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Biomedical subjects

S Dhar

Publications and source records attributed to S Dhar.

At least 37 records · Page 2Linked to original sources
PubMed2000

Recurrent arterial embolization from a metastatic germ cell tumor invading the left atrium.

Arterial embolization of a malignant tumor is extremely rare. We report an unusual case of a young adult man who presented with acute lower limb ischemia and a mass in the right lung and left atrium. These clinical manifestations were the result of metastases and embolization from a germ cell tumor and were the first indication of malignancy in this patient. The importance of appropriate investigations in the subsequent treatment is stressed.

Adult↗
PubMed2000

Metastatic pancreatic adenocarcinoma to the heart diagnosed antemortem.

Pancreatic tumors frequently metastasize widely, though it is rare to diagnose pancreatic cardiac metastases in the antemortem state. We report an unusual case of metastatic pancreatic adenocarcinoma to the right atrium. Transesophageal echocardiography showed that the tumor was attached to the superior aspect of the right atrium, prolapsing through and obstructing the tricuspid valve in diastole and retracting back into the right atrium during systole. The tumor was excised, and histologic examination confirmed the presence of moderately differentiated adenocarcinoma with a papillary architectural pattern and with desmoplastic stroma, features comparable to the original primary pancreatic neoplasm.

Adenocarcinoma↗
PubMed2000

Antitumour activity of suramin analogues in human tumour cell lines and primary cultures of tumour cells from patients.

Suramin has shown promising antitumour activity against several tumour types, both in vitro and in vivo, but the clinical utility of this compound is hampered by its unfavourable toxicity profile. In the present study, the semi-automated fluorometric microculture cytotoxicity assay (FMCA) was employed for evaluation of the cytotoxicity of seven suramin analogues in vitro in a panel of human tumour cell lines and in primary cultures of tumour cells from patients. Like suramin, the analogues showed little sensitivity to resistance mechanisms involving P-glycoprotein, topoisomerase II, multidrug resistance associated protein and glutathione-mediated drug resistance. In the cell line panel, NF067 and FCE 26644 showed activity comparable with suramin. All analogues were less potent than suramin in patient cells except for FCE 26644. Correlation to suramin activity patterns in the cell line panel was highest for NF037 and low to moderate for the remaining analogues. In patient cells, high correlation coefficients were obtained for FCE 26644, NF110, NF031 and NF037. The results indicate that the cytotoxic activity of suramin on patient tumour cells is shared by the analogues with FCE 26644 being the most active. The pharmacophore for cytotoxicity in patient cells may be different from that observed in the cell lines.

Antineoplastic Agents↗
PubMed2000

Differential activity of topotecan, irinotecan and SN-38 in fresh human tumour cells but not in cell lines.

The topoisomerase I inhibitors topotecan irinotecan (CPT-11) and its metabolite SN-38 were studied in a panel of cell lines and in primary tumour cells from patients, using a non-clonogenic cytotoxicity assay. All three substances showed similar activity patterns in the panel of cell lines established to classify the drugs mechanistically. In the patient tumour cells the drugs had different effects. In haematological and ovarian cancer samples, SN-38 was much more potent than topotecan, followed by irinotecan, while in colorectal cancer samples only irinotecan showed substantial activity. This in vitro activity pattern seems to agree with clinical experiences to date. The inactivity of SN-38 in colorectal cancer suggests irinotecan may also have some other role in addition to being a prodrug to SN-38. This study raises questions as to the role and relevance of early preclinical model systems in anticancer drug development, and suggests that important information can be obtained from studies using primary cultures of human tumour cells.

Antineoplastic Agents↗
PubMed2000

2-Hydroxy-5-

The title compound, C(14)H(12)N(2)O(4), shows an E conformation about the diazenyl N atoms. The crystal structure features layers of molecules with the primary connection between the layers afforded by carboxylic acid dimer motifs; no evidence for extensive pi-pi stacking between the layers was found.

Journal Article↗
PubMed2000

On the relationships between the fixed-f1, fixed-f2, and fixed-ratio phase derivatives of the 2f1-f2 distortion product otoacoustic emission.

For primary frequency ratios, f2/f1, in the range 1.1-1.3, the fixed-f1 ("f2-sweep") phase derivative of the 2f1-f2 distortion product otoacoustic emission (DPOAE) is larger than the fixed-f2("f1-sweep") one. It has been proposed by some researchers that part or all of the difference between these delays may be attributed to the so-called cochlear filter "build-up" or response time in the DPOAE generation region around the f2 tonotopic site. The analysis of an approximate theoretical expression for the DPOAE signal [Talmadge et al., J. Acoust. Soc. Am. 104, 1517-1543 (1998)] shows that the contributions to the phase derivatives associated with the cochlear filter response is small. It is also shown that the difference between the phase derivatives can be qualitatively accounted for by assuming the approximate scale invariance of cochlear mechanics. The effects of DPOAE fine structure on the phase derivative are also explored, and it is found that the interpretation of the phase derivative in terms of the phase variation of a single DPOAE component can be quite problematic.

Humans↗
PubMed2000

An analysis of quasi-frequency-modulated noise and random-sideband noise as comparisons for amplitude-modulated noise.

Experiments were performed to determine under what conditions quasi-frequency-modulated (QFM) noise and random-sideband noise are suitable comparisons for AM noise in measuring a temporal modulation transfer function (TMTF). Thresholds were measured for discrimination of QFM from random-sideband noise and AM from QFM noise as a function of sideband separation. In the first experiment, the upper spectral edge of the noise stimuli was at 2400 Hz and the bandwidth was 1600 Hz. For sideband separations up to 256 Hz, at threshold sideband levels for discriminating AM from QFM noise, QFM was indiscriminable from random-sideband noise. For the largest sideband separation used (512 Hz), listeners may have used within-stimulus envelope correlation in the QFM noise to discriminate it from the random-sideband noise. Results when stimulus bandwidth was varied suggest that listeners were able to use this cue when the carrier was wider than a critical band, and the sideband separation approached the carrier bandwidth. Within-stimulus envelope correlation was also present in AM noise, and thus QFM noise was a suitable comparison because it made this cue unusable and forced listeners to use across-stimulus envelope differences. When the carrier bandwidth was less than a critical band or was wideband, QFM noise and random-sideband noise were equally suitable comparisons for AM noise. When discrimination thresholds for QFM and random-sideband noise were converted to modulation depth and modulation frequency, they were nearly identical to those for discrimination of AM from QFM noise, suggesting that listeners were using amplitude modulation cues in both cases.

Adult↗
PubMed2000

Inactivation of 14-3-3sigma influences telomere behavior and ionizing radiation-induced chromosomal instability.

Telomeres are complexes of repetitive DNA sequences and proteins constituting the ends of linear eukaryotic chromosomes. While these structures are thought to be associated with the nuclear matrix, they appear to be released from this matrix at the time when the cells exit from G(2) and enter M phase. Checkpoints maintain the order and fidelity of the eukaryotic cell cycle, and defects in checkpoints contribute to genetic instability and cancer. The 14-3-3sigma gene has been reported to be a checkpoint control gene, since it promotes G(2) arrest following DNA damage. Here we demonstrate that inactivation of this gene influences genome integrity and cell survival. Analyses of chromosomes at metaphase showed frequent losses of telomeric repeat sequences, enhanced frequencies of chromosome end-to-end associations, and terminal nonreciprocal translocations in 14-3-3sigma(-/-) cells. These phenotypes correlated with a reduction in the amount of G-strand overhangs at the telomeres and an altered nuclear matrix association of telomeres in these cells. Since the p53-mediated G(1) checkpoint is operative in these cells, the chromosomal aberrations observed occurred preferentially in G(2) after irradiation with gamma rays, corroborating the role of the 14-3-3sigma protein in G(2)/M progression. The results also indicate that even in untreated cycling cells, occasional chromosomal breaks or telomere-telomere fusions trigger a G(2) checkpoint arrest followed by repair of these aberrant chromosome structures before entering M phase. Since 14-3-3sigma(-/-) cells are defective in maintaining G(2) arrest, they enter M phase without repair of the aberrant chromosome structures and undergo cell death during mitosis. Thus, our studies provide evidence for the correlation among a dysfunctional G(2)/M checkpoint control, genomic instability, and loss of telomeres in mammalian cells.

14-3-3 Proteins↗
PubMed2000

Meiotic telomere distribution and Sertoli cell nuclear architecture are altered in Atm- and Atm-p53-deficient mice.

The ataxia telangiectasia mutant (ATM) protein is an intrinsic part of the cell cycle machinery that surveys genomic integrity and responses to genotoxic insult. Individuals with ataxia telangiectasia as well as Atm(-/-) mice are predisposed to cancer and are infertile due to spermatogenesis disruption during first meiotic prophase. Atm(-/-) spermatocytes frequently display aberrant synapsis and clustered telomeres (bouquet topology). Here, we used telomere fluorescent in situ hybridization and immunofluorescence (IF) staining of SCP3 and testes-specific histone H1 (H1t) to spermatocytes of Atm- and Atm-p53-deficient mice and investigated whether gonadal atrophy in Atm-null mice is associated with stalling of telomere motility in meiotic prophase. SCP3-H1t IF revealed that most Atm(-/-) p53(-/-) spermatocytes degenerated during late zygotene, while a few progressed to pachytene and diplotene and some even beyond metaphase II, as indicated by the presence of a few round spermatids. In Atm(-/-) p53(-/-) meiosis, the frequency of spermatocytes I with bouquet topology was elevated 72-fold. Bouquet spermatocytes with clustered telomeres were generally void of H1t signals, while mid-late pachytene and diplotene Atm(-/-) p53(-/-) spermatocytes displayed expression of H1t and showed telomeres dispersed over the nuclear periphery. Thus, it appears that meiotic telomere movements occur independently of ATM signaling. Atm inactivation more likely leads to accumulation of spermatocytes I with bouquet topology by slowing progression through initial stages of first meiotic prophase and an ensuing arrest and demise of spermatocytes I. Sertoli cells (SECs), which contribute to faithful spermatogenesis, in the Atm mutants were found to frequently display numerous heterochromatin and telomere clusters-a nuclear topology which resembles that of immature SECs. However, Atm(-/-) SECs exhibited a mature vimentin and cytokeratin 8 intermediate filament expression signature. Upon IF with ATM antibodies, we observed ATM signals throughout the nuclei of human and mouse SECs, spermatocytes I, and haploid round spermatids. ATM but not H1t was absent from elongating spermatid nuclei. Thus, ATM appears to be removed from spermatid nuclei prior to the occurrence of DNA nicks which emanate as a consequence of nucleoprotamine formation.

Animals↗
PubMed2000

Receptor subtypes mediating depressor responses to microinjections of nicotine into medial NTS of the rat.

Microinjections (50 nl) of nicotine (0.01-10 microM) into the nucleus of the solitary tract (NTS) of adult, urethan-anesthetized, artificially ventilated, male Wistar rats, elicited decreases in blood pressure and heart rate. Prior microinjections of alpha-bungarotoxin (alpha-BT) and alpha-conotoxin ImI (specific toxins for nicotinic receptors containing alpha7 subunits) elicited a 20-38% reduction in nicotine responses. Similarly, prior microinjections of hexamethonium, mecamylamine, and alpha-conotoxin AuIB (specific blockers or toxin for nicotinic receptors containing alpha3beta4 subunits) elicited a 47-79% reduction in nicotine responses. Nicotine responses were completely blocked by prior sequential microinjections of alpha-BT and mecamylamine into the NTS. Complete blockade of excitatory amino acid receptors (EAARs) in the NTS did not attenuate the responses to nicotine. It was concluded that 1) the predominant type of nicotinic receptor in the NTS contains alpha3beta4 subunits, 2) a smaller proportion contains alpha7 subunits, 3) the presynaptic nicotinic receptors in the NTS do not contribute to nicotine-induced responses, and 4) EAARs in the NTS are not involved in mediating responses to nicotine.

Anesthesia↗
PubMed2000

Influence of ATM function on interactions between telomeres and nuclear matrix.

The ATM (ataxia telangiectasia mutated) gene product has been implicated in mitogenic signal transduction, chromosome condensation, meiotic recombination, and cell cycle control. The human ATM protein shows similarity to several yeast and mammalian proteins involved in meiotic recombination and cell cycle progression. Because of the homology of the human ATM gene to the TEL1 and rad3 genes of yeast, it has been suggested that mutations in ATM could lead to defective telomere maintenance. Recently, we have shown that the ATM gene product, which is defective in the cancer-prone disorder ataxia telangiectasia (AT), influences chromosome end associations and telomere length. A possible hypothesis explaining these results is that the defective telomere metabolism in AT cells is due to altered interactions between the telomeres and the nuclear matrix. These interactions were examined in nuclear matrix halos prior to and after irradiation. A difference was observed in the ratio of soluble and matrix-associated telomeric DNA between cells derived from AT and normal individuals. Treatment with ionizing radiation affected the ratio of soluble and matrix-associated telomeric DNA only in the AT cells. To test the hypothesis that the ATM gene product is involved in interactions between telomeres and the nuclear matrix, such interactions were examined in human cells expressing either a dominant-negative effect or complementation of the ATM gene. The phenotype of RKO colorectal tumor cells expressing ATM fragments containing a leucine zipper motif mimics the altered interactions of telomere and nuclear matrix seen in AT cells. Fibroblasts from AT individuals transfected with a wild-type ATM gene had corrected telomere-nuclear matrix interactions. In experiments designed to determine whether there is a link between the altered telomere-nuclear matrix interactions and defective telomere movement and clustering, a significant difference was observed in the ratio of soluble compared to matrix-associated telomeric DNA sequences in meiocytes of Atm(-/-) and control mice. These results suggest that the ATM gene influences the interactions between telomeres and the nuclear matrix and that alterations in telomere chromatin could be at least partly responsible for the pleiotropic phenotypes of the ATM gene. This paper summarizes our recent publications on the influence of inactivation of ATM on the interaction of telomeres with nuclear matrix in somatic and germ cells.

Animals↗
PubMed2000

Performance status of health care facilities changes with risk adjustment of HbA1c.

OBJECTIVE: To develop a risk adjustment method for HbA1c, based solely on administrative data and to determine the extent to which risk-adjusted HbA1c changes the identification of high- or low-performing medical facilities. RESEARCH DESIGN AND METHODS: Through use of pharmacy records, 204,472 diabetic patients were identified for federal fiscal year 1996 (FY96). Complete information (HbA1c levels, demographic data, inpatient records, outpatient pharmacy utilization records) was available on 38,173 predominantly male patients from 48 Veterans Health Administration (VHA) medical facilities. Hierarchical mixed-effects models were used to estimate risk-adjusted unique facility-level HbA1c. RESULTS: Predicted HbA1c demonstrated expected patterns for major factors known to influence glycemic control. Poorer glycemic control was seen in minorities and patients with greater disease severity, longer duration of disease (using treatment type or presence of amputation as surrogates), and more extensive comorbidity (measured by an adapted Charlson index). Better glycemic control was seen in Caucasians, older diabetic patients, and patients with higher outpatient utilization. The number of performance outliers was reduced as a result of risk adjustment. For mean HbA1c levels, 7 facilities that were initially identified as statistically significant outliers were no longer outliers after risk adjustment. For high-risk HbA1c (>9.5%) rates, 12 facilities that were initially identified as statistically significant outliers were no longer outliers after risk adjustment. CONCLUSIONS: Risk adjustment using only administrative data resulted in substantial changes in identification of high or low performers compared with non-risk-adjusted HbA1c. Although our findings are exploratory, risk adjustment using administrative data may be a necessary and achievable step in quality assessment of diabetes care measured by rates of high-risk HbA1c (>9.5%).

Adult↗
PubMed1999

CHS 828, a novel pyridyl cyanoguanidine with potent antitumor activity in vitro and in vivo.

A new class of recently discovered antineoplastic agents, the pyridyl cyanoguanidines, exert a potent antitumor activity in rodents after oral administration. Optimization in vitro and in vivo has resulted in the selection of the lead candidate CHS 828 (N-(6-chlorophenoxyhexyl)-N'cyano-N"-4-pyridylguanidine). CHS 828 was found to exert potent cytotoxic effects in human breast and lung cancer cell lines, with lesser effects on normal fibroblasts and endothelial cells. In a study using a panel of cell lines with different resistance patterns, the effects of CHS 828 showed a low correlation with the activity patterns of known anticancer agents, and no sensitivity to known mechanisms of multidrug resistance was observed. In nude mice bearing human tumor xenografts, CHS 828, at doses from 20 to 50 mg/kg/day p.o., inhibited the growth of MCF-7 breast cancer tumors and caused regression of NYH small cell lung cancer tumors. Oral administration of CHS 828 once weekly improved efficacy without increasing toxicity. CHS 828 was found to compare favorably with established chemotherapeutic agents such as cyclophosphamide, etoposide, methotrexate, and paclitaxel. In mice with NYH tumors, long-term survival (>6 months) was observed after treatment with CHS 828 was stopped. In conclusion, CHS 828 is an effective new antitumor agent, with a potentially new mechanism of action. CHS 828 is presently being tested in Phase I clinical trials in collaboration with the European Organization for Research and Treatment of Cancer.

Animals↗
PubMed1999

Erythrocyte associated haemato-biochemical changes in Babesia equi infection experimentally produced in donkeys.

Equine babesiosis, caused by Babesia equi and transmitted by ticks is of major economic importance in India. The adverse effects which B. equi organism and its metabolites inflict on red blood cells have not been reported. Erythrocytes were analysed for red cell membrane phospholipids, proteins and haemoglobin (Hb) concentration and plasma for malondialdehyde (MDA) in B. equi carrier donkeys before splenectomy (< 1% parasitaemia) and after splenectomy at 1-5, 5-15, 15-50 and >50% parasitaemia. Before splenectomy the mean values of membrane protein, phospholipids, plasma MDA and Hb were found to be 1.63 +/- 0.12 mg/ml PCV, 2.28 +/- 0.9 mg/ml PCV, 3.63 +/- 0.33 nmoles/ml plasma and 11.52 +/- 0.45 g/dl blood respectively. Erythrocyte membrane protein showed a significant increase at and beyond 5-15% parasitaemia, whereas a significant increase in total phospholipids and MDA level was observed at and beyond 50% parasitaemia. Though, a gradual decrease in Hb value was observed at various stages of parasitaemia and there was a sharp fall when parasitaemia reached more than 50%. Examination of blood smears showed phagocytosis of both healthy and infected erythrocytes.

Animals↗