Jerry W. McLarty

Local abnormalities in coagulation and fibrinolytic pathways predispose to alveolar fibrin deposition in the adult respiratory distress syndrome.

To determine the possible mechanism(s) promoting alveolar fibrin deposition in the adult respiratory distress syndrome (ARDS), we investigated the initiation and regulation of both fibrinolysis and coagulation from patients with ARDS (n = 14), at risk for ARDS (n = 5), and with interstitial lung diseases (ILD) (n = 8), and normal healthy individuals (n = 13). Bronchoalveolar lavage (BAL) extrinsic pathway inhibitor activity was increased in ARDS BAL compared with patients at risk for ARDS (P = 0.0146) or normal controls (P = 0.0013) but tissue factor-factor VII procoagulant activity was significantly increased in ARDS BAL compared with all other groups (P less than 0.001). Fibrinolytic activity was not detectable in BAL of 10 of the 14 patients with ARDS and low levels of activity were found in BAL of the other four ARDS patients. Depressed fibrinolysis in ARDS BAL was not due to local insufficiency of plasminogen; rather, there was inhibition of both plasmin and plasminogen activator. Plasminogen activator inhibitor 1 was variably detected and low levels of plasminogen activator inhibitor 2 were found in two ARDS BAL samples, but plasminogen activator inhibitor 2 was otherwise undetectable. ARDS BAL antiplasmin activity was, in part, due to alpha 2-antiplasmin. We conclude that abnormalities that result in enhanced coagulation and depressed fibrinolysis, thereby predisposing to alveolar fibrin deposition, occur in the alveolar lining fluids from patients with ARDS.

Incidence of Tracheal Stenosis and Other Late Complications After Percutaneous Tracheostomy

ObjectiveTo determine the incidence of tracheal stenosis, voice and breathing changes, and stomal complications after percutaneous dilatational tracheostomy (PDT). MethodsFrom December 1992 through June 1999, 420 critically ill patients underwent 422 PDTs. There were 340 (81%) long-term survivors, 100 (29%) of whom were interviewed and offered further evaluation by fiberoptic laryngotracheoscopy (FOL) and tracheal computed tomography (CT). Tracheal stenosis was defined as more than 10% tracheal narrowing on transaxial sections or coronal and sagittal reconstruction views. Forty-eight patients agreed to CT evaluation; 38 patients also underwent FOL. CT and FOL evaluations occurred at 30 ± 25 (mean ± standard deviation) months after PDT. ResultsTwenty-seven (27%) patients reported voice changes and 2 (2%) reported persistent severe hoarseness. Vocal cord abnormalities occurred in 4/38 (11%) patients, laryngeal granuloma in 1 (3%) patient, focal tracheal mucosal erythema in 2 (5%) patients, and severe tracheomalacia/stenosis in 1 (2.6%) patient. CT identified mild (11–25%) stenosis in 10 (21%) asymptomatic patients, moderate (26–50%) stenosis in 4 (8.3%) patients, 2 who were symptomatic, and severe (>50%) stenosis in 1 (2%) symptomatic patient. Ten patients (10%) reported persistent respiratory problems after tracheal decannulation, but only four agreed to be studied. Two patients had moderate stenosis, and one had severe stenosis. One patient’s CT scan was normal. No long-term stomal complications were identified or reported. ConclusionsSubjective voice changes and tracheal abnormalities are common after endotracheal intubation followed by PDT. Long-term follow-up of critically ill patients identified a 31% rate of more than 10% tracheal stenosis after PDT. Symptomatic stenosis manifested by subjective respiratory symptoms after decannulation was found in 3 of 48 (6%) patients.

Neural Networks for Full-Scale Protein Sequence Classification: Sequence Encoding with Singular Value Decomposition

A neural network classification method has been developed as an alternative approach to the search/organization problem of protein sequence databases. The neural networks used are three-layered, feed-forward, back-propagation networks. The protein sequences are encoded into neural input vectors by a hashing method that counts occurrences ofn-gram words. A new SVD (singular value decomposition) method, which compresses the long and sparsen-gram input vectors and captures semantics ofn-gram words, has improved the generalization capability of the network. A full-scale protein classification system has been implemented on a Cray supercomputer to classify unknown sequences into 3311 PIR (Protein Identification Resource) superfamilies/families at a speed of less than 0.05 CPU second per sequence. The sensitivity is close to 90% overall, and approaches 100% for large superfamilies. The system could be used to reduce the database search time and is being used to help organize the PIR protein sequence database.

A prehospital glasgow coma scale score < or = 14 accurately predicts the need for full trauma team activation and patient hospitalization after motor vehicle collisions.

BACKGROUND Trauma team activation protocols should ideally minimize the undertriage of seriously injured patients and eliminate unnecessary activations for those patients that do not require hospitalization. This study examined which physiologic parameter(s) most reliably predicted the need for hospitalization after motor vehicle collisions (MVCs). METHODS A prehospital triage tool using standard physiologic parameters was developed and prospectively analyzed for reliability in predicting subsequent patient admission at a Level II trauma center after MVCs. Data were collected on 4,014 consecutive patients, 2,880 (72%) of whom had all of the physiologic parameters reported and recorded. Patients who arrived in extremis, who were dead on arrival, or who died shortly after arrival despite appropriate trauma team activation were ineligible for the study. Multivariate stepwise logistic regression analysis was used to determine which parameters were associated with hospital admission. RESULTS The Glasgow Coma Scale (GCS) score was the only prehospital physiologic parameter providing a clinically identifiable difference between those patients admitted (13 +/- 4) and those discharged to home (15 +/- 0.5) (mean + SD) (relative risk for hospitalization, 2.24; 95% confidence interval, 1.86-2.70 for GCS score < 14). CONCLUSION The prehospital GCS score is a reliable physiologic parameter for predicting hospital admission after MVC. When obvious indicators (hypoxemia, multiple long bone fractures, focal neurologic deficits) for trauma team activation are lacking, the prehospital GCS score may be used to reduce overtriage and undertriage rates.

A potentially expanded role for enoxaparin in preventing venous thromboembolism in high risk blunt trauma patients.

BACKGROUND Venous thromboembolism (VTE) is a frequent and potentially life-threatening complication after trauma. The purpose of this study is to investigate the effectiveness of enoxaparin in preventing deep venous thrombosis (DVT) and pulmonary embolism (PE) after injury in patients who are at high risk for developing VTE. STUDY DESIGN A prospective single-cohort observational study was initiated for seriously injured blunt trauma patients admitted to a Level I trauma center during a 7-month period. Patients were eligible for the study if time hospitalized was > or = 72 hours, Injury Severity Score (ISS) was > or = 9, enoxaparin was started within 24 hours after admission, and one or more of the following high risk criteria were met: age > 50 years, ISS > or = 16, presence of a femoral vein catheter, Abbreviated Injury Score (AIS) > or = 3 for any body region, Glasgow Coma Scale (GCS) Score < or = 8, presence of major pelvic, femur, or tibia fracture, and presence of direct blunt mechanism venous injury. Patients with closed head injuries and nonoperatively treated solid abdominal organ injuries were also potential participants. The primary outcomes measured were thromboembolic events--either a documented lower extremity DVT by duplex color-flow doppler ultrasonography or a PE documented by rapid infusion CT pulmonary angiography or conventional pulmonary angiography. RESULTS There were 118 patients enrolled in the study. Two patients (2%) developed DVT, one of which was proximal to the calf (95% confidence interval, 0% to 6%). Two of 12 patients (17%) with splenic injuries who received enoxaparin failed initial nonoperative management. There were no other bleeding complications, and no clinical evidence or documented episodes of PE. One patient died from multiple system organ failure. CONCLUSIONS Enoxaparin is a practical and effective method for reducing the incidence of VTE in high risk, seriously injured patients. This study supports further investigation into the safety of enoxaparin prophylaxis in patients with closed head injuries and nonoperatively treated solid abdominal organ injuries.

Analysis of Asbestos Fiber Burden in Lung Tissue from Mesothelioma Patients

Mesothelioma is a rare neoplasm that occurs most frequently in individuals with previous asbestos exposure. Differences for risk of development of asbestos-related mesothelioma and lung cancer have been attributed to the various types of asbestos, as well as to the dimension of the inhaled fibers. In the present study, 55 individuals with the pathological diagnosis of mesothelioma were evaluated as to ferruginous body and fiber content in lung tissue. The procedures used in the analysis included tissue digestion and analysis of the collected material for ferruginous bodies by light microscopy and for uncoated fibers by analytical transmission electron microscopy. Forty-six of the samples had ferruginous body concentrations of over 1000/per gram dry weight of lung tissue. The majority of the cores of these ferruginous bodies were amosite. Likewise, the most common uncoated asbestos fiber in the tissue was amosite. Only a small percentage of each type of asbestos would have been visible by light microscopy or even potentially by electron microscopy if the magnification was not sufficient to detect those with thin (< 0.2 micron) diameters. The consistent finding in most of the cases was a considerable presence of asbestos, often of mixed types.

Motif identification neural design for rapid and sensitive protein family search

A new method, the motif identification neural design (MOTIFIND), has been developed for rapid and sensitive protein family identification. The method is an extension of our previous gene classification artificial neural system and employs new designs to enhance the detection of distant relationships. The new designs include an n-gram term weighting algorithm for extracting local motif patterns, an enhanced n-gram method for extracting residues of long-range correlation, and integrated neural networks for combining global and motif sequence information. The system has been tested and compared with several existing methods using three protein families, the cytochrome c, cytochrome b and flavodoxin. Overall it achieves 100% sensitivity and > 99.6% specificity, an accuracy comparable to BLAST, but at a speed of approximately 20 times faster. The system is much more robust than the PROSITE search which is based on simple signature patterns. MOTIFIND also compares favorably with BLIMPS, the Hidden Markov Model and PROFILESEARCH in detecting fragmentary sequences lacking complete motif regions and in detecting distant relationships, especially for members of under-represented subgroups within a family. MOTIFIND may be generally applicable to other proteins and has the potential to become a full-scale database search and sequence analysis tool.

Neural Networks for Molecular Sequence Classification

A neural network classification method has been developed as an alternative approach to the search/organization problem of large molecular databases. Two artificial neural systems have been implemented on a Cray supercomputer for rapid protein/nucleic acid sequence classifications. The neural networks used are three-layered, feed-forward networks that employ back-propagation learning algorithm. The molecular sequences are encoded into neural input vectors by applying an n-gram hashing method or a SVD (singular value decomposition) method. Once trained with known sequences in the molecular databases, the neural system becomes an associative memory capable of classifying unknown sequences based on the class information embedded in its neural interconnections. The protein system, which classifies proteins into PIR (Protein Identification Resource) superfamilies, showed a 82% to a close to 100% sensitivity at a speed that is about an order of magnitude faster than other search methods. The pilot nucleic acid system, which classifies ribosomal RNA sequences according to phylogenetic groups, has achieved a 100% classification accuracy. The system could be used to reduce the database search time and help organize the molecular sequence databases. The tool is generally applicable to any databases that are organized according to family relationships.

An Intervention Trial in High-Risk Asbestos-exposed Persons

Lung cancer, the treatment of which is essentially no more effective today than it was 20 years ago, remains the major cause of cancer mortality in the United States, killing more than 140,000 persons annually. Persons who are occupationally exposed to asbestos are at extremely high risk for lung cancer, from 10 to 50 or more times higher than normal—depending upon their smoking history. In the following discussion, we present the study design for an ongoing intervention trial among 750 asbestos workers in Tyler, Texas. β-Carotene and retinol are being used as the chemopreventive agents and an intermediate end point, sputum atypia, as the measure of response. Some results of baseline data analysis (before initiation of treatment) will be presented below. Findings of toxicity, recruitment, and compliance will also be discussed.

Bronchoalveolar lavage desmosine in bleomycin-induced lung injury in marmosets and patients with adult respiratory distress syndrome

Measurement of urinary desmosine in experimental models of emphysema has been used to demonstrate elastin catabolism. In order to evaluate the hypothesis that accelerated elastin degradation also occurs in association with acute lung injury characterized by fibrotic repair, we prepared acid hydrolysates of lung lavage (LL) and used a radioimmunoassay for desmosine to measure concentrations of this elastic-specific cross-link in LL. Lavage desmosine (pmol/100 microliter LL) was measured following bleomycin-induced lung injury in marmosets and was shown to be elevated at 1 week (median 6.0, range 5.1-7.8), 2 weeks (8.4, 6.2-8.7), and 4 weeks (7.6, 4.8-7.8) compared to control levels (1.8, 1.4-3.7). Elevations of lavage desmosine after bleomycin were temporarily associated with remodeling of the lung as indicated by increased total lung collagen, reduced diffusing capacity and lung compliance, and histologic evidence of pulmonary fibrosis. Bronchoalveolar lavage (BAL) desmosine was measured in patients with the Adult Respiratory Distress Syndrome (ARDS) and compared with patients at risk, patients with other interstitial lung diseases, and normal healthy controls. BAL desmosine (pmol/100 microliters) was not significantly different in patients with ARDS (3.2, 2.1-3.0), patients at risk for ARDS (2.8, 2.5-4.4), and those with interstitial lung disease (3.0, 1.7-5.3) compared to normal controls (2.9, 1.9-4.7). There were poor correlations of BAL desmosine with physiologic indices of severity of disease in patients with ARDS and those at risk. Accelerated elastolysis occurred in the lower respiratory tract during the evaluation of bleomycin-induced pulmonary fibrosis in marmosets but was undetectable in BAL of patients studied within the first 3 days of ARDS.