Intracranial Applications of Magnetic Resonance-guided Focused Ultrasound

The ability to focus acoustic energy through the intact skull on to targets millimeters in size represents an important milestone in the development of neurotherapeutics. Magnetic resonance-guided focused ultrasound (MRgFUS) is a novel, noninvasive method, which—under real-time imaging and thermographic guidance—can be used to generate focal intracranial thermal ablative lesions and disrupt the blood–brain barrier. An established treatment for bone metastases, uterine fibroids, and breast lesions, MRgFUS has now been proposed as an alternative to open neurosurgical procedures for a wide variety of indications. Studies investigating intracranial MRgFUS range from small animal preclinical experiments to large, late-phase randomized trials that span the clinical spectrum from movement disorders, to vascular, oncologic, and psychiatric applications. We review the principles of MRgFUS and its use for brain-based disorders, and outline future directions for this promising technology.     

The effects of ambient particulate matter on human adipose tissue

ABSTRACT

The effects of particulate matter (PM) air pollution on adipose tissue have mainly been studied in animal models. The aim of this study was to examine the potential associations between PM exposure and 25 cellular markers in human omental (OM) and subcutaneous (SC) adipose tissue. The PM exposure assessments for both PM_2.5 (PM <2.5 μm in diameter) and PM₁₀ (<10 μm) were based upon a novel hybrid satellite-based spatio-temporally resolved model. We calculated the PM exposure above the background threshold for 1 week (acute phase), 3 and 6 months (intermediate phase), and 1 year (chronic phase) prior to tissue harvesting and tested the associations with adipose cell metabolic effects using multiple linear regressions and heat maps strategy. Chemokine levels were found to increase after acute and intermediate exposure duration to PM₁₀. The levels of stress signaling biomarkers in the SC and OM tissues rose after acute exposure to PM₁₀ and PM_2.5. Macrophage and leucocyte counts were associated with severity of PM exposure in all three duration groups. Adipocyte diameter decreased in all exposure periods. Our results provide evidence for significant contribution of air pollutants exposure to adipose tissue inflammation as well as for pathophysiological mechanisms of metabolic dysregulation that may be involved in the observed responses.     

EGFR Mutation Testing Practice in Advanced Non-Small Cell Lung Cancer

Purpose

Testing tumor samples for the presence of a mutation in the epithelial growth factor receptor (EGFR) gene is recommended for advanced non-squamous non-small cell lung cancer (NSCLC) patients. We aimed to collect data about common practice among Medical Oncologists treating lung cancer patients, regarding EGFR mutation testing in advanced NSCLC patients.

Methods

An internet-based survey was conducted among members of the Israeli Society for Clinical Oncology and Radiotherapy involved in the treatment of lung cancer patients.

Results

24 Oncologists participated in the survey. The participants encompass the Oncologists treating most of the lung cancer patients in Israel. 79 % of them use EGFR testing routinely for all advanced NSCLC patients. Opinions were split regarding the preferable biopsy site for EGFR testing material. 60 % of participants recommend waiting for EGFR test results prior to initiation of first-line therapy.

Conclusions

EGFR testing is requested in Israel routinely by most treating Oncologists for all advanced NSCLC patients, regardless of histology. In most cases, systemic treatment is deferred until the results of this test are received.     

Impact of Texting Laws on Motor Vehicular Fatalities in the United States

Using a panel study design, we examined the effects of different types of texting bans on motor vehicular fatalities.We used the Fatality Analysis Reporting System and a difference-in-differences approach to examine the incidence of fatal crashes in 2000 through 2010 in 48 US states with and without texting bans. Age cohorts were constructed to examine the impact of these bans on age-specific traffic fatalities.Primarily enforced laws banning all drivers from texting were significantly associated with a 3% reduction in traffic fatalities in all age groups, and those banning only young drivers from texting had the greatest impact on reducing deaths among those aged 15 to 21 years. Secondarily enforced restrictions were not associated with traffic fatality reductions in any of our analyses.Motor vehicle safety has been described as one of the 10 great public health achievements in the United States in the past decade,1 with car manufacturers and highway engineers making significant improvements to car and roadway safety features.2 Despite these improvements, traffic fatalities remain one of the leading causes of death in the United States,3 with an estimated 32 788 such deaths in 2010.4 Thus, road traffic fatalities continue to be a significant public health concern,5,6 garnering much attention from state lawmakers.In an effort to reduce motor vehicle fatalities, states have enacted restrictions on drunk driving, implemented graduated driver’s license programs, and mandated seatbelt use and special licensing procedures for older adults. Most recently, states have focused on restricting texting while driving.7–9 Generally, states define texting as reading, manual composition, or sending of electronic communications—text messages, instant messages, or e-mails—via a portable electronic device. Portable electronic devices include mobile (i.e., cellular) phones, personal digital assistants, and laptop computers. Texting while driving is a serious threat to road safety,10–13 given that research has shown that mobile phone use is associated with impaired following distance,14 improper lane position,11,15 longer reaction times,11,14,16 and crashes,11,17 which can all lead to significant adverse public health outcomes, including death.18 Unlike talking on a mobile phone while driving, texting poses a unique threat in that it requires drivers to take their eyes off the road for several seconds at a time.14Our current understanding of the impact of texting laws on driving outcomes is limited. To our knowledge, 2 studies have empirically examined the impact of texting laws on adverse motor vehicle outcomes. The first was published by the Highway Loss Data Institute.19 It examined the relationship of collision claim frequency and texting bans in just 4 states (CA, LA, MN, and WA). The authors found that texting bans were associated with increased collision claims. They speculated that this increase might be due to drivers hiding their phones from view to avoid fines and, in so doing, taking their eyes off the road more than they did before the bans. More recently, Abouk and Adams20 published the first national-level study of texting bans’ impacts on traffic fatalities. They examined the impact of texting-while-driving bans on the occurrence of only single-vehicle, single-occupant accidents between 2007 and 2010. Their findings indicated that stronger bans that are applied to all drivers were associated with decreases in single-vehicle, single-occupant accidents.The purpose of this study is to add to the knowledge base concerning the effectiveness of texting laws, particularly by considering the varying stringency levels of these laws. Texting bans can be secondarily enforced (i.e., an officer must have another reason to stop a vehicle before citing a driver for texting while driving) or primarily enforced (i.e., an officer does not have to have another reason for stopping a vehicle). Furthermore, some states ban texting among learner’s permit holders, and some ban texting among all those aged 18 years, 21 years, or younger, and still other states ban all drivers from texting. Some states have no texting laws at all. We consider the impact of each of these policy nuances on traffic fatalities in 48 states over an 11-year period. Moreover, given that younger individuals are more likely to text while driving,21 we examine the impact of texting laws on age-specific traffic fatalities. Overall, this study will be of interest to policymakers, law enforcement personnel, and other stakeholders interested in improving roadway safety and, by extension, public health.     

Mapping white matter integrity in elderly people with HIV

People with HIV are living longer as combination antiretroviral therapy (cART) becomes more widely available. However, even when plasma viral load is reduced to untraceable levels, chronic HIV infection is associated with neurological deficits and brain atrophy beyond that of normal aging. HIV is often marked by cortical and subcortical atrophy, but the integrity of the brain's white matter (WM) pathways also progressively declines. Few studies focus on older cohorts where normal aging may be compounded with HIV infection to influence deficit patterns. In this relatively large diffusion tensor imaging (DTI) study, we investigated abnormalities in WM fiber integrity in 56 HIV+ adults with access to cART (mean age: 63.9 ± 3.7 years), compared to 31 matched healthy controls (65.4 ± 2.2 years). Statistical 3D maps revealed the independent effects of HIV diagnosis and age on fractional anisotropy (FA) and diffusivity, but we did not find any evidence for an age by diagnosis interaction in our current sample. Compared to healthy controls, HIV patients showed pervasive FA decreases and diffusivity increases throughout WM. We also assessed neuropsychological (NP) summary z‐score associations. In both patients and controls, fiber integrity measures were associated with NP summary scores. The greatest differences were detected in the corpus callosum and in the projection fibers of the corona radiata. These deficits are consistent with published NP deficits and cortical atrophy patterns in elderly people with HIV. Hum Brain Mapp 35:975–992, 2014. © 2013 Wiley Periodicals, Inc.     

A motor learning-based intervention to ameliorate freezing of gait in subjects with Parkinson’s disease

Freezing of gait (FOG) is an episodic gait disturbance that is commonly seen in Parkinson’s disease (PD). To date, treatment efficacy is limited. We tested the hypothesis that an intervention that utilizes motor learning provided through intensive cueing can alleviate this symptom. Fifteen subjects with PD suffering from FOG participated in a 6 week progressive motor learning program (three training sessions per week—open trial). A training session included FOG-provoking situations (e.g., turns). Prior to each presumed FOG provocation (e.g., just before a turn), rhythmic auditory stimulation (RAS) was elicited and the subject was trained to walk rhythmically, coordinate left–right stepping and to increase step size, utilizing the RAS cueing. Net training duration increased from week to week and secondary cognitive tasks while walking were added to increase FOG propensity. FOG symptom burden was assessed before, immediately, and 4 weeks after the training period. The mean number of FOG episodes (±SEM) per 10 m of walking in a standardized gait assessment decreased from 0.52 ± 0.29 in the pre-testing to 0.15 ± 0.04 in the post-testing (p < 0.05). The duration of FOG episodes decreased from 4.3 ± 2.1 to 2.6 ± 0.6 s (p < 0.05). Additional measures (e.g., FOG questionnaire, gait speed) varied in their responsiveness to the treatment. These effects were retained 4 weeks after the training. The results of this open label study support the possibility that a motor learning-based intervention is apparently effective in reducing FOG burden, suggesting that RAS can deliver ‘anti-FOG’ training.     

Melatonin inhibits nuclear factor kappa B activation and oxidative stress and protects against thioacetamide induced liver damage in rats

BACKGROUND/AIMS: Free radical-mediated oxidative stress has been implicated in the pathogenesis of acute liver injury. The aim of our study was to investigate whether melatonin, a potent free radical scavenger could prevent fulminant hepatic failure in rats. METHODS: Liver damage was induced by two consecutive injections of thioacetamide (TAA, 300 mg/kg/i.p.) at 24 h intervals. Treatment with melatonin (3 mg/kg/daily, i.p) was initiated 24 h prior to TAA. RESULTS: Twenty-four h after the second TAA injection, serum liver enzymes and blood ammonia were lower in rats treated with TAA+melatonin compared to TAA (P<0.001). Liver histology was significantly improved and the mortality in the melatonin-treated rats was decreased (P<0.001). The increased nuclear binding of nuclear factor kappa B in the livers of the TAA-treated rats, was inhibited by melatonin. The hepatic levels of thiobarbituric acid reactive substances, protein carbonyls and inducible nitric oxide synthase were lower in the TAA+melatonin-treated group (P<0.01), indicating decreased oxidative stress and inflammation. CONCLUSIONS: In a rat model of TAA-induced fulminant hepatic failure, melatonin improves survival and reduces liver damage and oxidative stress. The results suggest a causative role of oxidative stress in TAA-induced hepatic damage and suggest that melatonin may be utilized to reduce liver injury associated with oxidative stress.     

Direct measurement of the viscoelectric effect in water

The viscoelectric effect concerns the increase in viscosity of a polar liquid in an electric field due to its interaction with the dipolar molecules and was first determined for polar organic liquids more than 80 y ago. For the case of water, however, the most common polar liquid, direct measurement of the viscoelectric effect is challenging and has not to date been carried out, despite its importance in a wide range of electrokinetic and flow effects. In consequence, estimates of its magnitude for water vary by more than three orders of magnitude. Here, we measure the viscoelectric effect in water directly using a surface force balance by measuring the dynamic approach of two molecularly smooth surfaces with a controlled, uniform electric field between them across highly purified water. As the water is squeezed out of the gap between the approaching surfaces, viscous damping dominates the approach dynamics; this is modulated by the viscoelectric effect under the uniform transverse electric field across the water, enabling its magnitude to be directly determined as a function of the field. We measured a value for this magnitude, which differs by one and by two orders of magnitude, respectively, from its highest and lowest previously estimated values.

The viscoelectric effect concerns the change in the viscosity of polar liquids in the presence of an electric field (1–3). It arises from the interaction of the field with the dipolar molecules, and while its molecular origins are still not well understood (4–6), it has considerable relevance in areas ranging from surface potential measurements (7–9) and boundary lubrication (10) to nanofluidics and its applications (11–13). Knowing the magnitude of the viscoelectric effect is thus of clear importance. It was first measured by Andrade and Dodd (1–3) for a range of polar organic liquids, by monitoring their flow in a narrow channel between metal electrodes across which a known electric field E was applied, and quantified via a viscoelectric coefficient f using an empirical relation based on their results:η(E)= η0(1 + f∣E∣2),[1]a simplified analysis leading to such a relation is given in Ref. (8). Here, η₀ is the unperturbed bulk liquid viscosity (i.e., in the absence of any field). For the case of water, however, the most ubiquitous and important polar liquid, measurement of its viscosity in the presence of a strong, uniform field presents a strong challenge (as discussed later in this section), and to our knowledge no such direct measurements have been reported. Over the past six decades, therefore, the magnitude of the viscoelectric effect in water has been only indirectly estimated by extrapolation from its values for organic liquids (8), from estimates of its effect on electrokinetic phenomena (11, 14–19), or by other approaches (7, 12, 20, 21). These estimated values, as expressed in the viscoelectric coefficient f, vary over more than three orders of magnitude, ranging from f ∼10⁻¹⁷–2.5 × 10⁻¹⁴ (V/m)² (SI Appendix, Section 7). For completeness, we note that results contradictory to the viscoelectric model have also been reported (22) (i.e., suggesting a decreased water viscosity in an electric field). The reasons for the large span of these estimated f values were attributed to various factors such as solid/liquid coupling, varying ionic sizes, and varying water permittivity (12, 19); however, while these factors may play some role, there is no evidence that they could lead to such large discrepancies.We believe, rather, that the origin of the large variance in the estimated magnitude of the viscoelectric effect arises because none of the experimental studies on water to date in which the f values were estimated was direct, in the sense of probing how the water viscosity varied with field in a uniform electric field. In all cases, viscosity changes were assumed to occur only in the nonuniform, rapidly decaying electrostatic potential near charged surfaces immersed in water. Changes in electrophoretic mobility, electro-osmosis, or hydrodynamic dissipation or water mobility between similarly charged solid surfaces were then attributed to some mean viscosity increase in these thin surface-adjacent layers (7, 11, 12, 14–21). In practice, however, the effect on these electrokinetic phenomena of viscosity or water mobility changes in the thin layers where such nonuniform, rapidly decaying fields are present is not easy to quantify reliably, especially in the presence of salt ions (12). At the same time, measuring the viscosity of water in a uniform electric field between two surfaces at different potentials, as was done for the polar organic solvents (2, 3) and which would provide a direct determination of its viscoelectric effect, presents a considerable difficulty. This is due to two main factors and arises because, in contrast to organic solvents, water may self-dissociate. Firstly, the potential difference that may be applied between the surfaces across water is limited, if electrolysis is to be avoided (23, 24), and secondly, electrostatic screening implies that the field decays strongly (within a Debye screening length) away from the surfaces (25–27). Even in purified water with no added salt (as in the present study), the potential decays rapidly away from a charged surface (see, e.g., Fig. 1C), so that to measure viscosity in a uniform field between two surfaces, one would require flow channels of width of order some tens of nanometers or less, presenting a major challenge.Open in a separate windowFig. 1.Numerical solution to the nonlinearized PB equation with σ_mica = −8.1 mC/m², ψ_gold = 0.07 V, and ion concentration c_b = 8 × 10⁻⁵ M, corresponding to the conditions of Fig. 4A. (A) Surface potential on the mica surface and surface charge on the gold surface as a function of separation D. (B) Average electric field approximated as (|ψ_gold − ψ_mica|/D). (C) Local potential ψ as a function of distance d from the mica surface for different separations D. Dashed line in larger-scale inset is an eye guide of a linear approximation.In the present study, we overcome this by directly probing the viscosity of purified water across which a uniform electric field acts while it is confined between two surfaces in a surface force balance (SFB). In our experiments, a molecularly smooth gold surface at a controlled (positive) surface potential approaches an atomically smooth mica surface at constant surface (negative) charge density, so that a known electric field acts across the water-filled gap of width D between them; moreover, this field is very close to uniform at the most relevant surface separations (D ≲ 30 nm, Fig. 1C). The dynamics of approach is strongly modulated by the viscous damping due to squeeze-out of the water as D decreases, and hence by its viscosity in the uniform electric field; by monitoring the approach rate of the surfaces at high temporal (millisecond) and spatial (approximately angstrom) resolutions, we are able therefore to directly evaluate the magnitude of the viscoelectric effect (the value of f).