Prevalence of clozapine-induced sialorrhea and its effect on quality of life.

RATIONALE: Clozapine has proven to be superior to other antipsychotic drugs in the treatment of schizophrenia but is under-prescribed due to its potentially severe side effects. Clozapine-induced sialorrhea (CIS) is a frequent and extremely uncomfortable side effect, which remains understudied. OBJECTIVES: To examine the prevalence of diurnal and nocturnal CIS in a sample of patients treated with clozapine, and to evaluate its impact on quality of life. METHODS: We conducted a cross-sectional, observational study of 130 patients with schizophrenia spectrum disorders treated with clozapine. The prevalence of CIS was evaluated via specific sialorrhea scales. None of the patients included in the study was receiving a specific treatment for hypersalivation during the study period. Possible associations between sialorrhea and clinical and quality of life variables were analyzed. RESULTS: Of 130 subjects, 120 (92.3%) suffered from CIS. Eighty-one (62.31%) suffered from diurnal CIS, 115 (88.56%) from nocturnal CIS, and 85 (65.38%) suffered from both. Significant positive associations between quality of life and diurnal CIS (B = 0.417; p = 2.1e - 6, R2 = 0.156) and nocturnal CIS (B = 0.411; p = 7.7e - 6, R2 = 0.139) were detected. Thirty per cent of the subjects reported a moderate to severe negative impact of sialorrhea on their quality of life. CONCLUSIONS: The present study suggests that CIS is highly prevalent in patients with schizophrenia and has an important impact on quality of life in one-third of our sample. Therefore, the inclusion of a systematic evaluation and treatment of CIS in standard clinical practice is highly recommended. TRIAL REGISTRATION: Clinical Trials ( https://clinicaltrials.gov ) under reference NCT04197037.

Augmentation of EMDR with multifocal transcranial current stimulation (MtCS) in the treatment of fibromyalgia: study protocol of a double-blind randomized controlled exploratory and pragmatic trial.

BACKGROUND: Fibromyalgia (FM) is a generalized, widespread chronic pain disorder affecting 2.7% of the general population. In recent years, different studies have observed a strong association between FM and psychological trauma. Therefore, a trauma-focused psychotherapy, such as eye movement desensitization and reprocessing (EMDR), combined with a non-invasive brain stimulation technique, such as multifocal transcranial current stimulation (MtCS), could be an innovative adjunctive treatment option. This double-blind randomized controlled trial (RCT) analyzes if EMDR therapy is effective in the reduction of pain symptoms in FM patients and if its potential is boosted with the addition of MtCS. METHODS: Forty-five patients with FM and a history of traumatic events will be randomly allocated to Waiting List, EMDR + active-MtCS, or EMDR + sham-MtCS. Therapists and patients will be kept blind to MtCS conditions, and raters will be kept blind to both EMDR and MtCS. All patients will be evaluated at baseline, post-treatment, and follow-up at 6 months after post-treatment. Evaluations will assess the following variables: sociodemographic data, pain, psychological trauma, sleep disturbance, anxiety and affective symptoms, and wellbeing. DISCUSSION: This study will provide evidence of whether EMDR therapy is effective in reducing pain symptoms in FM patients, and whether the effect of EMDR can be enhanced by MtCS. TRIAL REGISTRATION: ClinicalTrials.gov NCT04084795 . Registered on 2 August 2019.

Calcitriol increases frataxin levels and restores mitochondrial function in cell models of Friedreich Ataxia.

Friedreich ataxia (FA) is a neurodegenerative disease caused by the deficiency of frataxin, a mitochondrial protein. In primary cultures of dorsal root ganglia neurons, we showed that frataxin depletion resulted in decreased levels of the mitochondrial calcium exchanger NCLX, neurite degeneration and apoptotic cell death. Here, we describe that frataxin-deficient dorsal root ganglia neurons display low levels of ferredoxin 1 (FDX1), a mitochondrial Fe/S cluster-containing protein that interacts with frataxin and, interestingly, is essential for the synthesis of calcitriol, the active form of vitamin D. We provide data that calcitriol supplementation, used at nanomolar concentrations, is able to reverse the molecular and cellular markers altered in DRG neurons. Calcitriol is able to recover both FDX1 and NCLX levels and restores mitochondrial membrane potential indicating an overall mitochondrial function improvement. Accordingly, reduction in apoptotic markers and neurite degeneration was observed and, as a result, cell survival was also recovered. All these beneficial effects would be explained by the finding that calcitriol is able to increase the mature frataxin levels in both, frataxin-deficient DRG neurons and cardiomyocytes; remarkably, this increase also occurs in lymphoblastoid cell lines derived from FA patients. In conclusion, these results provide molecular bases to consider calcitriol for an easy and affordable therapeutic approach for FA patients.

Eventos adversos en pacientes hospitalizados reportados por enfermería: un estudio multicéntrico en México / Nursing reported hospitalized patients adverse events: A multi-centric study in Mexico / Eventos adversos em pacientes hospitalizados relatados por enfermagem: um estudo multicéntrico no México

Introducción: Los eventos adversos (EA) son un daño no intencionado derivado de la atención sanitaria que se relacionan con los recursos humanos, los factores del sistema o las condiciones clínicas del paciente. Objetivo: Analizar factores relacionados con la calidad y la seguridad del paciente a través de los reportes de EA. Metodología: Diseño transversal, multicéntrico, realizado en 5 institutos nacionales de salud y en un hospital de alta especialidad, se estudiaron los EA ocurridos durante 18 meses, para lo cual se utilizó el instrumento SYREC 2007; análisis descriptivo y evaluación de asociación entre grado de evitabilidad y factores intrínsecos, extrínsecos y del sistema; se observaron los aspectos éticos vigentes. Resultados: Se analizaron un total de 540 EA, ocurrieron 55.5% en hombres, 58.7% estaban en estado de alerta, el 92.6% de los EA ocurrió en el servicio asignado, el 55.9% no se reportó a la familia, se consideró sin duda como evitable en el 70.5%, los factores del sistema estuvieron presentes en 80.6%, hubo asociación significativa entre estos y la evitabilidad del suceso. Discusión: Los principales resultados encontrados son coincidentes con otras investigaciones internacionales tales como: To err is human 1999, el estudio ENEAS de España 2006 y con el de prevalencia IBEAS 2010; en todos ellos se hizo evidente la necesidad de reforzar la cultura de la notificación de los EA y el clima para la seguridad del paciente, además de promover una reflexión interpersonal acerca de la calidad de los servicios asistenciales. Conclusiones: Los factores relacionados con el sistema tienen un mayor peso en la aparición de EA. Es de vital importancia su identificación a fin de poder evitarlos.

Introduction: Adverse events (AE) are unintended harms derived from human health attention, system factors, or clinical conditions in the patients. Objective: To analyze factors influencing the quality of patient healthcare and safety through the review of diverse records on AEs. Methodology: This transversal and multi-centric design study was carried out in five National Institutes of Health and a high specialty hospital. AEs in an 18 month period were studied using the SYREC 2007 instrument. Descriptive analysis, as well as assessments on the association between the preventability degree and the intrinsic, extrinsic, and system factors were all performed. Current ethical issues were observed. Results: A total of 540 AEs were analyzed; 55.5% occurred in men; 58.7% occurred during state of alertness; 92.6% occurred at the assigned service; 55.9% were not reported to the families; 70.5% were considered preventable; and system factors were present in 80.6% of them. A significant association between the AEs and the possibility to prevent them was found. Discussion: The main findings were consistent with those of other international studies including: ''To err is human'', 1999, the ENEAS study in Spain, 2006, and the IBEAS prevalence study, 2010. All of these studies emphasize the need to strengthen the culture of AE-notifying and to improve the patient safety climate, as well as to promote inter-personal reflections on to the quality of care services. Conclusions: System-related factors have the strongest influence on the occurrence of AEs, and thus, their identification becomes critical in order to enhance the quality of healthcare services.

Introdução: Os Eventos Adversos (EA) são um dano não intencionado derivado da atenção sanitária que se relaciona com os recursos humanos, os fatores do sistema ou as condições clínicas do paciente. Objetivo: Analisar fatores relacionados com a qualidade e a segurança do paciente a través dos relatórios de EA. Metodologia: Desenho transversal, multicéntrico, realizado em cinco Institutos Nacionais de Saúde e um hospital de alta especialidade, estudaram-se os EA ocorridos durante 18 meses, para o qual se utilizou o instrumento SYREC 2007; análise descritiva e avaliação de associação entre grau de evitabilidade e fatores intrínsecos, extrínsecos e do sistema; observaram-se os aspectos éticos vigentes. Resultados: Analisaram-se um total de 540 EA, ocorreram 55.5% em homens, 58.7% estavam em estado de alerta, o 92.6% o EA aconteceu no serviço assignado, o 55.9% não se informou à família, considerou-se sem dúvida como evitável no 70.5%, os fatores do sistema estiveram presentes em 80.6%, houve associação significativa entre estes e a evitabilidade do evento. Discussão: Os principais resultados encontrados são coincidentes com outras pesquisas internacionais tais como: ''To err is human'' 1999, o estudo ENEAS da Espanha 2006 e com o de prevalência IBEAS 2010; em todos eles se fez evidente a necessidade de reforçar a cultura da notificação dos EA e o clima para a segurança do paciente, além de promover una reflexão interpessoal acerca da qualidade dos serviços assistenciais. Conclusões: Os fatores relacionados com o sistema têm um maior peso na aparição de EA. É de vital importância sua identificação a fim de poder evitá-los.

Some practical considerations for linearity assessment of calibration curves as function of concentration levels according to the fitness-for-purpose approach.

Since linear calibration is mostly preferred for analytical determinations, linearity in the calibration range is an important performance characteristic of any instrumental analytical method. Linearity can be proved by applying several graphical and numerical approaches. The principal graphical criteria are visual inspection of the calibration plot, the residuals plot, and the response factors plot, also called sensitivity or linearity plot. All of them must include confidence limits in order to visualize linearity deviations. In this work, the graphical representation of percent relative errors of back-calculated concentrations against the concentration of the calibration standards is proposed as linearity criterion. This graph considers a confidence interval based on the expected recovery related to the concentration level according to AOAC approach. To illustrate it, four calibration examples covering different analytical techniques and calibration situations have been studied. The proposed %RE graph was useful in all examples, helping to highlight problems related to non-linear behavior such as points with high leverage and deviations from linearity at the extremes of the calibration range. By this way, a numerical decision limit which takes into account the concentration of calibration standards can be easily included as linearity criterion in the form of %RETh=2·C-0.11. Accordingly, this %RE parameter is accurate for the decision-making related to linearity assessment according to the fitness-for-purpose approach.

Histamine and mast cell activator compound 48/80 are safe but inefficient systemic adjuvants for gilthead seabream vaccination.

Histamine has a key role in the regulation of inflammatory and innate immune responses in vertebrates. Gilthead seabream (Sparus aurata L.), a marine hermaphrodite teleost of great commercial value, was the first fish species shown to possess histamine-containing mast cells (MCs) at mucosal tissues. MCs are highly abundant in the peritoneal exudate of gilthead seabream and compound 48/80 (Co 48/80), often used to promote MC activation and histamine release, is able to promote histamine release from gilthead seabream MCs in vitro and in vivo. The aim of the present study was to analyze the effect of histamine and Co 48/80 on the immune responses of gilthead seabream. For this purpose, histamine and Co 48/80 were intraperitoneally injected alone or combined with 109 heat-killed Vibrio anguillarum cells and their effects on head kidney and peritoneal exudate were analyzed. The results indicated that although histamine and Co 48/80 were both able to alter the percentage of peritoneal exudate and head kidney immune cell types, only Co 48/80 increased reactive oxygen species production by peritoneal leukocytes. In addition, histamine, but not Co 48/80, was able to slightly impair the humoral adaptive immune response, i.e. production of specific IgM to V. anguillarum. Notably, both histamine and Co 48/80 reduced the expression of the gene encoding histamine receptor H2 in peritoneal exudate leukocytes. These results show for the first time in fish that although systemic administration of histamine and Co 48/80 is safe, neither compound can be regarded as an efficient adjuvant for gilthead seabream vaccination.

Selective estrogen receptor modulators differentially alter the immune response of gilthead seabream juveniles.

17α-ethynylestradiol (EE2), a synthetic estrogen used in oral contraceptives and hormone replacement therapy, tamoxifen (Tmx), a selective estrogen-receptor modulator used in hormone replacement therapy, and G1, a G protein-coupled estrogen receptor (GPER) selective agonist, differentially increased the hepatic vitellogenin (vtg) gene expression and altered the immune response in adult gilthead seabream (Sparus aurata L.) males. However, no information exists on the effects of these compounds on the immune response of juveniles. This study aims, for the first time, to investigate the effects of the dietary intake of EE2, Tmx or G1 on the immune response of gilthead seabream juveniles and the capacity of the immune system of the specimens to recover its functionality after ceasing exposures (recovery period). The specimens were immunized with hemocyanin in the presence of aluminium adjuvant 1 (group A) or 120 (group B) days after the treatments ceased (dpt). The results indicate that EE2 and Tmx, but not G1, differentially promoted a transient alteration in hepatic vtg gene expression. Although all three compounds did not affect the production of reactive oxygen intermediates, they inhibited the induction of interleukin-1ß (il1b) gene expression after priming. Interestingly, although Tmx increased the percentage of IgM-positive cells in both head kidney and spleen during the recovery period, the antibody response of vaccinated fish varied depending on the compound used and when the immunization was administered. Taken together, our results suggest that these compounds differentially alter the capacity of fish to respond to infection during ontogeny and, more interestingly, that the adaptive immune response remained altered to an extent that depends on the compound.

Tamoxifen disrupts the reproductive process in gilthead seabream males and modulates the effects promoted by 17α-ethynylestradiol.

17α-Ethynylestradiol (EE2), which is used in oral contraceptives and hormone replacement therapy, is a well documented estrogenic endocrine disruptor and an aquatic contaminant. In the present study, adult male specimens of the marine hermaphrodite teleost gilthead (Sparus aurata L.) were fed a diet containing tamoxifen (Tmx), an estrogen receptor ligand used in cancer therapy, alone or combined with EE2, for 25 days and then fed a commercial diet for a further 25 days (recovery period). The effects of short (5days) and long (25 days) treatments on several reproductive and gonad immune parameters and the reversibility of the disruptive effects after the recovery period were examined. Our data showed that Tmx acted as an estrogenic endocrine disruptor as revealed by the increase in the hepatic transcription of the vitellogenin gene in males, the serum levels of 17ß-estradiol and the gonad expression levels of the estrogen receptor α and G protein-coupled estrogen receptor genes, and the recruitment of leukocytes into the gonad, a well known estrogenic-dependent process in gilthead seabream males. On the other hand, Tmx also increased sperm concentration and motility as well as the serum levels of androgens and the expression levels of genes that codify for androgenic enzymes, while decreasing the expression levels of the gene that code for gonadal aromatase. When applied simultaneously, Tmx and EE2 could act in synergy or counteract, each other, depending on the parameter measured. The disruptive effect of EE2 and/or Tmx was not reversible after a 25 day recovery period.

Brain structural changes in schizoaffective disorder compared to schizophrenia and bipolar disorder.

OBJECTIVE: Brain structural changes in schizoaffective disorder, and how far they resemble those seen in schizophrenia and bipolar disorder, have only been studied to a limited extent. METHOD: Forty-five patients meeting DSM-IV and RDC criteria for schizoaffective disorder, groups of patients with 45 matched schizophrenia and bipolar disorder, and 45 matched healthy controls were examined using voxel-based morphometry (VBM). RESULTS: Analyses comparing each patient group with the healthy control subjects found that the patients with schizoaffective disorder and the patients with schizophrenia showed widespread and overlapping areas of significant volume reduction, but the patients with bipolar disorder did not. A subsequent analysis compared the combined group of patients with the controls followed by extraction of clusters. In regions where the patients differed significantly from the controls, no significant differences in mean volume between patients with schizoaffective disorder and patients with schizophrenia in any of five regions of volume reduction were found, but mean volumes in the patients with bipolar disorder were significantly smaller in three of five. CONCLUSION: The findings provide evidence that, in terms of structural gray matter brain abnormality, schizoaffective disorder resembles schizophrenia more than bipolar disorder.

Particle trapping and structuring on the surface of LiNbO3:Fe optical waveguides using photovoltaic fields.

We report on the successful trapping and patterning of micro- and nanometric particles on the surface of LiNbO3 optical waveguides via photovoltaic tweezers. A waveguide configuration is used for the first time combined with this recently proposed technique. The electric field pattern is generated by light propagating in the waveguide, allowing us to separate the light channel with the region in which particles are deposited. Results on micro- and nanoparticle trapping, by two different deposition methods on two types of planar waveguides (by soft proton exchanged and by swift heavy ion irradiation), and using single-beam and two-beam interferometric configuration, are presented and discussed.

Specific and non-overlapping functions of testosterone and 11-ketotestosterone in the regulation of professional phagocyte responses in the teleost fish gilthead seabream.

Sex hormones, both estrogens and androgens, have a strong impact on immunity in mammals. In fish, the role of androgens in immunity has received little attention and contradictory conclusions have been obtained. However, it is well known that sex steroids are involved in fish growth, osmoregulation and gonad remodelation. In this study, we examine the in vitro effects of testosterone and 11-ketotestosterone, the two main fish androgens, on the professional phagocytes of the teleost fish gilthead seabream (Sparus aurata L.). Although both testosterone and 11-ketotestosterone failed to modulate the respiratory burst of seabream phagocytes, testosterone but not 11-ketotestosterone was able to increase the phagocytic ability of non-activated phagocytes. Curiously, 11-ketotestosterone was more powerful than testosterone at inducing the expression of its own receptor, namely androgen receptor b (ARb), in acidophilic granulocytes (AGs), but none of them affected the basal ARb expression levels in macrophages (MØ). Furthermore, although physiological concentrations of testosterone exerted a pro-inflammatory effect on both AGs and MØs, 11-ketotestosterone showed an anti-inflammatory effect in AGs and a strong pro-inflammatory effect in MØs. Interestingly, both androgens modulated the expression of toll-like receptors in these two immune cell types, suggesting that androgens might regulate the sensitivity of phagocytes to pathogens and damage signals. Testosterone and 11-ketotestosterone have a competitive effect, at least, on the modulation of the expression of some genes. Therefore, our results show for the first time a non-overlapping role for testosterone and 11-ketotestosterone in the regulation of professional phagocyte functions in fish.

In situ forming microparticle implants for delivery of sex steroids in fish: Modulation of the immune response of gilthead seabream by testosterone.

Current knowledge on the sensitivity of marine fish to androgenic environmental chemicals is limited, despite the growing interest in the effects of endocrine disrupting chemicals. To study in vivo the effects of testosterone (T) on the fish immune response, we used a microencapsulation implant technique, the in situ forming microparticle system, containing 1 mg T/kg body weight (T-ISM), in adult specimens of gilthead seabream (Sparus aurata L.), a species of great economic interest. We demonstrated that implants themselves (without T) have no significant effect on most of the parameters measured. In T-ISM implanted fish, T serum levels reached supraphysiological concentrations accompanied by a slight increase in 11-ketotestosterone and 17ß-estradiol levels 21 days post-implantation (dpi). Liver and head-kidney samples were processed 7 and 21 dpi to assess T-ISM effect on (i) the mRNA expression of genes involved in the metabolism of steroid hormones and in the immune response, and (ii) phagocyte activities. The expression profile of cytokines, chemokines and immune receptors was altered in T-ISM implanted animals that showed an early pro-inflammatory tendency, and then, a mixed pro-/anti-inflammatory activation during longer exposure. Furthermore, the enhancement of phagocytic activity and the production of reactive oxygen species by leukocytes 21 dpi in T-ISM implanted specimens suggest fine modulation of the innate immune response by T. Taken together, these data demonstrate for the first time the feasibility of using ISM implants in an aquatic species, and provide new data on the role played by T on the immune response in fish.

Sodium alginate as feed additive in cultured sea bream (Sparus aurata): does it modify the quality of the flesh?

The objective of this study was to evaluate the effect of sodium alginate obtained from brown seaweed as a prebiotic supplement to the feed of reared sea bream (Sparus aurata). Addition of the alginate to a control diet was investigated at both concentrations 2% and 5%. Proximate composition in the flesh were not modified significantly by sodium alginate inclusion in the diet of the sea bream; however the fat and ash content in the specimens supplemented with 5% alginate were found to be significantly higher than those found in individuals who were fed the control diet. No significant differences in mineral content, fatty acid profiles, cholesterol content, texture parameters and sensory acceptability among the three studied groups. Results obtained in this study offer support for the use of alginate as a feed additive in sea bream diets since no significant effects were found in the flesh quality and characteristics of commercial size sea bream.

Characterization of European sea bass transcripts by RNA SEQ after oral vaccine against V. anguillarum.

The European sea bass (Dicentrarchus labrax) is, along with the gilthead sea bream (Sparus aurata), one of the most extensively cultured species in European aquaculture productions. Massive mortalities may be caused by bacterial or viral infections in intensive aquaculture production. Evaluation of the efficacy of an oral vaccine against Vibrio anguillarum (Aquavac Vibrio Oral) in sea bass revealed specific immune gene expression profiles in the gut as well as protection of fish. In the present study, we performed RNA SEQ in two different tissues: the hind gut and the head kidney. For each tissue, one control sample (where a sample presents a pool of four to five individuals) and one sample after oral vaccine against V. anguillarum were submitted to 454 next-generation sequencing. In total, 269,043 sequences were obtained, 143,007 for head kidney and 125,036 for gut. The read lengths ranged from 40 to 706 bp with an average length of 348 bp. The total number of clustered sequences for head kidney is accounting to 49,089 (∼34 %) and for gut to 71,676 (~57 %). Differential expression was detected for 496 transcripts in head kidney and for 336 in gut. The results not only enrich the present collection of expressed sequence tag sequences including rare transcripts like leukocyte immune-type receptors, cullin, or supervillin but also show the efficacy of oral vaccination against V. anguillarum.

Metabolic adjustments of Dentex dentex to prolonged starvation and refeeding.

The particular metabolic strategies of the common dentex (Dentex dentex) to face a period of prolonged starvation and subsequent refeeding were assessed. Plasma metabolites, endogenous reserves, and the activity of key enzymes of intermediary metabolism in liver, white muscle, and heart were evaluated. Plasma glucose, total lipid, triglycerides, total-, HDL- and LDL-cholesterol, and protein levels, liver, and white muscle glycogen, and perivisceral, and muscle fat were significantly reduced by starvation, whereas liver lipid content was surprisingly increased. Those enzymes involved in phosphorylation and oxidation of glucose and lipid synthesis, as well as alanine aminotransferase activity, were significantly depressed in liver of starved fish. The increase in ß-hydroxyacyl-CoA dehydrogenase (HOAD) indicated an enhanced fatty acid oxidation during starvation. Part of the acetyl-CoA generated by ß-oxidation was oxidized in the hepatic Krebs cycle, as reflected the increased citrate synthase (CS) activity. The oxaloacetate required for the reaction catalized by CS activity would be supplied by aspartate aminotransferase (ASAT) activity whose activity was also enhanced. Glutamate dehydrogenase also increased to deaminate the glutamate produced by transaminases, especially by the increased ASAT activity. Liver gluconeogenesis of starved fish was maintained at the same rate that in controls, with glycerol playing an important role as glucogenic substrate. The increased hepatic ß-hydroxybutyrate dehydrogenase (ß-OHBDH) activity indicates that part of the acetyl-CoA arriving from ß-oxidation was being diverted for ketone bodies production with dentex liver playing an important role in providing ketone bodies as fuels for other tissues under such circumstances. Most enzyme activities in white muscle of starved dentex were significantly depressed. In heart, starvation induced an important inhibition of those enzymes involved in glucose and protein metabolism, whereas CS, HOAD, and ß-OHBDH activities were maintained at control levels. Although several biomarkers assayed returned to control values after refeeding, many others did not, which indicate that after 3 weeks of refeeding, pre-starved dentex is still experiencing a transient period of metabolic adjustments directed toward the restoration of body mass.