Clinicopathological Factors of Cervical Nodal Metastasis and the Concept of Selective Lateral Neck Dissection in the Surgical Management of Carcinoma Larynx and Hypopharynx and Its Outcome.

To study the clinicopathological and molecular factors which correlate with nodal metastasis in laryngeal and hypopharyngeal carcinoma, a retrospective analysis of 170 patients who underwent surgery for laryngeal and hypopharyngeal carcinoma at RCC, Trivandrum from 2006 to 2010 was done. The pathological nodal stage and levels of involvement were correlated with the clinicopathologic features of the primary disease. Neck node positivity was significantly more for lesions of pyriform sinus lesion (61%), with thyroid cartilage erosion (56%) and with base tongue involvement (88%). Other clinicopathological factors have no impact on the disease-free survival and overall survival for patients with pathologically N0 status. Elective lateral neck dissection is advisable in cases with laryngeal cartilage erosion, pyriform sinus, supraglottis and base tongue involvement.

Conformational features of the Aß42 peptide monomer and its interaction with the surrounding solvent.

Accumulation of the amyloid beta (Aß) peptide in the brain is responsible for debilitating neurodegenerative diseases, such as Alzheimer's disease (AD). We have carried out atomistic molecular dynamics simulations of the full-length Aß42 peptide monomer with a wide range of conformations at room temperature. Efforts have been made to probe the conformational features of different segments of the peptide, namely the two terminal segments (N-term and C-term), the central hydrophobic regions (hp1 and hp2) and the central turn region joining hp1 and hp2, and their nonuniform influence on the spatial arrangements and binding energies of the surrounding water molecules. Our calculations reveal fluctuating conformations of the monomers with the formation and breaking of different secondary structural elements. In particular, it is noticed that the Aß monomers exhibit a propensity to either retain or transform into a helical form toward the N-term region and a ß-strand-like form near the C-term segment. Besides, heterogeneous conformational flexibility of the Aß monomers has been found to be correlated with the corresponding nonuniform entropy gains. Additionally, our calculation further reveals a heterogeneous hydration environment around the peptide. It is found that irrespective of the Aß peptide conformations and their nonuniform fluctuations, water molecules around the hydrophobic hp1 and hp2 segments are relatively weakly bound. This is an important observation, as in the presence of other monomers such weakly bound water molecules around hp1 and hp2 are expected to be easily displaced during the hydrophobic collapse that leads to Aß aggregation.

Cross dimerization of amyloid-ß and αsynuclein proteins in aqueous environment: a molecular dynamics simulations study.

Self-assembly of the intrinsically unstructured proteins, amyloid beta (Aß) and alpha synclein (αSyn), are associated with Alzheimer's Disease, and Parkinson's and Lewy Body Diseases, respectively. Importantly, pathological overlaps between these neurodegenerative diseases, and the possibilities of interactions between Aß and αSyn in biological milieu emerge from several recent clinical reports and in vitro studies. Nevertheless, there are very few molecular level studies that have probed the nature of spontaneous interactions between these two sequentially dissimilar proteins and key characteristics of the resulting cross complexes. In this study, we have used atomistic molecular dynamics simulations to probe the possibility of cross dimerization between αSyn1-95 and Aß1-42, and thereby gain insights into their plausible early assembly pathways in aqueous environment. Our analyses indicate a strong probability of association between the two sequences, with inter-protein attractive electrostatic interactions playing dominant roles. Principal component analysis revealed significant heterogeneity in the strength and nature of the associations in the key interaction modes. In most, the interactions of repeating Lys residues, mainly in the imperfect repeats 'KTKEGV' present in αSyn1-95 were found to be essential for cross interactions and formation of inter-protein salt bridges. Additionally, a hydrophobicity driven interaction mode devoid of salt bridges, where the non-amyloid component (NAC) region of αSyn1-95 came in contact with the hydrophobic core of Aß1-42 was observed. The existence of such hetero complexes, and therefore hetero assembly pathways may lead to polymorphic aggregates with variations in pathological attributes. Our results provide a perspective on development of therapeutic strategies for preventing pathogenic interactions between these proteins.

Microscopic hydration properties of the aß1-42 Peptide monomer and the globular protein ubiquitin: a comparative molecular dynamics study.

Atomistic molecular dynamics simulations of eight selected conformations of a disordered protein, amyloid beta (1-42) (Aß), and a globular protein, ubiquitin (UBQ), have been carried out in aqueous media at 310 K. Detailed analyses were carried out to compare the microscopic properties of water molecules present in the hydration layers of these systems. It is noticed that irrespective of the conformational heterogeneity among the Aß monomers, water molecules hydrating their surfaces exhibit relatively faster dynamics as compared to water molecules hydrating UBQ. Importantly, the conformational heterogeneity of the Aß monomers has been found to affect the translational and rotational motions of hydration water molecules in a nonuniform manner. Detailed investigation of the timescale of hydrogen bond relaxations at the surface and their energetics revealed the possibility of heterogeneous confinement around different Aß conformations. The distribution of water density fluctuation around Aß conformations are broader compared to UBQ because of its predominant hydrophobic nature. Significant heterogeneity in the density fluctuation among the Aß monomers suggests that the structural propensities could affect the peptide's effective surface hydrophobicity.

Molecular dynamics simulation studies of the structural response of an isolated Aß1-42 monomer localized in the vicinity of the hydrophilic TiO 2 surface.

We have probed the effect of a model hydrophilic surface, rutile TiO(2), on the full-length amyloid beta (Aß(1-42)) monomer using molecular dynamics simulations. The rutile surface brings about sharp changes in the peptide's intrinsic behavior in a distance-dependent manner. The intrinsic collapse of the peptide is disrupted, while the ß-sheet propensity is sharply enhanced with increased proximity to the surface. The results may have implications for Aß self-assembly and fibrillogenesis on hydrophilic surfaces and should be taken into consideration in the design of novel nanomaterials for perturbing amyloidogenic behavior.

Critical roles of key domains in complete adsorption of Aß peptide on single-walled carbon nanotubes: insights with point mutations and MD simulations.

Owing to the influence of nanomaterials on biomacromolecular behavior, their potential applications are rapidly gaining attention. Based on atomistic molecular dynamics simulation studies we have recently reported that the full-length Aß peptide, whose self-assembly is associated with Alzheimer's disease, adsorbs rapidly on single-walled carbon nanotubes, thereby losing its natural propensity to collapse. Here, we investigate the mechanistic overlap between the peptide's compactification and its adsorption, while decoupling the roles of hydrophobicity and aromaticity via point mutations. The collapse mechanism is correlated with interactions between the central hydrophobic core (HP1) and the peptide's C-terminal domain, which are almost exactly compensated by interactions arising from the nanotube after complete adsorption. Adsorption is initiated by HP1 and consolidated by strong interactions arising from the N-terminal domain. Altering the hydrophobicity, but not the aromatic character, of the central residue in HP1 decreases the collapse probability. On the other hand, the adsorption propensity is dramatically reduced when either the hydrophobicity or the aromatic character in HP1 is compromised. The hydrophobicity of HP1 is responsible for dewetting transitions that facilitate its initial interactions with the nanotube, which then lead to very favorable interactions with the nanotube.

Potential cell sources for tissue engineering of heart valves in comparison with human pulmonary valve cells.

Current techniques to resolve heart valve defects involve the use of prosthetic and bioprosthetic materials. These materials lack the potential to grow and are not ideal, especially not for pediatric patients. Novel techniques like tissue engineering involve the use of biodegradable polymers coated with autologous myofibroblast and endothelial cells. We inspected morphological and marker gene expression differences between cells harvested from the saphenous vein, or from veins and arteries of the umbilical cord, and the cells they are designed to replace: the interstitial and endothelial cells of the pulmonary heart valve. We assessed the extent to which the endothelial cells from the inspected sources in vitro resemble endothelial cells of human pulmonary heart valves, and we found that myofibroblast cells, respective of their source, in vitro differ from the interstitial cells from human pulmonary heart valves regarding collagen and smooth muscle alpha-actin. Therefore we conclude that the cells isolated from the saphenous veins, or from veins and arteries of the umbilical cord might be feasible cell sources for tissue engineering of heart valve for the pulmonary position.

Evaluation of topical povidone-iodine in chronic suppurative otitis media.

OBJECTIVES: To evaluate if povidone-iodine (PVP-I) can be used topically in the treatment of chronic suppurative otitis media-tubotympanic disease and to compare it with ciprofloxacin hydrochloride ear drops. DESIGN: Prospective double-blind randomized study. SETTING: Academic tertiary medical center. PATIENTS: Forty patients with chronic suppurative otitis media were randomized into 2 groups. INTERVENTION: One group (19 patients) received 5% PVP-I ear drops, while the other group (21 patients) received 0.3% ciprofloxacin ear drops. Both were administered topically, 3 drops 3 times daily for 10 days. These patients were followed up at weekly intervals for up to 4 weeks after commencing therapy. RESULTS: Clinical improvement at the end of study was 88% in the PVP-I group and 90% in the ciprofloxacin group. The most commonly isolated organism was Pseudomonas aeruginosa. In vitro resistance to ciprofloxacin was seen in 17% of organisms, while no resistance was seen for PVP-I. CONCLUSIONS: To our knowledge, this is the first study to evaluate the efficacy of PVP-I as a topical agent in the treatment of chronic suppurative otitis media. The results show that clinically, topical PVP-I is as effective as topical ciprofloxacin, with a superior advantage of having no in vitro drug resistance. Also, there is an added benefit of reduced cost of therapy.