GSK-3ß orchestrates the inhibitory innervation of adult-born dentate granule cells in vivo.

Adult hippocampal neurogenesis enhances brain plasticity and contributes to the cognitive reserve during aging. Adult hippocampal neurogenesis is impaired in neurological disorders, yet the molecular mechanisms regulating the maturation and synaptic integration of new neurons have not been fully elucidated. GABA is a master regulator of adult and developmental neurogenesis. Here we engineered a novel retrovirus encoding the fusion protein Gephyrin:GFP to longitudinally study the formation and maturation of inhibitory synapses during adult hippocampal neurogenesis in vivo. Our data reveal the early assembly of inhibitory postsynaptic densities at 1 week of cell age. Glycogen synthase kinase 3 Beta (GSK-3ß) emerges as a key regulator of inhibitory synapse formation and maturation during adult hippocampal neurogenesis. GSK-3ß-overexpressing newborn neurons show an increased number and altered size of Gephyrin+ postsynaptic clusters, enhanced miniature inhibitory postsynaptic currents, shorter and distanced axon initial segments, reduced synaptic output at the CA3 and CA2 hippocampal regions, and impaired pattern separation. Moreover, GSK-3ß overexpression triggers a depletion of Parvalbumin+ interneuron perineuronal nets. These alterations might be relevant in the context of neurological diseases in which the activity of GSK-3ß is dysregulated.

Prolonged fixation and post-mortem delay impede the study of adult neurogenesis in mice.

Adult hippocampal neurogenesis (AHN) gives rise to new neurons throughout life. This phenomenon takes place in more than 120 mammalian species, including humans, yet its occurrence in the latter was questioned after one study proposed the putative absence of neurogenesis markers in the adult human hippocampus. In this regard, we showed that prolonged fixation impedes the visualization of Doublecortin+ immature neurons in this structure, whereas other authors have suggested that a dilated post-mortem delay (PMD) underlies these discrepancies. Nevertheless, the individual and/or additive contribution of fixation and the PMD to the detection (or lack thereof) of other AHN markers has not been studied to date. To address this pivotal question, we used a tightly controlled experimental design in mice, which allowed the dissection of the relative contribution of the aforementioned factors to the visualization of markers of individual AHN stages. Fixation time emerged as the most prominent factor globally impeding the study of this process in mice. Moreover, the visualization of other particularly sensitive epitopes was further prevented by prolonged PMD. These results are crucial to disambiguate current controversies related to the occurrence of AHN not only in humans but also in other mammalian species.

Response to Comment on "Impact of neurodegenerative diseases on human adult hippocampal neurogenesis".

Rakic and colleagues challenge the use of extensively validated adult hippocampal neurogenesis (AHN) markers and postulate an alternative interpretation of some of the data included in our study. In Terreros-Roncal et al., reconstruction of the main stages encompassed by human AHN revealed enhanced vulnerability of this phenomenon to neurodegenerative diseases. Here, we clarify points and ambiguities raised by these authors.

Response to Comment on "Impact of neurodegenerative diseases on human adult hippocampal neurogenesis".

Alvarez-Buylla and colleagues provide an alternative interpretation of some of the data included in our manuscript and question whether well-validated markers of adult hippocampal neurogenesis (AHN) are related to this phenomenon in our study. In Terreros-Roncal et al., reconstruction of the main stages of human AHN revealed its enhanced vulnerability to neurodegeneration. Here, we clarify ambiguities raised by these authors.

Impact of neurodegenerative diseases on human adult hippocampal neurogenesis.

Disrupted hippocampal performance underlies psychiatric comorbidities and cognitive impairments in patients with neurodegenerative disorders. To understand the contribution of adult hippocampal neurogenesis (AHN) to amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, dementia with Lewy bodies, and frontotemporal dementia, we studied postmortem human samples. We found that adult-born dentate granule cells showed abnormal morphological development and changes in the expression of differentiation markers. The ratio of quiescent to proliferating hippocampal neural stem cells shifted, and the homeostasis of the neurogenic niche was altered. Aging and neurodegenerative diseases reduced the phagocytic capacity of microglia, triggered astrogliosis, and altered the microvasculature of the dentate gyrus. Thus, enhanced vulnerability of AHN to neurodegeneration might underlie hippocampal dysfunction during physiological and pathological aging in humans.

[Tumor necrosis factor blocking agents: a review. Part I: Clinical efficacy evaluation]. / Lugar en terapéutica de los medicamentos antagonistas del factor de necrosis tumoral. Parte I: evaluación clínica.

Blockade of tumor necrosis factor with monoclonal antibodies, has emerged as one of the most promising therapies in some autoimmune conditions as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and Crohn s disease. They have shown effectiveness on reducing symptoms and modifying the progression of the disease. However, they disrupt the balance of inflammatory and immune responses and some risks associated with TNF-blockers have become apparent. The purpose of this article is to review the evidence about benefits and risk associated with the use of TNF-blockers in approved indications and to provide practical recommendations for its use in the management of these conditions.

[Tumor necrosis factor blocking agents: a review. Part II: safety and recommendations]. / Lugar en terapéutica de los medicamentos antagonistas del factor de necrosis tumoral. (2da de dos partes): de los efectos indeseados y recomendaciones.

Blockade of tumor necrosis factor with monoclonal antibodies, has emerged as one of the most promising therapies in some autoimmune conditions as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and Crohn's disease. They have shown effectiveness on reducing symptoms and modifying the progression of the disease. However, they disrupt the balance of inflammatory and immune responses and some risks associated with TNF-blockers have become apparent. The purpose of this article is to review the evidence about benefits and risk associated with the use of TNF-blockers in approved indications and to provide practical recommendations for its use in the management of this conditions.

[Partial bilateral rupture of the Achilles tendon associated to levofloxacin]. / Rotura parcial bilateral aquílea asociada a levofloxacino.

Fluoroquinolones-associated tendonitis and tendon rupture are well described in the literature but these are not frequently observed and related to the new agents of this group, as levofloxacin. This is probably due to the recent introduction and expansion. Although epidemiological studies are needed to know the frequency of that levofloxacin-induced tendinopathies, case-report could alert to the physicians about this possible severe adverse reaction. We present a case of bilateral Achilles tendonitis with partial spontaneous rupture probably associated to levofloxacin.

[Drug interactions in the prescription of medical patients at hospital discharge]. / Interacciones entre medicamentos prescritos al alta en un Servicio de Medicina Interna.

OBJECTIVES: To detect and evaluate the clinical significance of drugs interactions in patients discharged from hospital. MATERIAL AND METHODS: We retrospectively screened the medication for potential drug interactions of 412 patients discharged. Interactions were catalogued according to clinical importance following the Hansten and Horn's classification. RESULTS: Three hundred twenty-nine potential interactions were detected. The 39.9% of the patients had at least one potentially interacting drug combination. The 52.6% of the interactions were catalogued as Class 3, bearing in mind minimizing the risk of the interaction. We did not find any Class 1 or 2 interactions, which have potentially major severity. Oral anticoagulants and digoxin were the most frequently implicated drugs. The patient monitoring was well done in the 100% of the interactions of Oral anticoagulants with other drug, but in the interactions of digoxin with another, this control was not done adequately. One patient was rehospitalised due to high levels of digoxin, he had been discharged with two potential interactions. CONCLUSIONS: The frequently of potential drug interactions in medical patients at hospital discharged was high, but the clinical significance appear to be low.

Clinical pharmacology in primary care: a good mix?

Most drug use takes place in primary health care, under circumstances which are very different from those of the clinical trials where drugs are studied. If clinical pharmacology is to have a meaningful influence on the way drugs are used, it cannot afford to remain absent from this setting. We are clinical pharmacologists working in primary care. In this paper, we describe our activities and discuss our experience in this field.

[Oral anticoagulation]. / Anticoagulación oral.

The use of oral anticoagulants in the prevention of thrombotics processes, has experienced a considerable increase. In addition, there are a growing experience on the medical and socials consequences of the use of this drug. This has originated a much more pragmatic vision of the daily handling of the anticoagulated patient. In this article, we made are vision about the indications and the practical use, including some useful advices and criteria for the concomitant drug selection.

[Statin-induced rhabdomyolysis and renal failure: also with fluvastatine]. / Rabdomiolisis y fallo renal por estatinas: también con fluvastatina.

Hydroximetilglutaril-coenzima A reductase inhibitors (statin) have the potential to cause rhabdomyolysis. However, fluvastatin is rarely associated with rhabdomyolysis when compared to other statins. Differences in biochemical and pharmacokinetic properties between fluvastatin and the other statins have been invocated in order to explain the apparent comparative safety of fluvastatin. We present a case of rhabdomyolysis with acute renal failure in a patient receiving fluvastatin and, following the Karch-Lasagne algorithm, we present evidence that this case was an adverse reactions to fluvastatin.

[Use of beta-blockers for treatment of cardiac failure]. / Utilización de betabloqueadores en el tratamiento de la insuficiencia cardiaca.

The rationale for betablocker use in heart failure, based on neurohormonal physiology, has been established over the past 20 years. Recent trials have shown the unequivocal benefits of betablockers in patients with chronic systolic heart failure. The benefits include improve survival (35%) reduced need for hospitalization and improve of left ventricular function. However, betablockers may also make a patient with heart failure worse, especially when treatment begins and there is reluctance to use betablockade therapy. Complications can generally be avoided by starting with extremely low doses and increasing the dose very slowly. Despite this, further questions remain regarding the use of these agents in cardiac failure, including the role in the progression of the disease, the selection of individual betablocker, and the use in very severe disease or very old patients.

[Use of antibiotics in primary care: treatment of urinary infection]. / Uso de antibióticos en atención primaria: tratamiento de la infección urinaria.

OBJECTIVES: To analyse the primary care therapeutic approach to urinary tract infections (UTI), and, a secondary objective, to obtain information on the microbiological profile and resistance to antibiotics in this field, with the aim of making therapeutic recommendations. DESIGN: The UTI diagnosed through systematic checking of sediment and/or culture, requests from health centres are described. SETTING: 9 Health Centres in Palma (Mallorca) during November 1992. PATIENTS AND OTHER PARTICIPANTS: Out of 2,484 requests for sediment and/or uroculture, clinical history was found in 2,033. At the end there were 232 patients whose request for analysis was for suspected UTI, among whom there were 43 recurring cases, which meant a total of 275 cases. MEASUREMENTS AND MAIN RESULTS: The most frequent germ was Escherichia coli. 68% had complicated UTI. Empirical treatment was carried out in 60.7%. Treatment of the first episode of UTI was with quinolones in 73.3% of cases, with norfloxacine in 44.1%. There was a higher percentage of resistance of Escherichia coli to cotrimoxazole (49.0%), ampicilline-sulbactam (46.4%), ampicilline (42.0%) and cephalexin (31.4%). In 50 cases there was therapeutic failure, due (among the most commonly used drugs) to norfloxacine in 12.4%, to cotrimoxazole in 28.6%, to norfloxacine in 27.3% and to pipemidic in 18.9%. CONCLUSIONS: There are many more specific than empirical treatments as well as excessive use of drugs not recommended as first choice in primary care. The level of resistance to the new quinolones is considerable and is greater still for some antimicrobial drugs used for UTI.

[The introduction of generic pharmaceutical products into Galicia]. / Introducción de las especialidades farmacéuticas genéricas en Galicia.

OBJECTIVE: To know the evolution of the introduction of generic drugs (GDs) in Galicia. Secondarily, to evaluate its potential impact on pharmaceutical expenditure. DESIGN: Descriptive study of GDs utilization. Cost-minimization analysis. SETTING: Galician autonomous region, year 1998. MEASUREMENTS AND RESULTS: Using data from the prescription billing registry of Social Security we have selected the active ingredients corresponding to GDs with prescriptions in Galicia in 1997. We have analyzed the data for their oral single substance preparations by quarters. Consumption in DHDs of allopurinol, atenolol, captopril, naproxen and ranitidine remained stable during 1998. The market share for their GDs in quantitative terms relative to both total consumption of the active ingredients and to their pharmaceutical equivalents, showed an overall growing trend. The maximum observed value was seen for ranitidine at last quarter. Total expenditure (in final customer prices) during 1998 on the selected active substances was higher than 1864 million pesetas. Potential savings afforded by substitution for the lowest price GD prescribed in Galicia would reach 427 million pesetas. CONCLUSIONS: GDs market penetration in Galicia during 1998 was limited but increasing. Its utilization may afford estimated savings of 21-28% of the cost for the selected drugs. However, the expenditure on the above drugs was just 2.7% of total pharmaceutical expenditure.

[Prescription of platelet antiaggregants in secondary prevention of ischemic heart disease]. / Prescripción de antiagregantes plaquetarios en la prevención secundaria de la cardiopatía isquémica.

OBJECTIVE: To find out how many patients older than 64 years of age seen in a primary health care (PHC) centre receive antiplatelet drugs for secondary prevention of coronary heart disease (CHD), as well as by whom they are prescribed, which drug is chosen, and what are its contraindications, unwanted effects and motives for ending therapy. DESIGN: Description of all cases of CHD among patients older than 64, identified through the audit of clinical records. SETTING: Urban health care centre with 23,702 inhabitants, with 2,742 over 64, 2,660 of whom have clinical records. SUBJECTS: Patients over 64 with CHD, seen in the health centre within 1993. MEASUREMENTS AND INTERVENTIONS: Age, sex, type of CHD, therapy with a platelet aggregation inhibitor, drug used, dose, prescriptor, adverse events, contraindications. RESULTS: We identified 179 cases of CHD, a prevalence of 6.7%, of which 60.9% were male. 94 patients received an antiplatelet drug: aspirin (88.3%), dypiridamol and triflusal (5.3% each) and ticlopidine (1 case). 111 patients were adequately treated, including 84 given aspirin or ticlopidine, 12 patients in which therapy was ended due to adverse events, and 15 patients in which use of antiaggregant drugs was contraindicated. All prescriptions originating from general practitioners were for aspirin, while specialists prescribed other drugs in 11% of cases. CONCLUSION: Two-thirds of patients with CHD were correctly treated. Aspirin is the antiaggregant drug most frequently used, particularly among PHC physicians. Even low doses of aspirin were associated with interruptions of therapy due to adverse events.