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R Brower

Publications and source records attributed to R Brower.

13 recordsLinked to original sources
PubMed1994

Predicting immunoglobulin-like hypervariable loops.

A two-stage method is developed to search the conformational space of small protein segments for low energy structures. Central features of the method are efficient procedures for generating small, eight-backbone atom, local moves in Cartesian coordinates and for introducing geometric constraints in adaptable Monte Carlo procedures. This allows natural implementation of an adaptive simulated annealing algorithm, which achieves an effective trade-off between speed and acceptance ratio. The method is applied to the calculation of various immunoglobulin loops. We also develop data base derived rules for identifying constraint condition, and show that the incorporation of an identified side-chain constraint allows a 1.2 A all-backbone atom rms deviation prediction of a 9 residue long L1 loop.

Immunoglobulin Variable Region↗
PubMed1994

Monte Carlo study of the effect of beta 2-microglobulin on the binding cleft of the HLA-A2 complex.

Peptide recognition by class I products of the major histocompatibility complex requires association of the class I heavy chain with beta 2-microglobulin. We present results of Monte Carlo simulations of the beta-pleated sheet floor of the human class I MHC molecule, HLA-A2, with and without beta 2-microglobulin. We find a significant effect of beta 2-microglobulin on the side chains of residues near a region that would accommodate the C-terminus of a bound peptide. By modeling simultaneously each loop and its neighboring strand at either end of the class I cleft, we find that beta 2-microglobulin restricts the conformational space of residues that are central to binding peptides. The effect is most pronounced for R97 and H114 and somewhat less important for Y99 and Y116, the latter forming strong hydrogen bonds with neighboring residues in the heavy chain itself.

Amino Acid Sequence↗
PubMed1994

Observations of ventilation during resuscitation in a canine model.

BACKGROUND: Fear of infection limits the willingness of laymen to do cardiopulmonary resuscitation (CPR). This study assessed the time course of change in arterial blood gases during resuscitation with only chest compression (no ventilation) in an effort to identify the time for which ventilation could be deferred. METHODS AND RESULTS: Aortic pressures and arterial blood gases were monitored in seven 20- to 30-kg dogs in ventricular fibrillation (VF) at 2-minute intervals during chest compression alone (no ventilation) at 80 to 100 compressions per minute. Before the induction of ventricular fibrillation, all animals were intubated and ventilated with room air, 10 mL/kg. The endotracheal tube was removed when VF was induced. Pre-VF arterial pH, PCO2, and O2 saturation were (mean +/- SEM) 7.39 +/- 0.02, 27.0 +/- 1.5 mm Hg, and 97.5 +/- 0.5%, respectively, with aortic pressures being 143.2 +/- 5.7/116.2 +/- 4.6 mm Hg. At 4 minutes of chest compression alone, the corresponding values were 7.39 +/- 0.03, 24.3 +/- 3.1 mm Hg, and 93.9 +/- 3.0%, with an arterial pressure of 48.1 +/- 7.7/22.6 +/- 3.9 mm Hg. Mean minute ventilation during the fourth minute of CPR, measured with a face mask-pneumotachometer, was 5.2 +/- 1.1 L/min. CONCLUSIONS: These data suggest that in the dog model of witnessed arrest, chest compression alone during CPR can maintain adequate gas exchange to sustain O2 saturation > 90% for > 4 minutes. The need for immediate ventilation during witnessed arrest should be reexamined.

Animals↗
PubMed1994

Effect of hypoxia on lung fluid balance in ferrets.

To determine how hypoxia may alter determinants of pulmonary transvascular fluid flux, adult male ferrets were exposed to either room air (C) or hypoxia (H; FIO2 = 0.12) for 24 h. After anesthesia and ventilation with C or H, the mean pulmonary artery pressures were 18.4 +/- 2.2 (SEM) and 27.3 +/- 2.9 mm Hg, respectively (p < 0.025). The right lung was then removed for gravimetric analysis of lung water and the left lung was blood-perfused (approximately 142 ml/kg/min) and continuously weighed for 15 min at left atrial pressures of 20, 25, and 30 mm Hg. Filtration coefficient (Kf) was estimated from the slopes of the relationships of rate of weight gain versus change in vascular pressure over the last 5 min of each interval. Extravascular lung water/blood-free dry lung weight for C and H were 2.95 +/- 0.06 (SEM) and 3.53 +/- 0.09 ml/g, respectively (p < 0.01). Kf for C and H were 0.0645 +/- 0.0190 (SEM) and 0.0662 +/- 0.0085 ml/min/mm Hg/100 g, respectively (NS). In a second group of experiments, in which lungs were removed from ferrets after 24 h exposures to C or H, protein reflection coefficients (sigma) were estimated by comparing the increases in perfusate hematocrit and protein concentrations during edema formation. Reflection coefficients for albumin were 0.64 +/- 0.03 (SEM) and 0.39 +/- 0.07 with C and H, respectively (p < 0.01). The sigma values for IgG and IgM were not affected.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1994

Should inverse ratio ventilation be used in adult respiratory distress syndrome?

IRV-induced increases in MAP are clearly associated with shunt reduction, but we find no studies that show shunt reduction without increased end-expiratory alveolar pressure. On the other hand, various studies in humans with ARDS and hyaline membrane disease and animal models of acute lung injury indicate that shunt reduction does not occur with IRV if there is no increase in end-expiratory alveolar pressure (21), that shunt reduction is the same with IRV as with conventional ventilation with PEEP when there are comparable levels of end-expiratory volume or alveolar pressure (16, 32), and that shunt reduction is greater when MAP is raised with PEEP than with IRV (27). Improved ventilation-perfusion matching with IRV is theoretically unlikely and, given the high FIO2 used in ARDS, improvements in oxygenation from more even ventilation would not be great. Deadspace reduction by extended inspiratory phase ventilation may allow only minor improvements in gas exchange (14-16, 21, 25, 26, 34). Thus, there is little evidence to indicate that oxygenation can be maintained or improved with IRV while volotrauma risk is reduced. Some have suggested that IRV may promote gradual shunt reduction over hours or days, and that slower inspiratory airflow may reduce injurious parenchymal shear forces. However, these potentially salutary effects of IRV are unproven. On the other hand, there are potential deleterious effects of IRV, including increased risk of volotrauma and the requirements for heavy sedation and neuromuscular blockage. IRV remains of unproven value in the management of ARDS.

Humans↗
PubMed1993

Role of conserved regions of class I MHC molecules in the activation of CD8+ cytotoxic T lymphocytes by peptide and purified cell-free class I molecules.

To analyze the molecular interactions involved in CD8+ cytotoxic T lymphocyte (CTL) recognition quantitatively, we developed a cell-free antigen presenting system. Genetically engineered soluble H-2Dd molecules coated on plastic microtiter plates could present HIV envelope peptide to an antigen-specific CTL clone, inducing it to produce IFN-gamma in the absence of accessory cells and their accessory or co-stimulatory molecules. The peptide-MHC complexes were functionally stable for over 24 h. The magnitude of T cell activation was dependent on the concentrations of both class I MHC molecule and the peptide, but was more sensitive to the concentration of the MHC molecule than to that of peptide. This result suggests that one MHC molecule can play more than one role in activating the CTL. One such role is the interaction between CD8 and a conserved region of class I MHC, as suggested by the finding that holding the total MHC concentration constant with an irrelevant class I MHC molecule (H-2Kb engineered to have the same alpha 3 domain as H-2Dd) made the T cell response less sensitive to the change in concentration of the relevant MHC molecule (H-2Dd). The irrelevant class I MHC molecule (H-2Kb), unable to present this peptide by itself, augmented the T cell response at lower concentrations of peptide. These results suggest that the conserved alpha 3 domain of the class I MHC heavy chain as well as polymorphic regions play an important role in T cell activation and that T cell interaction with MHC molecules not presenting peptide can still augment the response.

Amino Acid Sequence↗
PubMed1993

Factors influencing measurement of protein reflection coefficient by filtered volume technique.

In isolated perfused organs, the protein reflection coefficient (sigma) can be estimated by comparing increases in hematocrit (Hct) and protein concentration (CP) during transvascular fluid filtration. In this study, we developed an equation for sigma to examine the potential influences of perfusate leak, evaporation, and hemolysis-induced changes in red blood cell volume and perfusate water. We also performed experiments in isolated ferret lungs to quantitate the magnitude of these potential sources of error and the effects of free hemoglobin on measurements of CP. These studies demonstrated that 1) perfusate leak does not cause an error because its effects on changes in Hct and CP counteract each other; 2) evaporation causes an overestimation of sigma, but in our experiments this effect was small; 3) hemolysis-induced changes in red blood cell and perfusate water volumes may cause an over- or underestimation of sigma, but these effects are small; 4) overestimations of CP due to increasing free perfusate hemoglobin concentration can cause substantial overestimations of sigma; and 5) values of sigma calculated from previous equations and from our equation were virtually identical, suggesting that the assumptions necessary for the previous equations were not significant sources of error. In agreement with previous workers, we conclude that the most important potential source of error is hemolysis-induced increases in free perfusate hemoglobin.

Animals↗
PubMed1989

Air trapping in the lungs during cardiopulmonary resuscitation in dogs. A mechanism for generating changes in intrathoracic pressure.

To test the hypothesis that during cardiopulmonary resuscitation, chest compression with an unobstructed trachea raises and maintains intrathoracic pressure by collapsing airways and trapping air in the lung, we studied 11 dogs (20-32 kg). An inflatable vest compressed the thorax after induction of ventricular fibrillation. First, tracheal airflow was measured by a pneumotachometer during vest inflation and deflation in nine of the dogs. As expected, during the initial phase of vest inflation of cycles after ventilation, air moved out of the lungs, but then airflow stopped. After vest deflation, however, more air moved out of the lungs in eight of the nine dogs; this occurrence indicated that a portion of the inspired tidal volume was trapped during vest inflation. During cycles without prior ventilation, the amount of air expired by chest compression decreased, paradoxically, at higher peak vest pressure (p less than 0.002); this occurrence indicated that air was trapped at the higher vest pressures. The change in right atrial pressure was higher on cycles after ventilation than on cycles without prior ventilation (79 +/- 12 vs. 67 +/- 12 mm Hg [mean +/- SEM], p less than 0.005), and lung volume was higher on cycles after ventilation (p less than 0.001). Next, a 5-Fr micromanometer was advanced down the airway in eight of the dogs. With the tip of the micromanometer 5-8 cm distal to the carina, a zone of high pressure was noted in seven dogs; this high pressure suggested a zone of airway collapse distal to the carina.(ABSTRACT TRUNCATED AT 250 WORDS)

Air↗
PubMed1988

Cyclic elevation of intrathoracic pressure can close the mitral valve during cardiac arrest in dogs.

Mitral valve closure during cardiopulmonary resuscitation may result from direct cardiac compression. An alternative hypothesis is that with a rise in intrathoracic pressure, mitral valve closure can occur but may be influenced by whether the lungs are inflated or deflated. To test this hypothesis, we placed a large-bore cannula into the thoraces of 11 dogs. Intrathoracic pressure was changed by inflating and deflating the thorax through the cannula while the airway was open, as well as by inflating and deflating the lungs with the thoracic cannula clamped. Mitral valve motion was observed with two-dimensional echocardiography from the right chest wall or esophagus in eight of the dogs. With a rise in intrathoracic pressure from thoracic inflation, all eight dogs showed closure of the mitral valve, while with thoracic deflation, all showed mitral valve opening. With lung inflation and deflation alone, however, the mitral valve remained open throughout the cycle. In seven dogs, with thoracic inflation, the peak gradient from the left ventricle to the left atrium was (mean +/- SEM) 18 +/- 4 mm Hg and the average gradient was 7 +/- 3 mm Hg, while with lung inflation alone, the average gradient was -1 +/- 1 mm Hg (p less than 0.01 vs. thoracic inflation). Thus, mitral valve closure, with concomitant retrograde pressure gradients, can be produced by intrathoracic pressure changes with accompanying lung deflation. With lung inflation alone, however, the mitral valve remains open, and there are no significant transmitral pressure gradients. We conclude that intrathoracic pressure changes can cause the mitral valve to close or to remain open, depending on how intrathoracic pressure is generated.

Animals↗
PubMed1985

Effect of lung inflation on lung blood volume and pulmonary venous flow.

Phasic changes in lung blood volume (LBV) during the respiratory cycle may play an important role in the genesis of the respiratory wave in arterial pressure, or pulsus paradoxus. To better understand the effects of lung inflation on LBV, we studied the effect of changes in transpulmonary pressure (delta Ptp) on pulmonary venous flow (Qv) in eight isolated canine lungs with constant inflow. Inflation when the zone 2 condition was predominant resulted in transient decreases in Qv associated with increases in LBV. In contrast, inflation when the zone 3 condition was predominant resulted in transient increases in Qv associated with decreases in LBV. These findings are consistent with a model of the pulmonary vasculature that consists of alveolar and extra-alveolar vessels. Blood may be expelled from alveolar vessels but is retained in extra-alveolar vessels with each inflation. The net effect on LBV and thus on Qv is dependent on the zone conditions that predominate during inflation, with alveolar or extra-alveolar effects being greater when the zone 3 or zone 2 conditions predominate, respectively. Lung inflation may therefore result in either transiently augmented or diminished Qv. Phasic changes in left ventricular preload may therefore depend on the zone conditions of the lungs during the respiratory cycle. This may be an important modulator of respiratory variations in cardiac output and blood pressure.

Animals↗
PubMed1983

Flexible transbronchial needle aspiration for staging of bronchogenic carcinoma.

Flexible transbronchial needle aspiration (TBNA) provides access to mediastinal lymph nodes, but its role in staging bronchogenic carcinoma is unknown. To determine the efficacy and safety of this procedure for staging the extent of mediastinal disease, the results of TBNA performed during fiberoptic bronchoscopy in 39 patients without known extrathoracic metastases were reviewed. Flexible TBNA was found to be a safe, effective method for determining the presence or absence of mediastinal metastases from bronchogenic carcinoma. Furthermore, TBNA results compare favorably with roentgenographic staging techniques, with the added advantage of providing cytopathologic information.

Adenocarcinoma↗