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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

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

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↗
PubMed2000

Nasal, pulmonary and autoinhaled nitric oxide at rest and during moderate exercise.

OBJECTIVE: To investigate nasal nitric oxide (NO) excretion, pulmonary NO excretion, and autoinhalation of nasally released NO at rest compared with that during moderate exercise in smokers and non-smokers. DESIGN: Prospective observational study. SETTING: University laboratory. PARTICIPANTS: Fourteen healthy adult volunteers. INTERVENTIONS: Breathing of NO-purified air supplied via a tube system at rest and during a bicycle-ergometer workload of 60 Watt over a time of 10 min. MEASUREMENT AND RESULTS: We examined nasal and pulmonary NO excretion in smoking (n = 7) and non-smoking (n = 7) adult human volunteers. At rest, we measured constant nasal NO excretion rates of 311 +/- 89 nl/min for non-smokers and 261 +/- 142 nl/min for smokers (mean +/- SD, n.s.). During 60 W exercise, nasal NO release remained unchanged, while pulmonary NO excretion doubled compared with the rates at rest (non-smokers: 40 +/- 21 nl/min versus 23 +/- 14 nl/min, p < 0.05; smokers: 41 +/- 8 nl/min versus 22 +/- 8 nl/min, p < 0.05). The differences between smokers and non-smokers in nasal or pulmonary NO excretion were not significant. To determine the autoinhaled amount of nasally released NO, we also measured the NO concentration within the nasopharynx of five volunteers during nasal breathing. The average inhaled NO concentration was 17.8 +/- 3.1 ppb at rest and this decreased to 9.3 +/- 1.8 ppb during exercise of 60 W, while minute ventilation approximately doubled from 9 +/- 2 to 21 +/- 3 l/min. CONCLUSION: Our results demonstrate that moderate exercise increased exclusively pulmonary NO excretion. Nasal NO release, which is 10 times higher at rest, was not changed. The decrease in autoinhaled NO concentration during exercise results from dilution of the continuous nasal release by the increased respiratory gas flow. The individual NO release allows no conclusion about smoking habits.

Adult↗
PubMed2000

The inherited nature of lung cancer: a pilot study.

The role of both primary and secondary cigarette smoke exposure in the causation of lung cancer appears certain. An estimated 90% of lung cancer is attributed to cigarette smoke. Remarkably, however, less then 20% of cigarette smokers develop lung cancer. Investigators have suggested that a genetic predisposition to lung cancer may contribute to familial aggregation of this cancer. To understand the contribution of familial aggregation to this type of cancer and potentially identify individuals and families, which may be important in identifying gene(s) responsible for lung cancer, we developed criteria for identification of high-risk families. We have tested the feasibility and utility of these criteria at three Denver, CO hospitals with very different patient populations. Four hundred eighteen individuals were diagnosed with lung cancer at these three hospitals between 1/1/95 and 8/31/95. Twenty-nine percent of individuals expired prior to the time of initial contact. Family history data were obtained on 182 individuals. To be considered positive (suggesting possible autosomal dominant inheritance of lung cancer), families must have at least two first-degree relatives with lung cancer, one of which must be diagnosed before the age of 55. Seventeen of 182 (9.3%) families in the study population met these criteria. We reviewed the remaining family histories that did not meet the established criteria and identified another 2.3% (5/182) of families had evidence for autosomal dominant transmission of lung cancer. An additional 15% (23/182) of families had histories which could not be classified without further information. This study suggests that at least 11.6% of individuals diagnosed with lung cancer will have a positive family history of lung cancer. Use of the criteria developed for this study may lead to an underestimation of the inherited etiology of lung cancer.

Adult↗
PubMed2000

What nursing home residents value in their doctors.

Patient satisfaction is influenced by multiple factors, and different populations are expected to define satisfaction in terms of their novel perspectives. Despite growing interest in patient satisfaction, an extensive literature search reveals no studies of nursing home residents' satisfaction with respect to medical care. In an initial qualitative study using transcripts of interviews conducted as part of a state quality control mandate, categories are identified that make up this population's construct of satisfaction and dissatisfaction. These categories serve as building blocks for designing future studies investigating these issues and allowing for comparison of nursing home residents' ideas of satisfaction and dissatisfaction to other older patients, including those in an outpatient geriatric setting.

Aged↗
PubMed2000

Glutamic acid decarboxylase autoantibodies in controlled and uncontrolled epilepsy: a pilot study.

There have been anecdotal reports of raised glutamic acid decarboxylase (GAD) autoantibodies in patients with refractory epilepsy. We measured serum GAD autoantibodies in 105 patients with idiopathic or symptomatic epilepsy. There was no significant difference in the absolute titre of GAD autoantibody between patients with controlled and uncontrolled epilepsy. However, four female patients with uncontrolled epilepsy had levels that were over three times above the highest detected in the seizure-free group, three of whom also tested positive for pancreatic islet cell antibodies. Larger scale studies, perhaps comparing different epilepsy syndromes, are required to determine the exact clinical role of GAD autoantibodies in epilepsy.

Adolescent↗
PubMed2000

Docking of sulfonamides to carbonic anhydrase II and IV.

Starting with a known active site of a protein and a database of compounds, one would like to quickly identify a few compounds that "dock" into the active site and obtain "good" binding free energies. The main goal of current automated docking procedures is to predict the "best" substrate-enzyme complex while other programs such as UHBD and DelPhi can be used to compute binding free energies. In this paper, we will focus on the application of docking methods and parameters to study substrate-enzyme interactions of a metalloenzyme system. Specifically, we report on the docking of sulfonamides to carbonic anhydrase II and IV, which are of interest due to their application in glaucoma therapy. Using a standard docking protocol, it is possible to correctly predict not only the orientation of inhibitors to a specific isozyme, but also determine the qualitative affinity for a group of inhibitor for an isozyme.

Algorithms↗