Prediction methods of maxillary canine impaction: a systematic review.

OBJECTIVE: To describe and assess the available evidence of prediction methods of maxillary canine impaction (MCI). MATERIAL AND METHODS: A systematic search was conducted through PubMed, Cochrane Library, Embase, EBSCOhost, Scopus, ScienceDirect, Bireme and Scielo until December 2020. This systematic review was conducted according to the PRISMA statement. The methodology of the selected studies was assessed using the Quality Assessment Tool for Diagnostic Accuracy Studies (QUADAS-2). RESULTS: A total of 2391 articles were identified in the first approach and after a 2-phase selection, 11 studies were included in qualitative analysis. Prediction methods were constructed using equation-based models, geometric measurements and computational methods from clinical and imaging data to predict palatal/buccal MCI. The quality of evidence was low to moderate due to the presence of risk of bias in most of the studies included. Three cohort studies with the best methodological quality proposed prediction models based on geometric measurements, canine position and facial growth pattern that would allow predicting MCI from CBCT, lateral and panoramic radiographs. CONCLUSIONS: The evidence is limited and most of the studies present a low methodological quality. However, it is possible to suggest that some prediction methods based on the position of the canine and facial growth pattern could predict palatal/buccal MCI in mixed dentition. Cohort studies with better methodological quality and long-term follow-up are needed to better validate a prediction model.

Effects of raloxifene on cognition in postmenopausal women with schizophrenia: a 24-week double-blind, randomized, parallel, placebo-controlled trial.

We assessed the utility of raloxifene (60 mg/day) as an adjuvant treatment for cognitive symptoms in postmenopausal women with schizophrenia in a 24-week, double-blind, randomized, placebo-controlled study. Patients were recruited from the inpatient and outpatient services of Parc Sanitari Sant Joan de Déu, Hospital Universitari Institut Pere Mata, and Corporació Sanitària Parc Taulí. Seventy eight postmenopausal women with schizophrenia were randomized to either adjunctive raloxifene or placebo. Sixty-eight began the clinical trial (37 women on raloxifene adjunct) and 31 on placebo adjunct. The outcome measures were: memory, attention and executive function. Assessment was conducted at baseline and at week 24. Between groups homogeneity was tested with the Student's t test for continuous variables and/or the Mann-Whitney U test for ordinal variables and the χ2 test or Fisher's exact test for categorical variables. The differences between the two groups in neuropsychological test scores were compared using the Student's t test. The sample was homogenous with respect to age, formal education, illness duration and previous pharmacological treatment. The addition of raloxifene to antipsychotic treatment as usual showed no differences in cognitive function. The daily use of 60 mg raloxifene as an adjuvant treatment in postmenopausal women with schizophrenia has no appreciable effect.ClinicalTrials.gov Identifier: NCT01573637.

Temporomandibular disorders in growing patients after treatment of class II and III malocclusion with orthopaedic appliances: a systematic review.

OBJECTIVE: To determine if the use of orthopaedic appliances in growing patients applied to correct Class II and III malocclusion is related to the development of temporomandibular disorders (TMD). MATERIAL AND METHODS: A systematic review was conducted between 1960 and July 2017, based on electronic databases: PubMed, Cochrane Library, Embase, Medline, Scopus, EBSCOhost, Scielo, Lilacs and Bireme. Controlled clinical trials (CCTs) and randomized controlled trials (RCTs) were identified. The articles were selected and analyzed by two authors independently. The quality of the evidence was determined according to the guidelines of the Cochrane Risk Bias Assessment Tool and the Cochrane Quality Study Guide. RESULTS: Seven articles were included, four CCTs and three RCTs. The studies were grouped according to malocclusion treatment in (a) class II appliances (n = 4) and (b) class III appliances (n = 3). The quality of evidence was low due to the high risk of bias, independent of the association reported. All studies concluded that the use of orthopaedic appliances would not contribute to the development of TMD. CONCLUSIONS: The quality of evidence available is insufficient to establish definitive conclusions, since the studies were very heterogeneous and presented a high risk of bias. However, it is suggested that the use of orthopaedic appliances to correct class II and III malocclusion in growing patients would not be considered as a risk factor for the development of TMD. High-quality RCTs are required to draw any definitive conclusions.

Sleep and awake bruxism in adults and its relationship with temporomandibular disorders: A systematic review from 2003 to 2014.

OBJECTIVE: In order to establish a relationship between bruxism and temporomandibular disorders (TMDs), a systematic review was performed. MATERIALS AND METHODS: A systematic research was performed based on PubMed, Cochrane Library, Medline, Embase, BIREME, Lilacs and Scielo data bases, between 2003 and 2014 including all languages. Descriptive clinical cases were identified. Two independent authors selected the articles. PICO format was used to analyse the studies and the Newcastle-Ottawa Scale (NOS) was used to verify the quality of the evidence. RESULTS: Thirty-nine studies (n = 39) were analysed in this review. According to bruxism diagnosis, articles were grouped as follows: polysomnographic diagnosis (PSG) (n = 7), clinical diagnosis (n = 11) and survey/self-report (n = 21). Thirty-three articles (n = 33) established a positive relation between bruxism and TMD and six (n = 6) did not. Quality of evidence was low to moderate. In general, the most part of the studies showed shortcomings on their design with bias risk, and also had a low sensitivity on bruxism diagnosis. CONCLUSIONS: The evidence based on PSG was not as conclusive as the studies that used surveys and clinical exam to diagnosis bruxism, when bruxism was related to TMD. Sleep bruxism could be associated with myofascial pain, arthralgia and joint pathology as disc displacement and joint noises. Although the evidence at present is inconclusive and does not provide information according to the type of bruxism (bruxism sleep and wakefulness), it is possible to suggest that bruxism would be associated with TMD.

Centric relation-intercuspal position discrepancy and its relationship with temporomandibular disorders. A systematic review.

OBJECTIVE: The objective of this study is to assess the relationship between centric relation-intercuspal position discrepancy (CR-ICP discrepancy) and temporomandibular disorders (TMDs), by systematically reviewing the literature. MATERIALS AND METHODS: A systematic research was performed between 1960 and 2016 based on electronic databases: PubMed, Cochrane Library, Medline, Embase, Scopus, EBSCOhost, BIREME, Lilacs and Scielo, including all languages. Analytical observational clinical studies were identified. Two independent authors selected the articles. PICO format was used to analyze the studies. The Newcastle-Ottawa Scale (NOS) was used to verify the quality of the evidence. RESULTS: Four hundred and sixty-seven potentially eligible articles were identified. Twenty studies were analyzed, being grouped according to intervention in studies in orthodontic patients (n = 3) and studies in subjects without intervention (n = 17). Quality of evidence was low, with an average score of 3.36 according to Newcastle-Ottawa Scale. In most studies, the presence of CR-ICP discrepancy is associated with the presence of muscle (pain) and joint disorders (noise, disc displacement, pain, crepitus, osteoarthritis and osteoarthrosis). However, the lack of consistency of the results reported reduces the validity of the studies making it impossible to draw any definite conclusions. CONCLUSIONS: Because of the heterogeneity of the design and methodology and the low quality of the articles reviewed, it is not possible to establish an association between CR-ICP discrepancy and TMD. The consequence of CR-ICP discrepancy on the presence of TMD requires further research, well-defined and validated diagnostic criteria and rigorous scientific methodologies. Longitudinal studies are needed to identify CR-ICP discrepancy as a possible risk factor for the presence of TMD.

Tolerogenic dendritic cells induce antigen-specific hyporesponsiveness in insulin- and glutamic acid decarboxylase 65-autoreactive T lymphocytes from type 1 diabetic patients.

Tolerogenic dendritic cells (tDC) constitute a promising therapy for autoimmune diseases, since they can anergize T lymphocytes recognizing self-antigens. Patients with type 1 diabetes mellitus (T1D) have autoreactive T cells against pancreatic islet antigens (insulin, glutamic acid decarboxylase 65 -GAD65-). We aimed to determine the ability of tDC derived from T1D patients to inactivate their insulin- and GAD65-reactive T cells. CD14+ monocytes and CD4+CD45RA- effector/memory lymphocytes were isolated from 25 patients. Monocyte-derived DC were generated in the absence (control, cDC) or presence of IL-10 and TGF-ß1 (tDC), and loaded with insulin or GAD65. DC were cultured with T lymphocytes (primary culture), and cell proliferation and cytokine secretion were determined. These lymphocytes were rechallenged with insulin-, GAD65- or candidin-pulsed cDC (secondary culture) to assess whether tDC rendered T cells hyporesponsive to further stimulation. In the primary cultures, tDC induced significant lower lymphocyte proliferation and IL-2 and IFN-γ secretion than cDC; in contrast, tDC induced higher IL-10 production. Lymphocytes from 60% of patients proliferated specifically against insulin or GAD65 (group 1), whereas 40% did not (group 2). Most patients from group 1 had controlled glycemia. The secondary cultures showed tolerance induction to insulin or GAD65 in 14 and 10 patients, respectively. A high percentage of these patients (70-80%) belonged to group 1. Importantly, tDC induced antigen-specific T-cell hyporesponsiveness, since the responses against unrelated antigens were unaffected. These results suggest that tDC therapy against multiple antigens might be useful in a subset of T1D patients.

Pulmonary hypertension secondary to arteriovenous fistula: a case report.

Pulmonary hypertension is a rare disease, associated with a significant deterioration in quality of life, usually not curable and with an ominous prognosis. It is classified into five groups according to similar pathophysiological, clinical, haemodynamic, and treatment options in each of them. However, group 5 is the least common, encompassing different types of aetiological, semiological, and management conditions. We present the case of a patient diagnosed with precapillary component pulmonary hypertension, with the finding of an arteriovenous fistula at the peripheral level. Interventional exclusion was performed, achieving remission of her disease.

Pseudo-multicomponent reactions.

Classical multicomponent reactions (MCRs) are domino-type one-pot processes in which three or more different reactants are combined sequentially in the same reactor to synthesize compounds containing all or almost all atoms coming from the reactants. Besides, pseudo-MCRs are also domino-type one-pot processes involving combinations of at least three reactants but in which at least one of them takes part in two or more reaction steps. In consequence, the products synthesized through pseudo-MCRs contain also all or almost all atoms but coming from two or more identical reactants. Thus, pseudo-MCRs differ from classical MCRs because the first ones appear to involve an assembly of a higher number of different components than those that are being truly assembled. However, pseudo-MCRs are also useful synthetic tools to generate libraries of complex compounds in few experimental steps, and although the repeated reactants may make them appear less diverse than classical MCRs, this can be offset by the higher number of reactants that can participate in this type of reaction. Overall, there are two types of pseudo-MCRs. The first are those in which the duplicated reagents participate in different steps of the corresponding reaction mechanism. The second kind of pseudo-MCRs are those in which one or more components react simultaneously with a main reagent containing two or more identical functional groups. These latter are known as repetitive pseudo-MCRs. Thus, the aim of the present review is to cover for the first time selected works mainly published in the last two decades about pseudo-MCRs and their repetitive versions toward the synthesis of novel, complex, and highly symmetrical molecules, often including their interesting applications in various fields of science and technology. The manuscript has been categorized considering the number of reagents participating in the corresponding pseudo-MCRs, aiming to give readers novel insights for their future investigations.

[Results of pancreaticoduodenectomy in the treatment of periampullary tumors]. / Resultados actuales de la pancreatoduodenectomía para el tratamiento de los tumores periampulares y análisis de factores pronósticos de sobrevida.

BACKGROUND: The diagnosis and treatment of periampullary tumors represents a challenge for current medicine. AIM: To review the results of pancreaticoduodenectomy (PDD) in the treatment of periampullary tumors and to identify risk factors that impact the long-term survival. PATIENTS AND METHODS: We performed a retrospective study of patients who underwent a PDD for periampullary tumors between 1993 and 2009. We reviewed perioperative results and long term survival. We performed a multivariate analysis for long-term survival. RESULTS: A PDD was performed in 181 patients aged 58 ± 12 years (98 females). Pyloric preservation was done in 53% and a pancreatogastric anastomosis was used in 94% of cases. Morbidity was 62% and postoperative mortality was 5.5%. Pancreatic cancer was the most frequent pathological finding in 41%, followed by ampullary cancer in 28% and distal bile duct cancer in 16%. Median survival was 17 months, with a five years survival of 24%. Survival for ampullary tumors was 28 months with a five years survival of 32%. The median and five years survival were 14 months and 16% for bile duct cancer and 11 months and 14% for pancreatic cancer. Multivariate analysis identified tumor type (pancreas /bile duct) and lymph node dissemination as independent predictors of mortality. CONCLUSIONS: One quarter of patients experienced long term survival. Mortality predictors were tumor type and lymph node dissemination.

Micromotion analysis of immediately loaded implants with Titanium and Cobalt-Chrome superstructures. 3D finite element analysis.

OBJECTIVE: The aim of this study was to evaluate the amount of micromotion of dental implants under immediate loading supported by Titanium (Ti) and Cobalt-Chrome (Co-Cr) superstructures. MATERIAL AND METHODS: A model of tridimensional half-edentulous maxilla with three dental implants was made using the Finite Element Analysis (FEA). Two standard and one zygomatic implants were connected to a superstructure with an elliptic section of 6x 3 mm (mm). Two study models were established. Model A: Titanium (Ti) alloy superstructure; Model B: Cobalt-Chrome (Co-Cr) alloy superstructure. To simulate an immediate-loading situation, a friction coefficient of 0.71 was applied between the implant and the bone surface. An axial load of 252.04 [N] was applied on standard and zygomatic implants. RESULTS: The Micromotion of dental implants was similar in both superstructure situations. The amount of micromotion was slightly higher in B1 and B3 models (Co-Cr alloy-superstructure) compared with A1 and A3 models (Titanium alloy superstructure). The micromotion values in two groups were greater than 150 µm in the incisive region (standard implant) and molar region (zygomatic). In general, the micromotion was higher on the implant that received the load with respect to the other implants. The greater difference was observed when the load was applied on the standard implant A1 (Model A1 = 189.12 µm) compared with standard implant B1(Model B1 = 263.25 µm). CONCLUSIONS: Within the limits of present study, all implants on different load application points showed micromotion; in general, the amount of micromotion was slightly higher in the implants connected with Co-Cr alloy superstructure.

Craniofacial growth predictors for class II and III malocclusions: A systematic review.

OBJECTIVE: To evaluate the validity of craniofacial growth predictors in class II and III malocclusion. MATERIAL AND METHODS: An electronic search was conducted until August 2020 in PubMed, Cochrane Library, Embase, EBSCOhost, ScienceDirect, Scopus, Bireme, Lilacs and Scielo including all languages. The articles were selected and analyzed by two authors independently and the selected studies was assessed using the 14-item Quality Assessment Tool for Diagnostic Accuracy Studies (QUADAS-2). The quality of evidence and strength of recommendation was assessed by the GRADE tool. RESULTS: In a selection process of two phases, 10 articles were included. The studies were grouped according to malocclusion growth predictor in (1) class II (n = 4); (2) class III (n = 5) and (3) class II and III (n = 1). The predictors were mainly based on data extracted from cephalometries and characterized by: equations, structural analysis, techniques and computer programs among others. The analyzed studies were methodologically heterogeneous and had low to moderate quality. For class II malocclusion, the predictors proposed in the studies with the best methodological quality were based on mathematical models and the Fishman system of maturation assessment. For class III malocclusion, the Fishman system could provide adequate growth prediction for short- and long-term. CONCLUSIONS: Because of the heterogeneity of the design, methodology and the quality of the articles reviewed, it is not possible to establish only a growth prediction system for class II and III malocclusion. High-quality cohort studies are needed, well defined data extraction from cephalometries, radiographies and clinical characteristics are required to design a reliable predictor.

Bottleneck Effect Explained by Le Bail Refinements: Structure Transformation of Mg-CUK-1 by Confining H2O Molecules.

The structure transformation of Mg-CUK-1 due to the confinement of H2O molecules was investigated. Powder X-ray diffraction (PXRD) patterns were collected at different H2O loadings and the cell parameters of the H2O-loaded Mg-CUK-1 material were determined by the Le Bail strategy refinements. A bottleneck effect was observed when one hydrogen-bonded H2O molecule per unit cell (18% relative humidity (RH)) was confined within Mg-CUK-1, confirming the increase in the CO2 capture for Mg-CUK-1.

Predicting the optimal depth of ultrasound-guided right internal jugular vein central venous catheters in neonates.

BACKGROUND: Poor positioning of a central venous catheter (CVC) can cause severe complications. The objective is to create a formula that predicts the optimal insertion depth of a real time ultrasound-guided CVC in the right internal jugular vein (RIJV) in newborns. METHODS: Between 2015 and 2017, 91 newborns that required a CVC were included in a prospective observational study. Variables such as gestational age, gender, weight, height, and neck length were studied. On the chest x-ray, the distance between the insertion site on the skin and the catheter tip was measured. RESULTS: Of the patients included, 50 (54.9%) were males and 40 (44.4%) females; 64 (70.3%) were preterm. Mean gestational age was 33.44 (25 to 41) weeks, weight 2020 (580 to 3980) g, and height 43.04 (26 to 53) cm. Variables were correlated with catheter length and an algorithm was modeled for the introduction method, in which the highest corrected determination coefficient was obtained for weight (R2 = 0.723). CONCLUSION: This study demonstrated that the weight of the newborn was the most significant individual predictor of optimal insertion depth of a CVC in the RIJV. The formula Y = 2.6 + 0.7 (weight in kg) that we suggest is practical and reproducible. LEVEL OF EVIDENCE: Level IV.

Epidemiological pattern of tattoo skin disease: a potential general health indicator for cetaceans.

The presence of tattoo skin disease (TSD) was examined in 1392 free-ranging and dead odontocetes comprising 17 species from the Americas, Europe, South Africa, New Zealand and Greenland. We investigated whether TSD prevalence varied with sex, age and health status. TSD was encountered in cetaceans from the Pacific and Atlantic Oceans as well as in those from the North, Mediterranean and Tasman Seas. No clear patterns related to geography and host phylogeny were detected, except that prevalence of TSD in juveniles and, in 2 species (dusky dolphin Lagenorhynchus obscurus and Burmeister's porpoise Phocoena spinipinnis), in adults was remarkably high in samples from Peru. Environmental factors and virus properties may be responsible for this finding. Sex did not significantly influence TSD prevalence except in the case of Peruvian P. spinipinnis. Generally, there was a pattern of TSD increase in juveniles compared to calves, attributed to the loss of maternal immunity. Also, in most samples, juveniles seemed to have a higher probability of suffering TSD than adults, presumably because more adults had acquired active immunity following infection. This holo-endemic pattern was inverted in poor health short-beaked common dolphins Delphinus delphis and harbour porpoises Phocoena phocoena from the British Isles, and in Chilean dolphins Cephalorhynchus eutropia from Patagonia, where adults showed a higher TSD prevalence than juveniles. Very large tattoos were seen in some adult odontocetes from the SE Pacific, NE Atlantic and Portugal's Sado Estuary, which suggest impaired immune response. The epidemiological pattern of TSD may be an indicator of cetacean population health.

Sistema de Gestión Hospitalaria para la atención de la pareja infértil. Centro Territorial de Holguín, 2021

Introducción: La infertilidad es una enfermedad del sistema reproductivo que altera el equilibrio biológico, psicológico y social de las parejas. En Cuba existe un programa para el tratamiento de la pareja infértil y el Ministerio de Salud Pública incluye en sus directrices implementar las bases organizativas, sistema de trabajo, indicadores, funciones y control que garanticen el perfeccionamiento del Programa para la óptima atención de parejas infértiles, y dentro de esto se incluye confeccionar bases de datos donde se registren las parejas tratadas por este motivo. Objetivos: Implementar un Sistema de Gestión Hospitalaria para la atención de la pareja infértil, en el Centro Territorial de Holguín. Métodos: Se realizó un estudio de desarrollo tecnológico, se confeccionó sobre el sistema de base de datos relacional postgreSQL, se empleó la herramienta Odoo con el objetivo de englobar en un único software todas las prestaciones que necesita la consulta. Se utilizó el lenguaje de programación Python. Resultados: SCAPI, permite gestionar la información de los pacientes y sus historias clínicas, está compuesto por módulos relacionados: configuración general, permite crear los perfiles de usuarios y los permisos para interactuar con el sistema; SCAPI muestra y gestiona toda la información relacionada con la historia clínica digital, la agenda de turnos, medios diagnósticos (estudios de reserva ovárica, espermogramas, ecografías ováricas, estudios hormonales, técnicas de baja y alta tecnología entre otros). Conclusiones: El Sistema de Gestión Hospitalaria para la atención de la pareja infértil, contribuye al objetivo de una mayor calidad de la atención al paciente pues gestiona la información de estos y sus historias clínicas de manera rápida, oportuna y fiable.

Introduction: Biological infertility is a disease of the reproductive system that alters the psychological and social balance of couples. In Cuba there is a program for the treatment of infertile women and the Ministry of Public Health includes in its guidelines to implement the organizational bases, work system, indicators, functions and control that guarantee the improvement of the Program, including databases where couples treated for this reason are registered. Objective: To implement a Hospital Management System for the infertile couple care in the Holguín Territorial Center. Methods: A study of technological development was carried out using postgre SQL relational database system, Odoo tool, and Python programming language. Results: SCAPI allows to manage the information of patients and their medical records; it is made up of modules that are related to each other: the general configuration module which allows you to create user profiles and permissions to interact with the system; the SCAPI module which shows and manages all the information related to the digital medical history, appointment schedules, and diagnostic means (ovarian reserve studies, spermograms, ovarian ultrasound, hormonal studies, low and high technology techniques, among others). Conclusions: Hospital Management System for the care of infertile couples allows managing fast, timely and reliable information on patients and their medical records during care consultations for infertile couples with the aim of achieving a higher quality of patient care.

Características clinicoepidemiológicas de pacientes sospechosos y confirmados con la COVID-19 en una comunidad con régimen de cuarentena / Clinical epidemiological characteristics of suspicious and confirmed patients with COVID-19 in a community with quarantine regime i: en

Introducción: Para una comunidad densamente poblada con alto riesgo epidemiológico, las enfermedades infecciosas pudieran presentar una rápida expansión. Objetivo: Describir las características clínicas y epidemiológicas de pacientes sospechosos y confirmados con la COVID-19 durante el régimen de cuarentena. Métodos: Se realizó un estudio descriptivo y transversal de 62 pacientes sospechosos y confirmados con la COVID-19, quienes se encontraban en régimen de cuarentena, pertenecientes al Consejo Popular Santa Bárbara de Santiago de Cuba, desde enero hasta febrero de 2021. La información se obtuvo de las encuestas epidemiológicas. Se analizaron las siguientes variables: edad, sexo, comorbilidades, tipo de caso, estado clínico, resultado del PCR, tipo de contacto, signos y síntomas. Resultados: Predominaron el sexo femenino (59,7 %) y los adultos mayores de 60 años de edad (32,3 %). Entre las comorbilidades, la hipertensión arterial (40,3 %) tuvo mayor frecuencia. Resultaron sintomáticos no confirmados 67,3 % de los pacientes. Sobresalieron los sospechosos (82,1 %) con contactos intradomiciliarios. Entre los signos y síntomas, la fiebre (41,2 %) y la diarrea (40 %) prevalecieron entre los confirmados. Todos los pacientes asintomáticos fueron positivos al virus (100,0 %). Conclusión: Se presentaron, en gran medida, las principales características clínicas y epidemiológicas de los pacientes sospechosos y confirmados con la COVID-19 en régimen de cuarentena, lo cual se convirtió en un importante instrumento para adoptar decisiones en escenarios de alto riesgo epidemiológico.

Introduction: For a community densely populated with high epidemiologic risk, infectious diseases could present a quick spreading. Objective: To describe the clinical and epidemiologic characteristics of suspicious and confirmed patients with COVID-19 during the quarantine. Methods: A descriptive and cross-sectional study of 62 suspicious and confirmed patients with COVID-19 who were in quarantine was carried out, belonging to the Santa Bárbara neighborhood in Santiago de Cuba, from January to February, 2021. The information was obtained from the epidemiologic surveys. The following variables were analyzed: age, sex, comorbidities, type of case, clinical state, result of the PCR, type of contact, signs and symptoms. Results: There was a prevalence of the female sex (59.7 %) and elderly over 60 years (32.3 %). Among the comorbidities, hypertension (40.3 %) had the greater frequency. There was a 67.3 % of symptomatic non confirmed patients. Suspicious patients with home contacts stood out with 82,1 %. Between the signs and symptoms, fever (41.2 %) and diarrhea (40 %) prevailed among those confirmed. All the asymptomatic patients were positive to the virus (100.0 %). Conclusion: The main clinical and epidemiologic characteristics of the suspicious and confirmed patients with COVID-19 in quarantine were presented to a great extent, which became an important instrument to adopt decisions in scenarios of high epidemiologic risk.

Subtly Modulating Glycogen Synthase Kinase 3 ß: Allosteric Inhibitor Development and Their Potential for the Treatment of Chronic Diseases.

Glycogen synthase kinase 3 ß (GSK-3ß) is a central target in several unmet diseases. To increase the specificity of GSK-3ß inhibitors in chronic treatments, we developed small molecules allowing subtle modulation of GSK-3ß activity. Design synthesis, structure-activity relationships, and binding mode of quinoline-3-carbohydrazide derivatives as allosteric modulators of GSK-3ß are presented here. Furthermore, we show how allosteric binders may overcome the ß-catenin side effects associated with strong GSK-3ß inhibition. The therapeutic potential of some of these modulators has been tested in human samples from patients with congenital myotonic dystrophy type 1 (CDM1) and spinal muscular atrophy (SMA) patients. We found that compound 53 improves delayed myogenesis in CDM1 myoblasts, while compounds 1 and 53 have neuroprotective properties in SMA-derived cells. These findings suggest that the allosteric modulators of GSK-3ß may be used for future development of drugs for DM1, SMA, and other chronic diseases where GSK-3ß inhibition exhibits therapeutic effects.

Diseases, lesions and malformations in the long-beaked common dolphin Delphinus capensis from the Southeast Pacific.

Miscellaneous lesions of the head, skull, teeth, trunk, appendages, skin and genital tract were observed in 120 of 930 long-beaked common dolphins Delphinus capensis taken in fisheries off Peru between 1985 and 2000. Seven subsamples were defined according to the varying field sampling protocols. Forty-two dolphins showed at least 2 types of injuries or diseases affecting 1 or more organs. The majority (5 of 7) of traumas encountered were diagnosed as caused by violent, fisheries-related interactions, and the skin in 20.4 % of specimens (n = 54) showed healed scars from such interactions. Prevalences of malformations and traumas of crania (n = 103) were 2.9 and 1.9%, respectively. Lytic cranial lesions were present in 31.1% of dolphins (n = 103) and accounted for 84.2% of all bone injuries. Skull damage diagnostic for Crassicauda sp. infestation was encountered in 26.5% of dolphins (n = 98) and did not differ among sex and age classes. Crassicauda sp. and tooth infections were responsible for, respectively, 78.8 and 6.1% of the lytic lesions. Adult dolphins showed a high prevalence of worn and broken teeth (35%, n = 20) as well as damaged alveoli (20%, n = 70). Prevalence of 'paired teeth', a congenital condition, was 9.4% (n = 32). Lesions of the head, body and appendages were present in 10 dolphins and included traumas, deformations (e.g. scoliokyphosis and brachygnathia) and chronic mastitis. Ovarian cysts suggestive of follicular cysts were observed in 1 of 24 females. Chronic orchitis affected 1 of 78 males. Of 12 dolphins 2 had vesicular lesions of the penis. Prevalence of cutaneous lesions, abnormalities and scars ranged between 1.8% (n = 56) and 48.2% (n = 27).

Raloxifene as an Adjunctive Treatment for Postmenopausal Women With Schizophrenia: A 24-Week Double-Blind, Randomized, Parallel, Placebo-Controlled Trial.

UNLABELLED: The potential therapeutic utility of estrogens in schizophrenia is increasingly being recognized. Raloxifene, a selective estrogen receptor modulator, appears to act similarly to estrogens on dopamine and serotonin brain systems. One previous trial by our team found that raloxifene was useful to improve negative, positive, and general psychopathological symptoms, without having the negative side effects of estrogens. In this study, we assess the utility of raloxifene in treating negative and other psychotic symptoms in postmenopausal women with schizophrenia exhibiting prominent negative symptoms. This was a 24-week, randomized, parallel, double-blind, placebo-controlled study. Patients were recruited from the inpatient and outpatient departments of Parc Sanitari Sant Joan de Déu, Hospital Universitari Institut Pere Mata, and Corporació Sanitària Parc Taulí. Seventy postmenopausal women with schizophrenia (DSM-IV) were randomized to either adjunctive raloxifene (38 women) or adjunctive placebo (32 women). Psychopathological symptoms were assessed at baseline and at weeks 4, 12, and 24 with the Positive and Negative Syndrome Scale (PANSS) and the Scale for the Assessment of Negative Symptoms (SANS). The addition of raloxifene (60 mg/d) to regular antipsychotic treatment significantly reduced negative (P = .027), general (P = .003), and total symptomatology (P = .005) measured with the PANSS during the 24-week trial, as compared to women receiving placebo. Also Alogia SANSS subscale improved more in the raloxifene (P = .048) than the placebo group. In conclusion, raloxifene improved negative and general psychopathological symptoms, compared with antipsychotic medication alone, in postmenopausal women with schizophrenia. These data replicate our previous results with a larger sample and a longer follow-up. TRIAL REGISTRATION: NCT01573637.