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Biomedical subjects

J G Clark

Publications and source records attributed to J G Clark.

At least 37 records · Page 2Linked to original sources
PubMed1997

Early detection of type III procollagen peptide in acute lung injury. Pathogenetic and prognostic significance.

The fibroproliferative reaction to acute lung injury may limit restoration of normal lung function and increase mortality in patients with acute lung injury. A biologic marker of collagen synthesis in the lung may be useful for studying the pathogenesis of acute lung injury and for identifying patients with acute lung injury who are at high risk for death and might benefit from new therapeutic modalities. Using an immunoassay, type III procollagen NH2 terminal peptide was measured in the pulmonary edema fluid of 44 patients with either acute lung injury or hydrostatic pulmonary edema (control group) within the first 24 h after endotracheal intubation for acute respiratory failure. Patients with acute lung injury (n = 33) or hydrostatic edema (n = 11) had the same degree of lung dysfunction as measured by the severity of oxygenation defect, the level of positive end-expiratory pressure, the decrease in static lung compliance, and the extent of infiltrates on the chest radiograph. However, the median procollagen III level was 5-fold higher in the pulmonary edema fluid of patients with acute lung injury than in the patients with hydrostatic pulmonary edema (p = 0.0001). Of the 33 patients with acute lung injury, 21 patients died and 12 lived. Nonsurvivors had significantly higher procollagen III levels than did survivors (p = 0.05). The positive and negative predictive values for nonsurvival for a procollagen III level > or = 1.75 U/ml were 74 and 83%, respectively. The relative risk of dying in the presence of a procollagen III value > or = 1.75 U/ml was 4.5 (95% CI, 0.7 to 27). Collagen synthesis in the lung, as reflected by elevated levels of procollagen III in pulmonary edema fluid, begins within the first 24 h of acute lung injury concurrent with the acute phase of increased endothelial and epithelial permeability to protein. This evidence suggests that fibrosing alveolitis begins much earlier in the course of clinical acute lung injury than has previously been appreciated. In addition, the presence of an elevated level of procollagen III is an early predictor of poor outcome. Thus, elevation of procollagen III in pulmonary edema fluid may have both pathogenetic and prognostic significance in patients with acute lung injury.

Adult↗
PubMed1995

Type III procollagen peptide in the adult respiratory distress syndrome. Association of increased peptide levels in bronchoalveolar lavage fluid with increased risk for death.

OBJECTIVE: To determine whether bronchoalveolar lavage fluid levels of the N-terminal peptide of type III procollagen (procollagen III) are increased in patients with the adult respiratory distress syndrome and, if so, whether increased procollagen III levels in lavage fluid are associated with increased fatality rates. DESIGN: Prospective cohort study. SETTING: Intensive care units of a tertiary care hospital affiliated with a medical school. PATIENTS: 117 consecutive patients with the adult respiratory distress syndrome prospectively identified on admission; 6 healthy volunteers served as controls. MEASUREMENTS: Bronchoalveolar lavage fluid procollagen III levels in 117 patients at 3, 7, and 14 days after onset of the adult respiratory distress syndrome (total of 196 lavage samples). RESULTS: The median procollagen III level was 1.75 U/mL (range, 0 to 13.4 U/mL) in lavage fluid obtained from patients with the adult respiratory distress syndrome. We detected procollagen III levels in lavage fluid from 80% of patients (94 of 117) but not in 6 normal volunteers. The overall fatality rate was 41% (48 of 117 patients). In a univariate analysis, the relative risk (RR) for death was increased in patients with procollagen III levels of 1.75 U/mL or more obtained on day 3 (RR, 2.4; 95% CI, 1.3 to 4.3), day 7 (RR, 2.7; CI, 1.4 to 5.4), and day 14 (RR, 2.7; CI, 1.1 to 6.3). Inclusion of other variables in a multivariate model only minimally decreased the risk associated with increased procollagen III levels. CONCLUSION: Increased levels of type III procollagen in bronchoalveolar lavage fluid are frequently detected in patients with the adult respiratory distress syndrome and are strongly associated with increased risk for fatal outcome independent of other variables related to fatality in patients with the syndrome.

Adolescent↗
PubMed1995

Investigating the validity of the Clinical Linguistic Auditory Milestone Scale.

The purpose of this investigation was to determine the validity of the Clinical Linguistic Auditory Milestone Scale (CLAMS) as a screening test to help physicians detect delays in language development. Language delays in children are often not diagnosed until about 3 years of age because (1) parents may not be aware of what constitutes normal language development, (2) diagnosis of a language problem is difficult for physicians to make because they see the child for brief periods of time, (3) there is a wide range of what constitutes normal language so professionals are reluctant to classify a child as delayed without thorough testing. The hypothesis for this investigation was that children who have language delays can be identified quickly and easily through the administration of the CLAMS. Subjects included 99 children between the ages of 1 and 3 years. The procedure had 3 parts: (1) parents completed a form consisting of questions such as parent occupation, number of children in the family, birth history, etc., (2) the CLAMS, a parent report that can be given while the child is seen by the physician, was administered, (3) the Sequenced Inventory of Communication Development (SICD), was administered to assess receptive and expressive language. The purpose for administering the SICD was to obtain a more in-depth picture of the child's ability to comprehend and use language, thereby providing data to determine the validity of the CLAMS as a screening device. Results indicated that the CLAMS is a valid instrument for identifying language delayed children.

Child Language↗
PubMed1995

SPARC participates in the branching morphogenesis of developing fetal rat lung.

Adhesion of cells to components of the extracellular matrix has been shown to be critical in normal lung development, particularly during the pseudoglandular stage, when conducting airways are forming through a process of branching morphogenesis. Expression of factors that inhibit cellular adhesion might also modulate branching morphogenesis. SPARC is a secreted glycoprotein that exhibits antiadhesive effects on cultured cells and is widely expressed in embryonic tissues. In this report, we examine the distribution of SPARC in fetal rat lung during development and its effect on the process of branching morphogenesis. Immunohistochemistry and in situ hybridization studies revealed that SPARC was present in the airway epithelial cells during the pseudoglandular stage of lung development, and in blood vessels and smooth muscle cells associated with airways during the canalicular and saccular stages of development. We used an in vitro model of rat lung branching morphogenesis to examine airway branching in the presence of: a) a neutralizing anti-SPARC antibody; or b) a synthetic peptide from a region of SPARC that, like the native protein, perturbs cell adhesion and diminishes the synthesis of fibronectin and thrombospondin 1. Lungs cultured in the presence of either reagent exhibited diminished branching and an abnormal morphology that was characterized in part by dilated airways. These findings implicate SPARC in the development of the airways.

Amino Acid Sequence↗
PubMed1995

Immunolocalization of transforming growth factor-alpha, epidermal growth factor (EGF), and EGF-receptor in normal and injured developing human lung.

The family of growth factors that includes epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) are thought to play a role in the regulation of fetal lung development and epithelial repair after injury. To further elucidate the potential role of these growth factors and their receptor in normal human lung development and in response to injury, their distribution was determined by immunohistochemistry in normal fetal lung, as well as both normal and injured postnatal human lung. We studied 14 specimens of human lung tissue: from three fetuses, four normal infants, two preterm infants with hyaline membrane disease, and five infants with late bronchopulmonary dysplasia (BPD). EGF, TGF-alpha, and EGF receptor (EGF-R) colocalized in airway epithelium in normal fetal and in postnatal human lung. They were also colocalized in scattered alveolar epithelial cells in postnatal lung. Large numbers of alveolar macrophages immunostained for EGF, TGF-alpha, and EGF-R in lungs with late stages of BPD. The colocalization of these growth factors suggests parallel expression of EGF family members. Moreover, the colocalization of these growth factors with their receptor in developing lung suggests that they may act through an autocrine mechanism. The prominent expression of these growth factors in alveolar macrophages in BPD suggests they may be involved with the pathogenesis of this disease.

Amino Acid Sequence↗
PubMed1994

Expression of TGF-alpha, EGF, and EGF receptor in fetal rat lung.

To define the distribution of transforming growth factor-alpha (TGF-alpha) and its relationship to epidermal growth factor (EGF) and EGF receptor in lung development and to determine whether epithelial cells produce TGF-alpha, we studied the expression of TGF-alpha, EGF, and their receptor in late-gestation fetal rat lung and in cultured fetal rat lung cells. TGF-alpha, EGF, and EGF receptor were colocalized in epithelial and smooth muscle cells of bronchioles and bronchi and in epithelial cells of saccules. Epithelial cells cultured from late-gestation fetal rat lung transcribe TGF-alpha and EGF receptor mRNA and produce TGF-alpha and EGF receptor proteins. Cultured fibroblasts contained EGF receptor mRNA, but no detectable TGF-alpha mRNA. These results demonstrate fetal lung epithelial cells are a source for TGF-alpha and suggest that TGF-alpha might act through an autocrine or paracrine mechanism with epithelial and mesenchymal cells. The colocalization of TGF-alpha and EGF suggests that these growth factors might act in parallel in lung development.

Animals↗
PubMed1994

Expression of transforming growth factor-alpha and epidermal growth factor receptor is increased following bleomycin-induced lung injury in rats.

To investigate the potential role of transforming growth factor-alpha (TGF-alpha) and the epidermal growth factor receptor (EGF-R) in the fibroproliferative response to acute lung injury, we determined lung steady-state TGF-alpha and EGF-R mRNA levels, TGF-alpha protein levels, and the distribution of TGF-alpha and EGF-R immunoreactive protein of bleomycin-injured and control rat lungs. At 2 and 4 days after a single intratracheal injection of bleomycin, TGF-alpha mRNA levels increased to 159% and 184% of control values, respectively. EGF-R mRNA levels increased to 163%, 314%, and 170% of control values at 1, 7, and 14 days after bleomycin instillation. TGF-alpha protein levels in whole lung extracts increased to 230% of control values at 4 days after bleomycin administration. TGF-alpha and EGF-R immunoreactivity was detected in macrophages, alveolar septal cells, and airway epithelium of control and bleomycin-injured animals with an apparent increase in the intensity and number of specifically immunostained cells following lung injury. TGF-alpha and EGF-R immunoreactive proteins were detected in foci of cellular proliferation and in areas of intraalveolar fibrosis. We conclude that TGF-alpha and the EGF-R are present in normal and bleomycin-injured rat lung and that the expression of this growth factor and its receptor are up-regulated following lung injury. These results suggest that increased expression of TGF-alpha and the EGF-R may be an important mechanism that modulates the fibroproliferative response to acute lung injury.

Amino Acid Sequence↗
PubMed1993

Expression of transforming growth factor-alpha in mid-gestation human fetal lung.

Transforming growth factor-alpha (TGF-alpha), a member of the epidermal growth factor (EGF) family, is a potent mitogen for several cell types. To investigate the possible role of TGF-alpha in the development of midgestation human fetal lung, we studied its distribution with immunohistochemistry and determined levels of steady-state TGF-alpha mRNA by Northern analysis of cellular RNA isolates from lung. Lung was obtained from fetuses at 10 to 22 wk of gestation (n = 14) and immunostained for TGF-alpha. TGF-alpha was localized in epithelial cells at all gestational ages examined. Immunostaining was particularly prominent in bronchiolar epithelial cells. TGF-alpha immunoreactivity was also associated with arterial smooth muscle cells, as well as with nerves. Occasional chondrocytes were also associated with TGF-alpha immunoreactivity. Total cellular RNA was isolated from lung tissue obtained from additional fetuses at gestational ages 10 to 24 wk (n = 22). TGF-alpha mRNA was present in RNA extracts of all fetal lungs studied. We conclude that TGF-alpha is probably produced in human fetal lung during mid-gestation. The prominent immunostaining of bronchiolar epithelial cells for TGF-alpha is consistent with its playing a role in distal airway formation.

Antibodies, Monoclonal↗
PubMed1993

Complications of fiberoptic bronchoscopy in thrombocytopenic patients.

STUDY OBJECTIVE: To determine the risk of epistaxis and pulmonary hemorrhage due to fiberoptic bronchoscopy (FOB) and bronchoalveolar lavage (BAL) in the presence of thrombocytopenia. DESIGN: Prospective study of all patients undergoing FOB with BAL with a 4.9-mm-diameter bronchoscope after bone marrow transplantation (BMT) during a 6-month period. SETTING: A single BMT center. PATIENTS: Forty-seven BMT recipients undergoing 66 FOB with BAL. Thrombocytopenia (platelets < 100,000/ml) was present in 58 (88 percent). Platelets were < 50,000/ml in 44 (67 percent) and < 20,000/ml in 13 (20 percent). In the thrombocytopenic patients, FOB with BAL was transnasal in 37 (64 percent), transoral in 5 (9 percent), and via endotracheal tube in 16 (28 percent). INTERVENTIONS: Fiberoptic bronchoscopy with BAL using a bronchoscope (Pentax FB-15H) (4.9-mm diameter). In one case, a pediatric bronchoscope (Pentax FB-10H; 3.5-mm diameter) was used in a 7-year-old patient. MEASUREMENTS AND RESULTS: The BAL was diagnostic in 22 of 47 patients studied (47 percent). Complications occurred in 7 of 58 (12 percent) thrombocytopenic patients (epistaxis and/or hemoptysis, 4; bradycardia, 2; bronchospasm, 1) of which all but 1 were minor and self-limiting. One life-threatening complication of severe epistaxis occurred during a transoral FOB in a patient with prior epistaxis (platelet count, 18,000/ml). One of 8 (13 percent) nonthrombocytopenic patients had hemoptysis. No patient had worsening fever or oxygenation at 4 h and no patient displayed worsening radiographic infiltrates suggestive of pulmonary hemorrhage attributable to the BAL at 24 h. CONCLUSIONS: We conclude that transnasal FOB in thrombocytopenic patients was safe, being associated with minor airway bleeding in 3 of 37 patients (8 percent). In conclusion, FOB with BAL, even via the transnasal route, may be performed with relative safety despite the presence of significant thrombocytopenia.

Adult↗
PubMed1993

Bronchiolitis associated with bone marrow transplantation.

New onset airflow obstruction after BMT is a relatively common complication and may be seen in as many as 11% of long-term survivors of allogeneic BMT with chronic GVHD. Bronchiolitis and, occasionally, obliterative bronchiolitis is seen in the majority of cases in which histopathology is available. The primary risk factors recognized are the presence of clinical chronic GVHD, administration of methotrexate as an immunosuppressive, and older recipient age. Improved control of chronic GVHD with effective agents such as cyclosporine likely will decrease the incidence of this airway disorder. The causes probably are multifactorial and donor cytotoxic T-lymphocyte interaction with host cells is a likely contributor in many cases. The clinical course is variable, but the process usually is fatal in cases with rapidly progressive or severe obstruction. Interventions are directed at immune suppression and at diagnosing and treating infections that frequently occur in association with the airflow obstruction.

Adrenal Cortex Hormones↗
PubMed1990

Collagen synthesis during lung development and during hyaline membrane disease in the nonhuman primate.

To assess maturational changes in collagen synthesis, lung tissue was obtained from healthy Macaca nemestrina monkeys at different ages, ranging from 68% of term gestation to adulthood. We hypothesized that infants delivered prematurely have a greater rate of collagen synthesis than do older animals because of their greater rate of lung growth during gestation. Secondly, we hypothesized that lung repair in infants with hyaline membrane disease (HMD) is associated with an additional increase in lung collagen synthesis rate. Therefore, lung tissue was obtained during the first week of life from monkeys delivered at 82% of term gestation, a stage at which half of them developed HMD. The rate of total protein synthesis in lung samples was determined by measuring the incorporation of [3H]proline; the rate of collagen synthesis was determined by measuring the conversion of proline into hydroxyproline. Premature monkeys had a higher rate of collagen synthesis (9.9 +/- 2.7 nmol/mg DNA/h) than did term infants (5.3 +/- 1.1) or older animals (2.1 +/- 0.4, p less than 0.05). There was no additional increase in rate of collagen synthesis in animals with HMD from 3 h (14.3 +/- 6.9) to 7 days of age (15.1 +/- 6.1); control premature animals also had no significant change during the first week of life (10.9 +/- 3.0 at 3 h; 11.6 +/- 4.6 at 7 days). The early stage of recovery from HMD in premature monkeys does not appear to be associated with an increase in collagen production beyond the already increased synthesis rate associated with lung growth.

Analysis of Variance↗
PubMed1989

Obstructive lung disease after allogeneic marrow transplantation. Clinical presentation and course.

To describe the clinical presentation and progression of obstructive lung disease after marrow transplantation, we examined a sequential sample of 35 patients who had allogeneic marrow transplantation between January 1980 and January 1987, were 16 years or older, had normal pulmonary function tests before transplantation, and developed airflow obstruction defined as FEV1/FVC less than 70% and FEV1 less than 80% predicted 50 days or more after transplantation. Cases were selected from 1029 adult (older than 16 years) patients who underwent allogeneic marrow transplantation during the same period. Patients with airflow obstruction presented with symptoms of cough, dyspnea, or wheezing, or a combination. In 80% the chest radiograph was normal. Airflow obstruction was diagnosed within 1.5 years after transplantation in 33 of 35 patients. Clinical, extensive, chronic graft-versus-host disease was present in 24 patients. Only 4 patients had a complete response to primary therapy of chronic graft-versus-host disease. Serum IgG and IgA levels were decreased in 15 and 25 patients, respectively. The FEV1 declined rapidly (decrease in FEV1 greater than 30% between tests) in 21 patients, but 14 patients with slowly progressive or reversible disease were identified. Mortality was 65% at 3 years after transplant, a significantly higher value (P = 0.016) than the 3-year mortality rate of 44% in a comparison group of 412 concurrent patients with chronic graft-versus-host disease who were 16 years or older, survived more than 80 days after transplantation, and had normal pulmonary function. We concluded that obstructive lung disease after marrow transplantation may be variable with respect to time of onset and rate of progression. Obstructive lung disease was frequently associated with serum immunoglobulin deficiency and clinical, extensive, chronic graft-versus-host disease that was not readily responsive to treatment. Mortality was high but long-term survivors were identified.

Adolescent↗
PubMed1989

Monocyte-derived growth factors in asbestos-induced interstitial fibrosis.

Asbestos-induced pulmonary fibrosis is thought to result from a series of cellular interactions involving the alveolar macrophage and the lung fibroblast. Although a dose-response relation has been established between asbestos exposure and the development of interstitial fibrosis, the majority of workers exposed even to high concentrations of asbestos do not develop radiographically evident interstitial fibrosis. As a means of understanding the pathogenesis of asbestos-induced fibrosis and the differential host response to the asbestos fiber, we studied the production of monocyte-derived growth factors in subjects with asbestosis (N = 5) and normal exposure-matched controls (N = 5). Under unstimulated culture conditions, the conditioned medium (CM) from monocytes from control subjects had a greater proliferative effect on fibroblasts than monocyte CM from patients with asbestosis. With CM from concanavalin A-stimulated monocytes, the proliferative response of the fibroblast was similar in those with asbestosis and control subjects. Freshly isolated monocytes from both normal subjects and patients with asbestosis did not express the gene for the B chain of platelet-derived growth factor (PDGF) as evaluated by hybridization with a PDGF-specific human cDNA probe. After 20 hr of culture in concanavalin A, monocytes from normal subjects expressed the gene for the B chain of PDGF while, under the same culture conditions, none of the monocyte preparations from patients with asbestosis produced mRNA for this growth factor. These data indicate that peripheral blood monocytes from patients with asbestosis compared to exposure-matched controls have a reduced capacity to produce growth factor activity as measured by mitogenic activity and mRNA levels for the B chain of PDGF. These results suggest that peripheral blood monocytes from patients with asbestosis may comprise a less mature population of cells compared to exposure-matched controls.

Animals↗