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Biomedical subjects

Sanjay Sharma

Publications and source records attributed to Sanjay Sharma.

At least 19 recordsLinked to original sources
PubMed2007

Structure-guided optimization of estrogen receptor binding affinity and antagonist potency of pyrazolopyrimidines with basic side chains.

2,3-Diarylpyrazolo[1,5-a]pyrimidines are estrogen receptor (ER) antagonists of modest potency that we have described previously. Guided by the crystal structure of an ER-ligand complex that we have obtained with one of these compounds, we prepared analogs that contain a basic side chain at the 2- or 3-aryl group and quickly found one that, according to the structure-based prediction, shows an increase in binding affinity and antagonist potency and a loss of residual agonist activity.

Cell Line, Tumor↗
PubMed2006

High accumulation of T regulatory cells prevents the activation of immune responses in aged animals.

In our previous in vivo study we demonstrated that young BALB/c mice effectively rejected the BM-185 tumor cells expressing enhanced GFP (EGFP) as a surrogate tumor Ag. In contrast, old BALB/c mice succumbed to the BM-185-EGFP tumors, indicating that there is a deficiency in old animals preventing the rejection of immunogenic tumors. There is cumulative evidence indicating that regulatory T (T(reg)) cells control the activation of primary and memory T cell responses. However, very little is known about whether there is a relation between T(regs) and the lack of immune responses in the aged. We evaluated young and aged animals, and our results demonstrated that there are significantly more CD4+CD25+FoxP3+ and CD8+CD25+FoxP3+ T(regs) in the spleen and lymph nodes of old animals when compared with the young. Depletion of CD25+ cells with anti-CD25 mAb induces the rejection of BM-185-EGFP cells, restores antitumor T cell cytotoxic activity, and results in the generation of a protective memory response against the BM-185 wild-type tumors in old mice. Furthermore, vaccination with CpG-oligodeoxynucleotide decreases the number of T(reg) cells in old animals to the same levels as young mice, restoring the primary and memory antitumor immune responses against BM-185-EGFP tumors. Taken together, these results indicate that there is a direct correlation between the expansion of T(reg) cells and immune deficiency in the old, and that depletion of these cells might be critical for restoring immune responses in aged animals.

Aging↗
PubMed2006

Ubiquitin-proteasome degradation of serum- and glucocorticoid-regulated kinase-1 (SGK-1) is mediated by the chaperone-dependent E3 ligase CHIP.

SGK-1 (serum- and glucocorticoid-regulated kinase-1) is a stress-induced serine/threonine kinase that is phosphorylated and activated downstream of PI3K (phosphoinositide 3-kinase). SGK-1 plays a critical role in insulin signalling, cation transport and cell survival. SGK-1 mRNA expression is transiently induced following cellular stress, and SGK-1 protein levels are tightly regulated by rapid proteasomal degradation. In the present study we report that SGK-1 forms a complex with the stress-associated E3 ligase CHIP [C-terminus of Hsc (heat-shock cognate protein) 70-interacting protein]; CHIP is required for both the ubiquitin modification and rapid proteasomal degradation of SGK-1. We also show that CHIP co-localizes with SGK-1 at or near the endoplasmic reticulum. CHIP-mediated regulation of SGK-1 steady-state levels alters SGK-1 kinase activity. These data suggest a model that integrates CHIP function with regulation of the PI3K/SGK-1 pathway in the stress response.

Animals↗
PubMed2006

Impact of visual impairment on service and device use by individuals with age-related macular degeneration (AMD).

PURPOSE: To assess the patient-reported use of services, supplements, and devices among individuals with age-related macular degeneration (AMD) and evaluate the impact of visual impairment level on this use. METHOD: Data for this study were collected using two instruments, the AMD Health and Impact Questionnaire and the Daily Living Tasks Dependent on Vision questionnaire (DLTV). Both questionnaires were mailed to members of the Macular Degeneration Partnership. The study was approved by an IRB and respondents provided consent before participating. Respondents' visual acuity (VA) was estimated using scores from the DLTV, while use of services and devices was collected from the AMD Questionnaire. De-identified data were analysed in SAS. RESULTS: Of 803 respondents, 56% were male and the mean age was 73 years. Use of services (e.g., counseling, rehabilitation), and devices significantly increased as VA decreased. Using standard US costs, costs for services, supplements, and devices ranged from 506-1619 US dollars depending on VA. CONCLUSION: There are substantial differences in service and device use with increased AMD severity. Delaying progression of AMD could result in considerable cost savings.

Aged↗
PubMed2006

Human Immunodeficiency Virus-Type 1 LTR DNA contains an intrinsic gene producing antisense RNA and protein products.

BACKGROUND: While viruses have long been shown to capitalize on their limited genomic size by utilizing both strands of DNA or complementary DNA/RNA intermediates to code for viral proteins, it has been assumed that human retroviruses have all their major proteins translated only from the plus or sense strand of RNA, despite their requirement for a dsDNA proviral intermediate. Several studies, however, have suggested the presence of antisense transcription for both HIV-1 and HTLV-1. More recently an antisense transcript responsible for the HTLV-1 bZIP factor (HBZ) protein has been described. In this study we investigated the possibility of an antisense gene contained within the human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR). RESULTS: Inspection of published sequences revealed a potential transcription initiator element (INR) situated downstream of, and in reverse orientation to, the usual HIV-1 promoter and transcription start site. This antisense initiator (HIVaINR) suggested the possibility of an antisense gene responsible for RNA and protein production. We show that antisense transcripts are generated, in vitro and in vivo, originating from the TAR DNA of the HIV-1 LTR. To test the possibility that protein(s) could be translated from this novel HIV-1 antisense RNA, recombinant HIV antisense gene-FLAG vectors were designed. Recombinant protein(s) were produced and isolated utilizing carboxy-terminal FLAG epitope (DYKDDDDK) sequences. In addition, affinity-purified antisera to an internal peptide derived from the HIV antisense protein (HAP) sequences identified HAPs from HIV+ human peripheral blood lymphocytes. CONCLUSION: HIV-1 contains an antisense gene in the U3-R regions of the LTR responsible for both an antisense RNA transcript and proteins. This antisense transcript has tremendous potential for intrinsic RNA regulation because of its overlap with the beginning of all HIV-1 sense RNA transcripts by 25 nucleotides. The novel HAPs are encoded in a region of the LTR that has already been shown to be deleted in some HIV-infected long-term survivors and represent new potential targets for vaccine development.

Base Sequence↗
PubMed2006

Unusual positron emission tomography findings in pulmonary amyloidosis: a case report.

Positron emission tomography (PET) has come to play an increasingly important role in the evaluation of pulmonary lesions, which are suspicious of malignancy. As is true for other techniques, PET gives false positive and negative results. We report a case of pulmonary amyloidosis with multiple pulmonary nodules showing different uptake of 18 F-fluorodeoxyglucose (FDG) on PET. There are limitations of specificity of FDG-PET in characterising pulmonary nodules and it is important to confirm a suspected malignancy with histology before potentially curative treatment is undertaken.

Aged, 80 and over↗
PubMed2006

Renal lymphangiomatosis: imaging and management of a rare renal anomaly.

Renal lymphangiomatosis is a rare developmental malformation resulting in the development of cystic masses in the peri-pelvic or peri-renal areas. We report our experience in the management of this rare anomaly. Herein, we also describe the successful laparoscopic ablation of an uncommon subcapsular variant of renal lymphangiomatosis, which failed percutaneous drainage.

Adult↗
PubMed2006

Fibromuscular dysplasia of the renal arteries: a radiological review.

Fibromuscular dysplasia is the most common cause of renovascular hypertension in young patients. Digital subtraction angiography is still the best investigation used to determine the location, extent and complication of renal artery involvement. String of beads appearance (reflecting multiple stenoses), aneurysms, focal or tubular stenosis are classic angiographic appearances. The aim of this pictorial essay is to illustrate the various imaging findings of renal artery fibromuscular dysplasia.

Fibromuscular Dysplasia↗
PubMed2006

Prognostic significance of hemoglobin level in patients with congestive heart failure and normal ejection fraction.

BACKGROUND: Previous studies have shown low hemoglobin (Hb) to have an adverse effect on survival in patients with congestive heart failure (CHF) and reduced left ventricular (LV) ejection fraction (EF); but its effect on survival in patients with CHF and normal EF is not known. HYPOTHESIS: This study sought to determine whether low Hb has an effect on survival in patients with both CHF and normal EF. METHODS: Detailed chart reviews were performed by medical residents on 2,246 patients (48% with normal EF) with a discharge diagnosis of CHF in a large tertiary care hospital from 1990 to 1999. The CHF diagnosis was validated using the Framingham criteria. Mortality data were obtained from the National Death Index. Survival analysis was performed using Kaplan-Meier and Cox regression models. RESULTS: By Kaplan-Meier analysis, low Hb (< 12 gm/dl) compared with normal hemoglobin was associated with a lower 5-year survival in patients with CHF and both normal (38 vs. 50%, p = 0.0008) and reduced (35 vs. 48%, p = 0.0009) EF. Using the Cox regression model, low Hb was an independent predictor of mortality after adjusting for age, gender, renal dysfunction, diabetes mellitus, hypertension, and EF in both groups of patients. CONCLUSION: Low Hb has an independent adverse effect on survival in patients with CHF and both normal and reduced EF in both groups of patients.

Aged↗
PubMed2006

High prevalence of clinically silent severe mitral regurgitation in patients with heart failure: role for echocardiography.

Mitral regurgitation (MR) is common in patients with congestive heart failure (CHF) and has adverse effects on prognosis. In view of the altered hemodynamics in CHF, we examined the accuracy of auscultation for its detection in CHF with reduced systolic function. We examined 370 patients on stable heart failure therapy enrolled in our CHF clinic, if they had a physical examination by one of the two senior cardiologists and an echocardiogram within 2 weeks after the physical examination. The MR murmur was graded 0 to 6 on physical examination. MR was graded 0 to 4 on echocardiography using standard echocardiographic criteria. The left ventricular (LV) ejection fraction was 21 +/- 12% and age was 65 +/- 15 years. By echocardiography MR was present in 345 patients (94%), being 1+ in 162 (44%), 2+ in 80 (22%), 3+ in 54 (15%), and 4+ in 51 (14%). The frequency of an audible MR murmur by physical examination was 4% in 1+ MR, 11% in 2+ MR, 13% in 3+ MR, and 37% in 4+ MR. The audibility of MR murmur was not related to age, sex, body size, LV size, ejection fraction, or left atrial size. In conclusion, grade 3 or 4+ MR is present in one third of patients with CHF and reduced ejection fraction, and is inaudible in three quarters of them by physical examination. Echocardiography is needed for its detection. Audibility of MR murmur cannot be predicted by body size, LV size, or LV function in these patients.

Aged↗
PubMed2006

Evaluation of the clinical age-related maculopathy staging system.

OBJECTIVE: To evaluate a clinical classification system, the Clinical Age-Related Maculopathy Staging (CARMS) system, for age-related maculopathy (ARM) using a simple grading scale designed for clinical practice and clinical research protocols. PARTICIPANTS: Two hundred forty-six male and female participants with various stages of ARM who were enrolled during the first 4 years of a longitudinal study were selected for the evaluation of the CARMS system. DESIGN: Cross-sectional comparison study. METHODS: The CARMS system divides patients into 5 mutually exclusive categories based on slit-lamp assessment of drusen, retinal pigment epithelial irregularities, geographic atrophy, retinal pigment epithelial detachment, and choroidal neovascularization. Fundus photographs and clinical data of the subjects were used to evaluate this scale. Clinical grades assigned for 492 eyes of 246 patients with varying stages of ARM were compared with grades obtained from photographs evaluated by a reading center. To compare grades obtained from an inexperienced grader with those of an experienced grader, observations based on photographs from 50 randomly selected patients were reviewed. To quantify intraobserver agreement for photographic grades, observations from one observer were compared with those made at a later date by the same observer. MAIN OUTCOME MEASURES: Reliability and validity of the CARMS system in grading various stages of ARM based on clinical examination and photography. RESULTS: The degree of overall agreement between the clinically assigned grade and photographic assessment for 492 eyes was substantial (exact overall agreement, 75%; unweighted kappa, 0.63; weighted kappa, 0.78). For advanced age-related macular degeneration, the sensitivity was 0.83, and specificity was 0.97. When assessing photographic grades, the degree of agreement between an inexperienced and an experienced grader was very high (unweighted kappa, 0.79; weighted kappa, 0.86), and the degree of intraobserver agreement was excellent (unweighted kappa, 0.92; weighted kappa, 0.97). CONCLUSIONS: The CARMS system, a 5-level clinical scale, is a valid and reliable staging system that can be used in both clinical practice and in clinical research protocols involving patients with all stages of ARM.

Aged↗
PubMed2006

Management of multiple intrahepatic recurrences after radiofrequency ablation of hepatocellular carcinoma with rhenium-188-HDD-lipiodol.

We tried to evaluate the role of dosimetry-guided transarterial radionuclide therapy (TART) with rhenium-188 (Re-188)-4-hexadecyl 1-2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol (HDD)-lipiodol in a patient with multiple intrahepatic recurrences after radiofrequency ablation of hepatocellular carcinoma (HCC). The dosimetry helped in delivering the maximum possible activity of Re-188, thus the radiation-absorbed dose, safely to the tumour without jeopardizing other organs. There was no procedure-related complication and the patient tolerated therapy well with no adverse effects. The lesions were completely ablated with a single dose of Re-188 and the patient has been disease free for the past 18 months. TART with Re-188-HDD-lipiodol appears to be a promising therapeutic option in patients with HCC who experience recurrence after percutaneous ablative therapy.

Adult↗
PubMed2006

The effect of imatinib mesylate (Glivec) on human tumor-derived cells.

Imatinib mesylate is a specific inhibitor of the Bcr-Abl protein tyrosine kinase that competes with ATP for its specific binding site in the kinase domain. It has activity against platelet-derived growth factor receptor alpha and beta (PDGFR-alpha and -beta), and c-kit, the receptor for stem cell factor. We have used a standardized ATP-tumor chemosensitivity assay and immunohistochemistry to determine the cytotoxicity of imatinib mesylate in tumor-derived cells from cutaneous and uveal melanoma, and ovarian carcinoma. Imatinib mesylate was tested at concentrations ranging from 2.0 to 0.0625 micromol/l alone and in combination with a cytotoxic drug (cisplatin, doxorubicin, paclitaxel or treosulfan). Imatinib mesylate showed low inhibition (IndexSUM>300) across the range of concentrations tested in this study, with few tumors exhibiting increasing inhibition with increased drug concentration. The median IC90 values for cutaneous and uveal melanoma and ovarian carcinoma were 13.2 micromol/l (4.0-294.3 micromol/l), 12.0 micromol/l (2.0-285.4 micromol/l) and 7.71 micromol/l (6.51-11.02 micromol/l), respectively. Imatinib mesylate potentiated the effect of different cytotoxics in 9% (5/54) of cases and had a negative effect in 13% (7/54) of cases, with no effect in the remainder. No correlation of effect was noted with c-kit, platelet-derived growth factor receptor-alpha or platelet-derived growth factor receptor-beta expression, assessed by immunohistochemistry. The signaling pathways mediated by activation of c-kit or platelet-derived growth factor receptor may act as antiapoptotic survival signals in some cancers and inhibition of these pathways may potentiate the activity of some cytotoxic drugs by inhibiting the survival signal. Growth inhibition, however, may reduce the efficacy of cytotoxic drugs, which tend to target proliferating cells preferentially, and clinical effects are therefore difficult to predict.

Adult↗
PubMed2006

Retinal nerve fiber layer analysis in the diagnosis of glaucoma.

PURPOSE OF REVIEW: The detection of optic disc and retinal nerve fiber layer damage and change is the cornerstone of glaucoma management. Assessment of the retinal nerve fiber layer for localized and diffuse damage has been traditionally based on clinical examination, with documentation of change primarily qualitative. With the latest improvements in optical imaging instruments, objective and quantitative measurements of the retinal nerve fiber layer are now possible. This review summarizes the results from recent cross-sectional studies evaluating the discriminating ability of automated retinal nerve fiber layer measurements to detect glaucoma, and from longitudinal studies assessing the ability to predict and monitor glaucomatous changes. RECENT FINDINGS: Numerous cross-sectional studies have documented good diagnostic accuracy of a scanning laser polarimeter (GDx VCC), the optical coherence tomograph (Stratus), and the Heidelberg Retina Tomograph retinal nerve fiber layer measurements for differentiating between healthy and glaucoma eyes. There are only limited data available on the ability of these retinal nerve fiber layer measurements to document change over time. SUMMARY: It is essential that the clinician understand the specific strengths and weaknesses of each technique so that only good quality retinal nerve fiber layer information will be used in conjunction with careful clinical examination and visual function testing for glaucoma management decisions. Longitudinal studies are needed to evaluate the ability of these instruments to document retinal nerve fiber layer change over time.

Diagnostic Imaging↗
PubMed2006

Pain and suffering disability index.

PURPOSE OF REVIEW: This report summarizes the increasing financial resources required to deal with personal injury tort cases and medical malpractice. The largest single component in personal injury torts is noneconomic damages, which encompasses 'pain and suffering' and punitive damage, the latter of which comprises only a small percentage. Overall, noneconomic damages account for 24% of the greater than US$250 billion spent annually on personal injury torts. RECENT FINDINGS: A pain and suffering disability index has been developed that quantifies the loss of life's value attributable to personal injury. Based upon time-tradeoff utility analysis, the value loss is predicated upon the values of people who have experienced the same degree of disability or injury as the plaintiff, only outside the courtroom environs. It is believed that the pain and suffering disability index will readily identify frivolous, personal injury torts, decrease the number of frivolous, personal injury torts, markedly decrease the variance of noneconomic tort settlements, facilitate the earlier settlement of personal injury tort cases, and decrease the proportion of personal injury tort cases progressing to jury trial. SUMMARY: The pain and suffering disability index is a novel instrument that quantifies the 'pain and suffering' associated with a personal injury tort according to the values of patients who have experienced a similar injury outside the courtroom environs.

Disability Evaluation↗