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Biomedical subjects

J M Nelson

Publications and source records attributed to J M Nelson.

At least 37 records · Page 2Linked to original sources
PubMed1997

Tyrosine kinase inhibitors. 6. Structure-activity relationships among N- and 3-substituted 2,2'-diselenobis(1H-indoles) for inhibition of protein tyrosine kinases and comparative in vitro and in vivo studies against selected sulfur congeners.

A small series of 2,2'-diselenobis(1H-indoles) was synthesized as redox-modified congeners of our earlier reported 2,2'-dithiobis(1H-indole) series. Utilizing chemistry similar to that developed earlier for the disulfur series, compounds were made from 2-halogeno-3-indolecarboxylic acid precursors bearing various polar functionality at the C-3 position and small alkyl substituents at the N-1 position of the indole nucleus. Additional compounds were derived from (R)- or (S)-tryptophan via a novel application of diselenium dichloride as an electrophilic source of diselenium, and a much improved process to a 2,2'-dithiobis(1H-indole) congener was developed utilizing disulfur dichloride as a source of disulfur. Against isolated epidermal growth factor receptor (EGFr), platelet-derived growth factor receptor (PDGFr), and v-src tyrosine kinases, compounds in this series displayed broad inhibitory activity with IC50 = 0.9 to > 100 microM vs EGFr, 3.4 to > 50 microM vs PDGFr, and 0.4-6.7 microM vs v-src. In general, compounds derived from tryptophan displayed the greatest potency against EGFr and those from 2-halogeno-3-indolecarboxylic acids greater potency against PDGFr and v-src. Enzyme kinetics studies showed that both classes of compounds display primarily noncompetitive inhibition with respect to either ATP or peptide substrate. The sulfhydryl reducing agent dithiothreitol (DTT) caused a general decrease in inhibition of the EGFr and v-src tyrosine kinases by both the diselenium and disulfur series with the reversal of enzyme inhibition occurring less readily within the diselenium series. In whole cell studies, compounds of this class were growth inhibitory against Swiss 3T3 mouse fibroblasts with IC50 values from 0.5 to 19.5 microM, and the observed SAR was different from that of the 2,2'-dithiobis(1H-indoles). A comparative study in the same cell line on the effects of the 2,2'-diselenobis(1H-indole) derived from (R)-tryptophan vs its disulfur congener on growth factor mediated tyrosine phosphorylation showed that this compound significantly inhibited EGFr and PDGFr (in response to its ligand) autophosphorylation with complete suppression at 25 and 5 microM, respectively. Tyrosine phosphorylation of an 85 kDa protein typically phosphorylated in response to bFGF was also exquisitely sensitive to this compound, and it displayed inhibitory effects on DNA, RNA, and protein synthesis at submicromolar concentrations. The disulfur congener exhibited a qualitatively similar pattern; however, its potency was 10-fold less. This same diselenium/disulfur pair was evaluated in vivo against the B16 melanoma, colon carcinoma 26, and M5076 sarcoma murine tumors, and the A431 epidermoid, and C6 glioma human tumor xenografts. At maximum tolerated doses (1.8 and 5.0 mg/kg/injection, respectively), neither the diselenium nor disulfur congener was effective against the C6 glioma when administered intraperitoneally on a d1-9 schedule. Studies were also carried out against the A431 epidermoid xenograft to evaluate the same pair of compounds via continuous subcutaneous infusion from Alzet miniosmotic pumps. The maximum dose that could be administered daily was limited by compound solubility. Neither compound produced an antitumor effect in a 7-day continuous infusion study. In the 27-day study, the disulfur compound was inactive whereas the diselenium compound produced a 10.8-day growth delay without appreciable treatment related weight loss. The in vitro and in vivo findings offer a mechanistic rationale as to why the 2,2'-diselenobis(1H-indoles) are more potent inhibitors than their disulfur congeners.

3T3 Cells↗
PubMed1997

Rocuronium versus succinylcholine for rapid-sequence induction using a variation of the timing principle.

STUDY OBJECTIVE: To determine if, using a variation of the "timing" principle, 0.6 mg/kg of rocuronium can achieve an onset time and intubating conditions similar to those achieved with succinylcholine. STUDY DESIGN: Prospective, randomized, double-blind clinical comparison. SETTING: Operating room in a university medical center. PATIENTS: 42 ASA physical status I and II patients undergoing general anesthesia for elective surgery. INTERVENTIONS: All patients were fitted with a Grass FT-10 force transducer attached to the thumb. Supramaximal stimulation was applied to the ulnar nerve with a variable current peripheral nerve stimulator. 22 patients (succinylcholine group) received a placebo bolus injection followed 20 seconds later by thiopental 4 to 5 mg/kg and succinylcholine 1 mg/kg; 20 additional patients (rocuronium group) received a bolus dose of rocuronium 0.6 mg/kg followed 20 seconds later by thiopental 4 to 5 mg/kg and a placebo bolus injection. MEASUREMENTS AND MAIN RESULTS: We measured the onset time from administration of the muscle relaxant to 95% twitch reduction and assessed the quality of intubating conditions 60 seconds after the induction of anesthesia. There was a significant difference in the mean onset time of rocuronium (72 sec) versus succinylcholine (42 sec, p < 0.0001). However, there was no significant difference in intubating conditions 60 seconds after administration of thiopental. CONCLUSION: Rocuronium given 20 seconds prior to thiopental provides intubating conditions equivalent to thiopental-succinylcholine for rapid-sequence inductions, circumventing rocuronium's longer onset time to 95% neuromuscular blockade.

Androstanols↗
PubMed1996

The importance of the postoperative anesthetic visit: do repeated visits improve patient satisfaction or physician recognition?

This study evaluates whether repeated postoperative visits by the anesthesiologist improve patient ability to recall the anesthesiologist's name and the patient's perception of and satisfaction with anesthesia services. In a randomized, prospective trial, 144 patients with an anticipated postoperative length of stay of at least three days were enrolled in three groups: Group A patients (n = 48) had one postoperative visit, Group B (n = 48) had two postoperative visits, and Group C (n = 48) had three postoperative visits. All postoperative visits were performed by the attending anesthesiologist on consecutive postoperative days. Patients were contacted two days after their last postoperative visit to complete a study questionnaire. Patients were able to recall the anesthesiologist's name significantly less frequently than the surgeon's name, and there was no difference in name recall among groups. Recall was not affected by patient age, sex, or ASA physical status; the mode of contact (telephone versus personal visit); the anesthesiologist's gender; the presence of preoperative medication; or the identity of the preoperative evaluator. Patients could identify the anesthesiologist's gender approximately 85% of the time, regardless of group, and were more likely to identify female anesthesiologists (P = 0.026, odds ratio 3.3). Patient evaluation of hospital, surgical, and anesthesia care was favorable in all groups and did not vary with group. Increasing the number of postoperative visits does not improve patient name recognition of the anesthesiologist or increase patient satisfaction with or perception of anesthesia services.

Age Factors↗
PubMed1996

Clastogenic effects of defined numbers of 3.2 MeV alpha particles on individual CHO-K1 cells.

Research to determine the effects of defined numbers of alpha particles on individual mammalian cells is helpful in understanding risks associated with exposure to radon. This paper reports the first biological data generated using the single-particle/single-cell irradiation system developed at Pacific Northwest Laboratory. Using this apparatus, CHO-K1 cells were exposed to controlled numbers of 3.2 MeV alpha particles, and biological responses of individual cells to these irradiations were quantified. Chromosomal damage, measured by the induction of micronuclei, was evaluated after no, one, two, three or five particle traversals. Exposures of up to five alpha particles had no influence on the total numbers of cells recovered for scoring. With increased numbers of alpha particles there was a decrease in the ratio of binucleated to mononucleated cells of 3.5%/hit, suggesting that alpha particles induced dose-dependent mitotic delay. A linear hit-response relationship was observed for micronucleus induction: Micronuclei/binucleated cell = 0.013 +/- 0.036 + (0.08 +/- 0.013) x D, where D is the number of particles. When the estimated dose per alpha-particle traversal was related to the frequency of induced micronuclei, the amount of chromosomal damage per unit dose was found to be similar to that resulting from exposures to alpha particles from other types of sources. Approximately 72% of the cells exposed to five alpha particles yield no micronuclei, suggesting the potential for differential sensitivity in the cell population. Additional studies are needed to control biological variables such as stage of the cell cycle and physical parameters to ensure that each cell scored received the same number of nuclear traversals.

Alpha Particles↗
PubMed1995

Relative lumbar and pelvic motion during loaded spinal flexion/extension.

STUDY DESIGN: This study analyzed relative lumbar and pelvic motion during sagittal plane trunk motion. Patterns of movement were compared during loaded trunk flexion and extension. OBJECTIVES: The purpose of this study was to examine the dynamic relationship between the lumbar spine and pelvis during trunk motion and to determine the effect of direction of lift (up vs. down) on lumbar-pelvic rhythm. SUMMARY OF BACKGROUND DATA: There is disagreement in the literature regarding whether rotations of the pelvis and lumbar spine occur sequentially or simultaneously during bending and lifting tasks. METHODS: Thirty healthy women, ranging in age from 19 to 35 years, participated in the study. The 3Space Tracker System, an electromagnetic tracking device, was used to monitor simultaneous lumbar and pelvic motion as subjects lifted and lowered a 9.5 kg box with knees extended. RESULTS: Although lumbar and pelvic motion occurred simultaneously during flexion and extension, there was greater separation of these movements during the "up lifts" than during the "down lifts." CONCLUSIONS: Lumbar-pelvic rhythm varied depending on whether the trunk was flexing or extending. During trunk flexion (down lift) there was a greater tendency for lumbar and pelvic rotations to occur simultaneously, whereas during extension (up life) they tended to occur more sequentially.

Adolescent↗
PubMed1995

Design of a benchtop alpha particle irradiator.

The design, construction and calibration of a convenient irradiator is described that provides controlled exposure to a uniform external source of well-characterized alpha particles at a dose-rate of 0.99 cGy min-1. The use of a precis- ion photographic shutter allows the accurate delivery of doses as low as 0.01 mGy (1 mrad) to cultured cells. Special features also include a helium environment and reciprocal collimator that permits the use of collimators with different transmission factors to achieve differing dose-rates. A simple method is described to characterize the energy spectrum of alpha particles by use of particle range as measured by track etch.

Alpha Particles↗
PubMed1995

Los Angeles County-University of Southern California Medical Center clinical pathology case conference: extreme hypermagnesemia in a neonate.

A preterm male infant born at 33 weeks of gestation developed respiratory depression and apnea at approximately 20 h after birth. Laboratory tests indicated severe hypermagnesemia, acidosis, and hypercalcemia. Cord blood and maternal blood concentrations of magnesium were normal. The effects and possible causes of hypermagnesemia are reviewed. The infant recovered with treatment, although the etiology of his hypermagnesemia remains unknown.

Acidosis↗
PubMed1995

Inhibition of basic fibroblast growth factor-mediated tyrosine phosphorylation and protein synthesis by PD 145709, a member of the 2-thioindole class of tyrosine kinase inhibitors.

PD 145709, which represents one member of a new structural class of tyrosine kinase inhibitors, the thioindoles, inhibited basic fibroblast growth factor (bFGF)-mediated tyrosine phosphorylation in Swiss 3T3 murine fibroblasts. Half-maximal suppression was attained when cells were exposed for 2 h to 4.5 microM. Little or no inhibition of epidermal growth factor (EGF)- or platelet-derived growth factor (PDGF)-mediated tyrosine phosphorylation was observed at concentrations as high as 50 microM. The inhibition of bFGF-mediated phosphorylation occurred rapidly with maximal effects occurring after the cells were exposed to PD 145709 for 90 min. Once established, the inhibition was irreversible and remained for at least 2 h after PD 145709 was removed from the extracellular medium. PD 145709 also inhibited bFGF-mediated phosphorylation as well as FGF receptor autophosphorylation in a human breast carcinoma, MDA-MB-134, which overexpresses the FGF1 receptor. PD 145709 caused an increase of c-jun mRNA in response to EGF, PDGF, bFGF and serum. This effect may be due to the fact that this compound was a potent inhibitor of protein synthesis in cells and may cause superinduction of growth factor-mediated gene expression similar to other inhibitors of protein synthesis. Inhibition of protein synthesis occurred in fibroblasts exposed to PD 145709 with half-maximal inhibition at 0.5 microM, but not in an in vitro translation system at concentrations as high as 20 microM. This indicates that an intact viable cell is necessary for inhibition to occur and is compatible with a mechanism by which PD 145709 interferes with signals or protein factors that are involved with the initiation or protein synthesis.

3T3 Cells↗
PubMed1995

Degloving injury from a helicopter rotor strike.

The incidence of helicopter accidents has decreased, but lethality remains considerable. Rotor strikes are deadlier than crash-related injuries. We describe a degloving injury caused by a helicopter tail rotor strike managed with rapid resuscitation and early split-thickness skin grafting.

Accidents, Aviation↗
PubMed1994

A specific inhibitor of the epidermal growth factor receptor tyrosine kinase.

A small molecule called PD 153035 inhibited the epidermal growth factor (EGF) receptor tyrosine kinase with a 5-pM inhibition constant. The inhibitor was specific for the EGF receptor tyrosine kinase and inhibited other purified tyrosine kinases only at micromolar or higher concentrations. PD 153035 rapidly suppressed autophosphorylation of the EGF receptor at low nanomolar concentrations in fibroblasts or in human epidermoid carcinoma cells and selectively blocked EGF-mediated cellular processes including mitogenesis, early gene expression, and oncogenic transformation. PD 153035 demonstrates an increase in potency over that of other tyrosine kinase inhibitors of four to five orders of magnitude for inhibition of isolated EGF receptor tyrosine kinase and three to four orders of magnitude for inhibition of cellular phosphorylation.

3T3 Cells↗
PubMed1994

The use of the Nordic questionnaire in an industrial setting: a case study.

The aims of this study were to identify: (1) whether patterns of reported injury are differentially affected by the structure of the interview and qualifications of the interviewer; and (2) whether the Nordic Questionnaire is sensitive enough to identify different patterns of reported injuries across two different workstations. To accomplish this the Standardized Nordic Questionnaire was administered by both a physiotherapist and an ergonomist to two similar but separate workstations of a manufacturing plant. Analysis of the injury-reporting frequencies produced results indicating increased reporting to the ergonomist in two of five upper limb and trunk body regions considered at one workstation and in one region at the other. Differences in reporting frequencies between workstations were also found. Physical demands analyses performed in each area confirmed that differing job requirements existed in the two workstations under consideration. Early identification of potential job-specific injuries by an in-house ergonomist can initiate appropriate intervention strategies prior to the onset of chronic injuries.

Journal Article↗
PubMed1994

The routine use of Rh-negative reagent red cells for the identification of anti-D and the detection of non-D red cell antibodies.

BACKGROUND: Before 1987, fewer than 50 patients per year at the authors' laboratory had a positive antibody detection test due to antepartum Rhesus immunoprophylaxis. However, after 1987, a marked increase was observed in the number of patients who had received Rh immune globulin (RhIG) during pregnancy as part of routine antepartum Rh immunoprophylaxis. In anticipation that an increased use of RhIG during pregnancy would increase the number of patients in whom anti-D was detected by this laboratory, a protocol was developed to abbreviate the process required to identify anti-D. Although this protocol was adopted primarily to address an anticipated increase in antenatal RhIG usage in women, it was also applied to alloimmunized Rh-negative males. STUDY DESIGN AND METHODS: When an Rh-negative patient (male or female) had a reactive screening test for unexpected antibodies and met certain other criteria, the patient's serum was tested with a three-vial set of Rh-negative reagent red cells (Rh-negative screening RBCs), instead of with panels of typed RBCs (panel RBCs), for the identification of anti-D or the detection of non-D antibodies. If the serum under test did not agglutinate or hemolyze Rh-negative screening RBCs, anti-D was identified and no further testing was performed. If the serum agglutinated or hemolyzed Rh-negative screening RBCs, conventional testing with panel RBCs was done to determine the antibody specificity. RESULTS: Rh-negative patients (n = 1174) who had reactive screening tests for unexpected antibodies were tested with Rh-negative screening RBCs; 1079 were found to have anti-D as a single antibody. Seven of these patients subsequently developed a non-D alloantibody, after transfusion or pregnancy, and one patient had anti-C that escaped detection at the time of initial testing with Rh-negative RBCs (a false-negative result). Ninety-two patients had anti-D in combination with a non-D antibody, and three patients had a non-D antibody but not anti-D. Use of the anti-D identification protocol actually reduced the laboratory workload by 176 College of American Pathologists workload units per month, in spite of a marked increase in the number of patients in whom anti-D was detected. No hemolytic transfusion reaction was attributed to the abbreviation of anti-D identification. CONCLUSION: The identification of anti-D may be abbreviated without jeopardizing patient safety. Such a protocol can reduce laboratory workload and might be particularly appealing to health care facilities that perform antibody detection testing on large numbers of Rh-negative pregnant women, especially if antepartum RhIG is administered routinely.

Erythrocytes↗
PubMed1994

Strategies for the discovery of novel tyrosine kinase inhibitors with anticancer activity.

We present a general drug discovery strategy to find novel inhibitors of tyrosine kinases. This scheme includes the production of initial protein targets for primary screening, an evaluation of enzyme potency and specificity, biochemical and biological effects on various cellular processes in whole-cell models, and strategies for in vivo evaluation of antitumor activity. These aspects are illustrated using a newly discovered class of tyrosine kinase inhibitors, the 2-thioindoles. Certain members of this class of compounds inhibit specific tyrosine kinases at low micromolar concentrations and exhibit a distinct structure-activity relationship, as well as enzyme specificity depending on the chemical substitution. These compounds suppress growth factor-mediated tyrosine phosphorylation and mitogenesis in viable cells and, in some cases, exhibit marked specificity for these effects depending on the substituents on the indole ring system. The issue is stressed that since inhibitors of signal transduction pathways represent an entirely new class of potential antitumor agents, distinct from past and currently used cancer therapies, alternative in vivo tumor models may be needed as well as different requirements for dose levels, scheduling and endpoint evaluation. These inherent difficulties emphasize a need for more basic research at the in vivo stage of drug evaluation to enhance model development and provide a better understanding of the pharmacology for these newer classes of drugs.

3T3 Cells↗
PubMed1993

In vitro and in vivo analysis of the inability of fetal rabbit wounds to contract.

Fetal rabbit wounds that are sutured show excellent repair without obvious scarring. In contrast, an unsutured wound in a rabbit fetus does not close, and it appears that the process of wound contraction does not occur. Experiments were carried out to illustrate the mechanisms responsible for the noncontraction of open fetal rabbit wounds. Results showed that the lack of wound contraction was not an artifact caused by rapid fetal growth. With regard to the ability of cultured fetal fibroblasts to show cytoplasmic muscle-induced cell contraction, we found that, in cultured fetal fibroblasts, cell contraction was induced by adenosine triphosphate. Contractile abilities of fetal-derived fibroblasts were equivalent to those of adult-derived fibroblasts. The fetal fibroblasts also demonstrated the generation of superior contractile activity when examined in a fibroblast-populated collagen lattice model. Finally, the ability of amniotic fluid to alter wound contraction was addressed by means of the fibroblast-populated collagen lattice in vitro model. Increasing concentrations of amniotic fluid inhibited fetal fibroblast lattice contraction. Therefore, rabbit amniotic fluid contains an inhibitor that may be partially responsible for the noncontraction of fetal rabbit wounds in utero.

Journal Article↗
PubMed1993

Obstetric hemorrhage and blood utilization.

Patients on a busy obstetric service were prospectively evaluated to determine which ones required blood transfusion. During the period January-April 1990, 5,528 deliveries were performed. Fifty-five patients (0.99%) received blood transfusions during their pregnancy and puerperium. The most common conditions associated with transfusion were trauma due to instrumental delivery (16), uterine atony (15), placenta previa (12), retained products of conception (4), abruptio placentae (4) and coagulopathy secondary to the HELLP syndrome (1). Platelets, fresh frozen plasma, whole blood and cryoprecipitate were administered to 7, 6, 1 and 1 patients, respectively. The transfusion rates by procedure were emergency cesarean hysterectomy for bleeding placenta previa or atony, 7/7 (100%); vacuum extraction, 7/114 (6.1%); forceps delivery, 12/285 (4.2%); uncomplicated cesarean delivery, 10/704 (1.4%); and spontaneous vaginal birth, 19/4,425 (0.4%). The hemorrhage and subsequent need for a blood transfusion were not necessarily due to the procedure except in the case of trauma due to instrumental vaginal delivery. The rate of transfusion of red blood cells for patients undergoing vaginal instrumental delivery was significantly higher than the rate for those undergoing cesarean delivery (relative risk, 2.8; 95% confidence interval, 1.5-5.2). The need for transfusion can be anticipated on the basis of antepartum causes in only 23.7% of patients ultimately receiving blood products.

Adult↗
PubMed1992

Ferritin-iron increases killing of Chinese hamster ovary cells by X-irradiation.

Stationary-phase Chinese hamster ovary cells were cultured in medium containing ferritin (approximately 19% iron by weight) added at concentrations ranging from 0 to 128 micrograms/ml. One set of cultures was unirradiated, and another set was exposed to 4.0 Gy of X-ray. Clonogenic cell survival was assessed in each set of cultures. In the absence of added ferritin, 4.0 Gy killed approximately 50% of the cells. In the absence of radiation, ferritin was not toxic at less than 48 micrograms/ml; above 48 micrograms/ml, toxicity increased with concentration. Apoferritin was not toxic at any concentration tested (up to 1000 micrograms/ml). Although 32 micrograms/ml ferritin, reflecting only a 3-6 fold increase in iron concentration over normal serum, was not toxic, it reduced the survival of X-irradiated cells by an additional 75%. These results indicate that a sublethal concentration of ferritin can be a potent radiosensitizer. This suggests the possibility that high body iron stores may increase susceptibility to radiation injury in humans.

Animals↗