Research Protocol for an Observational Health Data Analysis on the Adverse Events of Systemic Treatment in Patients with Metastatic Hormone-sensitive Prostate Cancer: Big Data Analytics Using the PIONEER Platform.

Combination therapies in metastatic hormone-sensitive prostate cancer (mHSPC), which include the addition of an androgen receptor signaling inhibitor and/or docetaxel to androgen deprivation therapy, have been a game changer in the management of this disease stage. However, these therapies come with their fair share of toxicities and side effects. The goal of this observational study is to report drug-related adverse events (AEs), which are correlated with systemic combination therapies for mHSPC. Determining the optimal treatment option requires large cohorts to estimate the tolerability and AEs of these combination therapies in "real-life" patients with mHSPC, as provided in this study. We use a network of databases that includes population-based registries, electronic health records, and insurance claims, containing the overall target population and subgroups of patients defined by unique certain characteristics, demographics, and comorbidities, to compute the incidence of common AEs associated with systemic therapies in the setting of mHSPC. These data sources are standardised using the Observational Medical Outcomes Partnership Common Data Model. We perform the descriptive statistics as well as calculate the AE incidence rate separately for each treatment group, stratified by age groups and index year. The time until the first event is estimated using the Kaplan-Meier method within each age group. In the case of episodic events, the anticipated mean cumulative counts of events are calculated. Our study will allow clinicians to tailor optimal therapies for mHSPC patients, and they will serve as a basis for comparative method studies.

Obesity, diabetes and risk of bone fragility: How BMAT behavior is affected by metabolic disturbances and its influence on bone health.

PURPOSE: Osteoporosis is a metabolic bone disease characterized by decreased bone strength and mass, which predisposes patients to fractures and is associated with high morbidity and mortality. Like osteoporosis, obesity and diabetes are systemic metabolic diseases associated with modifiable risk factors and lifestyle, and their prevalence is increasing. They are related to decreased quality of life, functional loss and increased mortality, generating high costs for health systems and representing a worldwide public health problem. Growing evidence reinforces the role of bone marrow adipose tissue (BMAT) as an influential factor in the bone microenvironment and systemic metabolism. Given the impact of obesity and diabetes on metabolism and their possible effect on the bone microenvironment, changes in BMAT behavior may explain the risk of developing osteoporosis in the presence of these comorbidities. METHODS: This study reviewed the scientific literature on the behavior of BMAT in pathological metabolic conditions, such as obesity and diabetes, and its potential involvement in the pathogenesis of bone fragility. RESULTS: Published data strongly suggest a relationship between increased BMAT adiposity and the risk of bone fragility in the context of obesity and diabetes. CONCLUSION: By secreting a broad range of factors, BMAT modulates the bone microenvironment and metabolism, ultimately affecting skeletal health. A better understanding of the relationship between BMAT expansion and metabolic disturbances observed in diabetic and obese patients will help to identify regulatory pathways and new targets for the treatment of bone-related diseases, with BMAT as a potential therapeutic target.

High rate of de novo esophagitis 5 years after sleeve gastrectomy: a prospective multicenter study in Spain.

BACKGROUND: Major concerns years after the sleeve gastrectomy (SG) include weight regain, development of hiatal hernia (HH) and gastroesophageal reflux disease, with esophagitis and Barrett's esophagus (BE). Both problems could be related, and the incidence of asymptomatic patients is troubling. OBJECTIVE: To study the incidence of reflux symptoms, esophagitis, BE, HH, and asymptomatic pathology and their relationship with weight regain in patients 5 years after undergoing SG at different bariatric centers in Spain. SETTING: Public and private hospitals with bariatric surgery units. METHODS: Prospective, multicenter, nonrandomized study involving 13 Spanish hospitals with a cumulative experience of 4,500 patients having undergone the SG procedure and patients who had been subjected to the procedure at least 5 years previously along with preoperative gastroscopy. The clinical history, preoperative gastroscopy, and technical details of the SG were recorded. A specific clinical questionnaire was given that recorded the intake volume, perception of satiety, and gastroesophageal reflux (GER) symptoms. Gastroscopy, pH-metry, and manometry studies were carried out, and the data were analyzed statistically. The study has been authorized by the official Spanish ethics committee CEI/CEIm Hospital Universitario Gran Canaria Dr Negrín (code 2019-216-1). RESULTS: One hundred and five patients who underwent SG and who had with at least 5 years of follow-up were included. All procedures were performed laparoscopically. The mean age of patients was 51.1 years, and 70.5% were women. The mean characteristics of the SG procedure were a 37.2F probe, at 4.6 cm from the pylorus, and a crura closure was performed in 5 cases. There were no major complications (Clavien-Dindo grade >3) or deaths. The average preoperative body mass index was 46.3 kg/m2, the minimum reached was 20.6 kg/m2, whereas the average after 5 years was of 34.5 kg/m2. GER, HH, and esophagitis symptoms went from 17.1%, 28.6%, and 5.7%, respectively, before the SG to 76%, 30.5%, and 31.4%, respectively, 5 years after the procedure. Symptoms persisted over the years in 37.1% of cases and presented de novo in 52.8% of cases. Fifty-three percent of manometries (n = 27, total 51) and 64% of pH-metries (n = 32, total 53; DeMeester average score was 65) were pathologic 5 years after the procedure. Concerning gastroscopies, 5 years after the procedure, HH was found in 33 patients (30.5% of total) and esophagitis in 32 patients (31.4% of total). Eighty patients (76%) had GER symptoms, and 25 patients (24%) were asymptomatic. Only 1 patient (.9%) developed BE. CONCLUSIONS: Our study has confirmed a high rate of both persistent and de novo esophagitis and hiatal hernia, many of which were asymptomatic, 5 years after SG had been performed. Weight regain and a striking increase in gastric capacity are risk factors indicative of esophagitis, even when patients are asymptomatic. We consider a control gastroscopy and the preventive use of proton pump inhibitors necessary in these cases regardless of symptoms. We recommend that a control gastroscopy should be performed in all cases regardless of symptoms 5 years after SG. Further studies are needed to validate these recommendations.

Helminth infection alters mood and short-term memory as well as levels of neurotransmitters and cytokines in the mouse hippocampus.

UNLABELLED: Helminthic infections are important causes of morbidity and mortality in many developing countries, where children bear the greatest health burden. The ability of parasites to cause behavioral changes in the host has been observed in a variety of host-parasite systems, including the Taenia crassiceps-mouse model. In murine cysticercosis, mice exhibit a disruption in the sexual, aggressive and avoidance predator behaviors. OBJECTIVE: The present study was conducted to characterize short-term memory and depression-like behavior, as well as levels of neurotransmitters and cytokines in the hippocampus of cysticercotic male and female mice. METHODS: Cytokines were detected by RT-PCR and neurotransmitters were quantified by HPLC. RESULTS: Chronic cysticercosis infection induced a decrease in short-term memory in both male and female mice, having a more pronounced effect in females. Infected females showed a significant increase in forced swimming tests with a decrease in immobility. In contrast, male mice showed an increment in total activity and ambulation tests. Serotonin levels decreased by 30% in the hippocampus of infected females whereas noradrenaline levels significantly increased in infected males. The hippocampal expression of IL-4 increased in infected female mice, but decreased in infected male mice. CONCLUSION: Our study suggests that intraperitoneal chronic infection with cysticerci in mice leads to persistent deficits in tasks dependent on the animal's hippocampal function. Our findings are a first approach to elucidating the role of the neuroimmune network in controlling short-term memory and mood in T. crassiceps-infected mice.

La melatonina como un factor promotor de la diferenciación neuronal: implicaciones en el tratamiento de las demencias / Melatonin as a neuronal differentiation factor: therapeutic implications for dementia

Dementias are progressive and neurodegenerative neuropsychiatry disorders, with a high worldwide prevalence. These disorders affect memory and behavior, causing impairment in the performance of daily activities and general disability in the elders. Cognitive impairment in these patients is related to anatomical and structural alterations at cellular and sub-cellular levels in the Central Nervous System. In particular, amyloid plaques and neurofibrillar tangles have been defined as histopathological hallmarks of Alzheimer's disease. Likewise, oxidative stress and neuroinflammation are implicated in the etiology and progression of the disease. Neuronal precursors from human olfactory neuroepithelium have been recently characterized as an experimental model to identify neuropsychiatric disease biomarkers. Moreover, this model not only allows the study of neuropsychiatric physiopathology, but also the process of neurodevelopment at cellular, molecular and pharmacological levels. This review gathers the evidence to support the potential therapeutic use of melatonin for dementias, based on its antioxidant properties, its anti-inflammatory effect in the brain, and its ability to inhibit both tau hyper-phosphorylation and amyloid plaque formation. Furthermore, since melatonin stimulates neurogenesis, and promotes neuronal differentiation by inducing the early stages of neuritogenesis and dendrite formation, it has been suggested that melatonin could be useful to counteract the cognitive impairment in dementia patients.

Las demencias son enfermedades neuropsiquiátricas, progresivas, neurodegenerativas y con una alta prevalencia a nivel mundial. Ocupan uno de los primeros lugares como enfermedades que causan incapacidad en los adultos mayores. En estos pacientes el Sistema Nervioso Central presenta alteraciones anatómico-estructurales a nivel celular y subcelular que se asocian con deficiencias cognitivas. En particular, en la enfermedad de Alzheimer se han caracterizado marcadores histopatológicos como las placas amiloides y las marañas neurofibrilares. Se sabe que el estrés oxidativo y la neuroinflamación participan en la etiología y el desarrollo de la enfermedad. Recientemente se caracterizó a los precursores neuronales del neuroepitelio olfatorio humano como un modelo experimental adecuado para identificar biomarcadores de rasgo y para estudiar la fisiopatología de diversas enfermedades neuropsiquiátricas, así como el proceso del neurodesarrollo, a nivel celular, molecular y farmacológico. En este trabajo se presenta la evidencia que sustenta que la melatonina puede ser útil en el tratamiento de las demencias, por su capacidad antioxidante, por su efecto anti-inflamatorio, así como por el efecto inhibidor de la hiperfosforilación de la proteina tau y de la formación de placas amiloides. Además, al estimular la formación de nuevas neuronas, la neuritogénesis en sus etapas tempranas y la formación de dendritas, la melatonina podría contribuir a contrarrestar la pérdida de las funciones cognitivas que se observa en estos padecimientos.

Uso de marcadores bioquímicos para valoración de riesgo de crisis convulsivas en el síndrome de supresión etílica / Biochemical markers for risk assessment of seizures in withdrawal syndrome

Withdrawal signs and symptoms are frequently minor but can develop into a severe, even fatal, condition. Clinical manifestations of the AWS begin as soon as the alcohol consumption is interrupted or diminished after a long period of ingestion of great quantities of alcohol. The clinical manifestations include symptoms of autonomic hyperactivity, like sweating, tachycardia over 100 bpm, tremor, insomnia, nausea or vomiting, transitive visual, tactile, or hearing hallucinations, or even illusions, psychomotor agitation, anxiety and epileptic crisis. Objective Our aim is to assess the usefulness of several biochemical markers and the risk of seizures associated with alcohol withdrawal. Methods This study included 52 inpatients which were assessed with the Ciwa-Ar scale in order to determine the severity of the withdrawal. They were assessed too with the AUDIT scale to determine the risk and abuse of the intake of alcohol. We also obtained a blood sample to determine the levels of several biomarkers (AST, ALT, GGT, FA, HOM-OCISTEINE, and MCV). We compared the two groups (patients with seizures vs. patients without seizures). Student T and Mann Whitney's U tests, and ROC curves were applied. Results We observed a statistical difference between the groups in the levels of alkaline phosphatase. The levels were higher in patients without seizures (148.8±69.58UI) compared with the patients with seizures (113±55.1UI). No differences were observed in other groups. Conclusion The patients with higher levels of alkaline phosphatase had major risk of seizures. There were no elevations in the serum level of homocisteine in both groups.

El síndrome de supresión etílica (SSE) incluye tanto una variedad de signos y síntomas orgánicos y cambios conductuales como modificaciones en la actividad electrofisiológica del Sistema Nervioso Central. No existen estudios clínicos que evalúen el uso de biomarcadores en pacientes con comorbilidades agudas, convulsiones ni delirium tremens, así que su utilidad en estos casos no ha sido valorada. Objetivo Nuestro objetivo es el de valorar el uso de diversos marcadores bioquímicos para determinar el riesgo de convulsiones en el síndrome de supresión etílica. Material y métodos Este estudio incluyó a 52 pacientes, evaluados a su ingreso con la escala Ciwa-Ar para determinar la gravedad de la supresión y la escala AUDIT para detectar riesgo y abuso en el consumo de alcohol. También se tomó una muestra sanguínea para determinar los niveles séricos de los biomarcadores (AST, ALT, GGT, FA, HOMOCISTEINA, VCM). La muestra se dividió en dos grupos (pacientes que convulsionaron vs. pacientes que no convulsionaron). Se utilizó la t de Student y U de Mann Whitney, así como curvas COR para determinar la sensibilidad y especificidad de los biomarcadores, así como la correlación de Pearson. Resultados La única diferencia significativa entre ambos grupos estuvo dada por la fosfatasa alcalina, cuyos niveles fueron más altos en los pacientes que no presentaron crisis convulsiva (148.8±69.58UI) que en aquellos que las presentaron (113±55.1UI). No se encontraron diferencias estadísticamente significativas para el resto de los biomarcadores. Conclusiones Los niveles bajos de fosfatasa alcalina traducen un riesgo mayor de presentar crisis convulsivas. No hubo elevación de los niveles de homocisteína en ninguno de los grupos.

Immune variations in bipolar disorder: phasic differences.

OBJECTIVES: To characterize the immunological variations of patients with a bipolar disorder (BD) diagnosis in manic (BDm) and depressive (BDd) phases, by the quantification of the serum levels of interleukin (IL)-1beta, -2, -4, -6 and tumor necrosis factor alpha (TNF-alpha). METHODS: Twenty physically healthy patients with a BD type I diagnosis and 33 matched controls were studied, after giving informed consent. The inclusion criteria included at least three weeks without any kind of psychopharmacological treatment, Young Mania Rating Scale score > or =20 for BDm (n = 10) and Hamilton Depression Rating Scale score > or =21 for BDd patients (n = 10). Exclusion criteria included any infectious diseases, allergies or any other kind of medical illness that required treatment with immunosuppressors, as well as any other diagnosis in Axis I. Physical and laboratory examinations were performed to rule out any clinical illness. Enzyme-linked immunosorbent assay (ELISA) was used to analyze the serum cytokines concentration. RESULTS: BD patients, when compared to controls, showed significant differences (p < or = 0.05) in the serum levels of the measured cytokines. The sub-group of BDd patients showed an increase in IL-6 and TNF-alpha, as well as a decrease in IL-2 concentration. The BDm sub-group, on the other hand, showed an increase in TNF-alpha and IL-4 values, with a low concentration of IL-1 and IL-2. The comparison between both sub-groups suggests that there is a distinctive cytokine pattern for the specific phases of the disorder: for mania, we found a high IL-4 and low IL-1beta and IL-6 concentration, while in the depressive phase, the inverse pattern was found. CONCLUSIONS: Our results show the existence of phasic differences in the serum levels of cytokines in BD.

Field accumulative behavior of organochlorine pesticides. The role of crabs and sediment characteristics in coastal environments.

The influence of intertidal crab beds on the concentrations of organochlorine (OC) pesticides in sediment was studied in two different coastal environments in Argentina. Samples of male burrowing crabs (Chasmagnathus granulatus) were collected for this study. Our field data showed lower bioaccumulation of OC pesticides in crabs from sediments with a higher total organic carbon (TOC) and higher clay content. Thus, concentrations in crabs depend on the physico-chemical characteristics of the sediment where they live more than on the OC pesticide concentrations in the environment. The distribution patterns in sediment from inside and outside crab burrows were similar for both coastal areas being HCHs > or = gamma-chlordane > p,p'-DDE for San Antonio Bay (SAO), and HCHs > p,p'-DDE > or = gamma-chlordane for Mar Chiquita (MCh) coastal lagoon. OC pesticide concentrations in sediment were significantly lower inside than outside crab burrows, irrespective of the sediment physico-chemical characteristics due to the bioturbation activity of C. granulatus.

Tryptophan and serotonin in blood and platelets of depressed patients: Effect of an antidepressant treatment

Abstract: Platelets llave serotonin (5-HT) uptake and storage mechanisms similar to those from neurons. In addition, they represent nearly 99% of blood 5-HT concentration. For these characteristics, platelets are considered useful biomarkers of the serotonergic synaptic neurotransmission, particularly in psychiatric disturbances such as depression. However, most studies which have evaluated platelet 5-HT concentrations in depression have not shown similar findings. It has been suggested that changes in plasma tryptophan (TRP) concentrations might modify 5-HT concentration in the brain, as well as in platelets. Likewise, decreased plasma concentrations of TRP have been found in depressed patients, and the selective 5-HT reuptake inhibitors (SSRIs) induce changes in platelet 5-HT concentration. Considering the controversy surrounding platelet 5-HT concentrations in depressed patients, and the fact that blood 5-HT and TRP have not been studied in the Mexican population, we decided to study 5-HT and tryptophan concentrations in blood and platelets from depressed and control Mexican subjects to evaluate a possible correlation with the severity of depression. The effect of fluoxetine and citalopram treatment on blood and platelet 5-HT and TRP concentrations in depressed patients was also studied. Material and methods Depressed patients The patients of this study were carefully selected and evaluated. Scales based on semi-structured interviews were applied (MINI and SCID-II) by clinical investigators to reduce any possible bias in patient selection. The influence of the seasonal variability on the 5-HT or TRP blood concentrations was controlled by pairing depressed patients and healthy subjects according to age, gender and, in the case of women, menstrual cycle phase. Patients with a complete remission of depression symptoms (defined as a score not higher than 5 points in the Hamilton's scale, and lower than 7 points in Beck's scale) were asked for a blood sample to measure platelet and blood concentrations of 5-HT and TRP. The patients were weighted before the treatment and after their improvement. Control subjects The control group was integrated by 30 healthy subjects, 24 women and 6 men, with an average age of 32.3 ± 10.8 years. Participants were recruited from the overall Mexican population, interviewed by a psychiatrist, and evaluated with the structured interview MINI and the SCID-II, all these to discard any psychiatric diagnose. None of them had received any pharmacological treatment during the three weeks prior to the study. Control and depressed women were paired according to their menstrual cycle phase. All participants received a detailed explanation of the study, and those who voluntarily accepted the stipulations signed an informed consent document. Control and patient subjects were clinically examined and studied with routine laboratory tests (blood count, blood chemistry, urinalysis, and thyroid function test). Blood sample procedures 5-HT and TRP measurements in total blood preparation were carried out according to the method described by Anderson, and were quantified by high performance liquid chromatography (HPLC). Statistical analysis The differences were statistically determined through an analysis of variance (ANOVA), with the assistance of the SPSS 12.00 (Statistical Software by SPPS Inc.). Results Results from laboratory tests, such as blood count, blood chemistry, thyroid function (T3, T4 and TSH) and urinalysis were normal in depressed subjects, as well as in healthy volunteers. Platelet number, blood 5-HT concentration, platelet content of 5-HT, and blood tryptophan concentration showed no significant differences in depressed patients in comparison to control subjects. 5-HT values in blood and platelet were significantly lower than the initial concentrations in patients after antidepressant treatment. Discussion and conclusions Discrepancies between our study and those found in the literature can be explained with three different approaches: ethnical, physiological, and methodological, as is further discussed. The significant decrease produced by the antidepressant treatment in blood and platelet serotonin concentration may be a consequence of the action of SSRIs, due to a 5-HT diminished uptake by the platelet. Considering our results, we conclude that: Blood and platelet 5-HT concentrations were not different between depressed patients and healthy volunteers. Blood TRP concentrations were not different between depressed patients and healthy volunteers. SSRIs (fluoxetine or citalopram) used in the treatment of depressed patients induced a significant decrease in blood and platelet content of 5-HT, and had no effect in TRP concentrations. Based on these results, neither blood/platelet 5-HT nor blood tryptophan concentrations seem to be good biological markers of depressive patients status. However, 5-HT, but not tryp-tophan, might be a reference point for pharmacological treatment effect.

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El sistema serotoninérgico en el paciente deprimido. Segunda parte

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Abstract: Nowadays there are increasing number of studies to support the crucial role of monoamines in depressive disorders. Among them are studies such as long-term treatment of antidepressants whose mechanism of action regulates monoamine metabolism, monoamine receptor density and post-mortem studies. An acute increase in monoamine concentration at the synaptic cleft might induce desensitization of brain auto- and hetero-receptors which explains the therapeutic antidepressive response. This has been proved by monoamine depletion studies in which an antidepressant effect or a patient relapse has been observed. Likewise, the antidepressive therapeutic response occurs earlier when auto-receptors are pharmacologically blocked at nervous and somatodendritic terminals. In the first part of this review, post-mortem studies related with the serotoninergic system were analyzed, as well as the usefulness of measuring serotonin, triptophan, and serotonin metabolite levels in different biological fluids of depressed patients. In this second part, alterations in platelet transporter and serotonin receptors are discussed as platelet is considered a neural serotoninergic model. Platelets are capable of storing and releasing serotonin in a similar manner as serotoninergic synaptosomes. Thus, platelets and serotoninergic synaptic terminals share biochemical and morphological properties. Serotonin transporter in platelets of depressed patients Due to the difficulty to obtain human brain samples and disagreements in the post-mortem studies, platelets have been suggested as a peripheral model to study neural serotonin uptake. The model is supported by the fact that platelet properties are similar to those of neuronal serotoninergic synaptic terminals. Serotonin studies in platelets have been useful in clinical aspects such as depressive disturbances. Radioligand studies in platelets from untreated depressed patients have shown a decrease in [H]-imipramine binding sites, compared to the binding in platelets from control subjects. Since that decrease has been consistently confirmed in studies on affective subjects, it has been proposed as a specific biomarker of depressed patients. Nevertheless, some researchers have not found similar results, and no explanation of the variability in the density of [H]-imipramine binding sites has been proposed. Serotonin receptor changes in depressed patients The hypothesis on receptor adaptative changes proposes that there is a depletion of monoaminergic neurotransmitters in depressed subjects which induces a compensatory regulation in the number and/or function of receptors. To explore this different techniques as the following have been developed: • Techniques to evaluate receptor density and affinity, including post-mortem radioligand binding to serotonin receptors in brain tissue and in platelets from depressed patients. • Techniques to evaluate receptor regulation and sensitivity by using neuroendocrine tests described below. Somatodendritic 5HT 1A autoreceptor dysfunction in depressive disorders Dysfunction of presynaptic somatodendritic 5HTja autoreceptors has been found in behavioral changes related to anxiety, depression and alcoholism. Neuroendocrine tests after the administration of 5-HT1a agonists have been used as an index of 5-HTta receptor function. It seems that azapirodecanediones increase plasmatic concentrations of prolactin, somatotropin, and adrenocortico-tropin; they also seem to decrease body temperature. In depressed patients, the hypothermia response, following presynaptic 5-HTta receptor stimulation, and the neuroendocrine response, following hypothalamus postsynaptic 5-HTta receptor stimulation, were both diminished. These findings suggest a desensitization or down-regulation of pre- and post-synaptic 5-HTja receptors in depressed patients. Platelet 5-HT 2A receptors in depressed patients Density and affinity Most radioligand studies have found an increase of platelet 5-HT2a receptors either in major depression patients or in attempted suicide patients. However, Rosel et al. studied platelets from depressed patients, finding an increment in the 5-HT2a platelet receptors affinity for [H]-ketanserin, but not in the receptors density. Functional capacity The evaluation of receptor function and sensitivity in platelets is performed after serotonin stimulation by using neuroendocrine tests and some other functional tests, such as platelet aggregation, morphological changes, quantification of intracellular calcium, and second messengers quantification. Despite being widely used, neuroendocrine tests are not completely reliable because they could be influenced by factors such as: stress on the hypothalamus-hypophysis axis, the lack of stereo-selective agonists and antagonists for different subtype serotonin receptors, and the effect of the drugs on other neurotransmitter systems. Other methodological aspects, such as: population heterogeneity, small samples, lack of variable control (i.e. age, sex, doses, diet, menstrual cycle), and placebo effects, are limitations to the neuroendocrine tests related to a single neurotransmitter system (serotonin). Results from platelet functional studies are contradictory as well. Platelet aggregation assays in depressed patients suggested a down-regulation of 5-HT2A receptors, compared to platelets from healthy subjects. However, some other studies have found no differences. Other platelet function responses mediated by 5-HT2A receptors, such as morphology changes, intracellular calcium, and phosphatidyl inositol hydrolysis, suggest a receptor up-regulation or hypersensitivity in depressed patients. Despite some disagreement among the results of platelet 5-HT2A receptor studies in depressed patients, most of them have reported an increase in 5-HT2A receptors density in these patients. However, suicidal behavior is clearly correlated to such an increase. Similar results have been observed in most post-mortem studies reporting an increase of 5-HT2A receptors in the prefrontal cortex. Protein synthesis and mRNA for 5-HT2A receptors are increased in prefrontal cortex and hippocampus in adolescent and adult suicide victims. These findings suggest that changes in the brain serotonergic system are related to depressive states and suicidal behavior. Human brain imaging techniques as well as molecular genetics studies may be additional tools to support the understanding of the neurobiology of depressive states, and their treatment.

El sistema serotoninérgico en el paciente deprimido. Primera parte

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Summary According to Spitzer et al., depression is a mood disorder characterized by sadness and accompanied by other symptoms such as irritability, anxiety, significant weight/appetite loss or gain, and feelings of guilt, worthlessness and hopelessness. Depressed patients are unable to accomplish everyday activities and may develop thoughts of death or suicide. Different neurotransmitters have been involved in the pathogenesis of depression; among them are noradrenaline, dopamine, gamma-aminobutyric acid, neuropeptides such as vasopressin and somatostatin, and endogenous opioids. However, serotonin (5-HT) has been the most studied and is suggested to play a central, but not exclusive, role in depression. This review analyzes studies which have involved serotonin as the vulnerable biochemical factor in depression. Postmortem studies Postmortem studies and 5-HT and 5-hydroxy-indolacetic acid quantification Many researchers have reported a decrease in 5-HT or its metabolite 5-hydroxy-indolacetic acid (5-HIAA) concentration in the brain stem of suicidal people. However, results are inconsistent since in other cerebral regions, such as the hypothalamus, cingulate and frontal cortex, no 5-HT or 5-HIAA concentrations have been found. Validity of postmortem results is limited by methodological issues as postmortem interval length, age of subjects, lack of assessment of nutritional status of suicide victims, drug abuse, medication, and differences in psychiatric diagnosis. Serotonin transporter and post-mortem studies Serotonin transporters are localized in cell presynaptic membranes in raphe and serotoninergic terminals projected to brain cortex. Radioligand studies have shown the occurrence of high affinity binding sites for [3H]-imipramine in human brain. Because of their localization in serotoninergic terminals and their likely participation in depression pathology, these binding sites have been suggested to be depression biomarkers. Early studies reported a decrease in [3H]-imipramine binding to prefrontal cortex in suicide victims with previous depression, as well as in occipital cortex and hippocampus in depressed patients who died of natural causes. These findings have been confirmed by other compound studies including [3H]-citalopram which has been identified as a more selective ligand for the serotonin transporter. A review by Purselle and Nemeroff of studies correlating depression, serotonin and suicide behavior found ambiguous data. These were likely due to methodological deficiencies such as a small sample size, deficient pairing criteria for control and treated groups, differences in radioligands, as well as disregarding comorbidity. These differences limit validation, comparison and interpretation of study results. Serotonin receptors and postmortem studies 5-HT 1A receptors. A decrease in 5-HT1A receptor density has been reported in suicidal depressed victims in the hippocampus, an important brain area for cognitive function. However, this receptor is highly sensitive to antidepressant treatment, which makes its determination rather ambiguous. On the other hand, no significant difference in brain cortex 5-HT1A receptors has been found between non-suicidal and suicidal subjects. 5-HT 1D receptors affinity has been reported to be decreased in depressed patients. 5-HT 2 receptors. Several researchers have observed an increase in postsynaptic 5-HT2 receptors in the frontal cortex and amygdala in suicidal depressed victims and depressed patients with no pharmacological treatment. An increase in 5-HT2A receptors has been reported in prefrontal cortex of suicidal adolescents, as well as higher levels of mRNA codifying for these receptors in prefrontal cortex and hippocampus. Tryptophan, serotonin, melatonin and 5-hydroxy-indolacetic acid in biological fluids Tryptophan in cerebrospinal fluid Findings on tryptophan levels in cerebrospinal fluid are controversial, for both normal and low levels have been found in depressed patients. Tryptophan in plasma Using the hypothesis of a decreased tryptophan availability to explain a low serotoninergic central activity in depressed patients does not stand due to different findings in levels of plasma-free tryptophan. Lower, normal and even higher levels of free tryptophan have been reported. Tryptophan availability might be influenced by neutral amino acids competing to cross the blood-brain barrier. Brain tryptophan levels might be modified if the free tryptophan/neutral amino acids ratio is reduced. It has been observed that depressed patients receiving antidepressants experienced a depressive relapse after receiving a low-tryptophan diet and returned to the remission state on returning to a regular food intake. Pharmacokinetic and pharmacodynamic factors might play a role in tryptophan availability in some depressed patients. Serotonin in cerebrospinal fluid Serotonin levels in cerebrospinal fluid are very low; this difficult carrying out studies in depressed patients. Serotonin in platelets Methodological and clinical criteria may explain the controversial results on platelet serotonin levels, which have found to be increased, decreased or unchanged. Serotonin in blood As platelet serotonin content includes 99% blood serotonin, serotonin blood levels might reflect brain serotonin content. After using fluvoxamine, a specific serotonin-reuptake inhibitor, the serotonin concentration in whole-blood preparation of patients was strongly reduced. After treatment with an unspecific mono-amine oxidase inhibitor, serotonin content was increased. Determination of 5-HT in whole blood preparation of patients treated with fluvoxamine might indicate a measure of drug compliance. Serotonin in plasma A significant decrease in plasma serotonin levels has been reported in depressed patients. Melatonin in plasma The melatonin synthesis use serotonine as building blocka. Melatonin have an important role in depression. It has been proposed that depressive states are a consequence of an inappropriate melatonin secretion. Therefore low plasmatic melatonin levels may be used as a biological marker for some types of depression. 5-HIAA in cerebrospinal fluid and plasma 5-HIAA, the major metabolite of 5-HT in plasma, has been suggested as a depression biomarker since cerebrospinal fluid 5-HIAA levels have found to be decreased in depressed patients. On the other hand, plasma 5-HIAA levels from untreated depressed patients were found to be significantly negatively correlated with severity of depression, despite the fact that the origin of plasma 5-HIAA is largely peripheral. 5-HIAA in urine Studies concerning urine 5-HIAA levels have been inconclusive in depression, likely due to the 5-HIAA urinary level variations from one day to another. Furthermore, the major fraction of 5-HIAA in blood as an intestinal precedence, therefore, blood 5-HIAA levels may not correlate with cerebral levels. Conclusion The serotoninergic system seems to be the neurotransmission system whose variations may explain every clinical manifestation in depressed patients. However, interpretation of measurements of tryptophan, serotonin, and its metabolites in biological fluids as an index of brain serotonin availability and function is difficult to achieve, mainly due to methodological discrepancies.

La plaqueta como marcador biológico periférico de la función serotoninérgica neuronal

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Abstract: Among all neurotransmitters, serotonin or 5-hydroxi-triptamine (5-HT) is probably the most studied in neuropsychopharmacology. Interest in this neurotransmitter is due to cumulative evidences showing that neuronal serotonergic systems are altered in depressed patients, as well as in several behavior dysfunctions like aggressiveness, impulsiveness, and suicide attempts, among others. Also, specific agonists and antagonists have been synthesized, which has enabled the characterization of the serotonergic receptor subtypes. Furthermore, highly selective inhibitors ofserotonin uptake have been developed, and these are capable of working in the synaptic terminals, as well as in other cell systems, such as platelets. This has allowed for the understanding and characterization of the action mechanisms of diverse psychoactive drugs interacting with the serotonergic system. Platelets have been proposed as an outlying model resembling that of serotonergic neurons due to the similarities they present in the uptake, storage, and serotonin release mechanisms, as well as the presence in platelet membranes of serotonin 5-HT2A receptors. The platelets have a serotonergic system consisting of four main components: 1. an uptake mechanism, 2. intracellular storage organelles, 3. serotonergic receptors in the plasmatic membrane, and 4. a mitochondrial enzyme, the monoamine oxidase (MAO), which metabolizes serotonin. All these elements show physiologic similarities with the neuronal serotonergic system. Serotonergic similarities in neurons and platelets In the Central Nervous System (SNC) serotonin acts mainly as an inhibitory neurotransmitter. The precursor for its synthesis is the aminoacid tryptophan. This is taken from the blood to the cerebral interstice, where it is taken up by the nervous terminals and converted into 5-hidroxytryptophan (5-HTP) by the enzyme tryptophan hydroxilase. The conversion to 5-HTP is a key regulatory step in serotonin synthesis, and is converted quickly in 5-HT by the action of the aromatic L-acid descarboxilase. However, platelets do not synthesize 5-HT, since they do not possess tryptophan hydroxilase. Thus they only display uptake, storage, and serotonin release functions. Serotonin actions The neurotransmitter functions of neuronal serotonin, generally inhibitory, depend on the serotonergic receptor characteristics it interacts with. Its action mechanism can be mediated through second messengers (metabotrophic receptors) or through a direct action over ionic channels (ionotrophic receptors). In the platelets, serotonin is stored in a slow replacement depot, where it can be released from by exocythotic mechanisms. Serotonin participates in the platelet activation that allows for their aggregation to each other for blood clotting process. Serotonin uptake To stop the serotonin neurotransmitter function, neuronal serotonin is taken up from the synaptic cleft by transporter proteins. The serotonin neuronal uptake is impelled by a proton gradient that requires ATP. The 5-HT uptake can follow two paths: the 5-HT can be metabolized by the MAO into 5-hydroxy-indolacetic acid, or it can be reintroduced into release vesicles in order to be reutilized as a neurotransmitter. The serotonin uptake by platelets occurs either by passive diffusion or by active transport mechanisms. Under physiological conditions, the active uptake mechanism is the most effective. This uptake is mediated by proteins similar to the ones required for the neuronal serotonin uptake in the brain. It requires energy and the presence of Na+ and Cl-. The platelet uptake system has a relatively high affinity (Kd) for 5-HT, being similar in magnitude from platelets to neurons. The platelet storage of 5-HT is located mainly in the dense bodies and in the storage granules. Serotonin transporters in platelets and synaptic terminals The main form of ending a serotonergic transmission pulse is by taking up 5-HT molecules from the synaptic cleft directed to reduce the serotonin concentration, which then stops the serotonergic neurotransmission. The uptake process involves a molecular recognition of 5-HT by the transporter, its binding, and passing through the membrane to be released within the cellular. Serotonin molecules bound to its transporter protein cross through the membrane using Na+ as a driving force. The return ofthe transporter to its original position requires K+ as the driving force to step this protein toward its original position. When a selective serotonin reuptake inhibitor is administered, the 5-HT concentration increases in the synaptic cleft, which enhances serotonin neurotransmission. This increase induces a down regulation cascade of both: serotonin autoreceptors (presynaptic) and postsynaptic receptors, that may finally reestablish the resting state of the neuron. It has been confirmed that the protein for neuronal as well as platelet serotonin uptake transport are synthesized by the same gene. Experimental evidence has shown that the platelet transporter presents the same functional and pharmacological characteristics than the neuronal transporter. Serotonergicreceptors Seven types of pre and post synaptic serotonin receptors, which have also several subtypes, have been characterized. Pre and post synaptic 5-HT 1 receptors . The 5-HT1 receptors are involved in both pre and post synaptic serotonergic neurotransmission. The presynaptic 5-HT1A receptors are autoreceptors. Due to their localization in the cellular body and in the dendrites, they have been named somatodendritic autoreceptors, which control the serotonin release. The postsynaptic receptors may play a role in hypothalamic thermoregulation. The presynaptic 5-HT1D receptors are autoreceptors that perform a regulation by blocking the 5-HT release. These receptors are not synthesized in platelets. Postsynaptic 5-HT 2 receptors . The 5-HT2 receptor subtypes are 5-HT2A,BandC. When postsynaptic 5-HT2Areceptors are bound to serotonin, they drive the transduction of neuronal impulses through the production of second messengers within the postsynaptic neuron. These second messengers induce the synthesis of intracellular proteins denominated transcription factors, which may regulate the expression of several neuronal genes. Platelet 5-HT2A receptors correspond to the neuronal 5-HT2A metabothropic receptors and induce alterations in platelet density and affinity. 5-HT 3 receptors . These receptors were originally described in the periphery, specifically as part of the enteric nervous system. In the CNS 5-HT3 receptors are densely present in the solitary tract nucleus and in the area postrema. These receptors are the onlymonoaminergic receptors consistingofionic channels operated by aminergic neurotransmitters. The stimulation of 5-HT3 receptors is responsible of several secondary effects of the selective inhibitors of serotonin reuptake (SISR). These effects are not mediated only in the CNS, but also in sites outside the brain, such as the intestine, which possess this type of receptors also. These receptors are not located in the platelets. 5HT 4-7 serotonergic receptors . These receptors are distributed throughout the body, where they stimulate the alimentary tract secretions and facilitate peristaltic reflexes. Their localization in serotonergic areas in the brain and platelets has not been established. Notwhithstanding their limitations, the characteristics reviewed support the conclusion that platelets can be used as partial models to study the neuronal serotonin 5-HT2 binding and uptake functions. As Alfred Pletscher stated: "although the incomplete of the pattern demands care in its application, they could have the advantage of the relative simplicity".

Land-based sources of marine pollution: organochlorine pesticides in stream systems.

BACKGROUND: Organochlorine pesticides (OCPs) have been dispersed ubiquitously in the environment. Bottom sediments act as sinks for these compounds and their concentrations often reflect the degree of anthropogenic pollution. This study was designed to evaluate the occurrence and distribution of OCPs in superficial streambed sediments and their relation to land use in two creeks that contribute to the coastal pollution of the southeastern region of Argentina. METHODS: Sampling sites were selected by a combination of land use and stream type. Las Brusquitas creek, which passes through vast agricultural areas, and La Tapera creek which originates in a natural wetland and passes through horticultural farming and urban areas. OCPs quantification was carried out by GC-ECD. RESULTS AND DISCUSSION: Results showed similar total OCP concentrations in sediments from both creeks in the range of 6-25 ng/g dry wt. However, when OCPs were expressed in ng/g total organic carbon (TOC), La Tapera creek presented 4-fold higher total levels as a consequence of a higher OCP input during the recent past in that watershed. La Tapera outfall showed 4-fold higher levels than that seen in Las Brusquitas, although both values were below the sediment quality criteria demanded to protect wildlife. Sigmaendosulfans, sigmaDDTs and sigmachlordanes were the main OCP group in all samples, with Endosulfan sulfate being the most frequent and abundant compound. The predominance of metabolites with respect to parent compounds suggests a contamination mainly by runoff from aged and weathered agricultural soils. CONCLUSIONS: Despite OCPs being banned, they still exist in creek sediments from the studied region, representing continuous contributions of land-based source contaminants to the marine environment. OUTLOOK: Future research on OCP levels in suspended sediments is recommended in order to determine the total OCP concentrations in the selected stream systems.

Organochlorine pesticides sequestered in the aquatic macrophyte Schoenoplectus californicus (C.A. Meyer) Soják from a shallow lake in Argentina.

This study was conducted in Los Padres Lake from Argentina in order to assess the ability of Schoenoplectus californicus to bioconcentrate organochlorine pesticides (OCPs). Bulrush tissues, superficial and near root sediments were collected from the input and the output creek areas. OCP analyses were carried out by GC-ECD. Samples from the input creek area showed the higher OCP levels as a result of contaminants washed down from upstream agricultural fields. Bulrush roots accumulated the highest concentrations of pollutants (30.2-45.7ngg(-1) dry weight). DDTs and chlordanes predominated in sediments and roots besides endosulfan sulfate. The sediments constitute the main source for these OCPs partitioning to bulrush. Stems mainly exposed to water column accumulated preferentially the less hydrophobic pesticides, such as HCHs and endosulfans. We have confirmed the important role of S. californicus in the contaminant removal from sediments. Therefore, this macrophyte can be used as a tool for field studies of OCP pollution monitoring and remediation.

The role of burrowing beds and burrows of the SW Atlantic intertidal crab Chasmagnathus granulata in trapping organochlorine pesticides.

The effect of crab beds and bioturbation activity of the SW Atlantic intertidal crab Chasmagnathus granulata on the organochlorine pesticide (OCP) concentrations in Bahía Blanca estuary, Argentina were studied. Total OCP concentration was significantly lower inside than outside the crab burrows. Nevertheless, the concentrations from outside the crab beds were lower than from outside crab burrows, which indicated that crab beds act as sinks of sediment-bound OCP due to the bioturbation activities of the crabs. The same distribution patterns were found in all sediments as well as in crabs, being cyclodienes>HCHs>DDTs, although large amounts of metabolites rather than the respective parental were found in the organism showing the capacity of C. granulata for metabolising parental compounds. These more water-soluble compounds are excreted by the faeces and finally removed by tidal flushing to the sea. Our results suggest that crabs when present play a role in the distribution of sediment-bound OCP and the crab beds are modifiers of the dynamic of organic pollutants in estuarine areas.

Dynamics of organochlorine pesticides in soils from a southeastern region of Argentina.

Monitoring of organochlorine pesticides (OCPs) was carried out to identify and quantify the contribution of point and nonpoint sources to the total OCP flux in a southeastern region of Argentina. Natural, recreational, and agricultural soils located in the surrounding of a lagoon were analyzed by gas chromatography with electron-capture detector. Physical and chemical characteristics (texture, humidity, and organic matter content) were determined at different depths (0-15 cm, 15-30 cm, and 45-55 cm). The pattern of OCP distribution was similar in all soil sampled, with DDT and metabolites > hexachlorocyclohexanes (HCHs) > heptachlor > chlordanes. The highest values of OCPs (656.1 ng/g dry wt) were found in the surface natural soil despite its never having received direct OCP application. This would be mainly due to the high organic matter content of the surface natural soils as well as its topographic position (highland hills), with main winds arriving from agricultural areas. Microorganism abundance and edaphic biota in the upper layer would justify the high levels of metabolites found. The agricultural soil (intensive tillage) also showed the highest OCP values (30.19 ng/g dry wt) in the surface horizon. Because of management practices, volatilization could have been one of the major causes of pesticide loss from this target area. Recreational soil showed the lowest OCP levels in the surface layer because of weathering that occurs when the nearby lagoon floods this zone. Our results show that, although most of these pesticides are banned, they are present in these soils and the atmospheric transport and deposition would be the major processes for distributing OCPs from target to natural areas.

Occurrence and distribution of organochlorine pesticides (OCPs) in tomato (Lycopersicon esculentum) crops from organic production.

Organochlorine pesticides (OCPs) were quantified by GC-ECD in tomato (Lycopersicon esculentum) during a vegetation period. Plants were harvested at 15, 60, and 151 days after seed germination. Leaves, stem, roots, and fruit (peel and flesh) were analyzed separately. The results showed that tomato plants were able to accumulate OCPs from soils, and a trend to reach the equilibrium among tissues at mature stages was also observed. Endosulfans comprised the main OCP group, probably due to its spray during summer months in the surrounding areas. Banned pesticides such as DDTs, heptachlor, and dieldrin were found. OCPs levels in the fruit were below the maximum residues limits (MRL) considered by the Codex Alimentarius. DDE/DDT and alpha-/gamma-HCH ratios of <1 would indicate recent inputs of DDT and lindane in the environment. The occurrence of OCPs in the study farm, where agrochemicals have never been used, is a result of atmospheric deposition of those pesticides.

Agricultural soil as a potential source of input of organochlorine pesticides into a nearby pond.

A study was conducted in the southeastern region of Buenos Aires province, Argentina, to assess an agricultural soil as a potential source of organochlorine (OC) pesticides for the aquatic biota of a nearby pond. We analyzed gamma-HCH (lindane), still in use, and the following banned compounds: DDT, DDE, DDD heptachlor, heptachlor epoxide, aldrin, dieldrin and endrin in soil, bulrush, grass shrimp and fish using gas chromatography with electron capture detection (GC-ECD). Among the OC pesticides, lindane was most dominant in the soil (32.6 ng/g dry wt in the upper and 173.9 ng/g dry wt in the lower horizon) and bulrush (1.9 pg/g lipid). Macrophyte also accumulated high levels of heptachlor epoxide (1.5 pg/g lipid). Heptachlor, although present in the soil, was below the detection limit in all aquatic biota studied. Its primary degradation product, heptachlor epoxide, was found in both soil and biota samples. DDT was found at low levels in the surface soil (6.8 ng/g dry wt), but at higher concentrations in fish (3.6 pg/g lipid), although levels were still below permissible levels for human consumption. Since most of the compounds were found in both soil and aquatic biota, our study suggests that agricultural soil could be an important source for OC pesticides in the nearby pond.

Comparación del análisis inmunoenzimático y la cromatografía de líquidos de alta eficiencia (EMIT y HPLC) para la medición de carbamacepina en muestras séricas / Comparison of enzyme immunoassay and high-performance liquid chromatography determination of carbamazepine in human serum

Se analizaron 40 muestras de suero de pacientes tratados con carbamacepina por inmunoanálisis enzimático (EMIT) y cromatografía de líquidos de alta eficiencia (HPLC) y se compararon los resultados. El método cromatográfico incluye la extracción de la carbamacepina con cloruro de metileno y su separación cromatográfica en una columna Nova Pak C18 usando una mezcla de acetonitrilo al 25 por ciento en agua pH 5.6. La detección se hizo en un detector de absorbancia a 215 nm. La correlación entre estos dos métodos fue de 0.93. Las bandas de confianza para la predicción de HPLC en función de EMIT calculadas mediante el criterio de Working-Hotelling, mostraron un error máximo de 1.1, 0.5 y 1.6 µg/ml en el rango bajo, medio y alto respectivamente con una probabilidad 0.05. La ecuación que expresa el comportamiento de la medición de carbamacepina por HPLC en función del EMIT es: HPLC = 0.824 x EMIT + 0.777 Posteriormente, se usó el método cromatográfico para determinar los niveles séricos predosis de carbamacepina y 10,11-epoxi-carbamacepina en 5 pacientes epilépticas que recibieron una dosis oral de 200 mg de carbamacepina cada 8 horas como único anticonvulsivante para el control de sus crisis.

Actividad de la monoamino-oxidasa plaquetaria en pacientes con depresión mayor con y sin melancolia: resultados preliminares / Activity of platelet monoamino-oxidase in major depressive illness: melancholic and non-melancholic patients: preliminary data

Se analizaron muestras sanguíneas de 99 pacientes libres de tratamiento (80 mujeres y 19 hombres) con diagnóstico de depresión mayor (DSM-III), 41 con melancolía y 58 sin melancolía. Se encontró que la actividad de la MAO plaquetaria fue significativamente mayor en las mujere que en los hombres, y en los pacientes con depresión mayor sin melancolía, que en aquellos con melancolía. No se encontraron correlaciones significativas de los valores de actividad de la enzima con la edad , ni con la severidad de la sintomatología depresiva medida por la EDH. Estos hallazgos coinciden con los de investigaciones previas al confirmar el hecho de que la mujer tiende a presentar una mayor actividad de la MAO plaquetária que el hombre, y apoyan la hipótesis de la presencia de una actividad enzimática elevada en las depresiones no endógenas. Sin embargo, para ubicar adecuadamente este posible marcador, deverán desarrolarse estudios cuidadosos, con un enfoque fenomenológico y controles adecuados, de las variables orgánicas y metodológicas que sabemos afectan la actividad de la MAO