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Biomedical subjects

J Daley

Publications and source records attributed to J Daley.

At least 55 records · Page 3Linked to original sources
PubMed1998

Vaccination with irradiated autologous melanoma cells engineered to secrete human granulocyte-macrophage colony-stimulating factor generates potent antitumor immunity in patients with metastatic melanoma.

We conducted a Phase I clinical trial investigating the biologic activity of vaccination with irradiated autologous melanoma cells engineered to secrete human granulocyte-macrophage colony-stimulating factor in patients with metastatic melanoma. Immunization sites were intensely infiltrated with T lymphocytes, dendritic cells, macrophages, and eosinophils in all 21 evaluable patients. Although metastatic lesions resected before vaccination were minimally infiltrated with cells of the immune system in all patients, metastatic lesions resected after vaccination were densely infiltrated with T lymphocytes and plasma cells and showed extensive tumor destruction (at least 80%), fibrosis, and edema in 11 of 16 patients examined. Antimelanoma cytotoxic T cell and antibody responses were associated with tumor destruction. These results demonstrate that vaccination with irradiated autologous melanoma cells engineered to secrete granulocyte-macrophage colony-stimulating factor stimulates potent antitumor immunity in humans with metastatic melanoma.

Cancer Vaccines↗
PubMed1998

Structure of the Drosophila projectin protein: isoforms and implication for projectin filament assembly.

The protein composition of the various muscle types in Drosophila melanogaster has been studied quite thoroughly and the analysis has revealed many differences involving the usage of muscle specific isoforms of a given protein, as well as the presence of proteins restricted to one muscle type. Drosophila projectin, the giant protein component of the third filament is quite unusual as it not only shows specific isoforms in various muscle types, but these isoforms are located at different sarcomeric locations, I band in the IFM and A band in synchronous muscles. This may suggest distinct functions for the projectin protein in various muscles, as well as a different set of protein interactions for each projectin isoform. Projectin is encoded by a single gene and the isoforms were proposed to be the result of alternative splicing of a primary transcript. Here, we report the nearly complete sequence of Drosophila projectin, as well as the possible splicing patterns used to generate different isoforms. The overall domain organization in projectin is composed of repeated motifs I and II in a few specific patterns, similar to its Caenorhabditis homolog, twitchin. Sequence similarity between twitchin and projectin further suggests how some domains may possibly be important for protein interactions and/or functions. Alternative splicing operates at the COOH terminus, leading to a shorter projectin protein lacking some of the terminal motifs II and unique sequence. These isoforms are discussed in view of projectin differential size and localization.

Alternative Splicing↗
PubMed1998

Participation of the CD94 receptor complex in costimulation of human natural killer cells.

Optimal proliferation and expansion of human NK cells require mitogenic cytokines together with cell contact-dependent co-stimulation. Production of mAb that can modulate human NK cell proliferation yielded NKH3, which recognizes the CD94 Ag. NKH3 immunoprecipitates contain approximately 70-kDa heterodimeric complexes consisting of a approximately 25-kDa glycoprotein and approximately 40- to 45-kDa molecules. Analysis by two-dimensional isoelectric focusing/SDS-PAGE suggests that several different 40- to 45-kDa species are present in the CD94 receptor complex in human NK cells. NKH3 reacted with essentially all resting NK cells, although CD94 is expressed at higher levels on the CD56(bright) (i.e., high level of CD56) CD16(dim/neg) (i.e., low level of or absent CD16) subpopulation than on the more abundant CD56(dim)CD16(bright) NK cell subset. Moreover, the Z199 mAb, which appears to recognize NKG2-A species that can form heterodimers with CD94, stained virtually all CD56(bright) NK cells, but only a subset of CD56(dim) NK cells. Ligation of CD94 augmented the proliferation of CD56(bright) NK cells in response to IL-2 or IL-15 by as much as 10-fold. Secretion of IFN-gamma by CD56(bright) NK cells stimulated with IL-2 or IL-15 was also enhanced up to 10-fold after CD94 ligation. CD94 mAb did not consistently costimulate proliferation of or IFN-gamma production by CD56(dim) NK cells cultured with IL-2 or IL-15. In contrast, irradiated K562 cells costimulated proliferation of both CD56(bright) and CD56(dim) NK cells. These results indicate that CD56(bright) and CD56(dim) NK cells can be costimulated through different receptors, which may allow these distinct NK cell subsets to be independently regulated in vivo.

Animals↗
PubMed1998

Independent association between acute renal failure and mortality following cardiac surgery.

PURPOSE: To determine whether there is an independent association of acute renal failure requiring dialysis with operative mortality after cardiac surgery. PATIENTS AND METHODS: The 42,773 patients who underwent coronary artery bypass or valvular heart surgery at 43 Department of Veterans Affairs Medical Centers between 1987 and 1994 were evaluated to determine the association between acute renal failure sufficient to require dialysis and operative mortality, with and without adjustment for comorbidity and postoperative complications. Crude and adjusted odds ratios (OR) and 95% confidence intervals (95% CI) were derived from logistic regression analysis. RESULTS: Acute renal failure occurred in 460 (1.1%) patients. Overall operative mortality was 63.7% in these patients, compared with 4.3% in patients without this complication. The unadjusted OR for death was 39 (95% CI 32 to 48). After adjustment for comorbid factors related to the development of acute renal failure (surgery type, baseline renal function, preoperative intraaortic balloon pump, prior heart surgery, NYHA class IV status, peripheral vascular disease, pulmonary rales, left ventricular ejection fraction below 35%, chronic obstructive pulmonary disease, systolic blood pressure, and the cross-product of systolic blood pressure and surgery type), the OR was 27 (95% CI 22 to 34). Further adjustment was made for seven postoperative complications (low cardiac output, cardiac arrest, perioperative myocardial infarction, prolonged mechanical ventilation, reoperation for bleeding or repeat cardiopulmonary bypass, stroke or coma, and mediastinitis), that were independently associated with operative mortality. The OR adjusted for comorbidity and postoperative complications associated with acute renal failure was 7.9 (95% CI 6 to 10). CONCLUSIONS: Acute renal failure was independently associated with early mortality following cardiac surgery, even after adjustment for comorbidity and postoperative complications. Interventions to prevent or improve treatment of this condition are urgently needed.

Acute Kidney Injury↗
PubMed1998

Growing use of laparoscopic cholecystectomy in the national Veterans Affairs Surgical Risk Study: effects on volume, patient selection, and selected outcomes.

OBJECTIVE: To study the introduction of laparoscopic cholecystectomy to the 43 tertiary-care university-affiliated Veterans Administration medical centers (VAMCs) participating in the National Veterans Affairs Surgical Risk Study from October 1991 through December 1993. SUMMARY BACKGROUND DATA: Previous studies in the private sector have documented growth in the number of cholecystectomies and falling clinical thresholds for cholecystectomy with the introduction of laparoscopic cholecystectomy. METHODS: The following were analyzed for changes over time: measures of patient preoperative risk, complexity of surgery, severity of biliary disease, numbers of procedures, postoperative length of stay, and 30-day postoperative mortality and general complication rates. RESULTS: The number of cholecystectomies performed laparoscopically increased, but the total number of cholecystectomies performed remained stable over time. The proportion of patients with acute cholecystitis, emergent cholecystectomies, and technically complex cholecystectomies did not change or increased slightly over time. Adjusted odds for postoperative general complications were lower for laparoscopic than for open cholecystectomy, but 30-day postoperative mortality and general complication rates for all cholecystectomies remained constant over time. Postoperative length of stay for all cholecystectomies fell significantly. Implementation rates of laparoscopic cholecystectomy varied widely between hospitals. Laparoscopic cholecystectomy was adopted more slowly and used in a lower percentage of cholecystectomies than in non-VA settings. CONCLUSIONS: In contrast to non-VA studies showing increases in overall cholecystectomy volume since the introduction of laparoscopic cholecystectomy, these VAMCs implemented laparoscopic cholecystectomy without growth in cholecystectomies or a change in the clinical threshold for cholecystectomy. Laparoscopic cholecystectomy was associated with better outcomes, but its introduction in the setting of stable cholecystectomy volume and biliary disease case mix did not change postoperative mortality and complication rates. The stable cholecystectomy volume and biliary disease case mix, slower adoption, and lower use of laparoscopic cholecystectomy contrast with previous reports and may result from differences in patients and organization and financing of VA versus non-VA settings.

Aged↗
PubMed1998

Outcome after proctectomy for rectal cancer in Department of Veterans Affairs Hospitals: a report from the National Surgical Quality Improvement Program.

OBJECTIVE: To define risk factors that predict adverse outcomes after proctectomy for cancer in Department of Veterans Affairs Medical Centers. SUMMARY BACKGROUND DATA: Accurate presurgical assessment of the risk of perioperative complications and death is important in planning surgical therapy. METHODS: The National VA Surgical Quality Improvement Program contains prospectively collected and extensively validated data on >287,000 patients. All patients undergoing proctectomy for rectal cancer from 1991 to 1995 who were registered in this data base were selected for study. Independent variables examined included 68 presurgical and 12 intraoperative clinical risk factors; dependent variables were 21 specific adverse outcomes. Stepwise logistic regression analysis was used to construct models predicting 30-day morbidity rates for each of the 10 most common complications and the 30-day mortality rate. RESULTS: Five hundred ninety-one patients were identified; 467 (79%) underwent abdominoperineal resection and 124 (21%) were treated with sphincter-saving procedures. Thirty percent of patients had one or more complications after proctectomy. Prolonged ileus, urinary tract infection, pneumonia, and deep wound infection were the most frequently reported complications. The 30-day mortality rate was 3.2% (19 deaths). For most complications, 30-day mortality rates were significantly higher for patients with complications than for those without. Thirty-day mortality rates for several complications exceeded 50%: cardiac arrest requiring cardiopulmonary resuscitation, deep venous thrombosis or thrombophlebitis, coma lasting >24 hours, acute renal failure, cerebrovascular accident, and pulmonary embolism. Four presurgical factors predicted a high risk of 30-day mortality in the logistic regression analysis: elevated blood urea nitrogen level, impaired sensorium, low serum albumin concentration, and partial thromboplastin time < or =25 seconds. CONCLUSIONS: Mortality rates after proctectomy in VA hospitals are comparable to those reported in other large series. Most postsurgical complications are associated with an increased 30-day mortality rate. Elevated presurgical blood urea nitrogen level, impaired sensorium, low serum albumin concentration, and partial thromboplastin time < or =25 seconds predict a high risk of 30-day mortality.

Adult↗
PubMed1998

The Department of Veterans Affairs' NSQIP: the first national, validated, outcome-based, risk-adjusted, and peer-controlled program for the measurement and enhancement of the quality of surgical care. National VA Surgical Quality Improvement Program.

OBJECTIVE: To provide reliable risk-adjusted morbidity and mortality rates after major surgery to the 123 Veterans Affairs Medical Centers (VAMCs) performing major surgery, and to use risk-adjusted outcomes in the monitoring and improvement of the quality of surgical care to all veterans. SUMMARY BACKGROUND DATA: Outcome-based comparative measures of the quality of surgical care among surgical services and surgical subspecialties have been elusive. METHODS: This study included prospective assessment of presurgical risk factors, process of care during surgery, and outcomes 30 days after surgery on veterans undergoing major surgery in 123 medical centers; development of multivariable risk-adjustment models; identification of high and low outlier facilities by observed-to-expected outcome ratios; and generation of annual reports of comparative outcomes to all surgical services in the Veterans Health Administration (VHA). RESULTS: The National VA Surgical Quality Improvement Program (NSQIP) data base includes 417,944 major surgical procedures performed between October 1, 1991, and September 30, 1997. In FY97, 11 VAMCs were low outliers for risk-adjusted observed-to-expected mortality ratios; 13 VAMCs were high outliers for risk-adjusted observed-to-expected mortality ratios. Identification of high and low outliers by unadjusted mortality rates would have ascribed an outlier status incorrectly to 25 of 39 hospitals, an error rate of 64%. Since 1994, the 30-day mortality and morbidity rates for major surgery have fallen 9% and 30%, respectively. CONCLUSIONS: Reliable, valid information on patient presurgical risk factors, process of care during surgery, and 30-day morbidity and mortality rates is available for all major surgical procedures in the 123 VAMCs performing surgery in the VHA. With this information, the VHA has established the first prospective outcome-based program for comparative assessment and enhancement of the quality of surgical care among multiple institutions for several surgical subspecialties. Key features to the success of the NSQIP are the support of the surgeons who practice in the VHA, consistent clinical definitions and data collection by dedicated nurses, a uniform nationwide informatics system, and the support of VHA administration and managerial staff.

Hospitals, Veterans↗
PubMed1998

A possible mechanism for alteration of human erectile function by digoxin: inhibition of corpus cavernosum sodium/potassium adenosine triphosphatase activity.

PURPOSE: Digoxin use has long been recognized to affect adversely male sexual function but the underlying mechanism is poorly understood. Digoxin is a known inhibitor of sodium/potassium adenosine triphosphatase (sodium pump), a plasma membrane enzyme that has a role in the regulation of smooth muscle tone. We investigated the effects of digoxin on human corpus cavernosum smooth muscle contractility and overall erectile function. MATERIALS AND METHODS: In human corporeal smooth muscle strips the in vitro effects of digoxin were assessed on sodium pump activity as measured by digoxin inhibitable uptake of 86rubidium, basal tone and endothelium dependent, neurogenic and nitric oxide donor induced relaxation. An in vivo prospective double-blind, placebo controlled, crossover, 4-period investigation was performed in 6 healthy male volunteers. The effects of digoxin on serum hormones, erectile function questionnaire, visual sexual stimulation and nocturnal penile tumescence were recorded. RESULTS: In vitro digoxin caused concentration dependent inhibition of 86rubidium uptake (half maximum effect at 0.01 microM.) and contraction of corporeal smooth muscle (half maximum effect at 0.8 microM.). Therapeutic concentrations of digoxin (2 nM.) also inhibited relaxation induced by acetylcholine and electrical field stimulation, which release nitric oxide from corpus cavernosum endothelial cells and nonadrenergic noncholinergic nerves, respectively. In vivo digoxin diminished penile rigidity during visual sexual stimulation and nocturnal penile tumescence testing compared to placebo without influencing libido or serum testosterone, estrogen or luteinizing hormone levels. CONCLUSIONS: Digoxin associated alteration of human erectile function may be explained, in part, by inhibition of corporeal smooth muscle sodium pump activity, which promotes contraction and impedes nitric oxide induced relaxation. Such findings suggest therapeutic use of digoxin for treatment of recurrent priapism states.

Adenosine Triphosphate↗
PubMed1998

Availability of cardiac technology: trends in procedure use and outcomes for patients with acute myocardial infarction.

This study examines temporal trends in the use and outcomes of cardiac procedures for patients hospitalized with acute myocardial infarction in Department of Veterans Affairs (VA) hospitals with and without invasive cardiac services. Between 1988 and 1994, there was striking overall growth in the use of cardiac procedures in the VA. Over this time period, the authors found persistent variation in the use of cardiac procedures but diminished differences in patient survival among patients admitted to different types of hospitals. Growth of cardiac procedure use and improvements in patient survival were most significant in hospitals without on-site invasive cardiac services. We were unable to determine whether survival gains were associated with increased procedure use or unmeasured improvements in the process of care. These trends raise intriguing questions about access to and outcomes of cardiac procedures in health systems composed of hospitals with and without a full complement of on-site invasive cardiac services.

Acute Disease↗
PubMed1998

Patterns of coordination and clinical outcomes: a study of surgical services.

OBJECTIVE: To test the hypothesis that surgical services combining relatively high levels of feedback and programming approaches to the coordination of surgical staff would have better quality of care than surgical services using low levels of both coordination approaches as well as those surgical service using low levels of either coordination approach. STUDY SETTING: A study sample of 44 academically affiliated surgical services that are part of the Department of Veterans Affairs. STUDY DESIGN: In a cross-sectional analysis, surgical services were assigned to one of three groups based on their scores on feedback and programming coordination measures: high on both measures; high on one measure, low on the other; and low on both. Univariate and multivariate analyses were used to assess differences among these groups with respect to three quality indicators: risk-adjusted mortality, risk-adjusted morbidity, and staff perceptions of quality. DATA COLLECTION/EXTRACTION METHODS: Risk-adjusted mortality and morbidity came from an outcomes reporting program within the Department of Veterans Affairs that entails the prospective collection of clinical data from patient charts. Data on coordination practices and perceived quality came from a survey of surgical staff at each of the 44 participating surgical services. PRINCIPAL FINDINGS: The group of surgical services using high feedback and high programming had the best perceived quality. This group also had the lowest morbidity, but the difference was statistically significant with respect to only one of the two other groups: the group with low feedback and low programming. No significant group differences were found for mortality. CONCLUSIONS: Study results provide partial support for the hypothesis that high levels of feedback and programming should be combined for optimal quality of care. Study results also suggest that staff coordination is more important for improving morbidity than mortality in surgical services.

Cross-Sectional Studies↗
PubMed1997

CD40-activated human B cells: an alternative source of highly efficient antigen presenting cells to generate autologous antigen-specific T cells for adoptive immunotherapy.

Multiple clinical trials have shown the efficacy of adoptively transferred allogeneic antigen-specific T cells for the treatment of viral infections and relapsed hematologic malignancies. In contrast, the therapeutic potential of autologous antigen-specific T cells has yet to be established since it has been technically difficult to generate sufficient numbers of these T cells, ex vivo. A major obstacle to the success of this objective derives from our inability to simply and rapidly isolate and/or expand large numbers of highly efficient antigen presenting cells (APCs) for repetitive stimulations of antigen-specific T cells in vitro. We show that autologous CD40-activated B cells represent a readily available source of highly efficient APC that appear to have several important advantages over other APCs for ex vivo T cell expansion including: (a) methodological simplicity necessary to generate continuously large numbers of APCs from just 50 cm3 of peripheral blood without loss of APC function; (b) capacity to induce high peak T cell proliferation and interferon-gamma production without IL-10 production; (c) ease in cryopreservation; and (d) markedly reduced cost. We, therefore, contend that CD40-activated B cells are an alternative source of highly efficient APCs with which to generate antigen-specific T cells ex vivo for autologous adoptive immunotherapy.

3T3 Cells↗