransmission is central to the disorder. Both creatine and myo-inositol were increased in the post-mortem brain but depleted with the medications. Lastly, the level of N-acetyl aspartate, a clinically important metabolic marker of neuronal viability, was found to be unchanged following chronic mood stabilizer treatment. These findings promise to provide new insight into the pathophysiology of bipolar disorder and may be used to direct research into novel therapeutic strategies.

Lipolysis and lipogenesis from glucose in human fat cells of different sizes. Effects of insulin, epinephrine, and theophylline.

Lipogenesis from glucose and lipolysis in human omental and subcutaneous fat cells were studied as functions of adipose cell size and number in adult females. Since subcutaneous fat cells were larger than those prepared from the greater omentum, a comparison could be made of the metabolism of different sizes of cells within individual subjects. Rates per cell of glyceride-glycerol and glyceride-fatty acid synthesis from glucose were similar in omental and subcutaneous fat cells incubated in the presence or absence of insulin. However, subcutaneous fat cells exhibited higher rates of basal lipolysis than omental fat cells and these differences were maintained when lipolysis was stimulated with theophylline. Different rates of lipolysis were not demonstrable after incubations with epinephrine, indicating that subcutaneous fat cells were less responsive to this hormone than smaller omental fat cells. Correlation and partial correlation analysis showed that differences in basal and theophylline-stimulated lipolysis between fat cells prepared from different subjects and between omental and subcutaneous fat cells could be accounted for by differences in adipose cell volume. In subcutaneous fat cells highly significant intercorrelations were demonstrated between cell volume, basal lipolysis, and the basal conversion of glucose to glyceride-glycerol. There was no correlation between fat cell volume, age, or relative obesity and the effects of theophylline or insulin on lipolysis or lipogenesis from glucose in vitro when the data were expressed as percentage changes above basal values.

Callous-unemotional traits moderate executive function in children with ASD and ADHD: A pilot event-related potential study.

Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are associated with varied executive function (EF) difficulties. Callous-unemotional (CU) traits, a proposed antecedent of adult psychopathy, are often associated with intact or enhanced EF. Here we test whether CU traits may therefore modulate EF in ASD and ADHD, in which EF is typically impaired. We collected CU traits and measured event-related potentials (ERPs) that index EF during a cued-continuous performance test (CPT-OX) in boys with ASD, ADHD, comorbid ASD+ADHD and typical controls. We examined attentional orienting at cues (Cue-P3), inhibitory processing at non-targets (NoGo-P3) and conflict monitoring between target and non-target trials (Go-N2 vs. NoGo-N2). In children with ASD, higher CU traits were associated with an enhanced increase in N2 amplitude in NoGo trials compared to Go trials, which suggests relatively superior conflict monitoring and a potential cognitive strength associated with CU traits. The results emphasise the importance of considering the effects of co-occurring traits in the assessment of heterogeneity of EF profiles in neurodevelopmental disorders.

Correlation of the production of plasminogen activator with tumor metastasis in B16 mouse melanoma cell lines.

The correlation between the production of plasminogen activator (PA) of tumors and their metastatic potential was studied. B16 melanoma cells and "B16 mets" cells (harvested from the pulmonary metastatic nodules of C57BL/6J mice bearing B16 isografts) were examined with respect to their fibrinolytic activity (FA) in tissue culture. B16 mets cells had a significantly higher FA than did B16 cells. F1 (a B16 subline with a lower incidence of metastasis) and F10 (a highly metastatic B16 subline) were also studied. F10 cells produced more FA than did F1 cells. The difference between the FA's of these tumors was due to differences in their PA production. Significant differences in PA production between F1 and F10 could be consistently observed when 10(5) or more cells were cultured for at least 24 hr. The cell-free supernatants harvested from 72-hr cultures of F10 cells had a higher FA than those harvested from F1 cultures. Results suggest that a quantitative difference in PA production between these 2 melanoma sublines does exist and that it may contribute to their different metastatic potential.

Techniques and errors in scintigraphic measurements of gastric emptying.

For the monitoring of gastric emptying, a gamma camera or scanner operating from one side of the patient is subject to variations of counting efficiency due to the changing depth of radioactivity. A double-headed scanner was used to investigate the effects of such changes. Tc-99m and In-113m were used as labels for the solid and liquid components of a meal. It was found that the depth of Tc-99m within the stomach decreased by a mean of 13 mm during the first half hour of emptying. Anterior detection alone underestimated emptying rates by an average of 26%. Death changes also introduced errors into "early emptying" measurements made unilaterally. Such artifacts of measurement may compromise mathematical analyses of emptying patterns.

The effect of povidone-iodine irrigation on perineal wound healing following proctectomy for carcinoma.

Fifty-six patients undergoing abdomino-perineal excision of the rectum for carcinoma were randomized to receive twice daily irrigation of the perineal wound with either 1% povidone-iodine (PVP-I) or normal saline for 5 days following surgery. The incidence of perineal wound infection, primary and delayed wound healing and persistent sinus formation was recorded. There was a highly significant reduction in perineal wound infection in the PVP-I group (P less than 0.01) and this was true even if perineal wound contamination had occurred during operation (P less than 0.05). Primary wound healing was significantly improved in the treatment group (P less than 0.02) and this was found also in the presence of contamination (P less than 0.005). There was no significant difference between the treated and control group in the incidence of delayed wound healing and persistent sinus formation.

The effect of posture on errors in gastric emptying measurements.

Scintigraphic gastric emptying measurements were made with subjects supine and upright using a dual-detector rectilinear scanner. Previously reported variations of the depth of activity during the course of a study were again found with both postures. Although there was no significant mean depth change in the group when upright, some individual variations were substantial. Measurements with a gamma camera demonstrated similar changes of depth of stomach contents with seated subjects. The resulting variations of attenuation of the emergent radiation lead to appreciable errors in the emptying rates determined by unilateral detection. In about half the cases the mean movement of a 99Tcm-labelled solid phase marker exceeded 1 cm; such a movement led to an average 20% error in emptying rate determination by an anterior detector. Depth changes of a liquid marker were less marked, exceeding 0.5 cm in half the subjects; this movement gave rise to an average 6% error when 113Inm was used as the tracer.

Comparison of extraperitoneal and transperitoneal methods of aorto-iliac reconstruction. Twenty years experience.

The operative technique of extraperitoneal approach to the aorta is described. The results of operation on the aorta using this technique are compared with those using the standard transperitoneal approach.

Double-blind comparison of captopril with nifedipine in hypertension complicated by intermittent claudication.

In a double-blind, crossover trial 12 patients with hypertension and peripheral arterial disease were randomized to three months' treatment with captopril 25-50 mg twice daily or nifedipine SR 20-40 mg twice daily. While both treatments were equally effective at lowering blood pressure, postexercise calf blood flow availability was greater during treatment with captopril (P less than 0.04). This was not reflected in walking capacity assessed by treadmill exercise. The results suggest that both captopril and nifedipine are appropriate antihypertensive agents in patients with peripheral arterial disease.

The effect of dopamine on renal function during aortic cross clamping.

Eighteen male patients undergoing elective surgical reconstruction of the abdominal aorta were divided into two groups. Patients in Group I (nine) were given dopamine intravenously, in a dose of 2 micrograms/kg/min, during the first half of the period of cross-clamping, whilst those in Group II received dopamine during the second half. Each patient acted as his own control and for each, three periods were examined, namely: pre-clamp, clamping with dopamine and clamping without dopamine. Dopamine infusion during aortic clamping caused a significant rise in sodium output (P less than 0.01), potassium output (P less than 0.05), creatinine clearance (P less than 0.05) and urine output (P less than 0.05). We conclude that dopamine infusion during aortic clamping helps to protect the kidney from any deleterious effect of clamping.