Travis S. Henry

Protein Phosphatase 2A Dephosphorylation of Phosphoserine 112 Plays the Gatekeeper Role for BAD-Mediated Apoptosis

ABSTRACT BAD, a proapoptotic molecule of the BCL2 family, is regulated by reversible phosphorylation. During survival, BAD is sequestered by 14-3-3 through serine 136 phosphorylation and is dissociated from BCL-XL through serine 155 phosphorylation. We report that phosphoserine 112 (pSer112) dephosphorylation functions as a gatekeeper for BAD-mediated apoptosis. During apoptosis, dephosphorylation of pSer112 preceded pSer136 dephosphorylation. Dephosphorylation of pSer112 accelerated dephosphorylation of pSer136, and inhibition of pSer112 dephosphorylation prevented pSer136 dephosphorylation, indicating that dephosphorylation of pSer112 is required for dephosphorylation of pSer136. Protein phosphatase 2A (PP2A) is the major pSer112 phosphatase. PP2A competed with 14-3-3 for BAD binding, and survival factor withdrawal enhanced PP2A association with BAD. Dephosphorylation of the critical residue, pSer136, could only be blocked by inhibition of all known subfamilies of serine/threonine phosphatases, suggesting that multiple phosphatases are involved in pSer136 dephosphorylation. Inhibition of PP2A rescued FL5.12 cells from apoptosis, demonstrating a physiologic role for PP2A-mediated pSer112 dephosphorylation. Thus, PP2A dephosphorylation of pSer112 is the key initiating event regulating the activation of BAD during interleukin-3 withdrawal-induced apoptosis.

Scoring of coronary artery calcium scans: History, assumptions, current limitations, and future directions

Coronary artery calcium (CAC) scanning is a reliable, noninvasive technique for estimating overall coronary plaque burden and for identifying risk for future cardiac events. Arthur Agatston and Warren Janowitz published the first technique for scoring CAC scans in 1990. Given the lack of available data correlating CAC with burden of coronary atherosclerosis at that time, their scoring algorithm was remarkable, but somewhat arbitrary. Since then, a few other scoring techniques have been proposed for the measurement of CAC including the Volume score and Mass score. Yet despite new data, little in this field has changed in the last 15 years. The main focus of our paper is to review the implications of the current approach to scoring CAC scans in terms of correlation with the central disease - coronary atherosclerosis. We first discuss the methodology of each available scoring system, describing how each of these scores make important indirect assumptions in the way they account (or do not account) for calcium density, location of calcium, spatial distribution of calcium, and microcalcification/emerging calcium that might limit their predictive power. These assumptions require further study in well-designed, large event-driven studies. In general, all of these scores are adequate and are highly correlated with each other. Despite its age, the Agatston score remains the most extensively studied and widely accepted technique in both the clinical and research settings. After discussing CAC scoring in the era of contrast enhanced coronary CT angiography, we discuss suggested potential modifications to current CAC scanning protocols with respect to tube voltage, tube current, and slice thickness which may further improve the value of CAC scoring. We close with a focused discussion of the most important future directions in the field of CAC scoring.

Congenital Thoracic Vascular Anomalies

Congenital vascular anomalies of the thorax represent an important group of entities that can occur either in isolation or in association with different forms of congenital heart disease. It is extremely important that radiologists have a clear understanding of these entities, their imaging characteristics, and their clinical relevance. The imaging armamentarium available to diagnose these diverse conditions is ample, and has evolved from such traditional methods as chest radiography, barium esophagography, and angiography to new modalities that include echocardiography, multidetector row CT (MDCT), and MR imaging. These imaging modalities have added safety, speed, and superb resolution in diagnosis and, as in the case of MDCT, provide additional information about the airway and lung parenchyma, resulting in a more comprehensive examination with greater anatomic coverage. This article reviews the most important congenital thoracic vascular anomalies, their embryologic foundation, clinical presentation, and imaging characteristics, especially those of MDCT.

Mapping the future of cardiac MR imaging: case-based review of T1 and T2 mapping techniques.

Cardiac magnetic resonance (MR) imaging has grown over the past several decades into a validated, noninvasive diagnostic imaging tool with a pivotal role in cardiac morphologic and functional assessment and tissue characterization. With traditional cardiac MR imaging sequences, assessment of various pathologic conditions ranging from ischemic and nonischemic cardiomyopathy to cardiac involvement in systemic diseases (eg, amyloidosis and sarcoidosis) is possible; however, these sequences are most useful in focal myocardial disease, and image interpretation relies on subjective qualitative analysis of signal intensity. Newer T1 and T2 myocardial mapping techniques offer a quantitative assessment of the myocardium (by using T1 and T2 relaxation times), which can be helpful in focal disease, and demonstrate special utility in the evaluation of diffuse myocardial disease (eg, edema and fibrosis). Altered T1 and T2 relaxation times in disease states can be compared with published ranges of normal relaxation times in healthy patients. In conjunction with traditional cardiac MR imaging sequences, T1 and T2 mapping can limit the interpatient and interstudy variability that are common with qualitative analysis and may provide clinical markers for long-term follow-up.

The use of pretest probability increases the value of high-resolution CT in diagnosing usual interstitial pneumonia

Background Recent studies have suggested that non-definitive patterns on high-resolution CT (HRCT) scan provide sufficient diagnostic specificity to forgo surgical lung biopsy in the diagnosis of idiopathic pulmonary fibrosis (IPF). The objective of this study was to determine test characteristics of non-definitive HRCT patterns for identifying histopathological usual interstitial pneumonia (UIP). Methods Patients with biopsy-proven interstitial lung disease (ILD) and non-definitive HRCT scans were identified from two academic ILD centres. Test characteristics for HRCT patterns as predictors of UIP on surgical lung biopsy were derived and validated in independent cohorts. Results In the derivation cohort, 64/385 (17%) had possible UIP pattern on HRCT; 321/385 (83%) had inconsistent with UIP pattern. 113/385 (29%) patients had histopathological UIP pattern in the derivation cohort. Possible UIP pattern had a specificity of 91.2% (95% CI 87.2% to 94.3%) and a positive predictive value (PPV) of 62.5% (95% CI 49.5% to 74.3%) for UIP pattern on surgical lung biopsy. The addition of age, sex and total traction bronchiectasis score improved the PPV. Inconsistent with UIP pattern demonstrated poor PPV (22.7%, 95% CI 18.3% to 27.7%). HRCT pattern specificity was nearly identical in the validation cohort (92.7%, 95% CI 82.4% to 98.0%). The substantially higher prevalence of UIP pattern in the validation cohort improved the PPV of HRCT patterns. Conclusions A possible UIP pattern on HRCT has high specificity for UIP on surgical lung biopsy, but PPV is highly dependent on underlying prevalence. Adding clinical and radiographic features to possible UIP pattern on HRCT may provide sufficient probability of histopathological UIP across prevalence ranges to change clinical decision-making.

Bronchiectasis: Mechanisms and Imaging Clues of Associated Common and Uncommon Diseases

Bronchiectasis is permanent irreversible dilatation of the airways and occurs in a variety of pathologic processes. Recurrent infection and inflammation and the resulting chemical and cellular cascade lead to permanent architectural changes in the airways. Bronchiectasis can confer substantial potential morbidity, usually secondary to recurrent infection. In severe cases of bronchiectasis, massive hemoptysis can lead to death. Thin-section computed tomography is the most sensitive imaging modality for the detection of bronchiectasis; findings include bronchial diameter exceeding that of the adjacent pulmonary artery and lack of normal tapering of terminal bronchioles as they course toward the lung periphery. The authors will review various causes of bronchiectasis, including common causes, such as recurrent infection or aspiration, and uncommon causes, such as congenital immunodeficiencies and disorders of cartilage development. The authors will also present an approach emphasizing the distribution (apical versus basal and central versus peripheral) and concomitant findings, such as nodules, cavities, and/or lymphadenopathy, that can assist in narrowing the differential diagnosis. Although an adequate understanding of these underlying causes in conjunction with their specific imaging appearances will allow radiologists to more confidently determine the process causing this common radiologic finding, clinical history and patient demographic characteristics play an integral role in determining a pertinent and concise differential diagnosis.

Differences in coronary plaque composition with aging measured by coronary computed tomography angiography

BACKGROUND Little is known about the independent impact of aging on coronary plaque morphology and composition in the era of cardiac computed tomography angiography (CCTA). METHODS We studied 1015 consecutive asymptomatic South Korean subjects (49 ± 10 years, 64% men) who underwent 64-slice CCTA during routine health evaluation. Coronary plaque characteristics were analyzed on a per-segment basis according to the modified AHA classification. Plaques with >50% calcified tissue were classified as calcified (CAP), plaques with <50% calcified tissue were classified as mixed (MCAP), and plaques without calcium were classified as non-calcified (NCAP). Multiple regression analysis was employed to describe the cross-sectional association between age tertile and plaque type burden (≥ 2 affected segments) after adjustment for other cardiovascular risk factors. RESULTS The prevalence of coronary plaque increased with age, (1st tertile: 7.5%, 3rd tertile: 38.5% [p<0.001]). The relative contribution of NCAP to overall plaque burden decreased with age from nearly 50% in the first tertile to approximately 20% in the third, while there was a reciprocal increase in both MCAP and CAP subtypes. In multivariable analysis, patients in the oldest tertile had a 2.5-fold increase in burden of NCAP, yet a nearly 40-fold increase in MCAP and 16-fold increase in CAP compared to the youngest tertile. In conclusion, CCTA is an effective method for measuring age-related differences in the burden of individual coronary plaque subtypes. Future research is needed to determine whether the increase in mixed and calcified plaques seen with aging produce an independent contribution to the age-related increase in cardiovascular risk.

Chest CT features of North American paragonimiasis.

OBJECTIVE The purpose of this study was to characterize the chest CT findings of North American paragonimiasis due to Paragonimus kellicotti in the largest (to our knowledge) case series reported to date and to compare the findings with those reported for paragonimiasis infections in other regions. MATERIALS AND METHODS A retrospective review was performed of chest CT examinations of eight patients with North American paragonimiasis treated at our institution between 2006 and 2010. Findings were characterized by site of involvement, including lungs and pleura, heart and pericardium, lymph nodes, and upper abdomen. RESULTS The most common chest CT findings in this case series were pleural effusions and internal mammary and cardiophrenic lymphadenopathy. Pulmonary parenchymal findings included peripheral lung nodules of 1-3.5 cm in size with surrounding ground-glass opacity; many nodules had a linear track to the pleural surface that may correspond to the worms burrow tunnel. Pericardial involvement (5/8 patients) and omental inflammation (5/7 patients), which are uncommon in Asian paragonimiasis, were common in this series. CONCLUSION Pleural and pulmonary features of North American paragonimiasis are generally similar to those reported from Asia. The presence of a track between a pulmonary nodule and the pleura may help distinguish paragonimiasis from mimickers, including chronic eosinophilic pneumonia, tuberculosis, fungal infection, or malignancy. Pericarditis, lymphadenopathy, and omental inflammation were more common in our series than in reports on paragonimiasis from other regions. These differences may be related to the infecting parasite species or to the fact that radiologic examinations in the present series were performed relatively early in the course of infection.

Multidisciplinary Approach to Hypersensitivity Pneumonitis.

Hypersensitivity pneumonitis (HP) may be a challenging diagnosis given the wide variability of its clinical, radiographic, and pathologic manifestations. A multidisciplinary approach to diagnosis is critical in maintaining a high specificity for HP. An in-depth knowledge of all 3 arms of the multidisciplinary approach helps clinicians, radiologists, and pathologists interpret their own findings in the context of the entire presentation. In some cases, the combination of clinical findings (ie, an identifiable exposure) and typical findings on high-resolution computed tomography is considered diagnostic of HP, and pathologic confirmation is not necessary. As many as 50% of patients do not have a clear exposure, however. These patients may be difficult to distinguish from idiopathic disorders. In these cases, high-resolution computed tomography and pathology are the primary data points that may suggest the correct diagnosis. The goal of this paper is to discuss recent advances in HP and to present the spectrum of clinical, radiographic, and pathologic findings.

The MUC5B promoter polymorphism and telomere length in patients with chronic hypersensitivity pneumonitis: an observational cohort-control study

SUMMARY Background Patients with hypersensitivity pneumonitis (HP) may develop lung fibrosis, which is associated with reduced survival. Families with pulmonary fibrosis can present with members diagnosed with idiopathic pulmonary fibrosis (IPF) or chronic HP (cHP), suggesting that fibrotic HP may share risk factors with IPF. Methods In an observational study of two independent cohorts of patients with cHP (UCSF n=145, UTSW n=72), we measured two common single nucleotide polymorphisms associated with IPF (MUC5B rs35705950 & TOLLIP rs5743890) and peripheral blood leukocyte telomere length and evaluated their associations with cHP disease, survival, and clinical-radiograph-pathologic features. Findings The frequency of the MUC5B minor allele, but not the TOLLIP minor allele, was significantly increased in cHP patients in both cohorts (UCSF MAF 24.4% & UTSW MAF 32.3%) compared to healthy controls (MAF 10.7%; p-values for comparison = <0.0001 for both cohorts) and similar to IPF (UCSF MAF 33.3% & UTSW MAF 32.0%, p-values for comparison=0.10 & 0.95, respectively). The MUC5B minor allele (adjusted OR 1.91, p=0.045) and shorter telomere length (adjusted OR 0.23, p=0.002) were associated with extent of radiographic fibrosis and other measures of lung remodeling and fibrosis in the combined cHP cohorts. Shorter telomere length had a significant association (adjusted HR 0.18, p=0.001) with reduced survival in the combined cHP cohorts. Interpretation The MUC5B promoter polymorphism rs35705950 and shorter telomere length are associated with extent of fibrosis in cHP. Shorter telomere length is associated with histopathology findings typical of usual interstitial pneumonia and reduced survival in cHP. Funding NIH grants KL2TR001870, T32HL098040, UL1TR001105, R01HL093096, and the Nina Ireland Program for Lung Health.