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Biomedical subjects

K Kelly

Publications and source records attributed to K Kelly.

At least 37 records · Page 2Linked to original sources
PubMed2001

Intravenous beta2-agonists for acute asthma in the emergency department.

BACKGROUND: Inhaled beta-agonist therapy is central to the management of acute asthma. The use of intravenous beta-agonist agents may also be beneficial in this setting. OBJECTIVES: To determine the benefit of intravenous (IV) beta2-agonists for severe acute asthma treated in the emergency department. SEARCH STRATEGY: Randomised controlled trials (RCT) were identified using the Cochrane Airways Group Register which is a compilation of systematic searches of MEDLINE, EMBASE, CINAHL, and CENTRAL as well as hand searching of 20 respiratory journals. Bibliographies from included studies and known reviews were also searched. Primary authors and content experts were contacted to identify eligible studies. SELECTION CRITERIA: Only RCTs were considered for inclusion. Studies were included if patients presented to the emergency department with acute asthma and were treated with IV selective or nonselective beta2-agonists versus placebo, inhaled beta2-agonists, or other standard of care. Pulmonary function, vital signs, arterial gasses, adverse effects, and/or clinical success could be reported as outcome measures. Two reviewers independently selected potentially relevant articles and selected articles for inclusion. Methodological quality was independently assessed using two scoring systems and two reviewers. DATA COLLECTION AND ANALYSIS: Data were extracted independently by two reviewers, and confirmed with corresponding authors. Missing data were obtained from authors or calculated from data present in the papers. Trials were combined using a random effects model for odds ratios (OR) or weighted mean differences (WMD) and reported with 95% confidence intervals (95% CI). MAIN RESULTS: From 746 identified references, 55 potentially relevant articles were identified and 15 were included. The trials included 584 patients. Overall, selective IV beta2-agonist use conferred no advantage over the comparator regimes. For example, it was associated with a lower PEFR after 60 mins compared to inhaled beta2-agonist, although the difference was not statistically significant (-24.7 l/min; 95%CI 2.9, -52.3). There was no difference in heart rate (4.5 bpm; 95% CI -4.9, 14.0). In the well performed blinded studies there was no difference in autonomic side effects between treatments (Odds Ratio 2.2 (95%CI 0.9, 5.7). REVIEWER'S CONCLUSIONS: There is no evidence to support the use of IV beta2-agonists in patients with severe acute asthma. These drugs should be given by inhalation. No subgroups were identified in which the IV route should be considered.

Acute Disease↗
PubMed2001

Treatment of extensive stage small cell lung cancer.

Over the past twenty years combination chemotherapy has continued to produce small survival gains for patients with SCLC. We enter the next century enthusiastic about the array of new chemotherapeutic agents to evaluate and fascinated by the biological agents with the hope of achieving dramatic improvements in survival for our patients with SCLC.

Adjuvants, Immunologic↗
PubMed2001

DNA topoisomerase IIalpha in multiple myeloma: a marker of cell proliferation and not drug resistance.

DNA topoisomerase IIalpha (topo IIalpha) is the target for a number of antineoplastic agents. Down-regulation of this enzyme is one form of drug resistance. Topo IIalpha is also involved in DNA replication and transcription and serves as an indicator of proliferation rate in many human malignancies. This study examines whether topo IIalpha is one of the mechanisms of chemoresistance commonly observed in multiple myeloma (MM) or alternatively, whether topo IIalpha is associated with tumor cell proliferation. Bone marrow (BM) biopsy sections from 72 cases of MM, stratified according to proliferative activity (bromodeoxyuridine uptake), were immunostained for topo IIalpha. Immunoreactivity with an additional marker of drug resistance, glutathione-S-transferase pi, and the proliferation marker Ki-67 were also examined. Topo IIalpha was expressed in 26 (36%) cases and correlated strongly with proliferative activity (P <.001). A role for drug resistance could not be supported, given this strong relationship with proliferation and the finding that glutathione-S-transferase pi expression in 57 (78%) cases was independent of topo IIalpha immunoreactivity. Topo IIalpha was identified in 91 to 100% of highly proliferative tumors, as evaluated by bromodeoxyuridine uptake or Ki-67 reactivity, respectively. Proliferation also correlated with the histologic grade of the MM. Therefore, topo IIalpha immunoreactivity is primarily a marker of cell proliferation in MM and as such is likely to have prognostic significance. Highly proliferative tumors are most likely to be sensitive to chemotherapeutic protocols using anti-topo IIalpha agents.

Adult↗
PubMed2001

Cyclin D1 and E2F-1 immunoreactivity in bone marrow biopsy specimens of multiple myeloma: relationship to proliferative activity, cytogenetic abnormalities and DNA ploidy.

Cyclin D1, encoded by the CCND1 gene, is immunohistochemically detectable in up to one-third of cases of multiple myeloma (MM). To examine the mechanism of cyclin D1 overexpression, we compared cyclin D1 immunoreactivity with the results of conventional cytogenetics to determine if the t(11;14)(q13;q32) or other abnormalities of 11q11-14 explained cyclin D1 overexpression. Karyotypic abnormalities were found in 45 out of 67 (67%) MM cases; the t(11;14) was present in seven cases (10%). Additional 11q11-14 abnormalities were not identified. The t(11;14) correlated with cyclin D1 upregulation in low to intermediately proliferative MM, but was not present in highly proliferative tumours (assessed using bromodeoxyuridine labelling index). Cyclin D1 indirectly activates the transcription factor E2F-1. In the bone marrow biopsy specimens of MM cases, E2F-1 was concurrently expressed with cyclin D1 (P = 0.001), indicating that cyclin D1 is functional. However, as neither E2F-1 nor cyclin D1 expression correlated with proliferative activity, the speculation that t(11;14) upregulates the CCND1 gene to induce higher proliferation and possibly more aggressive disease is not supported. We conclude that in low to intermediately proliferative MM cases, cyclin D1 is probably upregulated by t(11;14), but an alternative mechanism is more probable in highly proliferative MM.

Adult↗
PubMed2001

Inverse expression of P(k) and Luke blood group antigens on human RBCs.

BACKGROUND: Luke (LKE) is a high-frequency RBC antigen, related to the P blood group system. A LKE-negative phenotype is found in 1 to 2 percent of donors and may be associated with increased P(k). Because P(k) and similar glycolipids are receptors for shiga toxin on cell membranes, a LKE-negative phenotype could have implications for infections by Shigella dysenteriae and enterohemorrhagic Escherichia coli. STUDY DESIGN AND METHODS: Volunteer donors (n = 257) were serologically typed for LKE with a LKE MoAb, MC813-70. LKE-strong-positive, LKE-weak-positive and LKE-negative RBCs were analyzed for P(k), P, LKE, and shiga toxin binding by immunofluorescence flow cytometry, high-performance thin-layer chromatography, scanning densitometry, and high-performance thin-layer chromatography immunostaining. RESULTS: Among Iowa donors, 78.6 percent were LKE-strong-positive, 20.2 percent were LKE-weak-positive, and 1.2 percent were LKE-negative. There was an inverse expression of P(k) and LKE on RBCs. P(k) expression was increased on LKE-negative RBCs and was associated with increased shiga toxin binding. A LKE-active glycolipid was identified in the ganglioside fraction of LKE-strong-positive RBCs. CONCLUSION: A LKE-negative phenotype is associated with increased expression of P(k) on RBCs. Differences in P(k) and LKE expression may play a role in host susceptibility to infection with S. dysenteriae and E. coli.

Blood Donors↗
PubMed2001

Signal pathways which promote invasion and metastasis: critical and distinct contributions of extracellular signal-regulated kinase and Ral-specific guanine exchange factor pathways.

Approximately 50% of metastatic tumors contain Ras mutations. Ras proteins can activate at least three downstream signaling cascades mediated by the Raf-MEK-extracellular signal-regulated kinase family, phosphatidylinositol-3 (PI3) kinase, and Ral-specific guanine nucleotide exchange factors (RalGEFs). Here we investigated the contribution of RalGEF and ERK activation to the development of experimental metastasis in vivo and associated invasive properties in vitro. Each pathway contributes distinct properties to the metastatic phenotype. Following lateral tail vein injection, 3T3 cells transformed by constitutively active Raf or MEK produced lung metastasis that displayed circumscribed, noninfiltrating borders. In contrast, 3T3 cells transformed by Ras(12V,37G), a Ras effector mutant that activates RalGEF but not Raf or P13 kinase, formed aggressive, infiltrative metastasis. Dominant negative RalB inhibited Ras(12V,37G)-activated invasion and metastasis, demonstrating the necessity of the RalGEF pathway for a fully transformed phenotype. Moreover, 3T3 cells constitutively expressing a membrane-associated form of RalGEF (RalGDS-CAAX) formed invasive tumors as well, demonstrating that activation of a RalGEF pathway is sufficient to initiate the invasive phenotype. Despite the fact that Ras(12V,37G) expression does not elevate ERK activity, inhibition of this kinase by a conditionally expressed ERK phosphatase demonstrated that ERK activity was necessary for Ras(12V,37G)-transformed cells to express matrix-degrading activity in vitro and tissue invasiveness in vivo. Therefore, these experiments have revealed a hitherto-unknown but essential interaction of the RalGEF and ERK pathways to produce a malignant phenotype. The generality of the role of the RalGEF pathway in metastasis is supported by the finding that Ras(12V,37G) increased the invasiveness of epithelial cells as well as fibroblasts.

3T3 Cells↗
PubMed2001

Irinotecan in small-cell lung cancer: current data.

Irinotecan, a new topoisomerase I inhibitor, has significant activity in the treatment of untreated and previously treated patients with small-cell lung cancer (SCLC). In combination with cisplatin, a Japanese randomized trial showed a statistically significant survival advantage over cisplatin/etoposide in chemotherapy- naive patients with extensive-stage disease. This represents the first major advance in the treatment of extensive-stage SCLC in 20 years. Randomized trials in the United States are underway to confirm these impressive results. Meanwhile, trials incorporating irinotecan and cisplatin into treatment regimens for limited-stage disease are being conducted. Furthermore, irinotecan-containing regimens with other agents such as carboplatin, etoposide, and paclitaxel in first- or second-line therapies for SCLC are being evaluated. Preliminary results are encouraging. This article will highlight the exciting results achieved with irinotecan in SCLC and discuss its promising future in this disease.

Journal Article↗
PubMed2001

Nonoperative management of blunt splenic and hepatic trauma in the pediatric population: significant differences between adult and pediatric surgeons?

Although operative management was the preferred method of treating blunt abdominal trauma in the past, recent literature and practice recommend a nonsurgical approach to most pediatric splenic and hepatic injuries. The majority of data supporting the safety and efficacy of this nonoperative approach are derived from university trauma programs with a pediatric center where care was managed by pediatric surgeons only. To evaluate the applicability of this approach in a regional trauma center where pediatric patients are managed by pediatric and non-pediatric surgeons we reviewed the experience at a Level II community trauma center. Fifty-four children (16 years of age or less) were admitted between April 1992 and April 1998 after sustaining blunt traumatic splenic and/or hepatic injuries. There were 37 (69%) males and 17 (31%) females; the average age was 11 years (range 4 months to 16 years). Of the 54 patients 34 (63%) sustained splenic injuries, 17 (31%) sustained hepatic injuries, and three (6%) sustained both splenic and hepatic injuries. All of these injuries were diagnosed by CT scan or during laparotomy. The average Injury Severity Score was 14.9 with a range from four to 57. Of the 47 patients initially admitted for nonoperative management one patient failed nonoperative management and required operative intervention. In our study 98 per cent (46 of 47 patients) of pediatric patients were successfully managed nonoperatively. Complications of nonoperative management occurred in two patients. Both developed splenic pseudocysts after splenic injury, which required later operative repair. These data are comparable with those from university trauma programs and confirm that nonoperative management is safe in a community trauma center. The majority of children with blunt splenic and hepatic trauma can be successfully treated without surgery, in a regional trauma center treated by nonpediatric trauma surgeons, if the decision is based on careful initial evaluation, aggressive resuscitation, and close observation of their hemodynamic stability.

Adult↗
PubMed2001

Cisplatin, etoposide, and paclitaxel with granulocyte colony-stimulating factor in untreated patients with extensive-stage small cell lung cancer: a phase II trial of the Southwest Oncology Group.

PURPOSE: This study was designed to determine the efficacy and toxicity of cisplatin, etoposide, and paclitaxel (PET) in patients with extensive-stage small cell lung cancer (ES-SCLC). EXPERIMENTAL DESIGN: Chemo-naive adult patients with a performance status (PS) of 0-2 and adequate organ function were eligible. Patients received cisplatin 80 mg/m(2) i.v., etoposide 80 mg/m-2 i.v., and paclitaxel 175 mg/m(2) i.v. over a 3-h period on day 1 followed by etoposide 160 mg/m(2) p.o. on days 2 and 3 every 21 days for six cycles. G-CSF 5 microg/kg was injected s.c. on days 4-14. RESULTS: Eighty-eight patients were assessable. The median age was 60 years; 50% were male, 78% had PS of 0-1, 28% had PS of 2, 53% had multiple sites, and 13% had brain involvement. The overall response rate was 57% with 10 (12%) of 84 patients achieving a complete response. Median progression-free survival was 6 months [95% confidence interval (CI), 5-7 months] with a median survival of 11 months (95% CI, 8-13 months) and a 1-year survival rate of 43% (95% CI, 33-54%). Six patients (7%) died from toxicity. Grade 5 toxicity occurred in 3 (14%) of 22 patients (with a PS of 2) versus 3 (5%) of 61 patients (with a PS of 0-1; P, not significant). Grade 4 neutropenia developed in 40% of patients. Grade 3 nonhematological toxicities were primarily nausea (20%), vomiting (16%), and fatigue (14%). CONCLUSION: The survival result achieved was superior to prior SWOG experiences; however, the toxic death rate was unacceptably high in PS-2 patients. These results provide the largest database for the ongoing randomized Intergroup trial comparing PET to cisplatin+etoposide in PS-0-1 patients with ES-SCLC.

Adult↗
PubMed2000

APRIL/TRDL-1, a tumor necrosis factor-like ligand, stimulates cell death.

We have examined the activity of a new member of the tumor necrosis factor (TNF) family identified through Expressed Sequence Tag database searching using TNFalpha protein as the search query. We have termed this protein TNF-related death ligand-la (TRDL-1alpha). Traditional cDNA library screening identified two additional splice variants designated TRDL-1beta and TRDL-1gamma that differed from TRDL-1alpha by the deletion of two small regions within the protein coding region. TRDL-1alpha is identical in sequence to the recently described molecule, APRIL, that may induce cell proliferation. We found, however, that purified, FLAG-tagged TRDL-1alpha caused Jurkat cell death with kinetics that paralleled FasL. In vitro binding experiments demonstrated that TRDL-1alpha coprecipitated Fas and HVEM and suggested TRDL-1alpha as an alternate ligand for these receptors. TRDL-1 localized to chromosome 17p13.3 and its expression was widespread in normal tissues. Examination of 48 tumor samples revealed high levels of TRDL-1 expression in several tumors, including those from the gastrointestinal tract. Expression of TRDL-1 in COS-1 cells confirmed membrane association of TRDL-1, typical of TNF family members.

Amino Acid Sequence↗
PubMed2000

Nedocromil sodium vs. sodium cromoglycate for preventing exercise-induced bronchoconstriction in asthmatics.

BACKGROUND: Nedocromil sodium and sodium cromoglycate inhaled shortly before exercise appear to reduce the severity of exercise-induced bronchoconstriction. There is some debate over which drug may be more effective. OBJECTIVES: The objective of this review was to compare the effects on post-exercise lung function between prophylactic doses of nedocromil sodium (NSG) and sodium cromoglycate (SCG) in persons diagnosed with exercise-induced bronchoconstriction. SEARCH STRATEGY: Randomized controlled trials were identified from the Cochrane Airways Review Group Asthma Register which compiles searches of CINAHL, EMBASE, MEDLINE and CENTRAL, plus hand searches for trials in 20 journals. Bibliographies of relevant studies and review articles were searched and primary authors, content experts and manufacturers of drugs were contacted for additional relevant studies. No language restrictions were applied. SELECTION CRITERIA: Randomized controlled trials comparing NCS to SCG in prophylactic treatment of exercise-induced bronchoconstriction were eligible. Studies were included if: the participants, aged 6 or over, had a confirmed diagnosis of asthma with exercise-induced bronchoconstriction, were subjected to an exercise challenge sufficient to trigger bronchoconstriction, and the measures of lung function were reported as either changes in forced expiratory volume in one second or peak expiratory flow rate. DATA COLLECTION AND ANALYSIS: Data extraction and methodological quality assessments were conducted independently by two reviewers using standard forms and validated assessment criteria. In some cases results were extrapolated from graphs. Results from similar studies were pooled and reported as the weighted mean difference (WMD) or odds ratio (OR) with 95% confidence intervals (CI) using the random effects model. MAIN RESULTS: Of the 92 citations retrieved from the original search, a total of 8 studies were included in this review (117 participants). No significant difference was noted between NCS and SCG with respect to the maximum percent decrease in FEV1 (WMD = -0.88; 95% CI: -4.50, 2.74), complete protection (i.e. maximum % fall FEV1 still =>10%); OR = 0.95; 95% CI: 0.50 to 1.8, clinical protection (i.e. < 50% improvement over placebo); OR = 0.71; 95% CI: 0.36 to 1.39; unpleasant taste (OR = 6.85; 95% CI: 0.77, 60.73), or sore throat (OR = 3.46; 95% CI: 0.32, 37.48). For these pooled comparisons, no statistically significant heterogeneity was identified. Subgroup analyses based on age, dosage of medications and timing of exercise post-inhalation were consistent with the overall pooled analyses. REVIEWER'S CONCLUSIONS: No significant differences were evident between the effect of NCS and SCG during the immediate post-exercise period in adults and children with EIB with regards to pulmonary function - specifically maximum percent decrease in FEV1, complete protection, clinical protection, or side effects.

Administration, Inhalation↗
PubMed2000

Safety and efficacy of propofol with EDTA when used for sedation of surgical intensive care unit patients.

OBJECTIVE: To compare propofol with disodium edetate (EDTA) and propofol without EDTAwhen used for the sedation of critically ill surgical intensive care unit (ICU) patients. DESIGN: Prospective, randomised, multicentre trial. PATIENTS: A total of 122 surgical ICU patients who required intubation and mechanical ventilation. INTERVENTIONS: Patients were randomised to receive either propofol or propofol plus EDTA (propofol EDTA) by continuous infusion for sedation. MEASUREMENTS AND RESULTS: The addition of EDTA to propofol had no effect on calcium or magnesium homeostasis, renal function, haemodynamic function, or efficacy when used for the sedation of surgical patients in the ICU. The most common adverse events were hypotension, atrial fibrillation, and hypocalcaemia. In this trial, a greater number of serious adverse events and adverse events leading to withdrawal occurred in the propofol group relative to the propofol EDTA group. There was a significantly lower crude mortality rate at 7 and 28 days for the propofol EDTA group compared with the propofol group. There were no statistically significant differences between groups with respect to depth of sedation. CONCLUSION: The propofol EDTA formulation had no effect on calcium or magnesium homeostasis, renal function, or sedation efficacy compared with propofol alone when used for sedation in critically ill surgical ICU patients. There was a significant decrease in mortality in the propofol EDTA group compared with the propofol group. Further investigations are needed to validate this survival benefit and elucidate a possible mechanism.

Adolescent↗