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A measure of auditory prepulse inhibition (PPI) or sensory gating is the reduction of the scalp-recorded P1 event-related potential (ERP) after a sound that is preceded by 100-300 ms by a click as prepulse. This measure of sensory gating was adapted to study the effect of a prepulse on processing tones that were part of a "Go/no-go" discrimination. Methods: ERPs were recorded at right and left frontal and temporal sites on the scalp of groups of patients with schizophrenia (SCH, 8), obsessive compulsive disorder (OCD, 10) and healthy controls (CON, 19). Results: a) Both patient groups responded slower and showed more errors of omission than controls. b) A prepulse presented 100 ms (but not at 500 ms) before either tone reduced the P1 or P50 ERP amplitude on healthy controls, but showed a right temporal shift in the SCH patients. c) If the tone was the 'no-go' stimulus in the tone discrimination the prepulse reduced the N1 amplitude in both normal controls and SCH patients. This N100 amplitude was similar in records from over the left and right hemisphere of controls but was shifted to right temporal sites in the SCH group. d) OCD patients showed a relative predominance of the left hemisphere in the gating of frontal P1, N100 and P300 components, but early gating was not significantly impaired in this group. Conclusions: These results show a reduction of a PPI-like effect on early processing (e.g. P50/P1) that is more marked in the left hemisphere of SCH patients, and may affect channel selection for processing information about task-relevant sounds (e.g. N100)

Event-related potentials (ERPs) in schizophrenics have been reported to show a reduced P3 on the left and less frontal mismatch negativity. But the specificity of such findings to component, its locus, the type of eliciting event and patient group remains uncertain. Hence, we examined ERP topography for P3, N2 and 3 precursor peaks according to stimulus (3-tone oddball), attention condition (diffuse/focused) and four types of difference-waves (Mismatch negativity, Processing negativity, Negative difference (Nd) and the 'Goodin-Waveform'). Method: We contrasted ERPs in a 3-tone oddball task-form in 24 healthy (mean 18.5y of age) and 13 OCD (mean age 16.3 y) subjects with schizophrenic patients with high versus low ratings of active delusions and hallucinations (12 paranoid-hallucinatory, PH [mean age 18.5y]; 12 nonparanoid, NP [mean age 18.9y]) Results: 1. P3 peaks were delayed and reduced in NP and PH groups. Peaks in the midline were usual in the focused attention condition, but a right bias in diffuse attention (passive presentation). 2. P3 responses to irrelevant non-targets remained lateralised in NP, and small in OCD patients. All showed a small left and anterior bias in the P3-like peak recorded after subtraction in the difference waves. 3. Mismatch negativity (MMN) peaks shifted to the right in OCD, laterally to both sides in PH and more posteriorly in NP patients. 4. Frontal processing negativity was biased to the left (early) in NP and to the right (late) in PH groups. 5. Early peak topography in the difference waveforms reflected some of these later changes (e.g., for PH and NP groups the normal right bias in the P1-like peak was absent; the N1-like peak was reduced and widely distributed: for the NP group, the P2-like peak appeared smaller on the left). 6. In OCD patients, the peak latencies were topographically undifferentiated for P1 and P2, or delayed in the case of the N2 component. Conclusions: A) The OCD group showed an unusual regional allocation of processing effort. B) Before 200 ms, fronto-central activity was more widespread in both the PH and NP groups. C) NP patients, in particular, treated irrelevant stimuli anomalously. D) Lateralisation of negativity in target- and nontarget-derived difference waves may reflect differential disruption of the frontal-temporal dialogue in registering important vs. unimportant features. Indeed, the apparent left/right differences of negative difference (Nd) or processing negativity amplitude may not so much reflect amplitude differences as a delayed latency over left frontal areas in PH and over the right frontal areas in NP patients with schizophrenia.

Conditioned blocking (CB) refers to a delay in learning that a new stimulus, added during learning, has the same consequences as the conditioned stimulus already present. In animals such "learned inattention" depends on monoaminergic and limbic function and, thus, CB performance should be informative on selective information processing impairments found in subgroups of psychotic patients. Attenuated CB in acute schizophrenia has been reported to normalize rapidly. Method: This study examines in young patients the specificity of CB performance to illness, and its associations with symptoms, personality traits and monoaminergic metabolic status. Results: Performance: CB was attenuated in psychotic patients with nonparanoid symptoms (NP: n=12, mean age 17 years) with respect to obsessive compulsive (OCD: n=13, mean age 16 years) and healthy subjects (CON; n=29, mean age 18 years), but only a transient attenuation was observed in paranoid hallucinatory patients (PH: n=14, mean age 19 years). The severity of negative symptoms in psychosis and specific negative/positive symptoms in the NP/PH groups were associated with reduced CB. Outgoing personality traits in CON and OCD subjects correlated with CB. In NP patients attenuated CB was associated with increasing neurotic lability. In PH patients CB correlated positively with "manic" but negatively with psychotic or neurotic scores. Monoamines: Increased dopamine activity (24h urine samples) correlated positively with CB, but relative increases of noradrenaline metabolism in NP and serotonin metabolism in OCD patients interfered. Conclusions: Marked psychotic or neurotic traits and some negative symptom states were associated with reduced CB. The particular selective processing problems of NP patients may reflect inappropriate NA activity.

Childhood autism, overtly expressed as social indifference and repetitive motor patterns, in fact involves a range of problems covering sensory, attentional, cognitive, emotional, language as well as motor areas of function - 25 symptoms can be listed. Although a reduced verbal IQ and language difficulties are frequent, a major intervening variable may be problems with the development of a "theory-of-mind" ....the ability to comprehend the mental states of others. Prevalence rates per 10,000 of the population range from 2 to 16 in different countries, rising to 50 if one includes spectrum autistic disorder. A number of sometimes related organic associations and potentially separate aetiologies are described. Biology: Evidence for delayed neurotransmission (evoked potentials) and a lack of flexibility in physiological responses (signal detection, cross-modal integration) may underlie the attenuation of monitoring processes that lead to withdrawal and stereotypies. Neuropsychological task performance provides limited and qualified evidence for impaired frontal function, although this could explain event-related potential (ERP) evidence for more of a deficit with controlled attention (Nd) than in automatic processing (MMN). [ERPs also underline the difficulties in generating differential responses to relevant and irrelevant stimuli.] Imaging studies show some structural abnormalities in half the patients (e.g. ventricle volume increases), but indices of activation, though in the normal range do not appear situation-appropriate. Pharmacology: a) A significant proportion of autistic subjects show increased peripheral measures of serotonin and quite often raised dopamine metabolism - that in some high-functioning cases has been claimed to be beneficial. It is plausible that changes in monoaminergic transmission are inadequately compensated by changes in the other transmitter systems. b) With serotonin and dopamine responsible for inhibition/volume-control and for switching/flexibility we propose an imbalance of these systems that results in a stop-go form of neuronal communication that inevitably leads to anomalous responses at the whole organism level. c) At least 20 forms of pharmocotherapy have been attempted, the best with improvement limited to a few patients improving particular symptoms only. The best have proved to be dopamine or opioid antagonists, but at best - these have a limited and modest role to play in clinical care Conclusions: The impairment of children with autism manifests itself at many levels - treatment concepts must attempt to integrate these, with emphasis on the particular abilities and difficulties of the individual. The need is to synthesize the different levels of analysis for a psychobiological approach to be integrated into the wide-ranging remedial programmes currently practised..

Ecotin is a dimeric periplasmic protein from Escherichia coli that has been shown to inhibit potently many trypsin-fold serine proteases of widely varying Substrate specificity. To help elucidate the physiological function of ecotin. we examined the family of ecotin orthologues. which are present in a Subset of Gram-negative bacteria. Phylogenetic analysis suggested that ecotin has an exogenous target. possibly neutrophil elastase. Recombinant protein was expressed and Purified from E. coli, Yersinia pestis and Pseudomonas aeruginosa. all species that encounter the mammalian immune system, and also from the plant pathogen Pantoea citrea. Notably. the Pa. citrea variant inhibits neutrophil elastase 1000-fold less potently than the other orthologues. All four orthologues are dimeric proteins that potently inhibit (< 10 pM) the pancreatic digestive proteases trypsin and chymotrypsin, while showing more variable inhibition (5 pM to 24 muM) of the blood proteases Factor Xa, thrombin and urokinase-type plasminogen activator. To test whether ecotin does, in fact, protect bacteria from neutrophil elastase, an ecotin-deficient strain was generated in E. coli. This strain is significantly more sensitive in cell-killing assays to human neutrophil elastase, which causes increased permeability of the Outer membrane that persists even during renewed bacterial growth. Ecotin affects primarily the ability of E. coli to recover and grow following treatment with neutrophil elastase, rather than the actual rate of killing. This suggests that an important part of the antimicrobial mechanism of neutrophil elastase may be a periplasmic bacteriostatic effect of protease that has translocated across the damaged outer membrane.