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Recent and historical evidence is consistent with the view that atherosclerosis is an infectious disease or microbial toxicosis impacted by genetics and behavior. Because small bacterial-like particles, also known as nanobacteria have been detected in kidney stones, kidney and liver cyst fluids, and can form a calcium apatite coat we posited that this agent is present in calcified human atherosclerotic plaques. Carotid and aortic atherosclerotic plaques and blood samples collected at autopsy were examined for nanobacteria-like structures by light microscopy (hematoxylin-eosin and a calcium-specific von Kossa staining), immuno-gold labeling for transmission electron microscopy (TEM) for specific nanobacterial antigens, and propagation from homogenized, filtered specimens in culture medium. Nanobacterial antigens were identified in situ by immuno-TEM in 9 of 14 plaque specimens, but none of the normal carotid or aortic tissue (5 specimens). Nanobacteria-like particles were propagated from 26 of 42 sclerotic aorta and carotid samples and were confirmed by dot immunoblot, light microscopy and TEM. [3H]L-aspartic acid was incorporated into high molecular weight compounds of demineralized particles. PCR amplification of 16S rDNA sequences from the particles was unsuccessful by traditional protocols. Identification of nanobacteria-like particles at the lesion supports, but does not by itself prove the hypothesis that these agents contribute to the pathogenesis of atherosclerosis, especially vascular calcifications.

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Chirality and activity relationships are paramount to pharmaceutical design and synthesis. Generally, point chirality (enantiomeric R and S configurations) is emphasized most in molecules and drugs; however, axis chirality (present when structures adopt conformations with asymmetrical distributions of electron density) must also be considered as a stereogenic unit of interest. Together, stereogenic units and optical isomerism describe the chiral disposition of electron density about nuclei. In this essence, different components of chirality are always present in molecular systems. In assessing the different chiral parameters of pharmaceuticals, the cardiovascular drug carvedilol serves as an ideal example because both enantiomers produce different physiological effects. In the current study, R-and S-4-(2-hydroxypropoxy)carbazol (carvedilol fragment A), along with prochiral and chiral analogues, are studied to investigate the chiral components of carvedilol. Further, the effects of substituent variation about a stereocenter are investigated and discussed using conformational energy as a surrogate of structure (based on the fact that energy is a function of molecular spatial orientation) to determine the energetic equivalency of prochiral and chiral structures. Multidimensional conformational analysis (MDCA) was performed on selected structures using restricted Hartree-Fock (RHF) and density functional theory (DFT with the Becke 3LYP hybrid exchange-correlation functional) molecular orbital computations to elucidate the structural and energetic basis of chirality. The analogues had the following prochiral and chiral structures: R-CH 2 -OH, [R] and [S] R-CHMe-OH, and R-CMe 2 -OH, with substituent R being either MeCH 2 -or ArCH 2 -, where Ar is the carbazole moiety. Potential energy curves (PECs) of torsional angles χ 1 , χ 2 , χ 3 , and χ 10 for R-and S-4-(2-hydroxypropoxy)carbazol verified that all torsional angles are indeed enantiomeric. Correspondingly, the potential energy hypersurfaces (PEHSs) of R-and S-4-(2hydroxypropoxy)carbazol were also enantiomeric, as illustrated with optimizations of conformational minima; converged minima occurred in equivalent point chiral and axis chiral pairs. Similarly to R-and S-4-(2hydroxypropoxy)carbazol, achiral and chiral analogues analyzed by MDCA displayed axis chirality while chiral structures displayed both axis and point chirality. As such, the presence of point and axis chirality in molecular systems allows predictions to be made concerning the orientations of viable conformations of a respective PEHS. Further, the data indicate that chirality induced by an asymmetric distribution of electron density (axis chirality) is always present whenever a structure adopts asymmetric conformations. Like enantiomers of point chirality, axis chiral conformers also occur in pairs. Potential energy surfaces (PESs) were generated about the prochiral and chiral centers for all structures at the RHF/3-21G level of theory and used to test the equivalency of conformational energy between s...