Summary Chronic complex regional pain syndrome (CRPS) is a debilitating pain condition accompanied by autonomic abnormalities. We investigated gray matter morphometry and white matter anisotropy in CRPS patients and matched controls. Patients exhibited 1) a disrupted relationship between white matter anisotropy and whole-brain gray matter volume, 2) gray matter atrophy in a single cluster encompassing right insula, right ventromedial prefrontal cortex (VMPFC), and right nucleus accumbens, and 3) a decrease in fractional anisotropy in the left cingulum-callosal bundle. Reorganization of white matter connectivity in these regions was characterized by branching pattern alterations, and increased (VMPFC to insula) and decreased connectivity (VMPFC to basal ganglion). While regional atrophy differentially related to pain intensity and duration, the strength of connectivity between specific atrophied regions related to anxiety. These abnormalities encompass emotional, autonomic, and pain perception regions, implying that they likely play a critical role in the global clinical picture of CRPS.

Covalently closed circular duplex DNA's are now known to be widespread among living organisms. This DNA structure, originally identified in polyoma viral DNA,1' 2 has been assigned to the mitochondrial DNA's in ox3 and sheep heart,4 in mouse and chicken liver,3 and in unfertilized sea urchin egg.5 The animal viral DNA's-polyoma, SV40, rabbit7 and human8 papilloma-the intracellular forms of the bacterial viral DNA's 4X174,9 10lambda,", 12 1\113,13 and P2214 -and a bacterial plasmid DNA, the colicinogenic factor E2,15 have all been shown to exist as closed circular duplexes. Other mitochondrial DNA's'6' 17 and a portion of the DNA from boar sperm'8 have been reported to be circular, but as yet have not been shown to be covalently closed.The'physicochemical properties of closed circular DNA differ in several respects from those of linear DNA or of circular DNA containing one or more singlestrand scissions."9 The resistance to denaturation,2' 20 the sedimentation velocity in neutral and alkaline solution, and the buoyant density in alkaline solution are all enhanced in the closed circular molecules. These three effects are a direct consequence of the topological requirement that the number of interstrand crossovers must remain constant in the closed molecule.The principal methods currently used for the detection and the isolation of closed circular DNA are based on the first two general properties. In this communication we describe a method based on the buoyant behavior of closed circular DNA in the presence of intercalating dyes.The binding of intercalative dyes has recently been shown to cause a partial unwinding of the duplex structure in closed circular DNA. 22-24 In such molecules any unwinding of the duplex causes a change in the number of superhelical turns, so that the total number of turns in the molecule remains constant. A small and critical amount of dye-binding reduces the number of superhelical turns to zero. Further dye-binding results in the formation of superhelices of the opposite sign or handedness. The creation of these new superhelices introduces mechanical stresses into the duplex and a more ordered conformation into the molecule. These effects increase the free energy of formation of the DNA-dye complex. The maximum amount of dye that can be bound by the closed molecule is therefore smaller than by the linear or nicked circular molecule. Correspondingly, since the buoyant density of the DNA-dye complex23' 25 is inversely related to the amount of dye bound, the buoyant density of the closed circular DNA-dye complex at saturation is greater than that of the linear or nicked circular DNA-dye complex.23 Bauer and Vinograd have shown that the above effect results in a buoyant density difference of approximately 0.04 gm/ml in CsCl containing saturating amounts of ethidium bromide, an intercalating dye extensively studied by Waring26 and Le Pecq.27 1514

Chronic pain can be understood not only as an altered functional state, but also as a consequence of neuronal plasticity. Here we use in vivo structural MRI to compare global, local, and architectural changes in gray matter properties in patients suffering from chronic back pain (CBP), complex regional pain syndrome (CRPS) and knee osteoarthritis (OA), relative to healthy controls. We find that different chronic pain types exhibit unique anatomical ‘brain signatures’. Only the CBP group showed altered whole-brain gray matter volume, while regional gray matter density was distinct for each group. Voxel-wise comparison of gray matter density showed that the impact on the extent of chronicity of pain was localized to a common set of regions across all conditions. When gray matter density was examined for large regions approximating Brodmann areas, it exhibited unique large-scale distributed networks for each group. We derived a barcode, summarized by a single index of within-subject co-variation of gray matter density, which enabled classification of individual brains to their conditions with high accuracy. This index also enabled calculating time constants and asymptotic amplitudes for an exponential increase in brain re-organization with pain chronicity, and showed that brain reorganization with pain chronicity was 6 times slower and twice as large in CBP in comparison to CRPS. The results show an exuberance of brain anatomical reorganization peculiar to each condition and as such reflecting the unique maladaptive physiology of different types of chronic pain.

The red, cationic complex 2-hydroxyethanethiolato(2,2',2"-terpyridine)platinum(II), [(terpy)-Pt(SCH2CH20H)J+, binds strongly to DNA by a mechanism involving intercalation. By means of fluorescence spectroscopy, the platinum complex was shown to inhibit competitively the binding of the intercalating dye ethidium bromide to calf thymus DNA. This platinum complex increases the viscosity of calf thymus DNA, raises the melting temperature by up to 5°, and exhibits induced circular dichroism when bound to the DNA. The closed circular viral DNA from bacteriophage PM2 is unwound by the complex in a manner that is similar to that of ethidium bromide and with an unwinding angle that appears to be slightly less than that of ethidium. Studies of the related complex [(terpy)PtCll+, which has a substitutionally more labile chloride ligand, suggest that it also intercalates, especially at [DNA-PJ: [PtI ratios greater than 2. The potential utility of these new metallointercalation reagents as heavy atom probes in fiber diffraction or electron microscopic studies of the interaction process is discussed.

The antitumor drug cis-dichlorodiammineplatinum(II) (cis-DDP) and the inactive trans isomer bind and produce cooperative changes in closed and nicked circular duplex DNA's. Covalent binding of both platinum complexes to the closed circular DNA alters the degree of supercoiling, presumably by disrupting and unwinding the double helix. Electron micrographs show the platinated DNA's to be shortened by up to 50 percent of their original length. At similar ratios of bound platinum per nucleotide, the electrophoretic mobilities of the DNA's in gels containing the dye ethidium bromide are the same for both isomers. The only detectable difference in the binding of the two platinum isomers is an increase in the electrophoretic mobility in nondye gels of closed circular DNA having small amounts of bound cis-DDP that is not apparent for the trans complex.

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