Characterization and modulation of voltage-gated potassium channels in human lymphocytes in schizophrenia.

BACKGROUND: It is known that the immune system is dysregulated in schizophrenia, having a state similar to chronic neuroinflammation. The origin of this process is unknown, but it is known that T and B lymphocytes, which are components of the adaptive immune system, play an important role in the pathogenic mechanisms of schizophrenia. METHODS: We analysed the membrane of PBMCs from patients diagnosed with schizophrenia through proteomic analysis (n = 5 schizophrenia and n = 5 control). We found the presence of the Kv1.3 voltage-gated potassium channel and its auxiliary subunit ß1 (KCNAB1) and ß2 (KCNAB2). From a sample of 90 participants, we carried out a study on lymphocytes with whole-cell patch-clamp experiments (n = 7 schizophrenia and n = 5 control), western blot (n = 40 schizophrenia and n = 40 control) and confocal microscopy to evaluate the presence and function of different channels. Kv in both cells. RESULTS: We demonstrated the overexpression of Kv1.1, Kv1.2, Kv1.3, Kv1.6, Kv4.2, Kv4.3 and Kv7.2 channels in PBMCs from patients with schizophrenia. This study represents a groundbreaking exploration, as it involves an electrophysiological analysis performed on T and B lymphocytes from patients diagnosed of schizophrenia compared to healthy participants. We observed that B lymphocytes exhibited an increase in output current along with greater peak current amplitude and voltage conductance curves among patients with schizophrenia compared with healthy controls. CONCLUSIONS: This study showed the importance of the B lymphocyte in schizophrenia. We know that the immune system is altered in schizophrenia, but the physiological mechanisms of this system are not very well known. We suggest that the B lymphocyte may be relevant in the pathophysiology of schizophrenia and that it should be investigated in more depth, opening a new field of knowledge and possibilities for new treatments combining antipsychotics and immunomodulators. The limitation is that all participants received antipsychotic medication, which may have influenced the differences observed between patients and controls. This implies that more studies need to be done where the groups can be separated according to the antipsychotic drug.

Does Lithium Deserve a Place in the Treatment Against COVID-19? A Preliminary Observational Study in Six Patients, Case Report.

Lithium has shown the capacity to: a) inhibit the replication of several types of viruses, some of which are similar to the SARS-CoV-2 virus, b) increase the immune response by reducing lymphopenia, and c) reduce inflammation by preventing or reducing the cytokine storm. In the present study, we have treated six patients with severe COVID-19 infection with lithium carbonate. We found that lithium carbonate significantly reduced plasma reactive C-Protein levels, increased lymphocyte numbers and decreased the neutrophil-lymphocyte ratio, improving both inflammatory activity and the immune response in these patients. We propose that lithium carbonate may deserve a place in the treatment against COVID-19.

Mania as Debut of Cushing's Syndrome.

This is a case of a patient affected by Cushing syndrome that was admitted at the hospital due to hormonal problems. He had presented psychiatric symptoms that were mistakenly considered not directly connected to the pathology causing the clinical condition, but a mere psychological reaction to it.

Resin cutback technique for interim implant-supported crowns.

This report describes the direct fabrication of interim implant-supported crowns in a single clinical session by applying a preheated composite resin to a clear silicone matrix made by diagnostic waxing. This technique facilitates the fabrication of custom interim restorations with appropriate soft-tissue molding and enables an inexpensive, predictable, functional, and esthetic outcome after implant surgery.

Evaluación de la adherencia al tratamiento con antipsicóticos inyectables de liberación prolongada dentro de un programa de seguimiento farmacoterapéutico / Assessment of adherence to treatment with injectable extended-release antipsychotics within a pharmacotherapeutic follow-up program

Objetivo: Describir un programa de seguimiento farmacoterapéutico de antipsicóticos inyectables de liberación prolongada y evaluar la adherencia de los pacientes incluidos. Método: Se describe un programa de prescripción electrónica, validación y dispensación de antipsicóticos a salud mental y centros de salud, coordinado entre farmacia de hospital y de atención primaria. La adherencia al tratamiento se evaluó mediante un estudio prospectivo, observacional y transversal de un mes realizado en un área sanitaria a más de 500.000 habitantes, en el que se incluyeron todos los pacientes en tratamiento con un antipsicótico inyectable de liberación prolongada. Las variables recogidas fueron: medicamento administrado, frecuencia de admi nis tra ción, centro de administración y si el paciente acudía o no a la administración, considerando que acudía si lo hacía en ± 7 días. Resultados: Se incluyeron un total de 919 pacientes y 1.073 consultas programadas. En la recogida de datos participaron 11 unidades de salud mental y 40 centros de salud. En un 95,7% (1.027) de los casos, los pacientes acudieron a la administración del antipsicótico inyectable de liberación prolongada. No se encontraron diferencias en la adherencia entre los medicamentos ni entre frecuencias de administración, pero sí con respecto al centro donde se administraba el medicamento (unidades de salud mental frente a centros de salud), presentando una ligera mayor adherencia los pacientes de las unidades de salud mental (97,6% frente al 91,1%; p < 0,001). Conclusiones: La elevada adherencia conseguida revela que el programa de seguimiento descrito es efectivo. En el futuro son necesarios estudios de mayor duración que confirmen esta tendencia

Objective: To describe an injectable extended-release antipsychotic pharmacotherapeutic follow-up program and to assess adherence among patients included in the program. Method: A coordinated program is described involving hospital and primary care pharmacy, which included electronic prescription, reviewing, and dispensing of injectable antipsychotic agents in mental health and primary health care centers. Adherence to treatment was assessed in a 1-month prospective observational cross-sectional study which included all patients under treatment with injectable extended-release antipsychotics in a health area of more than 500,000 inhabitants. The variables collected were: medication administered, frequency of administration, administration center, and whether or not the patient attended the center. Patients were considered to have adhered to treatment if they had attended their appointments within a margin of ± 7 days. Results: A total of 919 patients and 1,073 appointments were included. Eleven mental health units and 40 primary health care centers participated in data collection. In 95.7 % (1,027) of cases, the patients attended the appointment. No differences were found in adherence between drugs or administration frequency. However, differences were found between mental health units and primary health care centers. Patient adherence was slightly higher in mental health units (97.6% vs 91.1%; P < 0.001). Conclusions: The high adherence rate shows that the described followup program is effective. Further long-term studies are needed to confirm this trend

Assessment of adherence to treatment with injectable extended-release antipsychotics within a pharmacotherapeutic follow-up program.

OBJECTIVE: To describe an injectable extended-release antipsychotic pharmacotherapeutic follow-up program and to assess  adherence among patients included in the program. METHOD: A coordinated program is described involving hospital and  primary care pharmacy, which included electronic prescription,  reviewing, and dispensing of injectable antipsychotic agents in mental  health and primary health care centers. Adherence to treatment was  assessed in a 1-month prospective observational cross-sectional study  which included all patients under treatment with injectable extended- release antipsychotics in a health area of more than 500,000  inhabitants. The variables collected were: medication administered,  frequency of administration, administration center, and whether or not  the patient attended the center. Patients were considered to have  adhered to treatment if they had attended their appointments within a  margin of ± 7 days. Results: A total of 919 patients and 1,073 appointments were included. Eleven mental health units and 40 primary health care centers participated in data collection. In 95.7 % (1,027) of cases, the  patients attended the appointment. No differences were found in  adherence between drugs or administration frequency. However,  differences were found between mental health units and primary health  care centers. Patient adherence was slightly higher in mental health units (97.6% vs 91.1%; P < 0.001). CONCLUSIONS: The high adherence rate shows that the described  followup program is effective. Further long-term studies are needed to  confirm this trend.

Objetivo: Describir un programa de seguimiento farmacoterapéutico de antipsicóticos inyectables de liberación prolongada y evaluar la  adherencia de los pacientes incluidos.Método: Se describe un programa de prescripción electrónica,  validación y dispensación de antipsicóticos a unidades de salud mental y  centros de salud, coordinado entre farmacia de hospital y de atención primaria. La adherencia al tratamiento se evaluó mediante un estudio  prospectivo, observacional y transversal de un mes realizado en un área  sanitaria a más de 500.000 habitantes, en el que se incluyeron  todos los pacientes en tratamiento con un antipsicótico inyectable de  liberación prolongada. Las variables recogidas fueron: medicamento  administrado, frecuencia de administración, centro de administración y  si el paciente acudía o no a la administración, considerando que acudía  si lo hacía en ± 7 días. Resultados: Se incluyeron un total de 919 pacientes y 1.073 consultas programadas. En la recogida de datos participaron 11  unidades de salud mental y 40 centros de salud. En un 95,7% (1.027)  de los casos, los pacientes acudieron a la administración del  antipsicótico inyectable de  liberación prolongada. No se encontraron  diferencias en la adherencia entre los medicamentos ni entre frecuencias  de administración, pero sí con respecto al centro donde se  administraba el medicamento (unidades de salud mental frente a  centros de salud), presentando una ligera mayor adherencia los  pacientes de las unidades de salud mental (97,6% frente al 91,1%; p <  0,001).Conclusiones: La elevada adherencia conseguida revela que el  programa de seguimiento descrito es efectivo. En el futuro son  necesarios estudios de mayor duración que confirmen esta tendencia.

Patterns of Membrane Protein Clustering in Peripheral Lymphocytes as Predictors of Therapeutic Outcomes in Major Depressive Disorder.

There is an utmost necessity of developing novel biomarkers of depression that result in a more efficacious use of current antidepressant drugs. The present report reviews and discusses a recent series of experiments that focused on analysis of membrane protein clustering in peripheral lymphocytes as putative biomarkers of therapeutic efficacy for major depressive disorder. This review recapitulates how the ideas were originated, and the main findings demonstrated that analysis of serotonin transporter and serotonin 2 A receptor clustering in peripheral lymphocytes of naïve depression patients resulted in a discrimination of two subpopulations of depressed patients that showed a differential response upon 8 weeks of antidepressant treatment. The paper also reviews the usefulness of animal models of depression for an initial evaluation of membrane protein clustering in lymphocytes, which provides a screening tool to determine additional proteins to be further evaluated in depression patients. Finally, the present review provides a brief discussion of the general field of biomarkers of depression in relation to therapeutic outcomes and suggests additional ideas to provide extra value to the reviewed studies.

Changes in Membrane Protein Clustering in Peripheral Lymphocytes in an Animal Model of Depression Parallel Those Observed in Naïve Depression Patients: Implications for the Development of Novel Biomarkers of Depression.

Naïve depression patients show alterations in serotonin transporter (SERT) and serotonin 2A (5HT2A) receptor clustering in peripheral lymphocytes, and these alterations have been proposed as a biomarker of therapeutic efficacy in major depression. Repeated corticosterone (CORT) induces a consistent depression-like phenotype and has been widely used as an animal model to study neurobiological alterations underlying the depressive symptoms. In this experiment, we used the CORT paradigm to evaluate whether depression-like behavior is associated with similar changes in the pattern of SERT and 5HT2A membrane protein clustering as those observed in depression patients. We also analyzed the clustering of other proteins expressed in lipid rafts in lymphocytes. Rats received daily CORT or vehicle injections for 21 consecutive days. Afterward they underwent the forced swim test to evaluate depression-like behavior, and isolated lymphocytes were analyzed by immunocytochemistry coupled to image-analysis to study clustering parameters of the SERT, 5HT2A receptor, dopamine transporter (DAT), Beta2 adrenergic receptor (ß2AR), NMDA 2B receptor (NR2B), Pannexin 1 (Pnx1), and prion cellular protein (PrPc). Our results showed that CORT increases the size of protein clusters for all proteins with the exception of ß 2AR, which is decreased. CORT also increased the number of clusters for Pnx1 and PrPc only. Overall, these results indicate that alterations in SERT and 5HT2A protein clustering in naïve depression patients are paralleled by changes seen in an animal model of depression. The CORT paradigm may be a useful screen for examining additional proteins in lymphocytes as a preliminary step prior to their analysis as biomarkers of depression in human blood samples.

Immediate Implant Placement by Interradicular Bone Drilling before Molar Extraction: Clinical Case Report with One-Year Follow-Up.

The placement of immediate implants in the posterior sector is a widespread procedure where the success and survival rates are similar to those of traditional protocols. It has several anatomical challenges, such as the presence of interradicular bone septa that hinder a correct three-dimensional positioning of the implant and may compromise primary stability and/or cause damage of neighboring structures. The aim of this article is to present the treatment and the one-year clinical follow-up of a patient who received immediate implant placement using an interradicular bone-drilling technique before the molar extraction.

Síndrome serotoninérgico frente a síndrome neuroléptico maligno: a propósito de un caso / Serotonin syndrome versus neuroleptic malignant syndrome: a case report

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Cytokines dysregulation in schizophrenia: A systematic review of psychoneuroimmune relationship.

INTRODUCTION: Schizophrenia is a multifactorial psychiatric disease with complex interactions among the brain and the immune system. A psycho-immune relationship underling schizophrenia is supported by several studies and integrates a specific area of knowledge - psychoneuroimmunology. METHODS: A systematic review was performed by 2009 Preferred Reporting Items (PRISMA) recommendations. Based on the inclusion/exclusion criteria, publications with relevant information (evaluated by the Joanna Briggs Institute Critical Appraisals tools to quality assessment) were included. RESULTS: In this review, we considered the inflammatory activity promoted by cytokine alterations in schizophrenia aetiology, which reflects the systemic comprehension of this disease in opposition to the traditional approach focused solely on the brain. We focus on the analysis of several specific outcomes, such as proinflammatory cytokines, sample sort, laboratory techniques, diagnosis scales and results of each publication. CONCLUSION: This systematic review confirms the existence of cytokines abnormalities in schizophrenia disease. Immune imbalances such as increased levels of some cytokines (either at protein level or at mRNA expression), cytokine mRNAs, as well as cytokine gene polymorphisms have been reported with a large support in schizophrenia. These findings provide a strong evidence of a concomitant process of inflammatory activity in schizophrenia illness course.

Functional and esthetic restorative treatment with preheated resins in a patient with ectodermic dysplasia: A clinical report.

Ectodermal dysplasia is a heterogeneous genetic condition affecting 1.6 to 22 per 100000 people. Oral manifestations associated with this condition include hyperdontia, hypodontia, microdontia, and conical teeth. Traditional treatment consists of a combination of orthodontic and rehabilitation therapies. The initial treatment stage uses removable prostheses and interim crowns for long periods, thus increasing risks for developing secondary caries. This clinical report describes the use of direct composite resin bonding with preheated compactable resins applied to vacuum-formed trays filled with clear silicone. This restorative treatment provides predictable, inexpensive, minimally invasive, functional, and esthetic recovery before orthodontic treatment.

Comparative study of two protocols for quantitative image-analysis of serotonin transporter clustering in lymphocytes, a putative biomarker of therapeutic efficacy in major depression.

BACKGROUND: The pattern of serotonin transporter clustering on the plasma membrane of lymphocytes extracted from human whole blood samples has been identified as a putative biomarker of therapeutic efficacy in major depression. Here we evaluated the possibility of performing a similar analysis using blood smears obtained from rats, and from control human subjects and depression patients. We hypothesized that we could optimize a protocol to make the analysis of serotonin protein clustering in blood smears comparable to the analysis of serotonin protein clustering using isolated lymphocytes. RESULTS: Our data indicate that blood smears require a longer fixation time and longer times of incubation with primary and secondary antibodies. In addition, one needs to optimize the image analysis settings for the analysis of smears. When these steps are followed, the quantitative analysis of both the number and size of serotonin transporter clusters on the plasma membrane of lymphocytes is similar using both blood smears and isolated lymphocytes. CONCLUSIONS: The development of this novel protocol will greatly facilitate the collection of appropriate samples by eliminating the necessity and cost of specialized personnel for drawing blood samples, and by being a less invasive procedure. Therefore, this protocol will help us advance the validation of membrane protein clustering in lymphocytes as a biomarker of therapeutic efficacy in major depression, and bring it closer to its clinical application.

Efficacy of prospective pharmacogenetic testing in the treatment of major depressive disorder: results of a randomized, double-blind clinical trial.

BACKGROUND: A 12-week, double-blind, parallel, multi-center randomized controlled trial in 316 adult patients with major depressive disorder (MDD) was conducted to evaluate the effectiveness of pharmacogenetic (PGx) testing for drug therapy guidance. METHODS: Patients with a CGI-S ≥ 4 and requiring antidepressant medication de novo or changes in their medication regime were recruited at 18 Spanish public hospitals, genotyped with a commercial PGx panel (Neuropharmagen®), and randomized to PGx-guided treatment (n = 155) or treatment as usual (TAU, control group, n = 161), using a computer-generated random list that locked or unlocked psychiatrist access to the results of the PGx panel depending on group allocation. The primary endpoint was the proportion of patients achieving a sustained response (Patient Global Impression of Improvement, PGI-I ≤ 2) within the 12-week follow-up. Patients and interviewers collecting the PGI-I ratings were blinded to group allocation. Between-group differences were evaluated using χ2-test or t-test, as per data type. RESULTS: Two hundred eighty patients were available for analysis at the end of the 12-week follow-up (PGx n = 136, TAU n = 144). A difference in sustained response within the study period (primary outcome) was not observed (38.5% vs 34.4%, p = 0.4735; OR = 1.19 [95%CI 0.74-1.92]), but the PGx-guided treatment group had a higher responder rate compared to TAU at 12 weeks (47.8% vs 36.1%, p = 0.0476; OR = 1.62 [95%CI 1.00-2.61]), and this difference increased after removing subjects in the PGx-guided group when clinicians explicitly reported not to follow the test recommendations (51.3% vs 36.1%, p = 0.0135; OR = 1.86 [95%CI 1.13-3.05]). Effects were more consistent in patients with 1-3 failed drug trials. In subjects reporting side effects burden at baseline, odds of achieving a better tolerability (Frequency, Intensity and Burden of Side Effects Rating Burden subscore ≤2) were higher in the PGx-guided group than in controls at 6 weeks and maintained at 12 weeks (68.5% vs 51.4%, p = 0.0260; OR = 2.06 [95%CI 1.09-3.89]). CONCLUSIONS: PGx-guided treatment resulted in significant improvement of MDD patient's response at 12 weeks, dependent on the number of previously failed medication trials, but not on sustained response during the study period. Burden of side effects was also significantly reduced. TRIAL REGISTRATION: European Clinical Trials Database 2013-002228-18 , registration date September 16, 2013; ClinicalTrials.gov NCT02529462 , retrospectively registered: August 19, 2015.

Schizophrenia: A review of potential biomarkers.

OBJECTIVES: Understanding the biological process and progression of schizophrenia is the first step to developing novel approaches and new interventions. Research on new biomarkers is extremely important when the goal is an early diagnosis (prediction) and precise theranostics. The objective of this review is to understand the research on biomarkers and their effects in schizophrenia to synthesize the role of these new advances. METHODS: In this review, we search and review publications in databases in accordance with established limits and specific objectives. We look at particular endpoints such as the category of biomarkers, laboratory techniques and the results/conclusions of the selected publications. RESULTS: The investigation of biomarkers and their potential as a predictor, diagnosis instrument and therapeutic orientation, requires an appropriate methodological strategy. In this review, we found different laboratory techniques to identify biomarkers and their function in schizophrenia. CONCLUSION: The consolidation of this information will provide a large-scale application network of schizophrenia biomarkers.

Reelin-Related Disturbances in Depression: Implications for Translational Studies.

The finding that reelin expression is significantly decreased in mood and psychotic disorders, together with evidence that reelin can regulate key aspects of hippocampal plasticity in the adult brain, brought our research group and others to study the possible role of reelin in the pathogenesis of depression. This review describes recent progress on this topic using an animal model of depression that makes use of repeated corticosterone (CORT) injections. This methodology produces depression-like symptoms in both rats and mice that are reversed by antidepressant treatment. We have reported that CORT causes a decrease in the number of reelin-immunopositive cells in the dentate gyrus subgranular zone (SGZ), where adult hippocampal neurogenesis takes place; that down-regulation of the number of reelin-positive cells closely parallels the development of a depression-like phenotype during repeated CORT treatment; that reelin downregulation alters the co-expression of reelin with neuronal nitric oxide synthase (nNOS); that deficits in reelin might also create imbalances in glutamatergic and GABAergic circuits within the hippocampus and other limbic structures; and that co-treatment with antidepressant drugs prevents both reelin deficits and the development of a depression-like phenotype. We also observed alterations in the pattern of membrane protein clustering in peripheral lymphocytes in animals with low levels of reelin. Importantly, we found parallel changes in membrane protein clustering in depression patients, which differentiated two subpopulations of naïve depression patients that showed a different therapeutic response to antidepressant treatment. Here, we review these findings and develop the hypothesis that restoring reelin-related function could represent a novel approach for antidepressant therapies.

Modeling the longitudinal latent effect of pregabalin on self-reported changes in sleep disturbances in outpatients with generalized anxiety disorder managed in routine clinical practice.

BACKGROUND: Anxiety disorders are among the most common psychiatric illnesses, with generalized anxiety disorder (GAD) being one of the most common. Sleep disturbances are highly prevalent in GAD patients. While treatment with pregabalin has been found to be associated with significant improvement in GAD-related sleep disturbance across many controlled clinical trials, mediational analysis has suggested that a substantial portion of this effect could be the result of a direct effect of pregabalin. Thus, the objective of this study was to model the longitudinal latent effect of pregabalin or usual care (UC) therapies on changes in sleep in outpatients with GAD under routine clinical practice. METHODS: Male and female GAD outpatients, aged 18 years or above, from a 6-month prospective noninterventional trial were analyzed. Direct and indirect effects of either pregabalin or UC changes in anxiety symptoms (assessed with Hamilton Anxiety Scale) and sleep disturbances (assessed with Medical Outcomes Study-Sleep Scale [MOS-S]) were estimated by a conditional latent curve model applying structural equation modeling. RESULTS: A total of 1,546 pregabalin-naïve patients were analyzed, 984 receiving pregabalin and 562 UC. Both symptoms of anxiety and sleep disturbances were significantly improved in both groups, with higher mean (95% confidence interval) score reductions in subjects receiving pregabalin: -15.9 (-15.2; -16.6) vs -14.5 (-13.5; -15.5), P=0.027, in Hamilton Anxiety Scale; and -29.7 (-28.1; -31.3) vs -24.0 (-21.6; -26.4), P<0.001, in MOS-S. The conditional latent curve model showed that the pregabalin effect on sleep disturbances was significant (γ =-3.99, P<0.001), after discounting the effect on reduction in anxiety symptoms. A mediation model showed that 70% of the direct effect of pregabalin on sleep remained after discounting the mediated effect of anxiety improvement. CONCLUSION: A substantial proportion of the incremental improvements in anxiety-related sleep disturbances with pregabalin vs UC were explained by its direct effect, not mediated by improvements in anxiety symptoms.

Pregabalin for the treatment of patients with generalized anxiety disorder with inadequate treatment response to antidepressants and severe depressive symptoms.

To evaluate the effectiveness of pregabalin in patients with resistant generalized anxiety disorder (GAD) and severe depressive symptoms, we carried out a post-hoc analysis of a multicenter, prospective, and observational 6-month study. We included patients who were at least 18 years old, fulfilled the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria for GAD, showed inadequate responses to previous courses of antidepressant treatment, had Montgomery-Asberg Rating Scale scores of at least 35, had not received pregabalin previously, and were prescribed pregabalin upon entry into this study. We included 1815 patients fulfilling the DSM-IV criteria for GAD, and 133 (7.3%) fulfilled the selection criteria for these analyses. Ninety-seven percent of the patients received pregabalin (mean dose: 222 mg/day) in combination with other psychotropics. The Hamilton Anxiety Scale total score was reduced by a mean of 20.3 points (95% confidence interval, 22.1-18.4) (57.2% reduction) at month 6. Pregabalin also ameliorated comorbid depressive symptoms, with a reduction in the mean score of the Montgomery-Asberg Rating Scale of 22.3 points (95% confidence interval, 24.2-20.4) (56.6% reduction). Our results suggest that pregabalin, as part of a combination regimen with antidepressants and/or benzodiazepines, might be effective for the treatment of patients with GAD who have shown inadequate response to previous antidepressants and have severe depressive symptoms.