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Biomedical subjects

G Raghu

Publications and source records attributed to G Raghu.

At least 19 recordsLinked to original sources
PubMed2006

High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis.

The aim of this prospective study was to determine the prevalence and characteristics of acid gastro-oesophageal reflux (GER) in patients with idiopathic pulmonary fibrosis (IPF). Sixty-five consecutive patients with well-defined IPF were subjected to 24-h pH monitoring and oesophageal manometry. A total of 133 consecutive patients with intractable asthma and symptoms of GER were used as comparisons. The prevalence of abnormal acid GER in IPF patients was 87%, with 76% and 63% demonstrating abnormal distal and proximal oesophageal acid exposures, respectively. Abnormal acid GER was significantly more common in IPF patients than asthma patients. Only 47% of IPF patients experienced classic GER symptoms. Despite treatment with standard doses of proton pump inhibitors (PPIs), 12 out of 19 patients receiving PPIs during the 24-h pH monitoring had abnormal oesophageal acid exposures by pH probe. There was no correlation between IPF severity and acid GER severity. In conclusion, abnormal acid gastro-oesophageal reflux is highly prevalent, but often clinically occult in patients with idiopathic pulmonary fibrosis. Standard doses of proton pump inhibitors may not suppress the acid gastro-oesophageal reflux in this population. Therefore, further studies are needed to determine if acid abnormal gastro-oesophageal reflux represents an important risk factor for idiopathic pulmonary fibrosis development or progression, and if optimal suppression of acid gastro-oesophageal reflux slows the progression of idiopathic pulmonary fibrosis and/or decreases episodic exacerbations of idiopathic pulmonary fibrosis.

Adult↗
PubMed2005

The timed walk test as a measure of severity and survival in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive disease with a median survival of approximately 3 yrs. Measurements of airflow and lung volumes at rest are generally used to monitor the clinical course in this disorder. This study was designed to determine if a modified version of the 6-min walk test, called the timed walk test, accurately characterises disease severity and survival in IPF. The study population consisted of 28 patients with well-characterised progressive IPF. The timed walk test and concurrent measures of disease severity were assessed at baseline. Participants were prospectively followed for > or =4 yrs to determine the relationship between parameters of the timed walk test and survival. There were strong correlations between the end-exercise saturation and walk-velocity parameters of the timed walk test and diffusing capacity, and arterial oxygen tension at rest. In univariate Cox proportional-hazards models, end-exercise saturation, change in saturation with exercise, walk distance and walk velocity were associated with survival. In unadjusted logistic regression models, odds of death at 2 yrs were associated with the same parameters. In conclusion, the timed walk test relates to disease severity and long-term outcome in progressive idiopathic pulmonary fibrosis.

Aged↗
PubMed2004

The epidemiology of interstitial lung disease and its association with lung cancer.

The criteria and terminology for diagnosing interstitial lung disease (ILD), a diverse range of pulmonary fibrotic disorders that affect the alveoli of the lungs, have been variable and confusing; however, there have been recent major improvements to an internationally agreed classification. Evidence from recent analyses of populations suggests that the incidence and prevalence rates of ILD are on the increase, particularly when the broad definition of ILD is used. In most patients with ILD a cause is not identified; nevertheless, among the established causes are a number of drug therapies and infections. Occupational causes are lessening in importance, while cigarette smoking is now an established risk factor. Radiation therapy for cancer is a well-established cause of ILD that usually, but not always, localises within the radiation portal and may occur later after completion of therapy. Similarly, exposure to drugs long after radiation therapy may be an aetiological factor for the development of ILD later in life, although the magnitude of this risk requires further epidemiological investigation. The possibility that ILD and lung cancer are associated has been recognised for >50 years, but it remains unclear whether ILD precedes lung cancer or vice versa. In this review, we examine the epidemiology of ILD and the basis for its association with lung cancer.

Carcinoma, Non-Small-Cell Lung↗
PubMed2001

Usual interstitial pneumonia.

Usual interstitial pneumonia (UIP) is a distinct histological lesion observed in idiopathic pulmonary fibrosis (IPF), but can be found in other etiologies. The diagnosis of UIP can be established by surgical lung biopsy or by high resolution thin section computed tomographic scans (provided the radiographic features are classical). Historically, patients labeled as "IPF'' encompassed a group of disorders including UIP as well as other idiopathic interstitial pneumonias, which differ from UIP in prognosis and responsiveness to therapy. Current recommendations from international consensus statements restrict the term IPF to patients with idiopathic UIP. The inciting cause(s) and pathogenesis of UIP have not been elucidated, but alveolar epithelial cell injury and dysregulation or altered phenotypic expression of fibroblasts are key elements. Inflammatory cells may play minor roles in initiating or propagating the fibrotic process. The prognosis of UIP is poor. Mean survival following diagnosis approximates 3 years. Current therapies are of unproven value. Corticosteroids or immunosuppressive agents have been most often used, but data affirming benefit are lacking. Single-lung transplantation is a viable option for patients failing medical therapy. Novel therapeutic strategies based upon inhibiting fibroproliferation or enhancing alveolar reepithelialization are desperately needed. In this article, we discuss diagnostic criteria for UIP (both histopathological and radiographic), natural history and clinical course, and therapeutic approaches (both current and future).

Journal Article↗
PubMed2000

Comparison of the efficacy and cost effectiveness of pre-emptive therapy as directed by CMV antigenemia and prophylaxis with ganciclovir in lung transplant recipients.

BACKGROUND: CMV disease remains a major complication of lung transplantation and attempts to prevent it have met with marginal success. In a previous study we documented that universal prophylaxis did not prevent CMV disease but merely delayed it, and was very costly. METHODS: We compared the efficacy and cost of pre-emptive therapy with ganciclovir, guided by CMV antigenemia, to that of historic controls that received universal prophylaxis with ganciclovir. CMV antigenemia assay was done routinely and pre-emptive therapy was initiated if greater than 25 CMV positive cells per 100,000 polymorphonuclear cells were found. RESULTS: Nineteen patients were enrolled; 6 of of whom received 12 courses of pre-emptive therapy. The incidence of CMV disease was 26% compared to 38% for the historical controls (p = 0.51). None of the patients that received pre-emptive therapy developed CMV disease following that therapy. Antigenemia failed to predict disease in 5 patients that developed it, and thus it is unknown if pre-emptive therapy could have prevented it. There was no mortality in either the study patients or historic controls directly related to CMV. The net savings with pre-emptive therapy was $2569 per patient. CONCLUSIONS: We conclude that pre-emptive therapy with ganciclovir is as safe and effective as universal prophylaxis in preventing CMV disease in lung transplant recipients, and is less expensive. The appropriate surveillance technique and timing remain to be determine to optimize the efficacy of pre-emptive therapy.

Adult↗
PubMed1999

alpha-thrombin inhibits interleukin-6-induced Stat3 signaling and gp130 gene expression in primary cultures of human lung fibroblasts.

Exposure of primary human lung fibroblasts (HLF) to interleukin-6 (IL-6) rapidly induced Stat3 (signal transducers and activators of transcription 3) tyrosine phosphorylation. In these cells, alpha-thrombin did not induce tyrosine phosphorylation of Stat3; however, it potently induced its serine phosphorylation. Interestingly, a short pretreatment of cells with alpha-thrombin significantly inhibited IL-6-induced tyrosine phosphorylation of Stat3. The inhibition by alpha-thrombin was attenuated if cells were pretreated with U0126, a specific inhibitor of the mitogen-activated protein (MAP) kinase kinase 1 (MAPKK1). Exposure of HLF cells to IL-6 induced a twofold increase in gp130 mRNA levels; however, alpha-thrombin inhibited this IL-6-induced response almost to control levels. These results demonstrate, for the first time, that in HLF cells alpha-thrombin inhibits IL-6-induced Stat3 signaling via activation of MAPKK1 and that this cross-talk regulates IL-6-induced gp130 gene expression.

Antigens, CD↗
PubMed1999

Isolation of efficient antivirals: genetic suppressor elements against HIV-1.

The development of general approaches for the isolation of efficient antivirals and the identification and validation of targets for drug screening are becoming increasingly important, due to the emergence of previously unrecognized viral diseases. The genetic suppressor element (GSE) technology is an approach based on the functional expression selection of efficient genetic inhibitors from random fragment libraries derived from a gene or genome of interest. We have applied this technology to isolate potent genetic inhibitors against HIV-1. Two strategies were used to select for GSEs that interfere with latent virus induction and productive HIV-1 infection based on the expression of intracellular and surface antigens. The selected GSEs clustered in seven narrowly defined regions of the HIV-1 genome and were found to be functionally active. These elements are potential candidates for the gene therapy of AIDS. The developed approaches can be applied to other viral pathogens, as well as for the identification of cellular genes supporting the HIV-1 life cycle.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Regulation of human lung fibroblast C1q-receptors by transforming growth factor-beta and tumor necrosis factor-alpha.

Transforming growth factor-beta (TGF-beta) and tumor necrosis factor-alpha (TNF-alpha) are two polypeptide mediators which are believed to play a role in the evolution of idiopathic pulmonary fibrosis (IPF). We have evaluated the effect of these two substances on the expression of receptors for collagen (cC1q-R) and globular (gC1q-R) domains of C1q and on type I collagen in human lung fibroblasts. Two fibroblast subpopulations differing in C1q receptor expression were obtained by culturing human lung explants in medium containing fresh human serum and heated plasma-derived serum and separating them based on C1q binding [Narayanan, Lurton and Raghu: Am J Resp Cell Mol Biol. 1998; 17:84]. The cells, referred to as HH and NL cells, respectively, were exposed to TGF-beta and TNF-alpha in serum-free conditions. The levels of mRNA were assessed by in situ hybridization and Northern analysis, and protein levels compared after SDS-polyacrylamide gel electrophoresis and Western blotting. NL cells exposed to TGF-beta and TNF-alpha contained 1.4 and 1.6 times as much cC1q-R mRNA, respectively, whereas in HH cells cC1q-R mRNA increased 2.0- and 2.4-fold. The gC1q-R mRNA levels increased to a lesser extent in both cells. These increases were not reflected in protein levels of CC1q-R and gC1q-R, which were similar to or less than controls. Both TGF-beta and TNF-alpha also increased procollagen [I] mRNA levels in both cells. Overall, TNF-alpha caused a greater increase and the degree of response by HH fibroblasts to both TGF-beta and TNF-alpha was higher than NL cells. These results indicated that TGF-beta and TNF-alpha upregulate the mRNA levels for cC1q-R and collagen and that they do not affect gC1q-R mRNA levels significantly. They also indicated different subsets of human lung fibroblasts respond differently to inflammatory mediators.

Amino Acid Sequence↗
PubMed1999

Treatment of idiopathic pulmonary fibrosis with a new antifibrotic agent, pirfenidone: results of a prospective, open-label Phase II study.

Idiopathic pulmonary fibrosis (IPF) is a progressive clinical syndrome of unknown etiology and fatal outcome. Currently available therapies are ineffective and associated with significant adverse effects. Pirfenidone, a new, investigational antifibrotic agent, was evaluated for its tolerability and usefulness in terminally ill patients with advanced IPF. Consecutive patients with IPF and deterioration despite conventional therapy or who were unable to tolerate or unwilling to try conventional therapy were treated with oral pirfenidone. Treatment was administered on a compassionate basis (open-label). Fifty-four patients were followed for mortality, change in lung function, and adverse effects. Their mean age was 62, mean duration of symptoms 4.6 yr, and time since lung biopsy was 3.2 yr. Conventional therapy was discontinued in 38 of 46 patients; the other eight were able to decrease their prednisone dosage and eight had no previous conventional treatment. One- and 2-yr survival was 78% (95% CI 66%, 89%) and 63% (95% CI 50%, 76%), respectively. Patients whose lung functions had deteriorated prior to enrollment appeared to stabilize after beginning treatment. Adverse effects were relatively minor. The results of this study are encouraging. Pirfenidone is a promising new treatment for IPF that is well tolerated.

Administration, Oral↗
PubMed1999

Isolation of a gene product expressed by a subpopulation of human lung fibroblasts by differential display.

Fibroblasts are the major cell type responsible for synthesizing matrix constituents in lung and other connective tissues. Evidence indicates that fibroblasts are heterogeneous, and that subpopulations with some distinct properties are clonally selected and expanded in fibrotic diseases. However, few distinct markers capable of demonstrating the presence of fibroblast subpopulations in tissues have been isolated so far. With the objective of identifying proteins that could detect fibroblast subpopulations, we compared the messenger RNA (mRNA) expression of two cultured human lung fibroblast subpopulations by differential display. Total RNA was obtained, complementary DNA (cDNA) was synthesized, and the polymerase chain reaction (PCR) products obtained with several primer pairs were compared. One 724-bp product, which was strongly expressed by one human lung fibroblast subpopulation, was identified and cloned. This product was poorly expressed by the other lung fibroblast subpopulation. The mRNA for the gene encoding this product was not detectable in human smooth-muscle cells, endothelial cells, or epithelial cells, although it was present in dermal fibroblasts. The mRNA was detected in normal and fibrotic human lungs. Search of the National Center for Biotechnology (NCBI) GenBank DNA database with the sequence obtained from this clone revealed no significant matches. However, a search of the NCBI database of expressed sequence tags (dBEST) revealed five different human expressed sequence tag (EST) clones corresponding to the LR8 cDNA sequence. Six additional mouse and one pig EST clones were identified that showed significant similarity to the human fibroblast cDNA. Composites of the entire coding sequences for the human fibroblast gene product and the mouse homologue were assembled from the respective overlapping EST sequences. The open reading frame identified for each composite sequence predicted protein products of 270 and 263 amino acids for the human and mouse sequences, respectively, which were 52% identical, with three gaps. At the amino acid level, no significant sequence similarity was detected with any other sequences in exhaustive searches of the NCBI DNA and protein databases or the Blocks databases. A PCR product with predicted length and sequence was obtained by using a sense primer upstream to LR8 and an antisense primer within LR8. Our results indicate that this differentially displayed product represents a previously undescribed protein that could be useful for distinguishing fibroblasts, and possibly fibroblast subpopulations, from other cell types in lungs and other tissues.

Amino Acid Sequence↗
PubMed1999

The accuracy of the clinical diagnosis of new-onset idiopathic pulmonary fibrosis and other interstitial lung disease: A prospective study.

STUDY OBJECTIVES: Presently, surgical (open or thoracoscopic) lung biopsy (SLB) is the gold standard for the diagnosis of new-onset idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases (ILDs). The accuracy of a clinical diagnosis of IPF and other subsets of ILD has never been established in prospective studies. We investigated the accuracy and validity of a clinical diagnosis of IPF and ILD other than IPF. DESIGN: Prospective, independent evaluation of patients and clinical data by an ILD expert, of chest radiographic and high-resolution computed tomography (HRCT) features by a chest radiologist, and of histologic features of lung biopsy by a pulmonary pathologist in consecutive patients referred for a diagnostic evaluation of ILD. SETTING: Tertiary university medical center with recognized expertise in management of ILD. PATIENTS: Community patients referred for further definitive diagnostic evaluation of new-onset, untreated nonspecific ILD. INTERVENTION: By comparing the histologic features of SLB in 59 patients consecutively referred for further diagnostic evaluation of new-onset ILD with the clinical and radiologic diagnoses, we determined the sensitivity and specificity of clinical diagnosis and radiologic diagnosis (based on chest radiograph and HRCT features alone) of IPF and ILD other than IPF. A specific clinical diagnosis was independently made by the ILD expert after a thorough clinical assessment that included evaluation of an HRCT scan and bronchoscopic findings. The chest radiographs and HRCT scans were separately reviewed by the chest radiologist, who made a radiologic diagnosis independently. All patients underwent SLB within a month of preoperative "clinical" diagnosis. The clinician's and radiologist's diagnoses were then compared with the gold standard of histologic diagnosis. MEASUREMENTS AND RESULTS: Prior to the clinical evaluation at our center, 85% of patients who underwent SLB had nondiagnostic transbronchial biopsy. The diagnosis of IPF and ILD other than IPF was accurately made by clinical features alone in 62% of cases. The correct radiographic diagnosis of non-IPF ILD was made in 58% of the cases. The sensitivity and specificity of the clinical diagnosis of ILD other than IPF were 88.8% and 40%, respectively. The sensitivity and specificity of the radiographic diagnosis of ILD other than IPF were 59% and 40%, respectively. However, the sensitivity and specificity of the diagnosis of IPF on clinical grounds were 62% and 97%, respectively. The sensitivity and specificity of the radiologic diagnosis of IPF were 78.5% and 90%, respectively. CONCLUSIONS: In a center with recognized expertise in the management of ILD, the specificity of diagnosis of new-onset IPF based on a thorough clinical assessment or HRCT features alone is very high (97% and 90%, respectively), but the sensitivity is low (62% and 78.5%, respectively). Thus, not all patients with new-onset IPF require SLB for diagnosis, but a diagnosis of IPF will be missed in nearly one third of new-onset IPF cases despite evaluation by experts. The relatively low sensitivity and specificity of the diagnosis of ILD other than IPF also emphasizes that an SLB is indicated in patients with ILD in whom the diagnosis is unclear.

Adult↗
PubMed1999

Assessment of health-related quality of life in patients with interstitial lung disease.

STUDY OBJECTIVES: Health-related quality of life associated with interstitial lung disease has received little attention in clinical studies because there have been no validated methods for directly measuring it. We have assessed the validity of several generic and respiratory-specific quality-of-life instruments in patients with interstitial lung disease. DESIGN: Cross-sectional study. SETTING: Outpatient pulmonary clinic at a university referral center. PATIENTS: Fifty patients with interstitial disease such as idiopathic pulmonary fibrosis, sarcoidosis, hypersensitivity pneumonitis, and asbestosis. INTERVENTIONS: Patients were administered four quality-of-life questionnaires, the Medical Outcomes Study Short Form 36 (SF-36), the Quality of Well-being scale (QWB), the Chronic Respiratory Questionnaire (CRQ), and the St. George's Respiratory Questionnaire (SGRQ). Patients concomitantly underwent pulmonary function testing and performed a 6-min walk. MEASUREMENTS AND RESULTS: Validation of these instruments was based on testing an a priori hypothesis that worse quality-of-life scores should correlate with more severe physiologic impairment demonstrated by pulmonary function tests, exercise tolerance on the 6-min walk, and dyspnea scores. Our patients, on average, had a moderate degree of physiologic impairment and demonstrated moderately decreased quality-of-life scores. Scores from all four quality-of-life questionnaires correlated significantly with 6-min walk distance and dyspnea score. Scores from the SF-36, QWB, and SGRQ showed significant correlation with FVC, FEV(1), and diffusing capacity as well. The SF-36 and SGRQ consistently showed the strongest correlation with physical impairment. CONCLUSIONS: Our findings indicate that preexisting quality-of-life instruments can be applied to patients with interstitial lung disease and suggest that the SF-36 and the SGRQ, in particular, are sensitive tools for assessing quality of life in these patients. Future intervention studies of patients with interstitial lung disease should consider using these measures.

Academic Medical Centers↗
PubMed1998

Respiratory failure and hypoventilation secondary to neurosarcoidosis.

We report a patient manifesting severe hypoventilation resulting from diaphragmatic paresis secondary to sarcoid. A 34yr-old female presented with chest pain. Chest radiograph revealed hilar adenopathy and left pleural effusion; computed tomography scan showed a 2-cm solid lesion in the aorto-pulmonary window. Bronchoscopy and thoracentesis failed to further identify the nature of the lesion. An episode of aspiration resulted in cardiopulmonary arrest, necessitating cardiopulmonary resuscitation. Electrodiagnostic findings were consistent with bilateral phrenic neuropathy with axon loss, suggesting a poor prognosis. Biopsy via mediastinoscopy revealed noncaseating confluent granulomas with many multinucleated epithelioid histiocytes consistent with the diagnosis of sarcoidosis. Eight months after initial diagnosis and immunosuppressive treatment, the patient was successfully extubated and became ambulatory. Upon tapering her prednisone, however, she became dyspneic and manifested hypoventilation secondary to muscle weakness. Her corticosteroids were increased, but she eventually died of an opportunistic lung infection 2 yr later. This case establishes phrenic neuropathy and peripheral polyneuropathy secondary to neurosarcoidosis as a cause of respiratory failure. It also illustrates the utility of phrenic and diaphragmatic electrodiagnosis in the evaluation as well as prognostication of such lesions.

Adult↗
PubMed1998

Elevated transforming growth factor-alpha levels in bronchoalveolar lavage fluid of patients with acute respiratory distress syndrome.

The acute respiratory distress syndrome (ARDS) frequently results in a fibroproliferative response that precludes effective alveolar repair. Transforming growth factor-alpha (TGF-alpha), a potent epithelial and mesenchymal cell mitogen, may modulate the response to lung injury. In this study, we determined whether bronchoalveolar lavage fluid (BALF) concentrations of TGF-alpha are increased during the first 2 wk after the onset of ARDS and, if so, whether increased TGF-alpha levels in lavage fluid are associated with increased levels of procollagen peptide III (PCP III), a biological marker of fibroproliferation, and with increased fatality rates. We enrolled 74 consecutive patients with ARDS prospectively identified on admission to the intensive care unit of a tertiary care hospital, and 11 patients with chronic interstitial lung disease. Thirteen healthy volunteers served as control subjects. TGF-alpha concentrations were measured in BALF recovered on Days 3, 7, and 14 after the onset of ARDS (total of 130 lavage samples). TGF-alpha was detected in the lavage fluid of 90% of patients with ARDS (67 of 74), and in 100% of patients with idiopathic pulmonary fibrosis (IPF) (10 of 10), but in none of 13 normal volunteers. At each day tested, the median lavage TGF-alpha level of patients with ARDS was significantly higher than that of normals. The overall fatality rate was 45% (33 of 74 patients). In a univariate analysis, the median TGF-alpha levels in nonsurvivors were 1.5-fold higher at Day 7 (p = 0.06) and 1.8-fold higher at Day 14 (p = 0.048). The fatality rate was 4 times higher (CI 1.6, 17.5) for patients with both increased lavage TGF-alpha and PCP III concentrations at Day 7 than for patients with low TGF-alpha and PCP III values, indicating a synergistic relationship between TGF-alpha and PCP III. We conclude that increased levels of TGF-alpha in BALF are common in patients with ARDS and that lavage TGF-alpha is associated with a marker of the fibroproliferative response in sustained ARDS.

Adolescent↗