Biomedical subjects

E Gordon

Publications and source records attributed to E Gordon.

At least 37 records · Page 2Linked to original sources

PubMed2000

The crystal structure of the penicillin-binding protein 2x from Streptococcus pneumoniae and its acyl-enzyme form: implication in drug resistance.

Penicillin-binding proteins (PBPs), the primary targets for beta-lactam antibiotics, are periplasmic membrane-attached proteins responsible for the construction and maintenance of the bacterial cell wall. Bacteria have developed several mechanisms of resistance, one of which is the mutation of the target enzymes to reduce their affinity for beta-lactam antibiotics. Here, we describe the structure of PBP2x from Streptococcus pneumoniae determined to 2.4 A. In addition, we also describe the PBP2x structure in complex with cefuroxime, a therapeutically relevant antibiotic, at 2.8 A. Surprisingly, two antibiotic molecules are observed: one as a covalent complex with the active-site serine residue, and a second one between the C-terminal and the transpeptidase domains. The structure of PBP2x reveals an active site similar to those of the class A beta-lactamases, albeit with an absence of unambiguous deacylation machinery. The structure highlights a few amino acid residues, namely Thr338, Thr550 and Gln552, which are directly related to the resistance phenomenon.

Acylation↗

PubMed2000

Synchronous cortical gamma-band activity in task-relevant cognition.

Widespread synchronous oscillatory activity, particularly in the gamma ('40 Hz') band, has been postulated to exist in the brain as a mechanism underlying binding. A new method of examining phase synchronicity across multiple electrode sites in specific EEG frequency bands as a function of time was employed, in a conventional cognitive ERP paradigm in 40 normal subjects. A significant late post-stimulus gamma synchronicity response occurred for task-relevant stimuli, whereas for task-irrelevant stimuli no such response was evident. However, an early response was seen for both task-relevant and irrelevant stimuli. This is the first empirical demonstration that widespread synchronous high frequency oscillations occur in humans in relation to cognition.

Acoustic Stimulation↗

PubMed2000

Gamma activity in schizophrenia: evidence of impaired network binding?

OBJECTIVES: Gamma ('40 Hz') rhythms may play a role in the integration of sensory processing activity. Impaired temporal integration may be a key feature of the associated disturbances in schizophrenia. This is the first study to examine the time course of Gamma activity induced in response to stimuli in this disorder. METHODS: Gamma activity induced in response to task-relevant and irrelevant auditory oddball stimuli was examined in 35 medicated schizophrenics and 35 age- and gender-matched normal controls. We employed a moving Welch window with short time FFT to examine the time course of Gamma amplitude. The amplitude spectrum for each time point was de-trended to eliminate any contribution of broad spectrum activity (EEG or EMG) to Gamma amplitude. RESULTS: For targets, schizophrenics showed a significant decrease in post-stimulus Gamma response amplitude in left hemisphere and frontal sites and an increase in right hemisphere and parieto-occipital sites (P<0.0009). The abnormalities correlated with PANSS general symptom scores. In the non-targets (at a different latency), schizophrenics showed a widespread Gamma decrease (P<0.0005). CONCLUSIONS: The Gamma findings in non-targets may reflect an abnormality in appropriately processing irrelevant stimuli. This could result in defective processing of the context (integration) of relevant target information.

Adult↗

PubMed2000

Misattribution of sensory input reflected in dysfunctional target:non-target ERPs in schizophrenia.

BACKGROUND: While numerous studies have found disturbances in the Event-Related Potentials (ERPs) of patients with schizophrenia linked to task relevant target stimuli (most notably a reduction in P300 amplitude), few have examined ERPs to task irrelevant non-targets. We hypothesize, from current models of dysfunction in information processing in schizophrenia, that there will be less difference between ERPs to targets and non-targets in patients with schizophrenia than in controls. METHODS: EEGs were recorded for 40 subjects with schizophrenia and 40 age and sex matched controls during an auditory oddball reaction time task. ERPs to the targets and non-targets immediately preceding the targets were averaged separately. RESULTS: There was a disturbance in ERPs to targets but also to non-targets (reduced N100 amplitude and earlier P200 latency) and the difference between target and non-target ERP components (N100 and P200 amplitude and P200 latency), was significantly reduced in the schizophrenic group compared with controls. CONCLUSIONS: These findings suggest a disturbance in processing task relevant and irrelevant stimuli, consistent with Gray's (1998) hypothesis of misattributions in the 'match:mismatch' of novel (target) and familiar (non-target) sensory input compared with stored information.

Adult↗

PubMed2000

Familial clustering of symptoms and disruptive behaviors in multiplex families with attention-deficit/hyperactivity disorder.

OBJECTIVE: To examine familial clustering of attention-deficit/hyperactivity disorder (ADHD), ADHD subtypes, symptoms, and oppositional behaviors in affected sibling pairs (ASPs) and their parents. METHOD: One hundred thirty-two ASPs, ranging in age from 5 to 25 years and ascertained through clinic and volunteer referrals, were examined for DSM-IV ADHD subtypes, oppositional defiant disorder (ODD), and conduct disorder (CD) with the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version (K-SADS-PL). Two hundred fifty-six parents in these families were assessed by means of the SADS-Lifetime version, Modified for the Study of Anxiety Disorders, Updated for DSM-IV (SADS-LA-IV), and the Behavioral Disorders supplement of the K-SADS-PL to determine ADHD, ODD, and CD. RESULTS: Fifty-five percent of families ascertained through an ASP have at least one parent with a lifetime diagnosis of ADHD. The frequency of ADHD in at least one parent was higher in families with at least one affected girl (63%) than in families with only affected boys (45%) (p = .02). There was no evidence that affected siblings or parents within ASP families showed similar patterns of ADHD symptoms, such as ADHD subtype classification. In contrast, CD significantly clustered in ASP families. CONCLUSIONS: The sex difference in prevalence of ADHD among ASPs is consistent with a model of inheritance in which girls require a greater loading of familial influences to develop ADHD. The lack of familial clustering of ADHD symptoms within ASP families suggests that hyperactive and inattentive symptoms reflect common familial underpinnings and not unique familial effects. In contrast, CD seems to reflect unique familial underpinnings distinct from those underlying ADHD.

Adolescent↗

PubMed2000

Late component ERPs are associated with three syndromes in schizophrenia.

Previous studies have revealed various abnormalities in late-component ERP amplitude and latency in schizophrenia, considered as a diagnostic category. The aim of this study was to investigate the within-sample associations between late-component ERPs and three primary syndromes of schizophrenia Reality Distortion, Psychomotor Poverty and Disorganisation. Subjects included 40 schizophrenics and 40 age and sex matched nonpsychiatric controls. Auditory ERPs (N100, N200, P200, P300) were elicited using an auditory oddball paradigm. Between-group analyses of target data showed reduced N100, N200 and P300 amplitude, increased P200 amplitude and delayed N200 latency in schizophrenics compared to controls. For non-target data, schizophrenics showed similarly reduced N100 amplitude and delayed N200 latency. Within-group analyses of target data showed that the three syndromes (determined by principal component analysis of PANSS ratings) were differentiated by ERP latency, but not amplitude (Disorganisation delayed left hemisphere P200 and P300 latency; Reality Distortion earlier global, midline and left hemisphere N200 latency; Psychomotor Poverty delayed posterior N100 latency). Notably, only Disorganisation showed a divergent pattern of associations with non-target ERP data: reduced P200 amplitude and delayed N100 latency.

Adolescent↗

PubMed1999

Visual scanpaths in schizophrenia: is there a deficit in face recognition?

There is substantial evidence that schizophrenics have deficits in face processing. We hypothesised that this difficulty is due to abnormalities in the visual scanning of faces. The specificity of these abnormalities to recognisable faces, the effect of task difficulty and their relationships to three primary symptom dimensions were examined. An infrared corneal reflection technique was used to record the visual scanpaths of 63 schizophrenics and 60 non-psychiatric controls while viewing non-degraded ('recognisable') and degraded ('not recognisable') faces. In the concurrent recognition task, subjects were asked to select the previously viewed face from among seven (exposure 1) or three (exposure 2) options. Both groups were unable to accurately recognise degraded faces, but schizophrenics were less accurate than controls for non-degraded faces in the more difficult task condition. Schizophrenics maintained a relatively 'restricted' scanpath style across both faces, but scanpath disturbances were most apparent for non-degraded faces. Analysis of fixation distribution to non-degraded faces showed that, unlike controls, schizophrenics did not concentrate their fixations on salient features. Scanpath aberrations showed only minimal associations with symptom dimensions. These results suggest that schizophrenic individuals have a specific deficit in the visual scanning of faces, that is a distinct case of a fundamental problem in complex object processing.

Adult↗

PubMed1999

Eye movements reflect impaired face processing in patients with schizophrenia.

BACKGROUND: Impaired processing of faces in patients with schizophrenia may underlie aspects of disturbance in their social interaction. This study examined patterns of eye fixation in subjects with schizophrenia and non-psychiatric controls, while processing a high resolution picture of a neutral face and a nonbiological complex geometric stimulus. METHODS: Ten-second sequences of eye movement were recorded video-oculographically (50 samples/sec) while subjects were "free-viewing" the stimuli. An essential element of the study was customized software that ensured stimulus presentation on a video display only after subjects were fixated upon a centre-screen cue, so that all subjects began stimulus processing from the same point. RESULTS: Compared with the control group, subjects with schizophrenia exhibited reduced scanpath lengths and a tendency toward fewer fixations for the face stimulus. They also showed an initial relative right spatial hemineglect (for the first voluntary fixation) when viewing the Rey figure, but not when viewing the face stimulus. Overall, there were no significant differences between the schizophrenia and control groups in the lateral distribution of subsequent fixations for either stimulus. CONCLUSIONS: Disturbed spatial and temporal patterns of eye movement in some people with schizophrenia may reflect sub-optimal processing of face stimuli, that may predispose these individuals to dysfunctional interpretation of facial communication cues.

Adult↗

PubMed1999

Mutations in the active site of penicillin-binding protein PBP2x from Streptococcus pneumoniae. Role in the specificity for beta-lactam antibiotics.

Penicillin-binding protein 2x (PBP2x) isolated from clinical beta-lactam-resistant strains of Streptococcus pneumoniae (R-PBP2x) have a reduced affinity for beta-lactam antibiotics. Their transpeptidase domain carries numerous substitutions compared with homologous sequences from beta-lactam-sensitive streptococci (S-PBP2x). Comparison of R-PBP2x sequences suggested that the mutation Gln552 --> Glu is important for resistance development. Mutants selected in the laboratory with cephalosporins frequently contain a mutation Thr550 --> Ala. The high resolution structure of a complex between S-PBP2x* and cefuroxime revealed that Gln552 and Thr550, which belong to strand beta3, are in direct contact with the cephalosporin. We have studied the effect of alterations at positions 552 and 550 in soluble S-PBP2x (S-PBP2x*) expressed in Escherichia coli. Mutation Q552E lowered the acylation efficiency for both penicillin G and cefotaxime when compared with S-PBP2x*. We propose that the introduction of a negative charge in strand beta3 conflicts with the negative charge of the beta-lactam. Mutation T550A lowered the acylation efficiency of the protein for cefotaxime but not for penicillin G. The in vitro data presented here are in agreement with the distinct resistance profiles mediated by these mutations in vivo and underline their role as powerful resistance determinants.

Acylation↗

PubMed1999

Electrodermal activity in schizophrenia: a quantitative study using a short interstimulus paradigm.

BACKGROUND: Electrodermal activity in response to short interstimulus interval (ISI) stimulation allows aspects of information processing to be examined, but such paradigms cause skin conductance responses (SCRs) to overlap. A signal decomposition method was developed and employed to score the overlapped SCRs. This is the first application of the method to the study of schizophrenia. METHODS: Electrodermal activity of 30 medicated patients with schizophrenia and 50 normal controls was obtained using a conventional auditory oddball paradigm with an ISI of 1.3 sec. Tonic skin conductance level (SCL), phasic SCRs, SCR temporal dynamics, and a range of SCR variables in response to target tones were examined. RESULTS: The schizophrenic group showed reduced response rate, proportion of responders, SCR amplitude, rise time, peak latency, and steady-state response amplitude, over the trial compared with controls. There were no between-group differences in SCL or SCR onset time. CONCLUSIONS: The combined use of a conventional short ISI paradigm and the new SCR scoring method demonstrated new facets of electrodermal hyporeactivity in medicated patients with schizophrenia. The hyporeactivity could not be attributed to changes in tonic arousal or dysfunctions in peripheral sympathetic nerve conductance.

Acoustic Stimulation↗

PubMed1999

Numerical fourier transform spectroscopy of EMG half-waves: fragmentary-decomposition-based approach to nonstationary signal analysis.

A nonstationary signal analysis technique is introduced, which regards an oscillatory physiological signal as a sum of its fragments, presented in the form of a fragmentary decomposition (FD). The virtue of FD is that it is free of the necessity to choose a priori the basis functions intended for signal analysis or synthesis. FD uses an unchanged signal fragment between adjacent zero-crossings, as a natural basis function called the half-wave function (HWF). To show that such a function is a physically meaningful object, Fourier transform methods were employed, supported by the similar basis function (SBF) algorithm, which provides the means for numerical Fourier transform spectroscopy of separate half-waves and their frequency domain description in terms of both amplitude and phase. The application of this method to parameter identification of 751 EMG half-waves from the eye blink EMG records of ten normal subjects showed that HWF's frequency domain image represents a Gaussian distribution, which applies over a defined range of relative frequencies. This empirical evidence shows that HWFs are produced by a specific system of first-order nonlinear differential equations, whose dependency on a number of random factors is characteristic of deterministic chaos. The particular form of solutions indicates that statistical regularities relevant to the central limit theorem are likely to underlie the genesis of the mass potentials studied. FD shows potential utility in a range of nonstationary physiological signals.

Adolescent↗

PubMed1999

Peak gamma latency correlated with reaction time in a conventional oddball paradigm.

OBJECTIVE: To determine whether a relationship existed across trials between evoked gamma and reaction time in a conventional cognitive ERP paradigm. METHODS: Auditory oddball data in 40 normal subjects was examined. A moving Welch window and short time FFT were employed to elucidate the time course of gamma (29 to 45 Hz) activity in each single-trial target ERP. The time point with maximum total gamma amplitude (across all sites) was identified automatically, and the associated amplitude, power and latency of this peak was determined. Spearman's rank correlation was employed to examine the relationship of these measures with reaction time. RESULTS: A highly significant and robust correlation between peak gamma latency and reaction time was found (P = 0.000001). Further frequency analysis revealed that this relationship was primarily confined to the 37 to 41 Hz band. This narrow band finding, coupled with the fact that the finding remained after exclusion of possibly EMG contaminated epochs, indicated that the effect was not due to EMG contamination. No relationship between peak gamma amplitude or power and reaction time was found. CONCLUSIONS: Peak evoked gamma latency was correlated with reaction time and seems likely to have functional significance in relation to stimulus processing.

Adult↗

PubMed1999

Simultaneous EEG and EDA measures in adolescent attention deficit hyperactivity disorder.

Adolescent unmedicated ADHD males and age- and sex-matched normal control subjects were examined simultaneously using EEG and EDA measures in a resting eyes-open condition. ADHD adolescents showed increased absolute and relative Theta and Alpha1 activity, reduced relative Beta activity, reduced skin conductance level (SCL) and a reduced number of non-specific skin conductance responses (NS.SCRs) compared with the control subjects. Our findings indicate the continuation of increased slow wave activity in ADHD adolescents and the presence of a state of autonomic hypoarousal in this clinical group.

Adolescent↗

PubMed1999

Different psychopathological models and quantified EEG in schizophrenia.

BACKGROUND: This study compared the ability of two different models of psychopathology in schizophrenia to account for findings in the quantified electroencephalogram (qEEG) recorded from midline sites in a group of 40 subjects with schizophrenia. The first model was based on the positive and negative syndrome dichotomy, the second was a tripartite model that resembled Liddle's syndromes of psychomotor poverty, disorganization and reality distortion (Liddle, 1987a). METHODS: A group of 40 subjects with predominantly chronic schizophrenia was assessed with the Positive and Negative Syndrome Scale (PANSS) prior to the acquisition of their quantified electroencephalogram. The relationship between EEG data and symptomatology was explored, initially with the PANSS positive and negative subscales and then with a tripartite model derived From a principal component analysis of the 14 positive and negative subscale items. RESULTS: The tripartite syndrome model showed a greater concordance with the qEEG of the subjects than the dichotomous model. 'Psychomotor poverty' was significantly positively correlated with both delta and beta power and 'reality distortion' was significantly positively correlated with alpha-2 power. No significant correlations between the positive and negative syndrome dichotomy and the qEEG were observed. CONCLUSIONS: This study lends support to the factor analysis of psychopathology, and specifically the tripartite syndrome model of schizophrenia, as a step in explicating the biological dimensions of the disorder.

Adolescent↗

PubMed1999

Brain imaging technologies: how, what, when and why?

OBJECTIVE: Innovations in physics and computing technology over the past two decades have provided a powerful means of exploring the overall structure and function of the brain using a range of computerised brain imaging technologies (BITs). These technologies offer the means to elucidate the patterns of pathophysiology underlying mental illness. The aim of this paper is to explore the current status and some of the future directions in the application of BITs to psychiatry. METHOD: Brain imaging technologies provide unambiguous measures of brain structure (computerised tomography and magnetic resonance imaging [MRI]) and also index complementary measures of when (electroencephalography, event related potentials, magnetoencephalography) and where (functional MRI, single photon emission computed tomography, positron emission tomography) aspects of brain activity occur. RESULTS: The structural technologies are primarily used to exclude a biological cause in cases of a suspected psychiatric disorder. The functional technologies show considerable potential to delineate subgroups of patients (that may have different treatment outcomes), and evaluate objectively the effects of treatment on the brain as a system. What is seldom emphasised in the literature are the numerous inconsistencies, the lack of specificity of findings and the simplistic interpretation of much of the data. CONCLUSION: Brain imaging technologies show considerable utility, but we are barely scratching the surface of this potential. Simplistic over-interpretation of results can be minimised by: replication of BIT findings, judicious combination of complementary methodologies, use of appropriate activation tasks, analysis with respect to large normative databases, control for performance, examining the data'beyond averaging', delineating clinical subtypes, exploring the severity of symptoms, specificity of findings and effects of treatment in the same patients. The technological innovation of BITs still far outstrips the sophistication of their use; it is essential that the meaning and mechanisms underlying BIT measures are always evaluated with respect to prevailing models of brain function across disciplines.

Brain↗

PubMed1999

A Jacksonian and biopsychosocial hypothesis concerning borderline and related phenomena.

OBJECTIVE: The aim of this paper is to develop an aetiological model for borderline personality disorder. METHOD: The postulates of Hughlings Jackson are used to provide a preliminary explanatory framework for borderline phenomena. As a necessary background to this discussion, the findings concerning abuse in the early history of borderline personality disorder (BPD) and other conditions, notably somatisation disorder and dissociative states, are briefly reviewed. Other data, including family studies, which might have significance in the aetiology of BPD are also reviewed. RESULTS: The hypothesis is put forward that the symptoms of BPD are due to the failure of 'experience-dependent' maturation of a cascade of neural networks, with prefrontal connections, which become active relatively late in development and which coordinate disparate elements of central nervous system function. These networks subserve higher psychological functions, including attentional focus and affect regulation. They also underpin the reflective function necessary to the emergence of self as the stream of consciousness, which appears at about the age of 4 years. CONCLUSION: Adverse developmental circumstances may produce an interrelated set of symptom clusters, with associated neural network disturbances that are amenable to investigation with psychometric and brain imaging techniques. Since these disturbances are seen as 'experience-dependent', they are considered reversible, at least in part.

Adolescent↗

PubMed1999

Dynamics of SCR, EEG, and ERP activity in an oddball paradigm with short interstimulus intervals.

Studies of concurrent central, and autonomic activity using a conventional event-related potential (ERP) oddball paradigms, are considered useful in elucidating the relationship between central and autonomic responses, but the autonomic response tends to overlap. A new method was used to decompose and score overlapping skin conductance responses (SCR). This method enabled examination of dynamic relationships of phasic SCR, prestimulus electroencephalogram (EEG), and ERP to auditory target stimuli in 50 normal adults. SCR amplitude was negatively correlated to EEG and N200 amplitude. The SCR amplitude changes over time exhibited an exponential decline opposite to those of N200, alpha, and beta. All the fitted exponential functions had a time constant of 1-2 min. The findings suggest that a N200 component, active in the auditory sensory discrimination, is concomitant with the SCR. The narrow range of the time constant may provide a clue to the conjoint processes underlying central and autonomic adaptive functions.

Adult↗

PubMed1999

Is the target-to-target interval a critical determinant of P3 amplitude?

The P3 amplitude is augmented by decrements in target-probability, increments in the number of nontargets preceding the target, and extensions of the interstimulus interval (ISI). Each of these changes prolongs the target-to-target interval (TTI) and, consequently, results attributed to these factors might, at least partially, be accounted for by the TTI. Recent research also indicates that the P3s elicited by targets in one-, two-, and three-stimuli tasks (in which the TTI remains invariant) are similar. However, the TTI has not been examined systematically in previous research. The present study had subjects listen to a randomized ISI (0.5, 1, 2, or 4 s) version of the auditory oddball task in which targets occurred after one, two, three, four, or five nontargets. Event-related potentials were analyzed based on ISI, sequential structure, and TTI. The study examined sequence and ISI effects independent of TTI effects and demonstrated that extensions of ISI affected N1 but not P3 amplitude, extensions of TTI enhanced P3 amplitude independent of sequential structure, and sequential structure failed to influence P3 amplitude when TTI was controlled.

Adult↗