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Biomedical subjects

G Raghu

Publications and source records attributed to G Raghu.

At least 37 records · Page 2Linked to original sources
PubMed1998

Increased prevalence of gastroesophageal reflux in patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal interstitial lung disease (ILD) of unknown etiology. Introduction of acid into the respiratory tree can produce pulmonary fibrosis. Gastroesophageal reflux (GER) has previously been associated with several other respiratory conditions, including pneumonia, bronchitis, and asthma. To investigate prospectively the possible association of GER and IPF, 17 consecutive patients with biopsy-proven IPF and eight control patients with ILD other than IPF underwent dual-channel, ambulatory esophageal pH monitoring. Sixteen of 17 patients with IPF had abnormal distal and/or proximal esophageal acid exposure compared with four of eight control patients (p = 0.02). In the patients with IPF, mean percent distal total (13.6 versus 3.34, p = 0.006), distal upright (12.4 versus 5.1, p = 0.04), distal supine (14.7 versus 0.88, p = 0.02), and proximal supine (7.48 versus 0.24, p = 0.04) esophageal acid exposure times were significantly greater than those in control patients. Only four patients with IPF (25%) with increased acid exposure had typical reflux symptoms such as heartburn or regurgitation. Patients with IPF have a high prevalence of increased esophageal acid exposure, usually without typical GER symptoms. GER in these patients tends to occur at night and extend into the proximal esophagus. Acid reflux may be a contributing factor in the pathogenesis of IPF.

Adult↗
PubMed1997

The cost of lung transplantation and the quality of life post-transplant.

As recently as the 1992 Report of the American Thoracic Society Workshop on Lung Transplantation, no QOL facts were given and no knowledge gaps related to QOL outcomes were cited. Even at the present time, the information in that area is based on a relatively small set of preliminary reports. Current information indicates that successful lung transplantation largely reverses the energy and physical mobility deficits reported by transplant candidates and that those improvements are sustained for at least several years after transplant. Recipients report improved health perceptions, fewer problems, and greater life satisfaction than candidates. The type and amount of QOL benefit appear to differ by underlying lung disorder, and recipients who develop obliterative bronchiolitis syndrome experience declines in QOL. Lung transplantation surgery is an expensive procedure initially, and costs remain high during follow-up. Little information is available on long-term QOL outcomes or cost-effectiveness. There is a compelling rationale for QOL research in lung transplantation. At the present time, some of the most challenging problems in transplantation, such as the selection of optimal timing for transplant and choice of immunosuppression medications, do not appear to have clear-cut survival or clinical benefits. Determination of the best approach to such problems is likely to hinge on patients' perceptions of the risk-to-benefit ratio, measured by their perceived QOL. Findings from QOL research need to be developed into interventions to enhance patient outcomes. As noted by Whitehead, QOL and potentially lethal noncompliance may be linked. Can we develop immune suppressive protocols that maintain clinical benefits while minimizing QOL burdens? Pilot studies suggest that QOL can be enhanced prior to transplant, and that health-related QOL prior to transplant may predict survival and clinical outcomes. As noted by Ramsey et al, multicenter studies are needed to achieve sufficient numbers for multivariate and subset analyses and to address issues such as the impact of diagnosis (indication for transplant) on QOL outcomes and cost-effectiveness. QOL and cost measures must be incorporated into large, longitudinal, multicenter clinical trials and observational studies to address those issues.

Activities of Daily Living↗
PubMed1997

Sarcoidosis associated with recurrent pancreatitis.

A 56-year-old previously healthy man had two episodes of unexplained pancreatitis in the setting of constitutional symptoms, recurrent palsy of the right seventh cranial nerve, and bilateral parotitis. Chest radiography revealed marked bilateral hilar lymphadenopathy, and sarcoidosis was diagnosed by bronchoscopy with transbronchial biopsy showing noncaseating granulomas. The pancreatitis and sarcoidosis responded to corticosteroid therapy but recurred after corticosteroid dosage was reduced. Retreatment with a higher dosage of corticosteroids led to resolution of pancreatitis; 3 months later, the patient remained well and without further recurrence of pancreatitis while taking the higher dose of corticosteroids. Clinically significant pancreatitis should be included as an unusual manifestation of sarcoidosis, and corticosteroid therapy should be considered in the management of pancreatitis associated with sarcoidosis.

Diagnosis, Differential↗
PubMed1997

Genetic predisposition of idiopathic pulmonary fibrosis.

The pulmonary parenchyma in interstitial fibrosis responds stereotypically to a variety of insults. The observation that only a small subset of persons exposed to known fibrogenic agents develop fibrosis and the induction of pulmonary fibrosis in genetically susceptible mice support a genetic predisposition. The description of familial idiopathic pulmonary fibrosis is the strongest evidence available supporting this hypothesis. Unfortunately, despite all the recent advances in molecular genetic techniques there have been few human studies to date. Given the poor prognosis and the lack of a cure for pulmonary fibrosis, future genetic studies will, it is hoped, clarify the pathogenesis of pulmonary fibrosis and lead to preventive measures and new therapeutic interventions. Idiopathic pulmonary fibrosis typically occurs in patients who are older than 50. The etiology is unknown.

Animals↗
PubMed1997

Relationship between soluble CD14, lipopolysaccharide binding protein, and the alveolar inflammatory response in patients with acute respiratory distress syndrome.

The effects of bacterial endotoxin (lipopolysaccharide, LPS) are amplified by lipopolysaccharide binding protein (LBP) and CD14, resulting in cellular activation at very low concentrations of LPS. To investigate the importance of this pathway in acute lung injury, we measured LPS, LBP, and soluble CD14 (sCD14) in the bronchoalveolar lavage fluid (BAL) of 82 patients with acute respiratory distress syndrome (ARDS). LBP and sCD14 increased markedly in BAL of patients with ARDS. sCD14 and LBP each were strongly related to BAL total protein and polymorphonuclear neutrophil (PMN) concentration, whereas LPS concentration was not. Multivariate analyses showed sCD14 to be strongly related to BAL total protein, even after controlling for LPS and LBP concentrations. sCD14 was strongly and independently related to PMN concentration, after controlling for BAL LPS, LBP, and interleukin-8 (IL-8). The BAL LPS concentration was not strongly related to either BAL total protein or BAL PMN. The BAL sCD14 and LBP values were similar in all subgroups of patients with ARDS, and were not related to survival. The serum LBP and sCD14 were elevated in ARDS, but were not related to BAL total protein, LBP, sCD14, PMN, or clinical outcome. Thus, LBP and sCD14 reach high concentrations in the lungs of patients with ARDS, and BAL sCD14 is strongly related to two major indices of lung inflammation: total protein and PMN concentration. CD14-dependent mechanisms may contribute to lung inflammation in ARDS.

Acute-Phase Proteins↗
PubMed1997

Distribution of receptors of collagen and globular domains of C1q in human lung fibroblasts.

Fibroblasts are the predominant cell type responsible for the synthesis of collagen and other matrix elements in normal and fibrotic lungs. We have previously reported that human lung fibroblasts are heterogeneous in C1q binding and that subpopulations differing in C1q binding can be isolated and subcultured. We have investigated the distribution of receptors for C1q-collagen domain (cC1q-R) and globular domain (gC1q-R) in adult human lung fibroblasts. Fibroblasts were isolated from cultures of adult human lung explants in medium containing fresh- or heated plasma-derived human sera and separated by FACS-cell sorting into populations binding to C1q with high- (HF) and low- (LF) fluorescence. The cC1q-R was obtained from fibroblast membrane preparations by affinity chromatography through an anti-cC1q-R antibody column and its distribution was determined by Western analysis. The presence of gC1q-R was determined by immunoblots using an anti-gC1q-R antibody raised against a synthetic peptide. The results showed that a 54 kD protein crossreacting with anti-cC1q-R antibody was produced by LF cells, but it was barely detectable in HF cultures. Immunostaining with anti-cC1q-R antibody revealed that most of the cells in LF cultures were positive while the HF cells were negative. A 38 kD protein recognized by anti-gC1q-R antibody was produced by lung fibroblasts; however, no differences were detected in its distribution between LF and HF cultures. SDS-polyacrylamide gel electrophoresis of membrane proteins binding to an affinity column of C1q-globular fragment showed that the HF cultures contain a approximately 51 kD protein, which was a minor component in LF membranes. These data show that cC1q-R is expressed predominantly by a population of human lung fibroblasts, while the 38 kD gC1q-R is produced by all cells. Another 51 kD protein appears to be produced by a separate population of fibroblasts which does not express cC1q-R. Our results indicate that two lung fibroblast subtypes may be distinguished based on production of the 54 kD putative cC1q-R and another 51 kD protein which binds to C1q-globular domain.

Adult↗
PubMed1997

The CD4/CD8 ratio in BAL fluid is highly variable in sarcoidosis.

Patients with pulmonary sarcoidosis frequently have increased numbers of lymphocytes and a high ratio of CD4+ to CD8+ T-lymphocytes (CD4/CD8 ratio) in bronchoalveolar lavage (BAL) fluid. Some investigators have suggested that these parameters can be used to distinguish sarcoidosis from other types of interstitial lung disease with a high degree of reliability. However, we hypothesized that the BAL CD4/CD8 ratio measured during the initial diagnostic evaluation of patients with biopsy-proven sarcoidosis is highly variable. BAL lymphocytes were analysed via flow cytometry to determine the CD4/CD8 ratio in a population of 86 patients with histological and clinical evidence of sarcoidosis, who underwent BAL as part of their initial diagnostic evaluation. In these patients, the CD4/CD8 ratio ranged 0.5-37.3, with a median value of 3.35 (mean 6.49). The CD4/CD8 ratio was greater than 4 in only 36 (42%) subjects. Ten patients (12%) had a CD4/CD8 ratio less than 1. The distribution of CD4/CD8 ratios was similar in the presence or absence of BAL lymphocytosis. In conclusion, the CD4/CD8 ratio in bronchoalveolar lavage fluid is highly variable in biopsy-proven sarcoidosis. Bronchoalveolar lavage lymphocyte subset determination is a diagnostic test with low sensitivity for this disease.

Adolescent↗
PubMed1997

Lung transplantation. Part II. Postoperative management and results.

In part I of this 2-part article on lung transplantation (Western Journal of Medicine 1996; 165:355-363), we reviewed the current indications and operative techniques of the procedure. In part II, we describe the postoperative management and results of lung transplantation. We also discuss current controversies, such as the use of marginal donors, living-related transplants, marginal recipients, and single-versus double-lung transplantation for emphysema or pulmonary hypertension.

Bronchial Diseases↗
PubMed1996

The recipient origin of posttransplant lymphoproliferative disorders in pulmonary transplant patients. A report of three cases.

BACKGROUND: An increased incidence of posttransplant lymphoproliferative disorders (PTLD) as a result of immunosuppression has been suggested in combined heart-lung transplantation compared with other solid organ transplants, and represents a significant source of morbidity and mortality among lung transplant patients. Although infection with the Epstein-Barr virus has been implicated in the pathogenesis of PTLD, it is unclear if the PTLD is of donor or recipient origin in lung transplant patients. METHODS: The case histories and histologic, immunophenotypic, and molecular genetic findings for the three patients who developed PTLD in the authors' transplantation program are presented. RESULTS: All three patients developed PTLD of B-cell immunophenotype with two patients having evidence of monoclonality by Southern blotting DNA gene rearrangement analysis. The site of involvement by PTLD was the lung in two patients and the small bowel in the third. In one patient, two separate pulmonary lesions were found to be comprised of distinct clonal populations, one exhibiting kappa and the other lambda light chain restriction and each having different immunoglobulin heavy chain gene rearrangements. The Epstein-Barr virus genome was present in the PTLD from all three patients. Polymerase chain reaction (PCR) amplification of a polymorphic huntington gene or annexin III locus was used to identify the PTLD in all three patients as being of recipient origin. CONCLUSIONS: PCR amplification of polymorphic genetic loci demonstrated the recipient origin of PTLD in these three pulmonary transplant patients.

Adult↗
PubMed1996

The multidrug resistance phenotype confers immunological resistance.

Multidrug resistance (MDR), which is due, in part, to the overexpression of P-glycoprotein, confers resistance to a variety of natural product chemotherapeutic agents such as daunorubicin, vincristine, and colchicine. RV+ cells are a P-glycoprotein overexpressing variant of the HL60 myeloid leukemia cell line. In addition to classic MDR, RV+ cells displayed relative resistance to complement-mediated cytotoxicity with both immunoglobulin G and M antibodies against different cell surface antigens, but not to antibody-dependent cellular cytotoxicity and lymphokine-activated killing. Complement resistance was reversed both by treatment with verapamil and with specific monoclonal antibodies (mAbs) capable of binding to P-glycoprotein and blocking its function. To further confirm that the resistance of RV+ cells was not a consequence of the selection of the cells on vincristine, a second system involving P-glycoprotein infectants was also investigated. K562 cells infected with the MDR1 gene, which were never selected on chemotherapeutic drugs, also displayed relative resistance to complement-mediated cytotoxicity. This MDR1 infection-induced resistance was also reversed by mAbs that bind to P-glycoprotein. Therefore, the MDR phenotype as mediated by P-glycoprotein provides resistance to complement-mediated cytotoxicity. The increased intracellular pH and the decreased membrane potential due to the MDR phenotype may result in abnormal membrane attack complex function. This observation may have implications for the possible mechanisms of action of P-glycoprotein and for a possible physiologic role for P-glycoprotein in protection against complement-mediated autolysis.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Nitrofurantoin-induced pulmonary toxicity during pregnancy: a report of a case and review of the literature.

Acute pulmonary reactions to nitrofurantoin are an uncommon side effect of therapy and can cause minor or life-threatening pulmonary dysfunction. Symptoms include fever, chills, cough, pleuritic chest pain, dyspnea. Rarely, pleural effusion and/or pulmonary hemorrhage may occur. Diagnosis is made by clinical suspicion and exclusion of other causes of respiratory compromise. Bronchoalveolar lavage (BAL) may be used to rule out infectious etiologies, and an increase in BAL fluid eosinophils is suggestive of drug-induced toxicity. The acute reaction to nitrofurantoin is believed to be mediated by an immune mechanism. Treatment is mainly discontinuation of the drug, however, corticosteroid therapy is recommended for severe reactions. A chronic reaction associated with long-term treatment with nitrofurantoin has also been reported and causes irreversible pulmonary fibrosis. Nitrofurantoin is commonly used to treat urinary tract infections during pregnancy. Despite the known pulmonary side effects of nitrofurantoin, there is no report of this toxicity occurring in pregnant patients. We present a case of respiratory failure occurring in a woman at 16 weeks' gestation who was being treated with nitrofurantoin for a urinary tract infection.

Adult↗
PubMed1996

Differential expression of the urokinase receptor in fibroblasts from normal and fibrotic human lungs.

Binding of urokinase-type plasminogen activator (uPA) to a specific receptor (uPAR) on human lung fibroblasts enables it to regulate cellular proteolysis and remodeling of the extracellular matrix. Binding studies with radiolabeled uPA indicated that both normal and fibrotic lung fibroblasts express the receptor, but cells from fibrotic tissues bound significantly more uPA (P < 0.001). Phorbol myristate acetate, lipopolysaccharide, transforming growth factor-beta (TGF-beta), and tumor necrosis factor-alpha (TNF-alpha) increased uPA binding and plasminogen activation at the cell surface, with a greater maximal effect on fibrotic than on normal fibroblasts. Excess unlabeled uPA, specific antibody, or antisense oligonucleotides inhibited uPA binding. Ribonuclease (RNase) protection assays showed higher levels of uPAR messenger ribonuleic acid (mRNA) in each of the five fibrotic cell lines than in normal fibroblasts. uPA was mitogenic for normal as well as fibrotic fibroblasts, indicating that receptor binding concurrently localizes cellular proteolytic activity and stimulates mitogenesis. Morphometry and immunohistochemical analysis showed that uPAR, as well as uPA, was increased in fibroblasts in fibrotic lung tissue. Increased expression of uPAR by fibrotic lung fibroblasts and enhanced urokinase binding induced by proinflammatory cytokines suggest a novel mechanism by which fibroblast-mediated matrix remodeling and proliferation may be regulated in interstitial lung diseases.

Base Sequence↗
PubMed1996

Monoclonal antibodies against P-glycoprotein, an MDR1 gene product, inhibit interleukin-2 release from PHA-activated lymphocytes.

P-glycoprotein (Pgp), a product of the human MDR1 gene, is a member of the ABC superfamily of transporters responsible for the trafficking of biologically active substances across the membrane. In tumors, Pgp is associated with multidrug resistance (MDR), the phenomenon characterized by the ability of cells to efflux structurally diverse lipophilic compounds. It has been demonstrated that Pgp is also expressed on various types of normal human tissues and cells, including hematopoietic stem cells, T, B, and natural killer (NK) cells. The normal physiologic function of Pgp in immune cells is unclear. In this study, we used highly specific and nontoxic monoclonal antibodies (mAbs) against external epitopes of Pgp (mAb UIC2, its monovalent Fab fragments, and mAb MRK16) to inhibit Pgp-mediated efflux and investigate a possible role of Pgp in activated T lymphocytes. We found that the treatment of phytohemagglutinin (PHA)-stimulated peripheral blood leukocytes (PBL) with these mAbs resulted in a significant reduction of interleukin-2 (IL-2) levels in the culture. Early activation events, as measured by intracellular calcium flux, expression of the CD69 early activation marker, and expression of IL-2 mRNA, were not affected by anti-Pgp mAbs. These results suggest that the Pgp efflux pump may be involved in the transport of IL-2 in T lymphocytes.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Lung transplantation. Part I. Indications and operative management.

In the past 8 years, lung transplantation has become a standard therapy for benign end-stage pulmonary disease. Rapid advances have occurred involving indications and operative management that have allowed pulmonary transplantation to be a viable option for an increasingly diverse patient population. In part I, we review the current indications and operative techniques, and in part II we will cover the postoperative management and results.

Humans↗
PubMed1995

Efficacy of a 6-week prophylactic ganciclovir regimen and the role of serial cytomegalovirus antibody testing in lung transplant recipients.

CMV is a frequently occurring pathogen in recipients of solid organ transplants, and those receiving lung transplants seem to be affected more frequently and more severely. Because the duration of prophylactic ganciclovir may influence the incidence of CMV disease in solid organ transplant recipients, we evaluated the efficacy of a 6-week prophylactic regimen in lung transplant recipients. We also evaluated the ability of a fourfold rise in CMV antibody titer to predict the development of CMV disease. Twenty-one consecutive lung transplant recipients were enrolled: 15 were CMV antibody-positive at the time of transplantation, and six were CMV antibody-negative and received a lung transplant from CMV-positive donors. Mean +/- SD follow-up was 430 +/- 157 days (range 178-730 days, median 449 days). The 6-week ganciclovir regimen prevented neither CMV infection (which occurred in 17/21 patients, 81%) nor CMV disease (seen in 8/21 patients, 38%). A fourfold rise in CMV antibody titer only preceded the onset of CMV disease in 3/13 instances (23%). We conclude that a 6-week regimen of ganciclovir prophylaxis does not prevent CMV infection or disease in lung transplant recipients and that a rise in serially obtained CMV antibody titers rarely precedes the development of CMV disease.

Antibodies, Viral↗
PubMed1995

Management and outcome of pregnant women with interstitial and restrictive lung disease.

OBJECTIVE: Our purpose was to describe our experience with management and outcome of restrictive lung disease in pregnancy. STUDY DESIGN: Between 1981 and 1994 nine pregnant women with interstitial and restrictive lung disease were prospectively managed and delivered at the University of Washington Medical Center. RESULTS: Three patients had severe disease, characterized by vital capacity < or = 1.5 L (50% predicted) or diffusing capacity < or = 50% predicted. Five patients had exercise-induced oxygen desaturation, and four required supplemental oxygen. Five patients required corticosteroids. One patient had an adverse outcome; she was delivered at 31 weeks and required mechanical ventilation for 72 hours. All other patients were delivered at or beyond 36 weeks with no adverse intrapartum or postpartum complications. All babies were at or above the 30th percentile for growth. CONCLUSIONS: Restrictive lung disease is tolerated in pregnancy. Exercise intolerance is common and patients may require early oxygen supplementation. Adequate fetal growth can be achieved.

Adrenal Cortex Hormones↗