Cognitive and oculomotor performance in subjects with low and high schizotypy: implications for translational drug development studies.

The development of drugs to improve cognition in patients with schizophrenia is a major unmet clinical need. A number of promising compounds failed in recent clinical trials, a pattern linked to poor translation between preclinical and clinical stages of drug development. Seeking proof of efficacy in early Phase 1 studies in surrogate patient populations (for example, high schizotypy individuals where subtle cognitive impairment is present) has been suggested as a strategy to reduce attrition in the later stages of drug development. However, there is little agreement regarding the pattern of distribution of schizotypal features in the general population, creating uncertainty regarding the optimal control group that should be included in prospective trials. We aimed to address this question by comparing the performance of groups derived from the general population with low, average and high schizotypy scores over a range of cognitive and oculomotor tasks. We found that tasks dependent on frontal inhibitory mechanisms (N-Back working memory and anti-saccade oculomotor tasks), as well as a smooth-pursuit oculomotor task were sensitive to differences in the schizotypy phenotype. In these tasks the cognitive performance of 'low schizotypes' was significantly different from 'high schizotypes' with 'average schizotypes' having an intermediate performance. These results indicate that for evaluating putative cognition enhancers for treating schizophrenia in early-drug development studies the maximum schizotypy effect would be achieved using a design that compares low and high schizotypes.

Investigating virtual reality navigation in amnestic mild cognitive impairment using fMRI.

Spatial navigation requires a well-established network of brain regions, including the hippocampus, caudate nucleus, and retrosplenial cortex. Amnestic Mild Cognitive Impairment (aMCI) is a condition with predominantly memory impairment, conferring a high predictive risk factor for dementia. aMCI is associated with hippocampal atrophy and subtle deficits in spatial navigation. We present the first use of a functional Magnetic Resonance Imaging (fMRI) navigation task in aMCI, using a virtual reality analog of the Radial Arm Maze. Compared with controls, aMCI patients showed reduced activity in the hippocampus bilaterally, retrosplenial cortex, and left dorsolateral prefrontal cortex. Reduced activation in key areas for successful navigation, as well as additional regions, was found alongside relatively normal task performance. Results also revealed increased activity in the right dorsolateral prefrontal cortex in aMCI patients, which may reflect compensation for reduced activations elsewhere. These data support suggestions that fMRI spatial navigation tasks may be useful for staging of progression in MCI.

Alterations in working memory networks in amnestic mild cognitive impairment.

Patients with amnestic mild cognitive impairment (aMCI) show preserved or mildly impaired working memory, despite their deficits in episodic memory. We aimed to identify performance and/or neural differences between aMCI patients and matched controls on a standard working memory fMRI task. Neuropsychological assessment demonstrated aMCI impairments in verbal and visual episodic long-term memory, with intact IQ and executive function. Participants completed a standard three-level N-back task where patients were unimpaired. Functional activations in the control group were found in expected areas, including the inferior parietal lobule and dorsolateral prefrontal cortex. Group differences were found in the insula and lingual gyrus and, in a region of interest analysis, in the hippocampus. In all cases, these were caused by an absence of task-related deactivations in the aMCI group. The results are consistent with reports of failure in task-related deacivations in aMCI and could be early indications of pathology.

The effects of ketamine and risperidone on eye movement control in healthy volunteers.

The non-competitive N-methyl-D-aspartate receptor antagonist ketamine leads to transient psychosis-like symptoms and impairments in oculomotor performance in healthy volunteers. This study examined whether the adverse effects of ketamine on oculomotor performance can be reversed by the atypical antipsychotic risperidone. In this randomized double-blind, placebo-controlled study, 72 healthy participants performed smooth pursuit eye movements (SPEM), prosaccades (PS) and antisaccades (AS) while being randomly assigned to one of four drug groups (intravenous 100 ng ml(-1) ketamine, 2 mg oral risperidone, 100 ng ml(-1) ketamine plus 2 mg oral risperidone, placebo). Drug administration did not lead to harmful adverse events. Ketamine increased saccadic frequency and decreased velocity gain of SPEM (all P < 0.01) but had no significant effects on PS or AS (all P > or = 0.07). An effect of risperidone was observed for amplitude gain and peak velocity of PS and AS, indicating hypometric gain and slower velocities compared with placebo (both P < or = 0.04). No ketamine by risperidone interactions were found (all P > or = 0.26). The results confirm that the administration of ketamine produces oculomotor performance deficits similar in part to those seen in schizophrenia. The atypical antipsychotic risperidone did not reverse ketamine-induced deteriorations. These findings do not support the cognitive enhancing potential of risperidone on oculomotor biomarkers in this model system of schizophrenia and point towards the importance of developing alternative performance-enhancing compounds to optimise pharmacological treatment of schizophrenia.

CFD simulation of anaerobic digester with variable sewage sludge rheology.

A computational fluid dynamics (CFD) model that evaluates mechanical mixing in a full-scale anaerobic digester was developed to investigate the influence of sewage sludge rheology on the steady-state digester performance. Mechanical mixing is provided through an impeller located in a draft tube. Use is made of the Multiple Reference Frame model to incorporate the rotating impeller. The non-Newtonian sludge is modeled using the Hershel-Bulkley law because of the yield stress present in the fluid. Water is also used as modeling fluid to illustrate the significant non-Newtonian effects of sewage sludge on mixing patterns. The variation of the sewage sludge rheology as a result of the digestion process is considered to determine its influence on both the required impeller torque and digester mixing patterns. It was found that when modeling the fluid with the Hershel-Bulkley law, the high slope of the sewage stress-strain curve at high shear rates causes significant viscous torque on the impeller surface. Although the overall fluid shear stress property is reduced during digestion, this slope is increased with sludge age, causing an increase in impeller torque for digested sludge due to the high strain rates caused by the pumping impeller. Consideration should be given to using the Bingham law to deal with high strain rates. The overall mixing flow patterns of the digested sludge do however improve slightly.

Acute and chronic posttraumatic stress disorder in motor vehicle accident victims.

OBJECTIVE: This study reports the rates of acute and chronic posttraumatic stress disorder (PTSD) in a suburban community study group of 122 victims of serious motor vehicle accidents and a comparison group of 42 (who had been involved in minor, non-motor-vehicle accidents) followed over 12 months. METHOD: Motor vehicle accident victims were systematically recruited and examined with comparison subjects at 1, 3, 6, 9, and 12 months after the accident. The authors used the Structured Clinical Interview for DSM-III-R to assess DSM-III-R axis I disorders including PTSD. RESULTS: One month after the accident, 34.4% of the motor vehicle accident victims met criteria for PTSD (versus 2.4% of the comparison subjects). Similarly, at 3 and 6 months, rates of PTSD were higher (25.2% and 18.2%) in the motor vehicle accident victims than in the comparison group. Female victims were 4.64 times more likely than male victims to have PTSD at 1 month. Victims with a history of PTSD were 8.02 times more likely at 1 month and 6.81 times more likely at 3 months to have PTSD than those without a history of PTSD. Having an axis II disorder increased the risk for PTSD at 6 months. After adjustment for a history of PTSD and potentially confounding variables, women were 4.39 times more likely than men to develop PTSD at 1 month but did not have a higher risk for chronic PTSD; at 6 months, those with an axis II disorder were at greater risk of PTSD. CONCLUSIONS: Rates of PTSD are high in victims of serious motor vehicle accidents and remain high 9 months later. Female victims have an increased risk of acute but not chronic PTSD. Individuals with a history of PTSD are at risk of acute and chronic PTSD. An axis II disorder increases the risk for chronic but not acute PTSD.

Assessment of characteristics of intrusive thoughts and their impact on distress among victims of traumatic events.

OBJECTIVE: This study examines the psychometric properties of the Intrusive Thoughts Questionnaire (ITQ) and its utility as a predictor of distress among trauma victims. METHOD: Victims of three types of trauma, a motor vehicle accident (N = 115), a hurricane (N = 182), and recovery work after an airline disaster (N = 159), completed the ITQ along with the Impact of Event Scale (IES) and the Symptom Checklist-90, Revised (SCL-90-R), at several different time points after their exposure. RESULTS: The ITQ was a reliable and valid instrument that was positively related to concurrent measures of distress as well as a predictor of long-term stress responding. Characteristics of intrusive thoughts reflecting the extent to which they were unwanted or controllable, were identified as key determinants of distress. CONCLUSIONS: The ITQ is a useful adjunct to current measures of intrusions, allowing for greater specificity in analyses of responses to trauma. Evaluation of characteristics of intrusions indicated that frequency of intrusions was neither the only predictor of distress nor the best predictor of trauma-related outcomes.

Chronic stress and natural killer cell activity after exposure to traumatic death.

OBJECTIVE: The present study examined the effects of working at the crash site of USAir Flight 427 on psychological, cardiovascular, and immunological sequelae of stress within 2 months of the recovery work and again 6 months after the crash. METHOD: A total of 159 workers at the crash site and 41 controls were examined within 2 months of the crash and again 6 months after the crash. Subjects were initially grouped according to whether they had contact with human remains. For a finer-grained analysis of exposure to bodies, subjects were also grouped by degree of exposure, determined by the area in which the workers were stationed. Dependent measures included intrusive thoughts, coping styles, and symptom reporting, as well as heart rate and blood pressure, and NK cell number and activity. RESULTS: Workers exposed to body parts at the actual crash site, and those who were exposed to remains without expecting to be, exhibited more symptoms of stress than workers who saw bodies and body parts at the morgue and those who did not see human remains. Non-morgue workers who were exposed to bodies or body parts had the highest levels of intrusive thoughts at both time points, and the highest NK cell activity at Time 1. NK activity in this group decreased to levels comparable with other groups at Time 2. CONCLUSIONS: Increased NK activity is unusual in chronic stress situations, and may be because of acute stress experienced as a result of being asked to talk and think about the crash. The finding that the more one was exposed to human remains the less distress he or she reported is discussed in terms of adaptation, expectancy, and control.

Acute and chronic distress and posttraumatic stress disorder as a function of responsibility for serious motor vehicle accidents.

In this study on the effects of attributions of responsibility for traumatic events, stress, coping, and symptoms of posttraumatic stress disorder (PTSD) were measured, including intrusive thoughts among 130 victims of serious motor vehicle accidents (MVAs) 14-21 days and 3, 6, and 12 months after their accident. MVA victims and 43 control participants were categorized by accident and attribution of responsibility for their accidents (self-responsible, other-responsible, and control). Although initially all MVA victims reported higher levels of intrusive thoughts and were more likely to meet criteria for PTSD diagnoses, only other-responsible participants continued to demonstrate increased distress 6 and 12 months postaccident. Self-responsible participants used more self-blame coping than other-responsible participants, although within the self-responsible group, use of self-blame was associated with more distress.

Effect of the serine protease inhibitor, aprotinin, on systemic haemodynamics and renal function in patients with hepatic cirrhosis and ascites.

1. Previous studies have documented activation of protease enzymes, such as the plasma kallikrein-kinin system, in hepatic cirrhosis. Increased plasma kinin generation could contribute to pathological systemic vasodilatation in cirrhosis, and reduced systemic vascular resistance has been suggested as a trigger to renal sodium retention in this disease. We investigated the effect of aprotinin, a protease inhibitor which binds to plasma kallikrein, on systemic haemodynamics and renal function in patients with hepatic cirrhosis and ascites. 2. Aprotinin was infused intravenously in high dosage (2 x 10(6) kallikrein inhibitory units loading, 1 x 10(6) kallikrein inhibitory units/h). 3. Of 13 patients, 10 had a low systemic vascular resistance (< 1200 dyn s cm-5) at baseline. In this group, eight showed an increase in systemic vascular resistance during aprotinin infusion. Overall, the increase in systemic vascular resistance was significant, and there was a small but significant increase in mean arterial pressure. In all patients, there were increases in renal plasma flow, glomerular filtration rate, and absolute and fractional urinary sodium excretion during aprotinin infusion. 4. Plasma renin activity, plasma angiotensin II and plasma aldosterone fell significantly during aprotinin infusion. Plasma prekallikrein, plasma noradrenaline and plasma atrial natriuretic peptide did not change. Plasma aprotinin concentration was 209 +/- 11 kallikrein inhibitory units/ml at the end of the infusion. 5. Before and during the infusion, there was a significant negative correlation between systematic vascular resistance and plasma renin activity. There was a positive correlation between the change in systemic vascular resistance and the change in renal plasma flow during aprotinin infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Portal and systemic hemodynamics and humoral factors in cirrhosis with and without ascites.

The pathogenesis of salt and water retention in cirrhosis remains unclear. Systemic and portal hemodynamic parameters, including cardiac output, portal pressure gradient and systemic vascular resistance, were measured in six patients with untreated ascites and in six patients with hepatic cirrhosis with no history of ascites. Renal blood flow, urinary volume, and humoral factors, including plasma renin, aldosterone, angiotensin II, and urine kallikrein, were measured. Significant differences were seen between the two groups in urine volume, urine sodium and fractional sodium excretion, plasma angiotensin II, and the ratio between plasma renin activity and urinary kallikrein excretion (PRA:UKallV). A strong correlation existed between urinary sodium excretion and the PRA:UKallV ratio. No significant differences were detected between the groups in portal, renal, and systemic hemodynamics. The present results suggest that humoral changes occur early in ascites. Altered relationships between intrarenal hormone systems, such as the renin-angiotensin and kallikrein-kinin systems, may be important in salt and water retention.

Vasoactive effects of aprotinin.

The protease inhibitor aprotinin was given a) in experimental septic shock, and b) in patients with hepatic cirrhosis and ascites, since in both conditions, activation of the plasma kallikrein-kinin system is associated with pathological systemic vasodilatation, which may trigger reflex neuroendocrine activation and renal solute retention. Given early in experimental sepsis, aprotinin maintained the arterial pressure, systemic vascular resistance (SVR), creatinine clearance and sodium excretion, all of which fell in controls. Aprotinin also blocked increases in pulmonary artery pressure and plasma renin activity (PRA). Given late in sepsis, aprotinin caused a rapid rise in arterial pressure and SVR towards baseline levels. In cirrhosis, aprotinin increased SVR in patients with low baseline values, and improved glomerular filtration rate, renal plasma flow and sodium excretion in all subjects; PRA was suppressed by aprotinin. Aprotinin reverses pathological systemic vasodilatation in these two conditions, and this is associated with a reduction in renin release and improved renal function.

The effects of acute insulin-induced hypoglycaemia on renal function in normal human subjects.

The effects of acute insulin-induced hypoglycaemia on renal function were studied in 8 normal male subjects. Plasma glucose (mean (SE) fell from 4.6(0.2) to 1.3(0.2) mmol l(-1), the nadir being coincident with the acute autonomic reaction, and returned to the basal value over the following 120 min. Glomerular filtration rate declined from 118(6) to 95(4) ml min-1 at the glucose nadir (p less than 0.01), and during the recovery phase returned to 118(7) ml min-1 (NS compared with basal). Renal plasma flow fell from 625(38) to 485(27) ml min-1 (p less than 0.01), rising to 545(46) ml min-1 during recovery from hypoglycaemia (NS compared with basal). Following hypoglycaemia, urinary excretion of sodium and dopamine were reduced significantly, but the albumin excretion rate was unchanged. Plasma concentrations of adrenaline, noradrenaline, angiotensin II, and plasma renin activity increased in response to hypoglycaemia. These acute changes in renal function are probably caused by sympatho-adrenal activation and secretion of catecholamines, but other hormones, such as angiotensin II, may be contributory.