Inhibition of endogenous phosphodiesterase 7 promotes oligodendrocyte precursor differentiation and survival.

During the development of the central nervous system (CNS), oligodendrocyte precursors (OPCs) are generated in specific sites within the neural tube and then migrate to colonize the entire CNS, where they differentiate into myelin-forming oligodendrocytes. Demyelinating diseases such as multiple sclerosis (MS) are characterized by the death of these cells. The CNS reacts to demyelination and by promoting spontaneous remyelination, an effect mediated by endogenous OPCs, cells that represent approximately 5-7 % of the cells in the adult brain. Numerous factors influence oligodendrogliogenesis and oligodendrocyte differentiation, including morphogens, growth factors, chemotropic molecules, extracellular matrix proteins, and intracellular cAMP levels. Here, we show that during development and in early adulthood, OPCs in the murine cerebral cortex contain phosphodiesterase-7 (PDE7) that metabolizes cAMP. We investigated the effects of different PDE7 inhibitors (the well-known BRL-50481 and two new ones, TC3.6 and VP1.15) on OPC proliferation, survival, and differentiation. While none of the PDE7 inhibitors analyzed altered OPC proliferation, TC3.6 and VP1.15 enhanced OPC survival and differentiation, processes in which ERK intracellular signaling played a key role. PDE7 expression was also observed in OPCs isolated from adult human brains and the differentiation of these OPCs into more mature oligodendroglial phenotypes was accelerated by treatment with both new PDE7 inhibitors. These findings reveal new roles for PDE7 in regulating OPC survival and differentiation during brain development and in adulthood, and they may further our understanding of myelination and facilitate the development of therapeutic remyelination strategies for the treatment of MS.

The methodology of surveillance for antimicrobial resistance and healthcare-associated infections in Europe (SUSPIRE): a systematic review of publicly available information.

OBJECTIVES: Surveillance is a key component of any control strategy for healthcare-associated infections (HAIs) and antimicrobial resistance (AMR), and public availability of methodologic aspects is crucial for the interpretation of the data. We sought to systematically review publicly available information for HAIs and/or AMR surveillance systems organized by public institutions or scientific societies in European countries. METHODS: A systematic review of scientific and grey literature following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines was performed. Information on HAIs and/or AMR surveillance systems published until 31 October 2016 were included. RESULTS: A total of 112 surveillance systems were detected; 56 from 20 countries were finally included. Most exclusions were due to lack of publicly available information. Regarding AMR, the most frequent indicator was the proportion of resistant isolates (27 of 34 providing information, 79.42%); only 18 (52.9%) included incidence rates; the data were only laboratory based in 33 (78.5%) of the 42 providing this information. Regarding HAIs in intensive care units, all 22 of the systems providing data included central line-associated bloodstream infections, and 19 (86.3%) included ventilator-associated pneumonia and catheter-associated urinary tract infections; incidence density was the most frequent indicator. Regarding surgical site infections, the most frequent procedures included were hip prosthesis, colon surgery and caesarean section (21/22, 95.5%). CONCLUSIONS: Publicly available information about the methods and indicators of the surveillance system is frequently lacking. Despite the efforts of European Centre for Disease Control and Prevention (ECDC) and other organizations, wide heterogeneity in procedures and indicators still exists.

A preliminary investigation of phoshodiesterase 7 inhibitor VP3.15 as therapeutic agent for the treatment of experimental autoimmune encephalomyelitis mice.

cAMP plays a significant role in signal transduction pathways controlling multiple cellular processes such as inflammation and immune regulation. cAMP levels are regulated by a family of phosphodiesterases (PDEs). We have studied the effects of a novel PDE7 inhibitor (PDE7i) treatment on mice with experimental autoimmune encephalomyelitis (EAE) a model of multiple sclerosis (MS) and compared it with another PDE7i. EAE was induced by immunizing C57BL/6J mice with myelin oligodendrocyte glycoprotein (MOG35-55) peptide. Mice were treated daily either from disease onset or from disease peak with each PDE7i and with fingolimod (used in therapy for MS patients) and disease evolution was followed by clinical symptoms. We examined neuropathology of spinal cord, ex vivo lymphocyte proliferation by [3H]-thymidine incorporation, TNFα by ELISA and cAMP-PDE mRNAs expression by in situ hybridization histochemistry (ISHH) in spinal cord of EAE mice treated with both PDE7 inhibitors. Treatment of EAE mice with the novel PDE7i, VP3.15 showed more efficacy in reducing clinical signs at 10mgkg-1 than the other PDE7i, BRL50481 and similar to fingolimod. VP3.15 acts on peripheral lymphocytes inhibiting their proliferation and TNFα secretion in a dose-dependent manner. PDE7i treatment alters the levels of PDE4B and PDE7 mRNA expression in EAE mice spinal cord. Given the interest in the development of new drugs for MS, including PDE7i as anti-inflammatory drugs, it is important to study the role played by PDE7 in neurodegenerative diseases with inflammatory component to better understand the beneficial and detrimental effects of a future therapy.

La Farmacoepidemiología como una estrategia útil en diabetes mellitus: experiencia en un Centro Sanitario de Mendoza, Argentina / Pharmacoepidemiology as a useful strategy in diabetes mellitus: experience in a Health Center in Mendoza, Argentina

Introducción: La diabetes mellitus (DM) es de importancia para la salud pública y la Farmacoepidemiología constituye una herramienta útil para controlarla.Objetivo: Determinar frecuencia, comorbilidades, dispensación y consumo de medicamentos en un Centro de Atención Primaria de la Salud de Mendoza, Argentina. Metodología: Se realizó un estudio descriptivo, observacional, transversal, retrospectivo en 700 pacientes adultos, se determinó frecuencia de DM, comorbilidades, dispensación y consumo de medicamentos. Resultados: Se encontró asociación entre sexo masculino y riesgo de DM. La DM tipo 2 fue la más frecuente. La hipertensión arterial fue la comorbilidad asociada a DM. Fármacos más dispensados: insulina y metformina, fármacos más consumidos: metformina luego enalapril. Conclusiones: El análisis farmacoepidemiológico permitió detectar problemas relacionados con la DM, sus comorbilidades y tratamientos. Estos estudios favorecen la prevención y tratamiento de la DM. (AU)

Introduction: Diabetes mellitus (DM) is essential for public health, and Pharmacoepidemiology is a useful tool to control it.Objective: To determine frequency, comorbidities, dispensation, and consumption of medicines in a Primary Health Care Center of Mendoza, Argentina. Methodology: A descriptive, observational, cross-sectional, retrospective study was carried out in 700 adult patients, frequency of DM, comorbidities, dispensation, and consumption of medications was determined. Results: Association between male sex and the risk of DM was found. Type 2 DM was the most frequent. Hypertension was the comorbidity associated with DM. Most dispensed drugs: insulin and metformin, most consumed drugs: metformin then enalapril. Conclusion: The pharmacoepidemiological analysis allowed to detect problems related to DM, its comorbidities, and treatments.These studies favor the prevention and treatment of DM. (AU)

Regulation by diet of the pancreas enzyme content of suckling goats.

To study pancreas enzyme content regulation when the diet was modified in suckling goats, a comparison was made between kids fed a milk replacer and ones fed maternal milk. A total of 25 preruminant Granadina breed goats were bottle-fed a milk replacer ad libitum from postnatal days 3 to 28 (until the age of 3 days kids had been fed colostrum). Body weight, pancreas weight, total protein concentration, and enzyme activities in pancreatic tissue were determined at 3, 7, 14, 21 and 28 days of age, and the results were compared to those previously obtained in kids fed maternal milk for the same period. Lipase activity was significantly lower in the group fed milk replacer, which was poorer in fat. Amylase activity was higher in this group, perhaps due to the starch products present in the milk substitute. However, the postnatal evolution of chymotrypsin activity followed a similar pattern regardless of diet. Our results seem to confirm that in preruminant kids there is a nutritional regulation of pancreatic amylase and lipase activities, depending on the amounts of their respective substrates in the diet, similar to that described in nonruminants.

[The low quality of home-made oral rehydration solution in Salvador, Bahia (Brazil)]. / A baixa qualidade do soro caseiro em Salvador, Brasil.

In 1988 a nation-wide campaign aiming to inform the Brazilian population about preparation and use of simple sugar/salt oral rehydration solution (ORS) was carried out. The campaign was massively shown by the media. This preliminary study assessed the quality of ORS prepared by 23 mothers of in-patient children from a pediatric hospital in Salvador, State of Bahia. Fourteen (60.9%) among the 23 mothers prepared solutions containing Na concentrations ranging from 30 to 80 mmol/L which is recommended by the World Health Organization. Eleven (47.8%) solutions contained glucose within the recommended range of 30 to 112 mmoI/L Only 6 (26%) out of the 23 mothers prepared ORS with simultaneously adequate Na and glucose concentrations. However, just 3 (13%) out of these 6 ORS also presented balanced electrolyte concentrations. Potential iatrogenicity due to high concentrations of Na and glucose was found in 30.4% and 43.5% of the solutions, respectively. These data raise serious concerns about the quality of home-made sugar/salt ORS, and therefore about its use as a safe agent in a campaign of diarrhoeal diseases control.

Glycogen synthase kinase-3 inhibitors as potent therapeutic agents for the treatment of Parkinson disease.

Parkinson's disease (PD) is a devastating neurodegenerative disorder characterized by degeneration of the nigrostriatal dopaminergic pathway. Because the current therapies only lead to temporary, limited improvement and have severe side effects, new approaches to treat PD need to be developed. To discover new targets for potential therapeutic intervention, a chemical genetic approach involving the use of small molecules as pharmacological tools has been implemented. First, a screening of an in-house chemical library on a well-established cellular model of PD was done followed by a detailed pharmacological analysis of the hits. Here, we report the results found for the small heterocyclic derivative called SC001, which after different enzymatic assays was revealed to be a new glycogen synthase kinase-3 (GSK-3) inhibitor with IC(50) = 3.38 ± 0.08 µM. To confirm that GSK-3 could be a good target for PD, the evaluation of a set of structurally diverse GSK-3 inhibitors as neuroprotective agents for PD was performed. Results show that inhibitors of GSK-3 have neuroprotective effects in vitro representing a new pharmacological option for the disease-modifying treatment of PD. Furthermore, we show that SC001 is able to cross the blood-brain barrier, protects dopaminergic neurons, and reduces microglia activation in in vivo models of Parkinson disease, being a good candidate for further drug development.

The potential role of glycogen synthase kinase 3 inhibitors as amyotrophic lateral sclerosis pharmacological therapy.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons. Lately, this disease has often been related to the protein kinase called glycogen synthase kinase 3 (GSK-3), through the experimental evidence of alterations of this enzyme on ALS patients. Therefore, there have been several experimental studies using GSK-3 inhibitors, in cellular and animal models and also in clinical studies that showed the potential of the therapeutic role of these molecules. GSK-3 inhibitors might play a pivotal role in the pharmacology of ALS disease with no curative treatment nowadays. In this review we give an overview of the current research in the area, showing all the evidences of the implication of dysfunctional GSK-3 in this disease on one hand, and on the other presenting the potential role of the GSK-3 inhibitors as a future pharmacological ALS therapy.

Evaluación de la calidad de vida en pacientes hemofílicos de Curicó, Región del Maule / Evaluation of quality of life in haemophilia patients from Curicó, Region del Maule

Despite the improvements in medical treatment over recent decades, hemophilia patients experience deterioration in their quality of life. This study provides a demographic and clinical characterization of hemophilia patients and how this affects their quality of life. This is based on a descriptive cross-sectional study on quality of life of 20patients with hemophilia from the Province of Curicó, Maule Region. The following antecedents were obtained from each patient: age, weight, height, severity of hemophilia, presence of hepatitis B virus, hepatitis C virus, human immunodeficiency virus and Chagas disease. To measure the quality of life the Short Form-36 survey was applied to each one of the patients. The average age was 35+/-16 years old and body mass index was 25+/-4 kg/m2. Regarding the severity level of the disease, in 55 percent of the patient it was found mild. More over, 25 percent of patients had hepatitis C. The most co-morbidity was for articular lesions. Quality of life is affected mainly by lack of sport and also due to the severity level of disease. The current challenge is to provide comprehensive care, both for patients and their families, where the main goal aims at restoring the sense of wellbeing, their right to be perceived as a person with capacity to develop.

Factores clínicos y demográficos predictores de éxito del misoprostol en el tratamiento médico del aborto espontáneo / Predictors of success of misoprostol in the treatment of first trimester spontaneous abortion

Objetivos: Determinar posibles predictores de éxito del misoprostol en el tratamiento del aborto espontáneo del primer trimestre. Método: Estudio observacional descriptivo y prospectivo, realizado entre febrero de 2009 y febrero de 2010. Inclusión consecutiva de 248 mujeres con diagnostico ecográfico de aborto espontáneo del primer trimestre con tratamiento médico o quirúrgico, siendo las pacientes las que eligieron la opción terapéutica de acuerdo a los criterios de inclusión para el manejo con misoprostol. En el grupo tratamiento médico se aplicó 800 mcg de misoprostol vaginal/24horas/2 dosis, considerándose como criterio de éxito un endometrio homogéneo con grosor <15 mm en la ecografía realizada al 8° día del tratamiento. Resultados: Influyen en la tasa de éxito del misoprostol la edad de las pacientes (mejor resultado cuanto más joven, p=0,025), número de embarazos (responden mejor las primigestas, p=0,024), existencia o no de abortos (p=0,05) o legrados previos (p=0,028) (la tasa de éxito del misoprostol es mayor en las mujeres que no tienen ningún aborto o legrado previo), y tipo de sangrado vaginal que aparece como efecto secundario del misoprostol (mejorando el pronóstico cuando dicho sangrado es igual o mayor que menstruación, p=0,041). Conclusiones: Hubo predictores de éxito del misoprostol que pueden orientar el manejo, sabiendo que hubo mejor resultado en pacientes jóvenes, primigestas, sin abortos ni legrados previos y con un sangrado vaginal igual o mayor que menstruación.

Objectives: To determine possible predictors of success of misoprostol in the treatment of first trimester spontaneous abortion. Methods: Descriptive observational study and prospectively from February 2009 to February 2010. It were included 248 women which were diagnosed by ultrasound of spontaneous abortion in the first trimester and received medical or surgical treatment, depending on the patient's own choice, provided that the established clinical conditions were present. The protocol applied in the medical treatment group was 800 mcg of vaginal misoprostol/24h/2 dose. It was considered as criteria of success, the presence of a homogeneous endometrium with a thickness <15 mm in the ultrasound examination performed on the 8 th day of treatment. Results: The following variables influence the success rate of misoprostol: patient age (the younger the better outcome, p = 0.025), number of pregnancies (primiparous respond better, p = 0.024), presence or absence of abortions ( p = 0.05) or previous curettage (p = 0.028) (the success rate of misoprostol is higher in women who have no previous abortion or curettage), and type of vaginal bleeding that occurs as a side effect of misoprostol (improving prognosis when bleeding is equal to or greater than the rule, p = 0.041). Conclusions: We found predictors of success of misoprostol, which can guide the management knowing that better results can get obtained in younger patients, primigravida, no previous abortions or curettage and with a vaginal bleeding equal to or greater than the rule.

[Clinical diagnosis versus autopsy]. / Diagnóstico clínico versus autópsia.

Records from 910 autopsies performed at a university hospital in Salvador, Bahia, Brazil were examined in order to assess the accuracy of clinical diagnoses of the patients' underlying causes of death. This study found inaccurate clinical diagnoses in 31% of the cases. The overall rate of diagnostic error appeared to remain fairly stable from 1970 to 1982, being highest for older patients. Thirty-six percent of the 263 cancer deaths were incorrectly diagnosed, and a number of pathologies considered relatively easy to diagnose were not always correctly identified--the underlying cause of death being incorrectly diagnosed in many of the fatalities caused by such ailments as arterial hypertension, chronic obstructive lung disease, pneumonia/bronchopneumonia, and schistosomiasis. Quite aside from their direct medical implications, diagnostic errors of the magnitude observed in this and other studies seriously jeopardize the quality of vital statistics and such statistics' usefulness for improving public health.

Clinical diagnosis versus autopsy.

Records from 910 autopsies performed at a university hospital in Salvador, Bahia, Brazil, were examined in order to assess the accuracy of clinical diagnoses of the patients' underlying causes of death. This study found inaccurate clinical diagnoses in 31% of the cases. The overall rate of diagnostic error appeared to remain fairly stable from 1970 to 1982, being highest for older patients. Thirty-six percent of the 263 cancer deaths were incorrectly diagnosed, and a number of pathologies considered relatively easy to diagnose were not always correctly identified. Quite aside from their direct medical implications, diagnostic errors of the magnitude observed in this and other studies seriously jeopardize the quality of vital statistics and such statistics' usefulness for improving public health.