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Biomedical subjects

S R Patel

Publications and source records attributed to S R Patel.

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

Focal angiogen therapy using intramyocardial delivery of an adenovirus vector coding for vascular endothelial growth factor 121.

BACKGROUND: Adenovirus (Ad) vector-mediated gene therapy strategies have emerged as promising modalities for the "biological revascularization" of tissues. We hypothesized that direct intramyocardial, as opposed to intracoronary, administration of an Ad vector coding for the vascular endothelial growth factor 121 cDNA (Ad(GV)VEGF121.10) would provide highly focal Ad genome levels, and increases in VEGF, ideal for inducing localized therapeutic angiogenesis. METHODS: Persistence and regional distribution of the vector were assessed by TaqMan real-time quantitative polymerase chain reaction technology and enzyme-linked immunosorbent assay, after intramyocardial Ad(GV)VEGF121.10 in the rat, and either intramyocardial or intracoronary (circumflex territory) vector in Yorkshire swine. Based on these results, we assessed the focal nature of the improved cardiac blood flow in a previously reported porcine myocardial ischemia model. RESULTS: Intramyocardial delivery of Ad(GV)VEGF121.10 in the rat resulted in local persistence of the Ad genome that decreased 1,000-fold over 3 weeks, with peak myocardial VEGF expression 24 to 72 h after vector delivery. After intramyocardial Ad(GV)VEGF121.10 in the circumflex distribution of pigs, Ad vector genome and VEGF protein levels were more than 1,000-fold and more than 90-fold higher, respectively, in this distribution than in other myocardial regions. In comparison, intracoronary injection yielded maximum myocardial Ad genome and VEGF levels 33-fold and 9-fold lower, respectively, than that after intramyocardial delivery. Angiograms obtained 28 days after intramyocardial Ad(GV)VEGF121.10 demonstrated rapid circumflex reconstitution via collaterals localized to the region of vector administration. CONCLUSIONS: These studies demonstrate that direct intramyocardial administration of Ad(GV)VEGF121.10 results in focal genome and VEGF levels, including focal angiogenesis, sufficient to normalize blood flow to the ischemic myocardium, findings that are relevant to designing human trials of gene therapy-mediated cardiac angiogenesis.

Adenoviridae↗
PubMed2000

Management of peritoneal and hepatic metastases from gastrointestinal stromal tumors.

The management of peritoneal and hepatic metastases from gastrointestinal stromal tumors is a challenging clinical problem. Currently available systemic therapeutic agents have very limited activity in this particular disease. Patients with disease confined to a single organ/region are therefore managed either by surgery or regional therapy e.g. intraperitoneal therapy or hepatic arterial chemoembolization, whereas those with multiple sites of involvement should be enrolled on experimental trials of new agents.

Clinical Trials as Topic↗
PubMed2000

Role of Sertoli cells in injury-associated testicular germ cell apoptosis.

This review examines experimental models of Sertoli cell injury resulting in germ cell apoptosis. Since germ cells exist in an environment created by Sertoli cells, paracrine signaling between these intimately associated cells must regulate the process of germ cell death. Germ cell apoptosis may be signaled by a decrease in Sertoli cell pro-survival factors, an increase in Sertoli cell pro-apoptotic factors, or both. The different models of Sertoli cell injury indicate that spermatogenesis is susceptible to disruption, and that targeting critical Sertoli cell functions can lead to rapid and massive germ cell death.

Androgens↗
PubMed2000

Reporting and concordance of methodologic criteria between abstracts and articles in diagnostic test studies.

OBJECTIVE: To evaluate the quality and concordance of methodologic criteria in abstracts versus articles regarding the diagnosis of trichomoniasis. STUDY DESIGN: Survey of published literature. DATA SOURCES: Studies indexed in MEDLINE (1976-1998). STUDY SELECTION: Studies that used culture as the gold or reference standard. DATA EXTRACTION: Data from abstract and articles were independently abstracted using 4 methodologic criteria: (1) prospective evaluation of consecutive patients; (2) test results did not influence the decision to do gold standard; (3) independent and blind comparison with gold standard; and (4) broad spectrum of patients used. The total number of criteria met for each report was calculated to create a quality score (0-4). MEASUREMENTS AND MAIN RESULTS: None of the 33 abstracts or full articles reported all 4 criteria. Three criteria were reported in none of the abstracts and in 18% of articles (95% confidence interval [95% CI] 8.6% to 34%). Two criteria were reported in 18% of abstracts (95% CI, 8.6% to 34%) and 42% of articles (95% CI, 27% to 59%). One criterion was reported in 42% of abstracts (95% CI, 27% to 59%) and 27% of articles (95% CI, 15% to 44%). No criteria were reported in 13 (39%) of 33 abstracts (95% CI, 25% to 56%) and 4 (12%) of 33 articles (95% CI, 4.8% to 27%). The agreement of the criteria between the abstract and the article was poor (kappa -0.09; 95% CI, -0.18 to 0) to moderate (kappa 0.53; 95% CI, 0.22 to 0.83). CONCLUSIONS: Information on methods basic to study validity is often absent from both abstract and paper. The concordance of such criteria between the abstract and article needs to improve.

Clinical Laboratory Techniques↗
PubMed2000

Bradycardia is associated with development of coronary collateral vessels in humans.

BACKGROUND: The development of mature coronary collateral vessels in patients with obstructive coronary artery disease (CAD) decreases the ischemic myocardial burden. Chronic bradycardia has been shown to stimulate formation of collateral vessels in experimental models. OBJECTIVE: To test our hypothesis that CAD patients with bradycardia would have better developed collateral circulation than would members of a control group. DESIGN: A retrospective study examining the relationship between bradycardia and the development of coronary collateral vessels in patients with obstructive CAD. METHODS: Admission electrocardiograms and rhythm tracings obtained during angiography of all patients presenting to the cardiac catheterization laboratory were screened from January to October 1997. Angiograms for patients with heart rates < or = 50 beats/min were reviewed. An equivalent number of consecutive patients with heart rates > or = 60 beats/min served as controls. Patients with acute myocardial infarction, with rhythms other than sinus, and without high grade obstructive CAD (< 70% stenosis) were excluded from the study. RESULTS: The study population consisted of 61 patients, 30 having heart rates < or = 50 beats/min (group A), and 31 controls with heart rates > or = 60 beats/min (group B). A significantly greater proportion of patients in group A than of matched controls was demonstrated to have developed collaterals (97 versus 55% in group B, P < 0.005). The mean collateral grades were 1.66 and 0.95 for subjects in groups A and B, respectively (P < 0.001). CAD patients with bradycardia are more likely (odds ratio 24, 95% confidence interval 5-146) to have angiographic coronary collaterals than are those with higher heart rates. CONCLUSION: Results of this study demonstrate that there is an association between bradycardia and growth of collateral vessels in patients with obstructive CAD. Bradycardic agents may be useful for promoting development of coronary collaterals in patients with atherosclerotic disease.

Aged↗
PubMed2000

Systematic review of diagnostic tests for vaginal trichomoniasis.

OBJECTIVE: To review critically and to summarize the evidence of diagnostic tests and culture media for the diagnosis of Trichomonas vaginitis. METHODS: We performed a systematic review of literature indexed in MEDLINE of studies that used Trichomonas culture as the reference standard (9,882 patients, 35 studies). Level I studies (5,047 patients, 13 studies) fulfilled at least two of three criteria: 1) consecutive patients were evaluated prospectively, 2) decision to culture was not influenced by test results, and 3) there was independent and blind comparison to culture. RESULTS: The sensitivity of the polymerase chain reaction technique (PCR) was 95% (95% CI 91% to 99%), and the specificity was 98% (95% CI 96% to 100%). One study was classified as Level I evidence (52 patients). The sensitivity of the enzyme-linked immunosorbent assay was 82% (95% CI 74% to 90%), and the specificity was 73% (95% CI 35% to 100%). The sensitivity of the direct fluorescence antibody was 85% (95% CI 79% to 90%), and the specificity was 99% (95% CI 98% to 100%). Sensitivities of culture media were 95% for Diamond's, 96% for Hollander, and 95% for CPLM. CONCLUSIONS: The sensitivity and specificity of tests to diagnose trichomoniasis vary widely.

Animals↗
PubMed2000

Multiple cadherin superfamily members with unique expression profiles are produced in rat testis.

Adhesion between germ and Sertoli cells is thought to be crucial for spermatogenesis. Cadherin superfamily proteins, including classic cadherins and protocadherins, are important mediators of cell-cell adhesion. Using a degenerate PCR cloning strategy, we surveyed the expression of cadherin superfamily members in rat testis. Similar to brain, testis expressed a large number of cadherin superfamily members: 7 classic cadherins of both types I and II, 14 protocadherins, 2 protocadherin-related cadherins, and 1 cadherin-related receptorlike protein. All three protocadherin families (alpha, beta, and gamma) were found in testis. Using a semiquantitative RT-PCR assay, messenger RNA expression was determined for each cadherin superfamily member during a postnatal developmental time-course and following ablation of specific testis cell types by ethanedimethanesulfonate, methoxyacetic acid, and 2,5-hexanedione. Diverse expression patterns were observed among the cadherins, suggesting that cadherin expression is cell type-specific in testis. The large number and variety of cadherin superfamily members found in testis supports a critical function for cadherin-mediated cell-cell adhesion in spermatogenesis.

Aging↗
PubMed2000

New agents in the treatment of soft-tissue sarcomas.

The list of agents with significant activity in soft-tissue sarcomas is very short and arguably, only includes doxorubicin and ifosfamide. Several other agents such as dacarbazine, cisplatin and etoposide, to name but a few, have marginal activity and are sometimes used in combination regimes. The need for the identification of new agents with activity against this disease is therefore paramount. Soft-tissue sarcomas are very rare and diverse and as a result, new drug trials are few and far fetched. The conventionally conducted Phase II trials, which include all histologies of soft-tissue sarcomas, run the risk of an inadequate assessment of the new drug in individual subsets, which may have variable biological behaviours. On the other hand, histology-specific Phase II trials are fraught with the problems of length due to the infrequent nature of the disease and the considerable running costs. The end result is that in this era of cost-containment, soft-tissue sarcomas are not high on the priority list of many funding agencies, thus explaining the lack of any significant progress over the past two decades. Efforts at optimising the dose intensity and schedule of administration of doxorubicin and ifosfamide, have resulted in superior activity when combined and improvement in the survival of patients with high-risk localised disease. However, efforts at identifying new agents with adequate activity have not had much success. Patients, physicians and pharmaceutical industries must be encouraged to participate in multidisciplinary clinical trials in order to improve cure rates for patients with advanced disease.

Angiogenesis Inhibitors↗
PubMed1999

Angiogenesis gene therapy: phase I assessment of direct intramyocardial administration of an adenovirus vector expressing VEGF121 cDNA to individuals with clinically significant severe coronary artery disease.

BACKGROUND: Therapeutic angiogenesis, a new experimental strategy for the treatment of vascular insufficiency, uses the administration of mediators known to induce vascular development in embryogenesis to induce neovascularization of ischemic adult tissues. This report summarizes a phase I clinical experience with a gene-therapy strategy that used an E1(-)E3(-) adenovirus (Ad) gene-transfer vector expressing human vascular endothelial growth factor (VEGF) 121 cDNA (Ad(GV)VEGF121.10) to induce therapeutic angiogenesis in the myocardium of individuals with clinically significant coronary artery disease. METHODS AND RESULTS: Ad(GV)VEGF121.10 was administered to 21 individuals by direct myocardial injection into an area of reversible ischemia either as an adjunct to conventional coronary artery bypass grafting (group A, n=15) or as sole therapy via a minithoracotomy (group B, n=6). There was no evidence of systemic or cardiac-related adverse events related to vector administration. In both groups, coronary angiography and stress sestamibi scan assessment of wall motion 30 days after therapy suggested improvement in the area of vector administration. All patients reported improvement in angina class after therapy. In group B, in which gene transfer was the only therapy, treadmill exercise assessment suggested improvement in most individuals. CONCLUSIONS: The data are consistent with the concept that direct myocardial administration of Ad(GV)VEGF121.10 to individuals with clinically significant coronary artery disease appears to be well tolerated, and initiation of phase II evaluation of this therapy is warranted.

Adenoviridae↗
PubMed1999

Safety of direct myocardial administration of an adenovirus vector encoding vascular endothelial growth factor 121.

A gene therapy strategy involving direct myocardial administration of an adenovirus (Ad) vector encoding the vascular endothelial growth factor 121 cDNA (Ad(GV)VEGF121.10) has been shown to be capable of "biological revascularization" of ischemic myocardium in an established porcine model [Mack, C.A. (1998). J. Thorac. Cardiovasc. Surg. 115, 168-177]. The present study evaluates the local and systemic safety of this therapy in this porcine ischemia model and in normal mice. Myocardial ischemia was induced in Yorkshire swine with an ameroid constrictor 21 days prior to vector administration. Ad(GV)VEGF121.10 (10(9) or 10(10) PFU), Ad5 wild type (10(9) PFU), AdNull (control vector with no transgene; 10(9) PFU), saline, or no injection (naive) was administered in 10 sites in the ischemic, circumflex distribution of the myocardium. Toxicity was assessed by survival, serial echocardiography, blood analyses, and myocardial and liver histology at 3 and 28 days after vector administration. All pigs survived to sacrifice, except for one animal in the Ad(GV)VEGF121.10 (10(10) PFU) group, which died as a result of oversedation. Echocardiograms of Ad(GV)VEGF121.10-treated pigs demonstrated no differences in pericardial effusion, mitral valve regurgitation, or regional wall motion compared with control pigs. Intramyocardial administration of Ad(GV)VEGF121.10 included only minimal myocardial inflammation and necrosis, and no hepatic inflammation or necrosis. Only a mild elevation of the white blood cell count was encountered on day 3, which was transient and self-limited in the Ad(GV)VEGF121.10 group as compared with the saline-treated animals. As a measure of inadvertent intravascular administration of vector, normal C57/BL6 mice received intravenous Ad(GV)VEGF121.10 (10(4), 10(6), 5 x 10(7), or 10(9) PFU), AdNull (5 x 10(7) or 10(9) PFU), or saline. Toxicity was assessed by survival, blood analyses, and organ histology at 3 and 7 days after vector administration. A separate group of C57/BL6 mice received intravenous AdmVEGF164 (Ad vector encoding the murine VEGF164 cDNA), Ad(GV)VEGF121.10, AdNull (10(8) PFU each group), or saline to assess duration of expression and safety of a homologous transgene. All mice survived to sacrifice except for 40% of the mice in the highest (10(9) PFU; a dose more than 10(3)-fold higher by body weight than the efficacious dose in pigs) Ad(GV)VEGF121.10 dose group, which died on days 5-6 after vector administration. The only differences seen in the blood analyses between treated and control mice were in the very high Ad(GV)VEGF121.10 dose group (10(9) PFU), which demonstrated an anemia as well as an increase in alkaline phosphatase when compared with all other treatment groups. Hepatic VEGF levels by ELISA in AdmVEGF164-treated mice did not persist beyond 14 days after vector administration, suggesting that persistent expression of a homologous VEGF gene transferred with an Ad vector is not a significant safety risk. Although this is not a chronic toxicity study, these data demonstrate the safety of direct myocardial administration of Ad(GV)VEGF121.10, and support the potential use of this strategy to treat human myocardial ischemia.

Adenoviruses, Human↗
PubMed1999

Waiting for microbiologic data to direct therapy against nosocomial infections in febrile surgical patients: are outcomes worsened?

HYPOTHESIS: Allowing adequate time for laboratory and culture results before initial treatment may be associated with a worse outcome in nosocomial infections. DESIGN: Cohort study of all episodes of nosocomial infection from December 10, 1996, to October 28, 1998. SETTING: Surgical services at a university hospital. PATIENTS AND METHODS: In surgical patients presenting with fever, 372 episodes of nosocomial infection were evaluated. Nosocomial infections were divided by time from fever to intervention (< or =12, 13-24, and >24 hours). These groups were subdivided by Acute Physiology and Chronic Health Evaluation II (APACHE II) scores into low (< or =10 [n = 114]), moderate (11-20 [n = 169]), and high severity of illness (>20 [n = 89]). Pneumonia and bloodstream infections were divided by APACHE II scores into low (< or =15 [n = 55 and n = 56, respectively]) or high severity of illness (>15 [n = 84 and n = 77, respectively]). MAIN OUTCOME MEASURES: Mortality, length of stay. RESULTS: No difference in outcome was seen between different time intervals from fever to intervention for nosocomial infections in patients with APACHE II scores of no more than 10. Patients treated more than 24 hours after fever were significantly younger than those treated at no more than 12 and 13 to 24 hours with APACHE II scores of 11 to 20 (P<.05) and more than 20 (P<.05). Mortality and length of stay for patients treated at later time intervals were comparable with those of patients treated earlier with similar APACHE II scores. There was no difference in outcome for patients with pneumonia or bloodstream infection. CONCLUSIONS: Episodes of infection in which treatment was withheld until initial microbiologic data were available (24 hours) did not have worse outcomes compared with those treated earlier. Waiting for laboratory and culture results to direct antibiotic therapy for nosocomial infections does not appear harmful and may be potentially beneficial.

APACHE↗
PubMed1999

Exogenous control of cardiac gene therapy: evidence of regulated myocardial transgene expression after adenovirus and adeno-associated virus transfer of expression cassettes containing corticosteroid response element promoters.

OBJECTIVE: Because of the relative inaccessibility of the heart for repeated gene therapy, it would be useful to regulate the expression of transgenes delivered in a single dose of a gene therapy vector. Incorporation into the vector of a regulatable promoter that is responsive to pharmacologic agents that are widely used and well tolerated in clinical practice represents such a control strategy. METHODS: A replication-deficient adenovirus or an adeno-associated virus containing a chimeric promoter composed of 5 glucocorticoid response elements and the murine thrombopoietin complementary DNA (AdGRE.mTPO or AAVGRE.mTPO) was administered to the hearts of Sprague-Dawley rats. Platelet levels were evaluated as a reporter of transgene activity with or without dexamethasone. For comparison, rats received a control adenovirus vector, AdCMV.mTPO or AdCMV.Null, and the control adeno-associated virus vector AAVCMV.luc, which encodes for the firefly luciferase (luc) gene. RESULTS: Platelet elevation in the AdGRE.mTPO group peaked 4 days after dexamethasone administration, with a return to baseline 1 week after the initial corticosteroid dose. Subsequent dexamethasone administration at 2 and 4 weeks resulted in similar but progressively decreased responses. The AAVGRE.mTPO group had 5 peak platelet levels to a minimum of 2.2-fold with respect to baseline without diminution with subsequent dexamethasone administrations out to 169 days. In contrast, the AdCMV.Null and AAVCMV.luc groups demonstrated no increase in platelet counts and the AdCMV.mTPO group demonstrated a slow rise to a single peak platelet count independent of dexamethasone administration. CONCLUSION: It may be possible to control on demand the expression of a gene transferred to the heart. This strategy should be useful in cardiac gene therapy.

Animals↗
PubMed1999

Six-month assessment of a phase I trial of angiogenic gene therapy for the treatment of coronary artery disease using direct intramyocardial administration of an adenovirus vector expressing the VEGF121 cDNA.

OBJECTIVE: To summarize the 6-month follow-up of a cohort of patients with clinically significant coronary artery disease who received direct myocardial injection of an E1-E3- adenovirus (Ad) gene transfer vector (Ad(GV)VEGF121.10) expressing the human vascular endothelial growth factor (VEGF) 121 cDNA to induce therapeutic angiogenesis. BACKGROUND: Therapeutic angiogenesis describes a novel approach to the treatment of vascular occlusive disease that uses the administration of growth factors known to induce neovascularization of ischemic tissues. METHODS: Direct myocardial injection of Ad(GV)VEGF121.10 into an area of reversible ischemia was carried out in 21 patients as an adjunct to conventional coronary artery bypass grafting (group A, n = 15) or as sole therapy using a minithoracotomy (group B, n = 6). RESULTS: No evidence of systemic or cardiac-related adverse events related to vector administration was observed up to 6 months after therapy. Trends toward improvement in angina class and exercise treadmill testing at 6-month follow-up in the sole therapy group suggest the effects of this therapy are persistent for > or =6 months. CONCLUSIONS: This study suggests that direct myocardial administration of Ad(GV)VEGF121.10 appears to be well tolerated in patients with clinically significant coronary artery disease. Initiation of phase II evaluation of this therapy appears warranted.

Adenoviridae↗
PubMed1999

Phytochrome D acts in the shade-avoidance syndrome in Arabidopsis by controlling elongation growth and flowering time.

Shade avoidance in higher plants is regulated by the action of multiple phytochrome (phy) species that detect changes in the red/far-red ratio (R/FR) of incident light and initiate a redirection of growth and an acceleration of flowering. The phyB mutant of Arabidopsis is constitutively elongated and early flowering and displays attenuated responses to both reduced R/FR and end-of-day far-red light, conditions that induce strong shade-avoidance reactions in wild-type plants. This indicates that phyB plays an important role in the control of shade avoidance. In Arabidopsis phyB and phyD are the products of a recently duplicated gene and share approximately 80% identity. We investigated the role played by phyD in shade avoidance by analyzing the responses of phyD-deficient mutants. Compared with the monogenic phyB mutant, the phyB-phyD double mutant flowers early and has a smaller leaf area, phenotypes that are characteristic of shade avoidance. Furthermore, compared with the monogenic phyB mutant, the phyB-phyD double mutant shows a more attenuated response to a reduced R/FR for these responses. Compared with the phyA-phyB double mutant, the phyA-phyB-phyD triple mutant has elongated petioles and displays an enhanced elongation of internodes in response to end-of-day far-red light. These characteristics indicate that phyD acts in the shade-avoidance syndrome by controlling flowering time and leaf area and that phyC and/or phyE also play a role.

Arabidopsis↗
PubMed1999

Therapeutic angiogenesis: protein and gene therapy delivery strategies.

Angioplasty and surgical bypass, the primary interventional therapies for the treatment of atherosclerosis, are limited by the development over time of native vessel restenoses and graft occlusions. Furthermore, these therapies are not options for a significant number of individuals in whom the extent of vascular pathology is especially severe or widespread. Angiogenesis, the growth of new vasculature, is a critical biological response to ischemia that provides collateralization, or 'biological revascularization' of vascular obstructions. Therapeutic angiogenesis is a strategy whereby one of several known 'angiogens', mediators that induce angiogenesis, can be administered to augment the native angiogenic processes and enhance the formation of collateral vasculature. This report describes the techniques available for providing therapeutic angiogenesis, including acute and sustained-release techniques to deliver protein angiogens and a number of gene therapy strategies to deliver genes coding for the angiogens.

Arteriosclerosis↗
PubMed1999

Long-term outcome of patients with American Joint Committee on Cancer stage IIB extremity soft tissue sarcomas.

PURPOSE: It has been suggested that patients with small (< 5 cm), high-grade extremity soft tissue sarcomas (STS) have an excellent overall prognosis and, consequently, may not require adjuvant therapies. PATIENTS AND METHODS: A comprehensive review of all patients with extremity STS treated at a tertiary care cancer hospital over a 9-year period (January 1984 to December 1992) was performed. Prognostic factors, treatment data, and long-term outcome were evaluated in the subset of 111 patients with American Joint Committee on Cancer stage IIB (G3/4, T1a/b) disease. RESULTS: The median tumor size was 3.0 cm (range, 0.6 to 4.9 cm), and 55 tumors (50%) were deep in location. All patients underwent surgical resection; 68 (61%) received pre- or postoperative radiotherapy, and 32 (29%) received doxorubicin-based chemotherapy. The median follow-up was 76 months. Forty patients (36%) experienced 59 recurrences. First recurrences occurred at local, regional, and distant sites in 21, five, and 14 patients, respectively. The 5-year actuarial local recurrence-free, distant recurrence-free, disease-free, and overall survival rates were 82%, 83%, 68%, and 83%, respectively. The presence of a microscopically positive surgical margin was an independent adverse prognostic factor for both local recurrence (relative risk [RR] = 3.75; 95% confidence interval [CI], 1.25 to 11.25; P =.02) and disease-free survival (RR = 2.57; 95% CI, 1.33 to 4.98; P =.005). CONCLUSION: Event-free outcome for this subset of patients with high-grade STS does not seem as favorable as previously reported by other investigators. Patients who undergo maximal surgical resection with microscopically positive margins represent a subset of T1 STS patients who warrant consideration for adjuvant therapies.

Adolescent↗