Publications

The clinical course of idiopathic pulmonary fibrosis (IPF) is variable; however, the long-term survival in IPF is poor. Prednisone has been the mainstay of therapy since its release for clinical use in 1948. Recently, prednisone combined with azathioprine or cyclophosphamide has been used. A number of other drug combinations have been tried with prednisone (e.g., methotrexate, colchicine, penicillamine, or cyclosporine) but have failed or are not well tolerated by the patient. Few high quality, prospective, controlled clinical trials have been performed. Thus, there is no good evidence to support the routine use of any specific therapy in the management of IPF. Additional large clinical trials are needed to confirm the potential usefulness of the newer agents (e.g., IFN-gamma1b, pirfenidone, N-acetylcysteine, coumadin, bosentan, or etanercept). This article examines the body of evidence supporting the current therapies and reviews the newer agents being tested in patients with IPF.

In the American Thoracic Society/European Respiratory Society consensus classification, idiopathic interstitial pneumonias are classified into seven clinicopathologic entities. The classification is largely based on histopathology, but depends on the close interaction of clinician, radiologist, and pathologist. An accurate diagnosis can be very difficult, especially when deciding between idiopathic pulmonary fibrosis and fibrotic nonspecific interstitial pneumonia; better diagnostic markers are needed. The prognosis of idiopathic pulmonary fibrosis is very poor, with median survival of 2-4 yr after the diagnosis, yet the course of individual patients is highly variable. Predicting prognosis in the individual patient is challenging but various clinical and radiologic variables have been identified. According to several recent clinical trials, the natural history of this disease may involve periods of relative stability punctuated by acute exacerbations of disease that result in substantial morbidity or death. Nonspecific interstitial pneumonia is characterized by a distinct histopathologic appearance and a better prognosis than idiopathic pulmonary fibrosis. However, there is still confusion and controversy over the relationship between idiopathic pulmonary fibrosis and fibrotic nonspecific interstitial pneumonia.

Congenital diaphragmatic hernia (CDH) is a common birth defect with a high mortality and morbidity. There have been few studies that have assessed copy number changes in CDH. We present array comparative genomic hybridization data for 29 CDH patients to identify and map chromosome aberrations in this disease. Three patients with 15q26.1-15q26.2 deletions had heterogeneous breakpoints that overlapped with the critical 4 Mb region previously delineated for CDH, confirming 15q26.1-15q26.2 as a critical region for CDH. The three other most compelling CDH-critical regions for genomic deletions based on these data and a literature review are located at chromosomes 8p23.1, 4p16.3-4pter, and 1q41-1q42.1. Based on these recurrent deletions at 15q26.1-15q26.2, we hypothesized that loss-of-function mutations in a gene or genes from this region could cause CDH and sequenced six candidate genes from this region in more than 100 patients with CDH. For three of these genes (CHD2, ARRDC4, and RGMA), we identified missense changes and that were not identified in normal controls; however, none of these alterations appeared unambiguously causal with CDH. These data suggest that CDH caused by chromosome deletions at 15q26.2 may arise because of a contiguous gene deletion syndrome or may have a multifactorial etiology. In addition, there is evidence for substantial genetic heterogeneity in CDH and diaphragmatic hernias can be non-penetrant in patients who have deletions involving CDH-critical regions.

HIV-1 often invades the CNS during primary infection, eventually resulting in neurological disorders in up to 50% of untreated patients. The CNS is a distinct viral reservoir, differing from peripheral tissues in immunological surveillance, target cell characteristics and antiretroviral penetration. Neurotropic HIV-1 likely develops distinct genotypic characteristics in response to this unique selective environment. We sought to catalogue the genetic features of CNS-derived HIV-1 by analysing 456 clonal RNA sequences of the C2-V3 env subregion generated from CSF and plasma of 18 chronically infected individuals. Neuropsychological performance of all subjects was evaluated and summarized as a global deficit score. A battery of phylogenetic, statistical and machine learning tools was applied to these data to identify genetic features associated with HIV-1 neurotropism and neurovirulence. Eleven of 18 individuals exhibited significant viral compartmentalization between blood and CSF (P < 0.01, Slatkin-Maddison test). A CSF-specific genetic signature was identified, comprising positions 9, 13 and 19 of the V3 loop. The residue at position 5 of the V3 loop was highly correlated with neurocognitive deficit (P < 0.0025, Fisher's exact test). Antibody-mediated HIV-1 neutralizing activity was significantly reduced in CSF with respect to autologous blood plasma (P < 0.042, Student's t-test). Accordingly, CSF-derived sequences exhibited constrained diversity and contained fewer glycosylated and positively selected sites. Our results suggest that there are several genetic features that distinguish CSF- and plasma-derived HIV-1 populations, probably reflecting altered cellular entry requirements and decreased immune pressure in the CNS. Furthermore, neurological impairment may be influenced by mutations within the viral V3 loop sequence.