Biomedical subjects

Steven J Mentzer

Publications and source records attributed to Steven J Mentzer.

At least 19 recordsLinked to original sources

PubMed2007

The murine bronchopulmonary microcirculation in hapten-induced inflammation.

OBJECTIVE: The clinical observation of central bronchial artery hypertrophy in chronic lung inflammation suggests the possibility that the bronchial circulation may also participate in adaptive responses in peripheral lung inflammation. METHODS: To investigate the potential role of the bronchial microcirculation in peripheral lung inflammation, we developed a murine model of lung inflammation using the intratracheal instillation of the peptide-hapten trinitrophenol in presensitized mice. RESULTS: Clinical parameters indicated a peak inflammatory response at 96 hours. Similarly, gross and microscopic evidence of inflammation was observed 96 hours after antigen instillation. Using a forced oscillation technique to probe peripheral lung mechanics at 96 hours, we detected no change in central airway resistance (P > .05), but a significant increase in peripheral tissue resistance (P < .05). The structure of the bronchial circulation was investigated by microsphere occlusion of the pulmonary circulation and corrosion casting of the bronchial circulation. SEM of the bronchial artery casts demonstrated (1) the presence of the peripheral bronchial circulation in mice, (2) interconnections of the two systems in the distal bronchial arteries and at the level of alveolar capillaries, and (3) functional evidence of increased bronchial perfusion of alveolar capillaries during mononuclear inflammation. CONCLUSION: These results suggest an important adaptive role of the bronchial circulation in pulmonary inflammation.

Animals↗

PubMed2006

A phase 1/2 trial of arginine butyrate and ganciclovir in patients with Epstein-Barr virus-associated lymphoid malignancies.

Malignancies associated with latent Epstein-Barr virus (EBV) are resistant to nucleoside-type antiviral agents because the viral enzyme target of these antiviral drugs, thymidine kinase (TK), is not expressed. Short-chain fatty acids, such as butyrate, induce EBV-TK expression in latently infected B cells. As butyrate has been shown to sensitize EBV(+) lymphoma cells in vitro to apoptosis induced by ganciclovir, arginine butyrate in combination with ganciclovir was administered in 15 patients with refractory EBV(+) lymphoid malignancies to evaluate the drug combination for toxicity, pharmacokinetics, and clinical responses. Ganciclovir was administered twice daily at standard doses, and arginine butyrate was administered by continuous infusion in an intrapatient dose escalation, from 500 mg/(kg/day) escalating to 2000 mg/(kg/day), as tolerated, for a 21-day cycle. The MTD for arginine butyrate in combination with ganciclovir was established as 1000 mg/(kg/day). Ten of 15 patients showed significant antitumor responses, with 4 CRs and 6 PRs within one treatment cycle. Complications from rapid tumor lysis occurred in 3 patients. Reversible somnolence or stupor occurred in 3 patients at arginine butyrate doses of greater than 1000 mg/(kg/day). The combination of arginine butyrate and ganciclovir was reasonably well-tolerated and appears to have significant biologic activity in vivo in EBV(+) lymphoid malignancies which are refractory to other regimens.

Adolescent↗

PubMed2006

Structural adaptations in the murine colon microcirculation associated with hapten-induced inflammation.

BACKGROUND: Blood flowing across the vascular endothelium creates wall shear stress, dependent on velocity of flow and vessel geometry, that tends to disrupt lymphocyte-endothelial cell adhesion. OBJECTIVE: The microcirculation in a murine model of acute colitis was investigated to identify structural adaptations during acute colitis that may facilitate transmigration. METHODS: In 2,4,6-trinitrobenzenesulphonic acid-induced acute colitis, the infiltrating cells and colonic microcirculation was investigated by cellular topographic mapping, corrosion casting and three-dimensional scanning electron microscopy (SEM). Colonic blood velocimetry was performed using intravital microscopy. RESULTS: Clinical and histological parameters suggested a peak inflammatory response at 96 h (p<0.001). The infiltrating cells were spatially related to the mucosal capillary plexus by three-dimensional topographic mapping (p<0.001). In normal mice, corrosion casting and three-dimensional SEM showed a polygonal mucosal plexus supplied by ascending arteries and descending veins. After 2,4,6-trinitrobenzenesulphonic acid stimulation, three-dimensional SEM showed preserved branch angles (p = 0.52) and nominal vessel lengths (p = 0.93), but a significantly dilated mucosal capillary plexus (p<0.001). Intravital microscopy of the mucosal plexus showed a greater than twofold decrease in the velocity of flow (p<0.001). CONCLUSIONS: The demonstrable slowing of the velocity of flow despite an increase in volumetric flow suggests that these microvascular adaptations create conditions suitable for leucocyte adhesion and transmigration.

Acute Disease↗

PubMed2006

Feature-guided clustering of multi-dimensional flow cytometry datasets.

BACKGROUND: Flow cytometry produces large multi-dimensional datasets of the physical and molecular characteristics of individual cells. The objective of this study was to simplify the cytometry datasets by arranging or clustering "objects" (cells) into a smaller number of relatively homogeneous groups (clusters) on the basis of interobject similarities and dissimilarities. RESULTS: The algorithm was designed to be driven by histogram features; that is, the relevant single parameter histogram features were used to guide multidimensional k-means clustering without an a priori estimate of cluster number. To test this approach, we simulated cell-derived datasets using protein-coated microspheres (artificial "cells"). The microspheres were constructed to provide 119 populations in 40 samples. The feature-guided (FG) approach accurately identified 100% of the predetermined cluster combinations. In contrast, an approach based on the partition index (PI) cluster validity measure accurately identified 83.2% of the clusters. Direct comparisons of the two methods indicated that the FG method was significantly more accurate than PI in identifying both the number of clusters and the number of objects within the clusters (p<.0001). CONCLUSION: We conclude that parameter feature analysis can be used to effectively guide k-means clustering of flow cytometry datasets.

Algorithms↗

PubMed2006

Multi-image particle tracking velocimetry of the microcirculation using fluorescent nanoparticles.

Particle tracking velocimetry provides a Lagrangian description of flow properties in the microcirculation. To determine the utility of fluorescent nanoparticles to provide Lagrangian coordinates, we tracked these particles both in vitro and in vivo. The particles had a neutral charge and fluorescence intensity greater than 1,000 times the PKH26-labeled red blood cells. At image acquisition rates of 60 frames per second, particles were tracked at velocities up to 4,000 microm/s. Morphometric changes reflecting streaking artifact were significant at velocities of 4,000 microm/s (P < 0.05), but not at lower velocities (P > 0.05). Intravital microscopy monitoring after intravenous injection of the particles demonstrated a circulation half-life that was inversely related to particle size: 500 nm nanoparticles demonstrated a smaller change in plasma concentration than larger particles. Regardless of the size of the particles, more than 50% of the recovered fluorescence was located in the liver. These results suggest that fluorescent nanoparticles provide a convenient and practical Lagrangian description of flow velocity in the microcirculation.

Animals↗

PubMed2006

Structural mapping of immunoglobulin subclasses using multiplexed bead flow cytometry.

Monoclonal hybridomas secrete immunoglobulin molecules with a single specificity and distinct class/subclass structure. The determination of immunoglobulin structure can be used to facilitate hybridoma colony management and predict monoclonality. In this report, we used multiplexed bead flow cytometry to define hybridoma class/subclass. The assay was sufficiently sensitive to detect 50 ng/mL of antibody. The multiplexed bead assay efficiently defined traditional class/subclass determinants as well as more subtle patterns of crossreactivity. Further, the assay was combined with Poisson statistics to provide a numerical estimate of hybridoma monoclonality. The sensitivity and flexibility of this approach suggests the utility of multiplexed bead flow cytometry in the early management of immunoglobulin-secreting hybridomas.

Animals↗

PubMed2006

Inflammation-responsive focal constrictors in the mouse ear microcirculation.

In many capillary exchange beds, blood flow is locally regulated by precapillary sphincter-like activity. In this study, we used intravascular tracers and scanning electron microscopy to investigate precapillary blood flow regulation in the mouse ear. Gelatin ink injections of the normal mouse ear demonstrated 6.8 +/- 2.3 axial vessels with a cutoff of detectable tracer in the early branches: 19 +/- 11 focal constrictions were observed along the 1st to 5th order branches of the axial vessels. A perfusion tracer consisting of biotinylated anti-endothelial lectins (Ricinus Communis Agglutin, Lycopersicon Esculentum and Griffonia Simplicifolia) was circulated for 30 min under physiological conditions. Subsequent enzyme histochemistry demonstrated no significant change in distal perfusion or in the number of focal constrictions (P > 0.05). Furthermore, the focal constrictions were unresponsive to vasodilators such as organic nitrates and prostaglandin E1. By contrast, the presence of oxazolone-induced inflammation resulted in significant and sustained vasodilatation for more than 96 h (P > 0.001). Scanning electron microscopy demonstrated discrete constricting bands morphologically distinct from known precapillary sphincters. These results suggest that these previously unappreciated inflammation-responsive precapillary constrictors regulate capillary recruitment in the mouse ear microcirculation.

Animals↗

PubMed2006

Multiframe particle tracking in intravital imaging: defining Lagrangian coordinates in the microcirculation.

The cellular composition of the microcirculation creates blood flow that can be unsteady and nonuniform. To obtain information about nonuniform cellular trajectories, we describe in vivo imaging techniques that provide both detailed tracking of individual particles as well as an approach to simultaneous multicolor particle tracking. Particularly relevant to biologic systems, Lagrangian methods provide information about the fate of individual particles and flow in the system.

Animals↗

PubMed2005

Vessel painting of the microcirculation using fluorescent lipophilic tracers.

Flexible approaches to defining microvessel morphometry are useful in the study of both acute and chronic structural changes of the microcirculation. In this report, we examined the utility of the intravascular infusion of lipophilic carbocyanine tracers in the structural assessment of the retina, skin, lung, and colon microcirculation. The microvessel labeling technique, here termed fluorescent vessel painting, involved the intravascular injection of sulfonated lipophilic carbocyanine tracers. The utility of vessel painting in morphometry was assessed using morphometric comparisons with corrosion casting and 2-dimensional and 3-dimensional scanning electron microscopy. The comparisons demonstrated that fluorescent vessel painting modestly overestimated the interbranch angles, interbranch distances, and vessel diameters of the 2D mucosal plexus of the colon. These differences were narrowed with the application of confocal microscopy. The advantages of fluorescence vessel painting included (1) the filling of all tissues including the relatively high resistance microvessels of the mouse skin, (2) the ability to use tissue counterstains such as DAPI, and (3) the prolonged stability of the lipophilic tracer after aldehyde fixation. These studies suggest the utility of fluorescent vessel painting as a complementary technique to corrosion casting in the morphometric study of the microcirculation.

Animals↗

PubMed2005

Surgical palliative care in thoracic diseases.

Most patients who have end stage thoracic disease have moderate to severe dyspnea. The dyspnea may be the result of the underlying lung disease, localized disease progression, or the accumulation of fluid within the chest. The most effectively treated clinical problem at the end of life is secondary fluid accumulation in the pleural space or pericardial sac. Focused surgical intervention can play an important role in treating effusive disease of the pleura and pericardium. Minimally invasive surgical interventions, such as the use of video thoracoscopy, can relieve dyspnea effectively and improve the quality of life for patients who have end stage thoracic disease.

Disease Progression↗

PubMed2004

Prevention, early detection, and management of complications after 328 consecutive extrapleural pneumonectomies.

OBJECTIVE: Extrapleural pneumonectomy for therapy of mesothelioma has been associated with significant perioperative mortality and morbidity. Postoperative complications of this procedure require a unique management approach. We developed treatment algorithms for most of the common complications of extrapleural pneumonectomy resulting in reduced mortality and hospital stay. Complications after extrapleural pneumonectomy were further analyzed to elucidate means of prevention, early detection, and treatment. METHODS: A total of 496 patients undergoing extrapleural pneumonectomy were reviewed for mortality rates, with a subset of 328 consecutive patients between 1980 and 2000 who were examined for detailed morbidity data by using a prospective clinical database. RESULTS: Median age was 58 years (range, 28-77 years), with a 10-day (range, 4-101 days) median length of stay. One hundred ninety-eight (60.4%) of 328 patients experienced minor and major complications, and 11 of 328 patients died, for an overall mortality rate of 3.4%. Complications included the following: atrial fibrillation (145 [44.2%]), prolonged intubation (26 [7.9%]), vocal cord paralysis (22 [6.7%]), deep vein thrombosis (21 [6.4%]), technical complications (patch dehiscence, hemorrhage, or both; 20 [6.1%]), tamponade (12 [3.6%]), acute respiratory distress syndrome (12 [3.6%]), cardiac arrest (10 [3%]), constrictive physiology (9 [2.7%]), aspiration (9 [2.7%]), renal failure (9 [2.7%]), empyema (8 [2.4%]), tracheostomy (6 [1.8%]), myocardial infarction (5 [1.5%]), pulmonary embolus (5 [1.5%]), and bronchopleural fistula (2 [0.6%]). Clinical data demonstrated the following: (1) prophylaxis for atrial fibrillation is recommended; (2) early ambulation, aspiration precautions, endoscopic assessment of the vocal cords, and avoidance of fluid overload are crucial; (3) perioperative diagnosis and aggressive management of deep vein thrombosis are important; (4) immediate reoperation and open cardiac massage are essential for relief of cardiac herniation and tamponade from cardiac patch dysfunction; (5) diaphragmatic patch dehiscence, hemorrhage, or both require immediate reoperation; (6) early signs of infection might indicate bronchopleural fistula or empyema and should be treated with thoracoscopic or open drainage and staged removal of patch material; and (7) excessive perioperative mediastinal shift is treated with a catheter placed intraoperatively. CONCLUSION: Complications after extrapleural pneumonectomy require a unique approach to management, and mortality can be minimized by early detection and aggressive treatment.

Adult↗

PubMed2004

Relationship between a history of antecedent cancer and the probability of malignancy for a solitary pulmonary nodule.

STUDY OBJECTIVES: To determine the probability of malignancy for a solitary pulmonary nodule (SPN) as a function of cancer history. SETTING AND DESIGN: Patients who had undergone resection of SPNs at Brigham and Women's Hospital between August 1989 and October 1998 were analyzed. The cohort was split into the following three groups: no history of cancer; history of lung cancer; and history of extrapulmonary malignancy. The histology of the SPN was determined after excision. Logistic regression was used to evaluate the effect of covariates on the probability of malignancy. MEASUREMENTS AND RESULTS: A total of 1,104 patients (55% women; median age, 64 years; age range, 17 to 88 years) underwent removal of 353 benign lesions (32%), 638 non-small cell lung cancers (NSCLCs) [58%], and 113 metastases (10%). Antecedent cancer history was significantly associated with final diagnosis (p < 0.0001), with SPNs being malignant in 63% of patients with no previous cancer, 82% of those with a history of lung cancer (NSCLC, 80%; metastases, 2%), and 79% of patients with history of extrapulmonary cancer (NSCLC, 41%; metastases, 38%). There was no difference in the cause of SPNs between patients with a history of a single cancer and those with a history of multiple cancers. The probability of a benign cause ranged between 62% for nodules < 1 cm to 17% when nodules were > 3 cm, if the patient had no history of cancer (p < 0.0001). The probability of an SPN being benign was cut in half if there was a history of cancer. Among patients with previous extrapulmonary malignancy, age, smoking history, and histology were predictors of diagnosis (p < 0.0001). These variables were used to construct a clinical score to predict the probability of an SPN being a NSCLC or metastasis in these patients. CONCLUSIONS: A history of cancer is an important predictor of the probability of malignancy in new SPNs. Metastases from previous cancer account for almost half of SPNs seen among patients in this subgroup. Diagnosis depends on the histology of previous malignancies, smoking history, age, and size of the SPN.

Adolescent↗

PubMed2003

Microangiectasias: structural regulators of lymphocyte transmigration.

The migration of lymphocytes into inflammatory tissue requires the migrating cell to overcome mechanical forces produced by blood flow. A generally accepted hypothesis is that these forces are overcome by a multistep sequence of adhesive interactions between lymphocytes and endothelial cells. This hypothesis has been recently challenged by results demonstrating wall shear stress on the order of 20 dyn/cm(2) in vivo and infrequent lymphocyte-endothelial adhesion at wall shear stress >1-2 dyn/cm(2) in vitro. Here, we show that lymphocyte slowing and transmigration in the skin is associated with microangiectasias, i.e., focal structural dilatations of microvessel segments. Microangiectasias are inducible within 4 days of the onset of inflammation and lead to a greater than 10-fold local reduction in wall shear stress. These findings support the hypothesis that a preparatory step to lymphocyte transmigration involves structural adaptations in the inflammatory microcirculation.

Animals↗

PubMed2003

Dynamic deformation of migratory efferent lymph-derived cells "trapped" in the inflammatory microcirculation.

The cellular immune response depends on the delivery of lymphocytes from the lymph node to the peripheral site of antigenic challenge. During their passage through the inflammatory microcirculaton, the migratory cells can become transiently immobilized or "trapped" in small caliber vessels. In this report, we used intravital microscopy and temporal area mapping to define the dynamic deformation of efferent lymph-derived mononuclear cells trapped in the systemic inflammatory microcirculation. Mononuclear cells obtained from the efferent lymph draining the oxazolone-stimulated microcirculation were labeled with fluorescent dye and reinjected into the feeding arterial circulation. Intravital video microscopy observed thousands of cells passing through the microcirculation; 35 cells were "trapped" in the oxazolone-stimulated microcirculation. Temporal area maps of the trapped cells demonstrated dramatic slowing and deformation. The cells were trapped in the microcirculation for a median of 8.90 sec (range 5-17 sec) prior to returning to the flow stream. During this period, the cells showed sustained movement associated with both antegrade locomotion (mean cell velocity = 7.92 microm/sec; range 1.16-14.23 microm/sec) and dynamic elongation (median cell length = 73.8 microm; range 58-144 microm). In contrast, efferent lymph-derived cells passing unimpeded through the microcirculation demonstrated rapid velocity (median velocity = 216 microm/sec) and spherical geometry (median diameter = 14.6 microm). Further, the membrane surface area of the "trapped" cells, calculated based on digital image morphometry and corrosion cast scanning electron microscopy, suggested that the fractional excess membrane of the cells in the efferent lymph was significantly greater than previous estimates of membrane excess. These data indicate that transient immobilization of efferent lymph-derived mononuclear cells in the systemic inflammatory microcirculation is rare. When "trapping" does occur, the shape changes and sustained cell movement facilitated by excess cell membrane may contribute to the return of the "trapped cells" into the flow stream.

Adjuvants, Immunologic↗

PubMed2003

The role of muscle flaps in pulmonary aspergillosis.

Pulmonary invades the lung parenchyma and vessels, causing necrotizing pneumonia and massive hemoptysis in immunocompromised patients. Medical treatment alone often fails to clear the organism. Early surgical intervention is advocated in localized disease to remove infection near pulmonary vessels. The resection is limited in an attempt to preserve as much lung function as possible. However, preexisting cavitations and lung disease predispose to postoperative space problems, including prolonged air leak, bronchopleural fistula, and empyema. Muscle flaps provide a solution to these problems by obliterating residual space and providing protective coverage to the bronchial stump. The authors present four cases of pulmonary aspergillosis treated by multimodality therapy and extrathoracic muscle flap transposition. Factors that may contribute to successful treatment include underlying condition of the host and history of cancer, radiation therapy, and great vessel involvement. Despite aggressive medical and surgical therapy, pulmonary aspergillosis has a poor prognosis.

Adult↗

PubMed2003

Visual representation of cell subpopulation from flow cytometry data.

Flow cytometric systems are useful for protein identification and expression analysis, especially characterizing particular lineage or sublineage of cells. We clustered flow cytometry data of bone marrow cells into subpopulations using a clustering algorithm with its physical characteristics (cell size and cell granularity) and different molecular composition (cell reactivity with monoclonal antibodies). To display the cell subpopulations, we created a colored map according to the mean of 5 flow cytometry parameters based on a cluster. Such a map can reveal subpopulation properties that are not evident in the widely used scatter plot.

Algorithms↗

PubMed2002

Physiological characterization of variability in response to lung volume reduction surgery.

This paper examines potential physiological mechanisms responsible for improvement after lung volume reduction surgery (LVRS). In 25 patients (63 +/- 9 yr; 11 men, 14 women), spirometry [forced expiratory volume in 1 s (FEV(1)) and forced vital capacity (FVC)], lung volumes [residual volume (RV) and total lung capacity (TLC)], small airway resistance, recoil pressures, and respiratory muscle contractility (RMC) were measured before and 4-6 mo after LVRS. Data were interpreted to assess how changes in each component of lung mechanics affect overall function. Among responders (DeltaFEV(1) > or = 12%; 150 ml), improvement was primarily due to an increase in FVC, not to FEV(1)-to-FVC ratio. Among nonresponders, FEV(1), FVC, and RV/TLC did not change after surgery, although recoil pressure increased in both groups. Both groups experienced a reduction in RMC after LVRS. In conclusion, LVRS improves function in emphysema by resizing the lung relative to the chest wall by reducing RV. LVRS does not change airway resistance but decreases RMC, which attenuates the potential benefits of LVRS that are generated by reducing RV/TLC. Among nonresponders, recoil pressure increased out of proportion to reduced volume, such that no increase in vital capacity or improvement in FEV(1) occurred.

Adult↗

PubMed2002

Outcomes and cost-effectiveness of alternative staging strategies for non-small-cell lung cancer.

PURPOSE: To identify the optimal strategy for staging the mediastinum of patients with known non-small-cell lung cancer (NSCLC), stratified by tumor (T) classification. METHODS: We used a decision-analytic model to compare the health outcomes and cost-effectiveness of three staging strategies: (1) chest computed tomography alone, (2) selective mediastinoscopy, and (3) routine mediastinoscopy. The overall effectiveness and cost of each strategy was a function of the proportion of patients accurately staged and the risks, benefits, and costs of the diagnostic tests and treatments used. Probability estimates and costs were derived from primary data and the literature. We adopted a societal perspective and calculated incremental cost-effectiveness ratios (ICERs) as cost per quality-adjusted life year (QALY) gained. RESULTS: Both mediastinoscopy strategies correctly identified more patients with mediastinal involvement (N2/N3 disease) and assigned them to multimodal regimens. Routine mediastinoscopy maximized quality-adjusted life expectancy in all patients, irrespective of T classification, and this result was robust to varying the model estimates over their reported ranges. In T1 patients, selective mediastinoscopy cost $24,500 per QALY gained, compared with $78,800 per QALY gained for routine mediastinoscopy. In T2 and T3 patients, the ICER of routine mediastinoscopy was more favorable ($42,800 and $53,400 per QALY gained, respectively). CONCLUSION: Routine mediastinoscopy maximizes quality-adjusted life expectancy in patients with known NSCLC, and its ICER compares favorably with other currently accepted medical technologies. The survival benefit and cost-effectiveness of this strategy are greater in patients with T2 and T3 tumors and are likely to improve with advances in multimodal therapy.

Adult↗