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Purpose . Molecular breast imaging (MBI) of 99m Tc-sestamibi with dual-headed, pixelated, cadmium-zinc-telluride (CZT) detectors is increasingly used in breast cancer care for screening/detecting lesions, monitoring response to therapy, and predicting risk of cancer. MBI as a truly quantitative tool in these applications, however, is limited due the lack of absolute 99m Tc-sestamibi uptake quantification. To help advance the field of quantitative MBI, we have developed a Monte Carlo simulation application of the GE Discovery NM 750b system. Methods . Our simulation consists of a two-step process using the Geant4 toolkit to model the detector and source geometry and to track photon interactions and a MATLAB script to model the charge transport within the pixelated CZT detector. Simulated detector and detector response model parameters were selected to match measured and simulated standard performance characteristics using various 99m Tc point-, line-, and film-sources in air. The final model parameters were verified by comparing the count profiles, energy spectra, and region of interest counts between simulated and measured images of a breast phantom with two spherical lesions in 5 cm thick medium of air or water. Results . Final performance characteristics with 99m Tc sources in air were: (1) energy resolution: 6.1% measured versus 5.9% simulated photopeak full-width at half-maximum (FWHM), (2) spatial resolution: mean error between measured and simulated FWHM of 0.08 mm across 4.4-14.0 mm FWHM range, and (3) sensitivity: 572 cpm/ μ Ci measured versus 567 cpm/ μ Ci simulated (<1% error). Good agreement was observed in the breast phantom line profiles through the spherical lesions and overall energy spectra, with <5% difference in sphere counts between simulated and measured data. Conclusion . A pixelated CZT charge transport and induction model was successfully implemented and validated to simulate imaging with the GE Discovery NM 750b system. This work will enable investigations improving MBI image quality and developing algorithms for uptake quantification., (© 2021 Institute of Physics and Engineering in Medicine.)

Context.—: Distinguishing the different types of amyloid is clinically important because treatments and outcomes are different. Mass spectrometry is the new gold standard for amyloid typing, but it is costly and not widely available. Therefore, immunolabeling remains the first step in identifying the most common types of amyloidosis. In amyloid subtyping, direct immunofluorescence works well when applied to frozen sections, but immunohistochemistry on formalin-fixed, paraffin-embedded material often yields poor results, particularly for light chain amyloidosis. Recently, paraffin immunofluorescence has been described as a valuable salvage technique in renal pathology when frozen sections are not available but it has not been evaluated for extra-renal diseases., Objectives.—: To evaluate the use of paraffin immunofluorescence for light-chain detection in extra-renal amyloidosis and other light-chain-associated diseases., Design.—: First, we compared the staining intensity of both light chains between paraffin immunofluorescence and immunohistochemistry on a retrospective cohort of 28 cases of amyloidosis that have been previously typed. Then, we studied the role of paraffin immunofluorescence as an addition to our classical immunohistochemistry panel for amyloidosis typing., Results.—: In the retrospective cohort, we found that paraffin immunofluorescence outperformed immunohistochemistry for light-chain detection. Then, in the prospective part of the study, we showed that the proportion of correctly classified cases increased from 50% to 71.9% with the adjunction of second-intention paraffin immunofluorescence to the immunohistochemistry procedure., Conclusions.—: We therefore view paraffin immunofluorescence as a significant addition to the routine workflow for detection of light-chain-related diseases., Competing Interests: The authors have no relevant financial interest in the products or companies described in this article., (© 2021 College of American Pathologists.)

Stripe rust, or yellow rust (Puccinia striiformis Westend. f. sp. tritic), is a disease of wheat (Triticum aestivum L.) historically causing significant economic losses in cooler growing regions. Novel isolates of stripe rust with increased tolerance for high temperatures were detected in the United States circa 2000. This increased heat tolerance puts geographic regions, such as the soft red winter wheat (SRWW) growing region of the southeastern United States, at greater risk of stripe rust induced losses. In order to identify sources of stripe rust resistance in contemporary germplasm, we conducted genome-wide association (GWA) studies on stripe rust severity measured in two panels. The first consisted of 273 older varieties, landraces, and some modern elite breeding lines and was evaluated in environments in the U.S. Pacific Northwest and the southeastern United States. The second panel consisted of 588 modern, elite SRWW breeding lines and was evaluated in four environments in Arkansas and Georgia. The analyses identified three major resistance loci on chromosomes: 2AS (presumably the 2NS:2AS alien introgression from Aegilops ventricosa Tausch; syn. Ae. caudata L.), 3BS, and 4BL. The 4BL locus explained a greater portion of variance in resistance than either the 2AS or 3BS loci in southeastern environments. However, its effects were unstable across different environments and sets of germplasm, possibly a result of its involvement in epistatic interactions. Relatively few lines carry resistance alleles at all three loci, suggesting that there is a pre-existing reservoir of enhanced stripe rust resistance that may be further exploited by regional breeding programs., (© 2021 The Authors. The Plant Genome published by Wiley Periodicals LLC on behalf of Crop Science Society of America.)

Radioembolization, also known as selective internal radiation therapy (SIRT), is firmly established in the management of patients with unresectable liver cancers. Advances in normal and tumor liver dosimetry and new knowledge about tumor dose response relationships have helped promote the safe use of higher prescribed doses, consequently transitioning radioembolization from palliative to curative therapy. The lungs are considered a critical organ of risk for radioembolization treatment planning. Unfortunately, lung dosimetry has not achieved similar advances in dose calculation methodology as liver dosimetry. Current estimations of lung dose are dependent on a number of parameters associated with data acquisition and processing algorithms, leading to poor accuracy and precision. Therefore, the efficacy of curative radioembolization may be compromised in patients for whom the lung dose derived using currently available methods unnecessarily limits the desired administered activity to the liver. We present a systematic review of the various methods of determining the lung shunt fraction (LSF) and lung mean dose (LD). This review encompasses pretherapy estimations and post-therapy assessments of the LSF and LD using both 2D planar and 3D SPECT/CT based calculations. The advantages and limitations of each of these methods are deliberated with a focus on accuracy and practical considerations. We conclude the review by presenting a lexicon to precisely describe the methodology used for the estimation of LSF and LD; specifically, category, agent, modality, contour and algorithm, in order to aid in their interpretation and standardization in routine clinical practice.

Purpose: A Positron Emission Tomography/Computed Tomography quality assurance program is necessary to ensure that patients receive optimal imaging and care. We summarize the AAPM Task Group (TG) 126 report on acceptance and quality assurance (QA) testing of PET/CT systems., Methods: TG 126 was charged with developing PET/CT acceptance testing and QA procedures. The TG aimed to develop procedures that would allow for standardized evaluation of existing short-axis cylindrical-bore PET/CT systems in the spirit of NEMA NU 2 standards without requiring specialized phantoms or proprietary software tools., Results: We outline eight performance evaluations using common phantoms and freely available software whereby the clinical physicist monitors each PET/CT system by comparing periodic Follow-Up Measurements to Baseline Measurements acquired during acceptance testing. For each of the eight evaluations, we also summarize the expected testing time and materials necessary and the recommended pass/fail criteria., Conclusion: Our report provides a guideline for periodic evaluations of most clinical PET/CT systems that simplifies procedures and requirements outlined by other agencies and will facilitate performance comparisons across vendors, models, and institutions., (© 2020 American Association of Physicists in Medicine.)

We recently established a role for the stretch-activated two-pore-domain K + (K2P) channel TREK-1 (K2P2.1) in inflammatory cytokine secretion using models of hyperoxia-, mechanical stretch-, and TNF-α-induced acute lung injury. We have now discovered the expression of large conductance, Ca 2+ -activated K + (BK) channels in human pulmonary microvascular endothelial cells and primary human alveolar epithelial cells using semiquantitative real-time PCR, IP and Western blot, and investigated their role in inflammatory cytokine secretion using an LPS-induced acute lung injury model. As expected, LPS induced IL-6 and CCL-2 secretion from pulmonary endothelial and epithelial cells. BK activation with NS1619 decreased LPS-induced CCL-2 but not IL-6 secretion from endothelial cells and had no effect on epithelial cells, although fluorometric assays revealed that BK activation hyperpolarized the plasma membrane potential (Em) of both cell types. Interestingly, BK inhibition (Paxilline) did not alter cytokine secretion or the Em in either cell type. Furthermore, LPS treatment by itself did not affect the Em or intracellular Ca 2+ concentrations. Therefore, we propose BK channel activation as a novel targeted approach to counteract LPS-induced CCL-2 secretion from endothelial cells. This protective effect appears to occur via Em hyperpolarization but independent of intracellular Ca 2+ concentrations.

We report the observation of a 75-year-old patient referred for cervical lymphadenopathies. A pre-lymphadenectomy blood work revealed an asymptomatic elevation of aPTT with low factor VIII (FVIII) levels and high anti-FVIII antibodies titers, consistent with acquired hemophilia A (AHA). Histological work-up of a cervical lymphadenopathy revealed benign follicular hyperplasia with IgG4 + lymphoplasmacytic infiltration; and serum IgG4 levels were markedly elevated, compatible with IgG4-related disease (IgG4-RD). He was successfully treated with a 9-month course of prednisone, secondarily associated with rituximab when an AHA relapse occurred. As this patient presented with an unusual association of rare diseases, we wondered whether there was a link between the two conditions. Our first hypothesis was that the anti-FVIII autoantibodies could be directly produced by the proliferating IgG4 + plasma cells as a result of broken tolerance to autologous FVIII. To test this assumption, we determined the anti-FVIII IgG subclasses in our patient and in a control group of 11 AHA patients without IgG4-RD. The FVIII inhibitor was mostly IgG4, with an anti-FVIII IgG4/IgG1 ratio of 42 at diagnosis and 268 at relapse in our patient; similar values were observed in non-IgG4-RD AHA patients. As a second hypothesis, we considered whether the anti-FVIII activity could be the result of a non-specific autoantibody production due to polyclonal IgG4 + plasma cell proliferation. To test this hypothesis, we measured the anti-FVIII IgG4/total IgG4 ratio in our patient, as well as in several control groups: 11 AHA patients without IgG4-RD, 8 IgG4-RD patients without AHA, and 11 healthy controls. We found that the median [min-max] ratio was higher in AHA-only controls (2.4 10 -2 [5.7 10 -4 -1.79 10 -1 ]), an oligoclonal setting in which only anti-FVIII plasma cells proliferate, than in IgG4-RD-only controls (3.0 10 -5 [2.0 10 -5 -6.0 10 -5 ]), a polyclonal setting in which all IgG4 + plasma cells proliferate equally. Our patient had intermediate ratio values (2.7 10 -3 at diagnosis and 1.0 10 -3 at relapse), which could plead for a combination of both mechanisms. Although no definitive conclusion can be drawn, we hypothesized that the anti-FVIII autoantibody production in our IgG4-RD AHA patient could be the result of both broken tolerance to FVIII and bystander polyclonal IgG4 + plasma cell proliferation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Sanges, Jeanpierre, Lopez, Russick, Delignat, Carpentier, Dubois, Dubucquoi, Guerrier, Hachulla, Hatron, Paris, Susen, Launay, Lacroix-Desmazes and Terriou.)

No targeted therapies exist to counteract Hyperoxia (HO)-induced Acute Lung Injury (HALI). We previously found that HO downregulates alveolar K 2P 2.1 (TREK-1) K + channels, which results in worsening lung injury. This decrease in TREK-1 levels leaves a subset of channels amendable to pharmacological intervention. Therefore, we hypothesized that TREK-1 activation protects against HALI. We treated HO-exposed mice and primary alveolar epithelial cells (AECs) with the novel TREK-1 activators ML335 and BL1249, and quantified physiological, histological, and biochemical lung injury markers. We determined the effects of these drugs on epithelial TREK-1 currents, plasma membrane potential (Em), and intracellular Ca 2+ (iCa) concentrations using fluorometric assays, and blocked voltage-gated Ca 2+ channels (Ca V ) as a downstream mechanism of cytokine secretion. Once-daily, intra-tracheal injections of HO-exposed mice with ML335 or BL1249 improved lung compliance, histological lung injury scores, broncho-alveolar lavage protein levels and cell counts, and IL-6 and IP-10 concentrations. TREK-1 activation also decreased IL-6, IP-10, and CCL-2 secretion from primary AECs. Mechanistically, ML335 and BL1249 induced TREK-1 currents in AECs, counteracted HO-induced cell depolarization, and lowered iCa 2+ concentrations. In addition, CCL-2 secretion was decreased after L-type Ca V inhibition. Therefore, Em stabilization with TREK-1 activators may represent a novel approach to counteract HALI.

A pilot project was conducted to determine the effect of common construction dusts as interferences in a new portable end-of-shift (EoS), direct-on-filter (DoF) sampling and analysis method for respirable crystalline silica (RCS), in this case, quartz. Construction dusts were prepared from plaster, drywall, cement and brick by grinding, aerosolizing, and collecting respirable dust with high flow rate cyclones. Filters were loaded with different levels of commercial α-quartz powder Min-u-Sil 5, and different levels of interfering dusts, singly and in combination. Samples were analyzed by Fourier Transform Infrared Spectroscopy (FTIR). Good correlations were found between nominal quartz loading (0 µg, 25 µg, 50 µg, and 100 µg) adjusted for quartz in the interfering dust and FTIR absorbance alone and in the presence of all interfering dusts. The slopes of the correlations were similar whether the loading was quartz without interference, or with plaster, drywall, and cement dusts, regardless of quantity. The results show that (a) plaster and drywall dusts do not interfere substantially; (b) cement does not interfere, but a change in the intercept suggests an effect on the background absorbance of the filter; and (c) in addition to having a substantial quartz content, brick dust contains an additional material, probably a silicate mineral, which interferes with the quartz peak. Thus, the presence of cement leads to lower quartz values and brick leads to higher values, but overall, 83% of the quartz contents predicted from the calibration data agreed within 50% of the adjusted nominal loadings within the range 20-110 µg. This result is encouraging given the high levels of interfering dusts. Nine samples loaded with smaller amounts of all four dusts together gave results within 25% of the adjusted nominal loadings. A single mixture addition of the dusts to the filter gave tighter variance in results than sequential additions. Unexpectedly, the two Certified Reference Materials (CRMs) 1878a and 1878b, gave different results when used to calibrate XRD analysis of Min-u-Sil 5.

Background: The absence of asthma may rule out a diagnosis of eosinophilic granulomatosis with polyangiitis in patients with hypereosinophilic syndrome (HES) and features of vasculitis., Objective: To describe eosinophilic vasculitis (EoV) as a possible manifestation of HES in asthma-free patients., Methods: We screened our hospital database and the literature for patients with HES who met the following 4 criteria: (1) histopathological or clinical features of EoV (biopsy-proven vasculitis with predominant eosinophilic infiltration of the vessel wall and/or features of vasculitis with tissue and/or blood hypereosinophilia [absolute eosinophil count >1.5 G/L]); (2) no other obvious causes of reactive eosinophilia, organ damage, and vasculitis; (3) the absence of antineutrophil cytoplasmic antibodies; and (4) the absence of current asthma., Results: Ten of our 83 (12%) asthma-free patients with HES and 107 additional cases in the literature met the criteria for EoV. After a critical analysis of the patients' clinical and laboratory characteristics and outcomes, we identified 41 cases of single-organ EoV (coronary arteritis, n = 29; temporal arteritis, n = 8; cerebral vasculitis, n = 4). Of the remaining 76 patients with EoV, the most frequent manifestations (>10%) were cutaneous vasculitis (56%), peripheral neuropathy (24%), thromboangiitis obliterans-like disease (16%), fever (13%), central nervous system involvement (13%), deep venous thrombosis (12%), and nonasthma lung manifestations (12%). Blood hypereosinophilia more than 1.5 G/L was observed in 79% of patients, and necrotizing vasculitis was observed in 44%., Conclusions: Our results suggest that idiopathic EoV (HES-associated vasculitis) can be classified as an eosinophilic-rich, necrotizing, systemic form of vasculitis that affects vessels of various sizes in asthma-free patients., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Light chain cast nephropathy is the most common form of kidney disease in patients with multiple myeloma. Light chain casts may occasionally show amyloid staining properties, that is, green birefringence after Congo red staining. The frequency and clinical significance of this intratubular amyloid are poorly understood. Here, we retrospectively assessed the clinicopathological features of 60 patients with histologically proven light chain cast nephropathy with a specific emphasis on intratubular amyloid, especially, its association with extrarenal systemic light chain amyloidosis. We found intratubular amyloid in 17 cases (17/60, 28%) and it was more frequent in patients with λ light chain gammopathy (13/17 in the 'intratubular amyloid' group vs 19/43 in the 'no intratubular amyloid' group, P=0.02). Pathological examination of extrarenal specimens showed that intratubular amyloid was significantly associated with the occurrence of systemic light chain amyloidosis (5/13 in the 'intratubular amyloid' group vs 0/30 in the 'no intratubular amyloid' group, P=0.001). Our results indicate that first, intratubular amyloid is not a rare finding in kidney biopsies of patients with light chain cast nephropathy, and, second, it reflects an amyloidogenic capacity of light chains that can manifest as systemic light chain amyloidosis. Thus, intratubular amyloid should be systematically screened for in kidney biopsies from patients with light chain cast nephropathy and, if detected, should prompt a work-up for associated systemic light chain amyloidosis.

We previously proposed a role for the two-pore domain potassium (K2P) channel TREK-1 in hyperoxia (HO)-induced lung injury. To determine whether redundancy among the three TREK isoforms (TREK-1, TREK-2, and TRAAK) could protect from HO-induced injury, we now examined the effect of deletion of all three TREK isoforms in a clinically relevant scenario of prolonged HO exposure and mechanical ventilation (MV). We exposed WT and TREK-1/TREK-2/TRAAK-deficient [triple knockout (KO)] mice to either room air, 72-h HO, MV [high and low tidal volume (TV)], or a combination of HO + MV and measured quasistatic lung compliance, bronchoalveolar lavage (BAL) protein concentration, histologic lung injury scores (LIS), cellular apoptosis, and cytokine levels. We determined surfactant gene and protein expression and attempted to prevent HO-induced lung injury by prophylactically administering an exogenous surfactant (Curosurf). HO treatment increased lung injury in triple KO but not WT mice, including an elevated LIS, BAL protein concentration, and markers of apoptosis, decreased lung compliance, and a more proinflammatory cytokine phenotype. MV alone had no effect on lung injury markers. Exposure to HO + MV (low TV) further decreased lung compliance in triple KO but not WT mice, and HO + MV (high TV) was lethal for triple KO mice. In triple KO mice, the HO-induced lung injury was associated with decreased surfactant protein (SP) A and SPC but not SPB and SPD expression. However, these changes could not be explained by alterations in the transcription factors nuclear factor-1 (NF-1), NKX2.1/thyroid transcription factor-1 (TTF-1) or c-jun, or lamellar body levels. Prophylactic Curosurf administration did not improve lung injury scores or compliance in triple KO mice., (Copyright © 2017 the American Physiological Society.)

Background: Dengue is a major public health problem worldwide. Assessment of adaptive immunity is important to understanding immunopathology and to define correlates of protection against dengue virus (DENV). To enable global assessment of CD4 + T cell responses, we mapped HLA-DRB1-restricted DENV-specific CD4 + T cell epitopes in individuals previously exposed to DENV in the general population of the dengue-endemic region of Managua, Nicaragua., Methods: HLA class II epitopes in the population of Managua were identified by an in vitro IFNγ ELISPOT assay. CD4 + T cells purified by magnetic bead negative selection were stimulated with HLA-matched epitope pools in the presence of autologous antigen-presenting cells, followed by pool deconvolution to identify specific epitopes. The epitopes identified in this study were combined with those previously identified in the DENV endemic region of Sri Lanka, to generate a "megapool" (MP) consisting of 180 peptides specifically designed to achieve balanced HLA and DENV serotype coverage. The DENV CD4MP 180 was validated by intracellular cytokine staining assays., Results: We detected responses directed against a total of 431 epitopes, representing all 4 DENV serotypes, restricted by 15 different HLA-DRB1 alleles. The responses were associated with a similar pattern of protein immunodominance, overall higher magnitude of responses, as compared to what was observed previously in the Sri Lanka region. Based on these epitope mapping studies, we designed a DENV CD4 MP 180 with higher and more consistent coverage, which allowed the detection of CD4 + T cell DENV responses ex vivo in various cohorts of DENV exposed donors worldwide, including donors from Nicaragua, Brazil, Singapore, Sri Lanka, and U.S. domestic flavivirus-naïve subjects immunized with Tetravalent Dengue Live-Attenuated Vaccine (TV005). This broad reactivity reflects that the 21 HLA-DRB1 alleles analyzed in this and previous studies account for more than 80% of alleles present with a phenotypic frequency ≥5% worldwide, corresponding to 92% phenotypic coverage of the general population (i.e., 92% of individuals express at least one of these alleles)., Conclusion: The DENV CD4 MP 180 can be utilized to measure ex vivo responses to DENV irrespective of geographical location.

We report on 11 cases of specific polysaccharide antibody deficiency (SPAD) revealed in adulthood by severe infections with encapsulated bacteria. Given that immunoglobulin replacement therapy can effectively prevent the recurrence of bacterial infections in this context, SPAD should be considered once other antibody deficiencies have been ruled out., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

In this article, we will summarize recent progress in understanding the mechanical origins of rigidity, strength, resiliency and stress transmission in the MT cytoskeleton using reconstituted networks formed from purified components. We focus on the role of network architecture, crosslinker compliance and dynamics, and molecular determinants of single filament elasticity, while highlighting open questions and future directions for this work., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Nationwide screening of 411 emerging contaminants and other regulated compounds, including parent molecules and transformation products (TPs) having various uses and origins, was done at 494 groundwater sites throughout France during two sampling campaigns in the Spring and the Fall of 2011. One hundred and eighty substances (44% of the targeted compounds) were quantified in at least one sampling point. These included pharmaceuticals, industrial products, pesticides, their transformation products and other emerging compounds. Fifty-five compounds were quantified in more than 1% of the samples. Both regulated and emerging compounds were found. Among the unregulated compounds, acetaminophen, carbamazepine, perfluorinated compounds, dioxins/furans, tolyltriazole, bisphenol A, triazine transformation products, and caffeine were quantified in more than 10% of the samples analyzed. Concentrations exceeding the threshold of toxicological concern of 0.1 μg/L were found for tolyltriazole, bisphenol A and some of the triazine transformation products (DEDIA). These new results should help the water resource managers and environmental regulators develop sound policies regarding the occurrence and distribution of regulated and emerging contaminants in groundwater., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Infants born with intrauterine growth retardation (IUGR) are at increased risk of adverse pulmonary outcomes at birth, including meconium aspiration and persistent pulmonary hypertension. Preterm infants with IUGR are at especially high risk of developing bronchopulmonary dysplasia (BPD), a disease hallmarked by alveolar hypoplasia. Although vitamin A supplementation has been shown to decrease the incidence of BPD or death in preterm very low birth weight infants, its potential to reduce BPD or death in preterm infants with IUGR remains unknown. We used a well-characterized rat model of caloric restriction to mimic IUGR and determine the impact of IUGR on lung development. We hypothesized that retinoic acid treatment would preserve alveolar formation through increases in key signaling molecules of the retinoic acid signaling pathway. Our results showed that alveolar hypoplasia caused by caloric restriction can be reversed with refeeding, and that retinoic acid prevents the alveolar hypoplasia coincident with the increased expression of elastin and retinoic acid receptor-α and decreased transforming growth factor-β activity in developing rat lungs. These findings suggest that alveolar hypoplasia attributable to caloric restriction is reversible, and raises the possibility that retinoic acid therapy may prove a useful strategy to prevent adverse pulmonary sequelae such as BPD in preterm infants with IUGR.

Residual upper pleural spaces after subtotal pulmonary resection continues to pose great challenge for the thoracic surgeon. Although not all residual spaces deserve surgical attention, only in special situation (empyema with or without bronchopleural fistula). It increases morbidity, mortality, hospital stays, and costs. Transposition of extrathoracic muscle flaps has been the cornerstone of treatment of this complication. Sometimes use of latissimus or serratus muscle might have been compromised by the incision for the original operation. In this situation the pectoralis major muscle flap (PMF) can be used successfully to reach and obliterate upper residual pleural space by anterior approach. The technique has never been specifically described before in the literature. We describe our technique for mobilization of PMF by anterior approach to obliterate residual upper space after major pulmonary resections.

Alveolar formation is hallmarked by the transition of distal lung saccules into gas exchange units through the emergence of secondary crests and an exponential increase in surface area. Several cell types are involved in this complex process, including families of epithelial cells that differentiate into alveolar type I and II cells. Subsets of cells expressing Clara cell secretory protein (CCSP) have been identified in both lung and bone marrow compartments, and are described as a progenitor/stem cell pool involved in airway regeneration and alveolar homeostasis. Whether these cells also participate in alveolar formation during postnatal development remains unknown. Based on their regenerative capacity, we asked whether these cells participate in alveogenesis. We used a previously described transgenic mouse model (CCSP-tk) in which Ganciclovir exposure selectively depletes all cells with CCSP promoter activity through intracellular generation of a toxic metabolite of thymidine kinase. Our results showed that Ganciclovir treatment in newborn CCtk mice depleted this cell population in lung airways and bone marrow, and was associated with alveolar hypoplasia and respiratory failure. Hypoplastic lungs had fewer alveolar type I and II cells, with impaired secondary crest formation and decreased vascular endothelial growth factor expression in distal airways. These findings are consistent with a model in which a unique population of cells with CCSP promoter activity that expresses vascular endothelial growth factor participates in alveolar development.