Sulodexide in venous disease.

Sulodexide is a glycosaminoglycan extracted from porcine intestinal mucosa. The purpose of this review is to discuss sulodexide's complex pharmacological profile and its clinical applications for venous disease. Sulodexide has wide-ranging biological effects on the vascular system, including antithrombotic, profibrinolytic, anti-inflammatory, endothelial protective and vasoregulatory effects. Sulodexide has emerged as a potential therapeutic option for the management of chronic venous insufficiency, including venous ulceration, and the prevention of recurrent venous thromboembolism, with a low rate of major bleeding complications. Sulodexide's pleiotropic vascular effects may facilitate the management of common venous disorders.

A genome-wide association study of antidepressant response in Koreans.

We conducted a three-stage genome-wide association study (GWAS) of response to antidepressant drugs in an ethnically homogeneous sample of Korean patients in untreated episodes of nonpsychotic unipolar depression, mostly of mature onset. Strict quality control was maintained in case selection, diagnosis, verification of adherence and outcome assessments. Analyzed cases completed 6 weeks of treatment with adequate plasma drug concentrations. The overall successful completion rate was 85.5%. Four candidate single-nucleotide polymorphisms (SNPs) on three chromosomes were identified by genome-wide search in the discovery sample of 481 patients who received one of four allowed selective serotonin reuptake inhibitor (SSRI) antidepressant drugs (Stage 1). In a focused replication study of 230 SSRI-treated patients, two of these four SNP candidates were confirmed (Stage 2). Analysis of the Stage 1 and Stage 2 samples combined (n = 711) revealed GWAS significance (P = 1.60 × 10(-8)) for these two SNP candidates, which were in perfect linkage disequilibrium. These two significant SNPs were confirmed also in a focused cross-replication study of 159 patients treated with the non-SSRI antidepressant drug mirtazapine (Stage 3). Analysis of the Stage 1, Stage 2 and Stage 3 samples combined (n = 870) also revealed GWAS significance for these two SNPs, which was sustained after controlling for gender, age, number of previous episodes, age at onset and baseline severity (P = 3.57 × 10(-8)). For each SNP, the response rate decreased (odds ratio=0.31, 95% confidence interval: 0.20-0.47) as a function of the number of minor alleles (non-response alleles). The two SNPs significantly associated with antidepressant response are rs7785360 and rs12698828 of the AUTS2 gene, located on chromosome 7 in 7q11.22. This gene has multiple known linkages to human psychological functions and neurobehavioral disorders. Rigorous replication efforts in other ethnic populations are recommended.

Association of the choline acetyltransferase gene with responsiveness to acetylcholinesterase inhibitors in Alzheimer's disease.

INTRODUCTION: The response to acetylcholinesterase inhibitors (AChEIs) of Alzheimer's disease (AD) patients varies depending on the genetic characteristics of the patient. We have examined the association of response to AChEIs and genetic polymorphisms in AD patients. METHODS: 158 patients with AD underwent treatment with AChEIs, and the therapeutic effect was assessed with the Korean version of the Mini Mental State Examination (K-MMSE). The association of 25 SNPs located in 3 genes (CHAT, CHT and ACHE) with changes in the K-MMSE score was analyzed. RESULTS: The response to AChEIs in AD patients was significantly associated with 2 SNPs on the intronic region of CHAT rs2177370 (uncorrected P=0.0025, FDR controlled P=0.026) and rs3793790 (uncorrected P=0.0024, FDR controlled P=0.026). CONCLUSION: The results of our study confirmed again that genetic polymorphism of CHAT has an influence on drug response in AD.

Pathophysiology of hypercortisolism in depression: pituitary and adrenal responses to low glucocorticoid feedback.

OBJECTIVE: To test three theories of hypercortisolemia in depression-hypothalamic overdrive, impaired glucocorticoid feedback, or autonomous cortisol production. METHOD: We applied an overnight low-cortisol feedback strategy by administering metyrapone to hypercortisolemic depressed in-patients and control subjects. RESULTS: Under metyrapone, the increases of plasma adrenocorticotropic hormone (ACTH) concentrations and of basal and pulsatile ACTH secretion were not exaggerated in hypercortisolemic depressed patients compared with control subjects. ACTH approximate entropy (ApEn) did not differ at baseline or under metyrapone. Thus, neither hypothalamic overdrive nor irregular ACTH secretion was seen. We did not detect impaired cortisol feedback: the ACTH response was not reduced, and ApEn measures that are sensitive to feedback changes were comparable in both groups. Metyrapone disrupted cortisol secretory regularity in depressed and control subjects. On the baseline day, basal cortisol secretion was significantly increased and was highly irregular (high ApEn), and ACTH-cortisol cross-ApEn was markedly elevated in high-cortisol patients. CONCLUSION: Classical feed-forward overdrive and impaired feedback theories of hypercortisolemia in depression were not supported. Depressive hypercortisolemia may result from alternative pathophysiological mechanisms involving irregular basal hypersecretion of cortisol, associated with adrenal enlargement, possibly through splanchnic sympathetic activation of the adrenal cortex.

META060 inhibits multiple kinases in the NF-kappaB pathway and suppresses LPS--mediated inflammation in vitro and ex vivo.

OBJECTIVE: We investigated whether a novel candidate META060 targeted the inflammatory signal transduction without affecting constitutive COX-2 enzymatic activity in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. We also investigated its bioavailability in humans and its anti-inflammatory effect ex vivo. METHODS: We measured prostaglandin E(2), nitric oxide, TNFalpha and IL-6 by ELISA, COX-2 protein by Western blot, NF-kappaB nuclear binding by electrophoretic mobility shift assays, and NF-kappaB activation by luciferase assay. Kinase inhibitions were measured by cell-free assays. Bioavailability was tested in 4 human subjects consuming 940 mg META060. LPS-activated TNFalpha and IL-6 were measured in peripheral blood mononuclear cells (PBMC) isolated from 1 subject up to 6 hours post administration. RESULTS: META060 dose-dependently inhibited prostaglandin E(2) and nitric oxide formation, COX-2 abundance, and NF-kappaB activation. In cell-free assays, META060 inhibited multiple kinases in the NF-kappaB signaling pathway, including BTK, PI3K, and GSK3. META060 was detected in the plasma of the subjects; isolated PBMC were resistant to LPS-stimulated TNFalpha and IL-6 production. CONCLUSION: Without inhibiting COX-2 enzyme, META060 reduces the inflammation by inhibiting multiple kinases involved in NF-kappaB pathway, and may have potential as a safe anti-inflammatory therapeutic.

Nuclear gene silencing directs reception of long-distance mRNA silencing in Arabidopsis.

In plants, silencing of mRNA can be transmitted from cell to cell and also over longer distances from roots to shoots. To investigate the long-distance mechanism, WT and mutant shoots were grafted onto roots silenced for an mRNA. We show that three genes involved in a chromatin silencing pathway, NRPD1a encoding RNA polymerase IVa, RNA-dependent RNA polymerase 2 (RDR2), and DICER-like 3 (DCL3), are required for reception of long-distance mRNA silencing in the shoot. A mutant representing a fourth gene in the pathway, argonaute4 (ago4), was also partially compromised in the reception of silencing. This pathway produces 24-nt siRNAs and resulted in decapped RNA, a known substrate for amplification of dsRNA by RDR6. Activation of silencing in grafted shoots depended on RDR6, but no 24-nt siRNAs were detected in mutant rdr6 shoots, indicating that RDR6 also plays a role in initial signal perception. After amplification of decapped transcripts, DCL4 and DCL2 act hierarchically as they do in antiviral resistance to produce 21- and 22-nt siRNAs, respectively, and these guide mRNA degradation. Several dcl genotypes were also tested for their capacity to transmit the mobile silencing signal from the rootstock. dcl1-8 and a dcl2 dcl3 dcl4 triple mutant are compromised in micro-RNA and siRNA biogenesis, respectively, but were unaffected in signal transmission.

Pathophysiology of hypercortisolism in depression.

OBJECTIVE: The mechanisms mediating hypercortisolemia in depression remain controversial. Adopting the biomarker strategy, we studied adrenocorticotropin (ACTH) and cortisol dynamics in hypercortisolemic and non-hypercortisolemic depressed in-patients, and in normal volunteers. METHOD: Deconvolution analysis of 24-h pulsatile secretion, approximate entropy (ApEn) estimation of secretory regularity, cross-ApEn quantitation of forward and reverse ACTH-cortisol synchrony, and cosine regression of 24-h rhythmicity. RESULTS: Hypercortisolemia was strongly associated with melancholic and psychotic depressive subtypes. Hypercortisolemic patients had elevated ACTH and cortisol secretion, mediated chiefly by increased burst masses. Basal ACTH secretion was increased, ACTH half-life was reduced, and mean 24-h ACTH concentration was normal. Cortisol secretion was increased in a highly irregular pattern (high ApEn), with high ACTH --> cortisol cross-ApEn (impaired feedforward coupling). Cortisol-mediated feedback on the secretory pattern of ACTH was normal. Hypercortisolemic depressed patients had normal programming of the central hypothalamo-pituitary-adrenal (HPA) axis pulse generator: ACTH pulse frequency, cortisol pulse frequency, circadian acrophases, and ApEn of ACTH secretion were normal. Responsiveness of the adrenal cortex to endogenous ACTH was normal. Non-hypercortisolemic patients resembled hypercortisolemic patients on ACTH regulatory parameters but had low total cortisol secretion. CONCLUSION: Increased ACTH secretion occurs in depressed in-patients regardless of cortisolemic status, confirming central HPA axis overdrive in severe depression. Depressive hypercortisolemia results from an additional change in the adrenal cortex that causes ACTH-independent, disorderly basal cortisol release, a sign of physiological stress in melancholic/psychotic depression.

Fine mapping of the tomato I-3 gene for fusarium wilt resistance and elimination of a co-segregating resistance gene analogue as a candidate for I-3.

The I-3 gene from the wild tomato species Lycopersicon pennellii confers resistance to race 3 of the devastating vascular wilt pathogen Fusarium oxysporum f. sp. lycopersici. As an initial step in a positional cloning strategy for the isolation of I-3, we converted restriction fragment length polymorphism and conserved orthologue set markers, known genes and a resistance gene analogue (RGA) mapping to the I-3 region into PCR-based sequence characterised amplified region (SCAR) and cleaved amplified polymorphic sequence (CAPS) markers. Additional PCR-based markers in the I-3 region were generated using the randomly amplified DNA fingerprinting (RAF) technique. SCAR, CAPS and RAF markers were used for high-resolution mapping around the I-3 locus. The I-3 gene was localised to a 0.3-cM region containing a RAF marker, eO6, and an RGA, RGA332. RGA332 was cloned and found to correspond to a putative pseudogene with at least two loss-of-function mutations. The predicted pseudogene belongs to the Toll interleukin-1 receptor-nucleotide-binding site-leucine-rich-repeat sub-class of plant disease resistance genes. Despite the presence of two RGA332 homologues in L. esculentum, DNA gel blot and PCR analysis suggests that no other homologues are present in lines carrying I-3 that could be alternative candidates for the gene.

Application of the quartz crystal microbalance to the evaporation of colloidal suspension droplets.

An investigation into the evaporation of sessile droplets of latex and clay particle suspensions is presented in this work. The quartz crystal microbalance (QCM) has been used to study the interfacial phenomena during the drying process of these droplets. Characteristic changes of the crystal oscillating frequency and crystal resistance (damping of the oscillating energy) have been observed and related to the different stages of the evaporation process. Measurements have been made for latex particle sizes from 1.9 to 10 microm and for rough and polished crystals using drops from 0.3 to 1.5 microL. The behavior of the QCM is shown to depend strongly on the size of particles present and on the morphology of the crystal surface. One of the most striking features is a drastic damping of the oscillation energy and corresponding rise in frequency observed during the final stages of evaporation, particularly for the clay suspensions.

Inheritance and mapping of 11 avirulence genes in Phytophthora sojae.

Two new crosses involving four races (races 7, 16, 17, and 25) of the soybean root and stem rot pathogen Phytophthora sojae were established (7/16 cross; 17/25 cross). An F2 population derived from each cross was used to determine the genetic basis of avirulence towards 11 different resistance genes in soybean. Avirulence was found to be dominant and determined by a single locus for Avr1b, 1d, 1k, 3b, 4, and 6, as expected for a simple gene-for-gene model. We also observed several cases of segregation, inconsistent with a single dominant gene being solely responsible for avirulence, which suggests that the genetic background of the different crosses can affect avirulence. Avr4 and 6 cosegregated in both the 7/16 and 17/25 crosses and, in the 7/16 cross, Avr1b and 1k were closely linked. Information from segregating RAPD, RFLP, and AFLP markers screened on F2 progeny from the two new crosses and two crosses described previously (a total of 212 F2 individuals, 53 from each cross) were used to construct an integrated genetic linkage map of P. sojae. This revised genetic linkage map consists of 386 markers comprising 35 RFLP, 236 RAPD, and 105 AFLP markers, as well as 10 avirulence genes. The map is composed of 21 major linkage groups and seven minor linkage groups covering a total map distance of 1640.4cM.

Thyroid function in mixed and pure manic episodes.

OBJECTIVES: Associations of both overt thyroid disease as well as subclinical thyroid abnormalities with affective disorders have been well established. Similar associations have been reported with mixed mania and rapid cycling bipolar disorder. We tested for differences in overt and subclinical thyroid disease and subclinical differences in a large series of bipolar patients examined during mixed or pure manic episodes. METHODS: Rates of previously diagnosed thyroid disease were compared by sex, race and manic subtype (mixed versus pure) in 443 patients. Serum thyroid stimulating hormone (TSH) and free thyroxine (FT4) concentrations obtained from patients with no clinical thyroid disease collected during manic and mixed bipolar episodes were compared using ANOVA statistics. Race was also included in the model and age was covaried. RESULTS: Rates of thyroid disease, in particular hypothyroidism, were higher in females and white people, and increased with advancing age. No differences were noted between subjects sampled during mixed or pure manic episodes. In patients with no history of thyroid disease, serum TSH and FT4 concentrations did not differ between manic subtypes or between sexes. TSH levels however, were significantly lower in African Americans. CONCLUSIONS: We did not confirm past reports of associations of overt or subclinical thyroid disease with mixed manic episodes. African Americans had significantly lower serum TSH concentrations than white people, while FT4 levels did not differ.

Corticotropin secretory dynamics in humans under low glucocorticoid feedback.

To explore the mechanisms of homeostatic adaptation of the hypothalamo-pituitary-adrenal axis to an experimental low-feedback condition, we quantitated pulsatile (ultradian), entropic (pattern-sensitive), and 24-h rhythmic (circadian) ACTH secretion during high-dose metyrapone blockade (2 g orally every 2 h for 12 h, and then 1 g every 2 h for 12 h). Plasma ACTH and cortisol concentrations were sampled concurrently every 10 min for 24 h in nine adults. The metyrapone regimen reduced the amplitude of nyctohemeral cortisol rhythm by 45% (P = 0.0013) and delayed the time of the cortisol maximum (acrophase) by 7.1 h (P = 0.0002). Attenuated cortisol negative feedback stimulated a 7-fold increase in the mean (24-h) plasma ACTH concentration, which rose from 24 +/- 1.6 to 169 +/- 31 pg/ml (ng/liter) (P < 0.0001). Augmented ACTH output was driven by a 12-fold amplification of ACTH secretory burst mass (integral of the underlying secretory pulse) (21 +/- 3.1 to 255 +/- 64 pg/ml; P < 0.0001), yielding a higher percentage of ACTH secreted in pulses (53 +/- 3.5 vs. 92 +/- 1.3%; P < 0.0001). There were minimal elevations in basal (nonpulsatile) ACTH secretion (by 50%; P = 0.0049) and ACTH secretory burst frequency (by 36%; P = 0.031). The estimated half-life of ACTH (median, 22 min) and the calculated ACTH secretory burst half-duration (pulse event duration at half-maximal amplitude) (median, 23 min) did not change. Hypocortisolemia evoked remarkably more orderly subordinate patterns of serial ACTH release, as quantitated by the approximate entropy statistic (P = 0.003). This finding was explained by enhanced regularity of successive ACTH secretory pulse mass values (P = 0.032). In contrast, there was no alteration in serial ACTH interpulse-interval (waiting-time) regularity. At the level of 24-h ACTH rhythmicity, cortisol withdrawal enhanced the daily rhythm in ACTH secretory burst mass by 29-fold, elevated the mesor by 16-fold, and delayed the acrophase by 3.4 h from 0831 h to 1154 h (each P < 10(-3)). In summary, short-term glucocorticoid feedback deprivation primarily (>97% of effect) amplifies pulsatile ACTH secretory burst mass, while minimally elevating basal/nonpulsatile ACTH secretion and ACTH pulse frequency. Reduced cortisol feedback paradoxically elicits more orderly (less entropic) patterns of ACTH release due to emergence of more regular ACTH pulse mass sequences. Cortisol withdrawal concurrently heightens the amplitude and mesor of 24-h rhythmic ACTH release and delays the timing of the ACTH acrophase. In contrast, the duration of underlying ACTH secretory episodes is not affected, which indicates that normal pulse termination may be programmed centrally rather than imposed by rapid negative feedback. Accordingly, we hypothesize that adrenal glucocorticoid negative feedback controls hypothalamo-pituitary-adrenal axis dynamics via the 3-fold distinct mechanisms of repressing the mass of ACTH secretory bursts, reducing the orderliness of the corticotrope release process, and modulating the intrinsic diurnal rhythmicity of the hypothalamo-corticotrope unit.

Substance abuse in bipolar disorder.

BACKGROUND: High rates of substance abuse have been reported in the general population, with males more often affected than females. Although high rates of substance abuse have also been reported in bipolar patients, the relationship between substance abuse and bipolar disorder has not been well characterized. METHODS: Substance abuse histories were obtained in 392 patients hospitalized for manic or mixed episodes of bipolar disorder and rates of current and lifetime abuse calculated. Analyses comparing sex, subtype (manic vs. mixed) and clinical history variables were conducted. RESULTS: Rates of lifetime substance abuse were high for both alcohol (48.5%) and drugs (43.9%). Nearly 60% of the cohort had a history of some lifetime substance abuse. Males had higher rates of abuse than females, but no differences in substance abuse were observed between subjects in manic and mixed bipolar states. Rates of active substance abuse were lower in older age cohorts. Subjects with a comorbid diagnosis of lifetime substance abuse had more psychiatric hospitalizations. CONCLUSIONS: Substance abuse is a major comorbidity in bipolar patients. Although rates decrease in older age groups, substance abuse is still present at clinically important rates in the elderly. Bipolar patients with comorbid substance abuse may have a more severe course. These data underscore the significance of recognition and treatment of substance abuse in bipolar disorder patients.

Subtypes of mania determined by grade of membership analysis.

Classical descriptions of mania subtypes extend back to Kraepelin; however, in marked contrast to the study of depression subtypes, validation of mania subtypes by multivariate statistical methods has seldom been attempted. We applied Grade of Membership (GOM) analysis to the rated clinical features of 327 inpatients with DSM-III-R mania diagnoses. GOM is a type of latent structure multivariate analysis, which differs from others of this type in making no a priori distributional assumptions about groupings. We obtained 5 GOM Pure Types with good face validity. The major Kraepelinian forms of "hypomania," "acute mania," "delusional mania," and "depressive or anxious mania" were validated. The major new finding is of two mixed mania presentations, each with marked lability of mood. The first of these displayed a dominant mood of severe depression with labile periods of pressured, irritable hostility and paranoia, and the complete absence of euphoria or humor. The second mixed mania Pure Type displayed a true, incongruous mixture of affects: periods of classical manic symptoms with euphoria, elation, humor, grandiosity, psychosis, and psychomotor activation, switching frequently to moderately depressed mood with pressured anxiety and irritability. This multivariate analysis validated classical clinical descriptions of the major subtypes of mania. Two distinct forms of mixed manic episodes were identified. DSM-III-R criteria did not reliably identify either of these two natural groups of mixed bipolar patients. As occurs in depression, this clinical heterogeneity of mania may influence response to drug treatments.

MRI correlates of suicide attempt history in unipolar depression.

BACKGROUND: Suicide represents a major health problem in the United States, and prediction of suicide attempts is difficult. No structural neuroimaging studies have been done to specifically examine findings in patients who have attempted suicide. The objective of this study was to compare MRI findings in unipolar patients with and without a history of a suicide attempt. METHODS: In this post hoc analysis, 20 unipolar subjects with a history of a suicide attempt were matched by age and gender to unipolar subjects without a history of an attempt. Subjects were also matched on parameters such as cardiovascular history, electroconvulsive treatment history, and history of psychosis. Subjects with a history of any neurologic condition were excluded. There were no significant differences in age of onset of depression, number of episodes of depression, and Hamilton Depression scores between the two groups. T2-weighted magnetic resonance imaging (MRI) scans were rated using the Coffey and Boyko rating scales. RESULTS: Unipolar patients with a history of a suicide attempt demonstrated significantly more subcortical gray matter hyperintensities compared with patients without such a history. CONCLUSIONS: Patients with abnormal MRI findings may be at higher risk for mood disorders and suicide attempts because of disruption of critical neuroanatomic pathways. Gray matter hyperintensities in the basal ganglia may be especially associated with risk for suicide attempts.

Dimensions of self-rated mood in depressed, manic, and normal subjects.

Self-rated scales allow the comparison of subjective mood across the spectrum of manic, depressive, and euthymic states. This study examined the self-reported mood of manic, depressed, and normal subjects using a 23-item research instrument based on the Carroll-Klein model of bipolar disorder. The Multiple Visual Analog Scale (MVAS) measures the following dimensions: consummatory reward (seven items), incentive reward (two items), psychomotor speed (seven items), and central pain (seven items). The MVAS was completed by 31 manic inpatients, 43 depressed inpatients, and 29 normal volunteer subjects. Total scores, average item scores, and total dimension scores were obtained. Subjects also completed a global mood VAS and the Carroll Depression Scale (CDS). Groups were compared by analysis of variance (ANOVA) and post hoc Bonferroni-Dunn methods. In a separate post hoc analysis, the group of manic patients was divided at the median CDS score into "pure" and "dysphoric" manic subgroups. We found excellent congruence of average 23-item total MVAS scores with global VAS and CDS scores. Dimension scores on the MVAS conformed to the predictions of the Carroll-Klein model. Depressed patients differed significantly from both manic and normal subjects on each dimension. MVAS dimension scores of normal subjects did not differ significantly from those of manic patients. On the dimension of central pain, normal subjects had significantly less inhibited scores than the "pure" subgroup of manics. The results confirmed that the dimensions of the Carroll-Klein model are bipolar and orthogonal. By the MVAS technique, the self-reported mood of normal subjects is similar to the self-reported mood of manic patients on all dimensions of the Carroll-Klein model of bipolar disorder. The positive scores of both groups are clearly distinguished from the negative scores of depressed patients. Average MVAS scores of normal subjects approximated the conventional zero score only on the dimension of central pain. Normal subjects exhibit megalothymic (hyperthymia) on most dimensions of subjective mood. The negative MVAS scores of depressed patients are even more deviant from normal than the conventional scoring system would suggest.

Serum melanotransferrin, p97 as a biochemical marker of Alzheimer's disease.

The protein melanotransferrin (p97) is associated with the brain lesions of Alzheimer's disease (AD) and is a potential marker of the disorder. We measured serum p97 concentrations in 211 subjects: 71 patients with AD, 56 patients with non-AD-type dementia, and 84 normal control subjects. Serum p97 concentrations were elevated 3- to 4-fold in AD (median 15.00 pg/microl, interquartile range 10.20-17.00 pg/microl) as compared to non AD dementia (2.85 pg/microl, 1.93-7.15 pg/microl) and normal controls (3.20 pg/microl, 2.55-3.95 pg/microl). The mean elevation was significant at 13.54 +/- 3.72 pg/microl, even in the 38 subjects with mild AD (CDR stage 0.5-1). Receiver operating characteristic analyses confirmed an optimal diagnostic threshold of 10.0 pg/microl, which yielded over-all accuracy of 0.882 to 0.915. Serum p97 is a candidate marker of AD, even in the early stage when clinical diagnosis is most uncertain.

Frequencies of signs and symptoms in mixed and pure episodes of mania: implications for the study of manic episodes.

1. In a previous report the authors compared the frequency of 20 classical and mixed manic signs and symptoms in subjects meeting DSM-III-R criteria for Bipolar Disorder, manic or mixed. In that report, the authors commented that a possible limitation of the study was the diagnosis of mixed and pure mania using DSM-III-R criteria that may be too rigid The authors now address that issue, adopting a ROC-derived definition of mixed mania 2. Three hundred sixty-three subjects meeting DSM-III-R criteria for Bipolar Disorder, manic or mixed, were evaluated by rating 20 signs and symptoms of mania. The frequencies of these signs and symptoms were computed and compared for both mixed and pure subtypes, determined by the ROC-derived definition. 3. Mood lability, dysphoric mood, guilt, anxiety, and suicidality were more frequently observed in the mixed manic group In contrast, euphoria and grandiosity were more frequently observed in the pure manic group. Nonetheless, non-trivial rates of dysphoric mood, irritability and anxiety were still observed in the pure groups, despite the adoption of a less restrictive definition of mixed states. The current results are similar to the results obtained using DSM-III-R criteria for Bipolar Disorder, manic and mixed. Although rates of dysphoric mood, anxiety, lability, guilt and suicidality were lower in the manic group, each of these symptoms may be observed in pure manic episodes, underscoring the importance of recognition and evaluation of these features in formal studies of "pure" as well as mixed manic episodes.