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Biomedical subjects

D C Stokes

Publications and source records attributed to D C Stokes.

At least 19 recordsLinked to original sources
PubMed2000

Cloning, expression and gene organization of a human Neu5Ac alpha 2-3Gal beta 1-3GalNAc alpha 2,6-sialyltransferase: hST6GalNAcIV.

On the basis of the detection of expressed sequence tag ('EST') similar to the rat N-acetylgalactosamine alpha2,6-sialyltransferase (ST6GalNAc) III cDNA, we have identified a novel member of the human ST6GalNAc family. We have isolated a cDNA clone containing an open reading frame that codes for a type II membrane protein of 302 amino acids with a seven-amino-acid cytoplasmic domain, an 18-amino-acid transmembrane domain and the smallest described catalytic domain of 277 amino acids. This predicted sialyltransferase sequence is similar to the rat ST6GalNAc III (46.6%), but was found to be even more similar to the recently reported mouse ST6GalNAc IV (88.1%) on the basis of amino acid sequence identity. Northern-blot analysis showed that the newly identified gene is expressed constitutively in various adult human tissues as a 2.2kb transcript, but was also found to be expressed at lower levels in brain, heart and skeletal muscle as a 2.5kb transcript. Expression of the hST6GalNAc IV gene was investigated by reverse transcription PCR in various human cancer cells, and was found to be present in the majority of cell types with the exception of the carcinoma cell line T47D and pro-monocyte THP cells. The transient expression in COS-7 cells of the full-length cDNA led to the production of an active enzyme sharing the acceptor specificity of the ST6GalNAc family towards Neu5Ac alpha 2-3Gal beta 1-3GalNAc alpha-O-R (where 'R' denotes H, benzyl, or a peptidic chain). Detailed analysis in vitro of substrate specificity revealed that the enzyme required the trisaccharide Neu5Ac alpha 2-3Gal beta1-3GalNAc found on O-glycans and arylglycosides. In addition, we have clarified the genomic organization of ST6GalNAc IV gene.

Amino Acid Sequence↗
PubMed1999

Epidemiologic study of cystic fibrosis: design and implementation of a prospective, multicenter, observational study of patients with cystic fibrosis in the U.S. and Canada.

Cystic fibrosis (CF) is a complex illness characterized by chronic lung infection leading to deterioration in function and respiratory failure in over 85% of patients. An understanding of the risk factors for that progression and the interaction of these factors with current therapeutic strategies should materially improve the prevention of this progressive lung disease. The Epidemiologic Study of Cystic Fibrosis (ESCF) was therefore designed as a multicenter, longitudinal, observational study to prospectively collect detailed clinical, therapeutic, microbiologic, and lung function data from a large number of CF treatment sites in the U.S. and Canada. The ESCF also serves an important role as a phase-IV study of dornase alfa. To be eligible for enrollment, subjects must have the diagnosis of CF and receive the majority of their care at an ESCF site. In this paper, the authors present the ESCF study design in detail. Further, enrollment data collected at 194 study sites in 18,411 subjects enrolled from December 1, 1993 to December 31, 1995 are presented in summary form. This comprehensive study is unique in the detail of clinical data collected regarding patient monitoring and therapeutic practices in CF care. Two companion articles present data regarding practice patterns in cystic fibrosis care, including data on resource utilization and prescribing practices.

Adolescent↗
PubMed1996

Bronchoscopic airway evaluation facilitated by the laryngeal mask airway in pediatric patients.

The laryngeal mask airway (LMA) was introduced for clinical use in 1988. It represents a new concept in airway management. Its role has been described as filling the gap between tracheal intubation and the anesthesia face mask. It is inserted without direct visualization into the hypopharynx and when properly positioned forms a low pressure seal around the laryngeal inlet, allowing spontaneous as well as gentle positive pressure ventilation. Since its introduction, its indications and applications in anesthesia practice have increased. Although initially used as a means of delivering anesthesia and obviating the need for holding a mask on the patient, its position directly over the laryngeal inlet makes it a useful guide during flexible bronchoscopy. We report our experience in six pediatric patients and describe an anesthetic technique for bronchoscopy using the LMA for general anesthesia with spontaneous ventilation.

Anesthesia, General↗
PubMed1996

Aerosolized recombinant human DNase in hospitalized cystic fibrosis patients with acute pulmonary exacerbations.

The goal of this study was to evaluate the safety and efficacy of recombinant human DNase (rhDNase) in hospitalized patients with cystic fibrosis (CF) experiencing acute pulmonary exacerbations. Eighty patients with documented CF were enrolled at 11 CF centers when admitted for antibiotic therapy. Patients were at least 5 yr old with a forced vital capacity (FVC) > or = 35% of predicted and an oxygen saturation > or = 90% on a fraction of inspired oxygen (FIO2) < 0.5. Patients were randomized to receive rhDNase 2.5 mg in 2.5 ml excipient twice a day (n = 43) or 2.5 ml excipient alone twice daily (n = 37) along with conventional treatment for exacerbations. Administration of rhDNase was not associated with acute adverse events or deaths, and no patients experienced allergic or anaphylactic reactions. Although forced expiratory volume in one second (FEV1) and FVC improved in both treatment groups during the double-blind period, there were no statistically significant differences in the mean change from baseline in FEV1 or FVC between the two groups. rhDNase therapy is safe and well tolerated in CF patients with acute exacerbations requiring hospitalization, but the study did not demonstrate a statistically significant therapeutic effect of rhDNase when added to a regimen of antibiotics and chest physical therapy.

Acute Disease↗
PubMed1995

Serial pulmonary function studies in children treated for newly diagnosed Hodgkin's disease with mantle radiotherapy plus cycles of cyclophosphamide, vincristine, and procarbazine alternating with cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine.

BACKGROUND: The pulmonary toxicity of bleomycin-containing chemotherapy combined with mantle radiotherapy in children treated for Hodgkin's disease was longitudinally assessed. METHODS: The results of serial pulmonary function studies in 37 children, newly diagnosed and treated at St. Jude Children's Research Hospital between September 23, 1983, and June 30, 1988, with cyclophosphamide, vincristine, and procarbazine (COP) alternating with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) plus low dose mantle radiotherapy are analyzed. All patients had pulmonary function studies at least before the first bleomycin dose, after completion of radiotherapy, and serially upon discontinuation of therapy. Bleomycin therapy was withheld whenever measured carbon monoxide diffusing capacity was less than 50% of the predicted value. RESULTS: Vital capacity, diffusing capacity, and diffusing capacity per unit of alveolar volume declined during the first 6 months of therapy but improved there after. At 2 years postdiagnosis, diffusing capacity per unit of alveolar volume remained significantly reduced. Only one patient was symptomatic at the 2-year point. The survival rate of these patients was 95% at a median follow up of 93 months. CONCLUSION: If bleomycin is with held when diffusing capacity is diminished to 50% predicted, clinical compromise of pulmonary function appears to be minimal in pediatric patients receiving alternating cycles of COP/ ABVD in combination with low-dose mantle radiotherapy. Survival was excellent, even with reduction of the total bleomycin dose.

Adolescent↗
PubMed1994

Pulmonary complications of tissue transplantation in children.

Pediatric bone marrow transplantation and transplantation of solid organs rapidly expanded during the 1980s. Antibiotic therapy for bacterial pneumonias, improved transplant preparative regimens, and improvements in prevention and therapy of graft-versus-host disease have made possible significant improvements in overall bone marrow transplant survival. Despite these advances, pulmonary complications of transplantation remain major causes of morbidity and mortality in pediatric transplant patients. Fungal and cytomegalovirus infections have emerged as the major posttransplant pulmonary infections whereas idiopathic interstitial pneumonias and bronchiolitis obliterans are the major noninfectious pulmonary problems. Recent developments in antiviral therapy for cytomegalovirus pneumonia offer hope that the dismal prognosis of cytomegalovirus pneumonia in transplant patients can be improved. New early detection methods for cytomegalovirus using polymerase chain reaction may also help identify patients for prophylactic therapy and prevent development of cytomegalovirus pneumonitis. Early diagnosis and treatment for fungal pneumonias and other opportunistic pathogens remain significant challenges in immunocompromised transplant patients.

Bone Marrow Transplantation↗
PubMed1993

Reversal of dopamine-refractory septic shock by diethyldithiocarbamate, an inhibitor of endothelium-derived relaxing factor.

Septic shock occurs when endotoxin and other bacterial substances induce the release of host products that act in concert to alter the circulation. Recently, investigators have speculated that endothelium-derived relaxing factor (EDRF), a potent endotoxin-inducible vasodilator, plays an important role in the pathogenesis of septic shock. Diethyldithiocarbamate (DTC), a copper chelator lacking intrinsic vasoactivity, inactivates EDRF. Intravenous DTC was compared with placebo and dopamine in 12 matched sets of 3 rabbits with induced Escherichia coli sepsis. Median levels of bacteremia and endotoxemia were similar in the 3 treatment groups. DTC-treated animals had higher mean arterial pressure and lower heart rates and blood lactate concentrations than either placebo- or dopamine-treated animals (P = .013, P < .001, and P = .001, respectively). These effects were independent of plasma catecholamine concentrations. DTC can reverse septic shock that is refractory to conventional therapy, and these results suggest that EDRF is an important mediator of septic shock.

Animals↗
PubMed1991

Postsepsis bradycardia in children with leukemia.

OBJECTIVE: We observed sinus bradycardia in a small number of children with hematologic malignancies who were recovering from sepsis. Our objective was to define this symptom complex and attempt to delineate its etiology. DESIGN: Retrospective chart review. SETTING: A pediatric ICU in a children's oncology hospital. PATIENTS: Children admitted to the ICU over a 24-month period who developed persistent bradycardia (heart rate less than 5% for age for greater than 1 hr) after an episode of sepsis. MEASUREMENTS AND MAIN RESULTS: Seven children developed postsepsis bradycardia. Six patients had a primary diagnosis of acute myelogenous leukemia and one patient had acute lymphocytic leukemia. All patients had positive blood cultures (Streptococcus mitis, n = 4; Escherichia coli, n = 2; and Klebsiella pneumoniae, n = 1). All seven children were clinically recovering from sepsis when the bradycardia developed. Neither hypotension nor other symptom was associated with the bradycardia. No therapy was given for the bradycardia. Echocardiograms and ECGs were normal in all patients, except for the presence of bradycardia. Bradycardia persisted for 24 to 72 hrs. After that time, heart rates slowly increased to the normal range for age. CONCLUSIONS: We speculate that this syndrome may result from alterations in beta-adrenergic receptor function or an unidentified humoral factor produced by the invading organism or as part of the host's response to sepsis. Prior drug therapy or the underlying illness may predispose to this condition, since all the patients had acute leukemia. As the bradycardia was clinically insignificant, invasive therapeutic or diagnostic strategies were not indicated.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Binding of polymyxin B to rat alveolar macrophages.

The specific binding of radiolabeled polymyxin B (PmB) to rat alveolar macrophages was investigated. PmB retained its ability to inhibit lipopolysaccharide-induced tumor necrosis factor production by macrophages as long as one of five amino groups on PmB was unbound. Binding was saturable and temperature- and time-dependent, reaching steady state by 30 min at 37 degrees C and by 18 h at 4 degrees C. Macrophages had approximately 1.6 X 10(7) (Kd = 0.28 nM) PmB binding sites per cell. Lipid A had no appreciable effect on the number of sites. Binding did not occur to rat platelets, L929 fibroblast cells, a rat thymoma cell line, or precursor monocytic and myeloid cell lines. Precursor cells activated with 12-O-tetradecanoylphorbol-13-acetate acquired binding similar to that seen in alveolar macrophages, but L929 fibroblasts did not. Binding sites were sensitive to trypsin but not to phospholipase C. PmB may interact with specific binding sites involved in lipopolysaccharide-induced activation, production, or release of tumor necrosis factor by macrophages, inhibiting the effects of lipopolysaccharide on macrophages.

Animals↗
PubMed1990

Effects of corticosteroids on postnatal lung and airway growth in the ferret.

To investigate the influence of corticosteroids on postnatal lung and airway growth, young male ferrets were given cortisone acetate (20 mg/kg im daily) beginning at 8 wk of age. At 19 wk of age pulmonary function was measured. The lungs were excised for measurements of recoil pressures and wet and dry weights. The dimensions of central and peripheral airways were estimated from analysis of bronchial casts. Corticosteroid-treated animals were shorter and tended to be lighter than control animals but were heavier in relation to length. Total lung capacity was reduced in proportion to the reduction in body size. Lung recoil and wet-to-dry weight ratios were nearly identical. Maximal expiratory flows were reduced in proportion to the reduction in body size. Size-corrected airway conductance was reduced, suggesting a sensitivity of central airways to growth suppression by corticosteroids. Peripheral airways, on the other hand, were not smaller in treated animals and were larger in proportion to body size. In the ferret corticosteroid administration is associated with a suppression of lung parenchymal growth similar to that of overall body growth. The peripheral airways may be less sensitive and the central airways more sensitive to the effect of corticosteroids on growth.

Airway Resistance↗
PubMed1990

The lungs and airways in achondroplasia. Do little people have little lungs?

Achondroplasia is a unique model of the effects of skeletal dysplasia and dwarfism on the respiratory system. We measured chest dimensions, spirometry, lung volumes, maximal expiratory flow volume curves, nasal and airways resistance, closing volume, maximal inspiratory/expiratory pressures, and tracheal area by acoustic reflection in 12 healthy subjects with achondroplasia. Anterior-posterior thoracic diameter was mildly reduced in men. Vital capacity for all subjects was 108 percent +/- 18.6 percent (SD) of that predicted for achondroplastic subjects, but was reduced when compared with values for people of average stature that were predicted, based on either sitting height or thoracic height. The reduction was relatively greater in male than in female subjects. The RV/TLC and FRC/TLC ratios were normal. Other measurements were similar to those in average-statured adults. We conclude that achondroplasia results in a reduction in vital capacity out of proportion to what would be expected if these subjects had normal limb size. Although the lungs may be small, they are functionally normal, as are the airways.

Achondroplasia↗
PubMed1989

Early detection and simplified management of obstructed Hickman and Broviac catheters.

Thrombotic occlusion of Hickman and Broviac central venous catheters is a serious obstacle to their long-term use. Because resistance to flow (R) through a catheter of lumen radius, r, is proportional to 1/r4, we hypothesized that measurement of R would provide an objective and sensitive monitor for partial occlusions. Our measurements showed that median R at a flow of 17 mL/min was 0.7 cmH2O/mL/min in normally functioning Hickman catheters, and 4.1 cmH2O/mL/min in Broviac catheters. In obstructed catheters, which by subjective standards resisted flushing or blood withdrawal, median R was 3.0 cmH2O/mL/min for Hickman and 5.6 cmH2O/mL/min for Broviac catheters, representing significant increases. In a series of obstructed lines in which urokinase was administered, R decreased from 7.7 to 4.5 in Hickman catheters and from 5.6 to 4.2 in obstructed Broviac catheters. The elevated resistance in Hickman catheters after urokinase suggested that residual catheter obstruction was present even though catheter function returned to normal. Elevated R was seen with abnormal venograms in seven of 13 patients. Four patients had normal R values and abnormal venograms, and two patients had elevated R values with normal venograms. Measurement of resistance in Hickman and Broviac catheters provides a simple technique that can supplement or replace venography in the serial assessment and treatment of partial obstruction.

Acute Disease↗
PubMed1989

Role of flexible bronchoscopy in the diagnosis of pulmonary infiltrates in pediatric patients with cancer.

We reviewed 60 consecutive flexible bronchoscopies done during a 36-month period in 48 pediatric cancer patients with undiagnosed pulmonary infiltrates. Diagnostic procedures during bronchoscopy included 40 brushings, 50 bronchoalveolar lavages, and 6 transbronchial and mucosal biopsies. A total of 16 specific diagnoses were made by bronchoscopy (27% diagnostic yield), including infection (12), pulmonary leukemia (3), and lymphoma (1). The largest proportion of specific diagnoses came from lavage (14/50) and the smallest from brushings (1/40). Biopsies were also useful for selected patients. The low overall yield for bronchoscopy was probably due to the routine use of empiric broad-spectrum antibiotics and antifungal therapy, as well as trimethoprim-sulfamethoxazole prophylaxis for Pneumocystis carinii pneumonitis. Subsequent specific diagnoses were obtained by other procedures (open biopsy, needle aspiration, or autopsy) for 10 patients with negative bronchoscopy results and 3 patients with diagnostic bronchoscopies. These additional diagnoses included 7 infections (Pneumocystis carinii (1), Candida tropicalis (1), cytomegalovirus (1), and Aspergillus (4), and 6 other diagnoses with nonspecific histologic findings. A positive bronchoscopy result may be useful, but negative bronchoscopy findings do not justify delaying other diagnostic procedures or discontinuing antibiotic and antifungal therapy in children with cancer and pulmonary infiltrates.

Adolescent↗
PubMed1989

Polymyxin B prevents lipopolysaccharide-induced release of tumor necrosis factor-alpha from alveolar macrophages.

Polymyxin B (PmB) blocks many of the toxic effects of lipopolysaccharide by mechanisms that are not yet understood. The production of tumor necrosis factor-alpha (TNF-alpha) by isolated rat alveolar macrophages in response to lipopolysaccharide and macrophage-activating factor was blocked by PmB at concentrations of 100, 10, and 1 micrograms/ml. Gentamicin enhanced rather than inhibited TNF production at the 100-micrograms/ml concentrations and had no effect at low concentration. Similar inhibitory effects were induced by PmB in an in vivo model in which rat macrophage TNF production was stimulated by intratracheally injected lipopolysaccharide. Because many of the effects of lipopolysaccharide are mediated by TNF, this inhibition provides a mechanism to explain the protection afforded by PmB against lipopolysaccharide-induced toxicity.

Animals↗
PubMed1989

A prospective study of Hickman/Broviac catheters and implantable ports in pediatric oncology patients.

We prospectively studied the continuous function and complication rates of 286 central venous catheters consecutively placed in 264 children and young adults at a single institution over a 19-month period (median follow-up, 376 days). Externalized catheters (91 Hickman [H], 113 Broviac [B]) and implantable ports (n = 82) were compared for complications, including infection and thrombosis. The most frequent major complication of all catheters was infection, although the rates of infection varied with the duration of catheter use and were generally lower than reported by others. Overall, when catheter failures (removal) for infection, obstruction, or dislodgement were considered, ports had a significantly longer failure-free duration of use (P = .0024) than did externalized catheters. Likewise, ports had a significantly longer infection-free (P less than .01) duration of use than H and B catheters. However, differences in patient age and clinical characteristics among the three catheter groups may have affected the outcome. In analysis of pairs matched for diagnosis, therapy, and age, ports had lower infection rates than did B catheters after 100 days (P = .053). This difference became significant at 400 days of catheter use (P = .029). Although there was a trend toward lower rates of infections for ports v H catheters, this difference was not significant. In view of our results in matched pairs, selection of catheter type based on clinical characteristics and patient preferences remains a reasonable therapeutic approach despite the apparent advantages of ports. The superiority of ports for long-term use (greater than 100 days) needs to be confirmed in a large randomized clinical trial.

Adolescent↗
PubMed1989

Effect of antioxidants in experimental Escherichia coli septicemia.

Free radicals have been implicated in the pathogenesis of gram-negative bacterial sepsis. We assessed the effectiveness of antioxidants and chelators to alter oxidative injury in established severe experimental Escherichia coli septicemia. One hour after challenge by intraperitoneal injection of bacteria, 36 rabbits were treated with moxalactam and randomized in sets of three to receive either placebo, superoxide dismutase (SOD), or a combination of antioxidants and chelators consisting of SOD, sodium thiosulfate, alpha-tocopherol, deferoxamine, and diethyldithiocarbamate. Throughout the course of treatment, levels of bacteremia and endotoxemia were similar among the three experimental groups. Neither antioxidant-treated group was significantly different from the control group in mean arterial blood pressure, leukocyte count, platelet count, core temperature, blood lactate, oxygenation or survival. Arterial pH and [HCO3-] were significantly lower in the antioxidant combination group compared to the control and SOD groups (P less than .01). In this model, antioxidant and chelator therapy does not substantially ameliorate established septicemia.

Animals↗