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Objective Port-wine birthmark (PWB) is a common occurrence in the newborn, and general pediatricians, dermatologists, and ophthalmologists are often called on to make an assessment of risk for Sturge-Weber syndrome (SWS) due to workforce shortages in pediatric neurologists and MRI’s low sensitivity for SWS brain involvement in infants. We therefore aimed to develop a quantitative EEG (qEEG) approach to safely screen young infants with PWB for SWS risk and optimal timing of diagnostic MRI. Methods Forty-eight infants (prior to first birthday) underwent EEG recording. Signal processing methods compared voltage between left and right sides using a previously defined pipeline and diagnostic threshold. In this test sample, we compared sensitivity/specificity of the qEEG metric against MRI performed after the first birthday. We also used likelihood ratio testing to determine whether qEEG adds incremental information beyond topographical extent of PWB, another risk marker of brain involvement. Results qEEG helped predict SWS risk in the first year of life (p = 0.031), with a sensitivity of 50% and a specificity of 81%. It added about 40% incremental information beyond PWB extent alone (p = 0.042). Conclusion qEEG adds information to risk prediction in infants with facial PWB. Significance qEEG can be used to help determine whether to obtain an MRI in the first year of life. The data collected can assist in developing a predictive model risk calculator that incorporates both PWB extent and qEEG results, which can be validated and then employed in the community.

Background Sturge-Weber syndrome is a rare neurovascular disorder associated with capillary malformation, seizures, cognitive impairments, and stroke-like episodes (SLEs), arising from a somatic activating mutation in GNAQ. Studies suggest this mutation may cause hyperactivation of the mammalian target of rapamycin pathway. Sirolimus is an mammalian target of rapamycin inhibitor studied in other vascular anomalies and a potentially promising therapy in Sturge-Weber syndrome. Methods Ten patients with Sturge-Weber syndrome brain involvement and cognitive impairments were enrolled. Oral sirolimus was taken for six months (maximum dose: 2 mg/day, target trough level: 4-6 ng/mL). Neuropsychological testing, electroencephalography, and port-wine score were performed at baseline and after six months on sirolimus. Neuroquality of life, adverse events, and Sturge-Weber Syndrome Neurological Score (neuroscore) were recorded at each visit. Results Sirolimus was generally well tolerated; one subject withdrew early. Adverse events considered related to sirolimus were mostly (15/16) grade 1. A significant increase in processing speed was seen in the overall group (P = 0.031); five of nine patients with available data demonstrated statistically rare improvement in processing speed. Improvements were seen in the neuroquality of life subscales measuring anger (P = 0.011), cognitive function (P = 0.015), and depression (P = 0.046). Three subjects experiencing SLEs before and during the study reported shortened recovery times while on sirolimus. Conclusions Sirolimus was well tolerated in individuals with Sturge-Weber syndrome and may be beneficial for cognitive impairments, especially in patients with impaired processing speed or a history of SLE. A future, randomized, placebo-controlled trial of sirolimus in patients with Sturge-Weber syndrome is needed to further understand these potentially beneficial effects.

Children with autism spectrum disorder (ASD) have difficulties perceiving and producing skilled gestures, or praxis. The inferior parietal lobule (IPL) is crucial to praxis acquisition and expression, yet how IPL connectivity contributes to autism-associated impairments in praxis as well as social-communicative skill remains unclear. Using resting-state functional magnetic resonance imaging, we applied independent component analysis to test how IPL connectivity relates to praxis and social-communicative skills in children with and without ASD. Across all children (with/without ASD), praxis positively correlated with connectivity of left posterior-IPL with the left dorsal premotor cortex and with the bilateral posterior/medial parietal cortex. Praxis also correlated with connectivity of right central-IPL connectivity with the left intraparietal sulcus and medial parietal lobe. Further, in children with ASD, poorer praxis and social-communicative skills both correlated with weaker right central-IPL connectivity with the left cerebellum, posterior cingulate, and right dorsal premotor cortex. Our findings suggest that IPL connectivity is linked to praxis development, that contributions arise bilaterally, and that right IPL connectivity is associated with impaired praxis and social-communicative skills in autism. The findings underscore the potential impact of IPL connectivity and impaired skill acquisition on the development of a range of social-communicative and motor functions during childhood, including autism-associated impairments.

Autism spectrum disorder (ASD) consists of altered performance of a range of skills, including social/communicative and motor skills. It is unclear whether this altered performance results from atypical acquisition or learning of the skills or from atypical "online" performance of the skills. Atypicalities of skilled actions that require both motor and cognitive resources, such as abnormal gesturing, are highly prevalent in ASD and are easier to study in a laboratory context than are social/communicative skills. Imitation has long been known to be impaired in ASD; because learning via imitation is a prime method by which humans acquire skills, we tested the hypothesis that children with ASD show alterations in learning novel gestures via imitation. Eighteen participants with ASD and IQ > 80, ages 8-12.9 years, and 19 typically developing peers performed a task in which they watched a video of a model performing a novel, meaningless arm/hand gesture and copied the gesture. Each gesture video/copy sequence was repeated 4-6 times. Eight gestures were analyzed. Examination of learning trajectories revealed that while children with ASD made nearly as much progress in learning from repetition 1 to repetition 4, the shape of the learning curves differed. Causal modeling demonstrated the shape of the learning curve influenced both the performance of overlearned gestures and autism severity, suggesting that it is in the index of learning mechanisms relevant both to motor skills and to autism core features. Autism Res 2020, 13: 777-784.. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Imitation is a route by which humans learn a wide range of skills, naturally and in therapies. Imitation is known to be altered in autism spectrum disorder (ASD), but learning via imitation has not been rigorously examined. We found that the shape of the learning curve is altered in ASD, in a way that has a significant impact both on measures of autism severity and of other motor skills.

Mirror overflow is involuntary movement that accompanies unilateral voluntary movement on the opposite side of the body, and is commonly seen in Attention-Deficit/Hyperactivity Disorder (ADHD). Children with ADHD show asymmetry in mirror overflow between dominant and non-dominant hand, yet there are competing mechanistic accounts of why this occurs. Using EEG during a sequential, unimanual finger-tapping task, we found that children with ADHD exhibited significantly more mirror overflow than typically developing (TD) controls, especially during the tapping of the non-dominant hand. Furthermore, source-level EEG oscillation analysis revealed that children with ADHD showed decreased alpha (8-12 Hz) event-related desynchronization (ERD) compared with controls in both hemispheres, but only during tapping of the non-dominant hand. Moreover, only the ERD ipsilateral to the mirror overflow during non-dominant hand movement correlated with both magnitude of overflow movements and higher ADHD symptom severity (Conners ADHD Hyperactivity/Impulsiveness scale) in children with ADHD. TD controls did not show these relationships. Our findings suggest that EEG differences in finger-tapping in ADHD are related primarily to voluntary movement in the non-dominant hand. Our results are also consistent with the Ipsilateral Corticospinal Tract (CST) Hypothesis, which posits that the atypical persistence of mirror overflow in ADHD may originate in the sensorimotor areas ipsilateral to mirror overflow and be transmitted via non-decussating CST fibers.

Mirror overflow is involuntary movement that accompanies unilateral voluntary movement on the opposite side of the body, and is commonly seen in Attention-Deficit/Hyperactivity Disorder (ADHD). Children with ADHD show asymmetry in mirror overflow between dominant and non-dominant hand, yet there are competing mechanistic accounts of why this occurs. Using EEG during a sequential, unimanual finger-tapping task, we found that children with ADHD exhibited significantly more mirror overflow than typically developing (TD) controls, especially during the tapping of the non-dominant hand. Furthermore, source-level EEG oscillation analysis revealed that children with ADHD showed decreased alpha (8–12 Hz) event-related desynchronization (ERD) compared with controls in both hemispheres, but only during tapping of the non-dominant hand. Moreover, only the ERD ipsilateral to the mirror overflow during non-dominant hand movement correlated with both magnitude of overflow movements and higher ADHD symptom severity (Conners ADHD Hyperactivity/Impulsiveness scale) in children with ADHD. TD controls did not show these relationships. Our findings suggest that EEG differences in finger-tapping in ADHD are related primarily to voluntary movement in the non-dominant hand. Our results are also consistent with the Ipsilateral Corticospinal Tract (CST) Hypothesis, which posits that the atypical persistence of mirror overflow in ADHD may originate in the sensorimotor areas ipsilateral to mirror overflow and be transmitted via non-decussating CST fibers.

Objective:To determine safety and perform a preliminary assessment of dose-dependent efficacy of dextromethorphan in normalizing electrographic spikes, clinical seizures, and behavioral and cognitive functions in girls with Rett syndrome.Methods:We used a prospective randomized, open-label trial in fast metabolizers of dextromethorphan to examine the effect of dextromethorphan on core clinical features of Rett syndrome. Interictal spike activity and clinical seizures were determined using EEG and parent reporting. Cognitive data were obtained using the Mullen Scales of Early Learning and Vineland Adaptive Behavior Scales, while behavioral data were obtained from parent-completed checklists, the Aberrant Behavior Checklist–Community Version, and the Screen for Social Interaction. Anthropometric data were obtained according to the National Health and Nutrition Examination Survey. The Rett Syndrome Severity Scale provided a clinical global impression of the effect of dextromethorphan on clinical severity.Results:Dextromethorphan is safe for use in 3- to 15-year-old girls with Rett syndrome. Thirty-five girls were treated with 1 of 3 doses of dextromethorphan over a period of 6 months. Statistically significant dose-dependent improvements were seen in clinical seizures, receptive language, and behavioral hyperactivity. There was no significant improvement in global clinical severity as measured by the Rett Syndrome Severity Scale.Conclusions:Dextromethorphan is a potent noncompetitive antagonist of the NMDA receptor channel that is safe for use in young girls with Rett syndrome. Preliminary evidence suggests that dextromethorphan may improve some core features of Rett syndrome.Classification of evidence:This study provides Class IV evidence that dextromethorphan at various doses does not change EEG spike counts over 6 months, though precision was limited to exclude an important effect.

Functional connectivity differences between children with autism spectrum disorder (ASD) and typically developing children have been described in multiple datasets. However, few studies examine the task-related changes in connectivity in disorder-relevant behavioral paradigms. In this paper, we examined the task-related changes in functional connectivity using EEG and a movement-based paradigm that has behavioral relevance to ASD. Resting-state studies motivated our hypothesis that children with ASD would show a decreased magnitude of functional connectivity during the performance of a motor-control task. Contrary to our initial hypothesis, however, we observed that task-related modulation of functional connectivity in children with ASD was in the direction opposite to that of TDs. The task-related connectivity changes were correlated with clinical symptom scores. Our results suggest that children with ASD may have differences in cortical segregation/integration during the performance of a task, and that part of the differences in connectivity modulation may serve as a compensatory mechanism. Autism Res 2017. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary Decreased connectivity between brain regions is thought to cause the symptoms of autism. Because most of our knowledge comes from data in which children are at rest, we do not know how connectivity changes directly lead to autistic behaviors, such as impaired gestures. When typically developing children produced complex movements, connectivity decreased between brain regions. In children with autism, connectivity increased. It may be that behavior-related changes in brain connectivity are more important than absolute differences in connectivity in autism.

Abnormal functional connectivity was reported as one of the underlying characteristics of autism spectrum disorder (ASD). Considering the motor deficits in ASD, we utilized praxis to investigate the neural mechanisms of ASD during motor task. Since the previous functional connectivity studies reported divergent results, we explored the properties of the functional connectivity using graph metrics to address brain organization alterations of ASD. We proposed the use of eLORETA to investigate the cortical connectivity during praxis based on a cohort of 45 high-functioning ASD (HFA) children and 45 typically developing (TD) children. The between-group comparison revealed higher clustering coefficient and lower global efficiency for HFA relative to TD while the between-phase comparison suggested decreasing global efficiency, increasing characteristic path length for TD. Nodal metrics exhibited significant differences between groups in frontal and occipital regions. These regions also showed significant changes of nodal metrics and connection strengths between baseline and praxis execution for TD. However, there were no significant changes in global, nodal metrics and connection strengths between phases for HFA. Our study suggested that cortical connectivity in ASD exhibited lower overall efficiency and a deficit in reorganization, which deepens the understanding of abnormal brain organization in ASD.

The chapters in this Handbook reveal the breadth of brilliant imaging and analysis techniques designed to fulfill the mandate of cognitive neuroscience: to understand how anatomical structures and physiological processes in the brain cause typical and atypical behavior. Yet merely producing data from the latest imaging method is insufficient to truly achieve this goal. We also need a mental toolbox that contains methods of inference that allow us to derive true scientific explanation from these data. Causal inference is not easy in the human brain, where we are limited primarily to observational data and our methods of experimental perturbation in the service of causal explanation are limited. As a case study, we reverse engineer one of the most influential accounts of a neuropsychiatric disorder that is derived from observational imaging data: the connectivity theories of autism spectrum disorder (ASD). We take readers through an approach of first considering all possible causal paths that are allowed by preliminary imaging-behavioral correlations. By progressively sharpening the specificity of the measures and brain/behavioral constructs, we iteratively chip away at this space of allowable causal paths, like the sculptor chipping away the excess marble to reveal the statue. To assist in this process, we consider how current imaging methods that are lumped together under the rubric of “connectivity” may actually offer a differentiated set of connectivity constructs that can more specifically relate notions of information transmission in the mind to the physiology of the brain.

IntroductionChildren with disorders of consciousness (DOC) represent the highest end of the acquired brain injury (ABI) severity spectrum for survivors and experience a multitude of functional impairments. Current clinical management in DOC uses behavioural evaluation measures and interventions that fail to (1) describe the physiological consequences of ABI and (2) elicit functional gains. In paediatric DOC, there is a critical need to develop evidence-based interventions to promote recovery of basic responses to improve rehabilitation and aid decision-making for medical teams and caregivers. The purpose of this investigation is to examine the safety, tolerability and feasibility of transcranial direct current stimulation (tDCS) in children with DOC.Methods and analysisThis study is an open-label dose escalation trial evaluating the safety, tolerability and feasibility of tDCS in 10 children (5–17 years) receiving inpatient rehabilitation for DOC. This study will follow a modified rule-based design, allowing for intrapatient escalation, where a cohort of patients will be assigned to an initial tDCS current of 0.5 or 1 mA based on participant’s head circumference and according to the safety data available in other paediatric populations. The subsequent assignment of increased current (1 or 2 mA) according to the prespecified rules will be based on the clinical observation of adverse events in the patients. The study will include up to three, 20 min sessions of anodal tDCS (sham, 0.5 or 1 mA, 1 or 2 mA) applied over the dorsolateral prefrontal cortex. The primary outcomes are adverse events, pain associated with tDCS and intolerable disruption of inpatient care. Secondary outcomes are changes in electroencephalography (EEG) phase-locking and event-related potential components and the Coma Recovery Scale-Revised total score from prestimulation to poststimulation.Ethics and disseminationThe Johns Hopkins IRB (#IRB00174966) approved this study. Trial results will be disseminated through journals and conferences.Registration numberNCT03618849.

Biological treatment development for syndromal neuropsychiatric conditions such as autism has seen slow progress for decades. Speeding drug discovery may result from the judicious development and application of biomarker measures of brain function to select patients for clinical trials, to confirm target engagement and to optimize drug dose. For neurodevelopmental disorders, electrophysiology (EEG) offers considerable promise because of its ability to monitor brain activity with high temporal resolution and its more ready application for pediatric populations relative to MRI. Here, we discuss conceptual/definitional issues related to biomarker development, discuss practical implementation issues, and suggest preliminary guidelines for validating EEG approaches as biomarkers with a context of use in neurodevelopmental disorder drug development.

Children with autism spectrum disorders (ASD) have long been known to have deficits in the performance of praxis gestures; these motor deficits also correlate with social and communicative deficits. To date, the precise nature of the errors involved in praxis has not been clearly mapped out. Based on observations of individuals with ASD performing gestures, we hypothesized that the simultaneous execution of multiple movement elements is especially impaired in affected children. We examined 25 school-aged participants with ASD and 25 age-matched controls performing seven simultaneous gestures that required the concurrent performance of movement elements and nine serial gestures, in which all elements were performed serially. There was indeed a group × gesture-type interaction (P

Epilepsy is known to occur in a higher-than-expected proportion of individuals with autism spectrum disorders (ASDs). Prior studies of this heterogeneous disorder have suggested that intelligence quotient (IQ) may drive this relationship. Because intellectual disability (ID) is, independently of ASD, a risk factor for epilepsy, current literature calls into question the long-understood unique relationship between ASD and epilepsy. Second, data have been unclear about whether developmental regression in ASD is associated with epilepsy. Using two cohorts from an online research registry, totaling 6,975 children with ASD, we examined the independent role of four ASD severity measures in driving the relationship with epilepsy: ID, language impairment, core ASD symptom severity, and motor dysfunction, controlling for two known relevant factors: age and sex. We also examined whether developmental regression and epilepsy have an independent statistical link. All four ASD severity factors showed independent statistical associations with epilepsy in one cohort, and three in the other. ID showed the largest relative risk (RR) in both cohorts. Effect sizes were modest. Regression similarly showed an independent statistical association with epilepsy, but with small effect size. Similar to previous work, ID showed the greatest contribution to RR for epilepsy among children with ASD. However, other ASD severity markers showed statistical associations, demonstrating that the ASD-epilepsy association is not reducible to the effect of ID. Inconsistencies in the literature may be due to underpowered studies, yet moving forward with larger-n studies, clinical significance and scientific relevance may be dictated by effect size and not merely statistical significance. Autism Res 2019, 12: 1251-1259. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Epilepsy is known to occur more often in individuals with autism spectrum disorders (ASDs) than is the case in the general population. The association between ASD and epilepsy is of interest because studying the two disorders in combination may help advance our understanding of genetic, molecular, and cellular mechanisms-as well as therapies-for both. Recent studies have suggested that intelligence quotient (IQ) alone in individuals with ASD may account for the increased prevalence of epilepsy. However, our approach was to look at a range of severity factors relevant to ASD and to look for correlations between each severity factor and epilepsy, within two large samples of children with ASD. In summary, we found that each severity factor-presence of intellectual disability, presence of language atypicalities, ASD-specific symptoms severity, and presence of motor issues-independently predicted a small increased risk for epilepsy, countering the argument that IQ alone is a risk factor. We also examined whether epilepsy is associated with developmental regression. Although severe epilepsy syndromes such as Landau-Kleffner syndrome are known to cause autistic-like symptoms following developmental regression, there is controversy about whether other forms of epilepsy are associated with the more common developmental regression seen in many young children with epilepsy. Indeed, we found a small association between epilepsy and developmental regression.

Objective: We sought to examine the prevalence of EEG abnormalities in Smith-Lemli-Opitz syndrome (SLOS) as well as the relationship between interictal epileptiform discharges (IEDs) and within-subject variations in attentional symptom severity. Methods: In the context of a clinical trial for SLOS, we performed cross-sectional and repeated-measure observational studies of the relationship between EEG findings and cognitive/behavioral factors on 23 children (aged 4–17 years). EEGs were reviewed for clinical abnormalities, including IEDs, by readers blinded to participants9 behavioral symptoms. Between-group differences in baseline characteristics of participants with and without IEDs were analyzed. Within-subject analyses examined the association between the presence of IEDs and changes in attention-deficit/hyperactivity disorder (ADHD) symptoms. Results: Of 85 EEGs, 43 (51%) were abnormal, predominantly because of IEDs. Only one subject had documented clinical seizures. IEDs clustered in 13 subjects (57%), whereas 9 subjects (39%) had EEGs consistently free of IEDs. While there were no significant group differences in sex, age, intellectual disability, language level, or baseline ADHD symptoms, autistic symptoms tended to be more prevalent in the “IED” group (according to Autism Diagnostic Observation Schedule–2 criteria). Within individuals, the presence of IEDs on a particular EEG predicted, on average, a 27% increase in ADHD symptom severity. Conclusions: Epileptiform discharges are common in SLOS, despite a relatively low prevalence of epilepsy. Fluctuations in the presence of epileptiform discharges within individual children with a developmental disability syndrome may be associated with fluctuations in ADHD symptomatology, even in the absence of clinical seizures.

INTRODUCTION: Patterns and predictors of recovery from encephalitis are poorly understood. METHODS: This study examined functional status and reviewed charts of all children who presented to a pediatric inpatient rehabilitation facility with encephalitis between 1996 and 2010. Functional status at admission and discharge from inpatient rehabilitation was evaluated using the Functional Independence Measure for Children (WeeFIM) Self-care, Mobility, Cognitive, and Total Developmental Functional Quotient scores (DFQ, % of age-appropriate function). Charts were reviewed to characterize key clinical features and findings. RESULTS: Of the 13 children identified, the mean age was 9 years (range 5–16) with 54% males. Mean WeeFIM Total DFQ at admission was 37 (range: 15–90) and at discharge was 64 (range: 16–96). Average change in WeeFIM Total DFQ from admission to discharge was 26.7 (range 0–55, p< 0.001). WeeFIM domain scores improved between admission and discharge (Self-Care: p< 0.001, Cognition: p< 0.01, Mobility: p< 0.001). Eleven children displayed significant impairments in functional skills, defined as DFQ of 85, at discharge. Key clinical features and findings were diverse and not related to functional outcome. CONCLUSIONS: Results suggest that significant functional improvement in children with encephalitis occurs during inpatient rehabilitation. Further research is necessary to identify predictors of outcome in children with encephalitis.

During the past decade, the disrupted connectivity theory has generated considerable interest as a pathophysiologic model for autism spectrum disorder (ASD). This theory postulates that deficiencies in the way the brain coordinates and synchronizes activity among different regions may account for the clinical symptoms of ASD. This review critically examines the current structural and functional connectivity data in ASD and evaluates unresolved assumptions and gaps in knowledge that limit the interpretation of these data. Collectively, studies often show group alterations in what are thought of as measures of cerebral connectivity, although the patterns of findings vary considerably. There are three principal needs in this research agenda. First, further basic research is needed to understand the links between measures commonly used (e.g., diffusion tensor imaging, functional magnetic resonance imaging, electroencephalography) and other (e.g., histologic, computational) levels of analysis. Second, speculated causes of inconsistencies in the literature (e.g., age, clinical heterogeneity) demand studies that directly evaluate these interpretations. Third, the field needs well-specified mechanistic models of altered cerebral communication in ASD whose predictions can be tested on multiple levels of analysis.

There is considerable lay discussion that children with Attention-Deficit/Hyperactivity Disorder (ADHD) have increased difficult with multitasking, but there are few experimental data. In the current study, we examine the simultaneous processing of two stimulus-response tasks using the psychological refractory period (PRP) effect. We hypothesized that children with ADHD would show a greater PRP effect, suggesting a prolonged “bottleneck” in stimulus-response processing. A total of 19 school-aged children with ADHD showed a prolonged PRP effect compared with 25 control children, suggesting a higher cognitive cost in ADHD for multi-tasking.

Aim To review recent developments in the understanding, diagnosis, and treatment of Sturge–Weber syndrome (SWS). Method Members of the Brain Vascular Malformation Consortium Sturge–Weber Syndrome National Workgroup contributed their expertise to review the literature and present promising directions for research. Results The increasing number of reports dealing with SWS over the last decade reflects progress in the diagnosis and understanding of the neurological involvement. The proliferation of centers and advocacy groups to care for patients with SWS and to stimulate research has aided the development of new insights into the clinical manifestations and the pathophysiology of neurological progression, and the development of novel hypotheses to direct future research. Many key questions remain, but the tools and networks to answer them are being developed. Interpretation This review summarizes important new knowledge and presents new research directions that are likely to provide further insights, earlier diagnosis, improved treatments, and possibly, prevention of this syndrome.

Aware of parental reports of academic variability, we investigated month-to-month fluctuations in cognitive abilities and EEG status by repeated measures testing in six children with benign epilepsy with central-temporal spikes (BECTS). All showed greater than normal test-retest variability. Daytime EEG abnormalities were also variable. Short-term fluctuations in cognitive function appear common in children with BECTS, potentially impacting academic performance.

Internal action models refer to sensory-motor programs that form the brain basis for a wide range of skilled behavior and for understanding others’ actions. Development of these action models, particularly those reliant on visual cues from the external world, depends on connectivity between distant brain regions. Studies of children with autism reveal anomalous patterns of motor learning and impaired execution of skilled motor gestures. These findings robustly correlate with measures of social and communicative function, suggesting that anomalous action model formation may contribute to impaired development of social and communicative (as well as motor) capacity in autism. Examination of the pattern of behavioral findings, as well as convergent data from neuroimaging techniques, further suggests that autism-associated action model formation may be related to abnormalities in neural connectivity, particularly decreased function of long-range connections. This line of study can lead to important advances in understanding the neural basis of autism and, more critically, can be used to guide effective therapies targeted at improving social, communicative, and motor function.

Processing-speed deficits affect reading efficiency, even among individuals who recognize and decode words accurately. Children with ADHD who decode words accurately can still have inefficient reading fluency, leading to a bottleneck in other cognitive processes. This "slowing" in ADHD is associated with deficits in fundamental components of executive function underlying processing speed, including response selection. The purpose of the present study was to deconstruct processing speed in order to determine which components of executive control best explain the "processing" speed deficits related to reading fluency in ADHD. Participants (41 ADHD, 21 controls), ages 9-14 years, screened for language disorders, word reading deficits, and psychiatric disorders, were administered measures of copying speed, processing speed, reading fluency, working memory, reaction time, inhibition, and auditory attention span. Compared to controls, children with ADHD showed reduced oral and silent reading fluency and reduced processing speed-driven primarily by deficits on WISC-IV Coding. In contrast, groups did not differ on copying speed. After controlling for copying speed, sex, severity of ADHD-related symptomatology, and GAI, slowed "processing" speed (i.e., Coding) was significantly associated with verbal span and measures of working memory but not with measures of response control/inhibition, lexical retrieval speed, reaction time, or intrasubject variability. Further, "processing" speed (i.e., Coding, residualized for copying speed) and working memory were significant predictors of oral reading fluency. Abnormalities in working memory and response selection (which are frontally mediated and enter into the output side of processing speed) may play an important role in deficits in reading fluency in ADHD, potentially more than posteriorally mediated problems with orienting of attention or perceiving the stimulus.

To evaluate cortical auditory function, including speech recognition, in children with benign rolandic epilepsy (BRE).Fourteen children, seven patients with BRE and seven matched controls, underwent audiometric and behavioral testing, simultaneous EEG recordings, and auditory-evoked potential recordings with speech and tones. Speech recognition was tested under multiple listening conditions.All participants demonstrated normal speech recognition abilities in quiet, as well as normal peripheral and subcortical auditory function. BRE patients performed significantly worse than controls when speech recognition was tested under adverse listening conditions, including background noise. Five BRE patients who were impaired on two or more tests had centrotemporal spiking on awake EEG. There were no significant group differences in the latency or amplitude of early N100 cortical responses to speech or tones. Conversely, the mismatch negativity, a preattentive index of cortical processing that is elicited passively, was absent or prolonged for speech, but not tones, in BRE patients as compared to controls.Children with BRE demonstrated specific speech recognition impairments. Our evoked potential findings indicate that these behavioral impairments reflect dysfunction of nonprimary auditory cortex and cannot be attributed solely to attention difficulties. A possible association between auditory impairments and centrotemporal spiking (1/min) on awake EEG was identified. The pattern of speech recognition impairments observed is a known risk factor for academic difficulties in school-age children. Our results underscore the importance of comprehensive auditory testing, using behavioral and electrophysiological measures, in children with BRE.

Disorders of attention or learning commonly accompany neurodevelopmental disorders. The evaluation and diagnosis of these disorders is complex and does not always follow techniques used for typically developing children. These disorders are often underappreciated and inadequately addressed because they are overshadowed by the neurodevelopmental disorder. Nevertheless, failure to recognize, diagnose, and manage these disorders may result in unsuccessful community integration.

To ascertain whether there are differences in the histopathological appearance of tendinopathic Achilles and patellar tendons.In males, we studied biopsies from tendinopathic Achilles (N = 28; average age 34.1 yr) and patellar tendons (N = 28; average age 32.1), Achilles tendons (N = 21; average age 61.8 yr) from deceased patients with no known tendon pathology, and patellar tendons (N = 15; average age 28.3) from patients undergoing anterior cruciate ligament reconstruction. Hematoxylineosin stained slides were interpreted using a semiquantitative grading scale (0: normal to 3: maximally abnormal) for fiber structure, fiber arrangement, rounding of the nuclei, regional variations in cellularity, increased vascularity, decreased collagen stainability, and hyalinization. All slides were assessed blindly twice, the agreement between two readings ranging from 0.170 to 0.750 (kappa statistics).The highest mean score of tendinopathic Achilles tendons was not significantly different from that of tendinopathic patellar tendons (11.6 +/- 5 and 10.4 +/- 3, respectively). The ability to differentiate between an Achilles tendon and a patellar tendon was low.Tendinopathic Achilles and patellar tendons show a similar histological picture. It was not possible to identify whether a specimen had been harvested from an Achilles or a patellar tendon on the basis of histological examination. The general pattern of degeneration was common to both tendinopathic Achilles and patellar tendons. A common, as yet unidentified, etiopathological mechanism may have acted on both these tendon populations.

In this study we show that the characteristics of non-Hodgkin lymphoma (NHL) tumors in female Naval Medical Research Institute (NMRI, USA) mice fed mistletoe lectin (ML)-containing diets were different from those in mice fed control diet. The non-Hodgkin lymphoma tumor was originally established from a spontaneous tumor which developed in the inguinal region of a male mouse. Mice (five animals per group) were fed a lactalbumin (LA)-based control diet or a diet which provided up to 10mg lectin per day. At the highest daily intake (10mg lectin) the degree of mitotic activity in tumors was reduced by 75% and the nuclear area had diminished by 21%. The overall level of lymphocyte infiltration (CD3 positive cells) in tumors from mistletoe lectin fed mice was increased by a factor of two. Other morphological studies showed a high incidence of apoptotic bodies in non-Hodgkin lymphoma tumors obtained from mice fed mistletoe lectin diets. The feeding of such diets thus produced several identifiable changes in the morphology of non-Hodgkin lymphoma tumors. These were consistent with the observed reduction in tumor mass. In 4/15 mice fed a mistletoe lectin diet for 11 days there was no longer evidence of viable tumor. The results show that this lectin exerts powerful anti-tumor effects when provided by the oral route.

To ascertain whether there is an association between tendinopathic and ruptured Achilles tendons, hypothesizing that the histopathological aspects of tendinosis in tendinopathic tendons are less advanced than those found in ruptured Achilles tendons.This was a comparative cohort study at a university teaching hospital. Histological examination was performed using hematoxylin and eosin and alcian blue/periodic acid-Schiff stained slides. The slides were interpreted using a semiquantitative grading scale assessing fiber structure, fiber arrangement, rounding of the nuclei, regional variations in cellularity, increased vascularity, decreased collagen stainability, hyalinization, and glycosaminoglycan. We calculated a pathology score giving up to three marks for each of the above variables, with 0 being normal and 3 being maximally abnormal. All the histology slides were assessed twice in a blinded manner, the agreement between two readings ranging from 0.170 to 0.750 (kappa statistics).We studied biopsy samples from the Achilles tendon of patients undergoing open repair for a subcutaneous rupture of their Achilles tendon (N = 35; average age (+/- SD), 48.4 +/- 16.9 yr; range, 26-80), biopsy specimens from the Achilles tendon of patients undergoing exploration for Achilles tendinopathy (N = 13; average age, 35.7 +/- 12.9 yr; range, 18-67) and specimens of Achilles tendons from individuals with no known tendon pathology (N = 16; average age, 65 +/- 19.1 yr; range, 46-82). The highest mean score of ruptured tendons was significantly greater than that of tendinopathic tendons (17.4 +/- 4.9 vs 10.5 +/- 6.1, P0.001), and highest mean score of tendinopathic tendons was greater that that of control tendons (10.5 +/- 6.1 vs 5.9 +/- 7.3) (P0.001).Ruptured and tendinopathic tendons are histologically significantly more degenerated than control tendons. The general pattern of degeneration was common to the ruptured and tendinopathic tendons, but there was a statistically significant greater degree of degeneration in the ruptured tendons. It is therefore possible that there is a common, as yet unidentified, pathological mechanism that has acted on both of these tendon populations.

The results presented in this study show that a switch from a non-protein diet (NPD) to one of a normal protein content (LA) on the day of subcutaneous injection of non-Hodgkin lymphoma tumour cells greatly favoured the development and growth of the tumour. Interestingly, however, inclusion of the plant lectin phytohaemagglutinin (PHA) in the LA diet appeared to compete with the effect of switch to the protein-rich diet, resulting in decreased tumour size and an increased incidence of necrosis. PHA was shown to induce hyperplasia of the gut even in the presence of the growing tumour. This observation together with the fact that gut hyperplasia also occurred in animals which were fed NPD supplemented with PHA, indicated the strength of PHA as a growth signal. It would seem likely that this 'normal' growth is able to compete with the tumour for important growth factors and nutrients, including polyamines, effectively starving the tumour for these molecules and resulting in its decreased rate of proliferation.

A child with Sturge-Weber syndrome and a left occipital leptomeningeal angioma developed focal seizures at 6 years of age that responded initially to oxcarbazepine. After 7 months of seizure freedom, the patient developed typical myoclonic-astatic seizures associated with generalized electrographic discharges, which worsened as oxcarbazepine was increased. The seizures and electroencephalogram improved dramatically in 3 weeks as the oxcarbazepine was withdrawn and valproic acid was initiated. This case demonstrates the importance of recognizing that children with epilepsy due to focal lesions can develop secondary bilateral synchrony that can be aggravated by medications that are effective for partial seizures. In such cases, treatment with a broad-spectrum antiepileptic may be advantageous.

Summary The EEG in Sturge-Weber syndrome (SWS) was theorized over 50 years ago as changing over time from normality to focal asymmetry to lastly epileptiform. We sought to validate these findings in a larger cohort today. Children with confirmed SWS and routine EEG at our center were evaluated retrospectively. An EEG score (0–3) was created and linked to patient current age, overall neurologic function, and seizure frequency. Eighty-one EEGs from 44 patients with SWS (mean age 2.0 years (range: 0.2–37.9 years)) were evaluated and assigned an EEG score. The mean age for patients with an EEG score of 0–1 (normal or focal slowing) was 3.2 years (SEM 0.6), whereas those with an EEG score of 2–3 (focal sharp waves or frequent spike-wave bursts) was 8.7 years (SEM 1.7) ( p =0.006). There was no correlation between the EEG score and either the SWS overall neuroscore or seizure subscore (measuring frequency). The EEG in patients with SWS does appear to evolve over time, becoming more abnormal with more frequent epileptiform activity, as suspected in smaller studies decades ago. This progressive change, however, did not correlate with the child's neurologic function or seizure frequency.

The major groups of enzymes involved in activating and detoxifying therapeutic drugs, not least several anti-cancer drugs, include the cytochromes P450 (P450s), epoxide hydrolase, and glutathione S-transferases (GSTs). The expression of these enzymes in malignant tumours is one possible mechanism of anti-cancer drug resistance. This study has investigated the presence, cellular localization, and distribution of drug-metabolizing enzymes in prostate cancer. The P450 subfamilies CYP1A, CYP2C, and CYP3A were present in 63, 25, and 61 per cent of tumours, respectively. Epoxide hydrolase was identified in 96 per cent of tumours. GST-alpha and GST-mu were expressed in 29 and 41 per cent of tumours, respectively, while there was no immunoreactivity for the pi form of GST. The absence of GST-pi in prostate cancer contrasts with the frequent expression of GST-pi observed in other types of malignant tumour. In non-neoplastic prostatic epithelium, there was expression of CYP1A, CYP2C, epoxide hydrolase, and the different forms of GST, while there was no apparent immunoreactivity for CYP3A.

The cytochrome P450 superfamily of enzymes play a central part in the metabolism of carcinogens and anti-cancer drugs. The expression, cellular localisation, and distribution of different forms of P450 and the functionally associated enzymes epoxide hydrolase and glutathione S-transferases have been investigated in oesophageal cancer and non-neoplastic oesophageal tissue using immunohistochemistry. Expression of the different enzymes was confined to epithelial cells in both non-neoplastic samples and tumour samples except the CYP3A was also identified in mast cells and glutathione S-transferase pi was present in chronic inflammatory cells. CYP1A was present in a small percentage of non-neoplastic samples but both CYP2C and CYP3A were absent. Epoxide hydrolase was present in half of the non-neoplastic samples and the different classes of glutathione S-transferase were present in a low number of samples. In carcinomas CYP1A, CYP3A, epoxide hydrolase, and glutathione S-transferase pi were expressed in at least 60% of samples. The expression of glutathione S-transferases alpha and mu were significantly less in adenocarcinoma compared with squamous carcinoma.

AIMS--To examine the distribution of PAI-1 antigen in normal and cirrhotic liver and liver with metastases. METHODS--Sections of normal and cirrhotic liver and liver with metastases were stained using the alkaline phosphatase antialkaline phosphatase (APAAP) technique and monoclonal antibody specific for plasminogen activator inhibitor (PAI-1). RESULTS--PAI-1 antigen was identified as discrete granules in the cytoplasm of hepatocytes in normal liver, particularly around portal tracts and central veins of the liver lobule. In cirrhotic liver a striking reduction of PAI-1 antigen was noted. In liver with metastases increased amounts of PAI-1 antigen were concentrated in hepatocytes around the margins of malignant deposits. CONCLUSIONS--Cirrhotic liver contains considerably less PAI-1 antigen than does normal liver, despite raised plasma concentrations of PAI-1. This may reflect release of hepatic PAI-1 into the circulation or decreased clearance of PAI-1 from the plasma. Secondary malignant deposits in the liver seem to stimulate production of PAI-1 in adjacent hepatocytes. This may influence the invasive process and may contribute to the thrombotic tendency associated with malignancy.

Many mutagenic nitroso compounds are also diabetogenic. Betel-nut (Areca catechu) chewing populations have an increased incidence of foregut cancers related to betel-nut nitrosamines which suggests that betel consumption could be diabetogenic. Young adult CD1 mice with a low spontaneous incidence of diabetes were fed betel nut in standard feed for 2–6 days. Single point (90 min) intra-peritoneal glucose tolerance tests were used to follow glucose tolerance up to 6 months of age. Glucose intolerance was defined as over 3 SD above mean control values. Glucose intolerance was found in 3 of 51 male and 4 of 33 female adult mice which were fed the betel diet (p

Background Cytochrome P-450, epoxide hydrolase, and glutathione S-transferase (GST) all play a key role in the metabolism of chemical carcinogens, mutagens, and various anti-cancer drugs. All these functionally associated enzymes might be involved in both the development of hepatocellular carcinoma and in determining the anti-cancer drug sensitivity of such tumors. Methods The expression of two forms of cytochrome P-450 (P-450 IA and P-450 IIIA), microsomal epoxide hydrolase, and three classes of cytosolic GST (alpha, mu, and pi) have been studied immunohistochemically in human hepatocellular carcinoma. Results The hepatocellular carcinomas were characterized by a consistently high expression of epoxide hydrolase and variable expression of the cytochromes P-450 and GST. Cytochrome P-450 IA and IIIA stained in 64.5% and 41.9% of the 31 hepatocellular carcinomas studied, respectively. Epoxide hydrolase was present in all tumors, and GST types alpha, pi, and mu were identified in 48.4%, 38.7%, and 74.2% of the hepatocellular carcinomas, respectively. Conclusions This study showed that the expression of xenobiotic-metabolizing enzymes in hepatocellular carcinoma is complex and the presence of different xenobiotic enzymes in hepatocellular carcinoma may contribute to the intrinsic drug resistance of these tumors.

AIMS: To study the localisation and distribution of albumin mRNA in normal liver and hepatocellular carcinoma by in situ hybridisation with an oligonucleotide probe. METHODS: A 51 base oligonucleotide was synthesised from a sequence at the 5' end of the human albumin gene and the probe was labelled at its 3' end with digoxigenin 11-dUTP. Formalin fixed, wax embedded sections of liver biopsy specimens were used to study the localisation and distribution of albumin mRNA. After in situ hybridisation the bound probe was visualised using a digoxigenin antibody conjugated with alkaline phosphatase. RESULTS: In normal liver albumin mRNA was detected in hepatocytes and no positive signal was observed in biliary epithelium, vascular endothelium, or Kupffer cells. In 75% (9/12) of the hepatocellular carcinomas studied a positive hybridisation signal was observed in tumour cells. CONCLUSIONS: Albumin mRNA can be detected in sections of formalin fixed, wax embedded liver, a digoxigenin labelled probe is ideally suited for in situ hybridisation of liver because there is no background from the detection system. The identification of albumin mRNA may be a useful marker of hepatocellular carcinoma, and the demonstration of albumin mRNA by in situ hybridisation overcomes the potential background problem associated with albumin immunohistochemistry.

Pulmonary lesions following paraquat poisoning are believed to be almost invariably fatal. The three patients reports here survived despite persistent radiological change. One of the patients died after taking a larger dose of paraquat one year later, and at necropsy histological changes attributable to the two episodes of paraquat poisoning were apparent.

Objective Many infants born with a facial port-wine (PW) birthmark will not develop brain involvement of Sturge–Weber syndrome (SWS). Previous studies have shown asymmetry in quantitative EEG (qEEG) correlates with degree of clinical impairment in children and adults with known SWS. We hope to determine if quantitative qEEG can be used as a method to predict which infants are most likely to develop SWS brain involvement on MRI. The current study looks at the ability of qEEG to differentiate between infants with radiographically demonstrated SWS and those without. Methods We first performed an observational study of qEEG results on eight infants with facial PW birthmark (four had SWS brain involvement). We recorded standard clinical EEGs and then derived a measure of asymmetry. We subsequently validated this threshold through a study of an additional nine infants with PW birthmark (five with SWS brain involvement). Results Quantitative EEG correctly identified infants with SWS brain involvement in all cases in the Validation cohort. This technique was at least as good as a pediatric electroencephalographer with extensive experience reading SWS EEGs. Conclusions This study demonstrates the ability for qEEG to discriminate between those infants with SWS brain involvement and those with neurologically asymptomatic PW birthmark. Significance This study represents an important step toward the development of a qEEG technique able to predict which infants with PW birthmark will develop SWS brain involvement.

OBJECTIVE--To audit the accuracy and impact on the frequency of operation of fine needle aspiration cytology of isolated thyroid swellings. DESIGN--Prospective analysis over six years of cytological predictions compared with histological findings. SETTING--Thyroid clinic serving the Grampian region. PATIENTS--395 Consecutive patients presenting with an isolated thyroid swelling, 307 of whom underwent surgical excision. Analysis was confined to a subgroup of 283 patients with satisfactory aspirates who were operated on. RESULTS--The positive predictive value of aspiration cytology for detecting malignant disease was 100% and the sensitivity 83%. The sensitivity for the detection of neoplasia (frank malignancy together with follicular adenomas) was 76%. The specificity was 58% and the overall accuracy 69%. Recalculation of data in previous papers with strict criteria showed the accuracy of aspiration cytology to be variable and lower than is widely accepted. Since the introduction of aspiration cytology 21% fewer operations for isolated thyroid swellings have been performed. CONCLUSIONS--As a basis of selection for surgical excision of isolated thyroid swellings according to prediction of neoplasia fine needle aspiration cytology is less reliable than is widely accepted. It is an adjunct to management rather than a definitive test, and negative cytological results do not exclude neoplastic disease. Further study should take account of the implications of repeated clinic attendances for review and aspiration as these may culminate in delayed surgical treatment.

Summary: Purpose: Sturge-Weber syndrome (SWS) is a neurocutaneous disorder with vascular malformations of the skin, brain, and eye. SWS results in ischemic brain injury, seizures, and neurologic deficits. We hypothesized that a decrease in quantitative EEG (qEEG) power, on the affected side, correlates with clinical severity in subjects with SWS. Methods: Fourteen subjects had 16-channel scalp EEG recordings. Data were analyzed using fast Fourier transform and calculation of power asymmetry. Blinded investigators assigned scores for clinical neurological status and qualitative assessment of MRI and EEG asymmetry. Results: The majority of subjects demonstrated lower total power on the affected side, usually involving all four frequency bands (delta, theta, alpha, and beta). qEEG asymmetry correlated strongly with neurologic clinical severity scores and MRI asymmetry scores. qEEG data generally agreed with the MRI evidence of regional brain involvement. In MRI-qEEG comparisons that did not agree, decreased power on qEEG in a brain region not affected on MRI was more likely to occur in subjects with more severe neurologic deficits. Conclusions: qEEG provides an objective measure of EEG asymmetry that correlates with clinical status and brain asymmetry seen on MRI. These findings support the conclusion that qEEG reflects the degree and extent of brain involvement and dysfunction in SWS. qEEG may potentially be a useful tool for early diagnosis and monitoring of disease progression in SWS. qEEG may prove useful, in severely affected individuals with SWS, for determining regions of brain dysfunction.

Objective To ascertain whether tendon samples harvested from patients with calcific insertional Achilles tendinopathy showed features of failed healing response, and whether abnormal quantities of type II collagen had been produced in that area by these tenocytes. Design Comparative laboratory study. Design University teaching hospitals. Patients Tendon samples were harvested from eight otherwise healthy male individuals (average age 47.5±8.4 years, range 38 to 60) who were operated for calcific insertional Achilles tendinopathy and from nine male patients who died of cardiovascular events (mean age 63.1±10.9 years) while in hospital. Interventions Open surgery for calcific insertional Achilles tendinopathy. Main Outcome Measure Semi-quantitative histochemical, immunohistochemical, and immunocytochemical methods to ascertain whether tendinopathic tendons were morphologically different from control tendons, and whether abnormal types of collagen were produced. Results Tenocytes from tendons from patients with calcific insertional Achilles tendinopathy exhibit chondral metaplasia, and produce abnormally high quantities of collagen type II and III. Conclusions The altered production of collagen may be one reason for the histopathological alterations described in the present study. Areas of calcific insertional Achilles tendinopathy have been subjected to abnormal loads. These tendons may be less resistant to tensile forces. Further studies should investigate why some tendons undergo these changes.

The expression of CYP1B1 has been identified in breast cancer using the reverse transcriptase-polymerase chain reaction and immunoblotting. CYP1B1 mRNA was expressed in the majority of breast tumours and immunoblotting of breast tumours identified a single protein band of molecular weight 60 kDa corresponding to the predicted molecular weight of human CYP1B1. This is the first study to identify CYP1B1 expression in a tumour where it may represent a previously unknown pathway for the metabolism of oestradiol and chemotherapeutic drugs.

The growth of a non-Hodgkin lymphoma, developing subcutaneously as a solid tumour in NMRI mice, is markedly diminished by including phytohaemagglutinin (PHA), a lectin present in raw kidney bean (Phaseolus vulgaris), in the diet. In the experiment described in this communication the effect of first allowing tumours to develop for 5 days before switching the mice to a diet containing PHA at different concentrations was tested to establish whether or not feeding the lectin at late times also resulted in reducing tumour growth. This switch of diet indeed proved to be effective in slowing down growth of the lymphoma tumour. The reduced rate of growth occurs in a dose-dependent manner. We have suggested that a competition between the gut epithelium undergoing PHA-stimulated hyperplasia and the developing tumour may occur for polyamines and other nutrients from a common body pool and this could be an important contributory factor with regard to the observed low level of tumour growth following the feeding of PHA-containing diet. Recent data which showed that the level of hyperplasia of the small bowel in response to feeding the PHA diets was higher in non-injected mice compared to those which had been injected with tumour cells substantiated the concept of competition between gut and tumour for nutrients and other requirements for growth.

The potential value of DNA aneuploidy, in distinguishing benign from malignant follicular thyroid neoplasms, was studied. The nuclear DNA content of 65 follicular thyroid neoplasms (52 adenomas and 13 carcinomas) was determined by flow cytometric analysis of paraffin embedded material; in 58 cases preparations were technically satisfactory. In 22 follicular neoplasms DNA analysis was also performed on fresh material obtained by fine needle aspiration of surgical specimens. Cell cycle analysis was performed on both fresh and fixed specimens. An aneuploid DNA profile was found on analysis of fixed tissue in eight of 45 (18 per cent) follicular adenomas and four of 13 (31 per cent) follicular carcinomas. DNA aneuploidy was also found in six of the 22 (27 per cent) fresh preparations from follicular adenomas. The frequency of DNA aneuploidy in apparently benign and malignant follicular neoplasms was similar. Follicular thyroid neoplasia are best regarded as a single entity with a low incidence of local and distant spread. All follicular neoplasia are therefore best excised.

In this study we have investigated the expression of a major family of cytochrome P450, cytochrome P450IA, in human breast carcinoma. Two closely related subfamilies (or forms) of cytochrome P450IA, cytochrome P450IA1 and cytochrome P450IA2 have been identified in rat and similar forms occur in man (Ioannides & Parke, 1990). The murine monoclonal antibody RM3 used in this study recognises rat cytochrome P450IA1 and not rat cytochrome P450IA2 and recognises a single band on immunoblots of human liver

The glutathione S-transferases (GSTs) are a multi-gene family of enzymes involved in detoxifying electrophilic compounds and the expression of these enzymes in tumours has been proposed as one important mechanism of anti-cancer drug resistance. In this study, the localization of the major cytoplasmic forms of GST has been studied in soft tissue sarcomas by immunohistochemistry. The alpha, mu, and pi forms of GST were identified in 59, 68, and 51 per cent of tumours, respectively. In addition, GST pi immunoreactivity was consistently identified in fibroblasts in adjacent non-neoplastic tissue. The presence of specific forms of GST in soft tissue sarcomas may contribute to the drug resistance frequently observed in these tumours.

Two major xenobiotic metabolizing sub-families of cytochrome P450 (cytochrome P450 1A and cytochrome P450 3A) have been identified in soft tissue sarcomas. Cytochrome P450 1A was present in 70 per cent and cytochrome P450 3A was present in 78 per cent of tumours, respectively. A high proportion (86 per cent) of those tumours which contained cytochrome P450 1A or cytochrome P450 3A demonstrated co-expression of both sub-families. In each tumour, cytochrome P450 immunoreactivity was identified in all tumour cells and there was no intra-tumour heterogeneity. These results indicate that expression of cytochrome P450 is a common molecular event in soft tissue sarcomas and that the presence of different sub-families of cytochrome P450 has implications both for the pathogenesis and for the treatment of these tumours. Cytochrome P450 expression may influence the intrinsic drug resistance of these tumours and also provide a molecular target for anti-cancer drugs which can be activated by cytochrome P450.

The prognostic accuracy of flow cytometric and static densitometric DNA analysis was compared in 31 patients who had undergone surgery for papillary thyroid carcinoma between 1959 and 1978 (median follow-up 18 years'). There were five deaths from papillary thyroid carcinoma. Three of six patients with DNA aneuploid tumours onflow cytometry died (P>0·05, Fisher's exact test) compared with four of eight patients whose tumours were found to be aneuploid by static densitometry (P

The preoperative diagnosis of some thyroid neoplasms remains difficult even with the routine use of fine-needle aspiration cytology. The potential of nuclear magnetic resonance imaging (MRI) to discriminate between different thyroid pathologies was explored prospectively and compared with the final pathology in a series of 37 patients. MRI yielded high-quality images of the thyroid swelling but did not provide additional information to differentiate benign from neoplastic lesions. MRI does not contribute to the routine management of thyroid swellings.