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Biomedical subjects

S Suresh

Publications and source records attributed to S Suresh.

At least 37 records · Page 2Linked to original sources
PubMed2003

Role of Joshi's external stabilisation system fixator in the management of idiopathic clubfoot.

PURPOSE: To explore the role of Joshi's external stabilisation system fixator in correcting cases of clubfoot peculiar to India, we studied cases of neglected clubfoot, dropout cases of plaster-of-paris cast treatment, or failed surgical procedures that had been followed for a minimum period of 2 years. METHODS: 26 children underwent 44 Joshi's external stabilisation system procedures at the Central Institute of Orthopaedics at the Safdarjung Hospital, New Delhi, between January 1998 and December 1999 for the conditions of interest. Three-dimensional correction was achieved by use of the distractor device. RESULTS: Excellent results were obtained in 77% of the cases, good results in 13%, and poor results in 9% of the cases. Complications in half of the cases were pintract infections, which eventually healed on an outpatient basis without any residual sequelae. CONCLUSION: The Joshi's external stabilisation system frame is ideally suited for the child in whom clubfoot deformities remain uncorrected by plaster-of-paris casts and manipulation, as well as for recurrent clubfoot. Casting after complete correction not only protects the osteopenic bones while the pin-tracts heal, but also maintains correction and allows gradual weightbearing.

Child↗
PubMed2003

Atrioventricular septal defect--associated anomalies and aneuploidy in prenatal life.

The present study was conducted to estimate the frequency of other-cardiac, extracardiac and chromosomal anomalies in fetuses with A VSD diagnosed in a prenatal diagnosis center, analysed from the database during the 54-month period extending from November 1997 to May 2002. One hundred and three fetuses were diagnosed with A VSD. Among them other-cardiac and extra cardiac anomalies were present in 56 and 75 cases respectively. Of the 22 fetuses that had undergone karyotyping, no metaphase was seen in one case. In the remaining 21, 15 (71.4%) turned out to be normal, three (14.2%) had trisomy 18, two (9.5%) had trisomy 13 and one had trisomy 21 (4.8%). We found that AVSD almost always occurs with other-cardiac or extracardiac anomalies, though the pattern may differ between populations. It seems to be less frequently associated with chromosomal anomalies (especially trisomy 21) in South India. The genetics of AVSD underscores the importance of a thorough understanding of the target population in prenatal decision-making.

Adolescent↗
PubMed2002

Synthesis of oligothiophene-bridged bisporphyrins and study of the linkage dependence of the electronic coupling.

A set of twelve porphyrin dimers has been prepared to give information on how the type of connectivity between a porphyrin core and a bridge can influence the interporphyrin electronic interaction. The new porphyrin systems are substituted directly at the meso position with an oligothiophene chain tethered either with a single C-C sigma bond, a trans ethylenyl group, or a acetylenyl group. The compounds are easily obtained by palladium-catalyzed cross-coupling reactions (Stille, Heck, and Sonogashira) between 5-iodo-10,15,20-(3,5-ditert-butylphenyl)porphyrin and the appropriate oligothiophene derivative. This synthetic approach is straightforward and very effective for preparing oligothiophene-based prophyrin systems. The absorption spectra and the fluorescence properties of the dimers demonstrated the crucial importance of the characteristics of the chemical bond used to connect the bridge to the porphyrin unit. The magnitude of the electronic communication can thus be significantly modulated by altering the type of bond connectivity used to link the chromophore to the bridge. The present work shows that an oligothiophene spacer is a viable class of linker for connecting porphyrins, and that a quaterthiophene appended with ethynyl linkages affords a high electronic interaction over a distance as large as 28 A. A detailed computational study of these dimers has clarified the conditions needed for a conjugated system to behave as a molecular wire. These conditions are full planarity of the molecule and proper energy matching between the frontier orbitals of the bridge and the porphyrin. Intermolecular energy transfer in asymmetrical dyads composed of a zinc porphyrin and a freebase porphyrin has been studied by fluorescence spectroscopy. In all systems, this process is more than 98% efficient, and its rate constant decreases steadily in the order 4ZH > 1ZH > 3ZH approximately 2ZH. Thus, the largest rate (kEnT = 1.2 x 10(11) s-1) was found in the dyad linked with bisethynyl quaterthiophene, which represents the longest bridge within the series. These results clearly demonstrate that strong communication and also efficient photoinduced processes can be promoted over a large distance if the electronic structure of the molecular connector is appropriately chosen.

Journal Article↗
PubMed2002

Nanocrystallization during nanoindentation of a bulk amorphous metal alloy at room temperature.

It is known that nanocrystallites can form in shear bands produced during severe bending or high-energy ball milling of thin ribbons of a metallic glass. We present direct experimental evidence that highly confined and controlled local contact at the ultrafine scale in the form of quasi-static nanoindentation of a bulk glassy metal alloy at room temperature can also cause nanocrystallization. Atomic force microscopy and transmission electron microscopy show that nanocrystallites nucleate in and around shear bands produced near indents and that they are the same as crystallites formed during annealing without deformation at 783 kelvin. Analogous to results from recent experiments with glassy polymers, our results are reasoned to be a consequence of flow dilatation inside the bands and of the attendant, radically enhanced, atomic diffusional mobility inside actively deforming shear bands.

Journal Article↗
PubMed2002

Fetal lung maturity analysis using ultrasound image features.

This pilot study was carried out to find the feasibility of analyzing the maturity of the fetal lung using ultrasound images. Data were collected from normal pregnant women at intervals of two weeks from the gestation age of 24 to 38 weeks. Images were acquired at two centers located at different geographical locations. The total data acquired consisted of 750 images of immature and 250 images of mature class. A region of interest of 64 x 64 pixels was used for extracting the features. Various textural features were computed from the fetal lung and liver images. The ratios of fetal lung to liver feature values were investigated as possible indexes for classifying the images into those from mature (reduced pulmonary risk) and immature (possible pulmonary risk) lung. The features used are fractal dimension, lacunarity, and features derived from the histogram of the images. The following classifiers were used to classify the fetal lung images as belonging to mature or immature lung: nearest neighbor, k-nearest neighbor, modified k-nearest neighbor, multilayer perceptron, radial basis function network, and support vector machines. The classification accuracy obtained for the testing set ranges from 73% to 96%.

Female↗
PubMed2002

Teaching first-year medical students physiology: does the human patient simulator allow for more effective teaching?

BACKGROUND: Although the Human Patient Simulator (HPS) is an effective teaching tool in many medical fields, literature supporting its use in the teaching of physiology to medical students is lacking. This study investigated the effectiveness of HPS-based teaching of cardiovascular physiology to first-year medical students. METHODS: Two hundred and ten first-year medical students were scheduled to our HPS laboratory with the purpose of demonstrating "physiology in action". Students were divided into groups of 19-25 each, and attended a lecture followed by a HPS session. Using a theatre-type simulator complete with mannequin, anaesthesia machine and monitors (METI, Sarasota FL), the scenarios of hypovolaemia, sepsis, and cardiac failure were run to demonstrate the physiological changes that occur with changes in preload, afterload, and cardiac contractility. Each student was given a true/false test before, and again after the HPS session, followed by a survey of their learning experience. RESULTS: There was marked improvement in test scores after the HPS session (82.1% vs. 64.6%, P < 0.001). Most of the students felt that HPS was a better teaching tool (94.5%) and raised more questions (76.5%) than lectures. They wanted more topics to be taught this way (96%), as they could apply and re-enforce textbook knowledge, and visualise real-time changes. However, they felt that their experience could have been enhanced with more time and smaller groups. DISCUSSION: HPS is an excellent teaching tool as it stimulates student curiosity and makes knowledge acquisition and understanding easier. It is highly desirable to be incorporated into the teaching of physiology.

Anesthesiology↗
PubMed2001

Graded materials for resistance to contact deformation and damage.

The mechanical response of materials with spatial gradients in composition and structure is of considerable interest in disciplines as diverse as tribology, geology, optoelectronics, biomechanics, fracture mechanics, and nanotechnology. The damage and failure resistance of surfaces to normal and sliding contact or impact can be changed substantially through such gradients. This review assesses the current understanding of the resistance of graded materials to contact deformation and damage, and outlines future research directions and possible applications for graded materials.

Journal Article↗
PubMed2001

Adenosine analogues as selective inhibitors of glyceraldehyde-3-phosphate dehydrogenase of Trypanosomatidae via structure-based drug design.

In our continuation of the structure-based design of anti-trypanosomatid drugs, parasite-selective adenosine analogues were identified as low micromolar inhibitors of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Crystal structures of Trypanosoma brucei, Trypanosoma cruzi, Leishmania mexicana, and human GAPDH's provided details of how the adenosyl moiety of NAD(+) interacts with the proteins, and this facilitated the understanding of the relative affinities of a series of adenosine analogues for the various GAPDH's. From exploration of modifications of the naphthalenemethyl and benzamide substituents of a lead compound, N(6)-(1-naphthalenemethyl)-2'-deoxy-2'-(3-methoxybenzamido)adenosine (6e), N(6)-(substituted-naphthalenemethyl)-2'-deoxy-2'-(substituted-benzamido)adenosine analogues were investigated. N(6)-(1-Naphthalenemethyl)-2'-deoxy-2'-(3,5-dimethoxybenzamido)adenosine (6m), N(6)-[1-(3-hydroxynaphthalene)methyl]-2'-deoxy-2'-(3,5-dimethoxybenzamido)adenosine (7m), N(6)-[1-(3-methoxynaphthalene)methyl]-2'-deoxy-2'-(3,5-dimethoxybenzamido)adenosine (9m), N(6)-(2-naphthalenemethyl)-2'-deoxy-2'-(3-methoxybenzamido)adenosine (11e), and N(6)-(2-naphthalenemethyl)-2'-deoxy-2'-(3,5-dimethoxybenzamido)adenosine (11m) demonstrated a 2- to 3-fold improvement over 6e and a 7100- to 25000-fold improvement over the adenosine template. IC(50)'s of these compounds were in the range 2-12 microM for T. brucei, T. cruzi, and L. mexicana GAPDH's, and these compounds did not inhibit mammalian GAPDH when tested at their solubility limit. To explore more thoroughly the structure-activity relationships of this class of compounds, a library of 240 N(6)-(substituted)-2'-deoxy-2'-(amido)adenosine analogues was generated using parallel solution-phase synthesis with N(6) and C2' substituents chosen on the basis of computational docking scores. This resulted in the identification of 40 additional compounds that inhibit parasite GAPDH's in the low micromolar range. We also explored adenosine analogues containing 5'-amido substituents and found that 2',5'-dideoxy-2'-(3,5-dimethoxybenzamido)-5'-(diphenylacetamido)adenosine (49) displays an IC(50) of 60-100 microM against the three parasite GAPDH's.

3T3 Cells↗
PubMed2001

Nanoindentation. Simulation of defect nucleation in a crystal.

Nanoindentation is the penetration of a surface to nanometre depths using an indenting device. It can be simulated using the Bragg bubble-raft model, in which a close-packed array of soap bubbles corresponds to the equilibrium positions of atoms in a crystalline solid. Here we show that homogeneous defect nucleation occurs within a crystal when its surface roughness is comparable to the radius of the indenter tip, and that the depth of the nucleation site below the surface is proportional to the half-width of the contact. Our results may explain the unusually high local stress required for defect nucleation in nano-indented face-centred cubic crystals.

Journal Article↗
PubMed2001

Conformational changes in Leishmania mexicana glyceraldehyde-3-phosphate dehydrogenase induced by designed inhibitors.

The glycolytic enzymes of trypanosomes are attractive drug targets, since the blood-stream form of Trypanosoma brucei lacks a functional citric acid cycle and is dependent solely on glycolysis for its energy requirements. Glyceraldehyde-3-phosphate dehydrogenases (GAPDH) from the pathogenic trypanosomatids T. brucei, Trypanosoma cruzi and Leishmania mexicana are quite similar to each other, and yet have sufficient structural differences compared to the human enzyme to enable the structure-based design of compounds that selectively inhibit all three trypanosomatid enzymes but not the human homologue. Adenosine analogs with substitutions on N-6 of the adenine ring and on the 2' position of the ribose moiety were designed, synthesized and tested for inhibition. Two crystal structures of L. mexicana glyceraldehyde-3-phosphate dehydrogenase in complex with high-affinity inhibitors that also block parasite growth were solved at a resolution of 2.6 A and 3.0 A. The complexes crystallized in the same crystal form, with one and a half tetramers in the crystallographic asymmetric unit. There is clear electron density for the inhibitor in all six copies of the binding site in each of the two structures. The L. mexicana GAPDH subunit exhibits substantial structural plasticity upon binding the inhibitor. Movements of the protein backbone, in response to inhibitor binding, enlarge a cavity at the binding site to accommodate the inhibitor in a classic example of induced fit. The extensive hydrophobic interactions between the protein and the two substituents on the adenine scaffold of the inhibitor provide a plausible explanation for the high affinity of these inhibitors for trypanosomatid GAPDHs.

Adenosine↗
PubMed2001

An investigation into the feasibility of fetal lung maturity prediction using statistical textural features.

Fetal lung and liver tissues were examined by ultrasound in 240 subjects during 24 to 38 weeks of gestational age in order to investigate the feasibility of predicting the maturity of the lung from the textural features of sonograms. A region of interest of 64 x 64 pixels is used for extracting textural features. Since the histological properties of the liver are claimed to remain constant with respect to gestational age, features obtained from the lung region are compared with those from liver. Though the mean values of some of the features show a specific trend with respect to gestation age, the variance is too high to guarantee definite prediction of the gestational age. Thus, we restricted our purview to an investigation into the feasibility of fetal lung maturity prediction using statistical textural features. Out of 64 features extracted, those features that are correlated with gestation age and less computationally intensive are selected. The results of our study show that the sonographic features hold some promise in determining whether the fetal lung is mature or immature.

Feasibility Studies↗
PubMed2000

A potential target enzyme for trypanocidal drugs revealed by the crystal structure of NAD-dependent glycerol-3-phosphate dehydrogenase from Leishmania mexicana.

BACKGROUND: NAD-dependent glycerol-3-phosphate dehydrogenase (GPDH) catalyzes the interconversion of dihydroxyacetone phosphate and L-glycerol-3-phosphate. Although the enzyme has been characterized and cloned from a number of sources, until now no three-dimensional structure has been determined for this enzyme. Although the utility of this enzyme as a drug target against Leishmania mexicana is yet to be established, the critical role played by GPDH in the long slender bloodstream form of the related kinetoplastid Trypanosoma brucei makes it a viable drug target against sleeping sickness. RESULTS: The 1.75 A crystal structure of apo GPDH from L. mexicana was determined by multiwavelength anomalous diffraction (MAD) techniques, and used to solve the 2.8 A holo structure in complex with NADH. Each 39 kDa subunit of the dimeric enzyme contains a 189-residue N-terminal NAD-binding domain and a 156-residue C-terminal substrate-binding domain. Significant parts of both domains share structural similarity with plant acetohydroxyacid isomeroreductase. The discovery of extra, fatty-acid like, density buried inside the C-terminal domain indicates a possible post-translational modification with an associated biological function. CONCLUSIONS: The crystal structure of GPDH from L. mexicana is the first structure of this enzyme from any source and, in view of the sequence identity of 63%, serves as a valid model for the T. brucei enzyme. The differences between the human and trypanosomal enzymes are extensive, with only 29% sequence identity between the parasite and host enzyme, and support the feasibility of exploiting the NADH-binding site to develop selective inhibitors against trypanosomal GPDH. The structure also offers a plausible explanation for the observed inhibition of the T. brucei enzyme by melarsen oxide, the active form of the trypanocidal drugs melarsoprol and cymelarsan.

Animals↗
PubMed1999

Structure-based design of submicromolar, biologically active inhibitors of trypanosomatid glyceraldehyde-3-phosphate dehydrogenase.

The bloodstream stage of Trypanosoma brucei and probably the intracellular (amastigote) stage of Trypanosoma cruzi derive all of their energy from glycolysis. Inhibiting glycolytic enzymes may be a novel approach for the development of antitrypanosomatid drugs provided that sufficient parasite versus host selectivity can be obtained. Guided by the crystal structures of human, T. brucei, and Leishmania mexicana glyceraldehyde-3-phosphate dehydrogenase, we designed adenosine analogs as tight binding inhibitors that occupy the pocket on the enzyme that accommodates the adenosyl moiety of the NAD+ cosubstrate. Although adenosine is a very poor inhibitor, IC50 approximately 50 mM, addition of substituents to the 2' position of ribose and the N6-position of adenosine led to disubstituted nucleosides with micromolar to submicromolar potency in glyceraldehyde-3-phosphate dehydrogenase assays, an improvement of 5 orders of magnitude over the lead. The designed compounds do not inhibit the human glycolytic enzyme when tested up to their solubility limit (approximately 40 microM). When tested against cultured bloodstream T. brucei and intracellular T. cruzi, N6-(1-naphthalenemethyl)-2'-(3-chlorobenzamido)adenosine inhibited growth in the low micromolar range. Within minutes after adding this compound to bloodstream T. brucei, production of glucose-derived pyruvate ceased, parasite motility was lost, and a mixture of grossly deformed and lysed parasites was observed. These studies underscore the feasibility of using structure-based drug design to transform a mediocre lead compound into a potent enzyme inhibitor. They also suggest that energy production can be blocked in trypanosomatids with a tight binding competitive inhibitor of an enzyme in the glycolytic pathway.

3T3 Cells↗
PubMed1999

The Niemann-Pick C1 protein resides in a vesicular compartment linked to retrograde transport of multiple lysosomal cargo.

Niemann-Pick C disease (NP-C) is a neurovisceral lysosomal storage disorder. A variety of studies have highlighted defective sterol trafficking from lysosomes in NP-C cells. However, the heterogeneous nature of additional accumulating metabolites suggests that the cellular lesion may involve a more generalized block in retrograde lysosomal trafficking. Immunocytochemical studies in fibroblasts reveal that the NPC1 gene product resides in a novel set of lysosome-associated membrane protein-2 (LAMP2)(+)/mannose 6-phosphate receptor(-) vesicles that can be distinguished from cholesterol-enriched LAMP2(+) lysosomes. Drugs that block sterol transport out of lysosomes also redistribute NPC1 to cholesterol-laden lysosomes. Sterol relocation from lysosomes in cultured human fibroblasts can be blocked at 21 degrees C, consistent with vesicle-mediated transfer. These findings suggest that NPC1(+) vesicles may transiently interact with lysosomes to facilitate sterol relocation. Independent of defective sterol trafficking, NP-C fibroblasts are also deficient in vesicle-mediated clearance of endocytosed [14C]sucrose. Compartmental modeling of the observed [14C]sucrose clearance data targets the trafficking defect caused by mutations in NPC1 to an endocytic compartment proximal to lysosomes. Low density lipoprotein uptake by normal cells retards retrograde transport of [14C]sucrose through this same kinetic compartment, further suggesting that it may contain the sterol-sensing NPC1 protein. We conclude that a distinctive organelle containing NPC1 mediates retrograde lysosomal transport of endocytosed cargo that is not restricted to sterol.

Amino Acid Sequence↗
PubMed1999

Localization of Niemann-Pick C1 protein in astrocytes: implications for neuronal degeneration in Niemann- Pick type C disease.

Niemann-Pick type C disease (NP-C) is an inherited neurovisceral lipid storage disorder characterized by progressive neurodegeneration. Most cases of NP-C result from inactivating mutations of NPC1, a recently identified member of a family of genes encoding membrane-bound proteins containing putative sterol sensing domains. By using a specific antipeptide antibody to human NPC1, we have here investigated the cellular and subcellular localization and regulation of NPC1. By light and electron microscopic immunocytochemistry of monkey brain, NPC1 was expressed predominantly in perisynaptic astrocytic glial processes. At a subcellular level, NPC1 localized to vesicles with the morphological characteristics of lysosomes and to sites near the plasma membrane. Analysis of the temporal and spatial pattern of neurodegeneration in the NP-C mouse, a spontaneous mutant model of human NP-C, by amino-cupric-silver staining, showed that the terminal fields of axons and dendrites are the earliest sites of degeneration that occur well before the appearance of a neurological phenotype. Western blots of cultured human fibroblasts and monkey brain homogenates revealed NPC1 as a 165-kDa protein. NPC1 levels in cultured fibroblasts were unchanged by incubation with low density lipoproteins or oxysterols but were increased 2- to 3-fold by the drugs progesterone and U-18666A, which block cholesterol transport out of lysosomes, and by the lysosomotropic agent NH4Cl. These studies show that NPC1 in brain is predominantly a glial protein present in astrocytic processes closely associated with nerve terminals, the earliest site of degeneration in NP-C. Given the vesicular localization of NPC1 and its proposed role in mediating retroendocytic trafficking of cholesterol and other lysosomal cargo, these results suggest that disruption of NPC1-mediated vesicular trafficking in astrocytes may be linked to neuronal degeneration in NP-C.

Amino Acid Sequence↗
PubMed1999

Apolipoprotein D gene expression in the rat brain and light and electron microscopic immunocytochemistry of apolipoprotein D expression in the cerebellum of neonatal, immature and adult rats.

Apolipoprotein D gene and protein expression were investigated in the rat brain and cerebellum, respectively, during development. Apolipoprotein D gene expression was first observed in embryonic day 12 rat brain, with a moderate increase in apolipoprotein D messenger RNA levels towards the later part (embryonic days 15-17) of gestation. In the postnatal rat brain, a marked induction of apolipoprotein D messenger RNA occurred at postnatal day 10, with progressively higher levels of apolipoprotein D messenger RNA observed up to postnatal day 20. Somewhat lower, but none the less high, levels of apolipoprotein D messenger RNA continued to be present in brains of adult animals. In the immature cerebellum (day 3 up to one- to two-week-old rats), there were many densely labeled apolipoprotein D-immunoreactive cells that had features of oligodendrocyte precursors. Purkinje neurons showed apolipoprotein D immunoreactivity in one- to two-week-old animals, after which there appeared to be some decrease in staining. Oligodendrocytes in the cerebella of two-week-old animals were strongly apolipoprotein D positive, with immunoreactivity declining in older animals. These results reveal a maturation-associated induction of apolipoprotein D gene expression in the rat brain, and expression of apolipoprotein D in glial (immature oligodendrocyte) cells in the immature cerebellum, followed by specific expression of apolipoprotein D in Purkinje neurons.

Aging↗