Application of an Intermittency Model for Laminar, Transitional, and Turbulent Internal Flows.

A turbulent transition model has been applied to fluid flow problems that can be laminar, turbulent, transitional, or any combination. The model is based on a single additional transport equation for turbulence intermittency. While the original model was developed for external flows, a slight modification in model constants has enabled it to be used for internal flows. It has been successfully applied to such flows for Reynolds numbers that ranged from 100 to 100,000 in circular tubes, parallel plate channels, and circular tubes with an abrupt change in diameters. The model is shown to predict fully developed friction factors for the entire range of Reynolds numbers as well as velocity profiles for both laminar and turbulent regimes.

Variations in differential gene expression patterns across multiple brain regions in schizophrenia.

Large-scale gene expression studies in schizophrenia (SZ) have generally focused on the dorsolateral prefrontal cortex. Despite a wealth of evidence implicating multiple other brain regions in the disease, studies of other brain regions have been less frequent and have rarely been performed in the same subjects. We analyzed postmortem gene expression in the frontal, cingulate, temporal, parietal and occipital cortices (Brodmann areas 8, 10, 44, 46, 23/31, 24/32, 20, 21, 22, 36/28, 7 and 17, respectively) as well as in the hippocampus, caudate nucleus and putamen of persons with schizophrenia and control subjects (N's = 13) using Affymetrix GeneChip microarrays. Under identical data filtering conditions, the superior temporal cortex (BA22) of schizophrenia subjects showed the maximal number of altered transcripts (approximately 1200) compared to controls. Anterior and posterior cingulate cortices (BA23/31, 24/32) and the hippocampus followed the superior temporal cortex with two-times lower numbers of altered transcripts. The dorsolateral prefrontal cortex (BA46), a frequent target of SZ-associated studies, showed substantially fewer altered transcripts (approximately 33). These regional differences in differentially expressed genes could not be accounted for by factors such as total numbers of genes expressed or the filtering conditions and criteria used for identification of differentially expressed genes. These findings suggest that the temporal and cingulate cortices and the hippocampal formation represent brain regions of particular abnormality in SZ and may be more susceptible to the disease process(es) than other regions thus far studied.

Occupancy of dopamine D2 receptors by the atypical antipsychotic drugs risperidone and olanzapine: theoretical implications.

RATIONALE: To examine the D2 occupancy of two commonly used antipsychotic medications and relate this to the D2 occupancy by endogenous dopamine in schizophrenia. OBJECTIVES: The aim of this study is to compare the occupancy of striatal D2 receptors by the atypical antipsychotic medications risperidone and olanzapine at fixed dosages and to estimate the effect on D2 occupancy by dopamine as a result of these treatments. METHODS: Seven patients with schizophrenia taking risperidone 6 mg/day and nine patients with schizophrenia taking olanzapine 10 mg/day underwent an [123I]IBZM SPECT scan after 3 weeks of treatment. The specific to non-specific equilibrium partition coefficient (V3") after bolus plus constant infusion of the tracer was calculated as [(striatal activity)/(cerebellar activity)]-1. D2 receptor occupancy was calculated by comparing V3" measured in treated patients to an age-corrected V3" value derived from a group of untreated patients with schizophrenia, previously published, according to the following formula: OCC=1-(V3" treated/V3" drug free). RESULTS: V3" was significantly lower in risperidone treated patients compared with olanzapine treated patients (0.23+/-0.06 versus 0.34+/-0.08, P=-0.01), which translated to a significantly larger occupancy in schizophrenic patients treated with risperidone compared to olanzapine (69+/-8% versus 55 +/-11%, P=0.01). Data from our previous study were used to calculate the occupancy of striatal D2 receptors by antipsychotic medications required to reduce the occupancy of these receptors by endogenous dopamine to control values. In medication-free patients with schizophrenia, the occupancy of striatal D2 receptors by endogenous dopamine is estimated at 15.8%. In healthy controls, the occupancy of striatal D2 receptors by dopamine is estimated at 8.8%. In order to reduce the dopamine occupancy of striatal D2 receptors in patients with schizophrenia to control values, 48% receptor occupancy by antipsychotic medications is required. CONCLUSIONS: These data indicate that the dosage of these medications, found to be effective in the treatment of schizophrenia, reduces DA stimulation of D2 receptors to levels slightly lower than those found in unmedicated healthy subjects.

Medications and verbal memory impairment in schizophrenia: the role of anticholinergic drugs.

BACKGROUND: We wished to assess the effect of three types of medication on verbal memory impairments in schizophrenia. METHOD: Forty-eight patients with schizophrenia and 40 healthy control subjects underwent a battery of verbal memory tasks, including free recall, recognition and short-term memory span. All the patients were on antipsychotic medication. In addition, 24 were taking anticholinergic drugs (benztropine) and 30 were taking benzodiazepines. A subsample of 39 had clinical ratings for depressive symptoms. Regression analyses were conducted on the memory measures in this subsample, with negative symptoms, depression, type of antipsychotic medication (conventional v. atypical), benzodiazepines and anticholinergic drugs as predictors. RESULTS: Type of antipsychotic medication made no significant contribution to memory deficits and benzodiazepine use made very little contribution. However, anticholinergic medication was a predictor of memory impairment, especially with regard to semantic organization. Complementary analyses revealed that patients taking any type of drug with anticholinergic activity (benztropine and/or antipsychotic agents) were significantly impaired relative to the other patients on measures reflecting free recall efficiency and semantic organization. CONCLUSIONS: Drugs with anticholinergic activity are the major pharmacological agents that contribute to the verbal memory deficit observed in patients with schizophrenia. These drugs appear to act by impeding semantic organization at encoding.

Respiratory variability in panic disorder.

Disordered breathing may play an important role in the pathophysiology of panic disorder. Several studies have now indicated that panic disorder patients have greater respiratory variability than normal controls. In this study, we examine baseline respiratory measures in four diagnostic groups to determine whether greater respiratory variability is specific to panic disorder and whether effective anti-panic treatment alters respiratory variability. Patients with panic disorder, major depression, or premenstrual dysphoric disorder, and normal control subjects underwent two respiratory exposures (5% and 7% CO(2) inhalation), while in a canopy system. Panic disorder patients returned after 12 weeks of either anti-panic medication or cognitive behavioral therapy, and were retested. Normal control subjects were also retested after a period of 12 weeks. Panic disorder patients had significantly greater respiratory variability at baseline than normal control subjects and patients with major depression. The premenstrual dysphoric patients also had greater variability than the normal control group. Panic disorder patients who panicked to 7% CO(2) inhalation had significantly greater baseline variability than panic disorder patients who did not panic. Anti-panic treatment did not significantly alter baseline respiratory variability. Our data suggest that increased respiratory variability may be an important trait feature for some panic disorder patients and may make them more vulnerable to CO(2)-induced panic.

Neurobiological mechanisms of social anxiety disorder.

OBJECTIVE: The authors critically surveyed several preclinical and clinical neurobiological models of social anxiety disorder. METHOD: The authors reviewed the recent literature regarding three animal models of particular relevance to social anxiety. They then examined the recent literature concerning clinical neurobiological aspects of social anxiety disorder, including the developmental neurobiology of anxiety, the genetics of fear and social anxiety, and challenge and imaging studies. RESULTS: The available animal models are useful paradigms for understanding the features of social subordination stress, attachment behavior, and environmental rearing, but they incompletely account for the known neurobiology of human social anxiety disorder. The clinical neurobiology literature surveyed implicates specific neurotransmitter system abnormalities, most notably of the dopamine system, but largely ignores neurodevelopmental processes and the functional interactions between neurotransmitters. Both heritable factors and environmental stress factors appear to be responsible for the onset of social anxiety disorder. CONCLUSIONS: Social anxiety disorder should be conceptualized as a chronic neurodevelopmental illness that might represent a fully compensated state in adulthood. Future investigations from this perspective are discussed.

Acute panic inventory symptoms during CO(2) inhalation and room-air hyperventilation among panic disorder patients and normal controls.

There is scant literature on anxiety symptoms induced during respiratory challenges developed to induce panic symptoms and attacks. Here we report on the prevalence of Acute Panic Inventory (API) symptoms during three consecutive respiratory challenges to patients with panic disorder (PD) and normal controls (NC). The challenges performed using a closed canopy system included voluntary room air hyperventilation (RAH), inhalation of 5% CO(2), and 7% CO(2)-enriched air. The PD patients were 41 men and 53 women whose mean age was 33.4 (SD = 8.55). The normal comparison group consisted of 35 men and 27 women with a mean age of 31.3 (SD = 9.21). The diagnosis of panic disorder was made using the Structured Clinical Interview for DSM-III-R. All potential normal controls underwent structured clinical interview using the Schedule for Affective Disorders and Schizophrenia-Lifetime Version Modified for the Study of Anxiety Disorders (SADS-LA), and must have been free of a lifetime history of anxiety disorders, affective disorders, substance use disorders, and schizophrenia. All participants also had a complete medical evaluation and were in good health. The experiment consisted of seven experimental epochs: three baseline/recovery periods each followed by a respiratory challenge, and then a final recovery epoch. The API was administered at the end of each epoch. Clinical staff trained and experienced in rating panic attacks rated participants' response during each challenge as panic or no panic. Three groups were defined for analysis: PD patients who panicked, PD patients who did not panic, and NC who did not panic. Staff ratings indicated that the 7% CO(2) challenge was the most panicogenic, followed by the 5% CO(2), and the RAH challenges. Conventional statistics (analysis of variance and partial correlations) indicated that many baseline symptoms as well as symptom increments differed across groups, and were associated with the outcome of panic/no panic during each challenge. However, logistic regression analysis indicated that only a few symptoms independently predicted the panic/no panic outcome because many symptoms were redundant. The symptom cluster of fear in general, dizziness, difficulties with concentrating, and doing one's job predicted panic to RAH. The cluster of fear in general, confusion, dyspnea, and twitching/trembling predicted the response to 5% CO(2). Finally, fear in general, confusion, twitching/ trembling and dizziness predicted the response to 7% CO(2). While univariate analyses indicated that many symptoms distinguished between panic and no panic outcome, logistic regression revealed that group differences were subsumed under a few prominent symptoms, namely, fear in general, confusion, dizziness, twitching/trembling, and dyspnea. The results are discussed in the context of patient (having a diagnosis of PD) and panic effects (rated as panicking to a challenge).

Therapists, therapist variables, and cognitive-behavioral therapy outcome in a multicenter trial for panic disorder.

The relationship between therapists and treatment outcome was examined in 14 highly trained therapists who participated in the Multicenter Collaborative Study for the Treatment of Panic Disorder. Overall, therapists yielded positive outcomes in their caseloads; yet, therapists significantly differed in the magnitude of change among caseloads. Effect sizes for therapist impact on outcome measures varied from 0% to 18%. Overall experience in conducting psychotherapy was related to outcome on some measures, whereas age, gender, gender match, and experience with cognitive-behavioral therapy (CBT) were not. Therapists with above- and below-average outcomes were rated similarly on measures of adherence and competency. The results suggest that therapists make a contribution to outcome in CBT for panic disorder, even when patients are relatively uniform, treatment is structured, and outcome is positive. Implications for future clinical outcome studies and for training clinicians are discussed.

Perceptual asymmetries in schizophrenia: subtype differences in left hemisphere dominance for dichotic fused words.

OBJECTIVE: Dichotic listening techniques have been used to study hemispheric dominance for language in schizophrenia. The authors' goal was to compare subjects with paranoid and undifferentiated subtypes of schizophrenia. METHOD: The Fused Rhymed Words Test was used to compare perceptual asymmetries in 16 patients with paranoid schizophrenia, 28 patients with undifferentiated schizophrenia, and 29 healthy comparison subjects. RESULTS: Patients with paranoid schizophrenia had the largest left hemisphere advantage and patients with undifferentiated schizophrenia had the smallest. The asymmetry of healthy subjects was intermediate. Hemisphere advantage varied as a function of gender only in the patients with undifferentiated schizophrenia. CONCLUSIONS: The findings support the hypotheses that undifferentiated schizophrenia is associated with underactivation of left hemisphere resources for verbal processing and that paranoid schizophrenia is characterized by preserved left hemisphere processing.

Event-related potentials in schizophrenia during tonal and phonetic oddball tasks: relations to diagnostic subtype, symptom features and verbal memory.

BACKGROUND: This study compares event-related potentials for paranoid patients (n = 13) versus matched undifferentiated patients and unmedicated patients (n = 14) versus matched healthy adults. METHODS: Event-related potentials of right-handed patients and control subjects were recorded from 30 electrodes during oddball tasks using consonant-vowel syllables or complex tones. Patients were also assessed using the Positive and Negative Syndrome Scale, the Thought Disorder Index, and the Wechsler Memory Scale. RESULTS: Paranoid patients did not differ from undifferentiated patients in N1 or P3 amplitude but showed larger N2 at frontocentral sites to phonetic stimuli, as well as larger N2 over left than right hemisphere. Unmedicated patients showed reduced N2, but not N1 or P3, compared to control subjects. CONCLUSIONS: The N2 findings are consistent with neuropsychological evidence of greater verbal abilities and left hemisphere dominance in paranoid than nonparanoid schizophrenia. The findings also confirm the relationship of P3 to total Brief Psychiatric Rating Scale score, negative symptoms, and verbal associative memory.

Variable foraging demand rearing: sustained elevations in cisternal cerebrospinal fluid corticotropin-releasing factor concentrations in adult primates.

BACKGROUND: The authors previously reported elevated cerebrospinal fluid (CSF) corticotropin-releasing factor (CRF) concentrations in juvenile primates nursed by mothers undergoing experimentally imposed unpredictable foraging conditions in comparison to normally reared controls. The purpose of the present study was to determine if these changes would endure into young adulthood. METHODS: Cisternal CSF samples were obtained from those unpredictably reared young adult primates who had been previously studied as juveniles and age-matched ad libitum normally reared controls. Samples were assayed for CSF CRF. RESULTS: Concentrations of CSF CRF were significantly elevated in the unpredictably reared sample in comparison to the ad libitum-reared control group. A significant positive correlation was noted between juvenile and young adult CSF CRF values within the unpredictably reared cohort. CONCLUSIONS: Disturbances of maternal-infant attachment processes have an enduring impact on primate CRF function into young adulthood. The CRF elevations following unpredictable maternal foraging conditions appear traitlike in nature.

Enhanced stress reactivity in paediatric anxiety disorders: implications for future cardiovascular health.

The aim was to clarify the developmental nature of associations between psychiatric illness and risk for cardiovascular disease by investigating differences in cardiac functioning between youth with anxiety disorders and healthy controls. Twenty-two children meeting DSM-IV criteria for either separation anxiety disorder, overanxious disorder, panic disorder/panic attacks, or social phobia and 12 healthy controls underwent continuous electrocardiogram and respiration rate monitoring during a 15 min baseline period and 15 min of exposure to 5% CO(2). Heart rate (HR) and high frequency heart rate variability (HRV), a non-invasive measure of cardiac parasympathetic control, were calculated. Youth with anxiety disorders had higher and less fluctuating HR during baseline. Data also suggested that probands showed diminished overall changes in HRV during baseline and CO(2) inhalation relative to controls. However, as respiration rate affects HRV, these findings were confounded by changes in respiration elicited by CO(2) inhalation. The data suggest that youth with anxiety disorders experience an elevated and less fluctuating HR in the face of a novel situation, possibly due to a failure to appropriately modulate HRV. In adults, sustained elevations in HR in conjunction with deficient vagal modulation predicts risk for future cardiovascular disease. As such, the current data suggest that the presence of an anxiety disorder may identify youth who exhibit autonomic profiles that place them at risk for cardiac disease.

Event-related brain potentials (ERPs) in schizophrenia for tonal and phonetic oddball tasks.

BACKGROUND: Prior studies using simple target detection ("oddball") tasks with pure tones have reported asymmetric reduction of the P3 event-related potential (ERP). This study investigated the time course and topography of ERPs recorded during both tonal and phonetic oddball tasks. METHODS: Event-related potentials of 66 patients (14 unmedicated) diagnosed with schizophrenia (n = 46) or schizoaffective disorder (n = 20) and 32 healthy adults were recorded from 30 scalp electrodes during two oddball tasks using consonant-vowel syllables or complex tones. Overlapping ERP components were identified and measured by covariance-based principal components analysis. RESULTS: Schizophrenic patients showed marked, task-independent reductions of early negative potentials (N1, N2) but not reduced P3 amplitude or abnormal P3 asymmetry. Task-related hemispheric asymmetries of the N2/P3 complex were similar in healthy adults and schizophrenic patients. Poorer task performance in patients was related to ERP amplitudes, but could not account for reductions of early negativities. CONCLUSIONS: The findings suggest that both patients and control subjects activated lateralized cortical networks required for pitch (right frontotemporal) and phoneme (left parietotemporal) discrimination. Task-independent reductions of negativities between 80 and 280 msec after stimulus onset suggest a deficit of automatic stimulus classification in schizophrenia, which may be partly compensated by later effortful processing.

Generalized anxiety disorder.

The diagnosis of generalized anxiety disorder (GAD) was first introduced in 1980 with the publication of the Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III) of the American Psychiatric Association. Prior to this, the diagnosis of "anxiety neurosis" was given to patients with symptoms similar to those now incorporated within the GAD category. Originally, GAD was created as a residual category within the anxiety disorders as a rubric for patients with serious anxiety problems but without panic attacks. Panic disorder therefore received far more research attention, and GAD was seen as a diagnosis of exclusion once panic disorder had been ruled out. It is now clear, however, that GAD is a serious psychiatric disorder that is more common than panic disorder and frequently encountered in primary care practice. Indeed, the primary care physician is more likely to see patients with pure GAD than is the psychiatrist. While the treatment of GAD is relatively straightforward, the diagnosis can be difficult. Hence, careful attention to several key symptomatic presentations is important.

Clinical and cognitive factors associated with verbal memory task performance in patients with schizophrenia.

OBJECTIVE: The authors have previously shown the role of depression, slowing of processing speed, and selective attention deficit in verbal memory task performance in schizophrenia. They wished to determine the specific contribution of each of these factors to various types of memory impairment. METHOD: The negative symptom score from the Positive and Negative Syndrome Scale, the Hamilton Depression Rating Scale score, a measure of processing speed, and a measure of selective attention were entered as predictors in regression analyses. Furthermore, analyses of covariance were conducted on the memory measures to test the significance of the differences between schizophrenic patients and healthy comparison subjects after control for processing speed and selective attention. RESULTS: Depression was associated only with deep encoding reflected by semantic clustering. Selective attention was associated only with superficial encoding reflected by serial recall. Slowing of processing speed was associated with both deep and superficial encoding. Negative symptoms were not associated with memory impairment except for the avolition item from the Scale for the Assessment of Negative Symptoms. Processing speed accounted for all the group differences on the memory measures that reflected superficial encoding. In addition, a subgroup of patients with no or minor depression was not significantly impaired on deep encoding relative to the healthy comparison group. CONCLUSIONS: The authors suggest that verbal memory impairment in schizophrenia is a consequence of depression and slowness, rather than a primary feature of the disease.