Biomedical subjects
Publications and source records attributed to D Johnson.
This article reviews selected physiological responses to trauma. These responses help the person to partly meet the challenge of the trauma by changing endocrine and metabolic functioning with the release of endogenous chemicals.
Point mutations and deletions in the p53 tumor suppressor gene occur frequently in advanced stage bladder tumors. To extend these observations to an in vitro model of bladder tumorigenicity, we have evaluated the presence of p53 mutations in a panel of bladder carcinoma cell lines. p53 alleles were cloned using the reverse transcriptase-polymerase chain reaction method, and exons 2-11 were sequenced. Of 11 cell lines examined, 5 cell lines had missense point mutations, and each overexpressed p53 protein on western blot analysis. Except for the HT-1197 cell line, these point mutations occurred in evolutionarily conserved domains, which are characteristic hot spots for mutations. HT-1197 encodes an unusual C-terminal point mutation in codon 365, within the basic motif tetramerization domain, suggesting a linkage between induction of a mutant p53 conformation and alterations in protein oligomerization. Six of 11 cell lines had wild-type levels of p53 expression, with 4 producing p53 proteins having either internal deletions or truncations, and 2 producing wild-type p53. Presence of wild-type p53 was found only in cell lines derived from either a low-grade, papillary tumor (RT4) or fetal bladder (FHs 738Bl). The T24 cell line was found to contain a novel p53 mutant having an in-frame deletion of tyrosine 126. This p53 mutant does not bind SV40 large T antigen, yet is expressed at low levels, comparable to cell lines containing wild-type p53 alleles. Our findings characterize p53 mutations in a panel of bladder carcinoma cell lines, and provide a model for testing the role of wild-type or mutant p53 cDNA to suppress or induce tumorigenic properties.
Explore the source record for details and available documents.
PURPOSE: Although numerous studies have examined morphologic changes in the trabecular meshwork of glaucomatous eyes, few have systematically looked for segmental variations around the circumference of the meshwork. If segmental variations occur, studies based on random sections or on single trabeculectomy specimens may not give a complete picture of the histologic changes in glaucoma. The purpose of this study was to determine the extent of segmental variability in human trabecular meshwork. METHODS: Eyes from five normal donors and eyes from five donors with primary open-angle glaucoma were obtained at autopsy. Histologic sections of each quadrant from nine of the normal eyes and eight of the glaucomatous eyes were analyzed. Light microscopy was used to measure the length of Schlemm's canal, the thickness of the trabecular lamellae, and the area of empty space in the juxtacanalicular (JCT) region. Transmission electron microscopy was used to examine the thickness of the JCT and the ultrastructural components of the JCT, which were quantitated with a computerized image analysis system. Ultrastructural analysis included JCT area, area of empty space, area of empty space touching Schlemm's canal, area of solid tissue, and area of sheath and tendon material. RESULTS: Differences among quadrants were qualitative rather than quantitative, because significant variations in structure were not found within single eyes. The variability among quadrants was similar for normal and glaucomatous eyes, with a coefficient of variation of approximately 20% for most tissue components. A greater variability was found for the thickness of the JCT. The largest variability was found for the area of empty space touching Schlemm's canal: 81.4% for normal eyes and 86.5% for glaucomatous eyes. No quadrant had consistently higher or lower values of any parameter. The length of Schlemm's canal did not differ significantly between normal and glaucomatous eyes (normal: 256.6 +/- 66.0 microns, glaucomatous: 298.8 +/- 57.7 microns), nor did the mean thickness of the trabecular lamellae (normal: 4.7 +/- 0.8 microns, glaucomatous: 4.8 +/- 0.5 microns). Light microscopy underestimated the total amount of empty space in the JCT by 20% compared with electron microscopy. CONCLUSIONS: Significant segmental differences were not found within single eyes in either normal or glaucomatous eyes. The magnitude of the variability of most tissue components was similar for normal and glaucomatous eyes. The most variable component was the area of empty space touching Schlemm's canal, which may represent the effective pathway for aqueous flow to enter Schlemm's canal. Future quantitative studies of the JCT should include samples from at least three quadrants per eye. Quantitative analysis of the JCT from a single quadrant, as occurs in the study of trabeculectomy specimens, may overestimate or underestimate the amount of solid tissue or empty space by 200%.
Demographic characteristics and risk factor data for 76,672 clients were studied to characterize the distribution of infection with human immunodeficiency virus (HIV) and the use of counseling and testing facilities in Houston, Tex. The number of clients who received free, voluntary HIV counseling and testing services between January 1990 and December 1992 doubled, while the seroprevalence rate declined from 6.1% to 2.9%. Rates were highest for white males, clients attending freestanding HIV testing sites, and those reporting male-to-male sexual contact. The number of females testing positive had increased by 67% over time and consisted almost entirely of blacks. Only 57% of clients who were tested returned for test results and received posttest counseling. Among those who were HIV negative, high-risk behaviors were frequently reported. Behavioral change must be reinforced, and priority must be given to contacting both seropositive and high-risk clients who seek testing.
The characterization of the enzymes responsible for drug metabolism in the human placenta is of great importance in determining the possible role the placenta plays in protecting the fetus from potentially fetotoxic drugs. We speculate that the placenta metabolizes cocaine, serving to protect the fetus from the drug's ill effects. Cholinesterase, the principle enzyme that metabolizes cocaine, has been hypothesized to be present yet is not well characterized in the human placenta. The purpose of this study was to quantify human placental acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activity. Human placentas were obtained from elective cesarean sections, and several lobules were thoroughly perfused with cold buffer to ensure minimal contamination from erythrocyte AChE. Subcellular fractions were then prepared from these lobules by using standard differential centrifugation techniques. Microsomes and cytosol were assayed for AChE and BChE activity by using a spectrophotometric assay. BChE activity was found in the cytosolic fraction of the placental villous tissue, whereas AChE activity was measured in the microsomal fraction. By demonstrating that BChE activity is present in human term placenta we have shown that this organ has the capacity to metabolize cocaine and may therefore serve as a metabolic barrier to fetal exposure to cocaine.
Endotoxin results in a granulocyte mediated loss of hypoxic pulmonary vasoconstriction (HPV). Dapsone blocks the granulocyte respiratory burst and might, therefore, preserve HPV following endotoxin. Isolated-perfused canine lobes (n = 6) were pretreated with 18 mg/kg dapsone (dapsone group), and compared to six lobes which did not receive dapsone (control group). Total pulmonary vascular resistance (Rtot) and arterial, middle (Rm), and venous segmental resistances were calculated by a vascular occlusion technique. We then administered endotoxin (2 mg/kg) and repeated measurements at 5, 30, and 90 min. The increase in Rm during 3% O2 compared to 35% O2 ventilation was used to define the presence of HPV. In the control group, following endotoxin, values of Rm did not change (P > 0.05) during 3% O2 ventilation (0.011 +/- 0.006 cm H2O/ml/min) compared with 35% O2 ventilation (0.014 +/- 0.005 cm H2O/ml/min). In the dapsone group, following endotoxin, values of Rm increased (P < 0.05) during 3% O2 ventilation (0.06 +/- 0.026 cm H2O/ml/min) compared with 35% O2 ventilation (0.03 +/- 0.015 cm H2O/ml/min). Changes in 6-keto PGF1 alpha or thromboxane B2 do not explain these observations. We conclude that in this experimental preparation, pretreatment with dapsone prevents the loss of HPV associated with endotoxin.
Explore the source record for details and available documents.
A pulmonary injury of varying severity occurs routinely after cardiopulmonary bypass. We studied the pulmonary complications of partial cardiopulmonary bypass in four groups of dogs to better define the injury and to evaluate the efficacy of two interventions (addition of a leukocyte filter or cyclooxygenase inhibition) on preservation of systemic oxygenation. All animals received a standard anesthetic (pentobarbital, morphine, and vecuronium) and, after sternotomy, three groups of animals received 3 hours of partial cardiopulmonary bypass. The animals were randomized to receive partial bypass alone (n = 6), indomethacin and bypass (n = 5), or a leukocyte filter and bypass (n = 5). A fourth group (n = 5) did not receive bypass and served as a time control. We measured blood gases and also obtained histologic samples to assess the degree of lung injury. We found that bypass alone caused a significant reduction (p < 0.05) in arterial oxygen tension 1 hour after the conclusion of bypass (175 +/- 53 mm Hg) compared with prebypass values (357 +/- 41 mm Hg). Pretreatment with indomethacin ameliorated the decrease in arterial oxygen tension from prebypass to postbypass values (477 +/- 50 mm Hg versus 339 +/- 57 mm Hg, respectively). Similarly use of a leukocyte filter reduced the decline in arterial oxygen tension from prebypass to postbypass values (440 +/- 71 mm Hg versus 311 +/- 73 mm Hg, respectively). We believe that indomethacin ameliorates the decline in systemic oxygenation associated with bypass by augmentation of hypoxic pulmonary vasoconstriction and that the leukocyte filter acted to reduce pulmonary edema and thereby minimized intrapulmonary shunt.
OBJECTIVE: To determine the effect of the presence of a patent foramen ovale on the right-to-left shunt in patients with respiratory failure who receive positive end-expiratory pressure (PEEP). DESIGN: Convenience sample with randomized application of PEEP. SETTING: General intensive care unit of a university teaching hospital. PATIENTS: A total of 46 mechanically ventilated patients with respiratory failure requiring an inspired oxygen concentration of at least 50% and a PEEP of at least 5 cm of H2O. INTERVENTION: Randomized application of PEEP (0 and 10 cm of H2O). MEASUREMENTS: A patent foramen ovale was detected by saline contrast transesophageal echocardiography. The alveolar-to-arterial oxygen difference and the right-to-left shunt were calculated from arterial and venous blood gas sampling. RESULTS: In patients without a patent foramen ovale (n = 39), the alveolar-to-arterial oxygen difference and the shunt fraction decreased (-50 mm Hg [95% CI, -21 to -67] and -0.05 [CI, -0.03 to -0.07], respectively) after adding PEEP (10 cm of H2O). In patients with a patent foramen ovale (n = 7), minimal changes were noted in the alveolar-to-arterial oxygen difference (4 mm Hg, P > 0.2), but the shunt fraction increased (0.05, CI, 0 to 0.09). Adding PEEP (10 cm of H2O) increased the shunt fraction in 6 of 7 (86%) patients with a patent foramen ovale, whereas the shunt increased in only 7 of 39 (18%) patients without a patent foramen ovale (P < 0.007). CONCLUSIONS: A patent foramen ovale was found in 7 of 46 patients (15%; CI, 6% to 29%) with acute respiratory failure. This condition is a common cause of lack of improvement in oxygenation with the addition of PEEP in the mechanically ventilated patient. In patients with a patent foramen ovale, the right-to-left shunt is usually increased by using PEEP.
Imipramine and desipramine were structurally modified by the attachment of spacer arms to the aromatic ring which were subsequently attached to bovine serum albumin. This approach utilized novel spacer arms and conjugation methods. This method yielded antisera with excellent selectivity and good titers. Rabbits were used to raise the antisera and the antibodies produced were characterized with respect to their cross-reactivity with imipramine, desipramine and hydroxy metabolites as well as selected structurally related compounds.
Amitriptyline and nortriptyline were structurally modified by the attachment of spacer arms to the aromatic ring which were subsequently attached to bovine serum albumin (BSA). Rabbits inoculated with these conjugates yielded polyclonal antisera with high selectivity and good titers. This approach required novel spacer arms and new conjugation methods. The antisera produced were characterized with respect to their cross-reactivity with amitriptyline, nortriptyline and their hydroxy metabolites as well as selected structurally related compounds.
BACKGROUND: Patients with metastatic (stage IV) non-small-cell lung cancer usually have a poor prognosis and disease refractory to chemotherapy. Three new agents--taxol, merbarone, and piroxantrone--have shown promising antitumor treatment in vitro and in animals. Taxol is an antimicrotubular agent that interferes with mitosis during cell division. Merbarone, a conjugate of thiobarbituric acid and aniline, is a topoisomerase II inhibitor, which thus inhibits DNA synthesis and tumor growth. Piroxantrone, an anthracenedione derivative, is a DNA intercalating agent that has shown potent antitumor activity in animal studies. PURPOSE: Our randomized phase II study was designed to evaluate the efficacy and toxicity of these agents in the treatment of stage IV metastatic non-small-cell lung cancer. METHODS: Eligible patients (119) were randomly assigned to receive one of the three treatments given every 3 weeks: 250 mg/m2 taxol by a 24-hour intravenous infusion, 1000 mg/m2 merbarone by continuous intravenous infusion through a central catheter daily for 5 days, or 150 mg/m2 piroxantrone by intravenous infusion over 1 hour. Patients had received no chemotherapy. Response and toxicity were evaluated every 3 weeks. RESULTS: Twenty-five patients were randomly assigned to receive taxol, 47 to receive merbarone, and 47 to receive piroxantrone. One of 44 assessable patients (2.3%) treated with piroxantrone had a complete response. Rates for partial response were 20.8% (five of 24 patients) and 5.7% (two of 35) for assessable patients treated with taxol or merbarone, respectively. One-year survival rates were 41.7%, 21.6%, and 22.6%, and median survival times were 24.1, 19.9, and 29.3 weeks for taxol, merbarone, and piroxantrone, respectively. These differences were not statistically significant, but this study was not designed to compare survival. In general, toxicity was manageable. With premedication, no anaphylaxis was observed with taxol. The most common toxic effects were leukopenia with taxol or piroxantrone treatment and thromboembolic complications with merbarone. Death directly related to treatment occurred in 4% (one patient), 11.4% (four), and 5% (two) of the assessable patients receiving taxol, merbarone, and piroxantrone, respectively. Cardiotoxicity and neurotoxicity occurred only occasionally in all three arms. CONCLUSION: On the basis of the response rate (20.8% partial response) and 1-year survival rate (41.7%), taxol is an active agent for the treatment of metastatic non-small-cell lung cancer. Merbarone and piroxantrone are relatively inactive. IMPLICATIONS: Further study of taxol is warranted. In future studies, taxol should be combined with other agents, and granulocyte colony-stimulating factor should be used to ameliorate myelosuppression.
To evaluate possible abnormal noradrenergic neuronal regulation in patients with posttraumatic stress disorder (PTSD), the behavioral, biochemical, and cardiovascular effects of intravenous yohimbine hydrochloride (0.4 mg/kg) were determined in 18 healthy male subjects and 20 male patients with PTSD. A subgroup of patients with PTSD were observed to experience yohimbine-induced panic attacks (70% [14/20]) and flashbacks (40% [8/20]), and they had larger yohimbine-induced increases in plasma 3-methoxy-4-hydroxyphenylglycol levels, sitting systolic blood pressure, and heart rate than those in healthy subjects. In addition, in the patients with PTSD, yohimbine induced significant increases in core PTSD symptoms, such as intrusive traumatic thoughts, emotional numbing, and grief. These data were consistent with a large body of preclinical data that indicated that uncontrollable stress produces substantial increases in noradrenergic neuronal function. We discuss the implications of these abnormalities in noradrenergic functional regulation in relation to the long-term neurobiological sequelae of severe uncontrollable stress and the pathophysiological relationship between PTSD and other anxiety disorders, such as panic disorder.
This paper focuses on mechanical inventiveness, the conception and development of new devices which require use of mechanical principles. In Phase 1 of the three-phase investigation, we studied 34 inventors who received between three and 82 agricultural and industrial patents. These inventors formed the original criterion group of mechanical inventors. Phase 2 of the investigation was the development of an inventiveness measure. From the criterion group of adult mechanical inventors, the Iowa Inventiveness Inventory (III) was developed to measure attitudes and characteristics of inventors. Subjects for Phase 3 of the study were 90 young inventors (40 males, 50 females), students (grades five to eight) who won local and regional invention contests and reached the state convention of Invent Iowa. In Phase 3, Invent Iowa state finalists in grades five to eight (n = 90) were administered the III and the Mechanical Reasoning test of the Differential Aptitude Tests. Characteristics of the young inventors, as delineated by these assessments, are provided.
The absorption and disposition kinetics of HI-6 were determined in Beagle dogs given single doses (25 mg kg-1) of the drug by the intravenous, intramuscular, and oral routes. Concentrations of the oxime in plasma and urine were measured by HPLC. A two-compartment open model was used to describe the disposition curve following intravenous drug administration while a one-compartment open model with first-order absorption adequately described the data following intramuscular or oral administration of the dose. Extravascular distribution of HI-6 was limited (Vss 203 ml kg-1) and the drug was eliminated rapidly after intravenous administration (t1/2 46.5 min, MAT 55.4 min). Systemic clearance was 3.68 ml min-1 x kg. A major fraction of the dose (63.7 per cent) was excreted in urine over a 24-h collection period. Following intramuscular drug administration, the absorption half-life (t1/2(a), 5.3 min), MAT (17.1 min), Cmax (70.37 micrograms ml-1) and tmax (15.9 min) indicate that the drug was rapidly absorbed. Systemic availability was 83.43 per cent after oral drug administration, absorption was preceded by a lag time (23.2 min). The t1/2(a) (41.5 min), MAT (81.6 min), Cmax (4.30 micrograms ml-1) and Tmax (90.6 min) indicate somewhat delayed absorption. Systemic availability (11.38 per cent) and the fraction of dose excreted unchanged in the urine (9.3 per cent) show that the drug was poorly absorbed. The apparent half-life (58.0 min) and MRT (137.6 min) following oral administration were significantly longer (p < 0.05) than following intravenous or intramuscular administration suggesting that the rate of absorption from the gastrointestinal tract decreases the elimination rate of the drug. In conclusion, HI-6 has limited distribution within the body, is rapidly eliminated mainly by renal excretion unchanged in the urine, and the bioavailability (i.e. rate and extent of absorption) of the drug varies with the route of administration.
Explore the source record for details and available documents.
The influence of parity on the risk of cancers of the female breast and reproductive organs is well established. However, non-reproductive sites have received less attention. Mail questionnaire data gathered from incident female cases (169 brain; 332 colon; 260 rectal; 145 kidney; and 169 pancreas cancers), and 821 population-based controls in Iowa (United States) were used to measure the effect of parity and age at first birth on risk of these malignancies. Relative to nulliparous women, ever-parous women were at significantly decreased risk of brain cancer (odds ratio [OR] = 0.44, 95 percent confidence interval [CI] = 0.3-0.7) and of colon cancer (OR = 0.67, CI = 0.5-0.97), after adjustment for age and other risk factors. The OR for the other sites did not differ significantly from 1.0. The lower risk of brain cancer among parous women was similar in younger and older age groups, in patients diagnosed with glioblastoma and astrocytoma, and among ever- and never-smokers. The findings for colon cancer are consistent with observations from other studies. In the context of limited laboratory and clinical evidence implicating hormones in brain neoplasia, these findings may suggest a role for hormonal factors in brain cancer etiology. Hormonal factors deserve more detailed future consideration as risk factors in brain cancer.