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Background: Molecular testing of the deceased (Molecular Autopsy) is an overlooked area in the United States healthcare system and is not covered by medical insurance, leading to ineffective care for surviving families of thousands of sudden unexpected natural deaths each year. We demonstrated the precision management of surviving family members through the discovery of a novel de novo pathogenic variant in a decedent., Methods: Forensic investigation and molecular autopsy were performed on an 18-year-old female who died suddenly and unexpectedly. Co-segregation family study of the first-degree relatives and functional characterization of the variant were conducted., Findings: We identified a novel nonsense variant, NP_000229.1:p.Gln1068Ter, in the long QT syndrome type II gene KCNH2 in the decedent. This finding correlated with her ante-mortem electrocardiograms. Patch clamp functional studies using transfected COS-7 cells show that hERG-ΔQ1068 has a mixed phenotype, with both gain- (negative voltage shift of steady-state activation curve, the positive shift of the steady-state inactivation curve, and accelerated activation) and loss-of function (reduced current density, reduced surface expression and accelerated deactivation) hallmarks. Loss of cumulative activation during rapid pacing demonstrates that the loss-of-function phenotype predominates. The wild-type channel did not rescue the hERG-ΔQ1068 defects, demonstrating haploinsufficiency of the heterozygous state. Targeted variant testing in the family showed that the variant in KCNH2 arose de novo, which eliminated the need for exhaustive genome testing and annual cardiac follow-up for the parents and four siblings., Interpretation: Molecular testing enables accurate determination of natural causes of death and precision care of the surviving family members in a time and cost-saving manner. We advocate for molecular autopsy being included under the healthcare coverage in US.

Auto neuronal synapses, or autapses, are aberrant structures where the synaptic contact of a neuron forms onto its own branch. The functions of autapses, however, remain unknown. Here, we introduce a simple patterning method for capturing a single-cell, in which we maintained the isolated cell until it reached maturity, and developed arrays of autapses for electrophysiological analysis using multi-electrode arrays (MEA). The pattern arrays were formed by selective patterning of poly-L-lysine and various cell repellent materials. We tested the efficiency of single neuron pattern formed according to materials and pattern dimensions. Autapse formation was verified by immunostaining synaptic markers and physiological measurements via recordings from MEA. The results demonstrated that our multiscale patterning method increased the number of autapses consisting of a single neuron, which matured to connect onto themselves. The proposed patterning method (4.06 ± 0.33 isolated single-cells mm -2 ) is at least twelve times more efficient and productive than the spray method (0.31 ± 0.10 isolated single-cells mm -2 ). The spontaneous activity of a single neuron on the patterned MEA occured after 11 d in vitro. The single neuron activity consisted of bursts followed by spike trains (the burst rate was 2.56 min -1 ). This indicates that our method could be used for electrophysiological analysis, including MEA.

Vascular networks are the first sites exposed to cationic polymer nanoparticles (NPs) administered intravenously, and thus function as a barrier for NPs reaching the target organ. While cationic polymer NPs have been intensively studied as non-viral delivery systems, their biological effects in human microvessels have been poorly investigated due to a lack of appropriate in vitro systems. Here, we employed a three-dimensional microvessel on a chip, which accurately models in vivo conditions. An open and perfused microvessel surrounded by pericytes was shown to reproduce the important features of living vasculature, including barrier function and biomarkers. Using this microvessel chip, we observed contraction of the microvascular lumen induced by perfused polyethylenimine (PEI)/DNA NPs. We demonstrated that the oxidative stress present when microvessels were exposed to PEI NPs led to rearrangement of microtubules resulting in microvessel contraction. Furthermore, the transcytotic behavior of PEI NPs was analyzed in the microvessel by monitoring the escape of PEI NPs from the microvascular lumen into the perivascular region, which was not possible in two-dimensional culture systems. With our new understanding of the different behaviors of cationic polymer NPs depending on their transcytotic route, we suggest that caveolae-mediated transcytosis is a powerful route for efficient extravascular transport., Statement of Significance: Microvascular networks are not only biological system constituting largest surface area in the body and but also first site exposed to nanoparticle in vivo. While cationic polymer NPs have been intensively studied as non-viral delivery systems, its biological effects in human microvessel have been poorly investigated due to lack of appropriate in vitro systems. Here, we microengineered an open and perfused 3D pericyte incorporated microvessel model which possesses same morphological characteristic of in vivo. Using the microengineered model, this study represents the first report of transcytotic behavior of NPs in 3D microvessel, and its effect on extravasation efficiency. Our study lays the groundwork for the integration of innovative technologies to examine blood vessel-nanoparticle interaction, which a critical but ill-defined phenomenon., (Copyright © 2018. Published by Elsevier Ltd.)

Fluorescent Au nanocrystals (AuNCs)-silica hybrid nanocomposite (FLASH) was synthesized by co-condensation of surface-modified AuNCs. Present FLASH nanocomposite exhibited four times the enhanced photoluminescence and photocatalytic activity compared to single nanocrystals. On the basis of these enhanced optical features, we successfully demonstrated in vitro fluorescence bioimaging of introduced FLASH to human cervical cancer cell line (HeLa). Beyond the confirmation of photocatalytic activity from the photodegradation of methylene blue as a model compound, the regional selective photodynamic therapy of HeLa cells under UV irradiation was also presented. Taken together the enhanced optical features and further potential in theranostic applications, we expect that the present FLASH can be a promising tool for nanobiotechnology field.

Purpose: Left heart disease is associated with left atrial enlargement and is a common cause of pulmonary hypertension (PH). We investigated the relationship between left atrium maximal axial cross-sectional area (LA-MACSA), as measured on chest computed tomography (CT), and PH due to left heart disease (World Health Organization group 2) in patients with right heart catheterization-proven PH., Materials and Methods: A total of 165 patients with PH who had undergone right heart catheterization with pulmonary artery pressure and pulmonary capillary wedge pressure (PCWP) measurements and nongated chest CTs were included. LA-MACSA, LA anterior-posterior, and LA transverse measurements were independently obtained using the hand-drawn region-of-interest and distance measurement tools on standard PACS by 2 blinded cardiothoracic radiologists. Nonparametric statistical analyses and receiver operating characteristic curve were performed., Results: Forty-three patients had group 2 PH (PCWP>15 mm Hg), and 122 had nongroup 2 PH (PCWP≤15 mm Hg). Median LA-MACSA was significantly different between the group 2 PH and nongroup 2 PH patients (2312 vs. 1762 mm, P<0.001). Interobserver concordance correlation for LA-MACSA was high at 0.91 (P<0.001). At a threshold of 2400 mm, LA-MACSA demonstrated 93% specificity for classifying group 2 PH (area under the curve, 0.73; P<0.001)., Conclusions: LA-MACSA is a readily obtainable and reproducible measurement of left atrial enlargement on CT and can distinguish between group 2 and nongroup 2 PH with high specificity.

A recent study demonstrated a significant role for leukotriene B4 (LTB4) causing pulmonary vascular remodeling in pulmonary arterial hypertension. LTB4 was found to directly injure luminal endothelial cells and promote growth of the smooth muscle cell layer of pulmonary arterioles. The purpose of this study was to determine the effects of LTB4 on the pulmonary adventitial layer, largely composed of fibroblasts. Here, we demonstrate that LTB4 enhanced human pulmonary artery adventitial fibroblast proliferation, migration, and differentiation in a dose-dependent manner through its cognate G-protein-coupled receptor, BLT1. LTB4 activated human pulmonary artery adventitial fibroblast by upregulating p38 mitogen-activated protein kinase as well as Nox4-signaling pathways. In an autoimmune model of pulmonary hypertension, inhibition of these pathways blocked perivascular inflammation, decreased Nox4 expression, reduced reactive oxygen species production, reversed arteriolar adventitial fibroblast activation, and attenuated pulmonary hypertension development. This study uncovers a novel mechanism by which LTB4 further promotes pulmonary arterial hypertension pathogenesis, beyond its established effects on endothelial and smooth muscle cells, by activating adventitial fibroblasts., (© 2015 American Heart Association, Inc.)

Nondestructive chemical processing of porous samples such as fixed biological tissues typically relies on molecular diffusion. Diffusion into a porous structure is a slow process that significantly delays completion of chemical processing. Here, we present a novel electrokinetic method termed stochastic electrotransport for rapid nondestructive processing of porous samples. This method uses a rotational electric field to selectively disperse highly electromobile molecules throughout a porous sample without displacing the low-electromobility molecules that constitute the sample. Using computational models, we show that stochastic electrotransport can rapidly disperse electromobile molecules in a porous medium. We apply this method to completely clear mouse organs within 1-3 days and to stain them with nuclear dyes, proteins, and antibodies within 1 day. Our results demonstrate the potential of stochastic electrotransport to process large and dense tissue samples that were previously infeasible in time when relying on diffusion.

Modulation of neural responses is frequently observed in the superior colliculus (SC), a retinorecipient midbrain structure that controls orienting and the localization of attention. Although behavioral contingencies that influence SC responses are well documented, the neural pathways and molecular mechanisms responsible for this modulation are not completely understood. Here, we illustrate a dopaminergic system that strongly impacts neural responses in the SC. After using RNA sequencing (RNA-seq) to detail the transcriptome of dopamine-related genes in the SC, we show that D1 receptors are enriched in the superficial visual SC, while D2 receptors segregate to the intermediate multimodal/motor SC. Retrograde injections into the SC consistently label A13, a small dopamine cell group located in the zona incerta. We surmise that A13 mimics dopaminergic effects that we observed in SC slices, which suggests that dopamine in the SC may reduce the tendency of an animal to orient or attend to salient stimuli., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Background Context: Superior vena cava (SVC) obstruction can cause the development of collateral vessels. During contrast-enhanced thoracic computed tomography (CT), contrast material may reflux into the collaterals such as paravertebral venous plexus. However, an unusual pseudopathologic vertebral body enhancement on CT in the presence of SVC obstruction has not been studied previously., Purpose: To demonstrate clinical presentation and imaging findings of pseudopathologic vertebral body enhancement in patients with SVC obstruction., Study Design: Retrospective study of diagnostic CT images examined at our clinic., Patient Sample: From March, 2009 to September, 2012, a retrospective radiologic database review was performed to identify patients with obstruction of SVC causing contrast reflux into collateral vessels and presented with an unusual vertebral body enhancement on thoracic CT. Thirteen patients (11 men, mean age 51.4 years) with vertebral body enhancement were enrolled., Outcome Measures: Enhancement patterns of vertebral bodies were classified as nodular enhancement with round shape occupying less than one-third of vertebral body or polygonal enhancement occupying greater than or equal to one-third of vertebral body on axial image. The locations of enhanced areas within vertebral bodies were described using right lateral/central/left lateral, anterior/posterior, and upper/middle/lower in the x-, y-, or z-axis directions, respectively., Materials and Methods: Enhancement patterns, locations, and the presence of a connection between vertebral body enhancement and the paravertebral venous plexus were evaluated., Results: A total of 39 vertebral body enhancements were found in the 13 patients, involving cervical (n=12), thoracic (n=25), or lumbar (n=2) vertebrae. Vertebral body enhancements showed a nodular (n=19) or a polygonal (n=20) pattern. The central portions of vertebral bodies were more frequently involved. The connection to the paravertebral venous plexus was observed in 34 lesions (87.2%)., Conclusions: Patients with SVC obstruction with extensive collateral vessels might exhibit a pseudopathologic vertebral enhancement. They tended to involve the central portion of the vertebral body, and most of them showed connection to the paravertebral venous plexus., (Copyright © 2015 Elsevier Inc. All rights reserved.)

A 50-year-old male visited the outpatient clinic and complained of fever, poor oral intake, and weight loss. A chest X-ray demonstrated streaky and fibrotic lesions in both lungs, and chest CT revealed multifocal peribronchial patchy ground-glass opacities with septated cystic lesions in both lungs. Cell counts in the bronchoalveolar lavage fluid revealed lymphocyte-dominant leukocytosis, and further analysis of lymphocyte subsets showed a predominance of cytotoxic T cells and few T helper cells. Video-assisted wedge resection of the left upper lobe was performed, and the histologic examination was indicative of a Pneumocystis jirovecii infection. Trimethoprim-sulfamethoxazole (TMP-SMX) was orally administered for 3 weeks; however, the patient complained of cough, and the pneumonia was aggravated in the follow-up chest X-ray and chest CT. Molecular studies demonstrated mutations at codons 55 and 57 of the dihydropteroate synthase (DHPS) gene, which is associated with the resistance to TMP-SMX. Clindamycin-primaquine was subsequently administered for 3 weeks replacing the TMP-SMX. A follow-up chest X-ray showed that the pneumonia was resolving, and the cough was also alleviated. A positive result of HIV immunoassay and elevated titer of HCV RNA indicated HIV infection as an underlying condition. This case highlights the importance of careful monitoring of patients with P. jirovecii pneumonia (PCP) during the course of treatment, and the molecular study of DHPS mutations. Additionally, altering the anti-PCP drug utilized as treatment must be considered when infection with drug-resistant P. jirovecii is suspected. To the best of our knowledge, this is the first case of TMP-SMX-resistant PCP described in Korea.

To describe the coronary CT findings of coronary-to-bronchial artery communication (CBAC) in chronic pulmonary disease. Coronary CT was performed in 15 patients with chronic pulmonary disease using 64-channel or greater multidetector CT. Among those patients, one or two CBACs were identified. A retrospective analysis of the CT findings was done to determine the originating artery, arterial course of the communications and other associated results. The main underlying pulmonary disease was bronchiectasis (n = 12). The origin of the CBAC was from the left atrial (n = 7) or sinoatrial (SA) nodal (n = 3) branch of the left circumflex artery in nine patients and the SA nodal branch of the right coronary artery in six patients. The CBAC was connected to the left bronchial artery in 11 patients and the right bronchial artery in five patients. The course of the CBAC passed through the interpulmonary venous bare area between reflections of the serous pericardium of the transverse and oblique sinuses in 13 patients. In three patients, it passed through the perivascular space around the left upper or lower pulmonary vein. In one patient, there were two communications-one through the interpulmonary venous bare area and the other through the perivascular space around the left lower pulmonary vein. There was no significant coronary arterial stenosis except in two patients. Bronchial arterial hypertrophy was found in all 15 patients. Detailed analysis of coronary CT can be a helpful guide for hemodynamic significance and clinical management including embolotherapy for CBAC in patients of chronic pulmonary disease with hemoptysis.

Coronary artery calcification (CAC) is frequently detected on low-dose CT (LDCT) of the thorax. Concurrent assessment of CAC and lung cancer screening using LDCT is beneficial in terms of cost and radiation dose reduction. The aim of our study was to evaluate the reliability of visual ranking of positive CAC on LDCT compared to Agatston score (AS) on electrocardiogram (ECG)-gated calcium scoring CT. We studied 576 patients who were consecutively registered for health screening and undergoing both LDCT and ECG-gated calcium scoring CT. We excluded subjects with an AS of zero. The final study cohort included 117 patients with CAC (97 men; mean age, 53.4 ± 8.5). AS was used as the gold standard (mean score 166.0; range 0.4-3,719.3). Two board-certified radiologists and two radiology residents participated in an observer performance study. Visual ranking of CAC was performed according to four categories (1-10, 11-100, 101-400, and 401 or higher) for coronary artery disease risk stratification. Weighted kappa statistics were used to measure the degree of reliability on visual ranking of CAC on LDCT. The degree of reliability on visual ranking of CAC on LDCT compared to ECG-gated calcium scoring CT was excellent for board-certified radiologists and good for radiology residents. A high degree of association was observed with 71.6% of visual rankings in the same category as the Agatston category and 98.9% varying by no more than one category. Visual ranking of positive CAC on LDCT is reliable for predicting AS rank categorization.

Sudden unexplained deaths (SUD) in apparently healthy individuals, for which the causes of deaths remained undetermined after comprehensive forensic investigations and autopsy, present vexing challenges to medical examiners and coroners. Cardiac channelopathies, a group of inheritable diseases that primarily affect heart rhythm by altering the cardiac conduction system, have been known as one of the likely causes of SUD. Adhering to the recommendations of including molecular diagnostics of cardiac channelopathies in SUD investigation, the Molecular Genetics Laboratory of the New York City (NYC) Office of Chief Medical Examiner (OCME) has been routinely testing for six major channelopathy genes (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, and RyR2) since 2008. Presented here are the results of cardiac channelopathy testing in 274 well-characterized autopsy negative SUD cases, all with thorough medicolegal death investigation including complete autopsy by NYC OCME between 2008 and 2012. The cohort consisted of 141 infants (92.9% younger than six-month old) and 133 non-infants (78.2% were between 19 and 58 years old). Among the ethnically diverse cohort, African American infants had the highest risks of SUD, and African American non-infants died at significantly younger age (23.7 years old, mean age-at-death) than those of other ethnicities (30.3 years old, mean age-at-death). A total of 22 previously classified cardiac channelopathy-associated variants and 24 novel putative channelopathy-associated variants were detected among the infants (13.5%) and non-infants (19.5%). Most channelopathy-associated variants involved the SCN5A gene (68.4% in infants, 50% in non-infants). We believe this is the first study assessing the role of cardiac channelopathy genes in a large and demographically diverse SUD population drawn from a single urban medical examiner's office in the United States. Our study supports that molecular testing for cardiac channelopathy is a valuable tool in SUD investigations and provides helpful information to medical examiners/coroners seeking cause of death in SUD as well as potentially life-saving information to surviving family members., (Published by Elsevier Ireland Ltd.)

Pulmonary hypertension (PH) is a serious condition that affects mainly young and middle-aged women, and its etiology is poorly understood. A prominent pathological feature of PH is accumulation of macrophages near the arterioles of the lung. In both clinical tissue and the SU5416 (SU)/athymic rat model of severe PH, we found that the accumulated macrophages expressed high levels of leukotriene A4 hydrolase (LTA4H), the biosynthetic enzyme for leukotriene B4 (LTB4). Moreover, macrophage-derived LTB4 directly induced apoptosis in pulmonary artery endothelial cells (PAECs). Further, LTB4 induced proliferation and hypertrophy of human pulmonary artery smooth muscle cells. We found that LTB4 acted through its receptor, BLT1, to induce PAEC apoptosis by inhibiting the protective endothelial sphingosine kinase 1 (Sphk1)-endothelial nitric oxide synthase (eNOS) pathway. Blocking LTA4H decreased in vivo LTB4 levels, prevented PAEC apoptosis, restored Sphk1-eNOS signaling, and reversed fulminant PH in the SU/athymic rat model of PH. Antagonizing BLT1 similarly reversed established PH. Inhibition of LTB4 biosynthesis or signal transduction in SU-treated athymic rats with established disease also improved cardiac function and reopened obstructed arterioles; this approach was also effective in the monocrotaline model of severe PH. Human plexiform lesions, one hallmark of PH, showed increased numbers of macrophages, which expressed LTA4H, and patients with connective tissue disease-associated pulmonary arterial hypertension exhibited significantly higher LTB4 concentrations in the systemic circulation than did healthy subjects. These results uncover a possible role for macrophage-derived LTB4 in PH pathogenesis and identify a pathway that may be amenable to therapeutic targeting.

Objective: The objective of our study was to evaluate the effect of organ-based tube current modulation and bismuth shielding on image quality and breast radiation dose in women undergoing low-dose chest CT., Subjects and Methods: From March 2011 through July 2011, 80 women prospectively underwent low-dose chest CT to screen for lung cancer. The patients were randomly assigned to a control group (n = 20), organ-based tube current modulation group (n = 20), breast shield group (n = 20), or breast shield plus organ-based tube current modulation group (n = 20). Axial slice images of the aortic arch, carina, and inferior pulmonary vein were used to analyze image quality. Three radiologists scored the image quality in terms of artifact and noise and then characterized the overall image quality as optimal (does not affect the diagnostic accuracy) or suboptimal (affects the diagnostic accuracy). Noise levels were measured in the anterior and posterior lung in each image. A phantom dose study was conducted to measure radiation dose., Results: Images with artifacts or noise were more frequently obtained in the breast shield groups; however, the overall image quality was not significantly different among the four groups. Measured noise levels in the anterior lung were significantly higher in the breast shield groups than the control group; however, no statistical significance was found among the four groups with regard to noise level in the posterior lung. In the phantom dose study, a 16-37.5% dose reduction in the breast was achieved using the breast shield, organ-based tube current modulation protocol, or both., Conclusion: The radiation dose in the female breast may be reduced using a breast shield or organ-based tube current modulation during low-dose chest CT with acceptable image quality. The use of organ-based tube current modulation reduced the radiation dose in the breast without inducing image quality deterioration.

Many chronic pulmonary diseases are associated with pulmonary hypertension (PH) and pulmonary vascular remodeling, which is a term that continues to be used to describe a wide spectrum of vascular abnormalities. Pulmonary vascular structural changes frequently increase pulmonary vascular resistance, causing PH and right heart failure. Although rat models had been standard models of PH research, in more recent years the availability of genetically engineered mice has made this species attractive for many investigators. Here we review a large amount of data derived from experimental PH reports published since 1996. These studies using wild-type and genetically designed mice illustrate the challenges and opportunities provided by these models. Hemodynamic measurements are difficult to obtain in mice, and right heart failure has not been investigated in mice. Anatomical, cellular, and genetic differences distinguish mice and rats, and pharmacogenomics may explain the degree of PH and the particular mode of pulmonary vascular adaptation and also the response of the right ventricle.

Background: The hereditary long QT syndrome is characterized by prolonged ventricular repolarization that can be caused by mutations to the KCNQ1 gene, which encodes the α subunits of the cardiac potassium channel complex that carries the I(Ks) current (the β subunits are encoded by KCNE1). In this study, we characterized a deleterious variant, KCNQ1-S277L, found in a patient who presented with sudden cardiac death in the presence of cocaine use., Methods: The KCNQ1-S277L mutation was analyzed via whole-cell patch clamp, confocal imaging, surface biotinylation assays, and computer modeling., Results: Homomeric mutant KCNQ1-S277L channels were unable to carry current, either alone or with KCNE1. When co-expressed in a 50/50 ratio with WT KCNQ1, current density was reduced in a dominant-negative manner, with the residual current predominantly wild type. There was no change in the activation rate and minimal changes to voltage-dependent activation for both KCNQ1 current and I(Ks) current. Immunofluorescence confocal imaging revealed reduced surface expression of mutant KCNQ1-S277L, which was biochemically confirmed by surface biotinylation showing a 44% decrease in mutant surface expression. Expression of KCNQ1-S277L with human ether-a-go-go-related gene (HERG) did not significantly affect HERG protein or current density compared to KCNQ1-WT co-expression., Conclusion: The KCNQ1-S277L mutation causes biophysical defects that result in dominant-negative reduction in KCNQ1 and I(Ks) current density, and a trafficking defect that results in reduced surface expression, both without affecting HERG/I(Kr) . KCNQ1-S277L mutation in the proband resulted in defective channels that compromised repolarization reserve, thereby enhancing the arrhythmic susceptibility to pharmacological blockage of I(Kr) current., (©2011, The Authors. Journal compilation ©2011 Wiley Periodicals, Inc.)

Objective: Our purpose was to evaluate the usefulness of integrated 18F-FDG PET/CT in the detection and characterization of nonpalpable supraclavicular lymph node metastasis in patients with the initial diagnosis of lung cancer., Subjects and Methods: This study was conducted from May 2005 to May 2006 and included 32 consecutively registered lung cancer patients in whom supraclavicular lymph nodes were not palpable but were identified on contrast-enhanced CT or exhibited increased FDG uptake on integrated PET/CT. Three patients had bilateral nodes, for a total of 35 nodes in the 32 patients. Results of cytologic analysis of a specimen obtained with sonographically guided fine-needle aspiration (n = 27), normal initial and follow-up sonographic findings (n = 3), and no change in the size of supraclavicular lymph nodes on follow-up sonography (n = 2) were the reference standards. The presence of supraclavicular lymph node metastasis was determined with integrated PET/CT (uptake greater than that of surrounding tissue) and contrast-enhanced CT (node short-axis diameter of 5 mm or more). The diagnostic efficacies of these methods in the detection of supraclavicular lymph node metastasis were compared., Results: Supraclavicular lymph node metastasis was diagnosed cytologically in 12 (34%) of 35 lesions. The diagnostic accuracies of integrated PET/CT and contrast-enhanced CT in the detection of supraclavicular lymph node metastasis were 71% and 66%, respectively; the difference was not statistically significant. Although the difference was not statistically significant, the sensitivity (92%) and negative predictive value (93%) of integrated PET/CT were higher than those of contrast-enhanced CT., Conclusion: Because of its high sensitivity and negative predictive value, integrated PET/CT is useful in the detection and characterization of nonpalpable supraclavicular lymph nodes in lung cancer patients.

Objective: The purpose of our study was to compare the diagnostic efficacies of helical dynamic CT and integrated PET/CT for the prediction of mediastinal nodal metastasis in stage T1 non-small cell lung cancer (NSCLC)., Materials and Methods: One hundred forty-three patients with stage T1 NSCLC underwent both helical dynamic CT and integrated PET/CT followed by surgical nodal staging. In helical dynamic CT, patients were regarded to have stage N2 disease when a nodule showed a peak enhancement > or = 110 H or a net enhancement > or = 60 H. In integrated PET/CT, nodes were regarded as positive for malignancy when they showed > or = 3.5 in maximum standardized uptake value with a discrete margin and more 18F-FDG uptake than mediastinal structures. Sensitivities, specificities, and accuracies for mediastinal nodal metastasis detection were compared for helical dynamic CT and integrated PET/CT using the McNemar test., Results: Of the 143 patients, 34 (24%) had positive mediastinal nodes. The sensitivity, specificity, and accuracy for mediastinal nodal metastasis prediction on helical dynamic CT were 65% (22 of 34 patients), 89% (97 of 109), and 83% (119 of 143), respectively, whereas those on integrated PET/CT were 56% (19 of 34), 100% (109 of 109), and 90% (128 of 143). The p values were 0.664, < 0.001, and 0.015., Conclusion: In stage T1 NSCLC, contrast-enhanced helical dynamic CT better predicts, but not significantly so, mediastinal nodal metastasis than PET/CT, whereas PET/CT shows perfect specificity and higher accuracy than helical dynamic CT.

Unlabelled: The purpose of our study was to assess the usefulness of integrated PET/CT using 18F-FDG for distinguishing thymic epithelial tumors according to the World Health Organization (WHO) classification., Methods: Thirty-three patients (age range, 34-68 y; mean age, 54.6 y) with thymic epithelial tumors, who underwent both integrated PET/CT and enhanced CT, were included. The clinicopathologic stages, maximum standardized uptake values (SUVs), and uptake patterns of tumors on integrated PET/CT images, and various enhanced CT findings, are described according to the simplified (low-risk [types A, AB, and B1] and high-risk [types B2 and B3] thymomas and thymic carcinomas) subgroups of the WHO classification. Discriminant analysis was performed to determine the relative capabilities of integrated PET/CT and enhanced CT findings to differentiate tumor subgroups., Results: Tumors included 8 low-risk thymomas, 9 high-risk thymomas, and 16 thymic carcinomas. The maximum SUVs of high-risk thymomas (P < 0.001) and low-risk thymomas (P < 0.001) were found to be significantly lower than those of thymic carcinomas. Homogeneous 18F-FDG uptake within tumors was more frequently seen in thymic carcinomas than in high-risk thymomas (P = 0.027) or low-risk thymomas (P = 0.001). The uptake pattern (homogeneous vs. heterogeneous) on integrated PET/CT images and the presence of mediastinal fat invasion on enhanced CT images were found to be useful for differentiating tumor subgroups. In addition, integrated PET/CT helped detect lymph node metastases, which were not identified on enhanced CT in 2 patients., Conclusion: Integrated PET/CT was found to be useful for differentiating subgroups of thymic epithelial tumors and for staging the extent of the disease.

Objective: The purpose of this study was to describe the dynamic CT findings of pulmonary sclerosing hemangioma presenting as a solitary pulmonary nodule and to compare these findings with histopathologic findings., Conclusion: On dynamic CT, sclerosing hemangioma has strong and rapid enhancement attributed histopathologically to the presence of hemangiomatous or papillary components in the tumor.

Voltage-gated potassium channels regulate cell membrane potential and excitability in neurons and other cell types. A precise control of neuronal action potential patterns underlies the basic functioning of the central and peripheral nervous system. This control relies on the adaptability of potassium channel activities. The functional diversity of potassium currents, however, far exceeds the considerable molecular diversity of this class of genes. Potassium current diversity contributes to the specificity of neuronal firing patterns and may be achieved by regulated transcription, RNA splicing, and posttranslational modifications. Another mechanism for regulation of potassium channel activity is through association with interacting proteins and accessory subunits. Here the authors highlight recent work that addresses this growing area of exploration and discuss areas of future investigation.

We present a case of bronchioloalveolar carcinoma manifesting as air-space consolidation with negative FDG uptake on integrated PET/CT in a 42-year-old woman. To know this pattern of uptake especially in the case of mucin-predominant lobar bronchioloalveolar carcinoma may help avoid misdiagnosis of this particular tumor.

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4; CD152) is a surface molecule of activated T cells with sequence homologous to CD28, and may act as a negative regulator of T-cell activation. In murine animal models, cross-linkage of CTLA-4 molecules on the cell surface results in decreased T-cell proliferation, accompanied by increased interleukin (IL)-2 production and apoptosis. To clarify the activation of peripheral blood T cells, we studied the CTLA-4 expression in 32 patients with atopic dermatitis who visited our institution, and 19 normal children who visited for pre-operative laboratory examination were used as normal controls. Whole blood was obtained from all subjects and stained with anti-CD3, anti-CD4, anti-CD8 monoclonal antibodies (mAb). After erythrocyte lysis with lysing solution, the cells were stained with anti-CTLA-4 mAb, and stained cells were analysed by fluorescence-activated cell sorter (FACScan) flow cytometer. Intracellular expression of CTLA-4 was significantly upregulated in peripheral blood CD3+ T cells (36.8%), CD4+ T cells (21.7%) and CD8+ T cells (18.7%) of patients with atopic dermatitis, compared with normal control (18.3%, 9.7%, 9.8%; respectively). Furthermore, CTLA-4-positive CD3+ T cells in patients with severe atopic dermatitis were significantly higher compared with milder group (42.8% vs. 32.2%). However, no significant difference was obtained in CD4+ and CD8+ T cells. Mean percentage of T cells expressing CTLA-4 in patients with atopic dermatitis was higher than the control group. These observations suggest the possibility that the disease activity can be correlated with the CTLA-4 level.

Study Objectives: Mycoplasma pneumoniae is a common cause of lower respiratory disease. Several studies have suggested that respiratory infection by M pneumoniae is associated with reactive airway disease and asthma. Interleukin (IL)-8 has been suggested to have a role in the pathogenesis of the allergic inflammation of bronchial asthma, and is well known to be expressed in bronchial epithelial cells., Measurements: An examination was carried out into the effect of M pneumoniae lysate (MPL) and the role of mitogen-activated protein kinases (MAPKs) and extracellular signal-regulated kinase (ERK) on IL-8 expression in human lung epithelial cells. A549 cells were seeded at a density of 5 x 10(4) cells per well and incubated in basal medium for a further 24 h. IL-8 levels were determined by an enzyme-linked immunosorbent assay. MAPK phosphorylation was assessed by Western blotting., Results: In A549 cells, MPL induced IL-8 release in a time- and dose-dependent manner. Pretreatment with PD 98059, which blocks the activation of MAPK/ERK kinase 1, inhibited MPL-induced IL-8 production by 64.4% at 25 micromol/L. Stimulation of A549 cells by MPL also caused an increase in the activity of ERK, compared with the nonstimulated cells. The MPL stimulation had no effect on the activities of p38., Conclusion: These observations suggest that activation of ERK by MPL may be one of the mechanisms that result in an increase of the production of IL-8.

We present a case of retroperitoneal arteriovenous malformation extending through the inferior vena cava into the heart, which was associated with dissection of the inferior vena cava in a 32-year-old female. Computed tomography and magnetic resonance imaging showed a double-lumen inferior vena cava and a rod-like solid component attached to a sac-like lesion in the right heart chambers. Digital subtraction angiography showed an arteriovenous malformation draining to the inner lumen of the inferior vena cava.

Sensitization to aeroallergens is associated with diminished lung function in adults. Little has been studied on the relationship between the inhalant allergen-specific IgE and pulmonary function in asthmatic children. This study was focused on four major inhalant allergens found in Korea, including Dermatophagoides pteronyssinus (Der p.), Dermatophagoides farinae (Der f.), and Alternaria- and German cockroach-specific IgEs, with evaluation of pulmonary function in relation to the amount of allergens. The parents or legal guardians of participants enrolled in this study gave informed consent. Fifty-five asthmatic patients and 48 nonasthmatic children were included. The amounts of specific IgE for the four specified inhalant allergens were determined by employing the CAP system FEIA. Forced expiratory volume in 1 sec (FEV(1))/forced vital capacity (FVC), FEV(1), and forced expiratory flow between 25% and 75% of FVC (FEF(25-75)) of subjects were evaluated through pulmonary function tests. In the asthmatic group, FEV(1), FEV(1)/FVC, and FEF(25-75) were significantly reduced (P < 0.05): reduction in FEV(1) (r = -0.44) and FEF(25-75) (r = -0.33) in association with the Der f.-specific allergen, and reduction in FEV(1) (r = -0.37) and FEF(25-75) (r = -0.34) in association with the Der p.-specific allergen, were observed. However, there was no significant correlation with German cockroach and Alternaria allergen. In the control group, no significant correlation was detectable between the allergen-specific IgE titers and the results of pulmonary function tests. In asthmatic patients, Der p.- and Der f.-specific IgEs, and not German cockroach and Alternaria, seem to play a considerable role in reduced pulmonary function among asthmatic children.

Objective: The purpose of our prospective study was to assess the image quality with respect to the radiation dose incurred by multidetector CT (MDCT) in patients with suspected bronchiectasis. SUBJECTS AND METHODS. Image clusters, composed of nine images, using MDCT (120 kVp, a 2.5-mm collimation, a pitch of 6, and 2.5-mm reconstruction intervals) were obtained at each of two levels-the azygous arch and the right inferior pulmonary vein-at 170, 100, 70, 40, 20, and 10 mA. Independently, two chest radiologists assessed and compared the quality of the images obtained at the six milliamperage exposures. Image quality was graded using a 5-point scale with lung and mediastinal window settings. Radiation doses were measured at each of the six milliamperage settings while scanning the whole lung of a thoracic phantom using MDCT., Results: The mean image quality scores at exposures of 170, 100, 70, 40, 20, 10 mA were as follows: 3.9, 3.7, 3.8, 3.2, 2.5, 1.6 at lung window settings and 4.1, 4.3, 4.0, 3.4, 2.3, 1.3 at mediastinal window settings, respectively. Images obtained at 70 mA were rated significantly better than those obtained at 40 mA or less (p < 0.01). The mean radiation dose at 170, 100, 70, 40, 20, 10 mA was 23.72, 14.39, 10.54, 5.41, 2.74, and 1.50 mGy, respectively., Conclusion: With a tube current setting as low as 70 mA, MDCT provides images of acceptable quality and volumetric data sets for the evaluation of bronchiectasis. The trade-off of using MDCT rather than conventional high-resolution CT is that the radiation dose is five times higher with MDCT (10.54 mGy) than with conventional high-resolution CT (2.17 mGy with parameters of 120 kVp, 170 mA, 1-mm collimation, and 10-mm intervals).