Adherence to quality indicators for emergency department treatment of acute poisoning according to patient sex. / Grado de cumplimiento de los indicadores de calidad según el sexo del paciente en las intoxicaciones agudas en urgencias.

OBJECTIVES: To study differences in the emergency department treatment of acute poisoning according to biological sex of patients and to assess adherence to care quality indicators. MATERIAL AND METHODS: Retrospective observational study including all cases of acute poisoning diagnosed in patients over the age of 14 years treated in a tertiary care hospital emergency department over a period of 4 years. We analyzed demographic variables, substance type and reason for acute poisoning, degree of adherence to quality indicators, and discharge destination. RESULTS: A total of 1144 cases were included; 710 patients (62.1%) were female and 434 (37.9%) were male. The proportion of deliberate self-poisoning was higher in females (52.3% vs 41.4% in males; P .001); unintentional poisoning was less frequent in females (in 24.9% vs in 30.3% of males; P = .047). Benzodiazepine poisoning was more frequent in females (in 49.6% vs 41.2%; P = .007). Street drug and alcohol poisoning was less common in females. Adherence to quality indicators was high (> 85%) for both sexes. CONCLUSION: The epidemiologic profile of poisoning is different in females and males. General emergency department adherence to quality indicators can be considered optimal. We detected no qualitative sex-related differences in the care of patients with acute poisoning.

OBJETIVO: Estudiar las diferencias dependiendo del sexo en la atención de pacientes con intoxicaciones agudas en urgencias y en el grado de cumplimiento de los indicadores de calidad (IC). METODO: Estudio observacional y retrospectivo, que incluyó todos los casos de intoxicación aguda de pacientes mayores de 14 años atendidos en el servicio de urgencias de un hospital terciario durante 4 años. Se analizaron variables demográficas, tipo de tóxicos y causa de la intoxicación, el grado de cumplimiento de los IC y destino al alta. RESULTADOS: Se registraron 1.144 casos, un 62,1% (n = 710) eran mujeres. Las mujeres tuvieron mayor número de intoxicaciones voluntarias (52,3% vs 41,4%; p 0,001) y menos de manera accidental (24,9% vs 30,3%; p = 0,047). Los fármacos más frecuentes en mujeres fueron las benzodiacepinas (49,6% vs 41,2%; p = 0,007), y las intoxicaciones por drogas de abuso y alcohol fueron menores que en hombres. Hubo un alto grado de cumplimiento en la mayoría de los IC (> 85%) en ambos sexos. CONCLUSIONES: El perfil epidemiológico de la intoxicación aguda en mujeres es diferente al de los hombres. En general se puede considerar como óptimo el cumplimiento de los IC en urgencias. No existen diferencias cualitativas en la asistencia del paciente intoxicado con respecto a su sexo.

Current status of fertility preservation in a Spanish tertiary public hospital: multidisciplinary approach and experience in over 1500 patients.

PURPOSE: Currently, 15% of gynaecological and 9% of haematological malignancies are diagnosed before the age of 40. The increased survival rates of cancer patients who are candidates for gonadotoxic treatments, the delay in childbearing to older ages, and the optimization of in vitro fertilisation techniques have all contributed to an increased interest in fertility preservation (FP) treatments. This study reviews the experience of the Fertility Preservation Programme (FPP) of a tertiary public hospital with a multidisciplinary approach. METHODS: This retrospective study included all the available (FP) treatments, performed in patients of childbearing age between 2006 and 2022. RESULTS: 1556 patients were referred to the FPP: 332 oocyte vitrification cycles, 115 ovarian cortex cryopreservation with 11 orthotopic autotransplantations, 175 gonadotropin-releasing hormone (GnRH) agonist treatments, 109 fertility-sparing treatments for gynaecological cancer, and 576 sperm cryopreservation were performed. Malignancy was the main indication for FP (the main indications being breast cancer in women and haematological malignancies in men), although non-oncological pathologies, such as endometriosis and autoimmune diseases, have increased in recent years. Currently, the most widely used FP technique is oocyte vitrification, the increase of which has been associated with a decrease in the use of cortex CP and GnRH agonists. CONCLUSIONS: The increase in FP treatment reflects the implementation of reproductive counselling in oncology programmes. A multidisciplinary approach in a tertiary public hospital allows individualised FP treatment for each patient. In recent years, there has been a change in trend with the introduction of new indications for FP and a change in techniques due to their optimisation.

Bariatric Surgery on Reproductive Outcomes: the Impact According to the Diagnosis of Polycystic Ovarian Syndrome and Surgical Procedures.

BACKGROUND: There is limited evidence on the impact of bariatric surgery (BS) on reproductive outcomes in the general population and specifically in patients with polycystic ovarian syndrome (PCOS) or the effect of different BS techniques. PURPOSE: The study aims to investigate the impact of BS on fertility, pregnancy, and newborn outcomes in reproductive age women who have undergone BS and the outcomes according to surgical procedure and PCOS diagnosis. MATERIALS AND METHODS: This was a retrospective, descriptive, cross-sectional study performed in women from 18-39 years undergoing BS in our centre from January 2005 to December 2010. We performed a telephone interview including a structured reproductive health survey on fertility, pregnancy, and offspring outcomes before and after BS. RESULTS: Of the women, 872 underwent BS during the study period, 298 were 18-39 years old, and reproductive data was obtained from 217. Women with regular menstrual cycles increased from 52.9% before BS to 72.9% 1 year after surgery. The percentage of patients with a time-to-pregnancy longer than 12 months was higher after laparoscopic sleeve gastrectomy (LSG) (17.8%) compared to laparoscopic Roux-en-Y gastric bypass (7.1%; p = 0.02). Menstrual regularity was less frequent in PCOS (n = 43) (26.0%) compared to non-PCOS women before BS (60.1%; p = 0.01), with no differences after surgery. Several perinatal results showed an improvement after BS, with a reduction in macrosomia rate and birth weight. CONCLUSION: BS was associated with an improvement in several reproductive outcomes. Menstrual regularity was especially improved in PCOS women. Further research may clarify the impact of LSG on fertility.

Protein kinase CK-1 inhibitors as new potential drugs for amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease where motor neurons in cortex, brain stem, and spinal cord die progressively, resulting in muscle wasting, paralysis, and death. Currently, effective therapies for ALS are lacking; however, identification of pathological TAR DNA-binding protein 43 (TDP-43) as the hallmark lesion in sporadic ALS suggests new therapeutic targets for pharmacological intervention. Pathological TDP-43 phosphorylation appears to drive the onset and progression of ALS and may result from upregulation of the protein kinase CK-1 in affected neurons, resulting in postranslational TDP-43 modification. Consequently, brain penetrant specific CK-1 inhibitors may provide a new therapeutic strategy for treating ALS and other TDP-43 proteinopathies. Using a chemical genetic approach, we report the discovery and further optimization of a number of potent CK-1δ inhibitors. Moreover, these small heterocyclic molecules are able to prevent TDP-43 phosphorylation in cell cultures, to increase Drosophila lifespan by reduction of TDP-43 neurotoxicity, and are predicted to cross the blood-brain barrier. Thus, N-(benzothiazolyl)-2-phenyl-acetamides are valuable drug candidates for further studies and may be a new therapeutic approach for ALS and others pathologies in which TDP-43 is involved.

Crosstalk between phosphodiesterase 7 and glycogen synthase kinase-3: two relevant therapeutic targets for neurological disorders.

Chronic neuroinflammation has been increasingly recognized as a primary mechanism underlying acute brain injury and neurodegenerative diseases. Enhanced expression of diverse pro-inflammatory agents in glial cells has been shown to contribute to the cell death that takes place in these disorders. Previous data from our group have shown that different inhibitors of the cyclic adenosine monophosphate (cAMP) specific phosphodiesterase 7 (PDE7) and glycogen synthase kinase-3 (GSK-3) enzymes are potent anti-inflammatory agents in different models of brain injury. In this study, we investigated cross-talk between PDE7 and GSK-3, two relevant therapeutic targets for neurological disorders, using a chemical approach. To this end, we compared specific inhibitors of GSK-3 and PDE7 with dual inhibitors of both enzymes with regard to anti-inflammatory effects in primary cultures of glial cells treated with lipopolysaccharide. Our results show that the GSK-3 inhibitors act exclusively by inhibition of this enzyme. By contrast, PDE7 inhibitors exert their effects via inhibition of PDE7 to increase intracellular cAMP levels but also through indirect inhibition of GSK-3. Activation of protein kinase A by cAMP results in phosphorylation of Ser9 of GSK-3 and subsequent inhibition. Our results indicate that the indirect inhibition of GSK-3 by PDE7 inhibitors is an important mechanism that should be considered in the future development of pharmacological treatments.

Unraveling phosphodiesterase surfaces. Identification of phosphodiesterase 7 allosteric modulation cavities.

The last findings of our group by using chemical genetic approaches have shown that PDE7 is an interesting target in neurodegenerative diseases. The following step in this travel to unravel PDE7 is the design of more selective inhibitors. In this sense we have proposed to perform an analysis of PDE7 surface to identify possible allosteric sites following by a docking study of different PDE7 inhibitors synthesized by our group. Thanks to these studies we have proved the existence of allosteric sites in PDE7 and we have been able to explain the binding modes of the employed PDE7 inhibitors.

Phosphodiesterase 7 inhibitor reduced cognitive impairment and pathological hallmarks in a mouse model of Alzheimer's disease.

Elevated levels of amyloid beta (Aß) peptide, hyperphosphorylation of tau protein, and inflammation are pathological hallmarks in Alzheimer's disease (AD). Phosphodiesterase 7 (PDE7) regulates the inflammatory response through the cyclic adenosine monophosphate signaling cascade, and thus plays a central role in AD. The aim of this study was to evaluate the efficacy of an inhibitor of PDE7, named S14, in a mouse model of AD. We report that APP/Ps1 mice treated daily for 4 weeks with S14 show: (1) significant attenuation in behavioral impairment; (2) decreased brain Aß deposition; (3) enhanced astrocyte-mediated Aß degradation; and (4) decreased tau phosphorylation. These effects are mediated via the cyclic adenosine monophosphate/cyclic adenosine monophosphate response element-binding protein signaling pathway, and inactivation of glycogen synthase kinase (GSK)3. Our data support the use of PDE7 inhibitors, and specifically S14, as effective therapeutic agents for the prevention and treatment of AD.

Identification in silico and experimental validation of novel phosphodiesterase 7 inhibitors with efficacy in experimental autoimmune encephalomyelitis mice.

A neural network model has been developed to predict the inhibitory capacity of any chemical structure to be a phosphodiesterase 7 (PDE7) inhibitor, a new promising kind of drugs for the treatment of neurological disorders. The numerical definition of the structures was achieved using CODES program. Through the validation of this neural network model, a novel family of 5-imino-1,2,4-thiadiazoles (ITDZs) has been identified as inhibitors of PDE7. Experimental extensive biological studies have demonstrated the ability of ITDZs to inhibit PDE7 and to increase intracellular levels of cAMP. Among them, the derivative 15 showed a high in vitro potency with desirable pharmacokinetic profile (safe genotoxicity and blood brain barrier penetration). Administration of ITDZ 15 in an experimental autoimmune encephalomyelitis (EAE) mouse model results in a significant attenuation of clinical symptoms, showing the potential of ITDZs, especially compound 15, for the effective treatment of multiple sclerosis.

Effect of phosphodiesterase 7 (PDE7) inhibitors in experimental autoimmune encephalomyelitis mice. Discovery of a new chemically diverse family of compounds.

Phosphodiesterase (PDE) 7 is involved in proinflammatory processes, being widely expressed both on lymphocytes and on certain brain regions. Specific inhibitors of PDE7 have been recently reported as potential new drugs for the treatment of neurological disorders because of their ability to increase intracellular levels of cAMP and thus to modulate the inflammatory process, as a neuroprotective well-established strategy. Multiple sclerosis is an unmet disease in which pathologies on the immune system, T-cells, and specific neural cells are involved simultaneously. Therefore, PDE7 inhibitors able to interfere with all these targets may represent an innovative therapy for this pathology. Here, we report a new chemically diverse family of heterocyclic PDE7 inhibitors, discovered and optimized by using molecular modeling studies, able to increase cAMP levels in cells, decrease inflammatory activation on primary neural cultures, and also attenuate the clinical symptoms in the experimental autoimmune encephalomyelitis (EAE) mouse model. These results led us to propose the use of PDE7 inhibitors as innovative therapeutic agents for the treatment of multiple sclerosis.

5-Imino-1,2-4-thiadiazoles and quinazolines derivatives as glycogen synthase kinase 3ß (GSK-3ß) and phosphodiesterase 7 (PDE7) inhibitors: determination of blood-brain barrier penetration and binding to human serum albumin.

5-Imino-1,2,4-thiadiazoles and quinazolines derivatives as glycogen synthase kinase 3ß (GSK-3ß) and phosphodiesterase 7 (PDE7) inhibitors were characterized for their ability to pass the blood-brain barrier (BBB) together with their human serum albumin (HSA) binding using high-performance liquid affinity chromatography (HPLAC) and circular dichroism (CD). To study the blood-brain barrier penetration, a parallel artificial membrane permeability assay (PAMPA) using a porcine brain lipid was employed. For the HPLAC investigation, HSA was previously covalently immobilized to the silica matrix of the HPLC column. This HSA-based column was used to characterize the high affinity binding sites of 5-imino-1,2,4-thiadiazoles and quinazolines derivatives to HSA. Displacement experiments in the presence of increasing concentrations of competitors known to bind selectively to the main binding sites of HSA were carried out to determine their possible binding site. The same drug-protein system was studied by CD. The analysed compounds were able to pass BBB, they present good drug-like properties and they showed a high affinity to HSA. Competition experiments showed an anticooperative interaction at sites I and II, and an independent binding at bilirubin binding site on HSA.

Neuroprotective efficacy of quinazoline type phosphodiesterase 7 inhibitors in cellular cultures and experimental stroke model.

A simple and efficient synthetic method for the preparation of quinazoline type phosphodiesterase 7 (PDE7) inhibitors, based on microwave irradiation, has been developed. The use of this methodology improved yields and reaction times, providing a scalable procedure. These compounds are pharmacologically interesting because of their in vivo efficacy both in spinal cord injury and Parkinson's disease models, as shown in previous studies from our group. Herein we describe for the first time that administration of one of the PDE7 inhibitors here optimized, 3-phenyl-2,4-dithioxo-1,2,3,4-tetrahydroquinazoline (compound 5), ameliorated brain damage and improved behavioral outcome in a permanent middle cerebral artery occlusion (pMCAO) stroke model. Furthermore, we demonstrate that these PDE7 inhibitors are potent anti-inflammatory as well as neuroprotective agents in primary cultures of neural cells. These results led us to propose PDE7 inhibitors as a new class of therapeutic agents for neuroprotection.

Phosphodiesterase 7 inhibition preserves dopaminergic neurons in cellular and rodent models of Parkinson disease.

BACKGROUND: Phosphodiesterase 7 plays a major role in down-regulation of protein kinase A activity by hydrolyzing cAMP in many cell types. This cyclic nucleotide plays a key role in signal transduction in a wide variety of cellular responses. In the brain, cAMP has been implicated in learning, memory processes and other brain functions. METHODOLOGY/PRINCIPAL FINDINGS: Here we show a novel function of phosphodiesterase 7 inhibition on nigrostriatal dopaminergic neuronal death. We found that S14, a heterocyclic small molecule inhibitor of phosphodiesterase 7, conferred significant neuronal protection against different insults both in the human dopaminergic cell line SH-SY5Y and in primary rat mesencephalic cultures. S14 treatment also reduced microglial activation, protected dopaminergic neurons and improved motor function in the lipopolysaccharide rat model of Parkinson disease. Finally, S14 neuroprotective effects were reversed by blocking the cAMP signaling pathways that operate through cAMP-dependent protein kinase A. CONCLUSIONS/SIGNIFICANCE: Our findings demonstrate that phosphodiesterase 7 inhibition can protect dopaminergic neurons against different insults, and they provide support for the therapeutic potential of phosphodiesterase 7 inhibitors in the treatment of neurodegenerative disorders, particularly Parkinson disease.