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Biomedical subjects

S Mazumdar

Publications and source records attributed to S Mazumdar.

At least 19 recordsLinked to original sources
PubMed2001

pH-induced conformational transition in the soluble CuA domain of Paracoccus denitrificans cytochrome oxidase.

The pH-induced conformational transition in the CuA domain of subunit II of cytochrome oxidase of Paracoccus denitrificans (PdII) has been investigated using various spectroscopic and stopped-flow kinetic methods. UV-visible absorption and circular dichroism studies showed that an increase in pH from 6 to 10 leads to a conformation change with pK(a) = 8.2 associated with the CuA site of the protein. The secondary structure of the protein was, however, shown to remain unchanged in these two conformational states. Thermal and urea-induced unfolding studies showed that the "low-pH" conformation is more stable compared to the "high-pH" conformation of the protein. Moreover, the overall stability of the protein was found to decrease on reduction of the metal centers in the low-pH form, while the oxidation state of the metal centers did not have any significant effect on the overall stability of the protein in the high-pH form. Stopped-flow pH-jump kinetic studies suggested that the conformational transition is associated with a slow deprotonation step followed by fast conformational equilibrium. The results are discussed in the light of understanding the pH-induced conformational change in the beta-barrel structure of the protein and its effect on the coordination geometry of the metal site.

Binding Sites↗
PubMed2001

Re-integerization of fractional charges in the correlated quarter-filled band.

Previous work has demonstrated the existence of soliton defect states with charges +/-e/2 in the limits of zero and infinite on-site Coulomb interactions in the one-dimensional (1D) quarter-filled band. For large but finite on-site Coulomb interaction, the low temperature 2kF bond distortion that occurs within the 4kF bond-distorted phase is accompanied by charge ordering on the sites. We show that a "re-integerization" of the defect charge occurs in this bond-charge-density-wave state due to a "binding" of the fractional charges. We indicate briefly possible implications of this result for mechanisms of organic superconductivity.

Journal Article↗
PubMed2001

Formation cross-sections of singlet and triplet excitons in pi-conjugated polymers.

Electroluminescence in organic light-emitting diodes arises from a charge-transfer reaction between the injected positive and negative charges by which they combine to form singlet excitons that subsequently decay radiatively. The quantum yield of this process (the number of photons generated per electron or hole injected) is often thought to have a statistical upper limit of 25 per cent. This is based on the assumption that the formation cross-section of singlet excitons, sigmaS, is approximately the same as that of any one of the three equivalent non-radiative triplet exciton states, sigmaT; that is, sigmaS/sigmaT approximately 1. However, recent experimental and theoretical work suggests that sigmaS/sigmaT may be greater than 1. Here we report direct measurements of sigmaS/sigmaT for a large number of pi-conjugated polymers and oligomers. We have found that there exists a strong systematic, but not monotonic, dependence of sigmaS/sigmaT on the optical gap of the organic materials. We present a detailed physical picture of the charge-transfer reaction for correlated pi-electrons, and quantify this process using exact valence bond calculations. The calculated sigmaS/sigmaT reproduces the experimentally observed trend. The calculations also show that the strong dependence of sigmaS/sigmaT on the optical gap is a signature of the discrete excitonic energy spectrum, in which higher energy excitonic levels participate in the charge recombination process.

Journal Article↗
PubMed2001

Paroxetine versus nortriptyline in the continuation and maintenance treatment of depression in the elderly.

Elderly depressed patients are vulnerable to recurrence of depression and benefit from long-term antidepressant therapy. Physicians increasingly use selective serotonin re-uptake inhibitors (SSRIs) as maintenance therapy, although in the absence of data showing that SSRIs are as efficacious as tricyclic antidepressants (TCAs) in the prevention of depression relapse and recurrence. Our objective was to evaluate, in an open trial, the efficacy of paroxetine versus nortriptyline for preventing recurrence of depression in the elderly. Elderly patients with major depression were randomly assigned in a double-blinded fashion to receive either paroxetine or nortriptyline for the acute treatment of depression. Patients who did not respond or tolerate their assigned medications were crossed over openly to the comparator agent. Patients whose depression remitted continued antidepressant medication (paroxetine n = 38; nortriptyline n = 21) during an open 18-month follow-up study. We examined the rates of and times to relapse and to termination of treatment for any reason. Paroxetine (PX) and nortriptyline (NT) patients had similar rates of relapse (16% vs. 10%, respectively) and time to relapse (60.3 weeks vs. 58.8 weeks, respectively) over 18 months. A lower burden of residual depressive symptoms and side effects during continuation and maintenance treatment was evident in nortriptyline-treated patients. Paroxetine and nortriptyline demonstrated similar efficacy in relapse and recurrence prevention in elderly depressed patients over an 18-month period.

Adrenergic Uptake Inhibitors↗
PubMed2001

Initial recovery patterns may predict which maintenance therapies for depression will keep older adults well.

BACKGROUND: Although active maintenance treatments appear superior to placebo in preventing depression recurrence in older adults, few data are available to guide maintenance modality selection to maximize the probability of continued wellness for a given patient. Patients' temporal patterns of acute treatment response may predict who requires which maintenance therapy to remain well. METHODS: Depression levels were observed over 16 weeks of combined nortriptyline (NT) and interpersonal psychotherapy (IPT) in 140 persons aged >or=60 years with recurrent major depression. Subjects were empirically classified into four groups: rapid, sustained responders; delayed, sustained responders; mixed responders without sustained improvement; prolonged nonresponders. Groups were compared on subsequent recovery rates and on time to depression recurrence after randomization to 3 years of combined maintenance therapy (monthly IPT with NT), monotherapy (either IPT or NT alone), or medication clinic with placebo. Pretreatment psychosocial and clinical variables were controlled. RESULTS: Initial response profile predicted ultimate recovery rates, as well as who remained well, given the maintenance treatment received. Rapid initial responders showed lower recurrence risk with either combined or monotherapy, relative to placebo. Specific types of monotherapy appeared equally effective in rapid responders. In initially mixed responders, only combined therapy was superior to placebo. It was marginally superior to monotherapy. For delayed responders, combined therapy was superior to placebo; monotherapy did not differ from the other maintenance conditions. Prolonged nonresponders did not benefit from maintenance treatment. LIMITATIONS: Subjects had only recurrent, unipolar depression. Initial response profile groups were established empirically and require replication. Sample sizes in initial response profile by maintenance treatment cells were small. CONCLUSION: The ability to match patients to maintenance treatments more likely to prevent recurrence may be enhanced by considering the temporal profile of initial response to acute treatment.

Aged↗
PubMed2001

Direct electrochemistry of heme proteins: effect of electrode surface modification by neutral surfactants.

Direct electrochemical studies on horse heart myoglobin and horseradish peroxidase (HRP) have been carried out using tin-doped indium oxide (ITO) and surfactant modified glassy carbon working electrodes. These proteins show very slow electron transfer kinetics at metal or untreated electrodes. Moreover, small amounts of surface-active impurity were drastically affects the electrode reaction of these proteins. The results showed that modification of the electrode surface with neutral surfactants significantly improves the electrochemical response of myoglobin as well as of HRP. The electrode response was found to depend on the structure of the surfactants. The amount of surfactant required per unit area of the electrode surface to promote the maximum electron transfer rate constants was found to be constant. This indicated that the surfactant molecules interacted with the electrode surface in a specific manner and anchored the protein molecules to align in the suitable orientation. The hydrophobicity of the surfactants rather than their charge was found to be crucial in promoting the electrode response of these proteins at the glassy carbon electrode.

Animals↗
PubMed2000

Ultrafast optical nonlinearity in the quasi-one-dimensional mott insulator Sr2CuO3

We report strong instantaneous photoinduced absorption in the quasi-one-dimensional Mott insulator Sr2CuO3 in the IR spectral region. The observed photoinduced absorption is to an even-parity two-photon state that occurs immediately above the absorption edge. Theoretical calculation based on a two-band extended Hubbard model explains the experimental features and indicates that the strong two-photon absorption is due to a very large dipole coupling between nearly degenerate one- and two-photon states. Room temperature picosecond recovery of the optical transparency suggests the strong potential of Sr2CuO3 for all-optical switching.

Journal Article↗
PubMed2000

Effect of Adriamycin on the boundary lipid structure of cytochrome c oxidase: pico-second time-resolved fluorescence depolarization studies.

The fluorescence dynamics of the dye 3,3'-diethyloxadicarbocyanine iodide (DODCI) was used to probe the microenvironment of cytochrome c oxidase (CcO) and cardiolipin. The dye was partitioned between an aqueous and a hydrophobic phase. The 'bound' and 'free' populations of DODCI could be separated by analysis of the time-resolved fluorescence decay of the dye. The anisotropy decay of the DODCI bound to CcO showed a unique 'dip and rise' shape that was analyzed by a combination of rotational correlation times with time-dependent weight factors for each lifetime component. Rotational dynamics studies revealed the existence of a restricted motion of the dye bound at the enzyme surface. Adriamycin, an anticancer, albeit cardiotoxic drug, was previously proposed to affect the surface structure of CcO, most likely by causing a disorder to the surface lipid arrangement. A drastic change in the rotational correlation time of the dye bound to the enzyme surface was observed, which suggested a depletion of cardiolipin layer due to complexation with the drug. The effect of Adriamycin on cardiolipin was drastic, leading to its phase separation. The present study suggests that the effect of Adriamycin on CcO is primarily a segregation of the cardiolipins.

Algorithms↗
PubMed2000

Binding of camphor to Pseudomonas putida cytochrome p450(cam): steady-state and picosecond time-resolved fluorescence studies.

The binding of camphor to cytochrome P450(cam) has been investigated by steady-state and time-resolved tryptophan fluorescence spectroscopy to obtain information on the substrate access channel. The fluorescence quenching experiments show that some of the tryptophan residues undergo changes in their local environment on camphor binding. The time-resolved fluorescence decay profile gives four lifetime components in the range from 99 ps to 4.5 ns. The shortest lifetime component assigned to W42 lies close to the proposed camphor access channel. The results show that the fluorescence of W42 is greatly affected on binding of camphor, and supports dynamic fluctuations involved in the passage of camphor through the access channel as proposed earlier on the basis of crystallographic, molecular dynamics simulation and site-directed mutagenesis studies.

Camphor↗
PubMed2000

Structural and conformational stability of horseradish peroxidase: effect of temperature and pH.

Detailed circular dichroism and fluorescence studies at different pHs have been carried out to monitor thermal unfolding of horseradish peroxidase isoenzyme c (HRPc). The change in CD in the 222 nm region corresponds to changes in the overall secondary structure of the enzyme, while that in the 400 nm region (Soret region) corresponds to changes in the tertiary structure around the heme in the enzyme. The temperature dependence of the tertiary structure around the heme also affected the intrinsic tryptophan fluorescence emission spectrum of the enzyme. The results suggested that melting of the tertiary structure to a pre-molten globule form takes place at 45 degrees C, which is much lower than the temperature (T(m) = 74 degrees C) at which depletion of heme from the heme cavity takes place. The melting of the tertiary structure was found to be associated with a pK(a) of approximately 5, indicating that this phase possibly involves breaking of the hydrogen-bonding network of the heme pocket, keeping the heme moiety still inside it. The stability of the secondary structure of the enzyme was also found to decrease at pH below 4.5. A 'high temperature' unfolding phase was observed which was, however, independent of pH. The stability of the secondary structure was found to drastically decrease in the presence of DTT (dithiothreitol), indicating that the 'high temperature' form is possibly stabilized due to interhelical disulfide bonds. Depletion of Ca(2+) ions resulted in a marked decrease in the stability of the secondary structure of the enzyme.

Calcium↗
PubMed2000

Redox-linked conformational changes in bovine heart cytochrome c oxidase: picosecond time-resolved fluorescence studies of cyanide complex.

Picosecond time-resolved fluorescence studies are carried out on cyanide-inhibited and heat-modified cytochrome c oxidase in aqueous lauryl maltoside surfactant solution, as well as in an aqueous vesicle, to understand the conformational changes associated with electron transfer and proton pumping activity of the enzyme. The tryptophan fluorescence decay profiles follow a four exponential model, which also matches the lifetime maxima obtained in a maximum entropy method analysis. The fast lifetime components are highly affected by the reduction and chemical modification of the enzyme. Changes in these lifetime components are related to the conformational changes in the vicinity of the heme centers of the enzyme. The cyanide-inhibited enzyme in the oxidized form shows a fluorescence decay profile similar to that of the native oxidized form, indicating that the conformational changes due to cyanide binding are very small. However, reduction of the cyanide-inhibited enzyme that leaves cyanide bound heme alpha3 oxidized causes a large increase in the fluorescence lifetimes, which indicates very significant conformational changes due to electron transfer to the dinuclear Cu(A) and heme alpha centers. A comparison of the tryptophan fluorescence decay of various other modified forms of the enzyme leads us to propose that the possible site of conformational coupling is located near heme alpha instead of the binuclear heme alpha3-Cu(B) center.

Animals↗
PubMed2000

Allelic variation in the serotonin transporter promoter affects onset of paroxetine treatment response in late-life depression.

The relationship of the serotonin transporter gene promoter region polymorphism (5-HTTLPR) to antidepressant response was examined in 95 elderly patients receiving a protocolized treatment for depression with paroxetine or nortriptyline. Patients were treated for up to 12 weeks and assessed weekly with clinical ratings and measurements of plasma drug concentrations. Twenty-one of the paroxetine-treated subjects were found to have the ll genotype and 30 had at least one s allele. There were no baseline differences between these groups in pretreatment Hamilton Rating Scale for Depression (HRSD) scores or anxiety symptoms. During acute treatment with paroxetine, mean reductions from baseline in HRSD were significantly more rapid for patients with the ll genotype than for those possessing an s allele, despite equivalent paroxetine concentrations. Onset of response to nortriptyline was not affected. Allelic variation of 5-HTTLPR may contribute to the variable initial response of patients treated with a selective serotonin reuptake inhibitor.

Adrenergic alpha-Agonists↗
PubMed2000

Role of angiotensin-converting enzyme inhibitor, lisinopril, on spermatozoal functions in rats.

Angiotensin-converting enzyme is present in the male reproductive system but its role in the physiology of reproduction is not known. To see the effect of angiotensin-converting enzyme on spermatozoal functions, lisinopril, an angiotensin-converting enzyme inhibitor, was administered orally using two different doses (10 and 20 mg/kg/day) to rats. Both short-term (2 weeks) and long-term (6 weeks) effects of the drug were observed. Lisinopril treatment resulted in a marked decrease in sperm density, sperm motility and zona pellucida penetration. Acrosome reaction by spermatozoa obtained from drug-treated animals was significantly lower when compared with spermatozoa from normal animals.

Acrosome↗
PubMed2000

Weight change in older depressed patients during acute pharmacotherapy with paroxetine and nortriptyline: a double-blind randomized trial.

The authors examined weight change in 32 elderly patients treated for 12 weeks with either nortriptyline or paroxetine during acute-phase pharmacotherapy. Random assignment to treatment and double-blind assessment of weight change were performed, including ascertainment of premorbid (i.e., pre-depression) weight. Pretreatment severity of depression was correlated with weight loss during the depressive episode and depression-related weight loss, in turn, correlated with weight regained during antidepressant treatment. There was no differential weight change associated with nortriptyline vs. paroxetine. Rather, subjects in both groups approximated their premorbid weights by 12 weeks of acute-phase pharmacotherapy with either agent. However, additional investigation of weight change during continuation and maintenance pharmacotherapy is necessary and would be clinically useful for the long-term management of elderly patients with depression.

Aged↗
PubMed1999

Nortriptyline and interpersonal psychotherapy as maintenance therapies for recurrent major depression: a randomized controlled trial in patients older than 59 years.

CONTEXT: Elderly patients with major depression are at high risk for recurrence, increased mortality, and chronic disability. OBJECTIVE: To determine the efficacy of maintenance nortriptyline hydrochloride and interpersonal psychotherapy (IPT) in preventing recurrence of major depressive episodes in patients older than 59 years. DESIGN: A 2 x 2 randomized, double-blind, placebo-controlled clinical trial, stratified by therapist. SETTING: University-based psychiatric research clinic. PATIENTS: Of a total of 187 patients with recurrent nonpsychotic unipolar major depression (average age, 67 years; one third aged > or =70 years) recruited through clinical referral and media announcements, 107 were fully recovered after open acute and treatment continuation with nortriptyline and IPT. These patients were randomly assigned to 1 of 4 maintenance therapy conditions. INTERVENTIONS: Monthly medication clinic with nortriptyline hydrochloride (80-120 ng/mL steady-state levels) (n = 24); medication clinic with placebo (n = 29); monthly maintenance IPT with placebo (n = 21); and monthly maintenance IPT with nortriptyline (n = 22). MAIN OUTCOME MEASURE: Recurrence of major depressive episode. RESULTS: The time to recurrence of a major depressive episode for all 3 active treatments was significantly better than for placebo. Recurrence rates over 3 years were as follows: nortriptyline and IPT, 20% (95% confidence interval [CI], 4%-36%); nortriptyline and medication clinic visits, 43 % (95% CI, 25%-61%); IPT and placebo, 64% (95% CI, 45%-83%); and placebo and medication clinic visits, 90% (95% CI, 79%-100%). Combined treatment with nortriptyline and IPT was superior to IPT and placebo and showed a trend to superior efficacy over nortriptyline monotherapy (Wald chi2 = 3.56; P = .06). Subjects aged 70 years and older had a higher and more rapid rate of recurrence than those aged 60 to 69 years. CONCLUSION: In geriatric patients with recurrent major depression, maintenance treatment with nortriptyline or IPT is superior to placebo in preventing or delaying recurrence. Combined treatment using both appears to be the optimal clinical strategy in preserving recovery.

Adrenergic Uptake Inhibitors↗
PubMed1999

Residual analysis in random regressions using SAS and S-PLUS.

A program package RRAP: Random Regression Residual Analysis Program using SAS [1] and S-PLUS [2] is available for performing random regression residual analysis. The PROCEDURE MIXED from SAS is used for statistical inference. Both elementary-level and individual-level residuals are used. The S-PLUS programs provide: (1) a transformation to orthogonalize the elementary-level correlated residuals for standard regression residual analyses; and (2) several statistics and plots for checking model assumptions, assessing model fitting and detecting outlying individuals. RRRAP starts with a SAS Macro RRRAPMAC on the data followed by a S-PLUS Program DoRRRAP on a UNIX system.

Models, Statistical↗
PubMed1999

Modeling adverse environmental impacts on the reproductive system.

When priority topics are being established for the study of women's health, it is generally agreed that one important area on which to focus research is reproduction. For example, increasing attention has been directed to environmental exposures that disrupt the endocrine system and alter reproduction. These concerns also suggest the need to give greater attention to the use of animal toxicologic testing to draw inferences about human reproductive risks. Successful reproduction requires multiple simultaneous and sequential processes in both the male and female, and the effect of toxicity on reproduction-related processes is time dependent. Currently, however, the risk assessment approach does not allow for the use of multiple processes or for considering the reproductive process response as a function of time. We discuss several issues in modeling exposure effects on reproductive function for risk assessment and present an overview of approaches for reproductive risk assessment. Recommendations are provided for an effective animal study design for determining reproductive risk that addresses optimization of the duration of dosing, observation of the effects of exposure on validated biomarkers, analysis of several biomarkers for complete characterization of the exposure on the underlying biologic processes, the need for longitudinally observed exposure effects, and a procedure for estimating human reproductive risk from the animal findings. An approach to characterizing reproductive toxicity to estimate the increased fertility risks in a dibromochloropropane (DBCP)-exposed human population is illustrated, using several reproductive biomarkers simultaneously from a longitudinal rabbit inhalation study of DBCP and an interspecies extrapolation method.

Animals↗