Sublime Microglia: Expanding Roles for the Guardians of the CNS

Recent findings challenge the concept that microglia solely function in disease states in the central nervous system (CNS). Rather than simply reacting to CNS injury, infection, or pathology, emerging lines of evidence indicate that microglia sculpt the structure of the CNS, refine neuronal circuitry and network connectivity, and contribute to plasticity. These physiological functions of microglia in the normal CNS begin during development and persist into maturity. Here, we develop a conceptual framework for functions of microglia beyond neuroinflammation and discuss the rich repertoire of signaling and communication motifs in microglia that are critical both in pathology and for the normal physiology of the CNS

Non-ischaemic cardiomyopathy, sudden death and implantable defibrillators: a review and meta-analysis

Objective: The recent Danish Study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on Mortality (DANISH) trial suggested that implantable cardioverter defibrillators (ICDs) do not reduce overall mortality in patients with non-ischaemic cardiomyopathy (NICM), despite reducing sudden cardiac death. We performed an updated meta-analysis to examine the impact of ICD therapy on mortality in NICM patients. Methods: A systematic search for studies that examined the effect of ICDs on outcomes in NICM was performed. Our analysis compared patients randomised to an ICD with those randomised to no ICD, and examined the endpoint of overall mortality. Results: Six primary prevention trials and two secondary prevention trials were identified that met the pre-specified search criteria. Using a fixed-effects model, analysis of primary prevention trials revealed a reduction in overall mortality with ICD therapy (RR 0.76, 95% CI 0.65 to 0.91). Conclusions: Although our updated meta-analysis demonstrates a survival benefit of ICD therapy, the effect is substantively weakened by the inclusion of the DANISH trial—which is both the largest and most recent of the analysed trials—indicating that the residual pooled benefit of ICDs may reflect the risk of sudden death in older trials which included patients treated sub-optimally by contemporary standards. As such, these data must be interpreted cautiously. The results of the DANISH trial emphasise that there is no ‘one size fits all’ indication for primary prevention ICDs in NICM patients, and clinicians must consider age and comorbidity on an individual basis when determining whether a defibrillator is appropriate

Bactericidal action of positive and negative ions in air

In recent years there has been renewed interest in the use of air ionisers to control of the spread of airborne infection. One characteristic of air ions which has been widely reported is their apparent biocidal action. However, whilst the body of evidence suggests a biocidal effect in the presence of air ions the physical and biological mechanisms involved remain unclear. In particular, it is not clear which of several possible mechanisms of electrical origin (i.e. the action of the ions, the production of ozone, or the action of the electric field) are responsible for cell death. A study was therefore undertaken to clarify this issue and to determine the physical mechanisms associated with microbial cell death. In the study seven bacterial species (Staphylococcus aureus, Mycobacterium parafortuitum, Pseudomonas aeruginosa, Acinetobacter baumanii, Burkholderia cenocepacia, Bacillus subtilis and Serratia marcescens) were exposed to both positive and negative ions in the presence of air. In order to distinguish between effects arising from: (i) the action of the air ions; (ii) the action of the electric field, and (iii) the action of ozone, two interventions were made. The first intervention involved placing a thin mica sheet between the ionisation source and the bacteria, directly over the agar plates. This intervention, while leaving the electric field unaltered, prevented the air ions from reaching the microbial samples. In addition, the mica plate prevented ozone produced from reaching the bacteria. The second intervention involved placing an earthed wire mesh directly above the agar plates. This prevented both the electric field and the air ions from impacting on the bacteria, while allowing any ozone present to reach the agar plate. With the exception of Mycobacterium parafortuitum, the principal cause of cell death amongst the bacteria studied was exposure to ozone, with electroporation playing a secondary role. However in the case of Mycobacterium parafortuitum, electroporation resulting from exposure to the electric field appears to have been the principal cause of cell inactivation. The results of the study suggest that the bactericidal action attributed to negative air ions by previous researchers may have been overestimated

Who benefits from a defibrillator—balancing the risk of sudden versus non-sudden death

Purpose of Review: Treatment with a defibrillator can reduce the risk of sudden death by terminating ventricular arrhythmias. The identification of patient groups in whom this function reduces overall mortality is challenging. In this review, we summarise the evidence for who benefits from a defibrillator. Recent Findings: Recent evidence suggests that contemporary pharmacologic and non-defibrillator device therapies are altering the potential risks and benefits of a defibrillator. Summary: Who benefits from a defibrillator is determined by both the risk of sudden death and the competing risk of other, non-sudden causes of death. The balance of these risks is changing, which calls into question whether historic evidence for the use of defibrillators remains robust in the modern era

Chronic heart failure: epidemiology, investigation and management

Heart failure (HF) is a clinical syndrome characterized by dyspnoea, fatigue and fluid retention accompanied by objective evidence of cardiac dysfunction. The syndrome affects around 2% of the adult population, men more commonly than women (<80 years old), with the incidence and prevalence rising steeply with age. HF causes substantial morbidity and reduced life expectancy, and coronary artery disease accounts for two-thirds of cases in developed countries. Investigation is important to ascertain the diagnosis, identify the aetiology (which may be reversible) and give some indication of prognosis. The diagnosis of HF confers a significantly increased risk of hospital admission and death. Treatment has been revolutionized by large randomized controlled clinical trials studying the effects of antagonists of the renin–angiotensin–aldosterone, neutral endopeptidase and sympathetic nervous systems, and the effects of device therapy. Cardiac transplantation remains an option for patients who are severely symptomatic (and at high risk) despite optimal use of such therapy

Peripheral nerve injury and TRPV1-expressing primary afferent C-fibers cause opening of the blood-brain barrier

<p>Abstract</p> <p>Background</p> <p>The blood-brain barrier (BBB) plays the crucial role of limiting exposure of the central nervous system (CNS) to damaging molecules and cells. Dysfunction of the BBB is critical in a broad range of CNS disorders including neurodegeneration, inflammatory or traumatic injury to the CNS, and stroke. In peripheral tissues, the vascular-tissue permeability is normally greater than BBB permeability, but vascular leakage can be induced by efferent discharge activity in primary sensory neurons leading to plasma extravasation into the extravascular space. Whether discharge activity of sensory afferents entering the CNS may open the BBB or blood-spinal cord barrier (BSCB) remains an open question.</p> <p>Results</p> <p>Here we show that peripheral nerve injury (PNI) produced by either sciatic nerve constriction or transecting two of its main branches causes an increase in BSCB permeability, as assessed by using Evans Blue dye or horseradish peroxidase. The increase in BSCB permeability was not observed 6 hours after the PNI but was apparent 24 hours after the injury. The increase in BSCB permeability was transient, peaking about 24-48 hrs after PNI with BSCB integrity returning to normal levels by 7 days. The increase in BSCB permeability was prevented by administering the local anaesthetic lidocaine at the site of the nerve injury. BSCB permeability was also increased 24 hours after electrical stimulation of the sciatic nerve at intensity sufficient to activate C-fibers, but not when A-fibers only were activated. Likewise, BSCB permeability increased following application of capsaicin to the nerve. The increase in permeability caused by C-fiber stimulation or by PNI was not anatomically limited to the site of central termination of primary afferents from the sciatic nerve in the lumbar cord, but rather extended throughout the spinal cord and into the brain.</p> <p>Conclusions</p> <p>We have discovered that injury to a peripheral nerve and electrical stimulation of C-fibers each cause an increase in the permeability of the BSCB and the BBB. The increase in permeability is delayed in onset, peaks at about 24 hours and is dependent upon action potential propagation. As the increase is mimicked by applying capsaicin to the nerve, the most parsimonious explanation for our findings is that the increase in permeability is mediated by activation of TRPV1-expressing primary sensory neurons. Our findings may be relevant to the development of pain and neuroplastic changes in the CNS following nerve injury. In addition, our findings may provide the basis for developing methods to purposefully open the BBB when needed to increase brain penetration of therapeutic agents that might normally be excluded by an intact BBB.</p

Microglia-independent peripheral neuropathic pain in male and female mice

ABSTRACT: The dominant view in the field of pain is that peripheral neuropathic pain is driven by microglia in the somatosensory processing region of the spinal dorsal horn. Here, to the contrary, we discovered a form of neuropathic pain that is independent of microglia. Mice in which the nucleus pulposus (NP) of the intervertebral disc was apposed to the sciatic nerve developed a constellation of neuropathic pain behaviours: hypersensitivity to mechanical, cold, and heat stimuli. However, NP application caused no activation of spinal microglia nor was pain hypersensitivity reversed by microglial inhibition. Rather, NP-induced pain hypersensitivity was dependent on cells within the NP which recruited macrophages to the adjacent nerve. Eliminating macrophages systemically or locally prevented NP-induced pain hypersensitivity. Pain hypersensitivity was also prevented by genetically disrupting the neurotrophin brain-derived neurotrophic factor selectively in macrophages. Moreover, the behavioural phenotypes as well as the molecular mechanisms of NP-induced pain hypersensitivity were not different between males and females. Our findings reveal a previously unappreciated mechanism for by which a discrete peripheral nerve lesion may produce pain hypersensitivity, which may help to explain the limited success of microglial inhibitors on neuropathic pain in human clinical trials

Anticoagulation therapy in heart failure and sinus rhythm: a systematic review and meta-analysis

Objective: Heart failure is a prothrombotic state, and it has been hypothesised that thrombosis and embolism cause non-fatal and fatal events in heart failure and reduced ejection fraction (HFrEF). We sought to determine the effect of anticoagulant therapy on clinical outcomes in patients with HFrEF who are in sinus rhythm. Methods: We conducted an updated systematic review and meta-analysis to examine the effect of anticoagulation therapy in patients with HFrEF in sinus rhythm. Our analysis compared patients randomised to anticoagulant therapy with those randomised to antiplatelet therapy, placebo or control, and examined the endpoints of all-cause mortality, (re)hospitalisation for worsening heart failure, non-fatal myocardial infarction, non-fatal stroke of any aetiology and major haemorrhage. Results: Five trials were identified that met the prespecified search criteria. Compared with control therapy, anticoagulant treatment did not reduce all-cause mortality (risk ratio [RR] 0.99, 95% CI 0.90 to 1.08), (re)hospitalisation for heart failure (RR 0.97, 95% CI 0.82 to 1.13) or non-fatal myocardial infarction (RR 0.92, 95% CI 0.75 to 1.13). Anticoagulation did reduce the rate of non-fatal stroke (RR 0.63, 95% CI 0.49 to 0.81, p=0.001), but this was offset by an increase in the incidence of major haemorrhage (RR 1.88, 95% CI 1.49 to 2.38, p=0.001). Conclusions: Our meta-analysis provides evidence to oppose the hypothesis that thrombosis or embolism plays an important role in the morbidity and mortality associated with HFrEF, with the exception of stroke-related morbidity

Transformation of the output of spinal lamina I neurons after nerve injury and microglia stimulation underlying neuropathic pain

<p>Abstract</p> <p>Background</p> <p>Disinhibition of neurons in the superficial spinal dorsal horn, via microglia – neuron signaling leading to disruption of chloride homeostasis, is a potential cellular substrate for neuropathic pain. But, a central unresolved question is whether this disinhibition can transform the activity and responses of spinal nociceptive output neurons to account for the symptoms of neuropathic pain.</p> <p>Results</p> <p>Here we show that peripheral nerve injury, local spinal administration of ATP-stimulated microglia or pharmacological disruption of chloride transport change the phenotype of spinal lamina I output neurons, causing them to 1) increase the gain of nociceptive responsiveness, 2) relay innocuous mechanical input and 3) generate spontaneous bursts of activity. The changes in the electrophysiological phenotype of lamina I neurons may account for three principal components of neuropathic pain: hyperalgesia, mechanical allodynia and spontaneous pain, respectively.</p> <p>Conclusion</p> <p>The transformation of discharge activity and sensory specificity provides an aberrant signal in a primarily nociceptive ascending pathway that may serve as a basis for the symptoms of neuropathic pain.</p