BackgroundMelanin pigments are ubiquitous in nature. Melanized microorganisms are often the dominating species in certain extreme environments, such as soils contaminated with radionuclides, suggesting that the presence of melanin is beneficial in their life cycle. We hypothesized that ionizing radiation could change the electronic properties of melanin and might enhance the growth of melanized microorganisms.Methodology/Principal FindingsIonizing irradiation changed the electron spin resonance (ESR) signal of melanin, consistent with changes in electronic structure. Irradiated melanin manifested a 4-fold increase in its capacity to reduce NADH relative to non-irradiated melanin. HPLC analysis of melanin from fungi grown on different substrates revealed chemical complexity, dependence of melanin composition on the growth substrate and possible influence of melanin composition on its interaction with ionizing radiation. XTT/MTT assays showed increased metabolic activity of melanized C. neoformans cells relative to non-melanized cells, and exposure to ionizing radiation enhanced the electron-transfer properties of melanin in melanized cells. Melanized Wangiella dermatitidis and Cryptococcus neoformans cells exposed to ionizing radiation approximately 500 times higher than background grew significantly faster as indicated by higher CFUs, more dry weight biomass and 3-fold greater incorporation of 14C-acetate than non-irradiated melanized cells or irradiated albino mutants. In addition, radiation enhanced the growth of melanized Cladosporium sphaerospermum cells under limited nutrients conditions.Conclusions/SignificanceExposure of melanin to ionizing radiation, and possibly other forms of electromagnetic radiation, changes its electronic properties. Melanized fungal cells manifested increased growth relative to non-melanized cells after exposure to ionizing radiation, raising intriguing questions about a potential role for melanin in energy capture and utilization.

These new guidelines represent a significant departure from previous recommendations that promoted specific lipid-level goals for patients that depended on level of risk. The new guidelines rely heavily on randomized, controlled trials involving fixed doses of statin medications in patients at risk for atherosclerotic cardiovascular disease. Four subgroups of patients were identified where benefits of statins outweigh risk. These included (1) those with clinically evident atherosclerotic cardiovascular disease; (2) primary low-density lipoprotein (LDL) cholesterol levels $190 mg/dL; (3) patients with type 1 or type 2 diabetes and LDL cholesterol levels $70 mg/dL; and (4) patients with a 10-year risk of atherosclerotic cardiovascular disease of at least 7.5% and an LDL cholesterol level $70 mg/dL. In addition, the new guidelines identify patients for whom data do not support statin therapy. These include those aged $75 years unless clinical atherosclerotic cardiovascular disease is present, those with a need for hemodialysis, or patients with New York Heart Association class II, III, or IV heart failure. In addition, the panel noted that there was no evidence to support use of nonstatin cholesterol-lowering drugs combined with statin therapy or in statin-intolerant patients.Comment: Adherence to the new guidelines will result in considerable changes in practice patterns that include avoidance of cholesterollowering therapy in certain patient groups and elimination of routine assessments of LDL cholesterol levels in patients receiving statin therapy because target levels are no longer emphasized. Additional changes include avoidance of nonstatin LDL cholesterol-lowering agents, more conservative use of statins in patients aged >75 years, and diminished use of surrogate markers, such as C-reactive protein or calcium scores, for selection of patients for statin therapy. Finally, the use of a new risk calculator in the new guidelines is likely to target larger numbers of patients for statin therapy.

Background and Purpose-MRI characterization of carotid plaque has been studied recently as a potential tool to predict stroke caused by carotid atherosclerosis. We performed a systematic review and meta-analysis to summarize the association of MRI-determined intraplaque hemorrhage, lipid-rich necrotic core, and thinning/rupture of the fibrous cap with subsequent ischemic events. Methods-We performed a comprehensive literature search evaluating the association of carotid plaque composition on MRI with ischemic outcomes. We included cohort studies examining intraplaque hemorrhage, lipid-rich necrotic core, or thinning/rupture of the fibrous cap with mean follow-up of ≥1 month and an outcome measure of ipsilateral stroke or transient ischemic attack. A meta-analysis using a random-effects model with assessment of study heterogeneity and publication bias was performed. Results-Of the 3436 articles screened, 9 studies with a total of 779 subjects met eligibility for systematic review.

Purpose:To assess quantitative susceptibility mapping (QSM) in the depiction of the subthalamic nucleus (STN) by using 3-T magnetic resonance (MR) imaging. Materials and Methods:This study was HIPAA compliant and institutional review board approved. Ten healthy subjects (five men, five women; mean age, 24 years 6 3 [standard deviation]; age range, 21-33 years) and eight patients with Parkinson disease (five men, three women; mean age, 57 years 6 14; age range, 25-69 years) who were referred by neurologists for preoperative navigation MR imaging prior to deep brain stimulator placement were included in this study. T2-weighted (T2w), T2*-weighted (T2*w), R2* mapping (R2*), phase, susceptibility-weighted (SW), and QSM images were reconstructed for STN depiction. Qualitative visualization scores of STN and internal globus pallidus (GPi) were recorded by two neuroradiologists on all images. Contrast-to-noise ratios (CNRs) of the STN and GPi were also measured. Measurement differences were assessed by using the Wilcoxon rank sum test and the signed rank test. Results:Qualitative scores were significantly higher on QSM images than on T2w, T2*w, R2*, phase, or SW images (P , .05) for STN and GPi visualization. Median CNR was 6.4 and 10.7 times higher on QSM images than on T2w images for differentiation of STN from the zona incerta and substantia nigra, respectively, and was 22.7 and 9.1 times higher on QSM images than on T2w images for differentiation of GPi from the internal capsule and external globus pallidus, respectively. CNR differences between QSM images and all other images were significant (P , .01). Conclusion:QSM at 3-T MR imaging performs significantly better than current standard-of-care sequences in the depiction of the STN.q RSNA, 2013Supplemental material: http://radiology.rsna.org/lookup /suppl

Melanized microorganisms are often found in environments with very high background radiation levels such as in nuclear reactor cooling pools and the destroyed reactor in Chernobyl. These findings and the laboratory observations of the resistance of melanized fungi to ionizing radiation suggest a role for this pigment in radioprotection. We hypothesized that the radioprotective properties of melanin in microorganisms result from a combination of physical shielding and quenching of cytotoxic free radicals. We have investigated the radioprotective properties of melanin by subjecting the human pathogenic fungi Cryptococcus neoformans and Histoplasma capsulatum in their melanized and non-melanized forms to sublethal and lethal doses of radiation of up to 8 kGy. The contribution of chemical composition, free radical presence, spatial arrangement, and Compton scattering to the radioprotective properties of melanin was investigated by high-performance liquid chromatography, electron spin resonance, transmission electron microscopy, and autoradiographic techniques. Melanin protected fungi against ionizing radiation and its radioprotective properties were a function of its chemical composition, free radical quenching, and spherical spatial arrangement.

BackgroundMelanin, a high-molecular weight pigment that is ubiquitous in nature, protects melanized microorganisms against high doses of ionizing radiation. However, the physics of melanin interaction with ionizing radiation is unknown.Methodology/Principal FindingsWe rationally designed melanins from either 5-S-cysteinyl-DOPA, L-cysteine/L-DOPA, or L-DOPA with diverse structures as shown by elemental analysis and HPLC. Sulfur-containing melanins had higher predicted attenuation coefficients than non-sulfur-containing melanins. All synthetic melanins displayed strong electron paramagnetic resonance (2.14·1018, 7.09·1018, and 9.05·1017 spins/g, respectively), with sulfur-containing melanins demonstrating more complex spectra and higher numbers of stable free radicals. There was no change in the quality or quantity of the stable free radicals after high-dose (30,000 cGy), high-energy (137Cs, 661.6 keV) irradiation, indicating a high degree of radical stability as well as a robust resistance to the ionizing effects of gamma irradiation. The rationally designed melanins protected mammalian cells against ionizing radiation of different energies.Conclusions/SignificanceWe propose that due to melanin's numerous aromatic oligomers containing multiple π-electron system, a generated Compton recoil electron gradually loses energy while passing through the pigment, until its energy is sufficiently low that it can be trapped by stable free radicals present in the pigment. Controlled dissipation of high-energy recoil electrons by melanin prevents secondary ionizations and the generation of damaging free radical species.

Melanoma is a cancer with a rising incidence, and metastatic disease is almost always lethal. We investigated the feasibility of targeting melanin, an intracellular melanocyte pigment, to deliver cytotoxic radiation to human melanoma cells in vivo by using a melanin-binding mAb (6D2). Nude mice bearing MNT1 pigmented human melanoma tumors were treated with mAb 6D2 labeled with 1.5 mCi (1 Ci ‫؍‬ 37 GBq) of the ␤-emitter 188-Rhenium ( 188 Re) and manifested inhibition of tumor growth and prolonged survival. mAb 6D2 bound tumor melanin and demonstrated no crossreactivity with normal melanized tissues in black mice. The mechanism of melanin targeting involved Ab binding to extracellular melanin released during tumor cell turnover or to dying cells with permeable membranes. In this approach, the cytotoxic radiation emanating from labeled Ab bound to melanin is presumably delivered by ''crossfire'' effect to the adjacent viable tumor cells. Our results establish the feasibility of targeting melanin released from dead melanoma cells in tumors with radiolabeled Abs to achieve a therapeutic effect. In contrast to conventional tumor antigens, melanin is insoluble, resistant to degradation, and can be expected to accumulate in targeted tissues, suggesting that the efficacy of therapy could increase with each subsequent treatment cycle.

Objective Diagnosis of amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS) is often difficult due to absence of disease biomarkers. Our aim was to investigate quantitative susceptibility mapping (QSM) of the motor cortex as a potential quantitative biomarker for the diagnosis of ALS and PLS. Materials and Methods Utilizing an institutional review board approved retrospective database, QSM images for 16 patients with upper motor neuron disease (12 with ALS and 4 with PLS; mean age 56.3; 56% male) and 23 control patients (mean age 56.6; 57% male) were reviewed. Two neuroradiologists, blinded to diagnosis, qualitatively assessed QSM, T2, T2*, and T2 FLAIR-weighted images. Relative motor cortex susceptibility (RMCS) was quantitatively calculated by subtracting adjacent white matter/CSF signal intensity from mean motor cortex susceptibility on the axial image most representative of the hand lobule, and receiver operating characteristic (ROC) analysis was performed. The Fisher’s exact and Student’s t tests were used to evaluate for statistical differences between the groups. Results Qualitatively, QSM had higher diagnostic accuracy than T2, T2*, or T2 FLAIR for the diagnosis of ALS/PLS. Quantitatively, RMCS was found to be significantly higher in patients with motor neuron disease than in control patients (46.0 and 35.0, respectively; p<0.001). ROC analysis demonstrated an area-under-the-curve of 0.88 (p<0.0001) and an optimal cutoff value of 40.5 ppb for distinguishing between control and ALS/PLS patients (sensitivity, 87.5%; specificity, 87.0%). Conclusions QSM is a sensitive and specific quantitative biomarker of iron deposition in the motor cortex in ALS and PLS.