Articles: function.
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Temporal lobe epilepsy is a common and frequently intractable seizure disorder. Its pathogenesis is thought to involve large-scale alterations to the expression of genes controlling neurotransmitter signalling, ion channels, synaptic structure, neuronal death, gliosis, and inflammation. Identification of mechanisms coordinating gene networks in patients with temporal lobe epilepsy will help to identify novel therapeutic targets and biomarkers. MicroRNAs (miRNAs) are a family of small non-coding RNAs that control the expression levels of multiple proteins by decreasing mRNA stability and translation, and could therefore be key regulatory mechanisms and therapeutic targets in epilepsy. ⋯ In the past 5 years, studies have found changes in miRNA levels in the hippocampus of patients with temporal lobe epilepsy and in neural tissues from animal models of epilepsy. Early functional studies showed that silencing of brain-specific miR-134 using antisense oligonucleotides (antagomirs) had potent antiseizure effects in animal models, whereas genetic deletion of miR-128 produced fatal epilepsy in mice. Levels of certain miRNAs were also found to be altered in the blood of rodents after seizures. In the past 18 months, functional studies have identified nine novel miRNAs that appear to influence seizures or hippocampal pathology. Their targets include transcription factors, neurotransmitter signalling components, and modulators of neuroinflammation. New approaches to manipulate miRNAs have been tested, including injection of mimics (agomirs) to enhance brain levels of miRNAs. Altered miRNA expression has also been reported in other types of refractory epilepsy and our understanding of how miRNA levels are controlled has grown, with studies on DNA methylation indicating epigenetic regulation. Biofluids (blood) of patients with epilepsy have shown differences in quantity of circulating miRNAs, implying diagnostic biomarker potential. WHERE NEXT?: Recent functional studies need to be replicated to build a robust evidence base. The specific cell types in which miRNAs execute their functions and their primary targets have to be identified, to fully explain the phenotypic effects of modulating miRNAs. Delivery of large molecules such as antisense inhibitors or mimics to the brain poses a challenge, and the multi-targeting effects of miRNAs create additional risks of unanticipated side effects. Potential genetic variation in miRNAs should be explored as the basis for disease susceptibility. The latest findings provide a rich source of new miRNA targets, but substantial challenges remain before their role in the pathogenesis, diagnosis, and treatment of epilepsy can be translated into clinical practice.
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Inhalation of hypertonic saline improves sputum rheology, accelerates mucociliary clearance and improves clinical outcomes of people with cystic fibrosis. ⋯ People with cystic fibrosis could be encouraged to inhale hypertonic saline before or during airway clearance techniques to maximise perceived efficacy and satisfaction, even though these timing regimens may not have any better effect on lung function than inhalation after airway clearance techniques. Given the long-term efficacy of hypertonic saline has only been established for twice-daily inhalations, clinicians should advise patients to inhale hypertonic saline twice daily. However, if only one dose per day is tolerated, the time of day at which it is inhaled could be based on convenience or tolerability until evidence comparing these regimens is available.
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Review
Macrolides for Clinically Significant Bronchiectasis in Adults: Who Should Receive this Treatment?
Long-term macrolide therapy offers an evidence-based treatment to reduce frequent exacerbations in stable adult patients with bronchiectasis. There is limited evidence that these agents also attenuate the decline in lung function and improve health-related quality of life. ⋯ Further work is needed to understand the optimal drug, dose, and regimen, the mechanisms behind these benefits, appropriate patient selection, sustainability of efficacy, potential long-term risk for the lung microbiome; and their use with or without inhaled antibiotic treatment. We reviewed the current evidence on long-term macrolides in adults with bronchiectasis.
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The critically ill, asplenic patient presents a variety of management challenges. Historically, the focus of the care of the asplenic population has been the prevention and management of infection, including the often-fatal overwhelming postsplenectomy infection with encapsulated organisms such as Streptococcus pneumoniae. ⋯ Because of the relatively small size of this population and the relative infrequency with which critical illness occurs in it, there are few controlled trials that can serve as a basis for therapeutic maneuvers; thus, optimal management requires an astute clinician with an understanding of the pathogenetic mechanisms underlying the reported consequences of splenectomy. The purpose of this review is to explore the pathophysiology of the asplenic state-impairment in adaptive immunity, loss of blood filtration, endothelial dysfunction, and dysregulated coagulation-and how it leads to infection, thrombosis, and pulmonary hypertension as well as to discuss the implications of these conditions on the management of the critically ill, splenectomized patient.
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Semin Respir Crit Care Med · Dec 2016
ReviewThe Role of Streptococcus pneumoniae in Community-Acquired Pneumonia.
Streptococcus pneumoniae (the pneumococcus) remains one of the most common causes of bacterial community-acquired pneumonia (CAP), encompassing infections mild enough to be treated on an outpatient basis, as well as those requiring hospital care, or even intensive care unit admission. This microorganism is associated with a significant burden of disease, causing substantial morbidity and mortality worldwide, and generating considerable health-care costs. ⋯ Such risk factors include extremes of age, lifestyle factors, including smoking and alcohol abuse, and various underlying comorbid conditions, including congenital and acquired immunodeficiencies. This article will review various aspects of pneumococcal CAP, including the burden of pneumococcal disease, risk factors for pneumococcal infection, the occurrence of cardiovascular events in patients with pneumococcal CAP, the apparently pivotal role of pneumolysin, a major virulence factor of the pneumococcus, in the pathogenesis of severe infection and associated cardiac dysfunction, empiric antibiotic treatment for pneumococcal CAP, as well as adjunctive therapies, specifically those which target pneumolysin, and, finally, the mortality of such infections.