Natural or artificially induced electrical activity changes can alter ion balance so as to briefly influence firing. An optogenetics study delineates one mechanism: Cl- shifts causing seconds-long ...excitability changes after silencing.
The extracellular ionic environment in neural tissue has the capacity to influence, and be influenced by, natural bouts of neural activity. We employed optogenetic approaches to control and ...investigate these interactions within and between cells, and across spatial scales. We began by developing a temporally precise means to study microdomain-scale interactions between extracellular protons and acid-sensing ion channels (ASICs). By coupling single-component proton-transporting optogenetic tools to ASICs to create two-component optogenetic constructs (TCOs), we found that acidification of the local extracellular membrane surface by a light-activated proton pump recruited a slow inward ASIC current, which required molecular proximity of the two components on the membrane. To elicit more global effects of activity modulation on 'bystander' neurons not under direct control, we used densely-expressed depolarizing (ChR2) or hyperpolarizing (eArch3.0, eNpHR3.0) tools to create a slow non-synaptic membrane current in bystander neurons, which matched the current direction seen in the directly modulated neurons. Extracellular protons played contributory role but were insufficient to explain the entire bystander effect, suggesting the recruitment of other mechanisms. Together, these findings present a new approach to the engineering of multicomponent optogenetic tools to manipulate ionic microdomains, and probe the complex neuronal-extracellular space interactions that regulate neural excitability.
•Glioblastoma can arise in areas of encephalomalacia.•We present two cases of glioblastoma after vascular brain injury.•The site of prior brain injury may influence the risk for malignant ...transformation.
Glioblastoma is the most common primary parenchymal brain malignancy, with median survival of less than one year. While there are likely multiple predisposing genetic and environmental factors in glioblastoma formation, chronic inflammation resulting from non-traumatic vascular brain injury is one proposed risk factor for oncogenesis. Here, we report two instances of glioblastoma arising within areas of encephalomalacia caused by remote vascular insults (one following aneurysmal subarachnoid hemorrhage and one following ischemic infarction), review the literature associating glioblastoma with prior brain injury, and discuss potential mechanisms for malignant transformation in injured brain tissue.
Optogenetic methodology enables direct targeting of specific neural circuit elements for inhibition or excitation while spanning timescales from the acute (milliseconds) to the chronic (many days or ...more). Although the impact of this temporal versatility and cellular specificity has been greater for basic science than clinical research, it is natural to ask whether the dynamic patterns of neural circuit activity discovered to be causal in adaptive or maladaptive behaviors could become targets for treatment of neuropsychiatric diseases. Here, we consider the landscape of ideas related to therapeutic targeting of circuit dynamics. Specifically, we highlight optical, ultrasonic, and magnetic concepts for the targeted control of neural activity, preclinical/clinical discovery opportunities, and recently reported optogenetically guided clinical outcomes.
Optogenetics has afforded us unprecedented new insights into diverse neural circuits and their functions. What will it take to be able to understand and treat neuropsychiatric disease in terms of circuits that doctors can manipulate?
The cardiovascular risk reduction associated with different statins for the prevention of cardiovascular disease and the cardiovascular risk increase associated with excess dietary intake of fat have ...been quantified. However, these relative risks have never been directly juxtaposed to determine whether an increase in relative risk by 1 activity could be neutralized by an opposing change in relative risk from a second activity. The investigators compared the increase in relative risk for cardiovascular disease associated with the total fat and trans fat content of fast foods against the relative risk decrease provided by daily statin consumption from a meta-analysis of statins in primary prevention of coronary artery disease (7 randomized controlled trials including 42,848 patients). The risk reduction associated with the daily consumption of most statins, with the exception of pravastatin, is more powerful than the risk increase caused by the daily extra fat intake associated with a 7-oz hamburger (Quarter Pounder®) with cheese and a small milkshake. In conclusion, statin therapy can neutralize the cardiovascular risk caused by harmful diet choices. In other spheres of human activity, individuals choosing risky pursuits (motorcycling, smoking, driving) are advised or compelled to use measures to minimize the risk (safety equipment, filters, seatbelts). Likewise, some individuals eat unhealthily. Routine accessibility of statins in establishments providing unhealthy food might be a rational modern means to offset the cardiovascular risk. Fast food outlets already offer free condiments to supplement meals. A free statin-containing accompaniment would offer cardiovascular benefits, opposite to the effects of equally available salt, sugar, and high-fat condiments. Although no substitute for systematic lifestyle improvements, including healthy diet, regular exercise, weight loss, and smoking cessation, complimentary statin packets would add, at little cost, 1 positive choice to a panoply of negative ones.
Background In clinical practice, mitral regurgitation (MR) is often assessed from the visual impression of the color Doppler image. It is recognized that repeated scanning can give different images ...and that different observers may grade the same images differently. In this study, we focus on a more intrinsic source of variability—intraobserver variability in grading of identical images, presented more than once at the same sitting. Furthermore, we look for evidence that observer grading is influenced by the severity of the immediately preceding case viewed. Methods Anonymous, 4-chamber color Doppler 2-dimensional video clips of MR were obtained from 60 unselected patients with MR. Six clips were identified by 2 observers as of contentious severity (either between mild and moderate or between moderate and severe). A 72-clip sequence was constructed from the 54 “uncontentious” selected cases of MR intermingled with 3 presentations of each of the 6 “contentious” images. Each contentious image was shown once without a designed order, once preceded by 3 clips of less severe MR, and once preceded by 3 clips of more severe MR. Results Only 1 (8%) of 12 observers gave consistent gradings for the triply presented images. More than 90% (11/12) of the observers reported a different grading of the same clip of MR in at least 1 of the 6 cases. The MR severity was changed in 51.4% of the triplets of identical images shown. Of 12 reporters, 5 (42%) showed classification variability between severe and nonsevere grades in at least 1 of the 6 cases. The direction of change showed no sign of consistency between observers ( P = .375). Conclusion Even a skilled observer cannot be relied upon to give an identical grading to an identical simple video clip of MR, when re-presented surreptitiously within a few minutes. Interobserver variability cannot therefore simply be blamed on differential levels of skill. Because, even under these ideal and dramatically simplified conditions, visual assessment is so variable, the future emphasis of echocardiographic MR grading may lie in integrating qualitative analysis with simple quantification methods.
The working diagnosis of urinary-tract infection, as a cause of coma, was not entirely convincing: white blood cells were not always present in the patient's urine; blood cultures were consistently ...negative; on blood testing, the white-cell count and concentration of C-reactive protein were normal; the patient had no fever. Risk factors for bacterial overgrowth syndrome, which is underdiagnosed in elderly patients,1 include anatomical alterations to the intestine, drugs that inhibit gastric acid secretion, diabetes, and advanced age.
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