Interference of the complex between NCS-1 and Ric8a with phenothiazines regulates synaptic function and is an approach for fragile X syndrome.

The protein complex formed by the Ca2+ sensor neuronal calcium sensor 1 (NCS-1) and the guanine exchange factor protein Ric8a coregulates synapse number and probability of neurotransmitter release, emerging as a potential therapeutic target for diseases affecting synapses, such as fragile X syndrome (FXS), the most common heritable autism disorder. Using crystallographic data and the virtual screening of a chemical library, we identified a set of heterocyclic small molecules as potential inhibitors of the NCS-1/Ric8a interaction. The aminophenothiazine FD44 interferes with NCS-1/Ric8a binding, and it restores normal synapse number and associative learning in a Drosophila FXS model. The synaptic effects elicited by FD44 feeding are consistent with the genetic manipulation of NCS-1. The crystal structure of NCS-1 bound to FD44 and the structure-function studies performed with structurally close analogs explain the FD44 specificity and the mechanism of inhibition, in which the small molecule stabilizes a mobile C-terminal helix inside a hydrophobic crevice of NCS-1 to impede Ric8a interaction. Our study shows the drugability of the NCS-1/Ric8a interface and uncovers a suitable region in NCS-1 for development of additional drugs of potential use on FXS and related synaptic disorders.

Metabolic and Clinical Outcomes in Type 1 Diabetes in the COVID-19 Pre- and Post-Vaccination Periods in Spain: The COVID-SED1 Study.

Aims: To evaluate the metabolic and clinical outcomes in the Spanish type 1 diabetes mellitus (T1D) population before and after COVID-19 vaccination. Methods: A retrospective observational study was carried out in Spanish public hospitals previously enrolled in the SED1 study. Adults and children with T1D were included and their clinical electronic records were reviewed. Clinical, laboratory, and glucometric parameters from continuous glucose monitoring (CGM) data corresponding to the periods before and after administering the first COVID-19 vaccination were analyzed. Results: A total of 26 centers and 228 patients participated in this new phase of the SED1 study and 187 were finally evaluable (mean age 37.5 ± 15.6 years, 56.7% women). Overall, 94.6% of the sample was vaccinated, and this percentage increased with higher levels of education (p-value = 0.027). In the pre- and post-vaccination periods, respectively, the number of patients with acute hyperglycemic decompensation was 6/161 (3.7%) and 7/161 (4.3%) (p = 1) and with acute hypoglycemic decompensation was 6/161 (3.7%) and 6/161 (3.7%) (p = 1). The HbA1c level was lower in the post-vaccination period(mean ± SD, mg/dL): pre-vaccination 7.4 ± 0.9; post-vaccination 7.2 ± 1.0, (-0.19; p-value = 0.0006). A total of 31.9% of patients (95% CI: 24.7-39.7) in the pre-vaccination period and 45.0% (IC95%: 37.1-53.1) in the post-vaccine period had HbA1c < 7% (p-value < 0.001). Glucometrics from CGM data also showed numerical improvements post-vaccination. Conclusions: The COVID-19 vaccination was highly accepted in the Spanish T1D population, with hesitancy about the COVID-19 vaccine being higher in those with lower educational levels. A mildly better glycemic control was observed in the post-vaccination period.

Bayesian analysis of the geographical variation of type 1 diabetes mellitus in under 15 yr olds in northeast Spain, 1991-2009.

OBJECTIVE: High variability has been observed in type 1 diabetes mellitus (DM1) incidence rates (IRs) in childhood. The aim of this study was to characterize DM1 in Aragón and to identify variations in the geographical pattern by gender. METHODS: A descriptive and ecological study was conducted to determine geographical variations in the DM1 incidence for the period 1991-2009. The source of information was the registry of DM1. To determine data completeness, a capture-recapture analysis was performed. Cases were georeferenced according to the Basic Healthcare Area (BHA) of residence. IRs for both genders, age group, 5 yr of diagnosis, and 95% confidence intervals (95% CIs) were calculated. Geographical pattern was studied applying Bayesian statistical model. The standardized incidence ratios (SIRs), smoothed SIR, and the posteriori risk probability (PRP) were represented cartographically for BHA stratified by gender. RESULTS: The completeness was 93.5%. The global IR was 19.2 cases/10(5) person-years (95% CI: 17.6-20.8), boys 21.4 (95% CI: 19.0-23.8) and girls 16.8 (95% CI: 14.7-19.1). The age-specific rates were significantly lower in the 0-4 year age group with respect to the groups of 5-9 and 10-14 years. For boys, areas with a statistically significant excess of risk were found in the north [smoothed SIR: 118-167.9 and PRP of what the smoothed SIR would be greater than 100 (PRP) above 0.8] and below average risk in the south (smoothed SIR: 65.9-79.1 and PRP less than 0.2). CONCLUSIONS: DM1 IR presented a north-south geographical pattern in boys. This pattern was not observed in girls or when both genders were considered together. Later studies should include gender as an essential variable.

Informal STEM learning: Examples from everyday spatial behaviors.

Introduction: Extensive research has shown a close relationship between spatial abilities and success in STEM disciplines because many STEM problems often require students to reason about spatial information. Everyday spatial behaviors may predate and facilitate the development of spatial skills. Therefore, the current study examined children's everyday spatial behaviors and their associations with broader child development outcomes and individual differences. Methods: Based on previous research, we developed an everyday spatial behaviors questionnaire for children (ESBQC). A total of 174 parents and their children aged 4-9 years old participated. In ESBQC, parents rated how much difficulty their children experience with different spatial behaviors, such as putting together a puzzle, retracing a route, or hitting a moving ball. Results: Factor analysis revealed 8 components in ESBQC. The internal reliabilities were relatively high. ESBQC was positively correlated with age but not with sex. Furthermore, ESBQC predicted sense of direction, even after considering age and bias associated with parent reports. Discussion: Our questionnaire may provide a useful tool for parents and other stakeholders to better understand everyday spatial behaviors and encourage interest and competence in spatial skills, ultimately promoting STEM learning in informal, everyday settings.

Clinical characteristics and management of type 1 diabetes in Spain. The SED1 study.

OBJECTIVES: To determine the sociodemographic and clinical profile of a representative sample of people with type 1 diabetes mellitus (DM1) in Spain and identify factors associated with glycemic control. MATERIAL AND METHODS: A cross-sectional observational study was carried out in adults and children with DM1 treated in 75 Spanish public hospitals, geographically distributed in order to be representative of the Spanish population. Within each center, the patients were included on a consecutive basis as they visited the clinic. They were interviewed, and their clinical histories were reviewed. A descriptive statistical analysis was made, and factors associated with HbA1c were analysed using multivariate linear regression analysis. RESULTS: A total of 647 patients were included: 55.3% females, aged 36.6 ±â€¯14.4 years, 97.2% Caucasians, BMI 24.7 ±â€¯4.4 kg/m2 (12.1% ≥ 30 kg/m2), and 74.0% had secondary / university education. A total of 20.2% were active smokers. The mean time from the diagnosis of DM1 was 17.9 ±â€¯12.0 years. A total of 48.7% presented comorbidities: 19.3% retinopathy and 16.4% hypothyroidism. As regards treatment for DM1, 76.5% received basal-bolus insulin therapy and 20.7% continuous subcutaneous insulin infusion (CSII); 51.0% of the patients used an insulin/carbohydrate ratio (ICR), with 4.6 ±â€¯1.6 self-monitored capillary blood glucose (SMCBG) measurements a day, and 24.8% used continuous glucose monitoring (CGM). The mean HbA1c value was 7.6 ±â€¯1.1% (30% below 7%). Metabolic control improved (lower HbA1c) with more daily SMCBG (B = -0.053; p = 0.009), a higher educational level (B = 0.461; P < 0.001), greater number of hypoglycemia episodes (B = -0.253; P = 0.018) and carbohydrate counting (B = -0.190; P = 0.048), and worsened the longer the duration of the disease (B = 0.010; P = 0.010), higher total dose of insulin (B = 0.010; P < 0.0001), poorer adherence to diet (B = 0.650; P < 0.0001) and a family history of DM (B = -0.233; P = 0.007). CONCLUSIONS: The management of patients with DM1 in Spain, as well as the treatment they receive, is similar to that seen in other Western countries. Blood glucose control is associated with educational level, disease duration, and the characteristics of treatment and self-care.

Clinical characteristics and management of type 1 diabetes in Spain. The SED1 study. / Características clínicas y manejo de la diabetes tipo 1 en España. Estudio SED1.

OBJECTIVES: To determine the sociodemographic and clinical profile of a representative sample of people with type 1 diabetes mellitus (DM1) in Spain and identify factors associated with glycemic control. MATERIAL AND METHODS: A cross-sectional observational study was carried out in adults and children with DM1 treated in 75 Spanish public hospitals, geographically distributed in order to be representative of the Spanish population. Within each center, the patients were included on a consecutive basis as they visited the clinic. They were interviewed, and their clinical histories were reviewed. A descriptive statistical analysis was made, and factors associated with HbA1c were analyzed using multivariate linear regression analysis. RESULTS: A total of 647 patients were included: 55.3% females, aged 36.6±14.4 years, 97.2% Caucasians, BMI 24.7±4.4kg/m2 (12.1% ≥30kg/m2), and 74.0% had secondary / university education. A total of 20.2% were active smokers. The mean time from the diagnosis of DM1 was 17.9±12.0 years. A total of 48.7% presented comorbidities: 19.3% retinopathy and 16.4% hypothyroidism. As regards treatment for DM1, 76.5% received basal-bolus insulin therapy and 20.7% continuous subcutaneous insulin infusion (CSII); 51.0% of the patients used an insulin/carbohydrate ratio (ICR), with 4.6±1.6 self-monitored capillary blood glucose (SMCBG) measurements a day, and 24.8% used continuous glucose monitoring (CGM). The mean HbA1c value was 7.6±1.1% (30% below 7%). Metabolic control improved (lower HbA1c) with more daily SMCBG (B=-0.053; p=0.009), a higher educational level (B=0.461; P<0.001), greater number of hypoglycemia episodes (B=-0.253; P=0.018) and carbohydrate counting (B=-0.190; P=0.048), and worsened the longer the duration of the disease (B=0.010; P=0.010), higher total dose of insulin (B=0.010; P<0.0001), poorer adherence to diet (B=0.650; P<0.0001) and a family history of DM (B=-0.233; P=0.007). CONCLUSIONS: The management of patients with DM1 in Spain, as well as the treatment they receive, is similar to that seen in other Western countries. Blood glucose control is associated with educational level, disease duration, and the characteristics of treatment and self-care.

Thienylhalomethylketones: Irreversible glycogen synthase kinase 3 inhibitors as useful pharmacological tools.

Thienylhalomethylketones, whose chemical, biological, and pharmaceutical data are here reported, are the first irreversible inhibitors of GSK-3beta described to date. Their inhibitory activity is likely related to the cysteine residue present in the ATP-binding site, which is proposed as a relevant residue for modulation of GSK-3 activity. The good cell permeability of the compounds allows them to be used in different cell models. Overall, the results presented here support the potential use of halomethylketones as pharmacological tools for the study of GSK-3beta functions and suggest a new mechanism for GSK-3beta inhibition that may be considered for further drug design.

A Reminder From the Devastation Hurricane Maria Left Behind.

On September 20, 2017, Hurricane Maria hit Puerto Rico, causing an unprecedented humanitarian crisis on a level that none of us have experienced before. The following editorial intends to show a physician's perspective of the impact of this storm on healthcare, particularly in triggering cardiovascular events.

Enzymatic and solid-phase synthesis of new donepezil-based L- and d-glutamic acid derivatives and their pharmacological evaluation in models related to Alzheimer's disease and cerebral ischemia.

Previously, we have described N-Bz-L-Glu[NH-2-(1-benzylpiperidin-4-yl)ethyl]-O-nHex (IQM9.21, L-1) as an interesting multifunctional neuroprotective compound for the potential treatment of neurodegenerative diseases. Here, we describe new derivatives and different synthetic routes, such as chemoenzymatic and solid-phase synthesis, aiming to improve the previously described route in solution. The lipase-catalysed amidation of L- and D-Glu diesters with N-benzyl-4-(2-aminoethyl)piperidine has been studied, using Candida antarctica and Mucor miehei lipases. In all cases, the α-amidated compound was obtained as the main product, pointing out that regioselectivity was independent of the reacting Glu enantiomer and the nature of the lipase. An efficient solid-phase route has been used to produce new donepezil-based L- and D-Glu derivatives, resulting in good yield. At micromolar concentrations, the new compounds inhibited human cholinesterases and protected neurons against toxic insults related to Alzheimer's disease and cerebral ischemia. The CNS-permeable compounds N-Cbz-L-Glu(OEt)-[NH-2-(1-benzylpiperidin-4-yl)ethyl] (L-3) and L-1 blocked the voltage-dependent calcium channels and L-3 protected rat hippocampal slices against oxygen-glucose deprivation, becoming promising anti-Alzheimer and anti-stroke lead compounds.

Thienyl and phenyl alpha-halomethyl ketones: new inhibitors of glycogen synthase kinase (GSK-3beta) from a library of compound searching.

Glycogen synthase kinase (GSK-3beta) plays a crucial role in Alzheimer's disease (AD). Its inhibition is a valid approach to the treatment of AD. In this initial letter, some thienyl and phenyl alpha-halomethyl ketones are described as new non-ATP competitive inhibitors of GSK-3beta. They are considered as lead compounds for designing and synthesizing new series, to carry out SAR studies, clear up the mechanism of action, and, in general, evaluate their therapeutical usefulness.

Non-cholinergic pharmacotherapy approaches to the future treatment of Alzheimer's disease.

Research on the molecular basis of Alzheimer's disease has elucidated pathogenic pathways from which a range of rational pharmacological interventions has emerged. The most promising strategies involve approaches to retarding, halting or preventing the formation or accumulation of beta amyloid plaques and neurofibrillary tangles. Other therapeutic approaches include those acting via excitatory amino acid receptors, limiting the oxidative stress and inflammatory response associated with dementia, molecules with nerve growth factor like activity. In the present article these and the other recent advances in the neurobiology and pharmacotherapy of AD will be reviewed.

Functional disability and mental impairment as predictors of mortality in community-dwelling elderly Puerto Ricans.

This is a prospective study that explores the role of functional impairment as predictor of one-year mortality in the elderly of rural Puerto Rico. Between September, 1987 and June 1988, 1901 elderly were interviewed at their place of residence. Besides obtaining social and demographic information, assessment of functional status using a modified Katz scale and determination of mental status using the Short Portable Mental Status questionnaire were performed. During the one-year follow-up period 43 participants died. Multiple logistic regression analysis showed that the presence of functional (OR = 5.31) and mental impairment (OR = 2.22) were independent predictors of mortality when adjusted for age, education, gender and income. These findings are consistent with those of other studies, where the presence of functional and mental impairment, detected on admission to a hospital or while living in the community, were associated to a higher mortality.

Dibenzo[1,4,5]thiadiazepine: a hardly-known heterocyclic system with neuroprotective properties of potential usefulness in the treatment of neurodegenerative diseases.

In this work we describe a new family of dibenzo[1,4,5]thiadiazepines (2-12) that showed an interesting in vitro biological profile, namely neuroprotective and antioxidant properties, as well as blockade of cytosolic calcium entry. They showed no cytotoxic effects and the majority were predicted as CNS-permeable compounds. In human neuroblastoma cells they displayed good neuroprotective properties against mitochondrial oxidative stress which, in many cases, almost reached the full protection (>90%) when compounds were incubated with cells 24 h before the addition of toxic stressors. In co-incubation conditions these figures were smaller, although some compounds maintained an interesting level of neuroprotection, higher than 50%. Four selected compounds (2, 5, 8, and 11) were found to be effective antioxidant agents by sequestering mitochondrial radical oxygen species (ROS). Moreover, compound 2 showed a remarkable calcium-channel modulating activity. The interest of these compounds is increased by the fact that dibenzo[1,4,5]thiadiazepine is a barely known structure that is not difficult to synthesize and presents very few described derivatives, opening a new and broad line of research in Medicinal Chemistry.

ITH12410/SC058: a new neuroprotective compound with potential in the treatment of Alzheimer's disease.

The neuroprotective profile of the dibenzothiadiazepine ITH12410/SC058 (2-chloro-5,6-dihydro-5,6-diacetyldibenzo[b,f][1,4,5]thiadiazepine) against several neurotoxicity models related to neurodegenerative diseases is herein described. ITH12410/SC058 protected SH-SY5Y cells against the loss of cell viability elicited by amyloid beta peptide and okadaic acid, a selective inhibitor of phosphoprotein phosphatase 2A that induces neurofibrillary tangle formation. Furthermore, ITH12410/SC058 is neuroprotective against several in vitro models of oxidative stress, that is, H2O2 exposure or incubation with rotenone plus oligomycin A in SH-SY5Y cells, and oxygen and glucose deprivation followed by reoxygenation in rat hippocampal slices. By contrast, ITH12410/SC058 was unable to significantly protect SH-SY5Y neuroblastoma cells against the toxicity elicited by Ca(2+) overload. Our results confirm the hypothesis that the dibenzothiadiazepine ITH12410/SC058 features its neuroprotective actions in a multitarget fashion, and is a promising drug for the treatment of neurodegenerative diseases.

New melatonin-N,N-dibenzyl(N-methyl)amine hybrids: potent neurogenic agents with antioxidant, cholinergic, and neuroprotective properties as innovative drugs for Alzheimer's disease.

Here, we describe a new family of melatonin-N,N-dibenzyl(N-methyl)amine hybrids that show a balanced multifunctional profile covering neurogenic, antioxidant, cholinergic, and neuroprotective properties at low-micromolar concentrations. They promote maturation of neural stem cells into a neuronal phenotype and thus they could contribute to CNS repair. They also protect neural cells against mitochondrial oxidative stress, show antioxidant properties, and inhibit human acetylcholinesterase (AChE). Moreover, they displace propidium from the peripheral anionic site of AChE, preventing the ß-amyloid aggregation promoted by AChE. In addition, they show low cell toxicity and can penetrate into the CNS. This multifunctional profile highlights these melatonin-N,N-dibenzyl(N-methyl)amine hybrids as useful prototypes in the research of innovative drugs for Alzheimer's disease.

Modulation of cAMP-specific PDE without emetogenic activity: new sulfide-like PDE7 inhibitors.

A forward chemical genetic approach was followed to discover new targets and lead compounds for Parkinson's disease (PD) treatment. By analysis of the cell protection produced by some small molecules, a diphenyl sulfide compound was revealed to be a new phosphodiesterase 7 (PDE7) inhibitor and identified as a new hit. This result allows us to confirm the utility of PDE7 inhibitors as a potential pharmacological treatment of PD. On the basis of these data, a diverse family of diphenyl sulfides has been developed and pharmacologically evaluated in the present work. Moreover, to gain insight into the safety of PDE7 inhibitors for human chronic treatment, we evaluated the new compounds in a surrogate emesis model, showing nonemetic effects.

Novel multitarget ligand ITH33/IQM9.21 provides neuroprotection in in vitro and in vivo models related to brain ischemia.

ITH33/IQM9.21 is a novel compound belonging to a family of glutamic acid derivatives, synthesized under the hypothesis implying that multitarget ligands may provide more efficient neuroprotection than single-targeted compounds. In rat hippocampal slices, oxygen plus glucose deprivation followed by re-oxygenation (OGD/Reox) elicited 42% cell death. At 1 µM, ITH33/IQM9.21 mitigated this damage by 26% and by 55% at 3 µM. OGD/Reox also elicited mitochondrial depolarization, overproduction of reactive oxygen species (ROS), enhanced expression of nitric oxide synthase (iNOS) and reduction of GSH levels. These changes were almost fully prevented when 3 µM ITH33/IQM9.21 was present during slice treatment with OGD/Reox. In isolated hippocampal neurons, ITH33/IQM9.21 reduced [Ca(2+)](c) transients induced by a high K(+) depolarizing solution or glutamate. In a photothrombotic model of stroke in mice, intraperitoneal injection of ITH33/IQM9.21 at 1.25 mg/kg, 2.5 mg/kg or 5 mg/kg given before and during 2 days after stroke induction, reduced infarct volume by over 45%. Furthermore, when the compound was administered 1 h post-stroke, a similar effect was observed. In conclusion, these in vitro and in vivo results suggest that ITH33/IQM9.21 exhibits neuroprotective effects to protect the vulnerable neurons at the ischemic penumbra by an effective and multifaceted mechanism, mediated by reduction of Ca(2+) overload, providing mitochondrial protection and antioxidant actions.

Utilidad de la determinación de cobre en periodo neonatal. Enfermedad de Menkes / Usefulness of Cu determination in the neonatal period. Menkes disease

Bajas concentraciones séricas de Cu en neonatos pueden ser la primera señal de una ingesta deficiente de este elemento o, alternativamente, de enfermedades genéticas que afectan su metabolismo. Desgraciadamente, es difícil la interpretación de las concentraciones de Cu en esta población, ya que están influenciadas por distintos factores, entre ellos la prematuridad, el tipo de alimentación y la presencia de un estado inflamatorio. Sin embargo, en el caso que aquí se describe fue la baja concentración sérica de Cu la primera pista para el diagnóstico de enfermedad de Menkes. Se demuestra así la utilidad de la determinación de Cu dentro de protocolos neurometabólicos y de retraso psicomotor en población neonatal y lactante (AU)

Low serum Cu concentrations in newborns can be the first indication of a severe Cu deficient intake or, alternatively, of genetic diseases affecting Cu metabolism. Unfortunately, interpretation of serum Cu concentrations in this population is difficult because they also influenced by several variables, such as, prematurity, type of feeding and inflammatory conditions. However, in the case described in this paper was a low serum Cu concentration the first clue for diagnosing Menkes disease. It is so demonstrated the usefulness of Cu determination within neurometabolic or psychomotor retardation protocols for newborn and infant populations (AU)

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.

Switching reversibility to irreversibility in glycogen synthase kinase 3 inhibitors: clues for specific design of new compounds.

Development of kinase-targeted therapies for central nervous system (CNS) diseases is a great challenge. Glycogen synthase kinase 3 (GSK-3) offers a great potential for severe CNS unmet diseases, being one of the inhibitors on clinical trials for different tauopathies. Following our hypothesis based on the enhanced reactivity of residue Cys199 in the binding site of GSK-3, we examine here the suitability of phenylhalomethylketones as irreversible inhibitors. Our data confirm that the halomethylketone unit is essential for the inhibitory activity. Moreover, addition of the halomethylketone moiety to reversible inhibitors turned them into irreversible inhibitors with IC(50) values in the nanomolar range. Overall, the results point out that these compounds might be useful pharmacological tools to explore physiological and pathological processes related to signaling pathways regulated by GSK-3 opening new avenues for the discovery of novel GSK-3 inhibitors.