ABSTRACT
Nitric oxide (NO) plays a pivotal role in integrating dopamine transmission in the basal ganglia and has been implicated in the pathogenesis of Parkinson disease (PD). The objective of this study was to ascertain whether the NO synthase inhibitor, 7-nitroindazole (7-NI), is able to reduce L-DOPA-induced dyskinesias (LIDs) in a non-human primate model of PD chronically intoxicated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Six Parkinsonian macaques were treated daily with L-DOPA for 3-4 months until they developed LIDs. Three animals were then co-treated with a single dose of 7-NI administered 45 min before each L-DOPA treatment. Dyskinetic MPTP-treated monkeys showed a significant decrease in LIDs compared with their scores without 7-NI treatment (p < 0.05). The anti-Parkinsonian effect of L-DOPA was similar in all three monkeys with and without 7-NI co-treatment. This improvement was significant with respect to the intensity and duration of LIDs while the beneficial effect of L-DOPA treatment was maintained and could represent a promising therapy to improve the quality of life of PD patients.
Subject(s)
Dyskinesia, Drug-Induced , Parkinson Disease , Parkinsonian Disorders , Animals , Levodopa/adverse effects , Antiparkinson Agents/adverse effects , Quality of Life , Parkinsonian Disorders/chemically induced , Parkinsonian Disorders/drug therapy , Dyskinesia, Drug-Induced/drug therapy , Dyskinesia, Drug-Induced/etiology , Parkinson Disease/drug therapy , PrimatesABSTRACT
Community-acquired pneumonia (CAP) continues to be an important cause of morbidity and mortality in adults. The aim of this study is to update the practical prevention guide for CAP through vaccination in Spain developed in 2016 and updated in 2018, based on available vaccines and evidence through bibliographic review and expert opinion. The arrival of COVID-19 as a new cause of CAP and the recent availability of safe and effective vaccines constitutes the most significant change. Vaccines against pneumococcus, influenza, pertussis and COVID-19 can help to reduce the burden of disease from CAP and its associated complications. The available evidence supports the priority indications established in this guide, and it would be advisable to try to achieve a widespread dissemination and implementation of these recommendations in routine clinical practice.
Subject(s)
COVID-19 , Community-Acquired Infections , Pneumonia, Pneumococcal , Adult , Community-Acquired Infections/prevention & control , Humans , Pneumococcal Vaccines , Pneumonia, Pneumococcal/prevention & control , SARS-CoV-2 , VaccinationABSTRACT
Community-acquired pneumonia (CAP) continues to be an important cause of morbidity and mortality in adults. The aim of this study is to update the 2016 practical prevention guidelines for CAP through vaccination in Spain, based on the available vaccines, as well as the evidence using a literature review and expert opinion. Vaccines against pneumococcus and influenza continue to be the main prevention tools available against CAP, and can contribute to reduce the burden of disease due to CAP and its associated complications. The available evidence supports the priority indications established in these guidelines, and it would be advisable to try to achieve a widespread dissemination and implementation of these recommendations in routine clinical practice.
Subject(s)
Influenza Vaccines/administration & dosage , Pneumococcal Vaccines/administration & dosage , Pneumonia, Pneumococcal/prevention & control , Adult , Community-Acquired Infections/prevention & control , Humans , Influenza, Human/prevention & control , Pneumonia, Pneumococcal/epidemiology , Practice Guidelines as Topic , SpainABSTRACT
Neuronal nitric oxide synthase (nNOS) is involved in the regulation of diverse intracellular messenger systems in the brain. Nitric Oxide (NO) contributes to inducing signaling cascades that involve a complex pattern of phosphorylation of DARPP-32 (in Thr-34), which controls the phosphoproteins involved in neuronal activation. However, the role of NO in the pathophysiology of Parkinson's disease (PD) and its effect in striatal neurons have been scarcely explored. In the present work, we investigate the effects of a nitric oxide synthase (NOS) inhibitor, 7-nitroindazole (7-NI) in the nigrostriatal pathway of striatal 6-hydroxydopamine (6-OHDA) lesioned rats. Our quantitative histological findings show that treatment with 7-NI significantly reduced 6-OHDA-induced dopaminergic damage in the dorsolateral striatum and Substantia Nigra pars compacta (SNpc). Moreover, 6-OHDA lesioned rats show a significant increase of nNOS(+) and Phospho-Thr34-DARPP-32(+) cells, accompanied by a consequent decrease of total DARPP-32(+) cells, which suggests an imbalance of NO activity in the DA-depleted striatum, which is also reflected in behavioral studies. Importantly, these effects are reverted in the group treated with 7-NI. These results show a clear link between the state of phosphorylation of DARPP-32 and parkinsonism, which is regulated by nNOS. This new evidence suggests a prominent role for nitric oxide in the neurotransmitter balance within the basal ganglia in the pathophysiology of experimental parkinsonism.
Subject(s)
Dopamine and cAMP-Regulated Phosphoprotein 32/metabolism , Dopamine/metabolism , Indazoles/pharmacology , Neostriatum/drug effects , Neurons/drug effects , Parkinson Disease, Secondary/metabolism , Signal Transduction/drug effects , Animals , Disease Models, Animal , Enzyme Inhibitors/pharmacology , Male , Neostriatum/metabolism , Neurons/metabolism , Nitric Oxide Synthase Type I/antagonists & inhibitors , Oxidopamine , Parkinson Disease, Secondary/chemically induced , Phosphorylation/drug effects , Rats , Rats, Sprague-DawleyABSTRACT
In the present work we analyze the cerebellum of chronic parkinsonian monkeys in order to clarify whether chronic mesencephalic depletion is associated with long term activation of the cerebellar neurons in chronic Parkinsonism. In our study, we observed a persistent activation of Purkinje cells in the cerebellum of chronic parkinsonian macaques, characterized by the expression of c-Fos, which correlated with dopaminergic degeneration. These results are compatible with the results observed in fMRI in Parkinson's disease patients, and may contribute to the understanding of additional alterations in the brain circuitry in Parkinsonism.
Subject(s)
Cerebellum/pathology , MPTP Poisoning/pathology , Purkinje Cells/pathology , Substantia Nigra/pathology , Animals , Cerebellum/metabolism , Chronic Disease , Disease Models, Animal , Dopamine/deficiency , Female , Macaca , Male , Organ Size , Proto-Oncogene Proteins c-fos/metabolism , Purkinje Cells/metabolism , Substantia Nigra/metabolismABSTRACT
UNLABELLED: This study analyses the serogroups/types (SGTs) and resistance to penicillin and erythromycin of 3921 strains isolated from 1990 to 1999 in children aged 0-14 y in Spanish hospitals of all the autonomous communities. Based on the age of the children, strains have been divided into five groups: 0-6 mo, > 6-1 y, > 1-2 y, > 2-5 y and > 5 y. While only eight SGTs were responsible for 80% of the infections in children from 6 mo to 2 y of age, this number increased to 11 and 16 for the groups > 2-5 y and > 5-14 y, respectively. SGTs 6, 14 and 19 were prevalent in blood and otic exudates. SGTs 1, 4, 5, 12 and 18 were more frequent in invasive disease but serotype 3 was clearly associated with otitis. Serotypes I and 5 were quite significant in children of over 2 y of age, and this should be taken into account in future vaccine formulations. CONCLUSION: Although high, the rate of penicillin resistance in the paediatric population has remained stable in recent years. Conversely, erythromycin resistance is still increasing in our country. Coverage by the 7-valent vaccine was 78 and 81% for blood and otic isolates, respectively. These coverage levels would be increased by 9% and 3% if 9-valent (plus 1 + 5 serotypes) were used and by an additional 2.6% and 7.6% using the 11-valent (plus 3 + 7) formulation.
