Modular and integrative activity reporters enhance biochemical studies in the yeast ER.

The yeast endoplasmic reticulum sequestration and screening (YESS) system is a broadly applicable platform to perform high-throughput biochemical studies of post-translational modification enzymes (PTM-enzymes). This system enables researchers to profile and engineer the activity and substrate specificity of PTM-enzymes and to discover inhibitor-resistant enzyme mutants. In this study, we expand the capabilities of YESS by transferring its functional components to integrative plasmids. The YESS integrative system yields uniform protein expression and protease activities in various configurations, allows one to integrate activity reporters at two independent loci and to split the system between integrative and centromeric plasmids. We characterize these integrative reporters with two viral proteases, Tobacco etch virus (TEVp) and 3-chymotrypsin like protease (3CLpro), in terms of coefficient of variance, signal-to-noise ratio and fold-activation. Overall, we provide a framework for chromosomal-based studies that is modular, enabling rigorous high-throughput assays of PTM-enzymes in yeast.

Modular and integrative activity reporters enhance biochemical studies in the yeast ER.

The yeast endoplasmic reticulum sequestration and screening (YESS) system is a generalizable platform that has become highly useful to investigate post-translational modification enzymes (PTM-enzymes). This system enables researchers to profile and engineer the activity and substrate specificity of PTM-enzymes and to discover inhibitor-resistant enzyme mutants. In this study, we expand the capabilities of YESS by transferring its functional components to integrative plasmids. The YESS integrative system yields uniform protein expression and protease activities in various configurations, allows one to integrate activity reporters at two independent loci and to split the system between integrative and centromeric plasmids. We characterize these integrative reporters with two viral proteases, Tobacco etch virus (TEVp) and 3-chymotrypsin like protease (3CL pro ), in terms of coefficient of variance, signal-to-noise ratio and fold-activation. Overall, we provide a framework for chromosomal-based studies that is modular, enabling rigorous high-throughput assays of PTM-enzymes in yeast.

Detection and epidemiology of plasmid-mediated AmpC ß-lactamase producing Escherichia coli in two Irish tertiary care hospitals.

This study determined the prevalence and distribution of plasmid-mediated AmpC (pAmpC) ß-lactamases in Irish Escherichia coli isolates. Clinical E. coli isolates (n=95) that were intermediate or resistant to cefoxitin and/or flagged by VITEK® 2 as potential AmpC-producers underwent confirmation using a MASTDISCS™ ESBL and AmpC Detection Kit. Multiplex PCR capable of detecting family-specific plasmid ampC genes was performed to detect the presence of these genes. Five PCR-negative isolates were selected for promoter analysis. PFGE and MLST were performed on E. coli isolates that harboured a plasmid ampC gene to determine their clonal relatedness. Plasmid ampC genes were detected in 19% (18/95) of phenotypic AmpC producing E. coli isolates. The CIT group was the most common plasmid family type (n=14); DHA (n=3) and ACC (n=1) groups were also detected. Promoter analysis showed that four isolates had multiple point mutations and one had a 1 bp insertion in the -10 box. PFGE demonstrated a polyclonal pattern for E. coli isolates. Furthermore, with the exception of two isolates with an identical sequence type (ST720), MLST analysis revealed that these isolates were not clonally related. This study revealed that there was a marked prevalence of pAmpC E. coli among phenotypic AmpC producing E. coli isolates but no evidence of cross-transmission of a single strain. Establishing the prevalence and clonality of these organisms is important in order to implement evidence-based infection control measures that reduce the spread of pAmpC ß-lactamase resistance in the hospital environment.

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.

Candidate gene analysis of 21q22: support for S100B as a susceptibility gene for bipolar affective disorder with psychosis.

A genome-wide scan in 60 bipolar affective disorder (BPAD) affected sib-pairs (ASPs) identified linkage on chromosome 21 at 21q22 (D21S1446, NPL = 1.42, P = 0.08), a BPAD susceptibility locus supported by multiple studies. Although this linkage only approaches significance, the peak marker is located 12 Kb upstream of S100B, a neurotrophic factor implicated in the pathology of psychiatric disorders, including BPAD and schizophrenia. We hypothesized that the linkage signal at 21q22 may result from pathogenic disease variants within S100B and performed an association analysis of this gene in a collection of 125 BPAD type I trios. S100B single nucleotide polymorphisms (SNPs) rs2839350 (P = 0.022) and rs3788266 (P = 0.031) were significantly associated with BPAD. Since variants within S100B have also been associated with schizophrenia susceptibility, we reanalyzed the data in trios with a history of psychosis, a phenotype in common between the two disorders. SNPs rs2339350 (P = 0.016) and rs3788266 (P = 0.009) were more significantly associated in the psychotic subset. Increased significance was also obtained at the haplotype level. Interestingly, SNP rs3788266 is located within a consensus-binding site for Six-family transcription factors suggesting that this variant may directly affect S100B gene expression. Fine-mapping analyses of 21q22 have previously identified transient receptor potential gene melastatin 2 (TRPM2), which is 2 Mb upstream of S100B, as a possible BPAD susceptibility gene at 21q22. We also performed a family-based association analysis of TRPM2 which did not reveal any evidence for association of this gene with BPAD. Overall, our findings suggest that variants within the S100B gene predispose to a psychotic subtype of BPAD, possibly via alteration of gene expression.

Genome-wide scan of bipolar disorder and investigation of population stratification effects on linkage: support for susceptibility loci at 4q21, 7q36, 9p21, 12q24, 14q24, and 16p13.

Bipolar disorder (BPD) is a complex genetic disorder with cycling symptoms of depression and mania. Despite the extreme complexity of this psychiatric disorder, attempts to localize genes which confer vulnerability to the disorder have had some success. Chromosomal regions including 4p16, 12q24, 18p11, 18q22, and 21q21 have been repeatedly linked to BPD in different populations. Here we present the results of a whole genome scan for linkage to BPD in an Irish population. Our most significant result was at 14q24 which yielded a non-parametric LOD (NPL) score of 3.27 at the D14S588 marker with a nominal P-value of 0.0006 under a narrow (bipolar type I only) model of affection. We previously reported linkage to 14q22-24 in a subset of the families tested in this analysis. We also obtained suggestive evidence for linkage at 4q21, 9p21, 12q24, and 16p13, chromosomal regions that have all been previously linked to BPD. Additionally, we report on a novel approach to linkage analysis, STRUCTURE-Guided Linkage Analysis (SGLA), which is designed to reduce genetic heterogeneity and increase the power to detect linkage. Application of this technique resulted in more highly significant evidence for linkage of BPD to three regions including 16p13, a locus that has been repeatedly linked to numerous psychiatric disorders.

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.

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.

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.

The clinical epidemiology of pure and mixed manic episodes.

INTRODUCTION: Few large clinical epidemiological studies have been undertaken comparing subjects meeting criteria for mixed and pure states of bipolar disorder. In part, the difficulty comparing these states emanates from confusion in their diagnostic separation. In the current report, we use a definition derived from receiver operating characteristic (ROC) curve analysis as an alternative to the DSM-IIIR/IV definition, and we compare the two subtypes of manic episodes. METHODS: Three hundred and sixty-six patients meeting DSM-IIIR criteria for bipolar disorder, manic or mixed, were categorized using newly described criteria for mixed states. The two subtypes were compared on demographic variables and clinical history variables, using multiple analysis of variance with post hoc univariate F tests. The same analyses were conducted using the DSM-IIIR-defined subtypes. RESULTS: Using the ROC criteria, 79 subjects (21.6%) were characterized as mixed, in contrast to 51 subjects (13.9%) using DSM-IIIR criteria for bipolar disorder, mixed. The ROC-defined mixed manic group comprised more Caucasians and more females. Age of first psychiatric hospitalization was earlier and duration of illness longer in the mixed group. First episodes were unlikely to be categorized as mixed (< 5%). When the DSM-IIIR definition was employed, differences were not demonstrated. CONCLUSIONS: An earlier age of first psychiatric hospitalization and increased duration of illness, as well as a lower frequency of mixed subtype of manic episode during first hospitalization, are compatible with the view that mixed manic episodes occur more frequently later in the course of bipolar disorder. Moreover, differences in race, sex, and clinical histories of subjects in mixed episodes tend to support the separation of mixed mania as a diagnostic subtype of bipolar disorder.

A prospective study of inter-episode consistency of manic and mixed subtypes of bipolar disorder.

BACKGROUND: Few studies have compared symptom presentations across manic or mixed episodes in manic-depressive patients. METHODS: In the current study we report on symptom presentations of 68 prospectively-evaluated subjects diagnosed with Bipolar Disorder during two discrete manic or mixed episodes. Each episode was categorized using DSM-IIIR criteria for Bipolar Disorder, manic or mixed, as well as a less restrictive definition for manic and mixed states derived from receiver operating characteristic (ROC) analysis of symptoms. RESULTS: The occurrence of mixed bipolar episodes was not random using either the DSM-IIIR or ROC-derived definitions of mixed episodes. LIMITATIONS: Subjects were not all fully medication-free at the time of evaluation which may have altered symptom presentation. The total duration of the study was limited, with the longest inter-episode interval under 6 years. CONCLUSIONS: Although there was variability in mixed symptomatology between episodes, the occurrence of mixed episodes was not random. Manic and mixed episodes tend to recur true to type.

Effect of transjugular intrahepatic portosystemic shunt on thrombocytopenia associated with cirrhosis.

Thrombocytopenia is a frequent complication of cirrhosis. Its pathogenesis is not well known, but it has been suggested that splenic congestion induced by portal hypertension may be a major contributory factor. However, the available data regarding the effect of portal decompression either by surgical shunts or transjugular intrahepatic portosystemic shunt (TIPS) on peripheral platelet count in cirrhotics is conflicting. We studied the effects of TIPS on platelet count and mean platelet volume, following a successful TIPS placement. The platelet count had a tendency to decrease but was not statistically significant (120,100 +/- 72,100/mm3 before TIPS vs 99,800 +/- 51,400/mm3 after TIPS). The mean platelet volume remained essentially unchanged (9.8 +/- 1.5 fL before TIPS and 9.9 +/- 1.5 fL after TIPS). These results confirm that TIPS has an unpredictable effect on platelet count in cirrhotic patients with thrombocytopenia. The lack of a consistent increase in the peripheral mean platelet volume following TIPS placement suggests that TIPS is unable to significantly enhance the release of platelets sequestered in the splenic compartment in portal hypertension.

Diagnostic depressive symptoms of the mixed bipolar episode.

BACKGROUND: There is not yet consensus on the best diagnostic definition of mixed bipolar episodes. Many have suggested the DSM-III-R/-IV definition is too rigid. We propose alternative criteria using data from a large patient cohort. METHODS: We evaluated 237 manic in-patients using DSM-III-R criteria and the Scale for Manic States (SMS). A bimodally distributed factor of dysphoric mood has been reported from the SMS data. We used both the factor and the DSM-III-R classifications to identify candidate depressive symptoms and then developed three candidate depressive symptom sets. Using ROC analysis we determined the optimal threshold number of symptoms in each set and compared the three ROC solutions. The optimal solution was tested against the DSM-III-R classification for crossvalidation. RESULTS: The optimal ROC solution was a set, derived from both the DSM-III-R and the SMS, and the optimal threshold for diagnosis was two or more symptoms. Applying this set iteratively to the DSM-III-R classification produced the identical ROC solution. The prevalence of mixed episodes in the cohort was 13.9% by DSM-III-R, 20.2% by the dysphoria factor and 27.4% by the new ROC solution. CONCLUSIONS: A diagnostic set of six dysphoric symptoms (depressed mood, anhedonia, guilt, suicide, fatigue and anxiety), with a threshold of two symptoms, is proposed for a mixed episode. This new definition has a foundation in clinical data, in the proved diagnostic performance of the qualifying symptoms, and in ROC validation against two previous definitions that each have face validity.