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Biomedical subjects

J Srinivasan

Publications and source records attributed to J Srinivasan.

At least 37 records · Page 2Linked to original sources
PubMed2001

Finger sucking digital deformities.

We report our experience with severe digital deformities caused by prolonged finger sucking. Our analysis of nine patients demonstrated that the deformity was mainly located in the proximal and middle phalanges of the affected digit(s). We have reviewed the literature, enumerated the common patterns of "finger sucking" and explained the resulting deformities. Corrective osteotomy, preferably at the metacarpal base level, is required in severe deformities.

Adolescent↗
PubMed2001

Techniques for cerebral bypass: practical laboratory for microvascular anastomosis.

The techniques used for microvascular anastomosis are best mastered in the laboratory setting. A variety of techniques for end-to-end and end-to-side anastomoses are described and illustrated. An understanding of these different modalities allows the surgeon to choose the appropriate technique for each clinical setting.

Anastomosis, Surgical↗
PubMed2001

Cerebral revascularization for moyamoya disease in adults.

Moyamoya disease is a rare entity that results in progressive occlusion of the arteries of the circle of Willis. In adults, this most commonly leads to intraventricular hemorrhage and less frequently to symptoms of ischemia. Without treatment, there is progressive deterioration of neurologic function and re-hemorrhage. Direct superficial temporal artery to middle cerebral artery bypass is considered the treatment of choice, although it's efficacy, particularly for hemorrhagic disease, remains uncertain.

Adult↗
PubMed2000

Calculating structures and free energies of complex molecules: combining molecular mechanics and continuum models.

A historical perspective on the application of molecular dynamics (MD) to biological macromolecules is presented. Recent developments combining state-of-the-art force fields with continuum solvation calculations have allowed us to reach the fourth era of MD applications in which one can often derive both accurate structure and accurate relative free energies from molecular dynamics trajectories. We illustrate such applications on nucleic acid duplexes, RNA hairpins, protein folding trajectories, and protein-ligand, protein-protein, and protein-nucleic acid interactions.

Base Sequence↗
PubMed1999

Activated Galpha subunits can inhibit multiple signal transduction pathways during Dictyostelium development.

Mutations impairing the GTPase activity of G protein Galpha subunits can result in activated Galpha subunits that affect signal transduction and cellular responses and, in some cases, promote tumor formation. An analogous mutation in the Dictyostelium Galpha4 subunit gene (Q200L substitution) was constructed and found to inhibit Galpha4-mediated responses to folic acid, including the accumulation of cyclic nucleotides and chemotactic cell movement. The Galpha4-Q200L subunit also severely inhibited responses to cAMP, including cyclic nucleotide accumulation, cAMP chemotaxis, and cellular aggregation. An analogous mutation in the Galpha2 subunit (Q208L substitution), previously reported to inhibit cAMP responses (K. Okaichi et al., 1992, Mol. Biol. Cell 3, 735-747), was also found to partially inhibit folic acid chemotaxis. Chemotactic responses to folic acid and cAMP and developmental aggregation were also inhibited by a mutant Galpha5 subunit with the analogous alteration (Q199L substitution). All aggregation-defective Galpha mutants were capable of multicellular development after a temporary incubation at 4 degrees C and this development was found to be dependent on wild-type Galpha4 function. This study indicates that mutant Galpha subunits can inhibit signal transduction pathways mediated by other Galpha subunits.

Animals↗
PubMed1999

The extracellular domain of the beta1 subunit is both necessary and sufficient for beta1-like modulation of sodium channel gating.

The type IIA voltage-gated sodium Na(+) channel from rat brain is composed of a large, pore-forming alpha subunit and the auxiliary subunits beta1 and beta2. When expressed in Xenopus oocytes, the beta1 subunit modulates the gating properties of the type IIA alpha subunit, resulting in acceleration of both inactivation and recovery from inactivation and in a negative shift in the voltage dependence of fast inactivation. The beta1 subunit is composed of an extracellular domain with a single immunoglobulin-like fold, a single transmembrane segment, and a small intracellular domain. A series of chimeras with exchanges of domains between the Na(+) channel beta1 and beta2 subunits and between beta1 and the structurally related protein myelin P0 were constructed and analyzed by two-microelectrode voltage clamp in Xenopus oocytes. Only chimeras containing the beta1 extracellular domain were capable of beta1-like modulation of Na(+) channel gating. Neither the transmembrane segment nor the intracellular domain was required for modulation, although mutation of Glu(158) within the transmembrane domain altered the voltage dependence of steady-state inactivation. A truncated beta1 subunit was engineered in which the beta1 extracellular domain was fused to a recognition sequence for attachment of a glycosylphosphatidylinositol membrane anchor. The beta1(ec)-glycosylphosphatidylinositol protein fully reproduced modulation of Na(+) channel inactivation and recovery from inactivation by wild-type beta1. Our findings demonstrate that extracellular domain of the beta1 subunit is both necessary and sufficient for the modulation of Na(+) channel gating.

Amino Acid Sequence↗
PubMed1999

Folic acid stimulation of the Galpha4 G protein-mediated signal transduction pathway inhibits anterior prestalk cell development in Dictyostelium.

In Dictyostelium discoideum, several G proteins are known to mediate the transduction of signals that direct chemotactic movement and regulate developmental morphogenesis. The G protein alpha subunit encoded by the Galpha4 gene has been previously shown to be required for chemotactic responses to folic acid, proper developmental morphogenesis, and spore production. In this study, cells overexpressing the wild type Galpha4 gene, due to high copy gene dosage (Galpha4HC), were found to be defective in the ability to form the anterior prestalk cell region, express prespore- and prestalk-cell specific genes, and undergo spore formation. In chimeric organisms, Galpha4HC prespore cell-specific gene expression and spore production were rescued by the presence of wild-type cells, indicating that prespore cell development in Galpha4HC cells is limited by the absence of an intercellular signal. Transplanted wild-type tips were sufficient to rescue Galpha4HC prespore cell development, suggesting that the rescuing signal originates from the anterior prestalk cells. However, the deficiencies in prestalk-specific gene expression were not rescued in the chimeric organisms. Furthermore, Galpha4HC cells were localized to the prespore region of these chimeric organisms and completely excluded from the anterior prestalk region, suggesting that the Galpha4 subunit functions cell-autonomously to prevent anterior prestalk cell development. The presence of exogenous folic acid during vegetative growth and development delayed anterior prestalk cell development in wild-type but not galpha4 null mutant aggregates, indicating that folic acid can inhibit cell-type-specific differentiation by stimulation of the Galpha4-mediated signal transduction pathway. The results of this study suggest that Galpha4-mediated signals can regulate cell-type-specific differentiation by promoting prespore cell development and inhibiting anterior prestalk-cell development.

Animals↗
PubMed1999

The bifrontal olfactory nerve-sparing approach to lesions of the suprasellar region in children.

Suprasellar masses in children include lesions such as craniopharyngiomas and germ cell neoplasms. The difficult location of these lesions and their proximity to important neural and vascular structures pose challenges to resection. We operated on 14 patients using a bifrontal craniotomy with removal of both orbital rims to provide access to suprasellar masses, even those with significant extension into the third ventricle. A complete resection was possible in 8/14 patients and 8/10 craniopharyngiomas. In 13 patients, the optic nerves were identified and preserved, and vision was stable or improved postoperatively. Postoperatively, 1 patient with hydrocephalus developed a CSF leak which was successfully treated with a ventriculoperitoneal shunt. No patient had a cosmetic defect related to orbital rim removal. The bifrontal approach used here enhanced the exposure of the suprasellar region and minimized manipulation of the optic apparatus and the carotid arteries. It may be used alone, or in conjunction with other approaches, to resect lesions in the suprasellar region.

Adolescent↗
PubMed1999

Observing communication skills for informed consent: an examiner's experience.

OBJECTIVE: To examine medical students' communication skills and competence regarding informed consent during an objective structured clinical examination (OSCE). METHOD: At the University of Toronto, 22 candidates wrote MCCQE part II as a prerequisite for medical licensure. The candidates' performance at one station involving informed consent was assessed using binary checklists and global ratings. Candidates were assessed for their clinical skills in approaching the problem, knowledge of subject matter, attitude towards the situation, and communication ability with the patient. RESULTS: Of the candidates, 90 per cent performed well and demonstrated their ability to effectively deal with the patient's physical concerns. Only 50 per cent performed relevant mental-status examinations; and 50 per cent of the candidates seemed to be biased and physician-centered. They were unable to acknowledge the associated psychological issues that might influence the patient's decision in the process of informed consent. Only a few expressed their concern and empathy, and were able to guide the patient in making an autonomous decision about surgical procedures. CONCLUSION: The OSCE seems to be an appropriate and effective means to evaluate clinical competence in psychiatry. The variation in candidates' performance, however, suggests a greater need to improve clinical skills, particularly those that are relevant to psychological considerations in obtaining informed consent and providing required information to patients. Thus, emphasis should be given in undergraduate teaching programs to addressing effective means of assessing patients' competency and their ability to give informed consent.

Aged↗
PubMed1998

Interaction of voltage-gated sodium channels with the extracellular matrix molecules tenascin-C and tenascin-R.

The type IIA rat brain sodium channel is composed of three subunits: a large pore-forming alpha subunit and two smaller auxiliary subunits, beta1 and beta2. The beta subunits are single membrane-spanning glycoproteins with one Ig-like motif in their extracellular domains. The Ig motif of the beta2 subunit has close structural similarity to one of the six Ig motifs in the extracellular domain of the cell adhesion molecule contactin (also called F3 or F11), which binds to the extracellular matrix molecules tenascin-C and tenascin-R. We investigated the binding of the purified sodium channel and the extracellular domain of the beta2 subunit to tenascin-C and tenascin-R in vitro. Incubation of purified sodium channels on microtiter plates coated with tenascin-C revealed saturable and specific binding with an apparent Kd of approximately 15 nM. Glutathione S-transferase-tagged fusion proteins containing various segments of tenascin-C and tenascin-R were purified, digested with thrombin to remove the epitope tag, immobilized on microtiter dishes, and tested for their ability to bind purified sodium channel or the epitope-tagged extracellular domain of beta2 subunits. Both purified sodium channels and the extracellular domain of the beta2 subunit bound specifically to fibronectin type III repeats 1-2, A, B, and 6-8 of tenascin-C and fibronectin type III repeats 1-2 and 6-8 of tenascin-R but not to the epidermal growth factor-like domain or the fibrinogen-like domain of these molecules. The binding of neuronal sodium channels to extracellular matrix molecules such as tenascin-C and tenascin-R may play a crucial role in localizing sodium channels in high density at axon initial segments and nodes of Ranvier or in regulating the activity of immobilized sodium channels in these locations.

Animals↗
PubMed1998

Molecular dynamics and continuum solvent studies of the stability of polyG-polyC and polyA-polyT DNA duplexes in solution.

Molecular dynamics simulation in explicit solvent and continuum solvent models are applied to investigate the relative stability of A- and B-form helices for two DNA sequences, dA10-dT10 and dG10-dC10 in three structural forms. One structural form is based on an unrestrained molecular dynamics (MD) trajectory starting from a canonical B-DNA structure, the second is based on a MD trajectory starting in a canonical B-DNA structure with the sugars constrained to be C2'-endo and the third simulation started from a canonical A-DNA structure with the sugars constrained to C3'-endo puckers. For the energetic analysis, structures were taken as snapshots from nanosecond length molecular dynamics simulations computed in a consistent fashion in explicit solvent, applying the particle mesh Ewald method and the Cornell et al. force field. The electrostatic contributions to solvation free energies are computed using both a finite-difference Poisson-Boltzmann model and a pairwise Generalized Born model. The non-electrostatic contributions to the solvation free energies are estimated with a solvent accessible surface area dependent term. To estimate the gas phase component of the relative free energy between the various structures, the mean solute internal energies (determined with the Cornell et al. molecular mechanics potential including all pairwise interactions within the solute) and estimates of the solute entropy (using a harmonic approximation) were used. Consistent with experiment, the polyG-polyC (GC) structures are found to be much more A-phillic than the polyA-polyT (AT) structures, the latter being quite A-phobic. The dominant energy components responsible for this difference comes from the internal and van der Waal energies. A perhaps less appreciated difference between the GC and AT rich sequences is suggested by the calculated salt dependence which demonstrates a significantly enhanced ability to drive GC rich sequences towards an A-form structure compared to AT rich sequences. In addition to being A-phobic, the AT structure also has a noticably larger helical repeat than GC and other mixed sequence duplexes, consistent with experiment. Analysis of the average solvent density from the trajectories shows hydration patterns in qualitative agreement with experiment and previous theoretical treatments.

Computer Simulation↗
PubMed1998

Continuum solvent studies of the stability of RNA hairpin loops and helices.

We apply continuum solvent models to investigate the relative stability of various conformational forms for two RNA sequences, GGAC(UUCG)GUCC and GGUG(UGAA)CACC. In the first part, we compare alternate hairpin conformations to explore the reliability of these models to discriminate between different local conformations. A second part looks at the hairpin-duplex conversion for the UUCG sequence, identifying major contributors to the thermodynamics of a much large scale transition. Structures were taken as snapshots from multi-nanosecond molecular dynamics simulations computed in a consistent fashion using explicit solvent and with long-range electrostatics accounted for using the Particle-Mesh Ewald procedure. The electrostatic contribution to solvation energies were computed using both a finite-difference Poisson-Boltzmann (PB) model and a pairwise Generalized Born model; non-electrostatic contributions were estimated with a surface-area dependent term. To these solvation free energies were added the mean solute internal energies (determined from a molecular mechanics potential) and estimates of the solute entropy (from a harmonic analysis). Consistent with experiment and with earlier solvated molecular dynamics simulations, the UUCG hairpin was found to prefer conformers close to a recent NMR structure determination in preference to those from an earlier NMR study. Similarly, results for the UGAA hairpin favored an NMR-derived structure over that to be expected for a generic GNRA hairpin loop. Experimental free energies are not known for the hairpin/duplex conversion, but must be close to zero since hairpins are seen in solution and duplexes in crystals; out calculations find a value near zero and illustrate the expected interplay of solvation, salt effects and entropy in affecting this equilibrium.

Computer Simulation↗