Barraquer-Simons Syndrome.

BACKGROUND: Barraquer-Simons syndrome (BSS) is a rare acquired lipodystrophy characterized by gradually symmetric subcutaneous fat loss in a craniocaudal distribution, associated with hypocomplementemia, diabetes and hypertriglyceridemia. Few investigators have studied body fat distribution with cross-sectional imaging techniques. METHODS: We present 2 cases of BSS with emphasis on phenotypic analysis through cross-sectional imaging. RESULTS: For the first time, we demonstrate bone marrow involvement and deep cervical and axillary fat sparing of Barraquer-Simons using magnetic resonance imaging. CONCLUSION: Phenotypic analysis in lipodystrophies such as Barraquer-Simons is an essential guide for future experiments. Therefore, careful analysis of cross-sectional imaging should be conducted in future studies as areas of involvement or fat sparing may be overlooked. The major contributions of our work are that this is the first time that deep cervical or nuchal and axillary fat sparing and bone marrow involvement has been documented in BSS.

Image quality in real-time teleultrasound of infant hip exam over low-bandwidth internet links: a transatlantic feasibility study.

Evolution of communication systems, especially internet-based technologies, has probably affected Radiology more than any other medical specialty. Tremendous increase in internet bandwidth has enabled a true revolution in image transmission and easy remote viewing of the static images and real-time video stream. Previous reports of real-time telesonography, such as the ones developed for emergency situations and humanitarian work, rely on high compressions of images utilized by remote sonologist to guide and supervise the unexperienced examiner. We believe that remote sonology could be also utilized in teleultrasound exam of infant hip. We tested feasibility of a low-cost teleultrasound system for infant hip and performed data analysis on the transmitted and original images. Transmission of data was accomplished with Remote Ultrasound (RU), a software package specifically designed for teleultrasound transmission through limited internet bandwidth. While image analysis of image pairs revealed statistically significant loss of information, panel evaluation failed to recognize any clinical difference between the original saved and transmitted still images.

A tele-ultrasound system for real-time medical imaging in resource-limited settings.

Ultrasound has great potential as an imaging technology in resource-limited environments. We present a novel tele-ultrasound approach designed to realize that potential by connecting a remote technician to a radiologist. Our preliminary system, based on open-source software and commercial off-the-shelf hardware, uses custom software and a satellite Internet connection to create this link. We also present the results of testing this system in both laboratory and real-world environments.

The feasibility of real-time transmission of sonographic images from a remote location over low-bandwidth Internet links: a pilot study.

OBJECTIVE: We sought to show that sonography can be performed in teleconference settings, "telesonography," in which a remotely located sonography interpreter can monitor the examination in real-time and guide the examiner with voice commands while the patient simultaneously undergoes imaging, albeit at low resolution, thus helping to overcome the lack of trained operators in certain areas. CONCLUSION: This system of image transfer offers the potential for sonography to be performed at a remote underdeveloped region and interpreted in real-time at a distant site by trained radiologists, thereby extending the presence of physicians in virtual space.

Highly efficient ligands for dihydrofolate reductase from Cryptosporidium hominis and Toxoplasma gondii inspired by structural analysis.

The search for effective therapeutics for cryptosporidiosis and toxoplasmosis has led to the discovery of novel inhibitors of dihydrofolate reductase (DHFR) that possess high ligand efficiency: compounds with high potency and low molecular weight. Detailed analysis of the crystal structure of dihydrofolate reductase-thymidylate synthase from Cryptosporidium hominis and a homology model of DHFR from Toxoplasma gondii inspired the synthesis of a new series of compounds with a propargyl-based linker between a substituted 2,4-diaminopyrimidine and a trimethoxyphenyl ring. An enantiomerically pure compound in this series exhibits IC50 values of 38 and 1 nM against C. hominis and T. gondii DHFR, respectively. Improvements of 368-fold or 5714-fold (C. hominis and T. gondii) relative to trimethoprim were generated by synthesizing just 14 new analogues and by adding only a total of 52 Da to the mass of the parent compound, creating an efficient ligand as an excellent candidate for further study.

Towards in silico lead optimization: scores from ensembles of protein/ligand conformations reliably correlate with biological activity.

Accurately ranking protein/ligand interactions and distinguishing subtle differences between homologous compounds in a virtual focused library in silico is essential in a structure-based drug discovery program. In order to establish a predictive model to design novel inhibitors of dihydrofolate reductase (DHFR) from the parasitic protozoa, Cryptosporidium hominis, we docked a series of 30 DHFR inhibitors with measured inhibition constants against the crystal structure of the protein. By including protein flexibility and averaging the energies of the 25 lowest protein/ligand conformers we obtained more accurate total nonbonded energies from which we calculated a predicted biological activity. The calculated and measured biological activities showed reliable correlations of 72.9%. Additionally, visual analysis of the ensemble of protein/ligand conformations revealed alternative ligand binding pockets in the active site. Using the same principles we then created a homology model of DHFR from Toxoplasma gondii and docked 11 inhibitors. A correlation of 50.2% between docking score and activity validates both the method and the model. The correlations presented here are particularly compelling considering the high structural similarity of the ligands and the fact that we have used structures derived from crystallographic data and homology modeling. These docking principles may be useful in any lead optimization study where accurate ranking of similar compounds is desired.

Discovery of (1R,5S)-N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]- 3-[2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide (SCH 503034), a selective, potent, orally bioavailable hepatitis C virus NS3 protease inhibitor: a potential therapeutic agent for the treatment of hepatitis C infection.

Hepatitis C virus (HCV) infection is the major cause of chronic liver disease, leading to cirrhosis and hepatocellular carcinoma, which affects more than 170 million people worldwide. Currently the only therapeutic regimens are subcutaneous interferon-alpha or polyethylene glycol (PEG)-interferon-alpha alone or in combination with oral ribavirin. Although combination therapy is reasonably successful with the majority of genotypes, its efficacy against the predominant genotype (genotype 1) is moderate at best, with only about 40% of the patients showing sustained virological response. Herein, the SAR leading to the discovery of 70 (SCH 503034), a novel, potent, selective, orally bioavailable NS3 protease inhibitor that has been advanced to clinical trials in human beings for the treatment of hepatitis C viral infections is described. X-ray structure of inhibitor 70 complexed with the NS3 protease and biological data are also discussed.

Analysis of complexes of inhibitors with Cryptosporidium hominis DHFR leads to a new trimethoprim derivative.

Cryptosporidiosis, an opportunistic infection affecting immunocompromised patients, the elderly, and children, is still an untreatable disease since the causative agent, Cryptosporidium hominis, is essentially resistant to all clinically used antimicrobial agents. In order to accelerate the design of new potent and selective inhibitors targeting dihydrofolate reductase of C. hominis (ChDHFR), we determined the structural basis for the potency of existing DHFR inhibitors using superpositions of the structure of ChDHFR with other species and analysis of active site complexes of ChDHFR bound to ligands exhibiting a wide range of IC(50) values. This information was used to develop an accurate docking model capable of identifying potent inhibitors in silico. A series of C7-trimethoprim derivatives, designed to exploit a unique pocket in ChDHFR, was synthesized and evaluated; 7-ethyl TMP has four times higher activity than TMP against ChDHFR.

2-cyano-3,12-dioxooleana-1,9(11)-diene-28-oic acid disrupts microtubule polymerization: a possible mechanism contributing to apoptosis.

The semisynthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) has several biological activities, including the induction of apoptosis in many cancer cell lines. To identify potential protein targets, immobilized biotinylated CDDO was used to screen the proteome of a human lymphoma cell line (U937) sensitive to CDDO-induced apoptosis. Tubulin was identified as one of several putative targets of CDDO. CDDO was shown to selectively bind to tubulin, with a dissociation constant of approximately 7 microM, and to disrupt microtubules both in vivo and in vitro. CDDO inhibits tubulin polymerization in vitro, possibly through interactions with a hydrophobic site on beta-tubulin. The CDDO-tubulin interaction may also involve a reversible 1,4-addition with a protein sulfhydryl group. Unlike other known spindle poisons, CDDO does not result in a temporal increase in the mitotic index. Rather, CDDO seems to initiate apoptosis early in M phase.