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Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing lung disease limited to the lungs and associated with the histologic appearance of usual interstitial pneumonia (UIP) on surgical lung biopsy. The estimated prevalence in the United States is between 35,000 and 55,000 cases,and evidence suggests that the prevalence is increasing for IPF. Risk factors associated with pulmonary fibrosis include smoking, environmental exposures, gastroesophageal reflux dis-ease, commonly prescribed drugs, diabetes mellitus, infectious agents, and genetic factors. The diagnosis requires a careful history and physical examination, characteristic physiological and radiological studies, and, in some cases, a surgical lung biopsy. The natural history of IPF is not known, but evidence supports the concept of a continuum of idiopathic interstitial pneumonias that may overlap in time. Most patients with IPF succumb to respiratory failure, cardiovascular disease, lung cancer, pulmonary embolism, infection, and other health problems. The median survival time for patients with IPF is less than 3 yr. Factors that predict poor outcome include older age, male gender, severe dyspnea, history of cigarette smoking, severe loss of lung function, appearance and severity of fibrosis on radiological studies, lack of response to therapy,and prominent fibroblastic foci on histopathologic evaluation. Conventional therapy (corticosteroids, azathioprine, cyclophosphamide) provides only marginal benefit. Lung transplantation should be considered for patients with IPF refractory to medical therapy. In light of the poor prognosis and lack of response to available anti-inflammatory therapy, alternative approaches to therapy are being pursued. Emerging strategies to treat patients with IPF include agents that inhibit epithelial injury or enhance repair, anti-cytokine approaches, agents that inhibit fibroblast proliferation or induce fibroblast apoptosis, and other novel approaches.
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PMID:Pulmonary fibrosis. 1613 Feb 30

Interest in peroxisome proliferator-activated receptors (PPARs) has steadily increased over the past 15 years. The recognition that subclasses of this receptor played critical roles in regulation of metabolism led to the development of synthetic ligands and their widespread application in the treatment of type 2 diabetes. At the same time, emerging evidence demonstrated that the influence of PPARs extends well beyond metabolism and diabetes. A salient example of this can be seen in studies that explore the role of PPARs in lung cell biology. In fact, current literature suggests that PPAR receptors may well represent exciting new targets for treatment in a variety of lung disorders. In an attempt to keep the scientific and medical communities abreast of these developments, a symposium sponsored by the American Federation for Medical Research entitled "PPARgamma: A Novel Molecular Target in Lung Disease" was convened on April 29, 2007, at the Experimental Biology Meeting in Washington, DC. During that symposium, 4 speakers reviewed the latest developments in basic and translational research as they relate to specific lung diseases. Jesse Roman, MD, professor and director of the Emory University Division of Pulmonary, Allergy, and Critical Care Medicine, reviewed the role of PPARgamma in the pathogenesis of lung cancer and its implications for therapy. Raju Reddy, MD, assistant professor of Medicine at the University of Michigan, presented data regarding the immunomodulatory role of PPARgamma in alveolar macrophages. Patricia J. Sime, MD, associate professor of Medicine, Environmental Medicine, and Oncology at the University of Rochester School of Medicine, discussed the antifibrogenic potential of PPARgamma ligands in pulmonary fibrosis. Finally, C. Michael Hart, MD, professor of Medicine at Emory University and chief of the Atlanta Veterans Affairs Medical Center Pulmonary Section, reviewed the role of PPARgamma in pulmonary vascular disease. This brief introduction to the symposium will provide background information about PPARs to facilitate the general reader's appreciation of the more in-depth and disease-specific discussions that follow.
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PMID:PPARgamma: a novel molecular target in lung disease. 1831 33

Endeavour (http://www.esat.kuleuven.be/endeavourweb; this web site is free and open to all users and there is no login requirement) is a web resource for the prioritization of candidate genes. Using a training set of genes known to be involved in a biological process of interest, our approach consists of (i) inferring several models (based on various genomic data sources), (ii) applying each model to the candidate genes to rank those candidates against the profile of the known genes and (iii) merging the several rankings into a global ranking of the candidate genes. In the present article, we describe the latest developments of Endeavour. First, we provide a web-based user interface, besides our Java client, to make Endeavour more universally accessible. Second, we support multiple species: in addition to Homo sapiens, we now provide gene prioritization for three major model organisms: Mus musculus, Rattus norvegicus and Caenorhabditis elegans. Third, Endeavour makes use of additional data sources and is now including numerous databases: ontologies and annotations, protein-protein interactions, cis-regulatory information, gene expression data sets, sequence information and text-mining data. We tested the novel version of Endeavour on 32 recent disease gene associations from the literature. Additionally, we describe a number of recent independent studies that made use of Endeavour to prioritize candidate genes for obesity and Type II diabetes, cleft lip and cleft palate, and pulmonary fibrosis.
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PMID:ENDEAVOUR update: a web resource for gene prioritization in multiple species. 1850 7

Coccidioidomycosis is endemic in the southwestern United States, resulting in 100,000 infections annually. The majority of these infections are asymptomatic or manifest as community-acquired pneumonia. In rare cases, patients can present with a mononuclear-cell predominant pyopneumothorax. The presence of spherules in tissue specimens is pathognomonic of this condition. A 72-year-old man born in Arizona with a heavy smoking history, presented with a 1-month history of weakness, night sweats, exertional dyspnea, and left pleuritic chest pain. The physical examination was remarkable for decreased breath sounds and dullness to percussion at the left lung base. His initial laboratory examination showed leukocytosis, eosinophilia, and elevated C-reactive protein. Computed tomography of the chest revealed a left lower lobe infiltrate, a cavity with air-crescent sign and hydropneumothorax. The pleural fluid was sampled and revealed an eosinophilic exudate with normal pH. Bacterial and fungal cultures of the pleural fluid were negative. Biopsy of the cavity wall showed chronic inflammation, fungal hyphae, and rare spherule-like structures. The surgical specimen culture grew Coccidioides immitis. Complement fixation for coccidioidomycosis performed on a serum sample was positive at a titer of 1:2 but a latex agglutinin test was negative. The patient was diagnosed with chronic fibrocavitary pneumonia with pyopneumothorax secondary to C. immitis infection and discharged on itraconazole for 1 year. Coccidioidomycosis can present in a variety of forms and should be part of the differential diagnosis in patients presenting with cavitation, air-crescent sign, eosinophilic pleural effusion, and hyphae and spherules on the tissue specimen. Chronic fibrocavitary pneumonia should be especially considered in patients who lived in endemic areas and have risk factors such as diabetes mellitus or pulmonary fibrosis related to smoking.
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PMID:Spherules, hyphae, and air-crescent sign. 1855 86

Glutathione (GSH) is a ubiquitous intracellular peptide with diverse functions that include detoxification, antioxidant defense, maintenance of thiol status, and modulation of cell proliferation. GSH is synthesized in the cytosol of all mammalian cells in a tightly regulated manner. The major determinants of GSH synthesis are the availability of cysteine, the sulfur amino acid precursor, and the activity of the rate-limiting enzyme, glutamate cysteine ligase (GCL). GCL is composed for a catalytic (GCLC) and modifier (GCLM) subunit and they are regulated at multiple levels and at times differentially. The second enzyme of GSH synthesis, GSH synthase (GS) is also regulated in a coordinated manner as GCL subunits and its up-regulation can further enhance the capacity of the cell to synthesize GSH. Oxidative stress is well known to induce the expression of GSH synthetic enzymes. Key transcription factors identified thus far include Nrf2/Nrf1 via the antioxidant response element (ARE), activator protein-1 (AP-1) and nuclear factor kappa B (NFkappaB). Dysregulation of GSH synthesis is increasingly being recognized as contributing to the pathogenesis of many pathological conditions. These include diabetes mellitus, pulmonary fibrosis, cholestatic liver injury, endotoxemia and drug-resistant tumor cells. Manipulation of the GSH synthetic capacity is an important target in the treatment of many of these disorders.
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PMID:Regulation of glutathione synthesis. 1860 45

Studies of uranium miners on the US Colorado Plateau have identified associations between exposure to radon progeny and risk of lung cancer. This study added 15 years of mortality follow-up for the 4,137 miners (primarily white or American Indian) in the Colorado Plateau cohort. The cohort experienced 209 new lung cancer deaths. For white miners, the standardized mortality ratio for lung cancer compared with the regional population was 3.99 (95% confidence interval: 3.43, 4.62) for the period 1991-2005. For American Indian miners, the lung cancer standardized mortality ratio was 3.27 (95% confidence interval: 2.19, 4.73). These standardized mortality ratios have not declined substantially since the 1980s. Internally standardized rate ratios by radon exposure category over the entire follow-up period are similar to those based on earlier follow-up, although estimates within smoking categories demonstrated improved precision. The apparent interaction between radon and smoking in causing lung cancer remains submultiplicative but greater than additive. Mortality rates from silicosis remain highly elevated in the cohort. Elevated mortality rates were observed from interstitial pulmonary fibrosis, multiple myeloma, and non-Hodgkin lymphoma. Significant trends were observed with increased radon exposure in silicosis and pulmonary fibrosis mortality and in the incidence of diabetes-related end-stage renal disease among white miners.
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PMID:Radon exposure and mortality among white and American Indian uranium miners: an update of the Colorado Plateau cohort. 1920 23

Lung transplantation has become a viable option for those cystic fibrosis (CF) patients with end-stage lung disease. Despite the challenges that the CF patients present, the survival seen after lung transplantation is more favorable than seen in patients with chronic obstructive pulmonary disease and pulmonary fibrosis. Although the CF patients with severe respiratory disease usually are infected with organisms that display in vitro resistance to the commonly used antibiotics, these patients usually have successful outcomes with transplantation. The other challenges include the presence of nontuberculous mycobacteria, the significant incidence of liver involvement, the development of an ileus or the development of the distal intestinal obstruction syndrome, and the presence of gastroesophageal reflux. Most of the patients have metabolic bone disease, even preoperatively, that warrants treatment, especially with the significant loss of bone density seen in the first year after transplant, thought to be related, in part, to the high dose of corticosteroids. Diabetes mellitus and its consequences are not uncommon. The malabsorption of fat seen in the pancreatic-insufficient patients complicates the absorption kinetics of the anti-rejection drugs. In May 2005 the United Network of Organ Sharing instituted a lung-allocation score to better distribute the donated lungs to those patients who would achieve the most benefit. This score uses several variables to balance the likelihood of the patients living one year with a transplant versus one year without a transplant. With this change in the allocation of organs, the median waiting times have significantly decreased, the mortality on the waiting list has decreased, and the number of CF patients transplanted has not changed. With substantial experience, more programs are now transplanting patients who require constant mechanical ventilation or patients who have undergone previous pleural procedures, especially in the treatment of a pneumothorax. The limiting factor now in lung transplantation is the number of organs available. Efforts to increase the donor pool, such as alveolar recruitment strategies to improve gas exchange, have been effective in allowing more patients to be transplanted. Lung transplantation is now an accepted form of therapy in those patients who are developing progressive respiratory failure.
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PMID:Lung transplantation in cystic fibrosis. 1946 64

Human stem cells are in evaluation in clinical stem cell trials, primarily as autologous bone marrow studies, autologous and allogenic mesenchymal stem cell trials, and some allogenic neural stem cell transplantation projects. Safety and efficacy are being addressed for a number of disease state applications. There is considerable data supporting safety of bone marrow and mesenchymal stem cell transplants but the efficacy data are variable and of mixed benefit. Mechanisms of action of many of these cells are unknown and this raises the concern of unpredictable results in the future. Nevertheless there is considerable optimism that immune suppression and anti-inflammatory properties of mesenchymal stem cells will be of benefit for many conditions such as graft versus host disease, solid organ transplants and pulmonary fibrosis. Where bone marrow and mesenchymal stem cells are being studied for heart disease, stroke and other neurodegenerative disorders, again progress is mixed and mostly without significant benefit. However, correction of multiple sclerosis, at least in the short term is encouraging. Clinical trials on the use of embryonic stem cell derivatives for spinal injury and macular degeneration are beginning and a raft of other clinical trials can be expected soon, for example, the use of neural stem cells for killing inoperable glioma and embryonic stem cells for regenerating beta islet cells for diabetes. The change in attitude to embryonic stem cell research with the incoming Obama administration heralds a new co-operative environment for study and evaluation of stem cell therapies. The Californian stem cell initiative (California Institute for Regenerative Medicine) has engendered global collaboration for this new medicine that will now also be supported by the US Federal Government. The active participation of governments, academia, biotechnology, pharmaceutical companies, and private investment is a powerful consortium for advances in health.
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PMID:New perspectives in human stem cell therapeutic research. 1951 78

Mutations of the LMNA gene have been shown to cause an autosomal dominant form of insulin resistance with familial partial lipodystrophy (PLD), frequently accompanied by diabetes. LMNA mutations are considered to be a rare cause of monogenic diabetes; however, they are probably sometimes misdiagnosed as type 2 diabetes (T2DM). We examined whether skin fold thickness measurements may be an effective screening procedure to select individuals with T2DM for molecular testing of the LMNA gene. We also aimed to search for mutations in diabetic patients with evident clinical features of lipodystrophy. Skin fold measurements were performed in 249 not pre-selected T2DM patients. The sum of two trunk skin fold measurements divided by the sum of two peripheral was obtained. Men with a skin fold ratio above 2.5 and women above 1.5 were selected for further molecular analysis of the LMNA gene by direct sequencing. We also examined eight patients presenting typical clinical features of lipodystrophy. We selected 16 patients with T2DM on the basis of skin fold measurements. LMNA gene sequencing in this group revealed no mutation that could be attributable to diabetic phenotype. However, in the group of subjects with apparent lipodystrophic phenotype, we identified one Arg482Gln mutation. This female, diagnosed with diabetes at the age of 51 years, was characterized by insulin resistance but, unlike previously reported LMNA Arg48Gln mutation carriers, she was not overweight. The patient also presented with chronic kidney disease and pulmonary fibrosis that could potentially be a part of the phenotype related to the identified LMNA mutation. We did not find the evidence that screening based on skin fold measurements alone could be an efficient approach to select T2DM patients for molecular testing of the LMNA gene; the presence of features typical for laminopathy seems to be required for such testing. A clinical picture related to the LMNA Arg482Gln mutation may be more diversified than it was previously considered and include low BMI and pulmonary fibrosis.
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PMID:LMNA gene mutation search in Polish patients: new features of the heterozygous Arg482Gln mutation phenotype. 1985 38

Pulmonary toxicity is one of the most serious adverse effects associated with a quick course of vincristine, bleomycin, and cisplatin neoadjuvant chemotherapy (NAC-VBP). The aim of this study was to evaluate pulmonary toxicity related to a quick course NAC-VBP. A total of consecutive 61 patients, who underwent at most 3 cycles of NAC-VBP every 10 days in the International Federation of Gynecology and Obstetrics (FIGO) stage IB-IIB cervical cancer from 1995 to 2007, were retrospectively analyzed. Of the 61 study subjects, 7 (11.5%) were identified to have pulmonary toxicity and 2 (3.3%) died of pulmonary fibrosis progression despite aggressive treatment and the use of a multidisciplinary approach. No factor predisposing pulmonary toxicity was identified. Initial symptoms were non-specific, but bronchiolitis obliterans organizing pneumonia and interstitial pneumonitis were characteristic findings by high-resolution computed tomography of the chest. The benefit of steroid therapy was uncertain and was associated with steroid-induced diabetes mellitus requiring insulin therapy in two patients. Fatal pulmonary toxicity is a major concern of a quick course NAC-VBP. In conclusion, these patients require special monitoring for bleomycin-induced pulmonary toxicity.
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PMID:Pulmonary toxicity after a quick course of combinatorial vincristine, bleomycin, and cisplatin neoadjuvant chemotherapy in cervical cancer. 2011 77


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