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Biomedical subjects

D Olson

Publications and source records attributed to D Olson.

At least 19 recordsLinked to original sources

From individuals to aggregations: the interplay between behavior and physics.

This paper analyses the processes by which organisms form groups and how social forces interact with environmental variability and transport. For aquatic organisms, the latter is especially important-will sheared or turbulent flows disrupt organism groups? To analyse such problems, we use individual-based models to study the environmental and social forces leading to grouping. The models are then embedded in turbulent flow fields to gain an understanding of the interplay between the forces acting on the individuals and the transport induced by the fluid motion. Instead of disruption of groups, we find that flows often enhance grouping by increasing the encounter rate among groups and thereby promoting merger into larger groups; the effect breaks down for strong flows. We discuss the transformation of individual-based models into continuum models for the density of organisms. A number of subtle difficulties arise in this process; however, we find that a direct comparison between the individual model and the continuum model is quite favorable. Finally, we examine the dynamics of group statistics and give an example of building an equation for the spatial and temporal variations of the group-size distribution from the individual-based simulations. These studies lay the groundwork for incorporating the effects of grouping into models of the large scale distributions of organisms as well as for examining the evolutionary consequences of group formation.

Animals

A humanized form of a CD4-specific monoclonal antibody exhibits decreased antigenicity and prolonged plasma half-life in rhesus monkeys while retaining its unique biological and antiviral properties.

Certain monoclonal antibodies (MAbs) directed against CD4 can efficiently block HIV-1 replication in vitro. To explore CD4-directed passive immunotherapy for prevention or treatment of AIDS virus infection, we previously examined the biological activity of a nondepleting CD4-specific murine MAb, mu5A8. This MAb, specific for domain 2 of CD4, blocks HIV-1 replication at a post-gp120-CD4 binding step. When administered to normal rhesus monkeys, all CD4+ target cells were coated with antibody, yet no cell clearance or measurable immunosuppression occurred. However, strong anti-mouse Ig responses rapidly developed in all monkeys. In the present study, we report a successfully humanized form of mu5A8 (hu5A8) that retains binding to both human and monkey CD4 and anti-AIDS virus activity. When administered intravenously to normal rhesus monkeys, hu5A8 bound to all target CD4+ cells without depletion and showed a significantly longer plasma half-life than mu5A8. Nevertheless, an anti-hu5A8 response directed predominantly against V region determinants did eventually appear within 2 to 4 weeks in most animals. However, when hu5A8 was administered to rhesus monkeys chronically infected with the simian immunodeficiency virus of macaques, anti-hu5A8 antibodies were not detected. Repeated administration of hu5A8 in these animals resulted in sustained plasma levels and CD4+ cell coating with humanized antibody for 6 weeks. These studies demonstrate the feasibility of chronic administration of CD4-specific MAb as a potential means of treating or preventing HIV-1 infection.

Amino Acid Sequence

Recycling of the urokinase receptor upon internalization of the uPA:serpin complexes.

The GPI-anchored urokinase plasminogen activator receptor (uPAR) does not internalize free urokinase (uPA) but readily internalizes and degrades uPA:serpin complexes in a process that requires the alpha2-macroglobulin receptor/low density lipoprotein receptor-related protein (alpha2MR-LRP). This process is accompanied by the internalization of uPAR which renders it resistant to phosphatidylinositol-specific phospholipase C (PI-PLC). In this paper we show that during internalization of uPA:serpins at 37 degrees C, analysed by FACScan, immunofluorescence and immunoelectron microscopy, an initial decrease of cell surface uPAR was observed, followed by its reappearance at later times. This effect was not due to redistribution of previously intracellular receptors, nor to the surface expression of newly synthesized uPAR. Recycling was directly demonstrated in cell surface-biotinylated, uPA:PAI-1-exposed cells in which biotinylated uPAR was first internalized and subsequently recycled back to the surface upon incubation at 37 degrees C. In fact, uPAR was resistant to PI-PLC after the 4 degrees C binding of uPA:PAI-1 to biotinylated cells, but upon incubation at 37 degrees C PI-PLC-sensitive biotinylated uPAR reappeared at the cell surface. Binding of uPA:PAI-1 by uPAR, while essential to initiate the whole process, was, however, dispensable at later stages as both internalization and recycling of uPAR could be observed also after dissociation of the bound ligand from the cell surface.

Animals

Case report: field-acquired subclinical Babesia equi infection confirmed by in vitro culture.

A horse with no prior clinical history of equine piroplasmosis tested negative for Babesia caballi and Babesia equi in the complement fixation test before importation into the United States from France. After 5 years in residence in the United States, the animal tested serologically positive for B. equi by the complement fixation test, the immunofluorescent antibody test, and Western blot analysis. The carrier status of the horse was confirmed by culture of B. equi parasites. In vitro culture offers an efficient and comparatively inexpensive method to determine the carrier status of horses suspected of harboring B. equi.

Animals

What is training?

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Journal Article

Delirium and right-hemisphere dysfunction in cognitively impaired older persons.

Cognitive impairment has been repeatedly shown to be a delirium risk factor. Much indirect evidence suggests that right-hemisphere dysfunction plays a particularly important role. This retrospective, case-controlled study, from a 148-patient memory loss clinic database, compared neuropsychological measures of hemispheric function in cognitively impaired elderly veterans with and without a history of delirium. Eleven study subjects had a history compatible with DSM-III-R criteria for delirium. Controls selected from the same database had no known history of delirium and were matched for Mini-Mental State Examination scores and Geriatric Depression Scale scores. Compared to the controls, subjects with a history of delirium had significantly lower scores on Object Assembly and Visual Reproduction (p < .05), tests that are predominantly right-hemisphere dependent. There were no significant differences in left-hemisphere measures. It is concluded that right-hemisphere dysfunction may prove to be an important risk factor for delirium.

Aged

Nonluteal estrous cycles of 3-week duration are initiated by anovulatory luteinizing hormone peaks in African elephants.

Previous attempts to characterize the estrous cycle of elephants have yielded conflicting estimates of cycle length and LH profiles. In order to establish artificial breeding programs in this species, resolution of these issues is needed. Therefore, four female African elephants housed at the Indianapolis Zoo were studied for approximately 6 mo beginning in December 1994. Blood was collected weekly, and the serum was immediately analyzed for progesterone (P4). Whenever the weekly concentration of P4 was found to be low, blood was collected one or four times per day. All serum samples were assayed for LH, and the daily samples were assayed for P4 and estradiol. Transient increases of serum LH (designated as peaks) were observed four times in each of the four females. Of these 16 LH peaks, 8 were classified as ovulatory LH (ovLH) peaks and 8 were classified as anovulatory LH (anLH) peaks. Peaks designated ovLH averaged 3.60 +/- 0.67 ng/ml (mean +/- SEM); serum P4 measured during these peaks began to increase 2-3 days before each ovLH peak and continued to increase for several weeks thereafter, reaching a peak of 675 +/- 35 pg/ml. The eight other LH peaks, designated anLH peaks, were of similar (p > 0.05) magnitude averaging 3.07 +/- 0.72 ng/ml, but the serum concentration of P4 remained very low (< 80 pg/ml) during and for several weeks after these peaks. Six peaks designated anLH occurred an average of 12.2 +/- 1.4 days after serum P4 had declined below 80 pg/ml. In each elephant, there was a regular sequence in which each ovLH peak was followed by a luteal-active period lasting about 60 days and then about 12 days later by one anLH peak. Each anLH peak was followed 19-22 days later by one ovLH peak, but serum P4 remained at nonluteal levels throughout this interval between peaks. The authors propose to designate this interval after the anLH peak and before the next ovLH peak as a nonluteal (i.e., low P4) estrous cycle of only 3-wk duration. Following each short nonluteal estrous cycle, there was a single ovLH peak that initiated one luteal-active estrous cycle lasting 10-11 wk until terminated by the next anLH peak. The present results demonstrate that nonpregnant African elephants, housed in the absence of males, alternate between short nonluteal estrous cycles and long luteal-active estrous cycles. Daily measurements of serum P4 can be used to distinguish between the two types of estrous cycles and thereby provide a clinical prediction about the optimum time for artificial insemination.

Animals

Sedation of critically ill patients during mechanical ventilation. A comparison of propofol and midazolam.

Propofol (P) and midazolam (M) are frequently given by continuous infusion for sedation in critically ill, mechanically ventilated patients. We compared these drugs with regard to: (1) time-to-awaken; (2) reproducibility of bedside assessments of level of sedation; (3) time-to-sedation; and (4) change in oxygen consumption (V O2) from awake to sedated state. Seventy-three patients were prospectively randomized to receive either P (n=37) or M (n=36). Wake-up times after stopping the drug were assessed by blinded and unblinded observers, by asking patients to perform simple tasks. Times to sedate were assessed by consensus agreement among nurses and investigators. Demographics and APACHE II scores were not different between P and M. The P group had a significantly narrower range of wake-up times with a higher likelihood of waking in less than 60 min. Blinded versus unblinded observations had excellent correlation. Average time to sedate and decrease in V O2 were not different. We conclude that in this patient population: (1) both P and M achieved optimal sedation in a large fraction of patients when administered by specified dosing protocols; (2) P had a faster, more reliable, wake-up time; (3) assessments of time-to-awaken were objective and reproducible; (4) time to sedation was not significantly different; (5) V O2 decreased similarly with both.

APACHE

Administration of low-dose dopamine to nonoliguric patients with sepsis syndrome does not raise intramucosal gastric pH nor improve creatinine clearance.

Tissue hypoxia resulting from regional blood flow abnormalities and oxygen extraction defects may underlie the pathogenesis of multiple system organ failure (MSOF) in sepsis. Low-dose dopamine (LDD) is widely employed to enhance splanchnic perfusion although data to support this approach are lacking. We assessed the effect of LDD on surrogate markers of renal and gastric perfusion. Sixteen nonoliguric mechanically ventilated patients with sepsis syndrome received LDD (3 micrograms/kg/min) or placebo in a double-blind crossover design experiment. Hemodynamics, gastric intramucosal pH (pHi) urine volumes, urinary sodium excretion, and cimetidine-corrected creatinine clearance were compared. Mortality for the group was 63%. LDD caused a significant increase in urine volume (88 +/- 58 to 115 +/- 70 ml/h, p = 0.02, 95% confidence interval for change 4.7 to 49 ml/h), but no significant change in any other parameter. We conclude that use of LDD results in diuresis but does not improve other markers of renal or gut perfusion. These data do not support the use of LDD to reduce risk of progression to MSOF in sepsis.

Adult

Xenobiotic metabolism enzyme gene expression in human bronchial epithelial and alveolar macrophage cells.

Human bronchial epithelial cells (BEC), a primary defense against inhaled materials, are the progenitor cells for bronchogenic carcinomas and have important metabolic capabilities. We used reverse transcriptase-polymerase chain reaction (RT-PCR) to identify xenobiotic metabolism enzymes expressed in primary BEC and alveolar macrophages (AM) of non-smoking volunteers. Cytochromes P450 (CYP) 1A1, 1B1, 2B7, 2E1, and 4B1 and microsomal epoxide hydrolase (mEH) were expressed in BEC but not AM. CYP2F1 was expressed in BEC, but it was expressed at barely detectable levels or not at all in AM. NADPH oxidoreductase (NADPH OR), microsomal glutathione transferase (GST 12), glutathione transferase mu, phenol sulfotransferase (PST), thermolabile phenol sulfotransferase (TL PST), and the clara cell-specific gene, CC10 were expressed in both BEC and AM. CYP3A4 and glucuronosyl transferases-1 and 2 were not expressed in either BEC or AM. In contrast to primary BEC, of the genes evaluated, the immortalized human bronchial epithelial cell line BEP2D constitutively expressed only CYP1A1, CYP2E1, NADPH OR, glucuronosyl transferase 1, GST 12, GST mu, PST, TL PST, and CC10. The loss of xenobiotic metabolism enzyme gene expression in the BEP2D cell line may result from either reduced exposure to inducing agents, or loss of differentiative characteristics in culture. It is clear from the data comparing BEC and AM that there are important intertissue differences in expression of xenobiotic metabolism enzymes.

Base Sequence

A technique for porcine hepatocyte harvest and description of differentiated metabolic functions in static culture.

Current bioartificial liver devices are based on the use of a large mass of hepatocytes exhibiting differentiated metabolic function. The pig has become a source of interest for the acquisition of such cells-however, harvesting a large mass of highly viable cells has met with difficulty. This study describes a technique for harvesting large quantities of hepatocytes at viabilities greater than 90% and also describes several features documenting differentiated function. Pigs, 6 to 10 kg body weight, underwent in situ two-step whole liver perfusion (ethylene glycol tetraacetic acid and collagenase) and ex vivo cell harvest. Harvests yielded an average of 19.5 billion cells with an average viability of 94.6%. Hepatocytes were then entrapped in type I collagen (3 x 10(5) cells/well) and cultured in serum-free media for 5 days. Pig hepatocytes produced stable amounts of albumin and maintained cytochrome P-450 and glucuronidation activity over 5 days, as shown by the metabolism of lidocaine and 4-methylumbelliferone. These data indicate that pig hepatocytes can be harvested with high yields and can retain viability and differentiated function over at least 5 days of culture, and therefore should prove to be an excellent source of hepatocytes for bioartificial liver devices.

Animals

Expression of relB is required for the development of thymic medulla and dendritic cells.

Dendritic cells (DC) derived from bone marrow are critical in the function of the immune system, for they are the primary antigen-presenting cells in the activation of T-lymphocyte response. Their differentiation from precursor cells has not been defined at a molecular level, but recent studies have shown an association between expression of the relB subunit of the NF-kappa B complex and the presence of DC in specific regions of normal unstimulated lymphoid tissues. Here we show that relB expression also correlates with differentiation of DC in autoimmune infiltrates in situ, and that a mutation disrupting the relB gene results in mice with impaired antigen-presenting cell function, and a syndrome of excess production of granulocytes and macrophages. Thymic UEA-1+ medullary epithelial cells from normal mice show striking similarities to DC and, interestingly, these cells are also absent in relB mutant mice. Taken together, these results suggest that relB is critical in the coordinated activation of genes necessary for the differentiation of two unrelated but phenotypically similar cells (DC and thymic UEA-1+ medullary epithelial cells) and is therefore a candidate for a gene determining lineage commitment in the immune system.

Amino Acid Sequence

PMA-induced down-regulation of the receptor for alpha 2-macroglobulin in human U937 cells.

Transcription and expression of the urokinase (uPA) receptor (uPAR) are strongly stimulated by PMA. As for uPAR, the expression of alpha 2-MR is regulated by PMA in U937 cells. Ligand blotting experiments with the 39 kDa receptor-associated protein RAP, a ligand for alpha 2-MR, indicated that alpha 2-MR levels first increased and then decreased after PMA treatment. FACscan as well as immunoblotting analysis with alpha 2-MR-specific antibodies showed an identical trend: alpha 2-MR levels increased within the first day of treatment with PMA, decreased at later times, and totally disappeared by three days of treatment. The effect of PMA was not due to transcriptional down-regulation, as the alpha 2-MR mRNA level did not decrease at later times. Sensitivity of U937 cells to uPA-saporin, a toxin conjugate that reguires binding to uPAR for killing activity, was also markedly decreased. These results suggest that uPAR-mediated endocytosis depends on alpha 2-MR expression.

Base Sequence

Congenital cytomegalovirus infection as a result of nonprimary cytomegalovirus disease in a mother with acquired immunodeficiency syndrome.

A pregnant woman with acquired immunodeficiency syndrome had nonprimary cytomegalovirus (CMV) viremia and died of complications from Pneumocystis carinii pneumonia and CMV sinusitis and pneumonitis. A boy was delivered by cesarean section at 34 weeks of gestation as the mother's health deteriorated and fetal distress developed. The infant died soon after delivery of interstitial pneumonitis and hyaline membrane disease with invasive CMV disease that affected the kidneys, adrenal glands, and placenta; the CMV strains from the mother and neonate were identical.

AIDS-Related Opportunistic Infections

In vivo administration of CD4-specific monoclonal antibody: effect on provirus load in rhesus monkeys chronically infected with the simian immunodeficiency virus of macaques.

Since monoclonal antibodies (MAb) specific for CD4 are potent inhibitors of HIV and SIV replication in vitro, we explored their potential usefulness in vivo as an AIDS therapy. The anti-CD4 MAb 5A8 binds to domain 2 of the CD4 molecule and inhibits virus replication and virus-induced cell fusion at a postvirus binding step. Administration of this MAb to normal rhesus monkeys coats all circulating and lymph node CD4 cells and induces neither CD4 cell clearance nor measurable immunosuppression. In the present study, monkeys chronically infected with the simian immunodeficiency virus of macaques (SIVmac) had stable levels of SIVmac provirus in PBMC prior to treatment as measured by a quantitative polymerase chain reaction technique. Six infected monkeys treated with anti-CD4 MAb demonstrated a significant decrease in SIVmac provirus level after 9 days. Of these monkeys, 3 had > 800 CD4 cells/microliter and developed strong antimouse Ig responses that prevented further treatment. The remaining 3 monkeys had < 800 CD4 cell/microliter and failed to develop antimouse Ig antibody responses. When treatment was continued for 12-21 days in these monkeys, a sustained or further decrease in SIVmac provirus load occurred over the extended treatment period. Four monkeys that received a control MAb of irrelevant specificity for 9-22 days showed either no significant change or a transient increase in SIVmac provirus. Thus, the passive administration of anti-CD4 MAb may exert a specific antiviral effect in controlling immunodeficiency virus infection in vivo.

Animals

Effect of cooling on oxygen consumption in febrile critically ill patients.

Hyperthermic critically ill patients are commonly cooled to reduce their oxygen consumption (VO2). However, no previous studies in febrile humans have measured VO2 during cooling. We cooled 12 febrile, critically ill, mechanically ventilated patients while measuring VO2 and CO2 production (VCO2) by analysis of inspired and expired gases. All patients were mechanically ventilated for hypoxemic, hypercapneic, or shock-related respiratory failure and had a mean APACHE II score of 22.4 +/- 7.7. As temperature was reduced from 39.4 +/- 0.8 to 37.0 +/- 0.5 degrees C, VO2 decreased from 359.0 +/- 65.0 to 295.1 +/- 57.3 ml/min (p < 0.01) and VCO2 decreased from 303.6 +/- 43.6 to 243.5 +/- 37.3 ml/min (p < 0.01). The respiratory quotient (RQ) did not change significantly, and calculated energy expenditure decreased from 2,481 +/- 426 to 1,990 +/- 33 kcal/day (p < 0.01). In 7 patients with right heart catheters, cardiac output decreased from 8.4 +/- 3.2 to 6.5 +/- 1.8 L/min (p < 0.01) as the oxygen extraction fraction also tended to decrease from a mean of 28.2 +/- 6.8 to 23.4 +/- 4.7% (p = 0.12) during cooling. Accordingly, cooling the febrile patient unloads the cardiorespiratory system and, in situations of limited oxygen delivery or hypoxemic respiratory failure, may thus facilitate resuscitation and minimize the potential for hypoxic tissue injury.

APACHE

Factors contributing to the stability of social relationships between individuals with mental retardation and other community members.

Stability of social relationships may be an important indicator of lifestyle quality. Fourteen community members identified as being in long-term, socially stable relationships with one or more individuals with mental retardation provided answers to a quantitatively oriented questionnaire and participated in a more open-ended qualitative interview. In general, results indicated that the stability of the relationships was influenced by (a) the community members having previously served as staff members to the individuals with mental retardation, (b) their willingness to overcome logistical barriers that might otherwise have impeded their friendships, (c) their perception that the relationships included reciprocal social support, and (d) other idiosyncratic variables.

Activities of Daily Living