Binding mode of conformations and structure-based pharmacophore development for farnesyltransferase inhibitors

Farnesyltransferase (FTase) is one of the prenyltransferase family enzymes that catalyse the transfer of 15-membered isoprenoid (farnesyl) moiety to the cysteine of CAAX motif-containing proteins including Rho and Ras family of G proteins. Inhibitors of FTase act as drugs for cancer, malaria, progeria and other diseases. In the present investigation, we have developed two structure-based pharmacophore models from protein–ligand complex (3E33 and 3E37) obtained from the protein data bank. Molecular dynamics (MD) simulations were performed on the complexes, and different conformers of the same complex were generated. These conformers were undergone protein–ligand interaction fingerprint (PLIF) analysis, and the fingerprint bits have been used for structure-based pharmacophore model development. The PLIF results showed that Lys164, Tyr166, TrpB106 and TyrB361 are the major interacting residues in both the complexes. The RMSD and RMSF analyses on the MD-simulated systems showed that the absence of FPP in the complex 3E37 has significant effect in the conformational changes of the ligands. During this conformational change, some interactions between the protein and the ligands are lost, but regained after some simulations (after 2 ns). The structure-based pharmacophore models showed that the hydrophobic and acceptor contours are predominantly present in the models. The pharmacophore models were validated using reference compounds, which significantly identified as HITs with smaller RMSD values. The developed structure-based pharmacophore models are significant, and the methodology used in this study is novel from the existing methods (the original X-ray crystallographic coordination of the ligands is used for the model building). In our study, along with the original coordination of the ligand, different conformers of the same complex (protein–ligand) are used. It concluded that the developed methodology is significant for the virtual screening of novel molecules on different targets.     

Exophytic gliomas of the spinal cord

Intradural extramedullary glial tumours of the spinal cord are rare. We report for such tumours arising from the dorsal cord. Myelography and operative findings were almost similar to that of an intradural neurofibroma. Surgical removal had resulted in rewarding neurological recovery. One of them had a recurrence after six years and was re-explored. Anterolateral attachment near the root entry zone suggests its origin probably from the spinal cord with an exophytic growth.     

Extended trans-septal approach for mitral valve surgery: Our early experience

Background Extended trans septal (ETS) approach for mitral valve surgery often divides the artery to the Sino-Atrial node. The clinical implication of this is contentious. We analyzed our early results with ETS approach. Methods Between June 1998 and September 2003 eleven patients underwent mitral valve surgery by ETS approach. Six were females. Age ranged from 19 years to 67 years (median 40 years). Six underwent mitral valve replacement (MVR). Four underwent aortic and mitral (double) valve replacement (DVR). One had mitral valve repair. Three had additional procedures (tricuspid valve repair=1, Coronary artery bypass=1, Aorto bifemoral graft=1). Cardiopulmonary bypass ranged from 64 minutes to 77 minutes (median 72 minutes) for MVR and 112 minutes to 178 minutes (median 140 minutes) for DVR. Aortic cross clamp times ranged from 39 minutes to 52 minutes (median 47 minutes) for MVR and 74 minutes to 120 minutes (median 95 minutes) for DVR. Results There was no mortality or morbidity attributed to the ETS approach. One early death in emergency DVR was due to heart failure. Three patients needed seqeuntial pacing in the immediate post-operative period. Nine out of ten survivors were back to their preoperative rhythms on hospital discharge (6 sinus rhythm; 3 atrial fibrillation). One patient with preoperative trifascicular block who underwent reoperation to fix a paravalvular mitral leak needed a permanent pacemaker (VVI). The follow-up ranged from 1 month to 64 months (median 6 months) and is 100% complete. There was no late death or new arrhythmia. Conclusions Extended trans septal approach is safe. It gives excellent exposure of the mitral valve. division of the sinus node artery is not deleterious in the short to intermediate term. Presented at the 50th Annual Meeting of IACTS. New Delhi, Feb. 2004.     

1.5 tesla magnetic resonance imaging of acute spinal trauma

Fifty patients with spinal injury above L2 were studied with MRI; forty-two had initial and followup studies permitting correlation of MRI abnormalities with neurologic improvement. Two discrete patterns of MRI abnormality were identified, presumably representing cord hemorrhage and edema respectively. A third pattern appeared to represent a mixed type of injury. The correlation between the MRI patterns of cord injury and neurologic recovery was excellent. The ability of MRI to demonstrate and characterize acute cord injury appears to exceed that of other diagnostic techniques.     

Aid for impacted foreign body ear

Foreign body ear is a common problem. When it is impacted it can tax the resorces of each of us. An attempt is made in this paper to make a customable foreign body removal hook using a lumbar puncture needle.     

Ante mortem diagnosis of human rabies using saliva samples: comparison of real time and conventional RT-PCR techniques.

BACKGROUND: Rabies is an enzootic and fatal disease and is still a major problem in developing countries. Ante mortem diagnosis in human cases is necessary for medical management of the patient and to ensure appropriate post-exposure treatment of contacts. Both conventional RT-PCR and Real time PCR (TaqMan) have been described for the detection of rabies virus RNA from saliva and tissue respectively, however to date, there have been no studies comparing conventional and real time PCR assays for detection of rabies virus nucleic acid using saliva samples for ante mortem diagnosis. OBJECTIVES: In this study, we evaluated the utility of conventional RT-PCR and SYBR Green I Real time PCR in the ante mortem diagnosis of rabies using saliva samples. STUDY DESIGN: Saliva samples collected from twenty-four patients presenting with typical clinical manifestations of rabies were tested in the two assays. RESULTS: Amongst the 24 samples tested, 21 samples (87.5%) were positive by either of the two molecular methods. Of these 21, rabies virus RNA was detected in 6/21 in the conventional RT-PCR assay while SYBR Green I Real time PCR could detect RNA in 18/21 samples. CONCLUSION: Real time PCR assay was more sensitive than conventional RT-PCR assay (sensitivity 75% versus 37%, p=0.0189). This study highlights the utility of molecular diagnostic tests in establishing ante mortem diagnosis of rabies using saliva samples within a few hours.