Humoral immunity in guamanians with amyotrophic lateral sclerosis and parkinsonism-dementia

Among Guamanian natives, serum IgA and IgG levels were found to be higher than normal in amyotrophic lateral sclerosis (ALS); serum IgA was higher and IgM lower than normal in parkinsonism-dementia (PD). IgA levels increased with age in ALS, PD, and normal subjects; IgG increased with age in ALS and IgM decreased with age in PD. Serum immunoglobulin (Ig) levels did not correlate with the duration of either disease. Immunodeficient ALS and PD patients had higher IgM and lower IgA levels than the other ALS and PD patients. Neither differences in viral antibody titers nor the presence of autoantibodies or circulating immune complexes could account for the variations in serum Ig levels between patients and controls. We conclude that differences in serum Ig levels in ALS and PD patients are probably due to repeated infections and abnormal immunoregulation accompanying immunodeficiency during the course of ALS and PD, rather than to a specific antiviral or autoimmune response.     

Insights into the control of attentional set in ADHD using the attentional blink paradigm

BACKGROUND: Previous work on visual selective attention in Attention Deficit Hyperactivity Disorder (ADHD) has utilised spatial search paradigms. This study compared ADHD to control children on a temporal search task using Rapid Serial Visual Presentation (RSVP). In addition, the effects of irrelevant singleton distractors on search performance were examined. METHOD: In each condition, subjects reported the identity of a red letter 'probe' in a sequence of white letters which appeared one after the other at a central fixation point. The temporal position of the probe varied from an initial target, which was distinguished by surrounding asterisks. The target was reported in addition to the probe in condition 2, but not in the baseline condition 1. In a third condition, the initial target was not reported, but one of the asterisks appeared as a colour singleton on some trials. RESULTS: All children displayed an 'attentional blink' with probe detection reduced when it appeared at close temporal relations relative to the target. This 'blink' reduced over time, and there were no group differences in the recovery of performance, although ADHD children made more errors overall. The ADHD group were also more vulnerable than controls to distraction from irrelevant singletons in condition 3. CONCLUSION: Although the basic mechanisms of selective attention were not impaired in children with ADHD, these children appeared to require more resources to execute the task and were more vulnerable to distraction by irrelevant singletons, indicating deficits in the maintenance of attentional control.     

Sustained neural activity associated with cognitive control during temporally extended decision making

Decision making has both cognitive and affective components, but previous neuroimaging studies in this domain predominantly have focused on affect and reward. The current study examined a decision-making paradigm that placed strong demands on cognitive control processes by making reward payoffs contingent upon decision-making history. Payoffs were maximized by choosing the option that, paradoxically, was associated with a lower payoff on the immediate trial. Temporal integration requirements were manipulated by varying, across conditions, the window of previous trials over which the reward function was calculated. The cognitive demands of the task were hypothesized to engage neural systems responsible for integrating and actively maintaining actions and outcomes over time and the top-down biasing of response selection. Brain activation was monitored with functional magnetic resonance imaging (fMRI) using a mixed-blocked and event-related design to extract both transient and sustained neural responses. A network of brain regions commonly associated with cognitive control functions, including bilateral prefrontal cortex (PFC), bilateral parietal cortex, and medial frontal cortex, showed selectively sustained activation during the task. Increasing temporal integration demands led to a shift from transient to sustained activity in additional regions, including right hemisphere dorsolateral and frontopolar PFC. These results demonstrate the contribution of cognitive control mechanisms to temporally extended decision-making paradigms and highlight the benefits of decomposing activation responses into sustained and transient components.     

The relationships among cognition, motivation, and emotion in schizophrenia: how much and how little we know

This article summarizes a workshop discussion focused on the current state of our understanding of the ways in which cognitive dysfunction in schizophrenia is related to, influenced by, or even leads to disturbances in areas such as emotion, motivation, and stress, as well as areas in need of further research. A major emphasis in the workshop discussion was the critical importance of motivation and its potential influence on cognitive function and learning in schizophrenia. As such, the members of the workshop suggested a number of questions regarding motivation that need further research, including (1) the definition and measurement of different components of motivation; (2) the relationship between intrinsic motivation and incentive drive and hedonic processing; (3) the integrity of motivational processes, incentive drive, and hedonic processing in schizophrenia; (4) the influence of cognitive deficits on motivational disturbances in schizophrenia; (5) the influence of antipsychotic medication on incentive drive and hedonic processing in schizophrenia; and (6) the relationships among cognitive function, stress, and the processing of aversive stimuli.     

Lack of evidence for elevated obstetric complications in childhood onset schizophrenia.

BACKGROUND: Pre-, peri-, and postnatal obstetric complications (OC) are reported to be more frequent in adult patients with schizophrenia and have been linked to both greater severity and to "earlier" age of onset (before either age 18 or 22) in studies of adult patients. We hypothesized that by extrapolation, patients with childhood-onset schizophrenia (COS), with very early onset and very severe illness, would have had more numerous or more salient OC compared with their healthy siblings. METHODS: We compared the obstetric records of 60 COS children and 48 healthy siblings using the Columbia Obstetrics Complication Scale, a comprehensive measurement scale consisting of 37 variables having included a separate scale for fetal hypoxia. RESULTS: Patients with COS did not have a higher incidence of OC than the healthy sibling control group with the exception of increased incidence of maternal vomiting. CONCLUSIONS: Obstetric complications, with the possible exception of maternal vomiting, are unlikely to play a major role in the etiopathogenesis of childhood-onset schizophrenia.     

Cardiovascular disease in relation to weight in deceased persons with schizophrenia

This study evaluated body mass index, body surface area, subcutaneous fat tissue, and coronary atherosclerosis by autopsy reports for people with schizophrenia who were deceased to evaluate the presence of cardiac atherosclerosis and its association with body weight. Included in the study were autopsy reports for 134 people with schizophrenia and 134 matched normal subjects who had died between January 1990 and December 2000 and whose family had donated brain tissue to Maryland Brain Collection. Cause of death due to cardiovascular disease was observed for 45.7% of people with schizophrenia and 42.3% of the control group (P = NS). Body weight, body mass index, body surface area, and subcutaneous fat were not significantly different between the 2 groups; however, a larger proportion of the schizophrenia group had high (33.3%) and low (20.9%) percentile body weight compared with controls (27.7% vs 10.0%). People with schizophrenia who were underweight had higher rates of cardiac death than the controls (37.7% vs 13%) (chi(2) = 5.79, P = .01); however, no difference was noted in the number of coronary arteries occluded. Twenty-three (48.9%) of 47 of the controls with abnormally high subcutaneous fat showed cardiac atherosclerosis, whereas only 15 (33.3%) of 45 of the schizophrenia group with abnormally high subcutaneous fat had atherosclerosis (P = NS). Overall, the percentage of deaths due to cardiovascular disease was not higher in people with schizophrenia; however, in normal controls, cardiovascular disease appears to be related more to weight than in people with schizophrenia. This may be related to intrinsic metabolic differences associated with schizophrenia, lifestyle differences, or effects of antipsychotic medications. Nonetheless, our study suggests that efforts for the prevention of coronary atherosclerosis in schizophrenia patients should go beyond weight control to target multiple risk factors such as smoking, dyslipidemia, and cardiac side effect of antipsychotic medications.     

Comprehensive practicum evaluation across nursing program

With the inception of a new competency-based nursing curriculum, faculty in a baccalaureate nursing program developed a comprehensive laboratory and clinical evaluation program aimed at progressive, criterion-based evaluation across four semesters of the nursing program. This article provides background for the development of the program, the resources needed, and specific evaluation activities for the four semesters targeted. Course content and program year competencies, progressively built from one semester to the next, guided the design of the practicum evaluations. Faculty report satisfaction with the ability of this program to determine whether student performance is consistent with competency achievement. Refinements have been made to alleviate student stress and evaluator consistency.     

Hexokinase II overexpression improves exercise-stimulated but not insulin-stimulated muscle glucose uptake in high-fat-fed C57BL/6J mice

The aim of the present study was to determine the specific sites of impairment to muscle glucose uptake (MGU) in the insulin-resistant high-fat-fed, conscious C57BL/6J mouse. Wild type (WT) and hexokinase II overexpressing (HK(Tg)) mice were fed either a standard diet or high-fat diet and studied at 4 months of age. A carotid artery and jugular veins had catheters chronically implanted for sampling and infusions, respectively, and mice were allowed to recovery for at least 5 days. Mice were fasted for 5 h and underwent a hyperinsulinemic-euglycemic clamp or saline infusion for 120 min. Separate groups of mice were studied during 30-min sedentary or treadmill exercise periods. A bolus of 2-deoxy[(3)H]glucose was administered 25 min before the end of each study for determination of R(g), an index of tissue-specific glucose uptake. Fasting blood glucose was increased in high-fat compared with standard diet-fed WT (194 +/- 4 vs. 171 +/- 4 mg/dl) but not HK(Tg) (179 +/- 5 vs. 171 +/- 3 mg/dl) mice. High-fat feeding created hyperinsulinemia in both WT and HK(Tg) mice (58 +/- 8 and 77 +/- 15 micro U/ml) compared with standard diet-fed mice (21 +/- 2 and 20 +/- 1 micro U/ml). R(g) was not affected by genotype or diet during either saline infusion or sedentary conditions. HK II overexpression augmented insulin-stimulated R(g) in standard diet-fed but not high-fat-fed mice. Exercise-stimulated R(g) was impaired by high-fat feeding in WT mice, but this impairment was largely rectified in HK(Tg) mice. In conclusion, high-fat feeding impairs both insulin- and exercise-stimulated MGU, but only exercise-stimulated MGU was corrected by HK II overexpression.     

Catalytic activity and isoform-specific inhibition of rat cytochrome p450 4F enzymes

Arachidonic acid is omega-hydroxylated to 20-hydroxyeicosatetraenoic acid (20-HETE), which has effects on vasoactivity and renal tubular transport and has been implicated in the regulation of blood pressure. Cytochrome p450 (p450) 4A isoforms are generally considered the major arachidonic acid omega-hydroxylases; however, little is known about the role of rat CYP4F isoforms in 20-HETE formation. The rat CYP4F isoforms, CYP4F1, CYP4F4, CYP4F5, and CYP4F6, were heterologously expressed in Escherichia coli, and their substrate specificity in fatty acid metabolism was characterized. Substrate-binding assays indicated that leukotriene B(4) (LTB(4)) and arachidonic acid bound CYP4F1 and CYP4F4 in a type-I manner with a K(s) of 25 to 59 microM, and lauric acid bound CYP4F4 poorly. Reconstituted CYP4F1 and CYP4F4 catalyzed the omega-hydroxylation of LTB(4) with a K(m) of 24 and 31 microM, respectively, and CYP4F5 had minor activity in LTB(4) metabolism. Importantly, CYP4F1 and CYP4F4 catalyzed the omega-hydroxylation of arachidonic acid with an apparent k(cat) of 9 and 11 min(-1), respectively. Lauric acid was a poor substrate for all of the CYP4F isoforms, and CYP4F6 had no detectable fatty acid omega-hydroxylase activity. The p450 omega-hydroxylase inhibitors 17-octadecynoic acid, 10-undecynyl sulfate, and N-methylsulfonyl-12,12-dibromododec-11-enamide showed isoform-specific inhibition of CYP4F1- and CYP4F4-catalyzed omega-hydroxylation of arachidonic acid and potency differences between the CYP4A and CYP4F isoforms. These data support a significant role for CYP4F1 and CYP4F4 in the formation of 20-HETE and identify p450 inhibitors that can be used to understand the relative contribution of the CYP4A and CYP4F isoforms to renal 20-HETE formation.