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.     

Laparoscopic cholecystectomy for left-sided gallbladder (sinistroposition).

Transposition of the gallbladder to the left side without situs inversus viscerum is rare. These gallbladders are situated under the left lobe of the liver between Segment III and IV or on Segment III to the left of the falciform ligament. Because routine preoperative studies may not detect the anomaly, it may provide the surgeons with an unusual surprise during laparoscopy. Awareness of the unpredictable confluence of the cystic duct into the common bile duct and selective use of intraoperative cholangiography aid in the safe laparoscopic management of this unusual problem.     

Does multi-vessel off-pump coronary artery bypass grafting reduce post operative morbidity compared to on-pump CABG?

Background Cardiopulmonary bypass (CPB) may contribute to the complications and it is assumed that eliminating cardiopulmonary bypass has the potential of reducing post operative morbidity after coronary artery bypass grafting (CABG). The study was carried out to compare mortality and morbidity in the off-pump and on-pump CABG groups. Methods We prospectively analysed 200 patients undergoing CABG. Group A consists of 100 patients underwent multi-vessel off-pump CABG and group B consists of 100 patients underwent CABG with CPB. The incidence of complications (mortality, re-exploration for bleeding, myocardial infarction, atrial fibrillation, neurological events, new onset renal failure (s. creatinine>1.6 mg/dL) pulmonary complications, length of ICU stay and hospital stay were recorded, analysed and compared. Results OPCAB patients received 2.73±0.61 grafts/patient and on-pump CABG patients received 3.39±0.75 grafts/patient (p value<0.00001). There was no significant statistical difference in mortality, incidence of stroke between OPCAB and CABG with CPB patients. Length of ICU stay was 32.84±4.22 vs 44.85±7.18 hrs (p value<0.00001) and hospital stay was 6.52±0.69 vs 7.94±0.92 days (p value<0.00001) between group A and group B respectively. Incidence of atrial fibrillation was less in OPCAB group 7% vs 12% although it was statistically not significant (p value 0.33). It was observed in our study that there was no significant deference in worsening of existing renal failure between on-pump CABG and OPCAB 6% vs 2% (P value 0.28). Blood utilization was significantly less in OPCAB group (p value<0.001). Conclusion There was no statistically significant difference in terms of mortality, incidence of stroke and new onset renal failure in both groups. But there was lesser incidence of post operative atrial fibrillation, worsening of existing renal failure in off-pump group though statistically not significant. There was significant reduction in blood utilization, length of ICU and hospital stay in OPCAB group.     

Localized echo-volume imaging methods for functional MRI

To perform true three-dimensional activation experiments in the human brain, dedicated localized echo-volume imaging (L-EVI) methods were developed. Three-dimensional acquisition allows generation of activation maps with minimal vascular enhancement related to inflow effects. The rapid acquisition of the L-EVI (～100 msec) reduces signal instabilities caused by motion, facilitating the detection of the small intensity changes expected with brain activation. Single-shot L-EVI was performed on normal volunteers at 1.5 T, imaging a three-dimensional predefined volume (240 × 45 × 45 mm³) in the superior portion of the brain with a spatial resolution of 3.75 × 5 × 5 mm³. Increased brain coverage was achieved with a multi-volume imaging (three-shot) version, which simultaneously achieved effective suppression of signals from cerebrospinal fluid. In addition, both asymmetric spin-echo (ASE) and spin-echo (SE) versions of the technique were used to detect blood oxygenation level dependent (BOLD) signal changes in the motor cortex with a finger-tapping paradigm. Images obtained by the L-EVI sequence were qualitatively comparable to standard multislice two-dimensional echo-planar images. Both ASE and SE functional MRI (fMRI) experiments showed consistent activation in the contralateral primary sensorimotor cortex. Furthermore, significant differences in location and magnitude of activation was observed between the two methods, confirming theoretical predictions.     

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.     

Self-inflicted specific pattern burns in psychiatric patients

Self-inflicted burns represent a major social and medical problem for society. Differences have been demonstrated between patients who attempt suicide and those who deliberately harm themselves without any intention of killing themselves. These self-inflicted injuries may resemble injuries that are intentionally inflicted by others and may require investigation by protective services. Little is known about these specific pattern burn injuries in psychiatric patients.