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.

Glycine transport in mouse eggs and preimplantation conceptuses.

At least two Na+-dependent systems for glycine transport became detectable, while another became undetectable during preimplantation development of mouse conceptuses. Glycine was taken up by a process in eggs and cleavage-stage conceptuses which closely resembles system Gly. Mediated transport at these stages was more rapid at higher Cl- concentrations, sigmoidally related to the exogenous Na+ concentration, and strongly inhibited by sarcosine but not by amino acids with larger side chains. Moreover, neither Li+ nor choline could substitute for Na+ in stimulating glycine transport. System Gly was the only mediated process detected for glycine uptake in unfertilized and fertilized eggs and two-cell conceptuses, but two, less conspicuous, sarcosine-resistant, Na+-dependent components of transport also appeared to be present in eight-cell conceptuses. One of the latter components seemed to remain relatively inconspicuous when conceptuses formed blastocysts, while system Gly became undetectable. In contrast, the other less conspicuous component in eight-cell conceptuses appeared to become the most conspicuous transport process in blastocysts. The latter process, previously designated system B0,+, was shown here also to interact strongly with a broad scope of zwitterionic and cationic amino acid structures. Moreover, transport of glycine via system B0,+ was more rapid at higher Cl- concentrations, and this Na+-dependent process as well as Na+-independent leucine uptake were inhibited by choline. Furthermore, Na+-dependent amino acid transport in two-cell conceptuses and blastocysts was inhibited by 1.0 or 10 mM ouabain, but the inhibition was incomplete at both concentrations. Since Na+/K+-ATPase has not been detected in two-cell conceptuses, inhibition of amino acid transport by ouabain may not have been due solely to an effect on this enzyme. The level of system Gly activity decreased during the development of eight-cell conceptuses from eggs, and this decrease could contribute to an associated decline in intracellular glycine. Since other amino acids begin to compete strongly with glycine for transport when system B0,+ replaces system Gly in conceptuses, this qualitative change in transport activity may help account for a further decrease in the glycine content of conceptuses, reported elsewhere to occur after they form blastocysts.

Inhibition of transport system b0,+ in blastocysts by inorganic and organic cations yields insight into the structure of its amino acid receptor site.

The most conspicuous, Na(+)-independent amino acid transport process in preimplantation mouse blastocysts was provisionally designated system b0,+ because it accepts some cationic and zwitterionic amino acids about equally well as substrates. Although system b0,+ is not Na(+)-stimulated, it has not been determined if it is inhibited by Na+, or if its activity is affected by most other ions. Therefore, we measured uptake of amino acids by blastocysts in isotonic solutions of different ionic and nonionic osmolites. Na(+)-independent L-leucine uptake was unaffected by the ion concentration, but L-lysine transport was several-fold faster in isotonic solutions of non-electrolytes than in similar solutions of inorganic and organic salts or zwitterions. The Km value for 'Na(+)-independent' L-lysine transport was about 10-fold higher in isotonic salt solutions than in solutions of nonionic osmolites, whereas the Km value for L-leucine transport was about the same in either type of solution. Therefore, inorganic and organic cations and the cationic portions of zwitterions appear to compete with cationic but not zwitterionic amino acids for system b0,+ receptor sites. The cation, harmaline, was a particularly strong competitive inhibitor of 'Na(+)-independent' L-lysine uptake by system b0,+, even in isotonic salt solutions, whereas it inhibited L-leucine uptake noncompetitively. Moreover, harmaline appeared to compete with inorganic cations for the lysine receptor sites of system b0,+. Harmaline also has been found by other investigators to competitively inhibit L-lysine uptake by the Na(+)-independent system asc1 in horse erythrocytes, whereas it noncompetitively inhibits alanine uptake by the same system. Similarly, harmaline noncompetitively inhibits L-alanine uptake by the Na(+)-dependent system ASC in human erythrocytes, but it appears to compete for binding with L-alanine's cosubstrate, Na+. In addition, others have found that the positively-charged side chains of cationic amino acids seem to take the place of Na+ needed near side chains in order for zwitterionic amino acids to be transported by systems ASC and y+. We conclude that system b0,+ may be similar to systems asc1, ASC and y+, and that each of these systems may be a variant of the same ancestral transport process. We speculate that since it appears to accept a broader scope of substrates and to interact with a wider variety of cations than do systems asc1, ASC or y+, system b0,+ may more closely resemble the proposed ancestral transport process than any of the other contemporary systems.

Changes in the activities of amino acid transport systems b0,+ and L during development of preimplantation mouse conceptuses.

Uptake of leucine, lysine, and arginine was predominantly Na(+)-independent in mouse conceptuses through the 8-cell stage of development, and two components of saturable transport were detected for each of these amino acids. Uptake of cationic substrates from solutions near 1 microM was inhibited most strongly by bulky cationic and zwitterionic amino acids whose carbon skeletons do not branch at the alpha or beta positions. By this criterion, system b0,+ accounted for most of the Na(+)-independent arginine and lysine transport in eggs and conceptuses throughout preimplantation development. A small, leucine-resistant, cation-preferring component of amino acid transport was also detected in these cells. Leucine uptake was inhibited most strongly by bicyclic, branched-chain or benzenoid, zwitterionic amino acids in eggs and conceptuses prior to formation of blastocysts. Therefore, it appeared to be taken up mainly by system L, while system b0,+ accounted for a smaller portion of leucine uptake during this developmental period. In blastocysts, in contrast, system L was less conspicuous, and system b0,+ was primarily responsible for Na(+)-independent leucine uptake. The Vmax values for transport of amino acids by system b0,+ increased by up to 30-fold in conceptuses between the 1-cell and blastocyst stages. In contrast, the Vmax value for leucine transport via system L decreased while the Km value increased between these two developmental stages. Although several explanations for these changes are possible, we favor the hypothesis that the density of system L transport sites in plasma membranes decreases while the number of system b0,+ sites increases during development of blastocysts from 1-cell conceptuses.

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.

Characterization of psychotic conditions. Use of the domains of psychopathology model.

BACKGROUND: Previous factor analytic studies of patients with schizophrenia have consistently demonstrated the presence of 3 psychopathological domains labeled positive, negative, and disorganized. This study examined whether similar domains can be seen in disorders other than schizophrenia, and the degree to which such domains are independent of diagnostic categorization. METHODS: Data from the Diagnostic and Statistical manual of Mental Disorders, Fourth Edition (DSM-IV) field trial involving 221 patients with schizophrenia and 189 patients with nonschizophrenia diagnoses were factor analyzed to study the nature of psychopathological domains in the 2 groups. Differential associations between each domain and selected clinical variables were assessed. RESULTS: Factor analysis yielded a similar 3-factor model of positive, negative, and disorganization domains for patients with schizophrenia as well as other diagnoses. Differential associations found between individual domains and clinical variables (premorbid functioning and negative domain; absence of remissions and disorganization domain) were similar in both schizophrenia and nonschizophrenia groups. CONCLUSIONS: The 3 psychopathological domains previously described in schizophrenia are not specific for that diagnosis. Differential associations found between individual domains and clinical variables were not limited by diagnostic categorization. The results suggest that these domains are not unique to schizophrenia and may each correspond to a discrete pathophysiologic condition.

Cortisol and sodium lactate-induced panic.

Sodium lactate infusions induce panic attacks in patients with panic disorder, but not in normal controls, by an unknown mechanism. We studied the plasma cortisol response to infusion of 0.5 mol/L of sodium lactate in 103 patients with panic disorder or agoraphobia with panic attacks, and 32 normal controls. Baseline cortisol levels did not distinguish early panickers from non-panickers and controls, but late panickers had significantly elevated baseline cortisol levels. In addition, a higher percentage of late panickers manifested an increase in cortisol during the baseline period compared with the other groups. Despite the fact that late panickers manifested elevated baseline cortisol levels, early panickers had significantly greater somatic distress as measured by the Acute Panic inventory. There was no increase in cortisol with lactate-induced panic, and cortisol levels fell significantly during the lactate infusion in all groups. Cortisol elevation occurred with moderate anxiety but not with severe panic anxiety. These results suggest different pathophysiologic mechanisms of early and late panic, and differences between anticipatory anxiety and panic anxiety.

Social phobia. Review of a neglected anxiety disorder.

While other anxiety disorders have recently become the subjects of increasing investigation, social phobia remains, except among behavior therapists, relatively unstudied. As a result, major uncertainties exist concerning classification, prevalence, severity, etiology, assessment, and treatment of social phobia. Existing findings do suggest that in its own right and as a comparison for other anxiety disorders, social phobia should prove a fertile area for psychobiological and clinical investigation.

Depression, distress, lymphocyte subsets, and human immunodeficiency virus symptoms on two occasions in HIV-positive homosexual men.

We evaluated the extent to which depressive disorders, psychiatric distress, and psychosocial stressors are related to three measures of human immunodeficiency virus (HIV) illness, both cross-sectionally and during a 6-month period, in a community sample of 124 HIV-positive homosexual men. The dependent variables are immune status measured by CD4 and CD8 cell subsets, number of signs and symptoms commonly associated with HIV infection, and a cumulative index of HIV illness stage. We chose to focus on CD4 cell count because it is the immune marker most closely linked to the clinical consequences of HIV infection. We found no relationships between the independent variables and immune status or illness stage. The HIV-positive men who were depressed or distressed or who reported more life stressors had no greater immunosuppression or more advanced illness stage than did the others, either concurrently or across occasions. We did find a suggestive pattern of association between depressive disorders, distress, and stressors and the number of HIV-related symptoms, which warrants further study.

Multidisciplinary baseline assessment of homosexual men with and without human immunodeficiency virus infection. II. Standardized clinical assessment of current and lifetime psychopathology.

Despite numerous reports of the psychiatric consequences of human immunodeficiency virus infection, few reports describe systematic diagnostic assessments of people with human immunodeficiency virus infection. We studied the results of standardized clinical assessments of current and lifetime psychopathology in a large group of homosexual men whose serologic status was known. Results indicated low rates of current mental disorders but very high rates of lifetime major depression and alcohol and other psychoactive substance abuse and dependence disorders. Measures of severity of psychopathology and functioning also indicated, on the whole, good current functioning. No significant relationship was found between stage of medical illness or immune status and any measure of psychiatric disturbance.

Schizophrenia after prenatal famine. Further evidence.

BACKGROUND: Suggestive findings of an earlier study that prenatal nutritional deficiency was a determinant of schizophrenia prompted us to undertake a second test of the hypothesis using more precise data on both exposure and outcome. METHODS: Among persons born in the cities of western Netherlands during 1944 through 1946, we compared the risk for schizophrenia in those exposed and unexposed during early gestation to the Dutch Hunger Winter of 1944/1945. The frequency of hospitalized patients with schizophrenia at age 24 to 48 years in the exposed and unexposed birth cohorts was ascertained from a national psychiatric registry. RESULTS: The most exposed birth cohort, conceived at the height of the famine, showed a twofold and statistically significant increase in the risk for schizophrenia (relative risk [RR] = 2.0; 95% confidence interval [CI] = 1.2 to 3.4; P < .01) in both men (RR = 1.9; 95% CI = 1.0 to 3.7; P = .05) and women (RR = 2.2; 95% CI = 1.0 to 4.7; P = .04). Among all birth cohorts of 1944 through 1946, the risk for schizophrenia clearly peaked in this exposed cohort. CONCLUSION: Prenatal nutritional deficiency may play a role in the origin of some cases of schizophrenia.

Physiological changes during carbon dioxide inhalation in patients with panic disorder, major depression, and premenstrual dysphoric disorder: evidence for a central fear mechanism.

BACKGROUND: Inhalation of carbon dioxide (CO(2)) has been shown to produce more anxiety in patients with panic disorder (PD) than in healthy comparison subjects or patients with most other psychiatric illnesses tested, although premenstrual dysphoric disorder (PMDD) may be an exception. Several reasons have been proposed to explain CO(2) breathing effects in PD. We examined differences in respiratory response to CO(2) breathing in 4 groups to address these issues. METHODS: Patients with PD (n = 52), healthy controls (n = 32), patients with PMDD (n = 10), and patients with major depression without panic (n = 21) were asked to breathe 5% and 7% CO(2). Continuous measures of respiratory physiological indices were made. RESULTS: Carbon dioxide breathing produced the expected increases in all 4 respiratory variables measured. More patients with PD and PMDD had panic attacks than did controls or patients with major depression. Subjects who experienced panic during 5% or 7% CO(2) inhalation had the most extreme increases regardless of diagnostic group. Among patients with PD, baseline end-tidal carbon dioxide levels were significantly lower in those who subsequently had a panic attack during 5% CO(2) breathing than those who did not. CONCLUSIONS: Although CO(2) breathing causes a higher rate of panic attacks in patients with PD than other groups (except PMDD), the physiological features of a panic attack appear similar across groups. Once a panic attack is triggered, minute ventilation and respiratory rate increase regardless of whether the subject carries a PD diagnosis. These findings are compatible with preclinical fear conditioning models of anxiogenesis.

Effect of innervation on heart rate response to mental stress.

Heart transplant recipients provide a useful model for study of the autonomic control of the cardiovascular response to mental stress. Utilizing the innervated native atrial tissue of heart transplant recipients as an internal control exposed to the same circulatory milieu as the denervated graft heart was exposed to, the effect of innervation on the heart rate response to a mentally stressful arithmetic task was examined in eight subjects. Compared with the graft, the innervated atrial tissue manifested a larger heart rate increase during the task, larger heart rate decrease after the task, and more rapid rate of change in heart rate during the task and recovery periods. Thus, cardiac denervation results in a chronotropic response to mental arithmetic-induced stress that is blunted and more gradual than that of the innervated heart but not completely eliminated. The cardiac chronotropic response to mental arithmetic stress is dependent on both humoral factors and, predominantly, its direct autonomic innervation.

Blood gas changes and hypophosphatemia in lactate-induced panic.

Alkalosis is prominent among the many physiologic and biochemical effects of sodium lactate infusion. Though this is partially due to the conversion of lactate to bicarbonate, the metabolic component, it may also be secondary to hyperventilation before and during the infusion, the respiratory component. We analyzed pH, carbon dioxide pressure, bicarbonate, and inorganic phosphate from patients with panic disorder and agoraphobia with panic attacks and from normal controls both before and during lactate infusion. Our findings extend earlier work demonstrating that many such patients are chronic hyperventilators. Both metabolic and respiratory alkalosis develop in all subjects during lactate infusion, but only hyperventilation-induced hypocapnia differentiates patients at the point of lactate-induced panic from nonpanicking patients and normal controls. Finally, low inorganic phosphate levels at baseline appear associated with patients who will panic during the subsequent lactate infusion. This last unexpected finding may reflect hyperventilation or an abnormality in intracellular glycolysis.

Ventilatory physiology of patients with panic disorder.

Thirty-one patients with DSM-III panic disorder or agoraphobia with panic attacks, 13 normal controls, and 12 patients with other anxiety disorders were studied during ventilatory challenge with room air hyperventilation and 5% carbon dioxide inhalation. Patients also underwent sodium lactate infusion. Among the patients with panic disorder, 58% panicked with sodium lactate, 39% with 5% CO2, and 23% with room air hyperventilation. Of the other patients, four panicked with sodium lactate, none with 5% CO2, and one with room air hyperventilation. One normal control panicked with both sodium lactate and 5% CO2. Panic with CO2 was associated with an exaggerated ventilatory response and increases in plasma norepinephrine level and diastolic blood pressure. Patients with panic disorder may have hypersensitive CO2 receptors that, when triggered, evoke a subjective panic associated with an exaggerated ventilatory response and consequent hypocapnic alkalosis.

Lactate provocation of panic attacks. I. Clinical and behavioral findings.

To assess the pharmacologic and phenomenologic comparability of lactate-induced and naturally occurring panic attacks, patients meeting DSM-III criteria for panic disorder or agoraphobia with panic attacks were infused with 0.5M racemic sodium lactate before and after successful drug treatment. Lactate-induced and naturally occurring panic attacks were symptomatically similar. Following treatment, the patients' response to lactate did not differ from that of normal controls, whereas the pretreatment panic rate was much higher. These data suggest that lactate acts, by as yet unidentified mechanisms, to trigger the same panic attacks as occur spontaneously in vulnerable persons.

Lactate provocation of panic attacks. II. Biochemical and physiological findings.

Thirty-one of 43 patients with panic disorder or agoraphobia with panic attacks and none of 20 normal controls panicked in response to infusions of sodium lactate. Before receiving lactate, patients showed higher heart rates than controls and also signs of hyperventilation. During lactate infusion, patients who did not panic, nevertheless, developed higher lactate and pyruvate levels and greater ionized calcium and pH changes than controls. Lactate-induced panic attacks were regularly accompanied by biological changes consistent with hyperventilation and central noradrenergic activation and irregularly by elevation of plasma norepinephrine and cortisol levels. Panic attacks were not associated with changes in epinephrine or calcium levels or pH. Baseline arousal increased the likelihood of panic during lactate infusion. It is hypothesized that lactate-induced panic primarily involves central noradrenergic discharge with inconsistent peripheral manifestations.

Familial transmission of simple phobias and fears. A preliminary report.

Preliminary data from a blind direct interview family study indicate a significantly higher risk for simple phobia among first-degree relatives (n = 49) of simple phobic probands (who had no other anxiety disorder) as compared with first-degree relatives (n = 119) of never mentally ill controls (31% vs 11%, relative risk = 3.3). Female relatives were more likely to be affected than male relatives (48% vs 13%), though this difference did not reach conventional significance in an age-corrected analysis. Significant between-group differences were not found in risks for (1) other anxiety, affective, and substance abuse disorders, and (2) simple irrational fears that did not meet disorder criteria. The results suggest that simple phobia is a highly familial disorder that does not transmit increased risk for other phobic or anxiety disorders. The specificity of increased risk among the relatives of simple phobics is consistent with the distinction between simple phobia, social phobia, and agoraphobia. However, complete delineation of the transmissional relationship between these illnesses requires assessment of the extent to which risk for simple phobia can be transmitted by individuals with other phobic or anxiety disorders. Replication of these preliminary findings in larger clinically and epidemiologically selected samples is needed.

Multidisciplinary baseline assessment of homosexual men with and without human immunodeficiency virus infection. I. Overview of study design.

Although much is known about the virus believed by most experts to be the cause of the acquired immunodeficiency syndrome and about its pathogenic actions, major areas of ignorance remain. Among these are the reasons for the varying time between infection with human immunodeficiency virus and development of acquired immunodeficiency syndrome, the relationship between neurologic and medical aspects of the disease, the time course of neuropsychological findings, and the prevalence of psychiatric morbidity. We assessed 124 homosexual men who were positive for human immunodeficiency virus and 84 who were negative for the virus. In this article we describe the study design, method of recruitment, and medical and demographic characteristics of the cohort, which will be followed up for 5 years.

Clinical improvement with fluoxetine therapy and noradrenergic function in patients with panic disorder.

BACKGROUND: Central noradrenergic (NA) dysregulation has provided a major theoretical framework for understanding the pathogenesis of panic disorder (PD). Using clonidine, an alpha 2-adrenergic receptor agonist, as a probe of NA function, we investigated the hypothesis that the antipanic efficacy of the selective serotonin reuptake inhibitors may be associated with normalization of a putatively dysregulated NA system. METHODS: We report further analyses on data from 17 subjects with PD and 16 healthy volunteers who underwent measurement of the plasma NA metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) immediately before and after oral clonidine administration. Thirteen patients with PD were rechallenged after 12 weeks during open fluoxetine hydrochloride treatment using the same clonidine paradigm; 13 healthy volunteers were rechallenged at 12 weeks, not having received treatment between challenges. RESULTS: Patients with PD, compared with healthy volunteers, have markedly elevated plasma MHPG volatility during the first clonidine challenge. Volatility describes the magnitude of within-subject plasma MHPG oscillatory activity as assessed by the root of the mean square successive difference. A greater degree of clinical global improvement was predicted by a greater magnitude of basal MHPG reduction with fluoxetine treatment. Antipanic response to fluoxetine was accompanied by a significant decrease of MHPG volatility to volunteer levels. Volunteer MHPG volatility remained unchanged from the first to second clonidine challenge. CONCLUSIONS: Further evidence is provided for the hypothesis of NA dysregulation in PD as reflected by elevations of within-subjects plasma MHPG volatility during clonidine challenge. Effective selective serotonin reuptake inhibitor-antipanic treatment in this clinical sample was paralleled by normalization of dysregulated NA function.