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Biomedical subjects

Sanjay Sharma

Publications and source records attributed to Sanjay Sharma.

At least 55 records · Page 3Linked to original sources
PubMed2005

The burden of age-related macular degeneration: a value-based medicine analysis.

PURPOSE: To assess the quality-of-life loss and the macroeconomic financial consequences associated with age-related macular degeneration (ARMD). METHODS: Time tradeoff utility analysis was performed to assess the quality-of-life diminution caused by ARMD (both dry and neovascular) in cohorts consisting of (1) patients with ARMD, (2) ophthalmologists asked to assume they had various degrees of severity of ARMD, (3) healthcare providers asked to assume they had various degrees of severity of ARMD, and (4) participants from the general community asked to assume they had various degrees of severity of ARMD. ARMD was classified according to vision in the better-seeing eye as (1) mild: 20/20 to 20/40, (2) moderate: 20/50 to 20/100, (3) severe: < or = 20/200, or (4) very severe: < or = 20/800. RESULTS: Mild ARMD caused a 17% decrement in the quality of life of the average patient, similar to that encountered with moderate cardiac angina or symptomatic human immunodeficiency virus syndrome. Moderate ARMD caused a 32% decrease in the average patient's quality of life, similar to that associated with severe cardiac angina or a fractured hip. Severe ARMD caused a 53% decrease in quality, more than that of dialysis, and very severe ARMD caused a 60% decrease in the average ARMD patient's quality of life, similar to that encountered with end-stage prostate cancer or a catastrophic stroke that leaves a person bedridden, incontinent, and requiring constant nursing care. Patients with varying degrees of severity of ARMD were found to have quality-of-life impairment ranging from 96% to 750% greater than that estimated by treating ophthalmologists for the same condition. An economic analysis based upon losses to the gross domestic product suggests that ARMD has approximately a $30 billion annual negative impact. The return on investment is therefore potentially high for both treatment with current ARMD therapies and the research costs invested in the development of new ARMD treatment modalities. CONCLUSIONS: ARMD is a major public health problem that has a devastating effect upon patients and marked adverse financial consequences for the economy.

Adult↗
PubMed2004

The in vitro effect of gefitinib ('Iressa') alone and in combination with cytotoxic chemotherapy on human solid tumours.

BACKGROUND: Activation of the epidermal growth factor receptor (EGFR) triggers downstream signaling pathways that regulate many cellular processes involved in tumour survival and growth. Gefitinib ('Iressa') is an orally active tyrosine kinase inhibitor (TKI) targeted to the ATP-binding domain of EGFR (HER1; erbB1). METHODS: In this study we have used a standardised ATP-based tumour chemosensitivity assay (ATP-TCA) to measure the activity of gefitinib alone or in combination with different cytotoxic drugs (cisplatin, gemcitabine, oxaliplatin and treosulfan) against a variety of solid tumours (n = 86), including breast, colorectal, oesophageal and ovarian cancer, carcinoma of unknown primary site, cutaneous and uveal melanoma, non-small cell lung cancer (NSCLC) and sarcoma. The IC50 and IC90 were calculated for each single agent or combination. To allow comparison between samples the IndexSUM was calculated based on the percentage tumour growth inhibition (TGI) at each test drug concentration (TDC). Gefitinib was tested at concentrations ranging from 0.0625-2 microM (TDC = 0.446 microg/ml). This study represents the first use of a TKI in the assay. RESULTS: There was heterogeneity in the degree of TGI observed when tumours were tested against single agent gefitinib. 7% (6/86) of tumours exhibited considerable inhibition, but most showed a more modest response resulting in a low TGI. The median IC50 value for single agent gefitinib in all tumours tested was 3.98 microM. Interestingly, gefitinib had both positive and negative effects when used in combination with different cytotoxics. In 59% (45/76) of tumours tested, the addition of gefitinib appeared to potentiate the effect of the cytotoxic agent or combination (of these, 11% (5/45) had a >50% decrease in their IndexSUM). In 38% of tumours (29/76), the TGI was decreased when the combination of gefitinib + cytotoxic was used in comparison to the cytotoxic alone. In the remaining 3% (2/76) there was no change observed. CONCLUSION: The in vitro model suggests that gefitinib may have differential effects in response to concomitant cytotoxic chemotherapy with the agents tested during this study. The mechanism involved may relate to the effect of TKIs on growth rate versus their effect on the ability of the cell to survive the stimulus to apoptosis produced by chemotherapy.

Adenocarcinoma↗
PubMed2004

Pars plana vitrectomy with internal limiting membranectomy for refractory diabetic macular edema without a taut posterior hyaloid.

BACKGROUND: This is a retrospective study designed to investigate the effect of pars plana vitrectomy (PPV) with internal limiting membrane (ILM) peeling on diabetic macular edema in eyes that do not have a taut hyaloid and have been refractory to standard laser treatment. METHODS: Review of 26 eyes of 20 patients consecutively were treated with PPV with ILM peel for refractory diabetic macular edema. Eyes were included if they had been unresponsive to conventional treatment defined as at least two focal laser applications by a retina specialist. Paired t-testing was performed to determine if a change in both optical coherence tomography (OCT)-measured retinal thickness and logarithm of the minimum angle of resolution (logMAR) visual acuity occurred prior to and following PPV with epiretinal membrane vitrectomy. In addition, we performed multivariate regression analysis to determine if any clinical variables predicted a change in visual acuity. RESULTS: The mean age in the sample was 65 years (range 29-81 years). The mean follow-up time was 242 days (range 35-939). Sixteen of the 26 eyes were phakic and the remaining ten were pseudophakic. There was a statistically significant improvement of mean visual acuity from a preoperative logMAR vision of 1.0 to a best postoperative vision of 0.75 (p=0.016, paired t-test). Thirteen (50%) of the 26 eyes gained at least two lines of best-corrected Snellen acuity, three (11.5%) had a decline of at least two lines, and ten (38.5%) showed stable visual acuity. Regression analysis demonstrated that baseline worse visual acuity was the only clinical variable that was associated with improvement in visual acuity (beta=0.602, p=0.016; R (2)=28.7). Fourteen eyes had preoperative and postoperative OCT. Thirteen eyes (93%) had a significant decrease in foveal thickness; with an average preoperative thickness of 575 mum compared to a postoperative average of 311 mum (t=3.65, p=0.002). No surgical complications were observed during the follow-up period. CONCLUSIONS: Surgery for refractory diabetic edema without a taut hyaloid is associated with a significant improvement in visual acuity and diminution of retinal thickness as measured by OCT. Further investigations are warranted to define the role of surgery in the management of persistent diabetic macular edema.

Adult↗
PubMed2004

A genomewide scan for early-onset coronary artery disease in 438 families: the GENECARD Study.

A family history of coronary artery disease (CAD), especially when the disease occurs at a young age, is a potent risk factor for CAD. DNA collection in families in which two or more siblings are affected at an early age allows identification of genetic factors for CAD by linkage analysis. We performed a genomewide scan in 1,168 individuals from 438 families, including 493 affected sibling pairs with documented onset of CAD before 51 years of age in men and before 56 years of age in women. We prospectively defined three phenotypic subsets of families: (1) acute coronary syndrome in two or more siblings; (2) absence of type 2 diabetes in all affected siblings; and (3) atherogenic dyslipidemia in any one sibling. Genotypes were analyzed for 395 microsatellite markers. Regions were defined as providing evidence for linkage if they provided parametric two-point LOD scores >1.5, together with nonparametric multipoint LOD scores >1.0. Regions on chromosomes 3q13 (multipoint LOD = 3.3; empirical P value <.001) and 5q31 (multipoint LOD = 1.4; empirical P value <.081) met these criteria in the entire data set, and regions on chromosomes 1q25, 3q13, 7p14, and 19p13 met these criteria in one or more of the subsets. Two regions, 3q13 and 1q25, met the criteria for genomewide significance. We have identified a region on chromosome 3q13 that is linked to early-onset CAD, as well as additional regions of interest that will require further analysis. These data provide initial areas of the human genome where further investigation may reveal susceptibility genes for early-onset CAD.

Adult↗
PubMed2004

Thrombotic microangiopathy associated with combined sirolimus and tacrolimus immunosuppression after intestinal transplantation.

Calcineurin inhibitor-induced thrombotic microangiopathy (TMA) has been described in up to 14% of solid-organ transplant recipients. Sirolimus has recently been described in two reports in association with TMA. Sirolimus is known to potentiate cyclosporine-induced nephrotoxicity, but such effect has not been shown with tacrolimus. We report two intestinal transplant patients who developed TMA while on a tacrolimus and sirolimus immunosuppressive regimen. This syndrome appeared soon after institution of or increase in sirolimus dosage and improved only after this medication was discontinued.

Adult↗
PubMed2004

Photodynamic therapy with verteporfin for subfoveal choroidal neovascularization in age-related macular degeneration: results of an effectiveness study.

OBJECTIVE: To determine the postapproval effectiveness of photodynamic therapy (PDT) with verteporfin for the treatment of predominantly classic subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration. METHODS: Forty-five consecutive patients treated with PDT for subfoveal CNV were compared with an untreated historical control group. Control patients had subfoveal CNV and were first seen by us within 1 year before Health Canada's approval of verteporfin. Both groups were followed up for the development of significant visual loss, stability, or improvement. Multivariate models were constructed to evaluate the effectiveness of PDT, controlling for multiple covariates (age, sex, baseline visual acuity, follow-up time, lesion size, and number of treatments). RESULTS: Significant differences were noted in the change in visual acuity between those who did and did not receive PDT (chi(2) = 5.9, P =.048). Patients who received PDT were 2.9 times (95% confidence interval, 0.9-9.1) less likely to develop a moderate (>2 lines) visual loss (chi(2) = 3.2, P =.07). Controlling for covariates, patients who received PDT were 13.7 times (95% confidence interval, 1.4-132.6) more likely to develop a visual improvement of at least 1 line. CONCLUSION: Compared with historical controls, PDT was demonstrated to be effective for the treatment of predominantly classic subfoveal CNV.

Adult↗
PubMed2004

Unrecognized left ventricular thrombus during reoperative coronary artery bypass grafting.

Left ventricular thrombus after myocardial infarction is relatively common but rarely threatening enough to warrant surgical removal at the time of coronary revascularization. The rare cases of ventricular thrombectomy described in the literature involve a pedunculated thrombus. We describe an urgent coronary revascularization procedure in a patient who had unrecognized left ventricular thrombus. The large clot was detected by transesophageal echocardiography after decannulation in a hemodynamically unstable patient. The thrombus was removed after placing the patient back on cardiopulmonary bypass emergently. He recovered and was discharged with no neurologic sequelae. Aggressive removal of clot using cardiopulmonary bypass is warranted even for the critically ill patient.

Aged↗
PubMed2004

Aberrant expression, processing and degradation of dystroglycan in squamous cell carcinomas.

The alpha- and beta- dystroglycan (DG) proteins are involved in epithelial cell development, formation of the basement membrane and maintenance of tissue integrity. Recently, specific changes in the expression patterns of DGs have been described in some cancers. We studied the expression and localisation of alpha- and beta-DG using Western blotting, immunohistochemistry and reverse transcriptase-polymerase chain reaction analyses in samples of normal oral mucosa, oral squamous cell carcinoma (SCC) and cancer cell lines. The alpha- and beta-DG were localised in the basal layers of normal oral mucosa.However, beta-DG expression in cancer tissues showed evidence of aberrant expression, processing and degradation. alpha-DG was altered in all oral cancer samples and cell lines, despite the persistent presence of DG mRNA in cancer cells. Using matrix metalloproteinase (MMP) inhibitors, we determined that beta-DG degradation in carcinoma cell lines can be mediated by MMPs but this process is highly variable, even in cells from the same cancer type. Considering the multifaceted role of DG in epithelial development, it appears that the role of DG degradation in cancer growth and spread, although currently poorly understood, may be important.

Animals↗
PubMed2004

Ex vivo characterization of XR11576 (MLN576) against ovarian cancer and other solid tumors.

XR11576 (MLN576) is a novel monophenazine with a mechanism of action that includes interaction with both topoisomerase (Topo) I and II. The aim of this study was to evaluate its cytotoxicity against fresh tumor cells taken from patients with a variety of solid tumors. Cells were obtained from 89 patients and exposed for 6 days to XR11576 alone, or in combination with doxorubicin, cisplatin, treosulfan, paclitaxel or vinorelbine. Cell survival was measured using the ATP-Tumor Chemosensitivity Assay (ATP-TCA). Immunohistochemical staining of Topo I, Topo IIalpha and MDR1 was performed on paraffin-embedded blocks in those tumors for which tissue was available (n = 49). Overall, the median IC90 and IC50 values of XR11576 in tumor-derived cells were 242 and 110 nM, respectively. In all samples XR11576 was more potent than the other cytotoxics tested. Breast and gynecological malignancies were most sensitive to XR11576, while the potency of this compound was slightly attenuated in gastrointestinal tumors, in which the median IC90 and IC50 values were 308 and 212 nM, respectively. Cases of synergism were identified when combining XR11576 with vinorelbine (nine of 30 samples) and doxorubicin (12 of 38 samples), while the addition of paclitaxel resulted in an antagonistic effect (CI50>1.2) in 38 of 42 tumors. A very modest correlation by linear regression analysis was found between the intensity of MDR1 staining and the IC50 of XR11576 (r = 0.311, p = 0.0312), but not with the IC90 (r = 0.247, NS). These data support the rapid introduction of XR11576 to clinical trials and suggest that it may be effective against a broad spectrum of tumor types.

Adult↗
PubMed2004

Ex vivo reversal of chemoresistance by tariquidar (XR9576).

The expression of P-glycoprotein (P-gp) has been demonstrated to confer resistance to several anticancer drugs, including anthracyclines, taxanes and vinca alkaloids. Tariquidar is a novel inhibitor of P-gp that has been shown to reverse resistance to cytotoxic drugs in tumor cell lines and mouse xenografts. We have used an ATP-based chemosensitivity assay (ATP-TCA) to compare the activity of cytotoxic drugs in combination with tariquidar against a variety of solid tumors (n = 37). The expression of P-gp was determined in a subset of solid tumor samples by immunohistochemistry (n = 16). Resistance was seen in 20 of 37 (54%) tumors tested with doxorubicin, in 27 of 34 (79%) samples tested with paclitaxel and 17 of 31 (55%) with vinorelbine. Tariquidar alone showed no activity over a wide range of concentrations up to 2 microM (n = 14). The median IC90s for doxorubicin, paclitaxel and vinorelbine, alone were 2.57, 27.4 and 15.5 microM. These decreased to 1.67 (p<0.0005), 20.6 (p<0.05) and 9.5 microM (p<0.001), respectively, in combination with tariquidar. Tariquidar also significantly decreased resistance in 14 of 20 (70%), six of 27 (22%) and six of 17 (35%) samples tested with doxorubicin, paclitaxel and vinorelbine, respectively. Immunohistochemical staining for P-gp was positive in nine of 16 (56%) samples and in all of these cases addition of tariquidar improved the activity of the cytotoxic. The results show that tariquidar is able to decrease resistance in a number of solid tumors resistant to cytotoxic drugs known to be P-gp substrates. These data support the introduction of tariquidar in combination with chemotherapy to clinical trials of patients expressing P-gp.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Visual outcomes and complications after multiple vitrectomies for diabetic vitreous hemorrhage.

PURPOSE: To determine the visual outcomes and complications after multiple vitrectomies for repeat diabetic vitreous hemorrhage. METHODS: A retrospective review during a 4-year period of patients requiring multiple vitrectomies for nonclearing vitreous hemorrhages with at least a 6-month follow-up. RESULTS: Of the 38 cases of multiple vitrectomies for diabetic vitreous hemorrhage, the initial visual acuity was 20/50 or better in 5%, between 20/60 and 20/400 in 37%, and worse than 20/400 in 58%. The final visual acuity after the last vitrectomy was 20/50 or better in 25%, between 20/60 and 20/400 in 47%, and worse than 20/400 in 28%. Patients had a mean improvement of 1.08 lines of visual acuity, and a statistically significant difference in logMAR visual acuity was noted when the last corrected visual acuity was compared with baseline acuity by way of paired t-testing. Although a trend toward visual improvement was noted in patients who underwent multiple vitrectomies, multivariate models failed to detect any association between number of surgeries or demographic variables and change in visual acuity. CONCLUSION: Multiple vitrectomies for recurrent diabetic vitreous hemorrhage can have a favorable anatomic outcome while maintaining ambulatory vision.

Diabetic Retinopathy↗