Improvement of Glycaemia and Endothelial Function by a New Low-Dose Curcuminoid in an Animal Model of Type 2 Diabetes.

Curcumin has been suggested as a promising treatment for metabolic diseases, but the high doses required limit its therapeutic use. In this study, a new curcuminoid is synthesised to increase curcumin anti-inflammatory and antioxidant potential and to achieve hypoglycaemic and protective vascular effects in type 2 diabetic rats in a lower dose. In vitro, the anti-inflammatory effect was determined through the Griess reaction, and the antioxidant activity through ABTS and TBARS assays. In vivo, Goto-Kakizaki rats were treated for 2 weeks with the equimolar dose of curcumin (40 mg/kg/day) or curcuminoid (52.4 mg/kg/day). Fasting glycaemia, insulin tolerance, plasma insulin, insulin signalling, serum FFA, endothelial function and several markers of oxidative stress were evaluated. Both compounds presented a significant anti-inflammatory effect. Moreover, the curcuminoid had a marked hypoglycaemic effect, accompanied by higher GLUT4 levels in adipose tissue. Both compounds increased NO-dependent vasorelaxation, but only the curcuminoid exacerbated the response to ascorbic acid, consistent with a higher decrease in vascular oxidative and nitrosative stress. SOD1 and GLO1 levels were increased in EAT and heart, respectively. Altogether, these data suggest that the curcuminoid developed here has more pronounced effects than curcumin in low doses, improving the oxidative stress, endothelial function and glycaemic profile in type 2 diabetes.

Effects of aerobic physical exercise on neuroplasticity after stroke: systematic review.

BACKGROUND: Stroke is among the leading causes of death and disability worldwide. Interventions for stroke rehabilitation aim to minimize sequelae, promote individuals' independence and potentially recover functional damage. The role of aerobic exercise as a facilitator of post-stroke neuroplasticity in humans is still questionable. OBJECTIVE: To investigate the impact of aerobic exercise on neuroplasticity in patients with stroke sequelae. METHODS: A systematic review of randomized clinical trials and crossover studies was performed, with searches for human studies in the following databases: PUBMED, EMBASE, LILACS and PeDRO, only in English, following the PRISMA protocol. The keywords used for selecting articles were defined based on the PICO strategy. RESULTS: This systematic review evaluated the impacts of aerobic exercise on neuroplasticity through assessment of neural networks and neuronal excitability, neurotrophic factors, or cognitive and functional assessment. Studies that evaluated the effects of aerobic exercise on neuroplasticity after stroke measured through functional resonance (fMRI) or cortical excitability have shown divergent results, but aerobic exercise potentially can modify the neural network, as measured through fMRI. Additionally, aerobic exercise combined with cognitive training improves certain cognitive domains linked to motor learning. Studies that involved analysis of neurotrophic factors to assess neuroplasticity had conflicting results. CONCLUSIONS: Physical exercise is a therapeutic intervention in rehabilitation programs that, beyond the known benefits relating to physical conditioning, functionality, mood and cardiovascular health, may also potentiate the neuroplasticity process. Neuroplasticity responses seem more robust in moderate to high-intensity exercise training programs, but dose-response heterogeneity and non-uniform neuroplasticity assessments limit generalizability.

Effects of aerobic physical exercise on neuroplasticity after stroke: systematic review / Efeitos do exercício físico aeróbico na neuroplasticidade após o acidente vascular cerebral: revisão sistemática de literatura

ABSTRACT Background: Stroke is among the leading causes of death and disability worldwide. Interventions for stroke rehabilitation aim to minimize sequelae, promote individuals' independence and potentially recover functional damage. The role of aerobic exercise as a facilitator of post-stroke neuroplasticity in humans is still questionable. Objective: To investigate the impact of aerobic exercise on neuroplasticity in patients with stroke sequelae. Methods: A systematic review of randomized clinical trials and crossover studies was performed, with searches for human studies in the following databases: PUBMED, EMBASE, LILACS and PeDRO, only in English, following the PRISMA protocol. The keywords used for selecting articles were defined based on the PICO strategy. Results: This systematic review evaluated the impacts of aerobic exercise on neuroplasticity through assessment of neural networks and neuronal excitability, neurotrophic factors, or cognitive and functional assessment. Studies that evaluated the effects of aerobic exercise on neuroplasticity after stroke measured through functional resonance (fMRI) or cortical excitability have shown divergent results, but aerobic exercise potentially can modify the neural network, as measured through fMRI. Additionally, aerobic exercise combined with cognitive training improves certain cognitive domains linked to motor learning. Studies that involved analysis of neurotrophic factors to assess neuroplasticity had conflicting results. Conclusions: Physical exercise is a therapeutic intervention in rehabilitation programs that, beyond the known benefits relating to physical conditioning, functionality, mood and cardiovascular health, may also potentiate the neuroplasticity process. Neuroplasticity responses seem more robust in moderate to high-intensity exercise training programs, but dose-response heterogeneity and non-uniform neuroplasticity assessments limit generalizability.

RESUMO Antecedentes: O acidente vascular cerebral (AVC) é a segunda causa principal de morte no mundo. Intervenções para reabilitação dos pacientes com AVC visam minimizar sequelas, promover sua independência e potencialmente recuperar danos funcionais. O papel do exercício aeróbico como facilitador da neuroplasticidade pós-AVC em humanos ainda é questionável. Objetivo: Investigar o impacto do exercício aeróbico na neuroplasticidade em pacientes com sequelas de AVC. Métodos: Foi realizada revisão sistemática de literatura, pesquisando nas seguintes bases de dados: PUBMED, EMBASE, LILACS e PeDRO. Foram selecionados trabalhos em língua inglesa, realizados apenas com humanos, seguindo o protocolo PRISMA. As palavras-chave utilizadas para a seleção de artigos foram definidas com base na estratégia PICO. Resultados: Esta revisão sistemática avaliou os impactos do exercício aeróbico na neuroplasticidade através da avaliação das redes neurais e da excitabilidade neuronal, por meio de fatores neurotróficos, por meio da avaliação cognitiva e funcional. Estudos que avaliaram os efeitos do exercício aeróbico sobre neuroplasticidade após o AVC medido através de ressonância funcional ou excitabilidade cortical, são controversos, mas há dados sugerindo uma modificação da rede neural na ressonância funcional após o exercício aeróbico. Há evidências de que, associar exercício aeróbico com treinamento cognitivo melhora certos domínios cognitivos ligados à aprendizagem motora. Estudos que envolveram a análise de fatores neurotróficos, como avaliação da neuroplasticidade, tiveram resultados conflitantes. Conclusões: Exercício aeróbico é uma intervenção terapêutica em programas de reabilitação, pois, além de proporcionar os benefícios no condicionamento físico, funcionalidade, humor e saúde cardiovascular, pode potencializar a neuroplasticidade.

Circulating Extracellular Vesicles: The Missing Link between Physical Exercise and Depression Management?

Depression is associated with an increased risk of aging-related diseases. It is also seemingly a common psychological reaction to pandemic outbreaks with forced quarantines and lockdowns. Thus, depression represents, now more than ever, a major global health burden with therapeutic management challenges. Clinical data highlights that physical exercise is gaining momentum as a non-pharmacological intervention in depressive disorders. Although it may contribute to the reduction of systemic inflammation associated with depression, the mechanisms underlying the beneficial physical exercise effects in emotional behavior remain to be elucidated. Current investigations indicate that a rapid release of extracellular vesicles into the circulation might be the signaling mediators of systemic adaptations to physical exercise. These biological entities are now well-established intercellular communicators, playing a major role in relevant physiological and pathophysiological functions, including brain cell-cell communication. We also reviewed emerging evidence correlating depression with modified circulating extracellular vesicle surfaces and cargo signatures (e.g., microRNAs and proteins), envisioned as potential biomarkers for diagnosis, efficient disease stratification and appropriate therapeutic management. Accordingly, the clinical data summarized in the present review prompted us to hypothesize that physical exercise-related circulating extracellular vesicles contribute to its antidepressant effects, particularly through the modulation of inflammation. This review sheds light on the triad "physical exercise-extracellular vesicles-depression" and suggests new avenues in this novel emerging field.

Improvement in circulating endothelial progenitor cells pool after cardiac resynchronization therapy: increasing the list of benefits.

BACKGROUND: Recent studies suggest that circulating endothelial progenitor cells (EPCs) may influence the response to cardiac resynchronization therapy (CRT). The aim of this study was to evaluate the effect of CRT on EPC levels and to assess the impact of EPCs on long-term clinical outcomes. POPULATION AND METHODS: Prospective study of 50 patients submitted to CRT. Two populations of circulating EPCs were quantified previously to CRT implantation: CD34+KDR+ and CD133+KDR+ cells. EPC levels were reassessed 6 months after CRT. Endpoints during the long-term follow-up were all-cause mortality, heart transplantation, and hospitalization for heart failure (HF) management. RESULTS: The proportion of non-responders to CRT was 42% and tended to be higher in patients with an ischemic vs non-ischemic etiology (64% vs 35%, p = 0.098). Patients with ischemic cardiomyopathy (ICM) showed significantly lower CD34+KDR+ EPC levels when compared to non-ischemic dilated cardiomyopathy patients (DCM) (0.0010 ± 0.0007 vs 0.0030 ± 0.0024 cells/100 leukocytes, p = 0.032). There were no significant differences in baseline EPC levels between survivors and non-survivors nor between patients who were rehospitalized for HF management during follow-up or not. At 6-month follow-up, circulating EPC levels were significantly higher than baseline levels (0.0024 ± 0.0023 vs 0.0047 ± 0.0041 CD34+KDR+ cells/100 leukocytes, p = 0.010 and 0.0007 ± 0.0004 vs 0.0016 vs 0.0013 CD133+/KDR+ cells/100 leukocytes, p = 0.007). CONCLUSIONS: Patients with ICM showed significantly lower levels of circulating EPCs when compared to their counterparts. CRT seems to improve the pool of endogenously circulating EPCs and reduced baseline EPC levels seem not to influence long-term outcomes after CRT.

Intrinsic Vascular Repair by Endothelial Progenitor Cells in Acute Coronary Syndromes: an Update Overview.

Bone marrow-derived endothelial progenitor cells (EPCs) play a key role in the maintenance of endothelial homeostasis and endothelial repair at areas of vascular damage. The quantification of EPCs in peripheral blood by flow cytometry is a strategy to assess this reparative capacity. The number of circulating EPCs is inversely correlated with the number of cardiovascular risk factors and to the occurrence of cardiovascular events. Therefore, monitoring EPCs levels may provide an accurate assessment of susceptibility to cardiovascular injury, greatly improving risk stratification of patients with high cardiovascular risk, such as those with an acute myocardial infarction. However, there are many issues in the field of EPC identification and quantification that remain unsolved. In fact, there have been conflicting protocols used to the phenotypic identification of EPCs and there is still no consensual immunophenotypical profile that corresponds exactly to EPCs. In this paper we aim to give an overview on EPCs-mediated vascular repair with special focus on acute coronary syndromes and to discuss the different phenotypic profiles that have been used to identify and quantify circulating EPCs in several clinical studies. Finally, we will synthesize evidence on the prognostic role of EPCs in patients with high cardiovascular risk.

In July 2019 the Portuguese Society of Myology was officially born: the first message from the founders.

The amazing behaviour and adaptation capacity of the skeletal muscle system call the attention of several scientists, including us. Thus, we have the pleasure to announce that it was born in the city of Coimbra, Portugal, the Portuguese Society of Myology (SPMyo), a society which the main aim is to spread skeletal muscle knowledge in the areas of muscle physiology, physiopathology and pharmacology in a multidisciplinary organization that reflects the different areas of the skeletal muscle study. The commitment of SPMyo is the progress of skeletal muscle awareness as well as its investigation, encouraging interdisciplinary, national and international collaboration. These goals will be achieved by organization of scientific meetings, formation courses, publications of books and other scientific and didactic materials. It is also a goal of the SPMyo to organize public events allowing general public to understand skeletal muscle system.

Aging Hallmarks: The Benefits of Physical Exercise.

World population has been continuously increasing and progressively aging. Aging is characterized by a complex and intraindividual process associated with nine major cellular and molecular hallmarks, namely, genomic instability, telomere attrition, epigenetic alterations, a loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. This review exposes the positive antiaging impact of physical exercise at the cellular level, highlighting its specific role in attenuating the aging effects of each hallmark. Exercise should be seen as a polypill, which improves the health-related quality of life and functional capabilities while mitigating physiological changes and comorbidities associated with aging. To achieve a framework of effective physical exercise interventions on aging, further research on its benefits and the most effective strategies is encouraged.

Impact of prior chronic statin therapy and high-intensity statin therapy at discharge on circulating endothelial progenitor cell levels in patients with acute myocardial infarction: a prospective observational study.

BACKGROUND: Endothelial progenitor stem cells (EPCs) are mobilized to the peripheral circulation in response to myocardial ischemia, playing a crucial role in vascular repair. Statins have been shown to stimulate EPCs. However, neither the impact of previous statin therapy on EPC response of acute myocardial infarction (AMI) patients nor the effect of post-AMI high-intensity statin therapy on the evolution of circulating EPC levels has yet been addressed. Therefore, we aimed to compare circulating EPC levels between patients receiving long-term statin therapy before the AMI and statin-naive patients and to assess the impact of high-intensity statin therapy at discharge on the evolution of circulating EPCs post-AMI. METHODS: This is a prospective observational study of 100 AMI patients. Circulating EPCs (CD45dimCD34 + KDR + cells) and their subpopulation coexpressing the homing marker CXCR4 were quantified by the high-performance flow cytometer FACSCanto II in whole blood, in two different moments: within the first 24 h of admission and 3 months post-AMI. Patients were followed up clinically for 2 years. RESULTS: Patients previously treated with statins had significantly higher levels of EPCs coexpressing CXCR4 (1.9 ± 1.4 vs. 1.3 ± 1.0 cells/1,000,000 events, p = 0.031) than statin-naive patients. In addition, the subanalysis of diabetics (N = 38) also revealed that patients previously on statins had significantly greater numbers of both CD45dimCD34 + KDR + CXCR4+ cells (p = 0.024) and CD45dimCD34 + KDR + CD133+ cells (p = 0.022) than statin-naive patients. Regarding the evolution of EPC levels after the AMI, patients not on a high-intensity statin therapy at discharge had a significant reduction of CD45dimCD34 + KDR + and CD45dimCD34 + KDR + CXCR4+ cells from baseline to 3 months follow-up (p = 0.031 and p = 0.005, respectively). However, patients discharged on a high-intensity statin therapy maintained circulating levels of all EPC populations, presenting at 3 months of follow-up significantly higher EPC levels than patients not on an intensive statin therapy. Moreover, the high-intensity statin treatment group had significantly better clinical outcomes during the 2-year follow-up period than patients not discharged on a high-intensity statin therapy. CONCLUSION: Chronic statin therapy prior to an AMI strongly enhances the response of EPCs to myocardial ischemia, even in diabetic patients. Furthermore, high-intensity statin therapy after an AMI prevents the expected decrease of circulating EPC levels during follow-up. These results reinforce the importance of an early and intensive statin therapy in AMI patients.

Reduced levels of circulating endothelial progenitor cells in acute myocardial infarction patients with diabetes or pre-diabetes: accompanying the glycemic continuum.

BACKGROUND: Diabetic patients have a significantly worse prognosis after an acute myocardial infarction (AMI) than their counterparts. Previous studies have shown that the number of circulating endothelial progenitor cells (EPCs) significantly increase early after an AMI in normoglycemic patients. However, it is well known that type 2 diabetes mellitus (DM) is associated with impaired function and reduced circulating EPCs levels. Nonetheless, few studies have analyzed EPCs response of diabetics to an AMI and the EPC response of pre-diabetic patients has not been reported yet. Therefore, we hypothesized that in the acute phase of an AMI, diabetic and pre-diabetics have lower circulating EPCs levels than patients with normal glucose metabolism. We also evaluated the possible capacity of chronic antidiabetic treatment in the recovery of EPCs response to an AMI in diabetics. METHODS: One-hundred AMI patients were prospectively enrolled in the study. Using the high-performance flow cytometer FACSCanto II, circulating EPCs (CD45dimCD34+KDR+ and CD45dimCD133+KDR+ cells) were quantified, within the first 24 hours of admission. In addition, as an indirect functional parameter, we also analyzed the fraction of EPCs coexpressing the homing marker CXCR4. RESULTS: We found that in the acute phase of an AMI, diabetic patients presented significantly lower levels of circulating CD45dimCD34+KDR+ and CD45dimCD133+KDR+ EPCs by comparison with nondiabetics, with a parallel decrease in the subpopulations CXCR4+ (p < 0.001). Indeed, this study suggests that the impaired response of EPCs to an AMI is an early event in the natural history of DM, being present even in pre-diabetes. Our results, also demonstrated that numbers of all EPCs populations were inversely correlated with HbA1c (r = -0.432, p < 0.001 for CD45dimCD34+KDR+ cells). Finally, this study suggests that previous chronic insulin therapy (but not oral antidiabetic drugs) attenuate the deficient response of diabetic EPCs to an AMI. CONCLUSION: This study indicates that there is a progressive decrease in EPCs levels, from pre-diabetes to DM, in AMI patients. Moreover, glycemic control seems to be determinant for circulating EPCs levels presented in the acute phase of an AMI and chronic insulin therapy may probably attenuate the deficit in EPCs pool seen in diabetics.

Circulating endothelial progenitor cells as a predictor of response to cardiac resynchronization therapy: the missing piece of the puzzle?

BACKGROUND: It would be important to better identify heart failure (HF) patients most likely to respond to cardiac resynchronization therapy (CRT). Because endothelial progenitor cells (EPCs) play a crucial role in the maintenance of vascular endothelium integrity, we hypothesize that patients who have higher circulating EPCs levels have greater neovascularization potential and are more prone to be responders to CRT. METHODS: Prospective study of 30 consecutive patients, scheduled for CRT. Echocardiographic evaluation was performed before implant and 6 months after. Responders to CRT were defined as patients who were still alive, have not been hospitalized for HF management, and demonstrated ≥15% reduction in left ventricular end-systolic volume (LVESV) at the 6-month follow-up. EPCs were quantified before CRT, from peripheral blood, by flow cytometry using five different conjugated antibodies: anti-CD34, anti-KDR, anti-CD133, anti-CD45, and anti-CXCR4. We quantified five different populations of angiogenic cells: CD133(+) /CD34(+) cells, CD133(+) /KDR(+) cells, CD133(+) /CD34(+) /KDR(+) cells, CD45(dim) CD34(+) /KDR(+) cells, and CD45(dim) CD34(+) /KDR(+) /CXCR4(+) cells. RESULTS: The proportion of responders to CRT at the 6-month follow-up was 46.7%. Responders to CRT presented higher baseline EPCs levels than nonresponders (0.0003 ± 0.0006% vs 0.0001 ± 0.0002%, P = 0.04, for CD34(+) /CD133(+) /KDR(+) and 0.0006 ± 0.0005% vs 0.0003 ± 0.0003%, P = 0.009, for CD45(dim) CD34(+) /KDR(+) /CXCR4(+) cells). In addition, baseline levels of CD45(dim) CD34(+) /KDR(+) /CXCR4(+) cells were positively correlated with the reduction of LVESV verified 6 months after CRT (r = 0.497, P = 0.008). CONCLUSIONS: High circulating EPCs levels may identify the subset of HF patients who are more likely to undergo reverse remodeling and benefit from CRT. Addition of EPCs levels assessment to current selection criteria may improve the ability to predict CRT response.

Challenges in vascular repair by endothelial progenitor cells in diabetic patients.

Endothelial progenitor cells (EPCs) are a special type of stem cells, derived from bone marrow that can be mobilized to the peripheral circulation in response to many stimuli. EPCs play a crucial role in the vascular repair, as well as in neovascularization processes. Recent studies have shown that EPCs are impaired, both in number and function, in diabetic patients independently of other cardiovascular risk factors. Accelerated atherosclerosis is probably the most devastating among diabetes complications and endothelial dysfunction might be the beginning of the atherosclerosis. The impairment of EPCs seems to significantly contribute to atherogenesis and atherosclerotic disease progression in diabetes. Autologous EPCs therapy represents a novel treatment option for vascular complications requiring therapeutic revascularization and vascular repair. Diabetic patients represent a population that may benefit from cell-based therapy; however the dysfunction of their endogenous cells may limit the feasibility of this approach. In fact, EPCs isolated from these patients for autologous cell transplantation may retain their dysfunctional characteristics in vivo and as a consequence display a reduced capacity to improve therapeutic neovascularization. In the present review, we summarize the most relevant mechanisms of EPC dysfunction in diabetes.

Stimulation of endothelial progenitor cells: a new putative effect of several cardiovascular drugs.

The role of vascular endothelium in cardiovascular disorders is well recognized. Mature endothelial cells contribute to the repair of endothelial injury, but they only have a limited capacity to do so. This has led to growing interest and further investigation into circulating endothelial progenitor cells (EPCs) and their role in vascular healing, repair, and postnatal neovascularization. The current perception of vascular health is that of a balance between ongoing injury and resultant vascular repair, mediated at least in part by circulating EPCs. Circulating EPCs play an important role in accelerating endothelialization at areas of vascular damage, and EPC enumeration is a viable strategy for assessing reparative capacity. Recent studies have shown that EPCs are affected both in number and function by several cardiovascular risk factors as well as various cardiovascular disease states, such as hypertension, hypercholesterolemia, and coronary artery disease. The present review summarizes the most relevant studies on the effects of cardiovascular drugs on vascular function and EPCs, focusing on their mechanisms of action.

Methamphetamine-induced early increase of IL-6 and TNF-alpha mRNA expression in the mouse brain.

The mechanisms by which methamphetamine (METH) causes neurotoxicity are not well understood. Recent studies have suggested that METH-induced neuropathology may result from a multicellular response in which glial cells play a prominent role, and so it is plausible to suggest that cytokines may participate in the toxic effects of METH. Therefore, in the present work we evaluated the effect of an acute administration of METH (30 mg/kg in a single intraperitoneal injection) on the interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha mRNA expression levels in the hippocampus, frontal cortex, and striatum of mice. We observed that METH did not induce changes in the IL-1beta mRNA expression levels in both hippocampus and striatum, with immeasurable levels in the frontal cortex. Regarding IL-6, METH induced an increase in the expression levels of this cytokine in the hippocampus and striatum, 1 h and 30 min post injection, respectively. In the frontal cortex, the increase in IL-6 mRNA levels was more significant and remained high even after 2 h. Moreover, the expression levels of TNF-alpha were increased in both hippocampus and frontal cortex 30 min post METH administration, with immeasurable levels in the striatum. We conclude that the pro-inflammatory cytokines IL-6 and TNF-alpha rapidly increase after METH administration, providing a new insight for understanding the effect of this drug of abuse in the brain.

Single or multiple injections of methamphetamine increased dopamine turnover but did not decrease tyrosine hydroxylase levels or cleave caspase-3 in caudate-putamen.

Methamphetamine (METH), leading to striatal dopamine (DA) nerve terminal toxicity in mammals, is also thought to induce apoptosis of striatal neurons in rodents. We investigated the acute effects induced by multiple injections of METH (4 x 5 mg/kg, i.p.) at 2-h intervals or a single injection of METH (20 mg/kg, i.p.) on terminal dopaminergic toxicity markers, including DA levels, DA turnover, and tyrosine hydroxylase (TH) immunoreactivity in rat caudate-putamen (CPu). We further investigated whether both treatment paradigms would change Bax and activate caspase-3 expression, thus triggering striatal apoptotic mitochondria-dependent biochemical cascades. The first injection of METH (5 mg/kg, i.p.) produced a significant release of DA that peaked 30 min and stayed above control levels up to 1.5 h within CPu. In another set of experiments, rats were killed 1 and 24 h following the last injection, for tissue DA and metabolite content measurement and Western blot analysis (24 h). Multiple doses induced DA depletion and increased turnover at both endpoints. Single-dose METH reproduced these effects at 24 h; however, turnover was significantly higher than that evoked by the multiple doses at 24 h. Although both paradigms evoked similar DA depletion, however, none of the dosing regimens induced changes in TH expression at 24 h. The former paradigm produced an increase in Bax expression in CPu not sufficient to induce cleavage of caspase-3 proenzyme at 24 h. This study suggests that both paradigm induced changes in striatal dopaminergic markers that are independent of terminal degeneration and striatal apoptotic mitochondria-dependent caspase-3 driven cascade within 24 h.

Causality assessment of adverse drug reactions: comparison of the results obtained from published decisional algorithms and from the evaluations of an expert panel.

PURPOSE: To compare the results of causality assessments of reported adverse drug reactions (ADR's) obtained from decisional algorithms with those obtained from an expert panel using the WHO global introspection method (GI) and to further evaluate the influence of confounding variables on algorithms ability in assessing causality. METHOD: Two hundred sequentially reported ADR's were included in this study. An independent researcher used algorithms, while an expert panel assessed the same reports using the GI, both aimed at evaluating causality. Reports were divided into three groups according to the presence, absence or lack of information on confounding variables. RESULTS: For the total sample, observed agreements between decisional algorithms compared with GI varied from 21% to 56%, average of 47%. When confounding variables were taken into account, agreements varied between 41% and 69%, average of 58%; 8% and 65%, average of 46% and 15% and 53%, average of 42% accordingly to the absence, lack of information or presence of confounding variables, respectively. The extend of reproducibility beyond chance was low for the total sample (average Kappa = 0.26) and within the groups considered. CONCLUSION: The overall observed agreement between algorithm and GI was moderate although poorly different from chance, confounding variables being a shortcoming of algorithms ability in assessing causality.

Nitric oxide production and nitric oxide synthase expression in platelets from heroin abusers before and after ultrarapid detoxification.

Prolonged heroin abuse has been associated with neurotoxicity. Thus, the involvement of nitric oxide (NO) in heroin-induced dopaminergic neurotoxicity could be a reasonable explanation for heroin-induced changes in brain. Enzymatically derived NO has been implicated in numerous physiological and pathological processes in the brain. Whereas during development NO participates in growing and maturation processes, excess NO production in the adult in response to inflammation, injury, or trauma, participates in both cell death and repair. The expression and activity of the inducible isoform of NO synthase (iNOS) play a pivotal role in sustained and elevated NO release. Recent evidence suggests that neurons can respond to proinflammatory stimuli and take part in brain inflammation. The effect of heroin abuse on platelet NO production and on expression of iNOS in drug addicts submitted to an ultrarapid detoxification was studied. The NO production was estimated from the nitrite concentration, and nitric oxide synthase was determined by Western blotting analysis. Results showed no difference in nitrite content of resting platelets between heroin abuser and control groups. However, after platelet stimulation, heroin abusers showed significantly lower nitrite values. The Western blotting analysis reinforced these results. After ultrarapid detoxification, platelet nitrite production in heroin abusers showed no differences compared to control subjects. Our results suggest that heroin consumption decreases the iNOS synthase expression and platelet NO production. Detoxification treatment restores these changes.