Prognostic significance of alarm symptoms in patients with gastric cancer (Br J Surg 2005; 92: 840-846).
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Adult↗
Biomedical subjects
S Mazumdar
Publications and source records attributed to S Mazumdar.
Cooperative density wave and giant spin gap in the quarter-filled zigzag electron ladder.
Strong cooperative interactions occur between four different broken symmetries involving charge ordering and bond distortions in the quarter-filled correlated zigzag electron ladder. The ground state is singlet, with spin gap several times larger than in the spin-Peierls state of the one-dimensional quarter-filled chain with the same parameters. We propose the quarter-filled zigzag electron ladder model for several different organic charge transfer solids with coupled pairs of quasi-one-dimensional stacks, in which the spin-gap transition temperatures are unusually high.
Journal Article↗
The utility of structure-activity relationship (SAR) models for prediction and covariate selection in developmental toxicity: comparative analysis of logistic regression and decision tree models.
Structure-activity relationship (SAR) models can be used to predict the biological activity of potential developmental toxicants whose adverse effects include death, structural abnormalities, altered growth and functional deficiencies in the developing organism. Physico-chemical descriptors of spatial, electronic and lipophilic properties were used to derive SAR models by two modeling approaches, logistic regression and Classification and Regression Tree (CART), using a new developmental database of 293 chemicals (FDA/TERIS). Both single models and ensembles of models (termed bagging) were derived to predict toxicity. Assessment of the empirical distributions of the prediction measures was performed by repeated random partitioning of the data set. Results showed that both the decision tree and logistic regression derived developmental SAR models exhibited modest prediction accuracy. Bagging tended to enhance the prediction accuracy and reduced the variability of prediction measures compared to the single model for CART-based models but not consistently for logistic-based models. Prediction accuracy of single logistic-based models was higher than single CART-based models but bagged CART-based models were more predictive. Descriptor selection in SAR for the understanding of the developmental mechanism was highly dependent on the modeling approach. Although prediction accuracy was similar in the two modeling approaches, there was inconsistency in the model descriptors.
Animals↗
Decision tree SAR models for developmental toxicity based on an FDA/TERIS database.
Humans are exposed to thousands of environmental chemicals for which no developmental toxicity information is available. Structure-activity relationships (SARs) are models that could be used to efficiently predict the biological activity of potential developmental toxicants. However, at this time, no adequate SAR models of developmental toxicity are available for risk assessment. In the present study, a new developmental database was compiled by combining toxicity information from the Teratogen Information System (TERIS) and the Food and Drug Administration (FDA) guidelines. We implemented a decision tree modeling procedure, using Classification and Regression Tree software and a model ensemble approach termed bagging. We then assessed the empirical distributions of the prediction accuracy measures of the single and ensemble-based models, achieved by repeating our modeling experiment many times by repeated random partitioning of the working database. The decision tree developmental SAR models exhibited modest prediction accuracy. Bagging tended to enhance the accuracy of prediction. Also, the model ensemble approach reduced the variability of prediction measures compared to the single model approach. Further research with data derived from animal species- and endpoint-specific components of an extended and refined FDA/TERIS database has the potential to derive SAR models that would be useful in the developmental risk assessment of the thousands of untested chemicals.
Abnormalities, Drug-Induced↗
Comment on "origin of giant optical nonlinearity in charge-transfer-mott insulators: a new paradigm for nonlinear optics".
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Comment↗
Progression to insulin-requiring diabetes in seronegative prediabetic subjects: the role of two HLA-DQ high-risk haplotypes.
AIMS/HYPOTHESIS: Most Caucasians with Type I (insulin-dependent) diabetes mellitus develop an autoimmune form of diabetes known as Type IA diabetes, based on the presence of humoral responses to islet autoantigens. Alleles at the HLA locus account for the strongest susceptibility to this form of diabetes, which requires insulin therapy. Because a number of patients who develop insulin-requiring diabetes are islet autoantibody negative, the HLA class II haplotypes, DQA1*0501-DQB1*0201 and DQA1*0301-DQB1*0302, were evaluated to assess whether they are an independent risk factor for progression to insulin requirement in first-degree relatives of Type I diabetic patients. METHODS: Both HLA-DQ genotyping and islet cell autoantibody assessment (insulin, GAD65, IA-2 autoantibodies and cytoplasmic islet cell antibodies) were evaluated prospectively in 74 relatives of Type I diabetic patients who developed diabetes treated with insulin (prediabetics) and in 426 control subjects who did not develop insulin-requiring diabetes. Based on the presence of DQA1*0501-DQB1*0201 and/or DQA1*0301-DQB1*0302, the number of HLA-DQ high-risk haplotypes was assigned as 0, 1 or 2. RESULTS: A higher prevalence of 2 HLA-DQ high-risk haplotypes was present in seronegative prediabetic subjects as compared to non-diabetic autoantibody negative first-degree relatives (33.3 % vs 10.1 % respectively; p < 0.05). Moreover, in seronegative relatives who developed insulin-requiring diabetes, the presence of 2 HLA-DQ high-risk haplotypes conferred an increased cumulative risk of developing insulin requirement of 27 % at 12.5 years of follow-up, compared to a risk of 6 % for non-diabetic relatives who were antibody-negative and had 0 or 1 HLA-DQ high-risk haplotypes (Log rank p = 0.01). CONCLUSION/INTERPRETATION: These data provide evidence for a phenotype, which is associated with the absence of conventional islet autoantibodies at initial screening, while usually remaining seronegative, and the presence of 2 HLA-DQ high-risk haplotypes with progression to clinical Type I diabetes after a prolonged follow-up. Given the fact that in humans the highest risk-conferring locus associated and linked to the disease is the HLA cluster, and that HLA-DQ molecules play a key role in the development of autoimmune diabetes, our observations imply that as yet unidentified immunologic abnormalities could well exist in seronegative relatives at risk of developing clinical diabetes and carrying 2 HLA-DQ high-risk haplotypes.
Adolescent↗
Direct observation of release of cytochrome c from lipid-encapsulated protein by peroxide and superoxide: a possible mechanism for drug-induced apoptosis.
Release of cytochrome c from inside lipid vesicles and from inside proteoliposomes formed by cytochrome c oxidase has been studied by spectrophotometric methods. The protein encapsulated inside vesicles did not form complex with sodium azide solution added externally. Both hydrogen peroxide and superoxide were found to cause release of cytochrome c from the lipid encapsulated protein, which was detected from the distinct spectral changes due to the formation of the azide complex of cytochrome c in the solution. Cytochrome c encapsulated inside proteoliposomes containing cytochrome c oxidase (CcO) did not release the cytochrome c during enzymatic turnover of CcO. The anticancer drug, doxorubicin, was found to inhibit the biochemical function of cytochrome c oxidase and release of cytochrome c was observed from the proteoliposome encapsulating the protein during the enzymatic turnover in the presence of doxorubicin. The results indicated that the inhibition of enzymatic activity by doxorubicin possibly leads to the formation of reactive oxygen species, which induce the release of cytochrome c from inside to outside of the membrane.
Apoptosis↗
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↗
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↗
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↗
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↗
Steady-state and time-resolved fluorescence studies on wild type and mutant chromatium vinosum high potential iron proteins: holo- and apo-forms.
Detailed circular dichroism (CD), steady-state and time-resolved tryptophan fluorescence studies on the holo- and apo- forms of high potential iron protein (HiPIP) from Chromatium vinosum and its mutant protein have been carried out to investigate conformational properties of the protein. CD studies showed that the protein does not have any significant secondary structure elements in the holo- or apo- HiPIP, indicating that the metal cluster does not have any effect on formation of secondary structure in the protein. Steady-state fluorescence quenching studies however, suggested that removal of the iron-sulfur ([Fe(4)S(4)](3+)) cluster from the protein leads to an increase in the solvent accessibility of tryptophans, indicating change in the tertiary structure of the protein. CD studies on the holo- and apo- HiPIP also showed that removal of the metal prosthetic group drastically affects the tertiary structure of the protein. Time-resolved fluorescence decay of the wild type protein was fitted to a four-exponentials model and that of the W80N mutant was fitted to a three-exponentials model. The time-resolved fluorescence decay was also analyzed by maximum entropy method (MEM). The results of the MEM analysis agreed with those obtained from discrete exponentials model analysis. Studies on the wild type and mutants helped to assign the fast picosecond lifetime component to the W80 residue, which exhibits fast fluorescence energy transfer to the [Fe(4)S(4)](3+) cluster of the protein. Decay-associated fluorescence spectra of each tryptophan residues were calculated from the time-resolved fluorescence results at different emission wavelengths. The results suggested that W80 is in the hydrophobic core of the protein, but W60 and W76 are partially or completely exposed to the solvent.
Apoproteins↗
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↗
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↗
Dieulafoy's lesion of the cecum: a rare cause of lower GI hemorrhage.
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Arteriovenous Malformations↗
Influence of serotonin-transporter-linked promoter region polymorphism on platelet activation in geriatric depression.
OBJECTIVE: Depression has been associated with increased platelet activation. Variations in the serotonin-transporter-linked promoter region (5-HTTLPR) polymorphism may influence the degree of activation. The authors examined the association among depression, platelet activation, and 5-HTTLPR genotype. METHOD: Elderly subjects with (N=61) and without (N=12) major depression were assessed for cognitive impairment, cardiovascular disease, and two indices of platelet activation. The depressed subjects were genotyped for the 5-HTTLPR polymorphism. RESULTS: The depressed subjects were older, were more cognitively impaired, and had higher platelet factor 4 and beta-thromboglobulin levels; cardiovascular disease was minimal in both groups. In the depressed group, subjects with the 5-HTTLPR l/l genotype had significantly higher platelet factor 4 and beta-thromboglobulin levels. CONCLUSIONS: Platelet activation is increased in elderly depressed patients, especially those with the 5-HTTLPR l/l genotype. This finding suggests how genetic differences may influence cardiovascular mortality in depressed patients with ischemic heart disease.
Aged↗
A double-blind randomized comparison of nortriptyline plus perphenazine versus nortriptyline plus placebo in the treatment of psychotic depression in late life.
OBJECTIVE: To conduct the first randomized study comparing the efficacy of an antidepressant alone versus an antidepressant plus a neuroleptic in the treatment of late-life psychotic depression. METHOD: The efficacy of nortriptyline plus placebo versus nortriptyline plus perphenazine was compared in 36 patients aged 50 years or older presenting with a major depressive episode with psychotic features (DSM-III-R criteria). Patients were started openly on nortriptyline treatment titrated to therapeutic levels. They were then randomly assigned under double-blind conditions to addition of perphenazine or placebo. Outcomes were compared in the 2 treatment groups using measures including the Hamilton Rating Scale for Depression (HAM-D) and the Brief Psychiatric Rating Scale (BPRS); side effects were assessed with the Geriatric Movement Disorder Assessment. RESULTS: Both treatments were well tolerated. Of the 36 randomly assigned patients, 2 (1 in each group) dropped out due to treatment-related adverse effects. Four additional patients dropped out for administrative reasons. Thirty patients received nortriptyline for at least 4 weeks combined with either perphenazine (N = 14) or placebo (N = 16) for at least 2 weeks (median = 9 weeks). There was no significant difference between the completers in the 2 treatment groups when comparing their scores on the HAM-D, the BPRS, its psychoticism subscale, or any side effects measure. Rates of response (defined as resolution of both depression and psychosis) did not differ significantly in the 2 groups (nortriptyline-plus-perphenazine group, 50% vs. nortriptyline-plus-placebo group, 44%). CONCLUSION: When treating older patients with psychotic depression, the addition of a moderate dose of a traditional neuroleptic to a tricyclic antidepressant was well tolerated but did not improve efficacy. This finding supports existing data suggesting that the pathophysiology (and thus the required treatment) of psychotic depression may be different early and late in life.
Affective Disorders, Psychotic↗
Treatment outcome in suicidal vs. non-suicidal elderly patients.
The authors investigated treatment outcome in elderly suicidal and non-suicidal patients with recurrent major depression. Patients without suicidal ideation in the current episode (Non-Ideators; n=150) were compared with 30 patients who expressed suicidal ideation (Ideators). Patients received combined pharmacotherapy and psychotherapy during acute and continuation treatment. Ideators had higher numbers of lifetime suicide attempts and reported significantly higher levels of depression, anxiety, and hopelessness before starting treatment. Ideators and Non-Ideators had almost identical remission rates (77% vs. 78%), but Ideators had higher relapse rates during continuation treatment (26% vs. 13%) and were more likely to receive augmentation pharmacotherapy. Anxiety and use of adjunctive medication, but not suicidal ideation, were negatively related to both remission and relapse. Our data suggest that elderly suicidal patients have an overall favorable treatment outcome. However, treatment response may be more brittle and may require the continuing use of adjunctive medications to prevent early relapse.
Aged↗