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1.  Utilization of CT Pulmonary Angiography in Suspected Pulmonary Embolism in a Major Urban Emergency Department 
Pulmonary Medicine  2013;2013:915213.
Objectives. We conducted a study to answer 3 questions: (1) is CT pulmonary angiography (CTPA) overutilized in suspected pulmonary embolism (PE)? (2) What alternative diagnoses are provided by CTPA? (3) Can CTPA be used to evaluate right ventricular dilatation (RVD)? Methods. We retrospectively reviewed the clinical information of 231 consecutive emergency department patients who underwent CTPA for suspected PE over a one-year period. Results. The mean age of our patients was 53 years, and 58.4% were women. The prevalence of PE was 20.7%. Among the 136 patients with low clinical probability of PE, a d-dimer test was done in 54.4%, and it was normal in 24.3%; none of these patients had PE. The most common alternative findings on CTPA were emphysema (7.6%), pneumonia (7%), atelectasis (5.5%), bronchiectasis (3.8%), and congestive heart failure (3.3%). The sensitivity and negative predictive value of CTPA for (RVD) was 92% and 80%, respectively. Conclusions. PE could have been excluded without CTPA in ~1 out of 4 patients with low clinical probability of PE, if a formal assessment of probability and d-dimer test had been done. In patients without PE, CTPA did not provide an alternative diagnosis in 65%. In patients with PE, CTPA showed the potential to evaluate RVD.
PMCID: PMC3783975  PMID: 24078873
2.  Association of cigarette smoking and CRP levels with DNA methylation in α-1 antitrypsin deficiency 
Epigenetics  2012;7(7):720-728.
Alpha-1 antitrypsin (AAT) deficiency and tobacco smoking are confirmed risk factors for Chronic Obstructive Pulmonary Disease. We hypothesized that variable DNA methylation would be associated with smoking and inflammation, as reflected by the level of C-Reactive Protein (CRP) in AAT-deficient subjects. Methylation levels of 1,411 autosomal CpG sites from the Illumina GoldenGate Methylation Cancer Panel I were analyzed in 316 subjects. Associations of five smoking behaviors and CRP levels with individual CpG sites and average methylation levels were assessed using non-parametric testing, linear regression and linear mixed effect models, with and without adjustment for age and gender. Univariate linear regression analysis revealed that methylation levels of 16 CpG sites significantly associated with ever-smoking status. A CpG site in the TGFBI gene was the only site associated with ever-smoking after adjustment for age and gender. No highly significant associations existed between age at smoking initiation, pack-years smoked, duration of smoking, and time since quitting smoking as predictors of individual CpG site methylation levels. However, ever-smoking and younger age at smoking initiation associated with lower methylation level averaged across all sites. DNA methylation at CpG sites in the RUNX3, JAK3 and KRT1 genes associated with CRP levels. The most significantly associated CpG sites with gender and age mapped to the CASP6 and FZD9 genes, respectively. In summary, this study identified multiple potential candidate CpG sites associated with ever-smoking and CRP level in AAT-deficient subjects. Phenotypic variability in Mendelian diseases may be due to epigenetic factors.
PMCID: PMC3414392  PMID: 22617718
68kDa (TGFBI); C-Reactive Protein (CRP); Chronic Obstructive Pulmonary Disease (COPD); Illumina GoldenGate Methylation Cancer Panel I; alpha-1 antitrypsin (AAT) deficiency; beta-induced; methylation; smoking behaviors; transforming growth factor
3.  In silico Design of Supramolecules from Their Precursors: Odd–Even Effects in Cage-Forming Reactions 
We synthesize a series of imine cage molecules where increasing the chain length of the alkanediamine precursor results in an odd–even alternation between [2 + 3] and [4 + 6] cage macrocycles. A computational procedure is developed to predict the thermodynamically preferred product and the lowest energy conformer, hence rationalizing the observed alternation and the 3D cage structures, based on knowledge of the precursors alone.
PMCID: PMC3697021  PMID: 23745577
4.  Survey of New York City Resident Physicians on Cause-of-Death Reporting, 2010 
Death certificates contain critical information for epidemiology, public health research, disease surveillance, and community health programs. In most teaching hospitals, resident physicians complete death certificates. The objective of this study was to examine the experiences and opinions of physician residents in New York City on the accuracy of the cause-of-death reporting system.
In May and June 2010, we conducted an anonymous, Internet-based, 32-question survey of all internal medicine, emergency medicine, and general surgery residency programs (n = 70) in New York City. We analyzed data by type of residency and by resident experience in reporting deaths. We defined high-volume respondents as those who completed 11 or more death certificates in the last 3 years.
A total of 521 residents from 38 residency programs participated (program response rate, 54%). We identified 178 (34%) high-volume respondents. Only 33.3% of all respondents and 22.7% of high-volume residents believed that cause-of-death reporting is accurate. Of all respondents, 48.6% had knowingly reported an inaccurate cause of death; 58.4% of high-volume residents had done so. Of respondents who indicated they reported an inaccurate cause, 76.8% said the system would not accept the correct cause, 40.5% said admitting office personnel instructed them to “put something else,” and 30.7% said the medical examiner instructed them to do so; 64.6% cited cardiovascular disease as the most frequent diagnosis inaccurately reported.
Most resident physicians believed the current cause-of-death reporting system is inaccurate, often knowingly documenting incorrect causes. The system should be improved to allow reporting of more causes, and residents should receive better training on completing death certificates.
PMCID: PMC3664206  PMID: 23660118
5.  Genetic, host, and environmental interactions in a 19 year old with severe chronic obstructive lung disease; observations regarding the pathophysiology of airflow obstruction 
A case of a 19-year-old with severe chronic obstructive pulmonary disease is presented. This case illustrates genetic (severe alpha-1 antitrypsin deficiency) and host factors (such as developmental diaphragmatic hernia and the innate response to injury), and environmental (high oxidative stress and lung injury) interactions that lead to severe chronic obstructive lung disease. The development of chronic lung disease was caused by lung injury under high oxidative and inflammatory conditions in the setting of a diaphragmatic hernia. In the absence of normal alpha-1 antitrypsin levels, a pro-elastolytic environment in the early period of lung growth enhanced the development of severe hyperinflation and precocious airflow obstruction.
PMCID: PMC3393337  PMID: 22791992
Swyer James Macleod syndrome; alpha-1 antitrypsin deficiency; bronchopulmonary dysplasia; chronic obstructive pulmonary disease
6.  Association of IREB2 and CHRNA3 polymorphisms with airflow obstruction in severe alpha-1 antitrypsin deficiency 
Respiratory Research  2012;13(1):16.
The development of COPD in subjects with alpha-1 antitrypsin (AAT) deficiency is likely to be influenced by modifier genes. Genome-wide association studies and integrative genomics approaches in COPD have demonstrated significant associations with SNPs in the chromosome 15q region that includes CHRNA3 (cholinergic nicotine receptor alpha3) and IREB2 (iron regulatory binding protein 2).
We investigated whether SNPs in the chromosome 15q region would be modifiers for lung function and COPD in AAT deficiency.
The current analysis included 378 PIZZ subjects in the AAT Genetic Modifiers Study and a replication cohort of 458 subjects from the UK AAT Deficiency National Registry. Nine SNPs in LOC123688, CHRNA3 and IREB2 were selected for genotyping. FEV1 percent of predicted and FEV1/FVC ratio were analyzed as quantitative phenotypes. Family-based association analysis was performed in the AAT Genetic Modifiers Study. In the replication set, general linear models were used for quantitative phenotypes and logistic regression models were used for the presence/absence of emphysema or COPD.
Three SNPs (rs2568494 in IREB2, rs8034191 in LOC123688, and rs1051730 in CHRNA3) were associated with pre-bronchodilator FEV1 percent of predicted in the AAT Genetic Modifiers Study. Two SNPs (rs2568494 and rs1051730) were associated with the post-bronchodilator FEV1 percent of predicted and pre-bronchodilator FEV1/FVC ratio; SNP-by-gender interactions were observed. In the UK National Registry dataset, rs2568494 was significantly associated with emphysema in the male subgroup; significant SNP-by-smoking interactions were observed.
IREB2 and CHRNA3 are potential genetic modifiers of COPD phenotypes in individuals with severe AAT deficiency and may be sex-specific in their impact.
PMCID: PMC3306733  PMID: 22356581
CHRNA3; Chronic obstructive pulmonary disease; Genetic association analysis; Genetic modifiers; IREB2
7.  Determinants of airflow obstruction in severe alpha‐1‐antitrypsin deficiency 
Thorax  2007;62(9):806-813.
Severe α1‐antitrypsin (AAT) deficiency is an autosomal recessive genetic condition associated with an increased but variable risk for chronic obstructive pulmonary disease (COPD). A study was undertaken to assess the impact of chronic bronchitis, pneumonia, asthma and sex on the development of COPD in individuals with severe AAT deficiency.
The AAT Genetic Modifier Study is a multicentre family‐based cohort study designed to study the genetic and epidemiological determinants of COPD in AAT deficiency. 378 individuals (age range 33–80 years), confirmed to be homozygous for the SERPINA1 Z mutation, were included in the analyses. The primary outcomes of interest were a quantitative outcome, forced expiratory volume in 1 s (FEV1) percentage predicted, and a qualitative outcome, severe airflow obstruction (FEV1 <50% predicted).
In multivariate analysis of the overall cohort, cigarette smoking, sex, asthma, chronic bronchitis and pneumonia were risk factors for reduced FEV1 percentage predicted and severe airflow obstruction (p<0.01). Index cases had lower FEV1 values, higher smoking histories and more reports of adult asthma, pneumonia and asthma before age 16 than non‐index cases (p<0.01). Men had lower pre‐ and post‐bronchodilator FEV1 percentage predicted than women (p<0.0001); the lowest FEV1 values were observed in men reporting a history of childhood asthma (26.9%). This trend for more severe obstruction in men remained when index and non‐index groups were examined separately, with men representing the majority of non‐index individuals with airflow obstruction (71%). Chronic bronchitis (OR 3.8, CI 1.8 to 12.0) and a physician's report of asthma (OR 4.2, CI 1.4 to 13.1) were predictors of severe airflow obstruction in multivariate analysis of non‐index men but not women.
In individuals with severe AAT deficiency, sex, asthma, chronic bronchitis and pneumonia are risk factors for severe COPD, in addition to cigarette smoking. These results suggest that, in subjects severely deficient in AAT, men, individuals with symptoms of chronic bronchitis and/or a past diagnosis of asthma or pneumonia may benefit from closer monitoring and potentially earlier treatment.
PMCID: PMC2117297  PMID: 17389752
8.  IL10 Polymorphisms Are Associated with Airflow Obstruction in Severe α1-Antitrypsin Deficiency 
Severe α1-antitrypsin (AAT) deficiency is a proven genetic risk factor for chronic obstructive pulmonary disease (COPD), especially in individuals who smoke. There is marked variability in the development of lung disease in individuals homozygous (PI ZZ) for this autosomal recessive condition, suggesting that modifier genes could be important. We hypothesized that genetic determinants of obstructive lung disease may be modifiers of airflow obstruction in individuals with severe AAT deficiency. To identify modifier genes, we performed family-based association analyses for 10 genes previously associated with asthma and/or COPD, including IL10, TNF, GSTP1, NOS1, NOS3, SERPINA3, SERPINE2, SFTPB, TGFB1, and EPHX1. All analyses were performed in a cohort of 378 PI ZZ individuals from 167 families. Quantitative spirometric phenotypes included forced expiratory volume in one second (FEV1) and the ratio of FEV1/forced vital capacity (FVC). A qualitative phenotype of moderate-to-severe COPD was defined for individuals with FEV1 ⩽ 50 percent predicted. Six of 11 single-nucleotide polymorphisms (SNPs) in IL10 (P = 0.0005–0.05) and 3 of 5 SNPs in TNF (P = 0.01–0.05) were associated with FEV1 and/or FEV1/FVC. IL10 SNPs also demonstrated association with the qualitative COPD phenotype. When phenotypes of individuals with a physician's diagnosis of asthma were excluded, IL10 SNPs remained significantly associated, suggesting that the association with airflow obstruction was independent of an association with asthma. Haplotype analysis of IL10 SNPs suggested the strongest association with IL10 promoter SNPs. IL10 is likely an important modifier gene for the development of COPD in individuals with severe AAT deficiency.
PMCID: PMC2176135  PMID: 17690329
chronic obstructive pulmonary disease; genetic modifiers; interleukin 10; family-based association analysis
9.  Pulmonary hypertension and chronic cor pulmonale in COPD 
Hypoxia and endothelial dysfunction play a central role in the development of pulmonary hypertension. Cor pulmonale is a maladaptive response to pulmonary hypertension. The presence of peripheral edema in cor pulmonale is almost invariably associated with hypercapnia. Correction of abnormalities of gas exchange and ventilation can ameliorate pulmonary hypertension and improve survival. This review focuses on new information about the pathogenesis and treatment of pulmonary hypertension in COPD including information derived from lung volume reduction surgery, the role of brain natriuretic peptide, exhaled nitric oxide for diagnosis, and the treatment of cor pulmonale with recently available specific pulmonary vasodilators.
PMCID: PMC2695205  PMID: 18229565
cor pulmonale; chronic obstructive pulmonary disease; pulmonary hypertension; brain natriuretic peptide; nitric oxide; phlebotomy

Results 1-9 (9)