Simvastatin Increases ADAMTS13 Expression in Podocytes

Introduction

ADAMTS13 is a specific von Willebrand factor–cleaving protease. Severe deficiency of ADAMTS13 is the main cause of thrombotic thrombocytopenic purpura. ADAMTS13 is mainly synthesized and released from hepatic stellate cells and endothelial cells, but is also expressed in other cells, including kidney podocytes. Simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, has a beneficial effect on atherosclerosis and also has anti-inflammatory and antithrombotic properties. A recent study indicates that ADAMTS13 reduces inflammatory plaque formation during early atherosclerosis in mice. In our study, we investigated the effects of simvastatin on inflammatory cytokines–induced ADAMTS13 expression in podocytes.

Materials and Methods

A conditionally immortalized mouse podocyte cell line was utilized to study the expression of ADAMTS13 in podocytes. The influence of TNF-α, IL-4, IL-6 and simvastatin on ADAMTS13 was investigated. ADAMTS13 mRNA levels in podocytes were measured by using real-time PCR and protein levels were detected by Western blotting.

Results

Simvastatin significantly up-regulated the expression levels of ADAMTS13 mRNA and protein in podocytes. IL-6 decreased ADAMTS13 expression, and TNF-α had no significant effects on ADAMTS13 expression in podocytes. IL-4 reduced ADAMTS13 mRNA expression but not its protein level. Simvastatin was able also reversed the inhibitory effect of IL-6.

Conclusions

We demonstrate that simvastatin increases the expression of ADAMTS13 in a dose-dependent manner in podocytes, which likely contributes to the antithrombotic property of statin. Different inflammatory cytokines have different effects on the levels of ADAMTS13 mRNA expression and protein within podocytes.     

Treatment with everolimus is associated with a procoagulant state

Introduction

Renal transplant recipients are at increased risk of venous thromboembolic events, which is in part caused by their treatment with maintenance immunosuppressive drugs. Because we observed an increased incidence of venous thromboembolic events in renal transplant recipients treated with the mTOR inhibitor (mTORi) everolimus, we aimed to identify prothrombotic mechanisms of this immunosuppressive drug.

Materials and Methods

In a single center study, nested in a multi-center randomized controlled trial, we measured parameters of coagulation, anti-coagulation and fibrinolysis in renal transplant recipients, receiving the mTORi everolimus (n = 16, mTOR group) and compared them to a similar patient group, receiving a calcineurin inhibitor and/or mycophenolate sodium (n = 20, non-mTOR group). All patients were at least 6 months following transplantation with a stable transplant function.

Results

The use of an mTORi was associated with significantly higher levels of von Willebrand factor, prothrombin fragment 1 + 2, thrombin-activatable fibrinolysis inhibitor and plasminogen activator inhibitor-1 as compared to a non-mTORi based immunosuppressive regimen.

Conclusions

Treatment with an mTORi leads to increased endothelial activation, thrombin formation and impaired fibrinolysis in renal transplant recipients. This suggests an increased risk of thrombotic events in renal transplant recipients treated with mTOR inhibitors. A prospective study to establish the precise risk of thrombotic events in these patients is urgently needed.     

Decreased serum angiogenin level in Alzheimer's disease

Background

It has been suggested that Alzheimer's disease (AD) is mediated by pathological angiogenesis. Vascular endothelial growth factor (VEGF), transforming growth factor β (TGF-β), and tumor necrosis factor α (TNF -α) may play important roles in inflammation and angiogenesis through effects on inflammatory cell infiltration or neovascularization in AD pathogenesis. A few studies on the roles of VEGF in AD have been reported recently. But, the results were inconsistent. Angiogenin, which is suspected to have a similar function as VEGF, however, has not yet been studied in patients with AD.

Objective

This study was performed to investigate the levels of angiogenin and vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptorI (VEGFR I), and vascular endothelial growth factor receptor II (VEGFR II) in serums of patients with AD, to compare their levels with control subjects, and to determine whether serum angiogenin, VEGF, VEGFR I, and VEGFR II levels are associated with Alzheimer's disease (AD).

Methods

Serum angiogenin, VEGF, VEGFR I, and VEGFR II levels were quantified at the time of diagnosis in 20 patients with definite AD, and 18 healthy controls, using a commercial ELISA kit.

Results

Patients with AD exhibited lower serum angiogenin (p = 0.003) and higher VEGF (p = 0.008) levels than control subjects. No difference in serum VEGFR I and VEGFR II concentrations was observed between AD patients and controls. There was a correlation between serum levels of angiogenin and cognitive function (MMSE-KC and CDR) in AD patients.

Conclusion

The increased serum level of VEGF and decreased serum angiogenin level were founded. Cognitive function was correlated with serum levels of angiogenin. Angiogenin may be involved in the pathogenesis of AD. Further study should be needed to evaluate the possibility of serum angiogenin as a biomarker of AD and as a predictor of disease progression.     

Brain-derived neurotrophic factor gene and protein expression in pediatric and adult depressed subjects

Background

Brain-derived neurotrophic factor (BDNF) is a member of a neurotrophin family and is involved in many physiological functions, including cell proliferation, migration, and differentiation, and neuron survival in the human nervous system. Abnormalities of BDNF have been implicated in the pathophysiology of depression based on observations that antidepressant drugs cause increases in the levels of BDNF in rat brains and its abnormalities have appeared in the serum of depressed patients and in postmortem brains of suicide victims.

Methods

We examined the gene expression of BDNF in the lymphocytes and protein expression in the platelets of adult and pediatric depressed patients during a drug-free period. We determined BDNF gene expression using a quantitative RT-PCR method and protein expression using the ELISA method.

Results

We observed that the gene expression of BDNF was significantly decreased in the lymphocytes of adult and pediatric depressed patients compared with normal control subjects. Similarly, the protein expression of BDNF was significantly decreased in the platelets of adult and pediatric depressed patients compared with normal control subjects.

Conclusions

To our knowledge, this is the first study that reports a decrease in BDNF gene expression in the peripheral cells of depressed patients. Because of the bidirectional movement of BDNF between the periphery and the CNS, the reduced gene expression in the lymphocytes and the protein expression in the platelets may be an index of similar abnormalities in the brain and could be a target for antidepressant drugs.     

Statins are Associated with Low Risk of Venous Thromboembolism in Patients with Cancer: A Prospective and Observational Cohort Study

Introduction

Patients with cancer are at risk of venous thromboembolism (VTE). Statin-use has been shown to be associated with low risk of VTE in patients without cancer, but data in cancer patients is scarce. The objective of this study was to evaluate the association of statins with risk of VTE in cancer patients in a prospective observational cohort study.

Materials and Methods

Patients with newly diagnosed cancer or progression of disease after remission were included and prospectively followed for a maximum of 2 years. Study endpoint was occurrence of symptomatic VTE.

Results

Patients (n = 1434) were followed over a median observation period of 729 days. VTE occurred in 107 (7.5%) patients. At study inclusion, 170 (11.9%) patients took statins. Simvastatin (n = 96) and atorvastatin (n = 48) were the most frequently prescribed statins. VTE occurred in 6 (3.5%) patients with statins. Patients with statins had a lower risk of VTE than patients without (subhazard ratio 0.43, 95% confidence interval 0.19 to 0.98; p = 0.04). In competing risk analysis, the cumulative probability of VTE in patients with statins was 2.94% after 12 months and 3.54% after 24 months, compared to 7.13% and 8.13% in the group without statins (Gray’s test: p = 0.04).

Conclusion

This study provides observational evidence for an association between statin use and low risk of VTE in patients with cancer. The role of statins for prevention of cancer-associated VTE needs to be confirmed in randomized, controlled trials.     

Unfractionated heparin attenuates lung vascular leak in a mouse model of sepsis:Role of RhoA/Rho kinase pathway

Introduction

Excessive vascular permeability is a characteristic feature of ALI. We have previously demonstrated that UFH prevents LPS-induced disruption of endothelial barrier function in vitro. It was the objective of this study to determine whether UFH may attenuate endotoxin-induced lung vascular leak in mice and to further explore the possible underlying mechanisms.

Methods

C57BL/6J mice were randomly divided into the control, LPS and LPS plus UFH groups. Sepsis was induced by intraperitoneal injection of LPS at a dose of 30 mg/kg. Mice in the LPS plus UFH group were intravenously received 8 units UFH (heparin sodium) diluted in 20 μl sterile saline at 0.5 h before the injection of LPS.

Results

1) UFH pretreatment attenuated LPS-induced histopathological changes in Lung at 6 h; 2) Pretreatment of mice with UFH ameliorated LPS-induced lung edema and lung vascular leak at 6 h; 3) UFH pretreatment dramatically inhibited RhoA and ROCK activation in the lung tissues of LPS-treated mice (3 and 6 h). 4) UFH pretreatment significantly down-regulated ROCK1 gene expression, but did not affect the increased expression of ROCK2 mRNA in the lung tissues of LPS-treated mice at 3 or 6 h.

Conclusion

These data suggest that UFH may attenuate endotoxin-induced lung vascular leak by regulating RhoA/Rho kinase pathway.     

The proinflammatory effect of C-reactive protein on human endothelial cells depends on the FcγRIIa genotype

Introduction

The stimulatory effects of CRP (C-reactive protein) on endothelial cells are mainly mediated via FcγRIIa. This receptor exists in two different allotypes bearing either arginine (R131) or histidine (H131) at the extracellular amino acid position 131 of the mature protein, but only FcγRIIa-R131 displays high avidity for CRP. This study investigated the role of the FcγRIIa genotype in CRP-stimulated endothelial cells.

Materials and Methods

We tested the effects of CRP on expression of the adhesion molecules ICAM-1, VCAM-1, and E-selectin, as well as the endothelial release of pro-inflammatory molecules as a function of the FcγRIIa-genotype (FcγRIIa-H/H131, FcγRIIa-H/R131, FcγRIIa-R/R131) in HUVEC (Human Umbilical Vein Endothelial Cells). HUVEC were grouped according to their FcγRIIa status by genotyping with an allele specific nested-PCR. The expression of ICAM-1, VCAM-1, and E-selectin on HUVEC was detected by flow cytometry. The release of soluble markers (sCD40L, IL-6, IL-8, MCP-1, tPA, sP-selectin, and sVCAM-1) was measured using a multiplex assay for flow cytometry.

Results and Conclusions

CRP-stimulated expression of ICAM-1 and E-selectin was dependent on the specific FcγRIIa-genotype, with most pronounced induction in HUVEC with the FcγRIIa-R/R genotype, followed by H/R and H/H. In accordance with this finding, the supernatants of stimulated HUVEC with the R/R genotype showed significantly higher levels of tPA, MCP-1, and IL-6.Our data show that CRP stimulates the expression of adhesion molecules and the release of soluble markers by HUVEC as a function of the FcγRIIa-genotype. These findings could be relevant in the context of risk stratification in patients with cardiovascular disease.     

Genistein as a neuroprotective antioxidant attenuates redox imbalance induced by β-amyloid peptides 25–35 in PC12 cells

Objective

Genistein (GEN), a principal component of soybean isoflavones, might possess the neuroprotective role through its antioxidant activity. However, the detailed mechanisms are unknown yet. The purpose of this study was to investigate whether GEN could alleviate oxidative damage induced by β-amyloid peptides 25–35 (Aβ25–35) in PC12 cells.

Methods

The PC12 cells were pre-incubated with or without GEN for 2 h following incubation with Aβ25–35 for another 24 h. MTT was used to assess the cell viability. Hoechst 33342 staining was applied to determine the apoptotic cells. Confocal laser scanning microscopy was implemented to examine the reactive oxygen species (ROS) levels. Mitochondrial membrane potential (MMP) was measured by flow cytometry. Reduced and oxidized glutathione (GSH/GSSG) ratio was analyzed by using assay kits. Western blot analysis was performed to assess the proteins expression of NF-E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and γ-glutamylcysteine synthetase (γ-GCS).

Results

GEN attenuated the cytotoxicity and partially prevented apoptosis induced by Aβ25–35. GEN dramatically attenuated ROS levels induced by Aβ25–35 in PC12 cells. In addition, GEN significantly reversed the reduction of MMP caused by Aβ25–35 to maintain the normal levels of the cells. The GSH/GSSG ratio in GEN pretreated groups significantly increased compared to the groups without GEN pretreatment. GEN reversed Aβ25–35 induced down regulation of the protein expression of γ-GCS, Nrf2 and HO-1.

Conclusion

GEN could alleviate the oxidative stress caused by Aβ25–35 treatment and maintain redox balance in PC12 cells, which might be associated with the regulation of Nrf2/HO-1 signal pathway.     

Effects of vaginal delivery,cesarean section and exposure to labor on endothelial function of pregnant women

Introduction

This study was undertaken to assess the influence of labor and cesarean section on endothelial function.

Materials and Methods

Flow-mediated vasodilatation (FMD) was measured before and after delivery for an assessment of endothelial function in three groups: (1) the Vaginal delivery group (with spontaneous labor or induction of labor, n = 48), (2) the Elective C/S group (with a cesarean planned, n = 20), and (3) the C/S after FP group (scheduled for vaginal delivery but required to have an emergency cesarean section because of failure in progress, n = 11).

Results

There were statistically significant changes between the antepartum and postpartum FMD values in the Vaginal delivery group and the Elective C/S group but not in the C/S after FP group (P < 0.001, P = 0.023 and P = 0.22 respectively).

Conclusions

These observations suggest that labor may enhance endothelial function and that cesarean section may impair endothelial function.     

Increased adhesive properties of neutrophils and inflammatory markers in venous thromboembolism patients with residual vein occlusion and high D-dimer levels

Background

Venous thromboembolism (VTE) develops via a multicellular process on the endothelial surface. Although widely recognized, the relationship between inflammation and thrombosis, this relationship has been mostly explored in clinical studies by measuring circulating levels of inflammatory cytokines. However, the role of inflammatory cells, such as neutrophils, in the pathogenesis of VTE is not clear in humans.

Aims

To evaluate the adhesive properties of neutrophils, erythrocytes and platelets in VTE patients and to correlate findings with inflammatory and hypercoagulability marker levels.

Methods

Study group consisted of twenty-nine VTE patients and controls matched according to age, gender and ethnic background. Adhesive properties of neutrophils, erythrocytes and platelets were determined using a static adhesion assay. Neutrophil adhesion molecules expressions were evaluated by flow cytometry. Inflammatory and hypercoagulability marker levels were evaluated by standard methods. Residual vein occlusion (RVO) was evaluated by Doppler ultrasound.

Results

No significant difference could be observed in platelet and erythrocyte adhesion between VTE patients and controls. Interestingly, VTE patients with high levels of D-dimer and RVO, demonstrated a significant increase in neutrophil adhesion, compared to controls and remaining patients. Inflammatory markers (IL-6, IL-8, TNF-α) were also significantly elevated in this subgroup, compared to other VTE patients. Adhesive properties of neutrophils correlated with IL-6 and D-dimer levels. Neutrophils adhesion molecules (CD11a, CD11b and CD18) were not altered in any of the groups.

Conclusion

These findings not only support the hypothesis of an association between inflammation and hypercoagulability, but more importantly, highlight the role of neutrophils in this process.     

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.     

Brain GABA levels in patients with bipolar disorder

Purpose

A growing body of research supports an important role for GABA in the pathophysiology of bipolar and other mood disorders. The purpose of the current study was to directly examine brain GABA levels in a clinical sample of bipolar patients.

General methods

We used magnetic resonance spectroscopy (MRS) to examine whole brain and regional GABA, glutamate and glutamine in 13 patients with bipolar disorder compared to a matched group of 11 healthy controls.

Findings

There were no significant differences in GABA, glutamate or glutamine between patients and controls.

Conclusions

Further research is needed to better characterize the GABAergic and glutamatergic effects of pharmacotherapy, anxiety comorbidity and clinical state in bipolar disorder.     

Changes in hippocampal connexin 36 mRNA and protein levels during epileptogenesis in the kindling model of epilepsy

Objective

Identification of key molecular changes occurring during epileptogenesis provides better understanding of epilepsy and helps to develop strategies to modify those changes and thus, block the epileptogenic process. Gap junctional communication is thought to be involved in epileptogenesis. This communication can be affected by changes in expression of gap junctional protein subunits called connexins (Cxs). One of the main brain regions involved in epileptogenesis is the hippocampus in which there is a network of gap junctional communication between different cell types.

Method

Cx36 and Cx43 expressions at both mRNA and protein level were measured in rat hippocampus during epileptogenesis in the kindling model of epilepsy.

Results

Cx36 expression at both mRNA and protein level was upregulated during acquisition of focal seizures but returned to basal level after acquisition of secondarily-generalized seizures. No change in Cx43 gene and protein expression was found during kindling epileptogenesis.

Conclusion

These results further point out the significance of Cx36 as a target to modify epileptogenic process and to develop antiepileptogenic treatments.     

Increased serum concentrations of pentosidine are related to presence and severity of coronary artery disease

Background

There are limited data regarding the contribution of advanced glycation end products (AGEs) in the presence of coronary artery disease (CAD). We investigated whether serum pentosidine and Nε-carboxymethyllysine (CML) were related to the presence and the severity of CAD.

Methods

69 Tunisian patients with CAD (≥ 50% obstruction in ≥ 1 coronary artery), 32 Tunisian patients without CAD but with potential cardiovascular risk factors and 60 Tunisian control subjects were included in a cross-sectional study. Patients were classified as CAD and non CAD patients according to angiographic results. The severity of CAD was assessed using the Gensini score. Serum pentosidine and CML were measured by LC-MS/MS.

Results

Serum pentosidine and CML concentrations were significantly higher in non-CAD patients vs control subjects (P < 0.001). Serum pentosidine concentrations were significantly higher in CAD patients vs non-CAD patients (P < 0.001). A multiple logistic regression analysis demonstrated that pentosidine was independently associated with the presence of CAD (OR = 1.52, 95% CI: 1.12-2.07, P = 0.007). The area under curve (AUC) determined by ROC analysis was 0.74 (95% CI: 0.64-0.84, P < 0.001) and the optimal cut-off value of pentosidine to predict the presence of CAD was 3.2 μmol/mol Lys, with 64% sensitivity and 78% specificity. Furthermore, in a multivariate stepwise regression analysis, pentosidine was independently correlated with Gensini score (standardized β = 0.46, 95% CI: 0.70-1.99, P < 0.001).

Conclusions

High concentrations of pentosidine show the presence and the severity of CAD with high sensitivity.     

Serum brain-derived neurotrophic factor predicts responses to escitalopram in chronic posttraumatic stress disorder

Introduction

Some studies have found that antidepressants increase serum brain-derived neurotrophic factor (BDNF) levels in patients with major depression and the expression of BDNF mRNA in limbic structures of rats.

Objectives

This study addressed whether the SSRI escitalopram increases serum BDNF levels in subjects with PTSD and whether BDNF levels are associated with treatment response.

Methods

Medically healthy male subjects (N = 16) with chronic PTSD completed a 12 week open-label trial of flexible dose (5–20 mg/day) escitalopram monotherapy. BDNF levels were obtained at baseline, and at weeks 4, 8 and 12.

Results

PTSD symptoms significantly declined over the course of the 12 week escitalopram treatment. Despite a substantial improvement in PTSD symptoms, there was virtually no change in BDNF levels over time. Nevertheless, mean BDNF levels across the trial were strongly correlated with the slope of PTSD symptoms over the 12 weeks (r = 0.58, p = 0.018). Lower mean BDNF was associated with a greater decrease in PTSD symptoms over the course of the trial.

Conclusions

PTSD subjects with low BDNF levels demonstrated the largest treatment response from an agent with putative neurotrophic effects.     

MiR-150 enhances the motility of EPCs in vitro and promotes EPCs homing and thrombus resolving in vivo

Introduction

Deep venous thrombosis (DVT) is one of the common peripheral vascular diseases. The recruitment and migration of bone marrow-derived endothelial progenitor cells (EPCs) to the sites of venous thrombus are necessary in the process of thrombus organization and recanalization. Our objective was to investigate the functional role of miR-150 in rat EPCs and its potential application in deep venous thrombosis.

Materials and Methods

Rat EPCs were cultured and transfected with miR-150 mimics and inhibitor. Wound healing assay, transwell migration assay and matrigel tube formation assay were performed to elucidate the effect of miR-150 of rat EPCs. Lentiviral construct expressing miR-150 was transfected into EPCs and the EPCs were injected to rat models of DVT. The rats were sacrificed on the day of 7 and 14 after the transplantation and the histological study was performed. Luciferase reporter assay and Western blot were performed to evaluate rat miR-150 regulates the expression of c-Myb.

Results

MiR-150 significantly promoted the migration and tube formation ability of EPCs in vitro and enhanced EPCs’ homing, organization and resolution ability in vivo. Overexpression of miR-150 significantly reduced the protein level of c-Myb and repressed the activity of a luciferase reporter containing both of the two predicted miR-150 binding sites in c-Myb 3’-UTR, indicating that c-Myb may be a miR-150 target gene.

Conclusion

MiR-150 enhanced the migration, tube formation, homing, thrombus recanalization and resolution ability of rat EPCs. Restoring miR-150 in EPCs revealed potential application in DVT therapy.     

Altered platelet calsequestrin abundance,Na/Ca exchange and Ca signaling responses with the progression of diabetes mellitus

Introduction

Downregulation of calsequestrin (CSQ), a major Ca^2 + storage protein, may contribute significantly to the hyperactivity of internal Ca^2 + ([Ca^2 +]_i) in diabetic platelets. Here, we investigated changes in CSQ-1 abundance, Ca^2 + signaling and aggregation responses to stimulation with the progression of diabetes, especially the mechanism(s) underlying the exaggerated Ca^2 + influx in diabetic platelets.

Materials and methods

Type 1 diabetes was induced by streptozotocin in rats. Platelet [Ca^2 +]_i and aggregation responses upon ADP stimulation were assessed by fluorescence spectrophotometry and aggregometry, respectively. CSQ-1 expression was evaluated using western blotting.

Results

During the 12-week course of diabetes, the abundance of CSQ-1, basal [Ca^2 +]_i and ADP-induced Ca^2 + release were progressively altered in diabetic platelets, while the elevated Ca^2 + influx and platelet aggregation were not correlated with diabetes development. 2-Aminoethoxydiphenyl borate, the store-operated Ca^2 + channel blocker, almost completely abolished ADP-induced Ca^2 + influx in normal and diabetic platelets, whereas nifedipine, an inhibitor of the nicotinic acid adenine dinucleotide phosphate receptor, showed no effect. Additionally, inhibition of Na⁺/Ca^2 + exchange induced much slower Ca^2 + extrusion and more Ca^2 + influx in normal platelets than in diabetic platelets. Furthermore, under the condition of Ca^2 +-ATPase inhibition, ionomycin caused greater Ca^2 + mobilization and Ca^2 + influx in diabetic platelets than in normal platelets.

Conclusions

These data demonstrate that platelet hyperactivity in diabetes is caused by several integrated factors. Besides the downregulation of CSQ-1 that mainly disrupts basal Ca^2 + homeostasis, insufficient Na⁺/Ca^2 + exchange also contributes, at least in part, to the hyperactive Ca^2 + response to stimulation in diabetic platelets.     

Resting brain perfusion in alcohol-induced psychotic disorder: A comparison in patients with alcohol dependence,schizophrenia and healthy controls

Introduction

Alcohol-induced psychotic disorder (AIPD), also known as alcohol hallucinosis, is a rare complication of alcohol abuse. The underlying pathophysiology is poorly understood, and the disorder needs to be differentiated from alcohol withdrawal delirium and schizophrenia. No brain-imaging studies in AIPD have been reported to date. Case reports of brain imaging in AIPD suggest possible dysfunction in the thalamus, basal ganglia, frontal lobes and cerebellum. Our aim was to prospectively compare resting brain perfusion (rCBF) in patients with AIPD, uncomplicated alcohol dependence, schizophrenia and healthy volunteers.

Methods

Single photon emission computed tomography (SPECT) was utilized to compare rCBF in patients with AIPD (n = 19), schizophrenia (n = 16), uncomplicated alcohol dependence (n = 20) and healthy volunteers (n = 19).

Results

Increased rCBF was demonstrated in the right calcarine area in patients with AIPD compared to healthy volunteers, with a trend towards increased rCBF to the frontal and temporal lobes and the right pallidum. Decreased left sided rCBF to the putamen, parietal, mid-frontal and mid-temporal lobes and heterogenous flow to the cerebellum were demonstrated in patients with AIPD when compared to patients with uncomplicated alcohol dependence. The left posterior cingulate and right cerebellum showed higher and lower rCBF respectively in patients with AIPD compared to patients with schizophrenia.

Conclusion

Our findings implicate the right occipital lobe and possibly the cerebellum in the pathogenesis of AIPD and have similarities with those previously reported in alcohol withdrawal. Reduced rCBF to the frontal lobes, thalamus and basal ganglia in AIPD as suggested in previous case reports could not be confirmed.     

Intensity of opiate withdrawal in relation to the 825C>T polymorphism of the G-protein beta 3 subunit gene

Objectives

The intensity of withdrawal in opiate dependence shows a high inter-individual variability. The 825C>T polymorphism (rs5443) of the G-protein beta 3 (GNB3) subunit gene has a strong influence on clinical signs of sympathetic activity in cardiac research. This study was carried out in order to test the hypothesis that carriers of the T allele have an increased sympathetic activity in opiate withdrawal.

Methods

Thirty-nine monovalent opiate addicted patients consecutively admitted to a detoxification ward were investigated. The main parameter for sympathetic activity was the pulse rate in the first 3 days after the regular end of gradual methadone reduction.

Results

Thirty-three out of 39 patients achieved a drug-free state: 22 carried a T allele (TT, CT), 11 belonged to the CC genotype group. The pulse rate was significantly (p < 0.05) raised in the T allele group compared to the CC genotype group on the first 2 days after stopping methadone administration. In addition, about a third of the T allele carriers needed clonidine treatment on the respective days, but only one patient among the 11 CC homozygotes. There was no significant difference between groups in systolic and diastolic blood pressures as well as in subjective withdrawal ratings.

Conclusion

A group difference regarding pulse rate could be observed in a small sample and despite a higher degree of concomitant clonidine medication in T allele carriers. The failure to detect group differences in blood pressure and self-rated withdrawal symptoms may be attributed to the more complex regulation of blood pressure and the known weak correlation between objective and subjective withdrawal symptoms.     

Biomarkers for post thrombotic syndrome: A case-control study

Introduction

There is limited knowledge on the etiology of post thrombotic syndrome (PTS), although several mechanisms have been proposed.The objectives are to explore the role of different pathogenic mechanisms for PTS, through measurement of an elaborate panel of biomarkers in patients with and without PTS.

Materials and Methods

Patients with a history of deep vein thrombosis (DVT) with PTS (cases) and without PTS after minimal 2 years follow-up (controls), were selected from the outpatient clinic of two Dutch hospitals. As a reference to the normal population healthy individuals (HI) without a history of venous thromboembolism were invited to participate. The population consisted of: 26 cases, 27 controls, and 26 HI.A panel of predefined biomarkers was measured in venous blood.

Results

D-dimer showed a decreasing trend from cases to controls to HI; p = 0.010. Thrombin/antithrombin complex levels were significantly higher in cases than in controls; p = 0.032, and HI; p = 0.017. APC-ratio was significantly lower in cases compared to controls; p = 0.032, and HI; p = 0.011. A significant trend of increasing proTAFI from cases, to controls, and HI; p = 0.002 was found. There were no differences in inflammatory markers (CRP, Interleukin-6, Interleukin-8). Thrombomodulin, tissue-plasminogen activator, and von Willebrand factor were higher in patients compared to HI. There was a significant trend of decreasing sVCAM, from cases, to controls, and HI; p = 0.029.

Conclusions

Patients with PTS displayed increased coagulation activity, an altered pattern of fibrinolytic marker expression, and increased endothelial activation. We found no evidence of systemic inflammation in patients with PTS at 63 months since the last DVT.