Differential brain activation during facial emotion discrimination in first-episode schizophrenia

Background

Aberrant brain activation during facial emotion discrimination has been described in chronic schizophrenia, while little is known about early stages of the illness. The aim of the current study was to investigate valence-specific brain activation of emotion discrimination in first-episode schizophrenia. These patients provide the advantage of lacking the effects of long-term medication and chronic illness course and can hence further enhance the understanding of underlying psychopathological mechanisms.

Methods

Using event-related fMRI, we investigated 18 first-episode schizophrenia patients and 18 matched healthy subjects during an explicit emotion discrimination task presenting happy, sad and neutral monochromatic facial expressions. A repeated measure analysis of variance (ANOVA) with the factors Group (patients, healthy subjects), Gender and Emotion (happy, sad, neutral) was performed on behavioural and functional data.

Results

Behavioural performance did not differ between groups. Valence-independent hypoactivations in patients were observed for the anterior cingulate and orbitofrontal cortex while hyperactivations emerged in the posterior cingulate and the precuneus. Emotion-specific group differences were revealed in inferior parietal and orbitofrontal brain areas and the hippocampus.

Conclusions

First-episode schizophrenia already affects areas involved in processing of both, emotions and primary facial information. Our study underlines the role of dysfunctional neural networks as the basis of disturbed social interactions in early schizophrenia.     

Urokinase plasminogen activator receptor levels in Behcet's disease

Purpose

To determine urokinase plasminogen activator receptor (uPAR) concentrations in Behcet patients with and without ocular involvement; and to investigate the associations between uPAR levels and clinical manifestations of Behcet's disease.

Methods

Sixty-four patients with Behcet's disease (31 patients with and 33 patients without ocular involvement) and 23 healthy control subjects were included in this study. A complete ophthalmologic examination was performed. Venous blood was collected from all patients and control subjects. Serum uPAR levels were determined by using human uPAR immunoassay (Quantikine) kits.

Results

There was no statistically significant difference in serum uPAR levels between the patients and the control subjects (p > 0.05). There were no statistically significant correlations between uPAR levels and age, gender, duration of the disease, clinical manifestations (genital ulcer, arthritis, skin lesions, ocular and vascular involvements) and activity of the disease.

Conclusion

This finding is important since this is the first study regarding uPAR levels in Behcet's disease.     

Temporal relationship of first-episode non-affective psychosis with cannabis use: A clinical verification of an epidemiological hypothesis

Background

We analyzed the association of age at onset of psychosis treatment (AOPT) with having a history of cannabis use in patients with a first episode of non-affective psychosis. We also investigated the impact on the AOPT of exposure to cannabis in adolescence, compared with young adulthood, and of the additional exposure to cocaine.

Method

We recruited 112 consecutive patients (66 men and 46 women; age range, 18-57 years) with a first psychotic episode. The composite international diagnostic interview (CIDI) was used to assess drug use and to define the age at onset of heaviest use (AOHU) of a drug, defined as the age when drug was used the most for each patient. The effect of cannabis and cocaine AOHU on AOPT was explored through Kruskal-Wallis and Mann-Whitney tests, and logistic regression. Sex-adjusted cumulative hazard curves and Cox regression models were used to compare the AOPT of patients with and without a history of cannabis use, or associated cocaine use.

Results

We found that the AOPT was significantly associated with the use of cannabis, independently of sex, use of cocaine, tobacco smoking or excessive alcohol consumption. There was a dose-response relationship between cannabis AOHU and AOPT: the earlier the AOHU the earlier the AOPT. Hazard curves showed that patients with a history of cannabis use had a higher hazard of having a first-episode psychosis than the rest of the patients (sex-adjusted log-rank χ² = 23.43, df = 1, p < 0.001). Their respective median AOPT (25th, 75th percentiles) were 23.5 (21, 28) and 33.5 years (27, 45) (for log-transformed AOPT, t = 5.6, df = 110, p < 0.001). The sex-adjusted hazard ratio of psychosis onset comparing both groups was 2.66 (95% CI, 1.74-4.05).

Conclusions

Our results are in favor of a catalytic role for cannabis use in the onset of psychosis.     

Seventeen-year clinical outcome of schizophrenia in Bali

Objective

To examine the 17-year clinical outcome of schizophrenia and its predictors in Bali.

Methods

Subjects were 59 consecutively admitted first-episode schizophrenia patients. Their clinical outcome was evaluated by standardized symptomatic remission criteria based on Positive and Negative Syndrome Scale (PANSS) scores and operational functional remission criteria at 17-year follow-up. The standardized mortality ratio (SMR) over 17 years was also calculated as another index of clinical outcome.

Results

Among these 59 patients, 43 (72.9%) could be followed-up, 15 (25.4%) had died, and one (1.7%) was alive but refused to participate in the study. Combined remission (i.e. symptomatic and functional remission) was achieved in 14 patients (23.7% of original sample). Duration of untreated psychosis (DUP) was a significant baseline predictor of combined remission. Mean age at death of deceased subjects was 35.7, and SMR was 4.85 (95% CI: 2.4-7.3), indicating that deaths were premature. Longer DUP was associated with excess mortality.

Conclusions

The long-term outcome of schizophrenia in Bali was heterogeneous, demonstrating that a quarter achieved combined remission, half were in nonremission, and a quarter had died at 17-year follow-up. DUP was a significant predictor both for combined remission and mortality.     

Additive effects of elevated C-reactive protein and exposure to Herpes Simplex Virus type 1 on cognitive impairment in individuals with schizophrenia

Objectives

We investigated the effect of elevated levels of C-reactive protein (CRP) and exposure to Herpes simplex virus type 1 (HSV-1) on the severity of cognitive impairment in individuals with schizophrenia.

Methods

We measured the levels of CRP and of antibodies to HSV-1 in serum samples from 588 individuals with schizophrenia by enzyme immunoassay tests. Cognitive functioning was measured with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and psychiatric symptoms with the Positive and Negative Syndrome Scale (PANSS). The effects of HSV1 and CRP on cognitive functioning were analyzed with linear and logistic regression analyses adjusting for demographic and clinical variables.

Results

The individuals with elevated CRP levels and HSV-1 seropositivity had lower RBANS cognitive scores. The strongest effect was found in individuals who had both serological evidence of HSV-1 exposure and elevated levels of CRP. These individuals had odds of 2.35 to have an RBANS Total score <= 60 as compared to individuals who were HSV-1 seronegative and who did not have elevated levels of CRP (p = .002). The risks of decreased cognitive functioning associated with HSV-1 exposure and elevated levels of CRP were independent and additive. There was no effect of HSV-1 exposure and CRP levels on the severity of symptoms as measured by the PANSS (all p > .5).

Conclusions

Elevated levels of CRP and exposure to HSV-1 are associated with the severity of cognitive impairment in schizophrenia. These findings indicate that infection and inflammation may play a major role in the cognitive deficits associated with schizophrenia.     

Reduced prepulse inhibition as an early vulnerability marker of the psychosis prodrome in adolescence

Background

The onset of psychosis is thought to be preceded by neurodevelopmental changes in the brain. However, the timing and nature of these changes have not been established. The aim of the present study was to determine whether three “classic” neurophysiological markers of schizophrenia are also characteristic of young adolescents (12-18 years) at ultra-high risk for psychosis (UHR).

Methods

63 young UHR individuals and 68 typically developing, age-, sex- and IQ-matched controls were recruited for neurophysiological assessment. Data for P50 suppression, prepulse inhibition (PPI) and smooth pursuit eye movements (SPEM) were gathered and compared.

Results

UHR individuals showed reduced PPI compared to controls, which became more pronounced when controls were directly compared to medication-naive UHR individuals (N = 39). There were no group differences in P50 or SPEM measures.

Conclusions

These results suggest that PPI is a relatively early vulnerability marker, while changes in other neurophysiological measures may only be detected or affected later during the illness course. Antipsychotic and antidepressant medication may aid in elevating PPI levels and potentially have a neuroprotective effect.     

Rapid antipsychotic response with ziprasidone predicts subsequent acute manic/mixed episode remission

Objective

To assess rapid antipsychotic efficacy with oral ziprasidone monotherapy in bipolar acute manic/mixed episodes with psychotic features, and predictive value of rapid antipsychotic response for subsequent acute manic/mixed episode remission.

Methods

Pooled analysis of two 3-week, randomized, double-blind, placebo-controlled trials of ziprasidone (40-160 mg/d) in inpatients with bipolar I disorder, and a current manic or mixed episode, with (n = 152) or without (n = 246) psychotic features. Psychosis improvement was evaluated by change in SADS-C psychosis score (sum of delusions, hallucinations, and suspiciousness items). Rapid antipsychotic response (?50% decrease in SADS-C psychosis score by Day 4) and acute manic episode response and remission (endpoint ?50% MRS decrease, and a MRS score ? 12, respectively) were analyzed.

Results

Significantly greater antipsychotic effects were observed by Day 4 with ziprasidone treatment (vs. placebo) and the magnitude of improvement increased significantly with time, in all subjects, in the subgroup of all psychotic subjects, and psychotic subjects with low baseline agitation (p < 0.05). Rapid antipsychotic response predicted subsequent acute manic episode remission independent of ziprasidone or placebo treatment received (p < 0.001, ROC AUC = 0.71) with significant improvement in accuracy of MRS remission prediction when compared to models using early changes in MRS score alone (p = 0.01).

Limitations

Post hoc analysis, use of 3 SADS-C psychosis items to assess psychosis.

Conclusions

The predictive value of rapid (Day 4) improvement in psychotic symptoms for subsequent (Day 21) remission of acute manic/mixed symptoms may facilitate enhanced therapeutics, in view of the current practice of brief hospitalization for patients with acute manic/mixed episodes with psychotic features.     

Temperament and character in individuals at ultra-high risk for psychosis and with first-episode schizophrenia: Associations with psychopathology,psychosocial functioning,and aspects of psychological health

Objective

The psychobiological model of temperament and character indicates that personality traits are heritable and, during development, constantly influence one’s susceptibility to schizophrenia. Our objective was to evaluate temperament and character in subjects at ultra-high risk (UHR) for psychosis and individuals with first-episode schizophrenia.

Methods

UHR for psychosis subjects (n = 50), first-episode schizophrenia patients (n = 33), and normal controls (n = 120) were compared on temperament and character dimensions, and correlation analysis of each personality dimension with psychopathologies, global and social functioning, and self-esteem. General and social self-efficacy reports were conducted. UHR subjects were followed-up for 24 months and the baseline personality dimensions were compared between the converted and non-converted groups.

Results

Both clinical groups showed abnormal personality traits in terms of temperament (higher harm avoidance, lower reward dependence and persistence) and character (lower self-directedness and cooperativeness). Psychosocial functioning and psychological health components were found to be correlated with some personality dimensions. The conversion rate of overt psychotic disorder was 25.0% at the 24-month follow-up. Baseline cooperativeness dimension was a significant predictive dimension for conversion into overt psychosis in the UHR group during the follow-up period.

Conclusion

Patients with first episode schizophrenia have a pervasively altered personality profile from normal controls. More importantly, this altered personality profile already emerged in putative prodromal, UHR individuals. The present findings indicate that certain personality traits can play a protective or vulnerable role in developing schizophrenia.     

Plasma factor VII: a potential marker of pre-eclampsia

Introduction

Normal pregnancy is associated with a local hypercoagulable state that becomes more profound in certain obstetric complications such pre-eclampsia (P-EC). Current literature on the levels of individual haemostatic factors in women with P-EC is limited and results are inconsistent. In this study we provide detailed investigation on the tissue factor (TF)-dependent pathway in women with P-EC.

Materials and Methods

Enzyme-linked immunosorbent assays (ELISA) were used to measure plasma factor (F) FVII, FVIIa, TF and tissue factor pathway inhibitor (TFPI) in healthy non-pregnant women (n = 22), normal pregnant women (n = 15), and women with P-EC (n = 20). All subjects were age matched. In addition, pregnant women were matched for gestational age, parity and were all at the third trimester.

Results

Plasma FVII levels were significantly higher in women with P-EC compared to the healthy non-pregnant (P < 0.001) or the normal pregnant groups (P < 0.001). No such significant trends were observed for plasma FVIIa, TF or TFPI levels. Plasma FVII levels can distinguish women with P-EC from healthy non-pregnant women or normal pregnant women at the third trimester, with high sensitivity (90%), specificity (80%), positive and negative predictive values (86%).

Conclusions

Plasma FVII levels are significantly elevated in women with P-EC, in the absence of comparable changes in other TF-dependent pathway factors (FVIIa, TF and TFPI). We propose the use of plasma FVII as a marker for P-EC.     

Primary atherothrombotic occlusive vascular events in premenopausal women with history of adverse pregnancy outcome

Objective

To determine if adverse pregnancy outcomes are associated with atherothrombotic occlusive vascular disease (AOVD) in premenopausal women.

Design

Retrospective matched case-control study.

Setting

Tertiary, university-affiliated medical center.

Population

Women aged less than 50 years treated for an AOVD (primary cerebrovascular, myocardial, or peripheral arterial ischemic event) from 1995 to 2004.

Method

The files were reviewed for classical risk factors for AOVD and complications of pregnancy (abortions, pregnancy-induced hypertension, preeclampsia, gestational diabetes, intrauterine growth restriction (IUGR), fetal loss and preterm delivery). Findings were compared with healthy women matched for age and body mass index.

Main outcome measures

Past pregnancy complications in premenopausal women with AOVD.

Results

Of the 101 women with AOVD, 53 had a myocardial ischemic event, 33 a cerebrovascular event, and 15 a peripheral ischemic arterial event. On multivariate analysis, IUGR (OR 8.41, 95% CI 2.36-29.9, p = 0.001) and more than one pregnancy complication (OR 13.7, 95% CI 1.56-120, p = 0.02) were found to be independent significant variables associated with AOVD.

Conclusion

IUGR and composite pregnancy complications are independent significant variables associated with AOVD in premenopausal period. Pregnancy outcome might serve as a means to identify patients who may require increased medical surveillance and preventive measures for later vascular disease.     

Winter birth excess in schizophrenia and in non-schizophrenic psychosis: sex and birth-cohort differences

Objective

Despite the fact that association between winter birth excess and schizophrenia in the northern Hemisphere is well established, possible sex or birth-cohort differences in this winter birth excess remain unclear. We aimed to evaluate sex and birth-cohort differences in the seasonal birth distribution of patients with schizophrenia or non-schizophrenic psychosis.

Method

The sample included 321 ICD-10 schizophrenia and 294 non-schizophrenic psychosis patients consecutively admitted into a psychiatric hospitalization unit in Granada, southern Spain, during a nine-year period (1998-2006). The distribution of births among the general population born over the same period as the patients was calculated.

Results

Among schizophrenia males (n = 258), it was possible to demonstrate that the observed proportion of winter birth (December, January or February) was significantly higher than expected. Among schizophrenia females (n = 63), although proportions were as in males and the effect size of the difference between observed and expected winter births was not lower than for men, only a statistical trend could be demonstrated. Among patients with non-schizophrenic psychosis, the observed proportion of winter birth was significantly higher than expected in women, but not in men. The sex-adjusted proportion of winter birth among schizophrenia patients born in the 1940's (a time period characterized by poor economy and widespread food restrictions because of the Spanish post-civil-war period) was significantly higher than among those born later; a difference that does not occur among patients with a non-schizophrenic psychosis.

Conclusions

Among schizophrenia patients born in winter there appear to be slight sex-differences and strong birth-cohort differences, possibly due to epidemiological factors such as poverty or maternal nutritional deprivation. Epidemiological findings related to winter birth excess among patients with schizophrenia must be identified in longitudinal studies.     

Soluble interleukin-2 receptor levels correlated with positive symptoms during quetiapine treatment in schizophrenia-spectrum disorders

Background

Some but not all antipsychotics have been shown to modulate plasma cytokine levels in schizophrenia patients. Thus far, the most consistent finding has been the increase in plasma levels of soluble interleukin (IL)-2 receptor (sIL-2R) associated with clozapine treatment. Quetiapine is a second-generation antipsychotic with a pharmacological profile similar to that of clozapine, but its immunomodulatory effects have not been investigated in schizophrenia yet. The purpose of this exploratory study was to examine the changes in plasma levels of sIL-2R in schizophrenia during quetiapine treatment and association with psychopathology.

Methods

Participants were 29 schizophrenia-spectrum disorder patients (DSM-IV criteria), and 28 healthy controls. Patients had a comorbid substance use disorder (cannabis > alcohol > cocaine), since quetiapine is increasingly used in this population of dual diagnosis. No participant suffered from infection or overt inflammatory diseases. On baseline, patients taking mostly second-generation antipsychotics were switched to quetiapine for a 12-week open-label trial. Five patients were drop-outs. Mean dose of quetiapine for trial completers (n = 24) was 466.6 mg ± 227.3. Psychiatric variables were evaluated with the Positive and Negative Syndrome Scale and the Calgary Depression Scale for Schizophrenia. Plasma sIL-2R levels were assessed at baseline, weeks 6 and 12 in patients, and in healthy controls, using sandwich immunoassay. Plasma IL-6 and IL-1 receptor antagonist (IL-1RA) were measured for comparison purposes.

Results

On baseline, plasma sIL-2R, IL-6 and IL-1RA levels were higher in dual-diagnosis patients, compared to controls. Plasma sIL-2R further increased after quetiapine treatment (p = 0.037), while plasma IL-6 and IL-1RA did not change. Clinical improvements were observed in positive, negative and depressive symptoms, and substance abuse severity (all p < 0.01). Interestingly, changes in sIL-2R levels during treatment were inversely correlated with changes in positive symptoms (r = − 0.524; p = 0.009). That is, increases in sIL-2R levels were associated with reductions in positive symptoms.

Conclusion

These data show that quetiapine elevates, like clozapine, sIL-2R levels in schizophrenia. Furthermore, the results suggest that sIL-2R alterations in schizophrenia rely on complex interplays between antipsychotics and the positive symptoms of the disorder. Future randomized controlled trials involving larger samples of schizophrenia patients are warranted to determine whether changes in plasma sIL-2R are quetiapine-related.     

Neurocognitive deficits in schizophrenia are associated with alterations in blood levels of neurosteroids: A multiple regression analysis of findings from a double-blind, randomized, placebo-controlled, crossover trial with DHEA

Background

While neurosteroids exert multiple effects in the central nervous system, their associations with neurocognitive deficits in schizophrenia are not yet fully understood. The purpose of this study was to identify the contribution of circulating levels of dehydroepiandrosterone (DHEA), its sulfate (DHEAS), androstenedione, and cortisol to neurocognitive deficits through DHEA administration in schizophrenia.

Methods

Data regarding cognitive function, symptom severity, daily doses, side effects of antipsychotic agents and blood levels of DHEA, DHEAS, androstenedione and cortisol were collected among 55 schizophrenia patients in a double-blind, randomized, placebo-controlled, crossover trial with DHEA at three intervals: upon study entry, after 6 weeks of DHEA administration (200 mg/d), and after 6 weeks of a placebo period. Multiple regression analysis was applied for predicting sustained attention, memory, and executive function scores across three examinations controlling for clinical, treatment and background covariates.

Results

Findings indicated that circulating DHEAS and androstenedione levels are shown as positive predictors of cognitive functioning, while DHEA level as negative predictor. Overall, blood neurosteroid levels and their molar ratios accounted for 16.5% of the total variance in sustained attention, 8-13% in visual memory tasks, and about 12% in executive functions. In addition, effects of symptoms, illness duration, daily doses of antipsychotic agents, side effects, education, and age of onset accounted for variability in cognitive functioning in schizophrenia.

Conclusions

The present study suggests that alterations in circulating levels of neurosteroids and their molar ratios may reflect pathophysiological processes, which, at least partially, underlie cognitive dysfunction in schizophrenia.     

Prolactin concentrations in newly diagnosed, antipsychotic-naïve patients with nonaffective psychosis

Background

Previous studies have found increased prolactin concentrations in antipsychotic-naïve patients with schizophrenia. However, the roles of other hormones, and of potentially confounding variables such as gender and smoking, have not been considered.

Methods

Blood from newly diagnosed, antipsychotic-naïve patients with nonaffective psychosis (13 women and 20 men) and matched controls (12 women and 21 men) was assayed for prolactin, as well as three other hormones that impact prolactin concentrations: thyrotropin-stimulating hormone (TSH), ghrelin, and cortisol.

Results

Patients had significantly higher prolactin concentrations: female patients had a mean [SD] of 37.1 ng/mL [24.9] vs. 13.5 ng/mL [7.2] for female control subjects (p = .001), while male patients had a mean of 15.3 ng/mL [9.5] vs. 7.6 ng/mL [2.2] for male control subjects (p = .006). Patients and control subjects did not differ on concentrations of TSH, ghrelin, or cortisol. The group differences could not be attributed to differences in age, gender, smoking, body mass index, ethnicity, or the socioeconomic status of the family of origin.

Conclusions

Increased prolactin concentrations in antipsychotic-naïve patients do not appear to be due to important confounding variables, or to the effects of elevated TSH, ghrelin, or cortisol.     

Influence of Klotho genotypes on plasma NO(x) levels in South Indian population

Introduction

Despite experimental evidences of the influence of the aging suppressor gene Klotho, on the modulation of endothelial nitric oxide synthase (eNOS) activity and nitric oxide (NO) production, the contribution of its variants to the phenotypic variance of plasma nitrite and nitrate (NO_x) has not been addressed to date. In the present study, we aimed to determine the influence of two exonic variants, KL-VS and C1818T of Klotho, on circulating NO_x levels in South Indian population.

Materials and Methods

We genotyped the two Klotho KL-VS and C1818T variants in 429 healthy South Indians and measured their plasma NO_x concentrations by the Griess method.

Results

Genotype frequencies were compared in subjects with low and high NO_x levels. An age-specific association of the Klotho C1818T variant was found with plasma NO_x levels in subjects aged > 40 years (p = 0.027); the CC homozygotes were more prevalent in the low compared to the high plasma NO_x group. However, the variant was not associated with plasma NO_x levels in subjects aged ≤ 40 years (p = 0.799). The KL-VS variant did not have any influence on plasma NO_x status (p = 0.260).

Conclusions

Our results suggest that the effect of Klotho C1818T variant on levels of plasma NO_x becomes pronounced with age probably implying the adaptive capability of Klotho alleles to meet the age-related increasing physiological load.     

The plasma levels of activated thrombin activatable fibrinolysis inhibitor and thrombomodulin in Behçet Disease and their association with thrombosis

Objective

To investigate the plasma levels of activated thrombin activatable fibrinolysis inhibitor (aTAFI) and thrombomodulin (TM) in Behçet disease (BD) and their relationship with thrombosis.

Methods

Plasma aTAFI and TM levels were measured by ELISA in 89 patients with BD (18 having venous thrombosis) and in 86 healthy controls.

Results

Compared with healthy controls, the BD group had significantly lower levels of aTAFI (13.49 ± 8.88 µg/ml vs. 26.76 ± 11.57 µg/ml, p < 0.0001) and significantly higher levels of TM (3.26 ± 1.85 ng/ml vs. 2.6 ± 0.69 ng/ml, p = 0.0003). Neither aTAFI, nor TM levels differed significantly between BD patients with and without thrombosis (p > 0.05). Despite a tendency to positive correlation (r = 0.37, p = 0.0004) between plasma levels of aTAFI and TM in healthy controls, there was a tendency for negative correlation (r = -0.51, p < 0.0001) between these two parameters in BD patients.

Conclusion

The plasma aTAFI and TM levels do not seem to be related with the presence of thrombosis observed in BD. Increased plasma TM levels in BD may simply reflect endothelial cell activation and dysfunction.     

In adults with Prader-Willi syndrome, elevated ghrelin levels are more consistent with hyperphagia than high PYY and GLP-1 levels

Objective

Prader-Willi syndrome (PWS) is a leading genetic cause of obesity, characterized by hyperphagia, endocrine and developmental disorders. It is suggested that the intense hyperphagia could stem, in part, from impaired gut hormone signaling. Previous studies produced conflicting results, being confounded by differences in body composition between PWS and control subjects.

Design

Fasting and postprandial gut hormone responses were investigated in a cross-sectional cohort study including 10 adult PWS, 12 obese subjects matched for percentage body fat and central abdominal fat, and 10 healthy normal weight subjects.

Methods

PYY[total], PYY[3-36], GLP-1[active] and ghrelin[total] were measured by ELISA or radioimmunoassay. Body composition was assessed by dual energy X-ray absorptiometry. Visual analog scales were used to assess hunger and satiety.

Results

In contrast to lean subjects (p < 0.05), PWS and obese subjects were similarly insulin resistant and had similar insulin levels. Ghrelin[total] levels were significantly higher in PWS compared to obese subjects before and during the meal (p < 0.05). PYY[3-36] meal responses were higher in PWS than in lean subjects (p = 0.01), but not significantly different to obese (p = 0.08), with an additional non-significant trend in PYY[total] levels. There were no significant differences in self-reported satiety between groups, however PWS subjects reported more hunger throughout (p = 0.003), and exhibited a markedly reduced meal-induced suppression of hunger (p = 0.01) compared to lean or obese subjects.

Conclusions

Compared to adiposity-matched control subjects, hyperphagia in PWS is not related to a lower postprandial GLP-1 or PYY response. Elevated ghrelin levels in PWS are consistent with increased hunger and are unrelated to insulin levels.     

Detection of endogenous tissue factor levels in plasma using the calibrated automated thrombogram assay

Background

The calibrated automated thrombogram (CAT) assay measures thrombin generation in plasma.

Objective

Use the CAT assay to detect endogenous tissue factor (TF) in recalcified platelet-rich plasma (PRP) and platelet-free plasma (PFP).

Methods

Blood from healthy volunteers was collected into citrate and incubated at 37 °C with or without lipopolysaccharide (LPS) for 5 hours. PRP and PFP were prepared and clotting was initiated by recalcification. Thrombin generation was measured using the CAT assay.

Results

The lag time (LT) was significantly shortened in PRP prepared from LPS-treated blood compared with untreated blood (10 ± 3 min versus 20 ± 6 min), and this change was reversed by the addition of inactivated human factor VIIa. LPS stimulation did not change the peak thrombin. Similar results were observed in PFP (21 ± 4 min versus 35 ± 5 min). LPS stimulation also significantly reduced the LT of PRP and PFP derived from blood containing citrate and a factor XIIa inhibitor. Finally, a low concentration of exogenous TF shortened the LT of PFP prepared from unstimulated, citrated blood without affecting the peak thrombin.

Conclusion

Changes in LT in the CAT assay can be used to monitor levels of endogenous TF in citrated plasma.     

Serum BDNF levels before treatment predict SSRI response in depression

Objectives

The “neurotrophin hypothesis” of depression posits a role of brain-derived neurotrophic factor (BDNF) in depression, although it is unknown whether BDNF is more involved in the etiology of depression or in the mechanism of action of antidepressants. It is also unknown whether pre-treatment serum BDNF levels predict antidepressant response.

Methods

Thirty un-medicated depressed subjects were treated with escitalopram (N = 16) or sertraline (N = 14) for 8 weeks. Twenty-five of the depressed subjects completed 8 weeks of antidepressant treatment and had analyzable data. Twenty-eight healthy controls were also studied. Serum for BDNF assay was obtained at baseline in all subjects and after 8 weeks of treatment in the depressed subjects. Depression ratings were obtained at baseline and after 8 weeks of treatment in the depressed subjects.

Results

Pre-treatment BDNF levels were lower in the depressed subjects than the controls (p = 0.001) but were not significantly correlated with pre-treatment depression severity. Depression ratings improved with SSRI treatment (p < 0.001), and BDNF levels increased with treatment (p = 0.005). Changes in BDNF levels were not significantly correlated with changes in depression ratings. However, pre-treatment BDNF levels were directly correlated with antidepressant responses (p < 0.01), and “Responders” to treatment (≥ 50% improvement in depression ratings) had higher pre-treatment BDNF levels than did “Non-responders” (p < 0.05).

Conclusions

These results confirm low serum BDNF levels in un-medicated depressed subjects and confirm antidepressant-induced increases in BDNF levels, but they suggest that antidepressants do not work simply by correcting BDNF insufficiency. Rather, these findings are consistent with a permissive or facilitatory role of BDNF in the mechanism of action of antidepressants.     

ADAMTS-13 activity in the presence of elevated von Willebrand factor levels as a novel mechanism of residual platelet reactivity in high risk coronary patients on antiplatelet treatment

Background

The pathophysiologic mechanisms leading to residual platelet reactivity (RPR) on antiplatelet therapy, a condition high prevalent in patients with acute coronary syndrome, are not yet elucidated. In the acute phase of coronary artery disease large amounts of ultra large VWF multimers (ULVWF) are released and cleaved by the activity of ADAMTS-13.

Objective

Aim of this study was to evaluate the relationships between VWF antigen (VWF:Ag) levels, collagen binding activity of VWF (VWF:CB), ADAMTS-13 and interleukin-6 (IL-6) levels in affecting platelet response to dual antiplatelet treatment.

Methods

In 159 acute coronary syndrome (ACS) patients undergoing percutaneous coronary interventions we measured platelet function by platelet aggregation with two agonists [1 mM arachidonic acid (AA) and 10 μM ADP]. We defined patients with RPR those with platelet aggregation by AA > 20% and/or ADP (10 µmol) > 70%.

Results

We found significantly lower ADAMTS-13 activity, elevated IL-6, VWF:Ag and VWF:CB levels in patients with RPR. A lower ADAMTS-13 activity was present in patients with VWF:Ag and VWF:CB in the upper tertile. At the multivariate analysis ADAMTS-13 activity and IL-6 were independent risk factors for RPR.

Conclusion

Our results indicate that ADAMTS-13 activity and IL-6 levels independently affect RPR and suggest that, by different pathways, both are involved in the variable response to antiplatelet therapy.