Biomedical subjects
Publications and source records attributed to S Dhar.
We report a case of fibrolamellar carcinoma presenting in a 26-year old female. The patient had gross ascites at presentation. Imaging studies (ultrasonography and computed tomography) strongly suggested extensive intraperitoneal drop metastases.
We evaluated the contribution of alcohol abuse to liver failure among patients undergoing liver transplantation by reviewing their records for alcohol consumption, hepatitis serology, and outcome. Anti-HCV was present in the serum of 42 patients (39%), while 35 had consumed more than 80 g/day of alcohol for at least 10 years, allowing patients to be divided into four groups: group I, hepatitis C alone (N = 31); group II, alcoholic liver disease alone (N = 24); group III, both hepatitis C and alcoholism (N = 11); and group IV, liver failure due to other causes (N = 41). Patients were followed for a mean of 29 months after transplantation (range 0-66). Twenty-eight (26%) died during follow up, while 11 (10%) required retransplantation. There were no other significant differences in patient or graft survival among patients in the four groups. Patients with both alcoholism and chronic hepatitis C comprise a large proportion of those undergoing liver transplantation and appear to do as well as those with other causes of liver failure, at least in the short term.
Radiotherapy plays a key role in the treatment of many tumors. It is difficult to determine what fraction of tumor cells survives after treatment with ionizing radiation. A convenient and sensitive biochemical assay could be efficacious in determining the potential success of radiotherapy. Since telomerase activity is frequently associated with the malignant phenotype, we sought to determine whether a correlation existed between ionizing radiation-induced cell killing and telomerase activity. We evaluated telomerase activity in two telomerase-positive and one telomerase-negative human cell line exposed to ionizing radiation. Telomerase activity was determined using a PCR-based telomeric repeat amplification protocol coupled with ELISA. We found ionizing radiation treatment to decrease the telomerase activity (in plateau phase cells of RKO, HeLa; and growing cells of RKO) in a dose-dependent manner, which correlated with cell death in in vitro tests as well as during tumor regression in nude mice. In contrast, growing HeLa cells after 24 h postradiation treatment showed an increase in telomerase activity, but there was no increase in the levels of mRNA of hTERT. To assess the sensitivity of the telomerase activity assay, we performed mixing experiments of HeLa and AG1522 cell extracts. These studies showed that telomerase activity could be detected in lysate equal to a single HeLa cell when mixed with 10,000 AG1522 cells. Our results indicate that even a few surviving neoplastic cells can be detected by telomerase activity assay. Therefore, detection of telomerase activity may be a useful monitor of radiotherapeutic efficacy and an early predictor of outcome.
High-resolution measurements of distortion product otoacoustic emissions (DPOAEs) from three different experimental paradigms are shown to be in agreement with the implications of a realistic "two-source" cochlear model of DPOAE fine structure. The measurements of DPOAE amplitude and phase imply an interference phenomenon involving one source in the region of strong nonlinear interaction of the primary waves (the strong "overlap" or generation region), and the other source region around the DPOAE tonotopic place. The component from the DPOAE place can be larger than the one from the generator region. These findings are supported by the analysis of the onset and offset of the DPOAE when the higher-frequency primary is pulsed on and off. The two-source hypothesis was further tested by adding a third tone closer in frequency to the DPOAE which modifies the amplitude of the component from the DPOAE place and leaves the one from the generator region unchanged. The results agree well with the model prediction that the variation with frequency, and implied latency, of the phase of the DPOAE tonotopic-place component are greater than the corresponding quantities for the component from the generation region.
Cells derived from ataxia telangiectasia (A-T) patients show a prominent defect at chromosome ends in the form of chromosome end-to-end associations, also known as telomeric associations, seen at G(1), G(2), and metaphase. Recently, we have shown that the ATM gene product, which is defective in the cancer-prone disorder A-T, influences chromosome end associations and telomere length. A possible hypothesis explaining these results is that the defective telomere metabolism in A-T cells are due to altered interactions between the telomeres and the nuclear matrix. We examined these interactions in nuclear matrix halos before and after radiation treatment. A difference was observed in the ratio of soluble versus matrix-associated telomeric DNA between cells derived from A-T and normal individuals. Ionizing radiation treatment affected the ratio of soluble versus matrix-associated telomeric DNA only in the A-T cells. To test the hypothesis that the ATM gene product is involved in interactions between telomeres and the nuclear matrix, we examined such interactions 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 similar to that of A-T cells. A-T fibroblasts transfected with wild-type ATM gene had corrected telomere-nuclear matrix interactions. Further, we found that A-T cells had different micrococcal nuclease digestion patterns compared to normal cells before and after irradiation, indicating differences in nucleosomal periodicity in telomeres. These results suggest that the ATM gene influences the interactions between telomeres and the nuclear matrix, and alterations in telomere chromatin could be at least partly responsible for the pleiotropic phenotypes of the ATM gene.
BACKGROUND: Stable and refractory vitiligo may be unresponsive to medical therapy. Melanocyte transplantation by punch grafting (PG) can restore the normal pigmentation. OBJECTIVE: To evaluate the efficacy of PG on repigmentation of vitiligo patches. METHODS: Autologous miniature PG was undertaken in 1,000 patients with stable and recalcitrant vitiligo. Test grafting (TG) was done in all the patients. Those who showed negative TG results were excluded from the study. RESULTS: Of the 1,000 patients, 880 (88%) showed positive TG results. In 656 (74.55%) patients, 90-100% repigmentation was achieved. In 93 (10.57%) patients, there was no spread of pigment, while in 21 (2.39%) patients depigmentation of the graft(s) was notices. Of various complications, polka dot appearance (43.98%) and colour mismatch (34.32%) were most frequent. CONCLUSION: Partial to near-total repigmentation of a vitiligo patch can be achieved by PG.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
This study compared the speech recognition performance of 12 hearing-impaired listeners fit with three commercially available behind-the-ear hearing aids in both directional and omnidirectional modes. One digitally programmable analog and two "true digital" hearing aids were selected as test instruments. Testing was completed in both "living room" and anechoic room environments. Speech recognition was examined using modified forms of the Hearing in Noise Test and the Nonsense Syllable Test. The single competing stimuli of these tests were replaced with five uncorrelated competing sources. Results revealed a significant speech recognition in noise advantage for all directional hearing aids in comparison to their omnidirectional counterparts. Maximum performance of the directional hearing aids did not significantly vary across circuit type, suggesting that processing differences did not affect maximum directional hearing aid performance. In addition, the results suggest that performance in one reverberant environment cannot be used to accurately predict performance in an environment with differing reverberation.
Drug activity patterns in 10 human tumor cell lines representing defined mechanisms of drug resistance, including cell lines with high expression of P-glycoprotein and multidrug resistance associated protein (MRP), have previously been used for prediction of mechanism of drug action. In the present study, this cell line panel was analyzed for cellular accumulation of the fluorescent probe calcein/AM [4'5'-bis(N,N-bis (carboxymethyl) aminomethyl) fluorescein acetoxymethyl ester] and compared with drug response patterns of 20 standard chemotherapeutic drugs. According to degree of correlation with the ability to exclude calcein/AM, topoisomerase II inhibitors and tubulin actives were at the top of the list although the correlations were of lower magnitude than those obtained from the drug response patterns of mechanistically similar drugs. There was a significant relationship between the rank-order of drugs based on correlation with calcein/AM accumulation and Pgp/MRP mediated drug resistance suggesting that compounds being substrates for these pumps were identified. In simulated drug response profiles, the impact of Pgp and MRP expressing cell lines on the mechanistic prediction was found to be marginal. The results indicate that the differential molecular function/expression in the cell line panel may identify drugs interacting with specific biochemical pathways. Furthermore, the presence of cell lines overexpressing drug efflux mechanisms in the panel do not significantly influence the mechanistic predictions.
m-L-sarcolysin (m-L-SL) is an isomer of melphalan (Mel) with the di(2-chloroethyl) amino group being substituted in the meta position of phenylalanine. By covalent conjugation of amino acids to m-L-SL, a peptide complex consisting of six m-L-SL-based oligopeptides known as peptichemio (PTC) was developed previously. In the present study, the cytotoxic activity pattern of the different oligopeptides of PTC was investigated in ten human tumour cell lines representing different mechanisms of cytotoxic drug resistance using the fluorometric microculture cytotoxicity assay (FMCA). In the cell line panel, L-prolyl-m-L-sarcolysyl-L-p-fluorophenylalanine (P2) was the most active oligopeptide, showing slightly lower mean IC50 values (2.6 vs 3.9 and 4.1 microg ml(-1)) than Mel and m-L-SL. The other five oligopeptides were less active than Mel. All active oligopeptides showed mechanistic similarity to Mel as judged by the correlation analysis of the cell line panel log IC50 values (R > or = 0.90), although P2 appeared to be less sensitive to GSH-mediated drug resistance. The relative activity of Mel and P2 was found to be related to degree of proliferation, P2 being more active towards low-proliferating cell lines. P2 and Mel were then further characterized in 49 fresh human tumour samples. In these samples P2 was considerably more active than Mel and showed a higher relative solid tumour activity (2.7 to 4.5-fold). However, the correlation of log IC50s between P2 and Mel in patient cells was high (R = 0.79), indicating a similar mechanism of action in this tumour model too. Cross-resistance with other standard drugs was lower for P2 than Mel. The results show that P2 is the most potent component of PTC and demonstrates a favourable activity profile compared with Mel. These data suggest that further investigation of P2 as a potential anti-tumour agent is warranted.
The optimal intensity relation between the two primaries used to generate Distortion Product Otoacoustic Emissions (DPOAEs) in unimpaired human ears, over a clinically relevant intensity range, was evaluated using a commercially available clinical device. The ILO92 was used to determine the level of the DPOAE at 2f1-f2 for 16 combinations of primary levels in the range of 40 to 80 dB SPL from 40 unimpaired, young adult ears. Data were collected between 1 and 6 kHz at 1, 1.5, 2, 3, 4, 5, and 6 kHz. The commonly used procedure of dropping data points less than 3 dB above the noise floor was compared to a power subtraction procedure. A multivariate ANOVA was performed to determine main effects of gender, ear, stimulus levels, frequencies, and interactions between stimulus levels and frequencies. An overall increase of DPOAE amplitude with increase in primary level was observed, along with a decrease of the optimal difference in primary levels as L2 was increased. Although the power subtraction and 3-dB drop paradigms yielded similar results at high stimulus levels, the power subtraction paradigm provided a more realistic indicator of DPOAE level when low level primaries were used. Possible mechanisms responsible for the level dependence of the optimal relationship between primaries and implications for clinical choice of primary levels are discussed.
Explore the source record for details and available documents.