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.     

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.     

In vitro comparison of dabigatran, unfractionated heparin, and low-molecular-weight heparin in preventing thrombus formation on mechanical heart valves

Introduction

Lifelong oral anticoagulation (OAC) therapy is required for the prevention of thromboembolic events after implantation of an artificial heart valve. Thromboembolism and anticoagulant-related bleedings account for ≈ 75% of all complications experienced by heart valve recipients (2-9% of patients per year). The present study investigated the efficacy of dabigatran, a new direct thrombin inhibitor for oral use, as compared to unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) in preventing thrombus formation on mechanical heart valves in vitro.

Material and Methods

Blood (230 ml) from healthy young male volunteers was anticoagulated either by dabigatran (1 μmol/l), UFH (150 IU), or LMWH (100 IU). Mechanical heart valve prostheses were placed in an in vitro thrombosis tester and exposed to the anticoagulated blood samples under continuous circulation at a rate of 75 beats per minute.

Results

In whole blood with no anticoagulant, the apparatus completely clotted in 15-20 minutes. When blood was treated with dabigatran, the mean thrombus weight was 164 ± 55 mg, in the UFH group 159 ± 69 mg, and in the LMWH group 182 ± 82 mg (p-value: 0.704). Electron microscopy showed no significant difference in thrombus formation in any group.

Conclusisons

Dabigatran was as effective as UFH and LMWH in preventing thrombus formation on mechanical heart valves in our in vitro investigation. Thus, we hypothesize that dabigatran etexilate might potentially be a useful and competitive orally administered alternative to UFH and LMWH for recipients of alloplastic heart valve prostheses.     

Sunshine-exposure variation of human striatal dopamine D2/D3 receptor availability in healthy volunteers

Background

In addition to the serotonergic system, the central dopaminergic system has been reported to be correlated with seasonality. The aim of this study was to explore the difference in striatal dopamine D₂/D₃ receptor availability between healthy volunteers who had a high-sunshine exposure and those who had a low exposure.

Methods

Sixty-eight participants were enrolled, and those in the upper and lower quartiles in terms of sunshine exposure were categorized into high- (n = 17) and low-sunshine-exposure (n = 18) subgroups. Single photon emission computed tomography with [¹²³I] iodo-benzamide was used to measure striatal dopamine D₂/D₃ receptor availability.

Results

Striatal dopamine D₂/D₃ receptor availability was significantly greater in the subjects with high-sunshine exposure than in those with low-sunshine exposure (F = 7.97, p = 0.01) after controlling for age, sex, and smoking status.

Limitations

Different subjects were examined at different time points in our study. In addition, the sex and tobacco use distributions differed between groups.

Conclusion

The central dopaminergic system may play a role in the neurobiological characteristics of sunshine-exposure variation.     

Oxytocin does not modify GH, ACTH, cortisol and prolactin responses to Ghrelin in normal men

Background

In order to test the possible effect of Oxytocin (OT) on Ghrelin-stimulated GH, PRL, ACTH and cortisol, ten healthy normal men were studied.

Methods

Tests: Ghrelin (0.2 μg/kg body weight (BW)) as an iv bolus; Ghrelin plus OT (2 IU as bolus plus 0.07 IU/min administered for 90 min).

Results

The administration of OT did not change GH, PRL, ACTH and cortisol release induced by Ghrelin.

Conclusions

The data suggests that in humans OT did not modulate the GH, PRL, ACTH and cortisol response to Ghrelin.     

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.     

Safety assessment and pharmacodynamics of a novel ultra low molecular weight heparin (RO-14) in healthy volunteers--a first-time-in-human single ascending dose study

Introduction

RO-14 is a novel ultra low molecular heparin. The purpose of this study was to evaluate the safety and pharmacodynamic profile of RO-14 in healthy males.

Materials and methods

We conducted a two-stage, single-center, open-label, randomized study. Two cohorts of 6 volunteers were randomly assigned to 12 single, ascending subcutaneous doses (1750-19950 IU of anti-FXa activity) in an alternating crossover fashion. Safety was assessed by spontaneous/elicited adverse events, medical examination and laboratory tests. Anti-FXa activity and anti-FIIa activity were assessed throughout the 24 hours after dosing. Dose proportionality and linearity of the anti-FXa activity were evaluated.

Results

All doses were well tolerated and there were no bleeding events. At the lowest dose, anti-FXa activity A_max was 0.16 (± 0.02) IU/mL and AUC_0-24 was 1.11 (± 0.24) IU*h/mL, At the highest dose anti-FXa activity A_max was 1.67 (± 0.15) IU/mL; AUC_0-24 was 21.48 (± 4.46) IU*h/mL and t½ was 8.05 h. Mean T_max (all doses) was 2.86 (± 0.39) h. RO-14 showed proportional and linear pharmacodynamics [normalized A_max among doses (p = 0.594) and normalized AUC_0-24 (p = 0.092), correlations between A_max-dose (R² = 0.89, p < 0.001) and AUC_0-24-dose (R² = 0.86, p < 0.001)]. Anti-FIIa activity was below the detection limit (0.1 IU/ml) at all dose levels. No clinically significant changes were observed in the platelet count, APTT, PT, TT, fibrinogen and antithrombin.

Conclusions

In this phase I study, RO-14 exhibited a good safety profile, anti-FXa activity for either prophylaxis or treatment of venous thromboembolism, linear pharmacodynamics, a longer elimination half-life than currently marketed low molecular weight heparin and no anti-FIIa activity.     

Pain due to osteoarthritis may impair the early outcome of deep brain stimulation in Parkinson's disease

Objective

To analyse postoperative pain due to osteoarthritis in patients with Parkinson's disease submitted to bilateral subthalamic nucleus stimulation.

Methods

Fifty-three parkinsonian patients (mean age, 59.9 ± 8.3 years; mean disease duration, 11.5 ± 4.2 years) referred for subthalamic nucleus stimulation were enrolled. Patients were prospectively asked to refer and describe any pain due to osteoarthritis they experienced at any time during the preoperative period and within the 6 postoperative months. Pre-existing pain due to osteoarthritis, therapeutic changes, parkinsonian motor disability and weight gain were assessed as explanatory factors for occurrence pain due to osteoarthritis after surgery.

Results

After surgery, thirty patients (57%) complained of pain due to osteoarthritis whereas all demonstrated great functional improvement. Twenty (67%) among the 30 experienced similar pain sensation before surgery. Symptoms occurred rapidly, between 4 and 26 postoperative weeks. Multiple stepwise regression analysis showed that pre-existing pain due to osteoarthritis, 6-month postoperative UPDRS III motor score and axial sub-score improvements in the off-drug/on-stimulation condition were accurate independent predictors of pain due to osteoarthritis after surgery (F(8, 41) = 2.20, p < 0.047).

Conclusion

Our results highlight the high prevalence of pain due to osteoarthritis arising shortly after subthalamic implantation. An accurate pain and osteo-articular assessment should be performed preoperatively in parkinsonian candidates for subthalamic nucleus stimulation in order to limit occurrence of complications in the early postoperative period.     

Brain derived neurotrophic factor, cardiopulmonary fitness and cognition in patients with coronary artery disease

Objective

To assess serum brain derived neurotrophic factor (BDNF) concentrations as a correlate of cardiopulmonary fitness and as a predictor of cognitive performance in subjects with coronary artery disease (CAD).

Methods

Serum BDNF concentrations were assayed by ELISA and fitness was assessed using a standardized exercise stress test. The Mini Mental Status Examination (MMSE), California Verbal Learning Test 2nd Ed., Stroop, Trail Making Test B and the Digit Symbol-Coding task were administered. The val66met BDNF genotype and serum interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) concentrations were determined as potential confounders.

Results

In subjects with CAD (n = 88; 85.2% male, mean age 62.8 ± 10.5 yr), cardiopulmonary fitness was associated with higher serum BDNF concentrations (β = .305, p = .013). Higher serum BDNF concentrations were associated with higher MMSE scores (F(1, 87) = 15.406, p < .0005) and better performance on the Digit Symbol-Coding task (F(1, 87) = 9.620, p = .003). IL-6, TNF-α and the val66met genotype did not influence these results.

Conclusion

Serum BDNF concentrations were associated with cardiopulmonary fitness, psychomotor processing speed and overall cognition in subjects with CAD.     

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.     

Factor XII Ofunato: Lys346Asn mutation associated with blood coagulation factor XII deficiency causes impaired secretion through a proteasome-mediated degradation

Introduction

Congenital blood coagulation factor XII (FXII) deficiency is a rare coagulation disease and an autosomal recessive trait. It is found by chance in many cases. We identified a novel mutation (Lys346Asn) in the FXII gene of a patient with FXII deficiency, designated as Factor XII Ofunato.

Methods

The proband was a 75-year-old Japanese woman with a prolonged activated partial thromboplastin time (52.8 s). The FXII activity and antigen were greatly reduced (activity, 5%; antigen, 4.5%). We analyzed FXII gene of this patient using a direct sequencing method and characterized mutant FXII through in vitro expression studies.

Results

Sequence analysis of the FXII gene revealed a G → C point mutation at nucleotide 9845, resulting in Lys346 (AAG) → Asn (AAC) replacement in the catalytic domain. Expression studies in Chinese hamster ovary cells demonstrated that mutant FXII (346 N-FXII) showed a lower level of accumulation in the cells than wild-type. Secretion of 346 N-FXII was greatly reduced in culture medium. We also investigated mRNA expression levels of wild-type and 346 N-FXII in transfected cells using quantitative RT-PCR. Both mRNA expressions were equivalent levels. Pulse-chase experiments showed that 346 N-FXII was extensively degraded intracellularly compared to wild-type. Using membrane-permeable inhibitors, we observed that degradation occurred in the pre-Golgi compartment and that proteasome apparently plays a central role in this process.

Conclusions

These results show that most 346 N-FXII is degraded intracellularly through endoplasmic reticulum-associated degradation as the protein quality control system, resulting in an insufficient secretion phenotype.     

OCT assessment of morphological changes of the optic nerve head and macula in idiopathic intracranial hypertension

Objective

To assess the morphologic changes of the optic nerve head and macula in patients with idiopathic intracranial hypertension (IIH) with optical coherence tomography (OCT).

Methods

Data was extracted from the medical records and Stratus OCT images of IIH patients.

Results

Ninety-one eyes of 48 IIH patients were divided into 3 groups according to their clinical optic disc appearance. Average retinal nerve fiber layer (RNFL) thickness was statistically different between the groups: normal optic disc/mild elevation group (N = 20) - 89 μm (95% CI, 80-98 μm), mild elevation group (N = 51) - 109 μm (95% CI, 101-117 μm), and papilledema group (N = 20) 124 μm (95% CI, 100-153 μm) (P = 0.004). Fast macular thickness map did not demonstrate a significant difference between the groups for most measured macular areas (N = 49 eyes).

Conclusions

Peripapillary RNFL measurements correlated with the clinical appearance of the optic discs, suggesting that OCT may assist in the follow up of IIH patients.     

Undiagnosed depression and its correlates in a predominantly immigrant Hispanic neurology clinic

Objective

Previous studies have reported a high incidence of depression in neurology clinics, however areas where there are predominantly underserved immigrants have not been studied.

Methods

Retrospective cohort study in an academic outpatient neurology clinic in Los Angeles, California. Newly referred patients (N = 318) were assessed consecutively for depression using a PHQ-9 questionnaire, accompanied by review of the assessment of the depressive disorder.

Results

The patient cohort consisted of 190 females (59%) and 130 males (41%), primarily of Hispanic descent (72%), with 8% Asian 11% white, and 5% African-American. Sixty-eight percent (68%) had depression, with 40% exhibiting moderate to severe depression. Patients who had moderate to severe depression (based on PHQ-9) were more likely to be unemployed (75.2% vs. 60.7%, p = 0.008), dependent on government income (29.5% vs. 20.4%, p = 0.06), and have headache or pain as the reason for referral (42.4% vs. 28.5%, p = 0.03). Severity of depression also significantly correlated with current treatment by psychiatrist, current antidepressant use, and less independent living. Patients with moderate to severe depression were more likely to have made ER visits in the last 12 months (0.9 vs. 0.7, p = 0.01) and were taking more medications (3.3 vs. 2.5, p = 0.03), compared to patient with mild or no depression.

Conclusion

The presence of moderate to severe depression significantly correlated with socioeconomic status, use of emergency room, and presence of headache/pain. Neurology clinics with predominantly underserved immigrant patients have a disproportionate amount of depression, which may be related to socioeconomic factors resulting in overutilization of scarce healthcare resources.     

Circulating platelet-derived microparticles and endothelium-derived microparticles may be a potential cause of microthrombosis in patients with osteonecrosis of the femoral head

Introduction

To test the hypothesis that the platelet microparticle (PMP) and endothelial microparticle (EMP) may contribute to the hypercoagulability associated with microvascular thrombosis in patients with nontraumatc osteonecrosis of the femoral head (ONFH).

Materials and methods

The study comprised 46 patients who had been diagnosed with ONFH and 20 control subjects. The plasma was ultracentrifuged, and then PMPs and EMPs were examined by the flow cytometry. The thrombotic and fibrinolytic disorders were investigated.

Results

The numbers of PMPs expressing P-selectin and CD42a and EMPs expressing E-selectin and CD31 in the ONFH patients were significantly higher than those in the controls (P < 0.001). The number of MPs was correlated with the level of the serum C-reactive protein (CRP) (r = 0.661, P < 0.001), but there was a poor correlation between the MPs counts and the risk factors for ONFH (P > 0.05). The mean levels PAI-1, F1 + 2, and TAT were higher in the patients with ONFH than in the controls (P < 0.05).

Conclusions

The elevated numbers of PMPs and EMPs may contribute to hypercoagulability in the ONFH patients. This may provide important pathophysiological insights into the hypercoagulability associated with nontraumatic ONFH and have implications for pharmacological prevention and treatment of ONFH.     

Neurological involvement in patients with falciparum malaria; frequency and prognostic value

Objective

The objective of this study was to evaluate the prognostic significance of neurological manifestations in falciparum malaria.

Methods

We analyzed adult patients with malaria admitted from 2001 to 2003, diagnosed by asexual forms of Plasmodium falciparum in peripheral blood films and identified cases of malaria with neurological involvement. A patient was classified as having neurological involvement if they reported or had one or more of the following symptoms; headache, altered mental status, seizures, neck rigidity, brisk reflexes, cranial neuropathy and hyper or hypotonia.

Results

A total of 454 patients were included in the study. Out of these, 123 (27%) were diagnosed as complicated (severe) malaria and 331 (73%) as uncomplicated malaria at admission. Overall 70 (15.4%) patients had evidence of neurological involvement at initial evaluation. Twenty-seven patients out of 123 (22%) with complicated malaria and 43 patients out of 331 (13%) with uncomplicated malaria had neurological involvement. Over all, 16 (4%) patients died, 13 (11%) had complicated malaria (n = 123) and 3 (1%) had uncomplicated malaria (n = 381). Mortality in patients having neurological involvement (n = 70) was 9 (13%) as compared to 7 (2%) in patients with malaria having no neurological involvement (n = 384). This difference was statistically significant (p = 0.012). Seizure was identified as predictor of mortality on Univariate analysis [OR 5.091 (1.835-14.121)].

Conclusion

Fifteen percent of patients with falciparum malaria admitted to our hospital had neurological symptoms and neurological involvement was associated with increased mortality.     

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.     

Purification, biochemical properties and antithrombotic effect of a novel Streptomyces enzyme on carrageenan-induced mice tail thrombosis model

Introduction

The prevalence of cardiovascular diseases, one of the major causes of worldwide mortality, is being increasingly reported. Safer, more effective, and less expensive thrombolytic drugs can possibly overcome the underlying problems associate with current thrombolytic drugs.

Methods

A thrombolytic enzyme was purified and characterized from a Streptomyces strain. Carrageenan induced tail-thrombosis mice model was used to evaluate in vivo antithrombotic effect of the enzyme.

Results

First 15 N-terminal amino acids of the purified enzyme were IAGGQAIYAGGGRRS, which are significantly different from the reported fibrinolytic enzymes. The enzyme exhibited 14.3 ± 2.3-fold stronger thrombolytic activity than that of plasmin. In carrageenan induced tail-thrombosis model, the enzyme caused reduction in frequency of thrombus. Tail-thrombus of the enzyme treated group was significantly shorter than the physiological saline treated group and the thrombus decrement was correlated with the enzyme dose.

Conclusions

The enzyme purified from the Streptomyces strain can be a potential candidate for the treatment of thrombosis.     

Pre-analytical and analytical variables affecting the measurement of plasma-derived microparticle tissue factor activity

Introduction

Elevated levels of tissue factor positive (TF⁺) microparticles (MPs) are observed in plasma from a variety of patients with an increased risk of thrombosis. We and others have described the measurement of TF activity in MPs isolated from plasma. The aim of this study was to investigate the effects of pre-analytical and analytical variables on TF activity of MPs isolated from blood of healthy volunteers either untreated or treated ex vivo with bacterial lipopolysaccharide.

Materials and methods

We evaluated the following parameters: use of different centrifugation speeds to isolate the MPs; comparison of TF activity of MPs isolated from platelet poor plasma versus platelet free plasma; effect of freeze/thaw on MP TF activity; and comparison of the MP TF activity assay with the measurement of TF protein by ELISA or flow cytometry.

Results

MPs prepared from platelet poor plasma by centrifugation at 20,000 × g or 100,000 × g for 15 minutes had similar levels of TF activity. However, significantly less TF activity was found in MPs isolated from platelet free plasma compared with platelet poor plasma. Interestingly, freeze/thawing of the plasma showed donor to donor variation in MP TF activity, with a moderate increase in some individuals.

Conclusion

TF⁺ MPs can be quantitatively isolated from platelet poor or platelet free plasma by centrifugation at 20,000 × g for 15 minutes. Measurement of MP TF activity in plasma may be used to detect a prothrombotic state in patients with various diseases.     

Adjunctive glycine in the treatment of obsessive-compulsive disorder in adults

Background

Recent preclinical findings, case reports and non-blinded studies have suggested that glutamatergic interventions may be efficacious for Obsessive-Compulsive Disorder (OCD).

Methods

We enrolled 24 adult outpatients with OCD on stabilized treatment regimens in a double-blind trial of adjunctive glycine, an NMDA glutamate receptor agonist. Participants were randomly assigned 1:1 to either placebo or glycine titrated to 60 g/day, with follow-up visits scheduled at 4, 8 and 12 weeks. Yale-Brown Obsessive Compulsive Scale (Y-BOCS) was the principal outcome measure.

Results

Regimen non-adherence, principally related to complaints about the taste and/or nausea, resulted in only 14 individuals who were evaluable by predetermined criteria. Those receiving glycine (n = 5) experienced a mean decrease of 6.04 points in Y-BOCS score, compared with a 1.00 point decrease for those receiving placebo (n = 9). Using a hierarchical linear model, compared with placebo, individuals who received glycine had an average 0.82 decrease in Y-BOCS score for each week they remained in the study, not quite reaching statistical significance (p = 0.053). Two of those receiving glycine were responders, versus none receiving placebo (p = 0.11, ns, Fisher exact). Despite the dropouts, two participants were known to have subsequently continued taking glycine through their regular treating psychiatrist for over a year.

Conclusions

The glycine condition approached efficacy for treatment of OCD in this study, with the high dropout rate related to problems with palatability and small sample size the principal caveats. This may indicate a new strategy for treatment of OCD, although confirmatory studies are clearly needed. (ClinicalTrials.gov NCT00405535.)