Instruments assessing anxiety in adults with intellectual disabilities: a systematic review

Background

In the last decades several instruments measuring anxiety in adults with intellectual disabilities have been developed.

Aim

To give an overview of the characteristics and psychometric properties of self-report and informant-report instruments measuring anxiety in this group.

Method

Systematic review of the literature.

Results

Seventeen studies studying 14 different instruments were found. Methodological quality as measured with the Quality Assessment of Diagnostic Accuracy Studies checklist was insufficient for four studies, sufficient for seven, and good for six. For self-report, the Glasgow Anxiety Scale for people with a learning disability appears most promising, with good internal consistency (a = 0.96), high test-retest reliability (r = 0.95), sensitivity (100%) and specificity (100%). For informant-report, the general anxiety subscale of the Anxiety, Depression and Mood Scale may be promising, with good internal consistency (a = 0.83 and a = 0.84) and excellent test-retest reliability (ICC = 0.78 and ICC = 0.92), but poor interrater reliability (ICC = 0.39).

Conclusions

Two instruments appear promising. However, these instruments have only been studied once or twice, whereas the methodological quality of these studies was varying.     

Is switching antidepressants following early nonresponse more beneficial in acute-phase treatment of depression?: a randomized open-label trial

Rationale

Treatment guidelines for major depressive disorder (MDD) recommend a continuous use of antidepressants for several weeks, while recent meta-analyses indicate that antidepressant efficacy starts to appear within 2 weeks and early treatment nonresponse is a predictor of subsequent nonresponse.

Objectives

We prospectively compared 8-week outcomes between switching antidepressants and maintaining the same antidepressant in early nonresponders, to generate a hypothesis on possible benefits of early switching strategy.

Method

Patients with MDD without any treatment history for the current episode were included. When subjects failed to show an early response (i.e., ≥ 20% improvement in the Montgomery-Åsberg Depression Rating Scale (MADRS)) to the initial treatment with sertraline 50 mg at week 2, they were randomly divided into two groups; in the Continuing group, sertraline was titrated at 50-100 mg, whereas sertraline was switched to paroxetine 20-40 mg in the Switching group. A primary outcome measure was a response rate (i.e., ≥ 50% improvement in the MADRS) at week 8.

Results

Among 132 subjects, 41 subjects showed early nonresponse. The Switching group (n = 20) showed a higher rate of responders than the Continuing group (n = 21) (75% vs. 19%: p = 0.002). Further, the Switching group was also superior in the rate of remitters (total score of ≤ 10 in the MADRS) (60% vs. 14%: p = 0.004) and continuous changes in the MADRS (19.0 vs. 7.5: p < 0.001).

Conclusions

Our preliminary findings suggest that patients with MDD who fail to show early response to an initial antidepressant may derive benefits from the early switching antidepressants in the acute-phase treatment of depression.     

Efficacy and bleeding risk of antithrombin supplementation in septic disseminated intravascular coagulation: A prospective multicenter survey

Introduction

Although supplementation with antithrombin (AT) concentrates has been widely accepted for the treatment of disseminated intravascular coagulation (DIC) in Japan, the effects and adverse effects have not been investigated.

Materials and Methods

We conducted a nonrandomized multi-institutional survey. A total of 729 septic DIC patients with AT activity levels of 70% or lower, who had undergone AT substitution at either 1500 IU/day or 3000 IU/day for consecutive 3 days were analyzed. Of these, 650 and 79 patients had received 1500 IU/day (AT1500 group) and 3000 IU/day (AT3000 group), respectively.

Results

Bleeding events were observed in 6.52% of patients (severe bleeding, 1.71%). A significant decrease in initial AT level (below 50%) was observed in 69.6% of patients in AT3000 group and 48.2% in AT1500 group, and this difference was significant (P < 0.01). A logistic-regression analysis conducted using age, gender, body weight, initial AT activity, and supplemented AT dose, revealed that higher initial AT activity (odds ratio (OR), 1.032; P < 0.001), AT dose of 3000 IU/day (OR, 1.912; P = 0.026), and age (OR, 0.985; P = 0.023) were significant factors for improved survival.

Conclusion

The risk of severe bleeding is less than 2%, and concomitant administration of heparin did not increase the risk. The survival in AT1500 group was 65.2%, while that in AT3000 group was 74.7%.     

Genome-wide association study of blood pressure response to methylphenidate treatment of attention-deficit/hyperactivity disorder

Objective

We conducted a genome-wide association study of blood pressure in an open-label study of the methylphenidate transdermal system (MTS) for the treatment of attention-deficit/hyperactivity disorder (ADHD).

Method

Genotyping was conducted with the Affymetrix Genome-Wide Human SNP Array 6.0. Multivariate association analyses were conducted using the software package PLINK. After data cleaning and quality control we tested 316,934 SNPs in 140 children with ADHD.

Results

We observed no genome-wide statistically significant findings, but a SNP in a K⁺-dependent Na⁺/Ca²⁺ exchanger expressed in vascular smooth muscle (SLC24A3) was included in our top associations at p < 1E-04. Genetic enrichment analyses of genes with ≥ 1 SNP significant at p < 0.01, implicated several functional categories (FERM domain, p = 5.0E-07; immunoglobulin domain, p = 8.1E-06; the transmembrane region, p = 4.4E-05; channel activity, p = 2.0E-04; and type-III fibronectins, p = 2.7E-05) harboring genes previously associated with related cardiovascular phenotypes.

Conclusions

The hypothesis generating results from this study suggests that polymorphisms in several genes consistently associated with cardiovascular diseases may impact changes in blood pressure observed with methylphenidate pharmacotherapy in children with ADHD.     

Influence of renal function and platelet turnover on the antiplatelet effect of aspirin

Introduction

Kidney disease predisposes to cardiovascular events. This study investigated the influence of renal function and platelet turnover on the antiplatelet effect of aspirin in patients with coronary artery disease.

Materials and Methods

We included 124 aspirin-treated patients with coronary artery disease and normal to moderately reduced renal function. All tests were performed one hour after aspirin ingestion. Renal function was assessed using creatinine, estimated glomerular filtration rate (eGFR), and cystatin C. The antiplatelet effect of aspirin was evaluated using the VerifyNow® Aspirin assay and multiple electrode aggregometry (MEA, Multiplate®) induced by collagen (1.0 μg/mL) and arachidonic acid (1.0 mmol/L). Von Willebrand factor was measured as a marker of endothelial dysfunction. Platelet turnover was evaluated by measurements of immature, reticulated platelets.

Results

Renal function did not influence the antiplatelet effect of aspirin evaluated by MEA (r = − 0.2-0.09, p = 0.03-0.77) or the VerifyNow® (r = − 0.12-0.11, all p-values > 0.1). In contrast, renal function correlated inversely with von Willebrand factor levels (r_creatinine = 0.48, p < 0.0001; r_eGFR = − 0.46, p < 0.001; r_{cystatin C} = 0.54, p < 0.0001). The number of immature platelets correlated with platelet aggregation according to MEA (r = 0.20-0.39, all p-values < 0.03), but not according to VerifyNow® (r = − 0.07, p = 0.50).

Conclusions

A reduced antiplatelet effect of aspirin may be explained by an increased number of immature platelets. Moderately impaired renal function was associated with high levels of von Willebrand factor, but not with a reduced antiplatelet effect of aspirin.     

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.     

Role of serotonergic-related systems in suicidal behavior: Data from a case-control association study

Objective

To investigate whether functional polymorphisms directly (HTR2A and SLC6A4 genes) or indirectly (IL-1 gene complex, APOE and ACE genes) related with serotonergic neurotransmission were associated with suicidal behavior.

Subjects and methods

227 suicide attempters, 686 non-suicidal psychiatric patients, and 420 healthy controls from a homogeneous Spanish Caucasian population were genotyped using standard methods.

Results

There were no differences in genotype frequencies between the three groups. The −1438A/G [χ² (df) = 9.80 (2), uncorrected p = 0.007] and IL-1α −889C/T [χ² (df) = 8.76 (2), uncorrected p = 0.013] genotype frequencies between impulsive and planned suicide attempts trended toward being different (not significant after Bonferroni correction). Suicide attempts were more often impulsive in the presence of −1438G/G or IL-1α −889C/T or C/C genotypes. There was interaction between the polymorphism 5-HTTLPR and age [LRT (df) = 6.84 (2), p = 0.033] and between the polymorphisms APOE and IL-1RA (86 bp)_n [LRT (df) = 12.21 (4), p = 0.016] in relation to suicide attempt lethality.

Conclusion

These findings further evidence the complexity of the association between genetics and suicidal behavior, the need to study homogenous forms of the behavior and the relevance of impulsive and aggressive traits as endophenotypes for suicidal behavior.     

High plasma nesfatin-1 level in patients with major depressive disorder

Aim

In the present study, our aim was to determine the changes in the plasma concentrations of a recently discovered peptide hormone nesfatin-1 in patients with major depressive disorder and then to make a comparison with the control group.

Method

Subjects in the patient group were randomly selected from Mustafa Kemal University, Medical School, Research and Training Hospital, Psychiatry Department, Outpatient Clinic and subjects in the control group were selected from healthy volunteers. Healthy control subjects were matched in terms of weight and body mass index. Hamilton Depression Rating Scale (HAM-D) was applied to both groups. ELISA method was used for measurement of plasma nesfatin-1 levels.

Results

The average nesfatin-1 level was statistically higher in patients with major depressive disorder than in the control group (p < 0.001). A positive correlation was observed between plasma nesfatin-1 levels and HAM-D scores both in the patient group (r = 0.59, p < 0.001) and in the control group (r = 0.58, p < 0.001).

Conclusion

Our findings suggest a possible relationship between major depressive disorder and high plasma nesfatin-1 level.     

Effect of VKORC1 - 1639 G > A polymorphism, body weight, age, and serum albumin alterations on warfarin response in Japanese patients

Introduction

To establish individualized warfarin therapy, we investigated the contribution of genetic variations of vitamin K epoxide reductase complex subunit 1 gene (VKORC1) - 1639 G > A and Cytochrome P450 2C9 gene (CYP2C9) and clinical factors on warfarin sensitivity in Japanese patients.

Materials and Methods

Genetic analyses of VKORC1 - 1639 G > A and CYP2C9 ?2, ?3, and ?4 were performed in 259 Japanese patients and 341 healthy subjects. We selected 259 patients who have been prescribed warfarin with a 1.5-3.0 range of prothrombin time normalized as an international normalized ratio for at least 3 months and investigated factors that contribute to individual variability in warfarin dose. Furthermore, multivariate analysis was performed to investigate a warfarin dosing algorithm.

Results and Conclusions

There were great inter-individual differences in warfarin maintenance dose in 259 patients, ranging from a minimum dose of 0.75 mg/day to a maximal dose of 8.00 mg/day. VKORC1 - 1639 G > A polymorphism, body weight, age, and serum albumin were found to affect the inter-individual variability. The dosing algorithm of warfarin maintenance dose was investigated by multivariate linear regression. The regression equation was able to account for 33.2% (R²_Adj = 0.332) of the overall variability in warfarin dose.     

Activated inflammatory cells participate in thrombus size through tissue factor and plasminogen activator inhibitor-1 in acute coronary syndrome: Immunohistochemical analysis

Introduction

Recent studies have suggested that circulating inflammatory cells augment the growth of thrombus in acute coronary syndrome (ACS). We therefore immunohistochemically analyzed thrombi in aspirates obtained from patients immediately after the onset of ACS.

Materials and Methods

Two hundred twenty samples were studied. Total thrombus area, white thrombus area, and red thrombus area were measured. As antibodies in immunohistochemical staining, myeloperoxidase (MPO), CD66b, CD68, p-selectin, tissue factor (TF) and PAI-1were employed respectively.

Results

The ratios of areas of red and white thrombi correlated with whole sample areas of enlarged thrombi (r = 0.48, p < 0.001). The immunohistochemical findings revealed granulocytes and macrophages aggregated around p-selectin-positive platelets that shared the boundary between white and red thrombi, a region where MPO and CD66b expression was abundant in neutrophils. The ratios (%) of MPO- and CD66b-positive cells significantly correlated with whole sample areas (r = 0.50; p < 0.001 and r = 0.49; p < 0.001, respectively). Neutrophils and macrophages within thrombi were positive for TF and PAI-1. Along the boundary between red and white thrombi, TF and PAI-1 positivity coincided with MPO-, CD66b- and CD68-positive cells. The ratios of cells positive for both TF and PAI-1 in this area significantly correlated with the whole sample area (r = 0.43, p < 0.001 and r = 0.60, p < 0.001, respectively).

Conclusions

These results suggested that enhanced activation of peripheral neutrophils together with increased TF and PAI-1 expression might comprise a considerable portion of thrombus enlargement.     

Auditory orienting and inhibition of return in schizophrenia: A functional magnetic resonance imaging study

Background

The brain mechanisms of cognitive-behavioral therapy (CBT), a highly effective treatment for pediatric obsessive-compulsive disorder (OCD), are unknown. Neuroimaging in adult OCD indicates that CBT is associated with metabolic changes in striatum, thalamus, and anterior cingulate cortex. We therefore probed putative metabolic effects of CBT on these brain structures in pediatric OCD using proton magnetic resonance spectroscopic imaging (¹H MRSI).

Method

Five unmedicated OCD patients (4 ♀, 13.5 ± 2.8) and 9 healthy controls (7 ♀, 13.0 ± 2.5) underwent MRSI (1.5 T, repetition-time/echo-time = 1500/30 ms) of bilateral putamen, thalamus and pregenual anterior cingulate cortex (pACC). Patients were rescanned after 12 weeks of exposure-based CBT. The Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) of OCD symptoms was administered before and after CBT.

Results

Four of 5 patients responded to CBT (mean 32.8% CY-BOCS reduction). Multiple metabolite effects emerged. Pre-CBT, N-acetyl-aspartate + N-acetyl-aspartyl-glutamate (tNAA) in left pregenual anterior cingulate cortex (pACC) was 55.5% higher in patients than controls. Post-CBT, tNAA (15.0%) and Cr (23.9%) in left pACC decreased and choline compounds (Cho) in right thalamus increased (10.6%) in all 5 patients. In left thalamus, lower pre-CBT tNAA, glutamate + glutamine (Glx), and myo-inositol (mI) predicted greater post-CBT drop in CY-BOCS (r = 0.98) and CY-BOCS decrease correlated with increased Cho.

Conclusions

Interpretations are offered in terms of the Glutamatergic Hypothesis of Pediatric OCD. Similar to ¹⁸FDG-PET in adults, objectively measurable regional MRSI metabolites may indicate pediatric OCD and predict its response to CBT.     

Platelet aggregation is dependent on platelet count in patients with coronary artery disease

Introduction

Platelet function testing in whole blood is widely used to evaluate the effect of antiplatelet agents, but it is not known whether results are affected by whole blood parameters. This study investigated the importance of platelet count, haematocrit, red blood cells (RBC), and white blood cells in whole blood platelet aggregometry.

Materials and methods

We included 417 patients with coronary artery disease on aspirin mono-therapy and 21 aspirin-naïve healthy individuals. Blood sampling was performed one hour after aspirin ingestion. The antiplatelet effect of aspirin was evaluated using the VerifyNow® Aspirin assay and multiple electrode aggregometry (MEA, Multiplate®) induced by collagen (1.0 μg/mL) and arachidonic acid (1.0 or 0.75 mmol/L). Measurements of whole blood parameters were performed to evaluate the three major cell lines in circulating blood.

Results

In patients, platelet count correlated significantly with platelet aggregation (MEA_collagen, p < 0.0001; MEA_{arachidonic acid}, p < 0.0001; VerifyNow®, p = 0.03). Haematocrit and RBC correlated inversely with MEA induced by collagen (p_haematocrit < 0.001; p_RBC = 0.07) and with VerifyNow® (p_haematocrit < 0.0001; p_RBC < 0.0001), but not with MEA induced by arachidonic acid (p_haematocrit = 1; p_RBC = 0.87). White blood cells correlated significantly with platelet aggregation (MEA_collagen, p < 0.001; MEA_{arachidonic acid}, p < 0.0001; VerifyNow®, p = 0.05). Similar associations were observed in aspirin-naïve healthy individuals.

Conclusions

Whole blood aggregometry is dependent on all major cell lines in whole blood. Importantly, platelet aggregation is significantly associated with platelet count even within the normal range.     

The novel P2Y12 antagonist AZD6140 rapidly and reversibly reduces platelet activation in diabetic rats

Introduction

Excessive platelet activation fundamentally contributes to cardiovascular events and mortality in patients with diabetes mellitus. Functional resistance has been described for current antiplatelet therapies in broad populations that include patients with diabetes. We investigated acute and chronic effects of AZD6140, a reversible oral rapid-onset P2Y₁₂ antagonist, on platelet reactivity in diabetic rats.

Materials and Methods

Diabetes was induced by streptozotocin injection in male Wistar rats. After 4 weeks, AZD6140 was administered (5 mg/kg by gavage) and achieved sufficient plasma levels within 30 minutes. Platelet reactivity was determined by ADP-induced P-selectin expression, aggregation and adhesion on fibrinogen coated membranes under arterial flow conditions.

Results

At 0.5 hour, AZD6140 strongly reduced ADP-induced P-selectin surface expression, inhibited ADP-induced platelet aggregation, and significantly reduced platelet adhesion to fibrinogen under arterial flow conditions. Chronic treatment with AZD6140 (10 mg/kg bid for 2 weeks, based on data obtained in the acute study) starting at day 14 reduced P-selectin surface expression on circulating platelets, indicating lower in vivo platelet activation. Platelet reactivity was improved 12 hours after the last dose, while basal platelet activity remained reduced. AZD6140 was rapidly absorbed in diabetic rats and inhibited platelet reactivity. Chronic treatment lowered in vivo platelet activation of circulating platelets.

Conclusion

AZD6140 inhibits platelet reactivity in diabetic rats rapidly and reversibly. Markers of tonic platelet activation, which were increased in diabetic rats, were lowered to levels comparable to non-diabetic rats following chronic treatment with AZD6140.     

Safety profile of tinzaparin versus subcutaneous unfractionated heparin in elderly patients with impaired renal function treated for acute deep vein thrombosis: the Innohep® in Renal Insufficiency Study (IRIS)

Introduction

Trials comparing the use of full dose unfractionated heparin (UFH) or low molecular weight heparins (LMWHs) in very elderly patients with impaired renal function are lacking. IRIS aimed to assess whether LMWH is at least as safe as UFH in this population.

Materials and methods

The study included renally impaired patients ≥ 70 years with acute symptomatic lower limb deep vein thrombosis (DVT). Patients were randomized to initial treatment with either tinzaparin 175 IU/kg once daily (n = 269) or activated partial thromboplastin time-adjusted UFH twice daily (n = 270). After acute management both groups received vitamin K antagonist to day 90.

Results

The trial was stopped prematurely due to a difference in mortality favoring the UFH group (11.5 vs. 6.3%; p = 0.035). Rates of clinically relevant bleedings by day 90 were similar in the tinzaparin (11.9%) and UFH (11.9%) groups, as were rates of confirmed recurrent venous thromboembolism (VTE) (2.6 vs. 1.1%; p = 0.34). As the mortality difference could not be explained by bleedings or recurrent VTE, a post-hoc analysis was performed. This identified six baseline characteristics significantly correlated with mortality, of which five were over-represented in the tinzaparin group.

Conclusion

The IRIS study was a challenging study involving patients (mean age 83 years) usually excluded from clinical studies, but its early termination has left questions unanswered. The mortality difference observed with tinzaparin vs. UFH in elderly, renally-impaired patients with DVT cannot be explained on the basis of bleedings or recurrent VTE, and may reflect an imbalance of mortality risk factors at baseline.     

Has the incidence of deep vein thrombosis in patients undergoing total hip/knee arthroplasty changed over time? A systematic review of randomized controlled trials

Background

There is a perception in the orthopaedic and thromboembolism community that the incidence of deep vein thrombosis (DVT) has decreased in patients undergoing total knee arthroplasty (TKA) or total hip arthroplasty (THA).

Objectives

To assess the incidence of DVT with warfarin thromboprophylaxis over time in patients undergoing elective TKA or THA.

Methods

The MEDLINE, EMBASE, and Cochrane Library databases were searched to October 2006, supplemented by a manual search of reference lists. Two reviewers independently extracted data on study characteristics, quality and the frequency of total, symptomatic and proximal DVT.

Results

Fourteen studies (4,423 patients) were included. Total and proximal DVT after TKA declined over time (r = − 0.75, p = 0.031; r = − 0.86, p = 0.007 respectively). Total and proximal DVT after THA did not change. The risk of developing DVT after TKA was significantly higher than after THA (OR 1.85, 95% CI 1.6 - 2.14; p < 0.0001). The risk of developing symptomatic DVT after THA was significantly higher than after TKA (OR 2.18, 95% CI 1.11 - 4.27; p = 0.012).

Conclusions

The incidence of DVT in patients undergoing elective TKA appears to have declined in patients receiving warfarin thromboprophylaxis.     

Enhanced platelet reactivity and thrombosis in Apoe-/- mice exposed to cigarette smoke is attenuated by P2Y12 antagonism

Introduction

Smoking increases the risk of acute arterial thrombosis, including myocardial infarction, likely due to multi-factorial effects on the vasculature. Heightened platelet reactivity may be among the adverse effects of smoke exposure.

Methods

To examine the effects of smoke exposure on platelet function in an atherosclerotic environment, Apoe-deficient female mice, maintained on a Western diet, were exposed (4 hrs/d, 5d/wk) to sidestream cigarette smoke in a whole-body exposure chamber for12 weeks. A separate group of wild type C57BL/6 J mice were also exposed to smoke in an identical fashion.

Results

In comparison to control Apoe-/- mice exposed to filtered ambient air, smoke-exposed Apoe-/- mice displayed a 1.8 ± 0.3 fold enhanced ADP-induced fibrinogen binding ex vivo (P < 0.001) and had a shorter time to thrombotic occlusion following ferric chloride injury of the carotid artery (median time to thrombosis of 8 vs. 13 min; P = 0.015). Administration of the direct-acting P2Y12 antagonist cangrelor blunted ex vivo fibrinogen binding and attenuated thrombosis (median time 20 min) in Apoe-/- mice exposed to sidestream smoke. The effects of smoke exposure required a proatherosclerotic background, as wild-type C57Bl/6 J mice exposed to smoke displayed similar fibrinogen binding and thrombotic occlusion times as did control mice.

Conclusions

Our results demonstrate that exposure to smoke heightens platelet reactivity and thrombosis in Apoe-/- mice and implicate signaling through platelet P2Y12 receptor as a mediator of the adverse consequence of smoke exposure. These results may partially explain the recent observations that smokers derive greater clinical benefit from the P2Y12 antagonist clopidogrel than do non-smokers.     

Antipsychotic dose and diminished neural modulation: a multi-site fMRI study

Background

The effect of antipsychotics on the blood oxygen level dependent signal in schizophrenia is poorly understood. The purpose of the present investigation is to examine the effect of antipsychotic medication on independent neural networks during a motor task in a large, multi-site functional magnetic resonance imaging investigation.

Methods

Seventy-nine medicated patients with schizophrenia and 114 comparison subjects from the Mind Clinical Imaging Consortium database completed a paced, auditory motor task during functional magnetic resonance imaging (fMRI). Independent component analysis identified temporally cohesive but spatially distributed neural networks. The independent component analysis time course was regressed with a model time course of the experimental design. The resulting beta weights were evaluated for group comparisons and correlations with chlorpromazine equivalents.

Results

Group differences between patients and comparison subjects were evident in the cortical and subcortical motor networks, default mode networks, and attentional networks. The chlorpromazine equivalents correlated with the unimotor/bitemporal (rho = − 0.32, P = 0.0039), motor/caudate (rho = − 0.22, P = 0.046), posterior default mode (rho = 0.26, P = 0.020), and anterior default mode networks (rho = 0.24, P = 0.03). Patients on typical antipsychotics also had less positive modulation of the motor/caudate network relative to patients on atypical antipsychotics (t₇₇ = 2.01, P = 0.048).

Conclusion

The results suggest that antipsychotic dose diminishes neural activation in motor (cortical and subcortical) and default mode networks in patients with schizophrenia. The higher potency, typical antipsychotics also diminish positive modulation in subcortical motor networks. Antipsychotics may be a potential confound limiting interpretation of fMRI studies on the disease process in medicated patients with schizophrenia.     

Circulating microparticles and risk of venous thromboembolism

Introduction

Circulating microparticles (MPs) may trigger a hypercoagulable state, leading to thrombotic complications. Data on their association with venous thromboembolism (VTE) are few and inconsistent.

Materials and methods

To investigate whether or not high levels of MPs are associated with an increased risk of VTE, we carried out a case-control study on 186 patients with a first, objectively diagnosed, episode of VTE and 418 healthy controls. Plasma levels of circulating MPs were measured by flow cytometry.

Results

Patients had higher median plasma levels of total MPs than controls (2184 per μL vs 1769 per μL, p < 0.0001). The risk of VTE increased progressively with increasing MPs, with a linear dose-response effect in the log odds. Individuals with MPs above the 90th percentile of the controls’ distribution (P₉₀ = 3263 per μL) had a 5-fold increased risk of VTE than those with MPs below the 10th percentile of controls (P₁₀ = 913 per μL), independently of sex, age, body mass index, thrombophilia, and plasma factor VIII levels [adjusted odds ratio: 5.30 (95%CI: 2.05-13.7)]. Using the 95th percentile of controls as cut-off (P₉₅ = 4120 per μL), the adjusted odds ratio was 2.20 (1.01-4.79) for individuals with MPs > P₉₅ compared with those having MPs ≤ P₉₅. After exclusion of individuals with antiphospholipid antibodies and hyperhomocysteinemia, the interaction between MPs > P₉₅ and thrombophilia increased the VTE risk from 1.63 (0.60-4.50) to 6.09 (1.03-36.1).

Conclusions

High levels of circulating MPs are a possible independent risk factor for VTE.     

Clustering of venous thrombosis events at the start of tamoxifen therapy in breast cancer: a population-based experience

Introduction

The epidemiology of tamoxifen and venous thromboembolism (VTE) is not well understood, and most data on tamoxifen toxicity are from adjuvant clinical trials. This study examined the relationship between the duration of tamoxifen use in female patients with breast cancer and the risk of VTE in a large population-based setting.

Materials and Methods

Retrospective electronic data extraction on tamoxifen utilization was undertaken among a cohort of 3572 women with breast cancer seen at Marshfield Clinic between January 1, 1994 and June 31, 2009. Observational follow-up extended until February, 2010.

Results

On initial exposure to tamoxifen, women had a clustering of VTE events. Cox proportional hazards regression, adjusting for multiple clinically-important covariates including age, body mass index, cancer stage, and concurrent diabetes, demonstrated that as use of tamoxifen continued in those without earlier VTE events, risk of subsequent VTE gradually increased, albeit at a lower rate (hazard ratio per year of tamoxifen duration = 1.225, P < 0.0001).

Conclusions

In our study population, initiating tamoxifen coincided with an initial clustering of VTE events, with risks due specifically to tamoxifen, increasing during continued exposure. Evidence suggested that the VTE clustering occurred in high risk individuals at initiation of tamoxifen therapy. Careful selection of patients for whom tamoxifen therapy is appropriate based on susceptibility to VTE is thus required prior to initiation of therapy.