Michael D Weiden, M.D.

Pulmonary Disability Evaluations In Fdny Rescue Workers Exposed To Wtc Particulates: A Pilot Study
Comfort AL; Weiden M; Naveed B; Ferrier N; Webber MP; Berger KI; Rom WN; Prezant DJ; Nolan A
2011 ;183:?-? #A4799, American journal of respiratory & critical care medicine
— id: 137900, year: 2011, vol: 183, page: ?, stat: Journal Article,

Low Serum Iga And Igg4 Levels Predict Accelerated Decline In Lung Function Of WTC Dust Exposed Firefighters
Ferrier NV; Nolan A; Naveed B; Rom WN; Comfort AL; Prezant DJ; Weiden MD
2011 ;183:?-? #A4773, American journal of respiratory & critical care medicine
— id: 137903, year: 2011, vol: 183, page: ?, stat: Journal Article,

Neutrophils Activate Alveolar Macrophages by Producing Caspase-6-Mediated Cleavage of IL-1 Receptor-Associated Kinase-M
Kobayashi, Hiroshi; Nolan, Anna; Naveed, Bushra; Hoshino, Yoshihiko; Segal, Leopoldo N; Fujita, Yoko; Rom, William N; Weiden, Michael D
2011 Jan 1;186(1):403-410, Journal of immunology
Alveolar macrophages (AMs) are exposed to respirable microbial particles. Similar to phagocytes in the gastrointestinal tract, AMs can suppress inflammation after exposure to nonpathogenic organisms. IL-1R-associated kinase-M (IRAK-M) is one inhibitor of innate immunity, normally suppressing pulmonary inflammation. During pneumonia, polymorphonuclear neutrophils (PMNs) are recruited by chemotactic factors released by AMs to produce an intense inflammation. We report that intact IRAK-M is strongly expressed in resting human AMs but is cleaved in patients with pneumonia via PMN-mediated induction of caspase-6 (CASP-6) activity. PMN contact is necessary and PMN membranes are sufficient for CASP-6 induction in macrophages. PMNs fail to induce TNF-alpha fully in macrophages expressing CASP-6 cleavage-resistant IRAK-M. Without CASP-6 expression, PMN stimulation fails to cleave IRAK-M, degrade IkappaBalpha, or induce TNF-alpha. CASP-6(-/-) mice subjected to cecal ligation and puncture have impaired TNF-alpha production in the lung and decreased mortality. LPS did not induce or require CASP-6 activity demonstrating that TLR2/4 signaling is independent from the CASP-6 regulated pathway. These data define a central role for CASP-6 in PMN-driven macrophage activation and identify IRAK-M as an important target for CASP-6. PMNs de-repress AMs via CASP-6-mediated IRAK-M cleavage. This regulatory system will blunt lung inflammation unless PMNs infiltrate the alveolar spaces
— id: 116209, year: 2011, vol: 186, page: 403, stat: Journal Article,

Biomarkers of metabolic syndrome predict accelerated decline of lung function in NYC firefighters that were exposed to world trade center particulates
Naveed B.; Comfort A.; Ferrier N.; Kwon S.; Rom W.N.; Prezant D.J.; Weiden M.D.; Nolan A.
2011 ;4(2):99-99, Clinical & Translational Science
OBJECTIVES/SPECIFIC AIMS: The first year post 9/11/2001, the FEV1 of FDNY rescue workers declined 439 mL, stabilizing to a 25 ml/yr decline in the subsequent 7 years. Airflow obstruction predominated in firefighters who sought a subspecialty pulmonary evaluation for treatment. We are investigating the relationship between biomarkers of metabolic syndrome (MS) and decline in lung function. METHODS/ STUDY POPULATION: Treatment cohort (N = 1720) was stratified by FEV1 into obstructed, FEV1 < 76% predicted (LLN), or normal airflow, FEV1>76%. A pilot analysis assayed 41 patients' serum drawn 5 months post 9/11 for 15 biomarkers of MS by Luminex, (obstructed N = 10, normal N = 31). All patients had normal pre-9/11 lung function. Serum cholesterol (CHOL) and triglycerides (TG) were available on 157 patients, 20/157 were obstructed. Data presented as means +/- SD; p values -0.05 by t-test considered significant. RESULTS/ANTICIPATED RESULTS: BMIs at time of serum sampling were no different between normal and obstructed individuals. At subspecialty PFT, obstructed patients had higher BMIs with an accelerated decline in lung function post 9/11, increased airway reactivity, and evidence of air trapping based on elevated RV when compared to normals. Obstructed subjects had significantly greater CHOL and CHOL/HDL ratios; higher levels of sE-Selectin, tPAI-1, and s-ICAM; and a trend towards elevated levels of TG and C-peptide. DISCUSSION/SIGNIFICANCE OF IMPACT: Blood drawn post-WTC exposure identified a subgroup of patients with markers of MS. This subgroup had subsequent increased weight gain and decline in lung function. The finding of MS biomarkers prior to lung function decline raises the possibility that the combination of irritant exposure and mediators of MS interact and promote lung injury
— id: 142066, year: 2011, vol: 4, page: 99, stat: Journal Article,

Biomarkers Of Metabolic Syndrome Predict Accelerated Decline Of Lung Function In NYC Firefighters That Were Exposed To Wtc Particulates
Naveed B; Comfort AL; Ferrier N; Kasturiarachchi KJ; Rom WN; Prezant DJ; Weiden MD; Nolan A
2011 ;183:?-? #A4795, American journal of respiratory & critical care medicine
— id: 137902, year: 2011, vol: 183, page: ?, stat: Journal Article,

WTC Dust Induces Gm-Csf In Serum Of Fdny Rescue Workers With Accelerated Decline Of Lung Function And In Cultured Alveolar Macrophages
Naveed B; Comfort AL; Ferrier N; Segal LN; Kasturiarachchi KJ; Kwon S; Chen LC; Gordon T; Cohen MD; Prophete C; Rom WN; Prezant DJ; Nolan A; Weiden M
2011 ;183:?-? #A4770, American journal of respiratory & critical care medicine
— id: 137901, year: 2011, vol: 183, page: ?, stat: Journal Article,

Metabolic Syndrome Biomarkers Predict Lung Function Impairment: A Nested Case-Control Study
Naveed B; Weiden MD; Kwon S; Gracely EJ; Comfort AL; Ferrier N; Kasturiarachchi KJ; Cohen HW; Aldrich TK; Rom WN; Kelly K; Prezant DJ; Nolan A
2011 Nov 17;:?-? #, American journal of respiratory & critical care medicine
RATIONALE: Cross-sectional studies demonstrate an association between metabolic syndrome and impaired lung function. OBJECTIVE: Define if metabolic syndrome biomarkers are risk factors for loss of lung function after irritant exposure. METHODS: A nested case-control study of FDNY personnel with normal pre-9/11 FEV1 and who presented for subspecialty pulmonary evaluation before 3/10/2008. We correlated metabolic syndrome biomarkers obtained within six months of World Trade Center Dust exposure with subsequent FEV1. FEV1 at subspecialty pulmonary evaluation within 6.5 years defined disease status; cases had FEV1<lower limit of normal (LLN) while controls had FEV1>/=LLN. MEASUREMENTS: Clinical data and serum sampled at the first monitoring exam within six months of 9/11/2001 assessed BMI, heart rate, serum glucose, Triglycerides/High Density Lipoprotein (HDL), Leptin, Pancreatic Polypeptide and Amylin. MAIN RESULTS: Cases and controls had significant differences in HDL<40 mg/dL with Triglycerides >/=150 mg/dL, heart rate >/=66 bpm, and Leptin >/=10,300 pg/mL. Each increased the odds of abnormal FEV1 at pulmonary evaluation by more than 2 fold, while Amylin >/=116 pg/mL decreased the odds by 84%, in a multi-biomarker model adjusting for age, race, BMI and WTC arrival time. This model had a sensitivity of 41%, a specificity of 86% and a ROC AUC of 0.77. CONCLUSION: Abnormal triglycerides and HDL, elevated heart rate and Leptin are independent risk factors of greater susceptibility to lung function impairment after 9/11/2001 while elevated Amylin is protective. Metabolic biomarkers are predictors of lung disease, and may be useful for assessing risk of impaired lung function in response to particulate inhalation
— id: 149814, year: 2011, vol: , page: ?, stat: Journal Article,

The Impact of the World Trade Center Attack on FDNY Firefighter Retirement, Disabilities, and Pension Benefits
Niles, J. K.; Webber, M. P.; Gustave, J.; Zeig-Owens, R.; Lee, R.; Glass, L.; Weiden, M. D.; Kelly, K. J.; Prezant, D. J.
2011 SEP ;54(9):672-680, American journal of industrial medicine
Background Our goal was to examine the effect of the World Trade Center (WTC) attack and subsequent New York City Fire Department (FDNY) rescue/recovery activities on firefighter retirements. We also analyzed the financial impact associated with the increased number and proportion of service-connected 'accidental'' disability retirements on the FDNY pension system. Methods A total of 7,763 firefighters retired between 9/11/1994 and 9/10/2008. We compared the total number of retirements and the number and proportion of accidental disability retirements 7 years before and 7 years after the WTC attack. We categorized WTC-related accidental disability retirements by medical cause and worked with the New York City Office of the Actuary to approximate the financial impact by cause. Results In the 7 years before 9/11 there were 3,261 retirements, 48% (1,571) of which were accidental disability retirements. In the 7 years after 9/11, there were 4,502 retirements, 66% (2,970) were accidental disability retirements, of which 47% (1,402) were associated with WTC-related injuries or illnesses. After 9/11, the increase in accidental disability retirements was, for the most part, due to respiratory-related illnesses. Additional increases were attributed to psychological-related illnesses and musculoskeletal injuries incurred at the WTC site. Pension benefits associated with WTC-related accidental disability retirements have produced an increased financial burden of over $826 million on the FDNY pension system. Conclusions The WTC attacks affected the health of the FDNY workforce resulting in more post-9/11 retirements than expected, and a larger proportion of these retirees with accidental disability pensions. Am. J. Ind. Med. 54:672-680, 2011. (C) 2011 Wiley-Liss, Inc
— id: 137126, year: 2011, vol: 54, page: 672, stat: Journal Article,

Inflammatory Biomarkers Predict Airflow Obstruction After Exposure to World Trade Center Dust
Nolan A; Naveed B; Comfort AL; Ferrier N; Hall CB; Kwon S; Kasturiarachchi KJ; Cohen HW; Zeig-Owens R; Glaser MS; Webber MP; Aldrich TK; Rom WN; Kelly K; Prezant DJ; Weiden MD
2011 Oct 13;:?-? #, Chest
Abstract BACKGROUND:The World Trade Center (WTC) collapse produced airflow obstruction in a majority of firefighters receiving subspecialty pulmonary evaluation (SPE) within 6.5 years post-9/11. METHODS:In a cohort of 801 never smokers with normal pre-9/11 FEV(1), we correlated inflammatory biomarkers and complete blood counts at monitoring entry within 6 months of 9/11/2001 with a median FEV(1) at SPE (34 months, IQR 25-57). Cases of airflow obstruction had FEV(1) < LLN (100/801; 70/100 had serum) while controls had FEV(1) >/= LLN (153/801; 124/153 had serum). RESULTS:From monitoring entry to SPE, years later, FEV(1) declined 12% in cases and increased 3% in controls. Cases had elevated serum MDC, GM-CSF, G-CSF and IP-10. Elevated GM-CSF and MDC increased the risk for subsequent FEV(1) < LLN by 2.5 fold (95% CI; 1.2-5.3) and 3.0 fold (1.4-6.1) in a logistic model adjusted for exposure, BMI, age on 9/11, and polymorphonuclear neutrophils. The model had sensitivity of 38% (95% CI 27-51), specificity of 88% (80-93). CONCLUSIONS:Inflammatory biomarkers can be risk factors for airflow obstruction following dust and smoke exposure. Elevated serum GM-CSF and MDC soon after WTC exposure were associated with increased risk of airflow obstruction in subsequent years. Biomarkers of inflammation may help identify pathways producing obstruction after irritant exposure
— id: 138730, year: 2011, vol: , page: ?, stat: Journal Article,

Regulatory t cells and th17 cells in bronchoalveolar lavage
Segal L; Kulkarni R; Nolan A; Weiden MD; Tse DB; Rom WN
2011 ;183:?-? #A4799, American journal of respiratory & critical care medicine
— id: 137898, year: 2011, vol: 183, page: ?, stat: Journal Article,

Disparity between proximal and distal airway reactivity during methacholine challenge
Segal, Leopoldo N; Goldring, Roberta M; Oppenheimer, Beno W; Stabile, Alexandra; Reibman, Joan; Rom, William N; Weiden, Michael D; Berger, Kenneth I
2011 Jun;8(3):145-152, COPD: Journal of Chronic Obstructive Pulmonary Disease
There is an increasing awareness of the role of distal airways in the pathophysiology of obstructive lung diseases including asthma and chronic obstructive pulmonary disease. We hypothesize that during induced bronchoconstriction: 1) disparity between distal and proximal airway reactivity may occur; and 2) changes in distal airway function may explain symptom onset in subjects with minimal FEV(1) change. 185 subjects underwent methacholine challenge testing (MCT). In addition to spirometry, oscillometry was performed at baseline and after maximum dose of methacholine; 33/185 also underwent oscillometry after each dose. Oscillometric parameters included resistance at 5 and 20 Hz (R(5,) R(20)) and heterogeneity of distal airway mechanics assessed by frequency dependence of resistance 5-20 Hz (R(5-20)) and reactance area (AX). R(5) varied widely during MCT (range -0.8 - 11.3 cmH(2)O/L/s) and correlated poorly with change in FEV(1) (r = 0.17). Changes in R(5) reflected changes in both R(20) and R(5-20) (r = 0.59, p<0.05; r = 0.87, p<0.0001). However, R(20) increased only 0.3 cmH(2)O/L/s, while R(5-20) increased 0.7 cmH(2)O/L/s for every 1cmH(2)O/L/s change in R(5,) indicating predominant effect of distal airway mechanics. 9/33 subjects developed symptoms despite minimal FEV(1) change (<5%), while R(5) increased 42% due to increased distal airway heterogeneity. These data indicate disparate behavior of proximal airway resistance (FEV(1) and R(20)) and distal airway heterogeneity (R(5-20) and AX). Distal airway reactivity may be associated with methacholine-induced symptoms despite absence of change in FEV(1). This study highlights the importance of disparity between proximal and distal airway behavior, which has implications in understanding pathophysiology of obstructive pulmonary diseases and their response to treatment
— id: 134171, year: 2011, vol: 8, page: 145, stat: Journal Article,

HIV-1 and Bacterial Pneumonia in the Era of Antiretroviral Therapy
Segal, Leopoldo N; Methe, Barbara A; Nolan, Anna; Hoshino, Yoshihiko; Rom, William N; Dawson, Rod; Bateman, Eric; Weiden, Michael D
2011 Jun;8(3):282-287, Proceedings of the American Thoracic Society
Community-acquired pneumonia affects approximately 4 million people in the United States, with 40,000 deaths per year. The incidence is increased about 35-fold in HIV-infected individuals, and this rate has decreased since the antiretroviral era has begun. Bacterial pneumonia has decreased from 5 to 20 cases per 100 person-years to less than 1 to 5 cases per 100 person-years in the era of antiretroviral therapy. HIV-1 infection impairs the function of neutrophils in the lung and infects CD4(+) cells and alveolar macrophages. Opportunistic infections dramatically increase local HIV replication in the lung cells, especially alveolar macrophages and CD4(+) cells. This enhanced replication increases viral mutations and provides opportunities for viral escape from latent reservoirs. Mortality is increased with more comorbidities in this highly susceptible population. Immunization with vaccines is recommended, especially pneumococcal vaccines, although the vaccine itself may stimulate viral replication. Recent studies show that the lower respiratory tract is a microbial reservoir in HIV-infected individuals rather than being a sterile environment, as originally thought. This may provide new opportunities for preventing opportunistic infections in HIV-infected subjects. Bacterial pneumonia presents an ongoing challenge in these high-risk individuals, particularly in studying the functions of the innate and acquired immune response
— id: 134318, year: 2011, vol: 8, page: 282, stat: Journal Article,

Azithromycin suppresses inflammatory cytokines and induces inhibatory transcription factors in alveolar macrophages
Segal, Leopoldo; Kulkarni, Rohan; Fujita, Yoko; Nolan, Anna; Rom, William N; Weiden, Michael
2011 ;183:?-? #A2853, American journal of respiratory & critical care medicine
— id: 137899, year: 2011, vol: 183, page: ?, stat: Journal Article,

Physician-Diagnosed Respiratory Conditions and Mental Health Symptoms Seven to Nine Years Following the World Trade Center Disaster
Webber MP; Glaser MS; Weakley J; Soo J; Ye F; Zeig-Owens R; Weiden MD; Nolan A; Aldrich TK; Kelly K; Prezant D
2011 Sep 1;54(9):661-671, American journal of industrial medicine
BACKGROUND: This study examines the prevalence of physician-diagnosed respiratory conditions and mental health symptoms in firefighters and emergency medical service workers up to 9 years after rescue/recovery efforts at the World Trade Center (WTC). METHODS: We analyzed FDNY physician and self-reported diagnoses by WTC exposure and quintiles of pulmonary function (FEV1%predicted). We used screening instruments to assess probable PTSD and probable depression. RESULTS: FDNY physicians most commonly diagnosed asthma (8.8%) and sinusitis (9.7%). The highest prevalence of physician-diagnosed obstructive airway disease (OAD) was in the lowest FEV1%predicted quintile. Participants who arrived earliest on 9/11 were more likely to have physician-diagnosed asthma (OR=1.4). 7% had probable PTSD. 19.4% had probable depression. CONCLUSIONS: Self-reported and physician-diagnosed respiratory conditions remain common, especially among those who arrived earliest at the WTC site. OAD was associated with the lowest pulmonary function. Since respiratory and mental health conditions remain prevalent, ongoing monitoring and treatment is important
— id: 137897, year: 2011, vol: 54, page: 661, stat: Journal Article,

Lung Function in Rescue Workers at the World Trade Center after 7 Years
Aldrich, TK; Gustave, J; Hall, CB; Cohen, HW; Webber, MP; Zeig-Owens, R; Cosenza, K; Christodoulou, V; Glass, L; Al-Othman, F; Weiden, MD; Kelly, KJ; Prezant, DJ
2010 APR 8 ;362(14):1263-1272, New England journal of medicine
Background: The terrorist attacks on the World Trade Center on September 11, 2001, exposed thousands of Fire Department of New York City (FDNY) rescue workers to dust, leading to substantial declines in lung function in the first year. We sought to determine the longer-term effects of exposure. Methods: Using linear mixed models, we analyzed the forced expiratory volume in 1 second (FEV(sub 1)) of both active and retired FDNY rescue workers on the basis of spirometry routinely performed at intervals of 12 to 18 months from March 12, 2000, to September 11, 2008. Results: Of the 13,954 FDNY workers who were present at the World Trade Center between September 11, 2001, and September 24, 2001, a total of 12,781 (91.6%) participated in this study, contributing 61,746 quality-screened spirometric measurements. The median follow-up was 6.1 years for firefighters and 6.4 years for emergency-medical-services (EMS) workers. In the first year, the mean FEV(sub 1) decreased significantly for all workers, more for firefighters who had never smoked (a reduction of 439 ml; 95% confidence interval [CI], 408 to 471) than for EMS workers who had never smoked (a reduction of 267 ml; 95% CI, 263 to 271) (P<0.001 for both comparisons). There was little or no recovery in FEV(sub 1) during the subsequent 6 years, with a mean annualized reduction in FEV(sub 1) of 25 ml per year for firefighters and 40 ml per year for EMS workers. The proportion of workers who had never smoked and who had an FEV(sub 1) below the lower limit of the normal range increased during the first year, from 3% to 18% for firefighters and from 12% to 22% for EMS workers, stabilizing at about 13% for firefighters and 22% for EMS workers during the subsequent 6 years. Conclusions: Exposure to World Trade Center dust led to large declines in FEV(sub 1) for FDNY rescue workers during the first year. Overall, these declines were persistent, without recovery over the next 6 years, leaving a substantial proportion of workers with abnormal lung function. N Engl J Med 2010;362:1263-72
— id: 109068, year: 2010, vol: 362, page: 1263, stat: Journal Article,

Accelerated spirometric decline in New York City firefighters with alpha-antitrypsin deficiency
Banauch, Gisela I; Brantly, Mark; Izbicki, Gabriel; Hall, Charles; Shanske, Alan; Chavko, Robert; Santhyadka, Ganesha; Christodoulou, Vasilios; Weiden, Michael D; Prezant, David J
2010 Nov;138(5):1116-1124, Chest
BACKGROUND: On September 11, 2001, the World Trade Center (WTC) collapse caused massive air pollution, producing variable amounts of lung function reduction in the New York City Fire Department (FDNY) rescue workforce. alpha-Antitrypsin (AAT) deficiency is a risk factor for obstructive airway disease. METHODS: This prospective, longitudinal cohort study of the first 4 years post-September 11, 2001, investigated the influence of AAT deficiency on adjusted longitudinal spirometric change (FEV) in 90 FDNY rescue workers with WTC exposure. Workers with protease inhibitor (Pi) Z heterozygosity were considered moderately AAT deficient. PiS homozygosity or PiS heterozygosity without concomitant PiZ heterozygosity was considered mild deficiency, and PiM homozygosity was considered normal. Alternately, workers had low AAT levels if serum AAT was </= 20 mumol/L. RESULTS: In addition to normal aging-related decline (37 mL/y), significant FEV(1) decline accelerations developed with increasing AAT deficiency severity (110 mL/y for moderate and 32 mL/y for mild) or with low AAT serum levels (49 mL/y). Spirometric rates pre-September 11, 2001, did not show accelerations with AAT deficiency. Among workers with low AAT levels, cough persisted in a significant number of participants at 4 years post-September 11, 2001. CONCLUSIONS: FDNY rescue workers with AAT deficiency had significant spirometric decline accelerations and persistent airway symptoms during the first 4 years after WTC exposure, representing a novel gene-by-environment interaction. Clinically meaningful decline acceleration occurred even with the mild serum AAT level reductions associated with PiS heterozygosity (without concomitant PiZ heterozygosity)
— id: 133833, year: 2010, vol: 138, page: 1116, stat: Journal Article,

Similar Exposure To World Trade Center (WTC) Dust Produced Variable Lung Function Decline: Defining Most And Least Effected Subgroups In The FDNY Cohort
Ferrier, Natalia; Nolan, Anna; Rom, Wiliam N; Comfort, Ashley L; Prezant, David J; Weiden, Michael D
2010 ;181:- #A1252, American journal of respiratory & critical care medicine
— id: 113679, year: 2010, vol: 181, page: , stat: Journal Article,

Neutrophils Activate Alveolar Macrophages By Producing Caspase-6 Mediated Cleavage Of Interleukin-1 Associated Kinase-M (IRAK-M) In Tuberculosis
Kobayashi, Hiroshi; Nolan, Anna; Naveed, Bushra; Comfort, Ashley L; Rom, William N; Hoshino, Yoshihiko; Weiden, Michael D
2010 ;181:- #A3221, American journal of respiratory & critical care medicine
— id: 113677, year: 2010, vol: 181, page: , stat: Journal Article,

WTC PM2.5 stimulates a more intense inflammatory response in human BAL cells than other ambient PM2.5 from NYC and surrounding environs
Naveed B.; Weiden M.D.; Rom W.N.; Prezant D.J.; Comfort A.; Chen L.; Kwon S.; Chen Y.; Gordon T.; Nolan A.
2010 ;3(2):S48-S48, Clinical & Translational Science
OBJECTIVES: Particulate matter (PM) exposure causes adverse health effects. The WTC collapse led to significant PM exposure and lung injury (Weiden et al. Chest 2009). The mechanism by which WTC PM causes pulmonary morbidity is not understood. We are investigating the differential cytokine effects on human alveolar cells, comparing ambient PM of WTC to ambient PM from NYC, South Bronx (SB) and Sterling Forest (SF), a rural area northwest of NYC. METHODS AND POPULATION: AM were obtained from Bronchoalveolar lavage (BAL) by adherence overnight. AM were exposed to 50mug/mL suspensions of WTC, SB, and SF PM2.5. Media alone was the negative control and 40 ng/mL of LPS was the positive control. After 24hrs, supernatants were collected and analyzed in duplicate using Human Cytokine Panel I (Millipore) on a Luminex-200. RESULTS: Fold induction of mediators was expressed as ratios of PM exposure/media alone. Exposure to WTC PM was markedly more inflammatory than SB and SF. The most significant inductions were of the leukocyte growth factors (GM-CSF, G-CSF), a promoter of angiogenesis (VEGF), the chemokine (RANTES) and the potent multifunctional cytokine IL-6. LPS caused a greater induction for all of the analytes when compared to WTC PM except for IL-1ra. SIGNIFICANCE OF STUDY: WTC PM2.5 produces a marked inflammatory effect in comparison to PM2.5 from both NYC, SB and rural sites. The large number of cytokines induced by WTC PM may drive airway injury and may be biomarkers for lung injury. WTC PM has been observed in induced sputum obtained 9 months after 9/11/2001 and so the elaboration of cytokines may underlie the severe and long lasting health effects produced by exposure to WTC PM
— id: 111408, year: 2010, vol: 3, page: S48, stat: Journal Article,

Microparticle Activity Is Increased In Murine Polymicrobial Sepsis
Naveed, Bushra; Weiden, Michael D; Comfort, Ashley L; Chen, Yingdi; Kwon, Sophia; Rom, William N; Nolan, Anna
2010 ;181:- #1375, American journal of respiratory & critical care medicine
— id: 113680, year: 2010, vol: 181, page: , stat: Journal Article,

WTC PM2.5 Stimulates A More Intense Inflammatory Response In Human BAL Cells Than Other Ambient PM2.5 From NYC And Surrounding Environs
Naveed, Bushra; Weiden, Michael D; Rom, William N; Prezant, David J; Comfort, Ashley L; Chen, Yingdi; Kwon, Sophia; Chen, Lung Chi; Gordon, Terry; Nolan, Anna
2010 ;181:- #A1158, American journal of respiratory & critical care medicine
— id: 113678, year: 2010, vol: 181, page: , stat: Journal Article,

Emerging exposures and respiratory health: world trade center dust
Rom, William N; Reibman, Joan; Rogers, Linda; Weiden, Michael D; Oppenheimer, Beno; Berger, Kenneth; Goldring, Roberta; Harrison, Denise; Prezant, David
2010 May;7(2):142-145, Proceedings of the American Thoracic Society
The attack on the World Trade Center (WTC) on 9/11/2001 produced a massive dust cloud with acute exposure, and the rubble pile burning over 3 months exposed more than 300,000 residents, rescue workers, and clean-up workers. Firefighters in the New York City Fire Department had significant respiratory symptoms characterized by cough, dyspnea, gastroesophageal reflux, and nasal stuffiness with a significant 1-year decline in FVC and FEV(1). Bronchial hyperreactivity measured by methacholine challenge correlated with bronchial wall thickening on CT scans. Compared with the NHANES III data for FVC and FEV(1), 32% of 2,000 WTC dust-exposed residents and clean-up workers were below the lower 5th percentile. The most common abnormality was a low FVC pattern, a finding similar to that also described for individuals in rescue and recovery activities. Among those complaining of respiratory symptoms and normal spirometry, almost half had abnormalities detected with impedance oscillometry consistent with distal airways' disease. Follow-up with the WTC Health Registry and the WTC Environmental Health Center will help discern whether treatment with anti-inflammatory medications or bronchodilators in those with respiratory symptoms may prevent the development of chronic obstructive pulmonary disease
— id: 109531, year: 2010, vol: 7, page: 142, stat: Journal Article,

Measurement of antiretroviral drugs in the lungs of HIV-infected patients
Twigg HL; Schnizlein-Bick CT; Weiden M; Valentine F; Wheat J; Day RB; Rominger H; Zheng L; Collman RG; Coombs RW; Bucy RP; Rezk NL; Kashuba AD
2010 Mar 1;4(2):247-251, HIV Therapy
AIMS: Prior studies have shown that HAART is associated with decreased HIV viral load in the lungs. The correlation between antiretroviral exposure in bronchoalveolar lavage (BAL) fluid and virologic response was evaluated in patients starting HAART and enrolled in The AIDS Clinical Trial Group Protocol 723. MATERIALS #ENTITYSTARTX00026; METHODS: A total of 24 subjects underwent blood and BAL sampling prior to starting HAART, and after 4 and 24 weeks of HAART. Drug concentrations and HIV RNA were measured in paired plasma and BAL samples. RESULTS: Antiretroviral drugs, including efavirenz, were detectable in BAL fluid of HIV-infected subjects beginning HAART. Efavirenz was also associated with a higher likelihood of clearing HIV RNA from the lungs. CONCLUSION: These results suggest the excellent pulmonary virologic response to antiretroviral therapy may, in part, be due to penetration of antiretroviral drugs into the alveolar compartment
— id: 138270, year: 2010, vol: 4, page: 247, stat: Journal Article,

Obstructive airways disease with air trapping among firefighters exposed to World Trade Center dust
Weiden, Michael D; Ferrier, Natalia; Nolan, Anna; Rom, William N; Comfort, Ashley; Gustave, Jackson; Zeig-Owens, Rachel; Zheng, Shugi; Goldring, Roberta M; Berger, Kenneth I; Cosenza, Kaitlyn; Lee, Roy; Webber, Mayris P; Kelly, Kerry J; Aldrich, Thomas K; Prezant, David J
2010 Mar;137(3):566-574, Chest
BACKGROUND: The World Trade Center (WTC) collapse produced a massive exposure to respirable particulates in New York City Fire Department (FDNY) rescue workers. This group had spirometry examinations pre-September 11, 2001, and post-September 11, 2001, demonstrating declines in lung function with parallel declines in FEV(1) and FVC. To date, the underlying pathophysiologic cause for this has been open to question. METHODS: Of 13,234 participants in the FDNY-WTC Monitoring Program, 1,720 (13%) were referred for pulmonary subspecialty evaluation at a single institution. Evaluation included 919 full pulmonary function tests, 1,219 methacholine challenge tests, and 982 high-resolution chest CT scans. RESULTS: At pulmonary evaluation (median 34 months post-September 11, 2001), median values were FEV(1) 93% predicted (interquartile range [IQR], 83%-101%), FVC 98% predicted (IQR, 89%-106%), and FEV(1)/FVC 0.78 (IQR, 0.72-0.82). The residual volume (RV) was 123% predicted (IQR, 106%-147%) with nearly all participants having normal total lung capacity, functional residual capacity, and diffusing capacity of carbon monoxide. Also, 1,051/1,720 (59%) had obstructive airways disease based on at least one of the following: FEV(1)/FVC, bronchodilator responsiveness, hyperreactivity, or elevated RV. After adjusting for age, gender, race, height and weight, and tobacco use, the decline in FEV(1) post-September 11, 2001, was significantly correlated with increased RV percent predicted (P < .0001), increased bronchodilator responsiveness (P < .0001), and increased hyperreactivity (P = .0056). CT scans demonstrated bronchial wall thickening that was significantly associated with the decline in FEV(1) post-September 11, 2001 (P = .024), increases in hyperreactivity (P < .0001), and increases in RV (P < .0001). Few had evidence for interstitial disease. CONCLUSIONS: Airways obstruction was the predominant physiologic finding underlying the reduction in lung function post-September 11, 2001, in FDNY WTC rescue workers presenting for pulmonary evaluation
— id: 109029, year: 2010, vol: 137, page: 566, stat: Journal Article,

Immunomodulation with recombinant interferon-gamma1b in pulmonary tuberculosis
Dawson, Rod; Condos, Rany; Tse, Doris; Huie, Maryann L; Ress, Stanley; Tseng, Chi-Hong; Brauns, Clint; Weiden, Michael; Hoshino, Yoshihiko; Bateman, Eric; Rom, William N
2009 ;4(9):e6984-e6984, PLoS ONE
BACKGROUND: Current treatment regimens for pulmonary tuberculosis require at least 6 months of therapy. Immune adjuvant therapy with recombinant interferon-gamma1b (rIFN-gammab) may reduce pulmonary inflammation and reduce the period of infectivity by promoting earlier sputum clearance. METHODOLOGY/PRINCIPAL FINDINGS: We performed a randomized, controlled clinical trial of directly observed therapy (DOTS) versus DOTS supplemented with nebulized or subcutaneously administered rIFN-gamma1b over 4 months to 89 patients with cavitary pulmonary tuberculosis. Bronchoalveolar lavage (BAL) and blood were sampled at 0 and 4 months. There was a significant decline in levels of inflammatory cytokines IL-1beta, IL-6, IL-8, and IL-10 in 24-hour BAL supernatants only in the nebulized rIFN-gamma1b group from baseline to week 16. Both rIFN-gamma1b groups showed significant 3-fold increases in CD4+ lymphocyte response to PPD at 4 weeks. There was a significant (p = 0.03) difference in the rate of clearance of Mtb from the sputum smear at 4 weeks for the nebulized rIFN-gamma1b adjuvant group compared to DOTS or DOTS with subcutaneous rIFN-gamma1b. In addition, there was significant reduction in the prevalence of fever, wheeze, and night sweats at 4 weeks among patients receiving rFN-gamma1b versus DOTS alone. CONCLUSION: Recombinant interferon-gamma1b adjuvant therapy plus DOTS in cavitary pulmonary tuberculosis can reduce inflammatory cytokines at the site of disease, improve clearance of Mtb from the sputum, and improve constitutional symptoms. TRIAL REGISTRATION: ClinicalTrials.gov NCT00201123
— id: 104334, year: 2009, vol: 4, page: e6984, stat: Journal Article,

Caspase 6 cleaves the macrophage inhibitor IRAK-M in contact dependent innate immune activation
Kobayashi H; Nolan A; Naveed B; Hoshino Y; Hoshino S; Rom WN; Weiden MD
2009 April;179:A5689-A5689, American journal of respiratory & critical care medicine
— id: 101390, year: 2009, vol: 179, page: A5689, stat: Journal Article,

Costimulatory molecules in the inflammatory response to PM2.5 exposure
Naveed B; Weiden MD; Nolan A; Kang GS; Rom WN; Chen LC
2009 April;179:A3138-A3138, American journal of respiratory & critical care medicine
— id: 101389, year: 2009, vol: 179, page: A3138, stat: Journal Article,

Differential role for CD80 and CD86 in the regulation of the innate immune response in murine polymicrobial sepsis
Nolan, Anna; Kobayashi, Hiroshi; Naveed, Bushra; Kelly, Ann; Hoshino, Yoshihiko; Hoshino, Satomi; Karulf, Matthew R; Rom, William N; Weiden, Michael D; Gold, Jeffrey A
2009 ;4(8):e6600-e6600, PLoS ONE
BACKGROUND: Inflammation in the early stages of sepsis is governed by the innate immune response. Costimulatory molecules are a receptor/ligand class of molecules capable of regulation of inflammation in innate immunity via macrophage/neutrophil contact. We recently described that CD80/86 ligation is required for maximal macrophage activation and CD80/86(-/-) mice display reduced mortality and inflammatory cytokine production after cecal ligation and puncture (CLP). However, these data also demonstrate differential regulation of CD80 and CD86 expression in sepsis, suggesting a divergent role for these receptors. Therefore, the goal of this study was to determine the individual contribution of CD80/86 family members in regulating inflammation in sepsis. METHODOLOGY/PRINCIPAL FINDINGS: CD80(-/-) mice had improved survival after CLP when compared to WT or CD86(-/-) mice. This was associated with preferential attenuation of inflammatory cytokine production in CD80(-/-) mice. Results were confirmed with pharmacologic blockade, with anti-CD80 mAb rescuing mice when administered before or after CLP. In vitro, activation of macrophages with neutrophil lipid rafts caused selective disassociation of IRAK-M, a negative regulator of NF-kappaB signaling from CD80; providing a mechanism for preferential regulation of cytokine production by CD80. Finally, in humans, upregulation of CD80 and loss of constitutive CD86 expression on monocytes was associated with higher severity of illness and inflammation confirming the findings in our mouse model. CONCLUSIONS: In conclusion, our data describe a differential role for CD80 and CD86 in regulation of inflammation in the innate immune response to sepsis. Future therapeutic strategies for blockade of the CD80/86 system in sepsis should focus on direct inhibition of CD80
— id: 101388, year: 2009, vol: 4, page: e6600, stat: Journal Article,

World Trade Center collapse produced airway injury and air trapping
Weiden MD; Ferrier N; Nolan A; Rom WN; Comfort A; Gustave J; Zheng S; Goldring R; Berger K; Cosenz K; Beringer A; Glass L; Lee R; Zeig-Owens R; Webber M; Prezant DJ
2009 ;179:A5852-A5852, American journal of respiratory & critical care medicine
— id: 101391, year: 2009, vol: 179, page: A5852, stat: Journal Article,

Trial of prophylactic inhaled steroids to prevent or reduce pulmonary function decline, pulmonary symptoms, and airway hyperreactivity in firefighters at the world trade center site
Banauch, Gisela I; Izbicki, Gabriel; Christodoulou, Vasilios; Weiden, Michael D; Webber, Mayris P; Cohen, Hillel; Gustave, Jackson; Chavko, Robert; Aldrich, Thomas K; Kelly, Kerry J; Prezant, David J
2008 Mar;2(1):33-39, Disaster medicine & public health preparedness
BACKGROUND: Inhaled corticosteroids (ICS) are the most effective anti-inflammatory treatment for asthmatics. This trial evaluated the effects of prophylactic ICS in firefighters exposed to the World Trade Center disaster. METHODS: Inhaled budesonide via a dry powder inhaler (Pulmicort Turbuhaler, AstraZeneca, Wilmington, DE) was offered on-site to New York City firefighters between September 18 and 25, 2001. One to 2 years later, firefighters (n = 64) who completed 4 weeks of daily ICS treatment were evaluated and compared with an age- and exposure-matched comparison group (n = 72) who did not use ICS. RESULTS: When spirometry results at the final visit were compared with those from the weeks following the 9/11 disaster, the treatment group had a greater increase in forced vital capacity (P = .009) and possibly a slower decline in forced expiratory volume at 1 second (P = .11), as well as a greater improvement in perceived well-being as assessed by the St George's Respiratory Questionnaire (P < .01). There was no difference in airway hyperreactivity and no evidence of adverse effects from ICS. CONCLUSIONS: Because the potential for hazardous exposures is great at many disasters, disease prevention programs based on environmental controls and respiratory protection are warranted immediately. Our results suggest that, pending further study with a larger sample, prophylactic ICS should be considered, along with respiratory protection, to minimize possible lung insult
— id: 78801, year: 2008, vol: 2, page: 33, stat: Journal Article,

Identification of annexin 1 as a novel autoantigen in acute exacerbation of idiopathic pulmonary fibrosis
Kurosu, Katsushi; Takiguchi, Yuichi; Okada, Osamu; Yumoto, Norio; Sakao, Seiichiro; Tada, Yuji; Kasahara, Yasunori; Tanabe, Nobuhiro; Tatsumi, Koichiro; Weiden, Michael; Rom, William N; Kuriyama, Takayuki
2008 Jul 1;181(1):756-767, Journal of immunology
Consistent with the hypothesis that pulmonary epithelial apoptosis is the key to the acute exacerbation of idiopathic pulmonary fibrosis (IPF), we conducted serological identification of Ags by recombinant expression cloning (SEREX) analysis using type II alveolar cell carcinoma (A549) cell lines to identify disease-related Abs. In a survey of Abs to the recombinant autoantigens identified by SEREX analysis, five Abs were identified as novel candidates for the acute exacerbation of IPF. Abs to annexin 1 were detected in 47 and 53% of the sera and bronchoalveolar lavage materials from patients with acute exacerbation of IPF. Some identical TCR Vbeta genes were identified in sequential materials obtained at 1-3 mo in all 10 acute exacerbation IPF cases, suggesting that some infiltrating CD4-positive T cells sharing limited epitopes expand by Ag-driven stimulation during disease extension. The CDR3 region of these identical TCR Vbeta genes showed high homology with the N-terminal portion of annexin 1, including in the HLA-DR ligand epitopes predicted by TEPITOPE analysis. By Western blotting analysis and observation of the CD4-positive T cell responses in bronchoalveolar lavage samples, the N-terminal portion of annexin 1 was cleaved and found to induce marked proliferative responses of CD4-positive T cells in three patients. Our study demonstrates that annexin 1 is an autoantigen that raises both Ab production and T cell response in patients with acute exacerbation of IPF, and that the N-terminal portion of annexin 1 plays some role in the pathogenesis of acute exacerbation in IPF patients
— id: 94496, year: 2008, vol: 181, page: 756, stat: Journal Article,

CD40 and CD80/86 act synergistically to regulate inflammation and mortality in polymicrobial sepsis
Nolan, Anna; Weiden, Michael; Kelly, Ann; Hoshino, Yoshihiko; Hoshino, Satomi; Mehta, Nehal; Gold, Jeffrey A
2008 Feb 1;177(3):301-308, American journal of respiratory & critical care medicine
RATIONALE: Costimulatory molecules, including the CD40-CD154 and CD80/86-CD28 dyads, play a prominent role in regulating inflammation in the adaptive immune response. Studies from our group and others suggest a potentially important role for these costimulatory cascades in innate immunity as well. OBJECTIVES: To determine the role of CD80/86 alone and in combination with CD40 in lethal polymicrobial sepsis in mice and humans. METHODS: The murine cecal ligation and puncture (CLP) model was used to determine the role of CD80/86 alone and in combination with CD40 using wild-type mice, CD80/86(-/-) mice, and novel CD40/80/86(-/-) mice. Expression of cell-bound and soluble costimulatory molecules was assessed in humans via ELISA and flow cytometry. MEASUREMENTS AND MAIN RESULTS: Lethal CLP was associated with up-regulation of CD40 and CD80/86 and their respective ligands CD28 and CD154 on innate effector cells. Blockade or deletion of CD80/86 attenuated mortality and inflammatory cytokine production during CLP. CD40/80/86(-/-) mice exhibited further reductions in mortality, lung injury, and inflammatory cytokine production compared with CD80/86(-/-) mice. Finally, humans with sepsis had increased monocyte expression of CD40 and CD80 compared with healthy control subjects; with higher levels in subjects requiring vasopressor support. Levels of soluble CD28 and CD154 were significantly higher in patients who died compared with those who lived. CONCLUSIONS: These data demonstrate a central role for CD40 and CD80/86 in the innate immune response and suggest that combined inhibition of CD40 and CD80/86 may improve mortality in sepsis. Expression of costimulatory molecules may serve as biomarkers for outcome in septic patients
— id: 78804, year: 2008, vol: 177, page: 301, stat: Journal Article,

Gene expression profiles of bronchoalveolar cells in pulmonary TB
Raju, Bindu; Hoshino, Yoshihiko; Belitskaya-Levy, Ilana; Dawson, Rod; Ress, Stanley; Gold, Jeffrey A; Condos, Rany; Pine, Richard; Brown, Stuart; Nolan, Anna; Rom, William N; Weiden, Michael D
2008 Jan;88(1):39-51, Tuberculosis (Edinburgh, Scotland)
The host response to Mycobacterium tuberculosis includes macrophage activation, inflammation with increased immune effector cells, tissue necrosis, and cavity formation, and fibrosis, distortion, and bronchiectasis. To evaluate the molecular basis of the immune response in the lungs of patients with active pulmonary tuberculosis (TB), we used bronchoalveolar lavage to obtain cells at the site of infection. Affymetrix GeneChip microarrays and cDNA nylon filter microarrays interrogated gene expression in bronchoalveolar lavage (BAL) cells from 11 healthy controls and 17 patients with active pulmonary TB. We found altered gene expression for 69 genes in TB versus normal controls that included cell surface markers, cytokines, chemokines, receptors, transcription factors, and complement components. In addition, TB BAL cell gene expression patterns segregated into 2 groups: one suggestive of a T helper type 1 (Th1) cellular immune response with increased signal transducer and activator of transcription-4 (STAT-4), interferon-gamma (IFN-gamma receptor), and monokine induced by IFN-gamma (MIG) expression with increased IFN-gamma protein levels in BAL fluid; the other group displayed characteristics of Th2 immunity with increased STAT-6, CD81, and IL-10 receptor expression. We were able to demonstrate that a Th2 presentation could change to a Th1 pattern after anti-tuberculous treatment in 1 TB patient studied serially. These gene expression data support the conclusion that pulmonary TB produces a global change in the BAL cell transcriptome with manifestations of either Th1 or Th2 immunity
— id: 74211, year: 2008, vol: 88, page: 39, stat: Journal Article,

Effect of highly active antiretroviral therapy on viral burden in the lungs of HIV-infected subjects
Twigg Iii, Homer L; Weiden, Michael; Valentine, Fred; Schnizlein-Bick, Carol T; Bassett, Roland; Zheng, Lu; Wheat, Joseph; Day, Richard B; Rominger, Helen; Collman, Ronald G; Fox, Lawrence; Brizz, Barbara; Dragavon, Joan; Coombs, Robert W; Bucy, R Pat
2008 Jan 1;197(1):109-116, Journal of infectious diseases
BACKGROUND: Human immunodeficiency virus (HIV) is readily detectable in the lungs of infected subjects and leads to an accumulation of CD8(+) lymphocytes in the alveolar space. Although highly active antiretroviral therapy (HAART) is effective in reducing viremia, less is known about its effect on tissue compartments. The AIDS Clinical Trials Group Protocol 723 Team evaluated the effect of HAART on lung viral load and cellular constituents. METHODS: Bronchoalveolar lavage (BAL) fluid and blood were collected before initiation of HAART and again at 4 and 24 weeks after initiation of therapy. The BAL cell differential was determined, lymphocyte phenotyping was performed, and acellular BAL fluid, plasma HIV RNA load, and BAL cell and peripheral blood mononuclear cell HIV RNA and DNA loads were measured. RESULTS: HAART induced a rapid decrease in HIV that was detectable in acellular BAL fluid and a slower decrease in the HIV RNA and DNA loads in BAL cells. HAART was associated with a significant decrease in the absolute number and percentage of CD8(+) alveolar lymphocytes. There was a significant correlation between residual BAL cell DNA at 24 weeks and the absolute number of CD4(+) lymphocytes in the alveolar space. CONCLUSION: HAART is associated with a significant decrease in the pulmonary HIV burden and a return of alveolar cellular constituents to normal
— id: 78802, year: 2008, vol: 197, page: 109, stat: Journal Article,

The CD80/86-CD28 interaction is significant to mortality in murine polymicrobial sepsis
Chitkara N; Ardilles EE; Gold JA; Weiden MD; Nolan A
2007 ;:A443-A443, American journal of respiratory & critical care medicine
— id: 101394, year: 2007, vol: , page: A443, stat: Journal Article,

Treatment with -1 antitrypsin confers protection from mortality in murine polymicrobial sepsis
Chitkara N; Ardilles EE; Gold JA; Weiden MD; Nolan A
2007 ;:A443-A443, American journal of respiratory & critical care medicine
— id: 101395, year: 2007, vol: , page: A443, stat: Journal Article,

Role of combined costimulatory molecule inhibition in sepsis
Gold JA; Nolan AM; Weiden MD
2007 ;:A900-A900, American journal of respiratory & critical care medicine
— id: 101393, year: 2007, vol: , page: A900, stat: Journal Article,

Exogenous interferon-alpha and interferon-gamma increase lethality of murine inhalational anthrax
Gold, Jeffrey A; Hoshino, Yoshihiko; Jones, Marcus B; Hoshino, Satomi; Nolan, Anna; Weiden, Michael D
2007 ;2(1):e736-e736, PLoS ONE
BACKGROUND: Bacillus anthracis, the etiologic agent of inhalational anthrax, is a facultative intracellular pathogen. Despite appropriate antimicrobial therapy, the mortality from inhalational anthrax approaches 45%, underscoring the need for better adjuvant therapies. The variable latency between exposure and development of disease suggests an important role for the host's innate immune response. Type I and Type II Interferons (IFN) are prominent members of the host innate immune response and are required for control of intracellular pathogens. We have previously described a protective role for exogenous Type I and Type II IFNs in attenuating intracellular B.anthracis germination and macrophage cell death in vitro. METHODOLOGY AND PRINCIPAL FINDINGS: We sought to extend these findings in an in vivo model of inhalational anthrax, utilizing the Sterne strain (34F2) of B.anthracis. Mice devoid of STAT1, a component of IFN-alpha and IFN-gamma signaling, had a trend towards increased mortality, bacterial germination and extrapulmonary spread of B.anthracis at 24 hrs. This was associated with impaired IL-6, IL-10 and IL-12 production. However, administration of exogenous IFN-gamma, and to a lesser extent IFN-alpha, at the time of infection, markedly increased lethality. While IFNs were able to reduce the fraction of germinated spores within the lung, they increased both the local and systemic inflammatory response manifest by increases in IL-12 and reductions in IL-10. This was associated with an increase in extrapulmonary dissemination. The mechanism of IFN mediated inflammation appears to be in part due to STAT1 independent signaling. CONCLUSIONS: In conclusion, while endogenous IFNs are essential for control of B.anthracis germination and lethality, administration of exogenous IFNs appear to increase the local inflammatory response, thereby increasing mortality
— id: 73818, year: 2007, vol: 2, page: e736, stat: Journal Article,

Mechanisms of polymorphonuclear neutrophil-mediated induction of HIV-1 replication in macrophages during pulmonary tuberculosis
Hoshino, Yoshihiko; Hoshino, Satomi; Gold, Jeffrey A; Raju, Bindu; Prabhakar, Savita; Pine, Richard; Rom, William N; Nakata, Koh; Weiden, Michael
2007 May 1;195(9):1303-1310, Journal of infectious diseases
BACKGROUND: Pulmonary tuberculosis (TB) can present with polymorphonuclear neutrophil (PMN)-predominant alveolitis. TB accelerates acquired immunodeficiency syndrome by increasing human immunodeficiency virus type 1 (HIV-1) replication and mutation in alveolar macrophages. A 16-kDa CCAAAT/enhancer-binding protein beta (C/EBP beta ) isoform is a strong transcriptional repressor of the HIV long terminal repeat (LTR) in resting alveolar macrophages, leading to latent viral infection; its expression is lost during TB, derepressing the HIV LTR. METHODS: Lung segments were sampled from HIV/Mycobacterium tuberculosis-coinfected patients by means of bronchoalveolar lavage. In vitro coculture experiments defined the mechanism of induction of HIV-1 infection in macrophages by PMNs. RESULTS: Lung segments from patients with PMN-predominant TB had a markedly elevated viral load. Direct contact between activated PMNs and macrophages stimulated HIV-1 replication and LTR transcription and down-regulated inhibitory C/EBP beta . Isolated PMN membranes substituted for PMN contact, derepressing the HIV-1 LTR. The lipid raft fraction of PMN membranes expressed CD40 ligand (CD40L), CD28, and leukocyte function-associated antigen 1 (LFA-1 [i.e., CD11a and CD18]), and PMN activation increased lipid raft expression of CD40L and CD28. Blocking antibodies to CD40L, CD28, and LFA-1 inhibited PMN membrane-mediated HIV-1 LTR derepression. Alternately, cross-linking of macrophage receptors for CD40L, CD28, and LFA-1 (CD40, CD80/86, and intercellular adhesion molecule 1) abolished inhibitory C/EBP beta expression. CONCLUSION: PMN-macrophage contact derepresses the HIV-1 LTR and enhances HIV-1 replication in alveolar macrophages during pulmonary TB. Derepression is mediated through costimulatory molecule signaling.
— id: 72865, year: 2007, vol: 195, page: 1303, stat: Journal Article,

World Trade Center "sarcoid-like" granulomatous pulmonary disease in New York City Fire Department rescue workers
Izbicki, Gabriel; Chavko, Robert; Banauch, Gisela I; Weiden, Michael D; Berger, Kenneth I; Aldrich, Thomas K; Hall, Charles; Kelly, Kerry J; Prezant, David J
2007 May;131(5):1414-1423, Chest
BACKGROUND: Previous reports suggest that sarcoidosis occurs with abnormally high frequency in firefighters. We sought to determine whether exposure to World Trade Center (WTC) 'dust' during the collapse and rescue/recovery effort increased the incidence of sarcoidosis or 'sarcoid-like' granulomatous pulmonary disease (SLGPD). METHODS: During the 5 years after the WTC disaster, enrollees in the Fire Department of New York (FDNY) WTC monitoring and treatment programs who had chest radiograph findings suggestive of sarcoidosis underwent evaluation, including the following: chest CT imaging, pulmonary function, provocative challenge, and biopsy. Annual incidence rates were compared to the 15 years before the WTC disaster. RESULTS: After WTC dust exposure, pathologic evidence consistent with new-onset sarcoidosis was found in 26 patients: all 26 patients had intrathoracic adenopathy, and 6 patients (23%) had extrathoracic disease. Thirteen patients were identified during the first year after WTC dust exposure (incidence rate, 86/100,000), and 13 patients were identified during the next 4 years (average annual incidence rate, 22/100,000; as compared to 15/100,000 during the 15 years before the WTC disaster). Eighteen of 26 patients (69%) had findings consistent with asthma. Eight of 21 patients (38%) agreeing to challenge testing had airway hyperreactivity (AHR), findings not seen in FDNY sarcoidosis patients before the WTC disaster. CONCLUSION: After the WTC disaster, the incidence of sarcoidosis or SLGPD was increased among FDNY rescue workers. This new information about the early onset of WTC-SLGPD and its association with asthma/AHR has important public health consequences for disease prevention, early detection, and treatment following environmental/occupational exposures
— id: 78805, year: 2007, vol: 131, page: 1414, stat: Journal Article,

Integration of HIV-1 caused STAT3-associated B cell lymphoma in an AIDS patient
Katano, Harutaka; Sato, Yuko; Hoshino, Satomi; Tachikawa, Natsuo; Oka, Shinichi; Morishita, Yasuyuki; Ishida, Takaomi; Watanabe, Toshiki; Rom, William N; Mori, Shigeo; Sata, Tetsutaro; Weiden, Michael D; Hoshino, Yoshihiko
2007 Nov-Dec;9(14-15):1581-1589, Microbes & infection
Signal transducer and activator of transcription 3 (STAT3) is a DNA-binding transcription factor activated by multiple cytokines and interferons. High expression of STAT3 has also been implicated in cancer and lymphoma. Here, we show a case of B cell lymphoma in which a defective human immunodeficiency virus 1 (HIV-1) integrated upstream of the first STAT3 coding exon. The lymphoma cells with anaplastic large cell morphology formed multiple nodular lesions in the lung of an acquired immunodeficiency syndrome (AIDS) patient with Kaposi's sarcoma. The provirus had a 5' long terminal repeat (LTR) deletion, but the 3' LTR had stronger promoter activity than the STAT3 promoter in reporter assays. Immunohistochemistry showed increased expression of STAT3 in the nuclei of lymphoma cells. Transfection of STAT3 resulted in transient cell proliferation in primary B cells in vitro. Although this is a very rare case of HIV-1-integrated lymphoma, these data suggest that up-regulation of STAT3 caused by HIV-1 integration resulted in the development of B cell lymphoma in this special case
— id: 78803, year: 2007, vol: 9, page: 1581, stat: Journal Article,

Firefighter's health and health effects of the world trade center collapse
Weiden, Michael; et al
Environmental and occupational medicine Philadelphia : Wolters Kluwer/Lippincott Williams & Wilkins, 2007,
— id: 5363, year: 2007, vol: , page: ?, stat: Chapter,

Macrophage expressed co-stimulatory molecules CD80/86 in murine polymicrobial sepsis
Ardilles EE; Gold JA; Weiden MD; Nolan A
2006 ;:A648-A648, American journal of respiratory & critical care medicine
— id: 101396, year: 2006, vol: , page: A648, stat: Journal Article,

Pulmonary function after exposure to the World Trade Center collapse in the New York City Fire Department
Banauch, Gisela I; Hall, Charles; Weiden, Michael; Cohen, Hillel W; Aldrich, Thomas K; Christodoulou, Vasillios; Arcentales, Nicole; Kelly, Kerry J; Prezant, David J
2006 Aug 1;174(3):312-319, American journal of respiratory & critical care medicine
RATIONALE: On September 11, 2001, the World Trade Center collapse created an enormous urban disaster site with high levels of airborne pollutants. First responders, rescue and recovery workers, and residents have since reported respiratory symptoms and developed pulmonary function abnormalities. OBJECTIVES: To quantify respiratory health effects of World Trade Center exposure in the New York City Fire Department. MEASUREMENTS: Longitudinal study of pulmonary function in 12,079 New York City Fire Department rescue workers employed on or before 09/11/2001. Between 01/01/1997 and 09/11/2002, 31,994 spirometries were obtained and the FEV(1) and FVC were analyzed for differences according to estimated World Trade Center exposure intensity. Adjusted average FEV(1) during the first year after 09/11/2001 was compared with the 5 yr before 09/11/2001. Median time between 09/11/2001 and a worker's first spirometry afterwards was 3 mo; 90% were assessed within 5 mo. MAIN RESULTS: World Trade Center-exposed workers experienced a substantial reduction in adjusted average FEV(1) during the year after 09/11/2001 (372 ml; 95% confidence interval, 364-381 ml; p < 0.001) This exposure-related FEV(1) decrement equaled 12 yr of aging-related FEV(1) decline. Moreover, exposure intensity assessed by initial arrival time at the World Trade Center site correlated linearly with FEV(1) reduction in an exposure intensity-response gradient (p = 0.048). Respiratory symptoms also predicted a further FEV(1) decrease (p < 0.001). Similar findings were observed for adjusted average FVC. CONCLUSIONS: World Trade Center exposure produced a substantial reduction in pulmonary function in New York City Fire Department rescue workers during the first year after 09/11/2001
— id: 69398, year: 2006, vol: 174, page: 312, stat: Journal Article,

Blockade of CD80/86 improves survival in a murine model of polymicrobial sepsis
Gold JA; Nolan A; Mehta NL; Weiden MD
2006 ;:A644-A644, American journal of respiratory & critical care medicine
— id: 101397, year: 2006, vol: , page: A644, stat: Journal Article,

Bronchial hyperreactivity and other inhalation lung injuries in rescue/recovery workers after the World Trade Center collapse
Banauch, Gisela I; Dhala, Atiya; Alleyne, Dawn; Alva, Rakesh; Santhyadka, Ganesha; Krasko, Anatoli; Weiden, Michael; Kelly, Kerry J; Prezant, David J
2005 Jan;33(1 Suppl):S102-S106, Critical care medicine
BACKGROUND: The collapse of the World Trade Center (WTC) on September 11, 2001 created a large-scale disaster site in a dense urban environment. In the days and months thereafter, thousands of rescue/recovery workers, volunteers, and residents were exposed to a complex mixture of airborne pollutants. METHODS: We review current knowledge of aerodigestive inhalation lung injuries resulting from this complex exposure and present new data on the persistence of nonspecific bronchial hyperreactivity (methacholine PC20 < or =8 mg/mL) in a representative sample of 179 Fire Department of the City of New York (FDNY) rescue workers stratified by exposure intensity (according to arrival time) who underwent challenge testing at 1, 3, 6, and 12 months post-collapse. RESULTS: Aerodigestive tract inflammatory injuries, such as declines in pulmonary function, reactive airways dysfunction syndrome (RADS), asthma, reactive upper airways dysfunction syndrome (RUDS), gastroesophageal reflux disease (GERD), and rare cases of inflammatory pulmonary parenchymal diseases, have been documented in WTC rescue/recovery workers and volunteers. In FDNY rescue workers, we found persistent hyperreactivity associated with exposure intensity, independent of airflow obstruction. One year post-collapse, 23% of highly exposed subjects were hyperreactive as compared with only 11% of moderately exposed and 4% of controls. At 1 yr, 16% met the criteria for RADS. CONCLUSIONS: While it is too early to ascertain all of the long-term effects of WTC exposures, continued medical monitoring and treatment is needed to help those exposed and to improve our prevention, diagnosis, and treatment protocols for future disasters
— id: 69399, year: 2005, vol: 33, page: S102, stat: Journal Article,

Role of macrophage costimulatory molecules in human sepsis
Mehta NL; Shih P; Nolan A; Weiden MD; Hoshino Y; Gold JA
2005 ;:A522-A522, American journal of respiratory & critical care medicine
— id: 101399, year: 2005, vol: , page: A522, stat: Journal Article,

Interleukin-10 induces inhibitory C/EBPbeta through STAT-3 and represses HIV-1 transcription in macrophages
Tanaka, Naohiko; Hoshino, Yoshihiko; Gold, Jeffrey; Hoshino, Satomi; Martiniuk, Frank; Kurata, Takeshi; Pine, Richard; Levy, David; Rom, William N; Weiden, Michael
2005 Oct;33(4):406-411, American journal of respiratory cell & molecular biology
Pulmonary tuberculosis (TB) has been characterized by inflammation with increased pro- or anti-inflammatory cytokines produced by macrophages. We have reported that IFN produces inhibitory C/EBPbeta and represses transcription of the HIV-1 LTR in macrophages. STAT-1 and type I IFN receptor knockout mice have macrophages that are defective in IFN signaling, yet LPS stimulation induces inhibitory C/EBPbeta, demonstrating that other cytokines can induce this repressor. LPS or Mycobacterium tuberculosis-derived lipoarabinomannan induce the anti-inflammatory cytokine interleukin (IL)-10, which represses the HIV-1 LTR in differentiated THP-1 macrophages by inducing inhibitory C/EBPbeta. In contrast, in undifferentiated THP-1 monocytes, IL-10 did not inhibit HIV-1 replication or induce C/EBPbeta. IL-10 signal transduction uses STAT-3, and macrophages from STAT-3-/- mice fail to produce inhibitory C/EBPbeta after LPS or IL-10 stimulation. Transfection of STAT-3 into THP-1 cells enhances C/EBPbeta promoter activity. THP-1 differentiation also increases STAT-3 protein, but not STAT-3 gene transcription, and induces a translational regulator, CUG-binding protein, that was essential for production of C/EBPbeta. Differentiation induced post-transcriptional regulation is required to produce inhibitory C/EBPbeta in response to IL-10. Only macrophages are able to repress HIV-1 LTR promoter activity and inhibit viral replication in response to IL-10 or type I IFN
— id: 58745, year: 2005, vol: 33, page: 406, stat: Journal Article,

Induced sputum assessment in New York City firefighters exposed to World Trade Center dust
Fireman, Elizabeth M; Lerman, Yehuda; Ganor, Eliezer; Greif, Joel; Fireman-Shoresh, Sharon; Lioy, Paul J; Banauch, Gisela I; Weiden, Michael; Kelly, Kerry J; Prezant, David J
2004 Nov;112(15):1564-1569, Environmental health perspectives
New York City Firefighters (FDNY-FFs) were exposed to particulate matter and combustion/pyrolysis products during and after the World Trade Center (WTC) collapse. Ten months after the collapse, induced sputum (IS) samples were obtained from 39 highly exposed FDNY-FFs (caught in the dust cloud during the collapse on 11 September 2001) and compared to controls to determine whether a unique pattern of inflammation and particulate matter deposition, compatible with WTC dust, was present. Control subjects were 12 Tel-Aviv, Israel, firefighters (TA-FFs) and 8 Israeli healthcare workers who were not exposed to WTC dust. All controls volunteered for this study, had never smoked, and did not have respiratory illness. IS was processed by conventional methods. Retrieved cells were differentially counted, and metalloproteinase-9 (MMP-9), particle size distribution (PSD), and mineral composition were measured. Differential cell counts of FDNY-FF IS differed from those of health care worker controls (p < 0.05) but not from those of TA-FFs. Percentages of neutrophils and eosinophils increased with greater intensity of WTC exposure (< 10 workdays or greater than or equal to 10 workdays; neutrophils p = 0.046; eosinophils p = 0.038). MMP-9 levels positively correlated to neutrophil counts (p = 0.002; r = 0.449). Particles were larger and more irregularly shaped in FDNY-FFs (1-50 microm; zinc, mercury, gold, tin, silver) than in TA-FFs (1-10 microm; silica, clays). PSD was similar to that of WTC dust samples. In conclusion, IS from highly exposed FDNY-FFs demonstrated inflammation, PSD, and particle composition that was different from nonexposed controls and consistent with WTC dust exposure
— id: 69400, year: 2004, vol: 112, page: 1564, stat: Journal Article,

Role of interferons in an in vivo model of inhalational anthrax
Gold JA; Jones MB; Levy DE; Hoshino Y; Nolan A; Weiden MD
2004 ;169:A230-A230, American journal of respiratory & critical care medicine
— id: 101401, year: 2004, vol: 169, page: A230, stat: Journal Article,

Exogenous gamma and alpha/beta interferon rescues human macrophages from cell death induced by Bacillus anthracis
Gold, Jeffrey A; Hoshino, Yoshihiko; Hoshino, Satomi; Jones, Marcus B; Nolan, Anna; Weiden, Michael D
2004 Mar;72(3):1291-1297, Infection & immunity
During the recent bioterrorism-related outbreaks, inhalational anthrax had a 45% mortality in spite of appropriate antimicrobial therapy, underscoring the need for better adjuvant therapies. The variable latency between exposure and development of disease suggests an important role for the host's innate immune response. Alveolar macrophages are likely the first immune cells exposed to inhalational anthrax, and the interferon (IFN) response of these cells comprises an important arm of the host innate immune response to intracellular infection with Bacillus anthracis. Furthermore, IFNs have been used as immunoadjuvants for treatment of another intracellular pathogen, Mycobacterium tuberculosis. We established a model of B. anthracis infection with the Sterne strain (34F(2)) which contains lethal toxin (LeTx). 34F(2) was lethal to murine and human macrophages. Treatment with IFNs significantly improved cell viability and reduced the number of germinated intracellular spores. Infection with 34F(2) failed to induce the latent transcription factors signal transducer and activators of transcription 1 (STAT1) and ISGF-3, which are central to the IFN response. Furthermore, 34F(2) reduced STAT1 activation in response to exogenous alpha/beta IFN, suggesting direct inhibition of IFN signaling. Even though 34F(2) has LeTx, there was no mitogen-activated protein kinase kinase 3 cleavage and p38 was normally induced, suggesting that these early effects of B. anthracis infection in macrophages are independent of LeTx. These data suggest an important role for both IFNs in the control of B. anthracis and the potential benefit of using exogenous IFN as an immunoadjuvant therapy
— id: 42240, year: 2004, vol: 72, page: 1291, stat: Journal Article,

Surfactant protein A modulates the inflammatory response in macrophages during tuberculosis
Gold, Jeffrey A; Hoshino, Yoshihiko; Tanaka, Naohiko; Rom, William N; Raju, Bindu; Condos, Rany; Weiden, Michael D
2004 Feb;72(2):645-650, Infection & immunity
Tuberculosis leads to immune activation and increased human immunodeficiency virus type 1 (HIV-1) replication in the lung. However, in vitro models of mycobacterial infection of human macrophages do not fully reproduce these in vivo observations, suggesting that there are additional host factors. Surfactant protein A (SP-A) is an important mediator of innate immunity in the lung. SP-A levels were assayed in the human lung by using bronchoalveolar lavage (BAL). There was a threefold reduction in SP-A levels during tuberculosis only in the radiographically involved lung segments, and the levels returned to normal after 1 month of treatment. The SP-A levels were inversely correlated with the percentage of neutrophils in BAL fluid, suggesting that low SP-A levels were associated with increased inflammation in the lung. Differentiated THP-1 macrophages were used to test the effect of decreasing SP-A levels on immune function. In the absence of infection with Mycobacterium tuberculosis, SP-A at doses ranging from 5 to 0.01 micro g/ml inhibited both interleukin-6 (IL-6) production and HIV-1 long terminal repeat (LTR) activity. In macrophages infected with M. tuberculosis, SP-A augmented both IL-6 production and HIV-1 LTR activity. To better understand the effect of SP-A, we measured expression of CAAT/enhancer binding protein beta (C/EBPbeta), a transcription factor central to the regulation of IL-6 and the HIV-1 LTR. In macrophages infected with M. tuberculosis, SP-A reduced expression of a dominant negative isoform of C/EBPbeta. These data suggest that SP-A has pleiotropic effects even at the low concentrations found in tuberculosis patients. This protein augments inflammation in the presence of infection and inhibits inflammation in uninfected macrophages, protecting uninvolved lung segments from the deleterious effects of inflammation
— id: 42242, year: 2004, vol: 72, page: 645, stat: Journal Article,

Molecular mechanisms of human immunodeficiency virus/tuberculosis interaction in the lung
Hoshino Y; Raju B; Weiden M
Tuberculosis Philadelphia : Lippincott Williams & Wilkins, 2004,
— id: 3966, year: 2004, vol: , page: 301, stat: Chapter,

Mycobacterium tuberculosis-induced CXCR4 and chemokine expression leads to preferential X4 HIV-1 replication in human macrophages
Hoshino, Yoshihiko; Tse, Doris B; Rochford, Gemma; Prabhakar, Savita; Hoshino, Satomi; Chitkara, Nishay; Kuwabara, Kenichi; Ching, Elbert; Raju, Bindu; Gold, Jeffrey A; Borkowsky, William; Rom, William N; Pine, Richard; Weiden, Michael
2004 May 15;172(10):6251-6258, Journal of immunology
Opportunistic infections such as pulmonary tuberculosis (TB) increase local HIV-1 replication and mutation. As AIDS progresses, alteration of the HIV-1 gp120 V3 sequence is associated with a shift in viral coreceptor use from CCR5 (CD195) to CXCR4 (CD184). To better understand the effect of HIV/TB coinfection, we screened transcripts from bronchoalveolar lavage cells with high density cDNA arrays and found that CXCR4 mRNA is increased in patients with TB. Surprisingly, CXCR4 was predominately expressed on alveolar macrophages (AM). Mycobacterium tuberculosis infection of macrophages in vitro increased CXCR4 surface expression, whereas amelioration of disease reduced CXCR4 expression in vivo. Bronchoalveolar lavage fluid from TB patients had elevated levels of CCL4 (macrophage inflammatory protein-1beta), CCL5 (RANTES), and CX3CL1 (fractalkine), but not CXCL12 (stromal-derived factor-1alpha). We found that M. tuberculosis infection of macrophages in vitro increased viral entry and RT of CXCR4, using HIV-1, but not of CCR5, using HIV-1. Lastly, HIV-1 derived from the lung contains CD14, suggesting that they were produced in AM. Our results demonstrate that TB produces a permissive environment for replication of CXCR4-using virus by increasing CXCR4 expression in AM and for suppression of CCR5-using HIV-1 by increasing CC chemokine expression. These changes explain in part why TB accelerates the course of AIDS. CXCR4 inhibitors are a rational therapeutic approach in HIV/TB coinfection
— id: 42732, year: 2004, vol: 172, page: 6251, stat: Journal Article,

BCL-6 mutations in pulmonary lymphoproliferative disorders: demonstration of an aberrant immunological reaction in HIV-related lymphoid interstitial pneumonia
Kurosu, Katsushi; Weiden, Michael D; Takiguchi, Yuichi; Rom, William N; Yumoto, Norio; Jaishree, Jagirdar; Nakata, Koh; Kasahara, Yasunori; Tanabe, Nobuhiro; Tatsumi, Koichiro; Mikata, Atsuo; Kuriyama, Takayuki
2004 Jun 1;172(11):7116-7122, Journal of immunology
We used a PCR and sequence procedure to analyze the Ig V(H) gene and the mutations in the 5' regulatory regions of BCL-6 genes in pulmonary lymphoproliferative disorders (mucosa-associated lymphoid tissue (MALT) lymphoma, HIV-related, EBV-related, and virus-negative lymphocytic interstitial pneumonia (LIP)). Eight of 20 (40%) pulmonary MALT lymphoma and 10 of 20 LIP (5 of 5 (100%) HIV-related, 2 of 5 (40%) EBV-related, and 3 of 10 (30%) virus-negative LIP) cases showed BCL-6 gene mutations. Intraclonal heterogeneity of the BCL-6 mutations was observed only in pulmonary MALT lymphoma cases whose Ig V(H) genes also showed intraclonal heterogeneity. Ongoing BCL-6 mutations might reflect re-entry into a germinal center pathway to further mutations. BCL-6 mutations in pulmonary MALT lymphoma and HIV-negative LIP showed some features (high transition to transversion ratio, standard polarity, and RGYW/WRCY bias) of Ig V(H) gene hypermutation, leading to the view that pulmonary MALT lymphomas and HIV-negative LIP are under the influence of germinal center hypermutation mechanisms. Because BCL-6 mutations in HIV-related LIP cases did not demonstrate features of Ig V(H) gene hypermutation, immunological reactions in HIV-related LIP are the result of a process different from that found in HIV-negative pulmonary lymphoproliferative disorders
— id: 42731, year: 2004, vol: 172, page: 7116, stat: Journal Article,

[Molecular pathogenesis in tuberculosis complicated with AIDS]
Nakata, Koh; Hoshino, Yoshihiko; Honda, Yoshihiro; Tanaka, Naohiko; Hebisawa, Akira; Weiden, Michael
2004 Nov;79(11):659-667, Kekkaku : [Tuberculosis]
HIV-1 infection is a major cause of worldwide epidemic of tuberculosis. There is increasing clinical evidence that coinfection with M. tuberculosis accelerates progression of AIDS. We found that, in vivo, HIV-1 load and mutation increase in involved lung segments in patients with pulmonary tuberculosis. We also reported that Mycobacterium tuberculosis stimulates HIV-1 replication by enhancing transcription on the 5' LTR in a macrophage cell line, THP-1, in vitro. In contrast, HIV-1 replication is suppressed by M. tuberculosis infection of monocytes derived macrophages (MDM) or differentiated monocytic THP-1 cells. We observed that HIV-1 5' LTR function was repressed in PMA differentiated THP-1 cells after co-infection with M. tuberculosis. Point mutations in C/EBP beta binding domains of the HIV-1 LTR negative regulatory element (NRE) abolished promoter repression. Monocyte-derived macrophages and differentiated THP-1 cells increased expression of the 16kDa inhibitory form of C/EBP after M. tuberculosis co-infection. Bronchoalveolar lavage cells obtained from normal controls and alveolar macrophages from uninflamed lung of tuberculosis patients also expressed the 16kDa inhibitory form of C/EBP. However, alveolar macrophages from lung segments involved with pulmonary tuberculosis had markedly reduced C/EBP expression. These data suggest that 16kDa isoform of C/EBP plays an important role for the control of HIV-1 replication in macrophages. We propose derepression of HIV-1 LTR mediated transcription as one mechanism for enhanced HIV-1 replication observed in pulmonary tuberculosis. Since the cellular immune response in pulmonary tuberculosis requires lymphocyte/macrophage interaction, a model system was developed in which lymphocytes were added to AM. Contact between lymphocytes and AM reduced inhibitory C/EBP beta, activated NF-kappaB and enhanced HIV-1 replication. If contact between lymphocytes and macrophages was prevented, inhibitory C/EBP beta expression was maintained and the HIV-1 long terminal repeat (LTR) was not maximally stimulated although NF-kappaB was activated. Antibodies which cross-linked macrophage expressed B-7, VCAM and CD-40 were used mimic lymphocyte contact. Cross-linking antibodies abolished inhibitory C/EBP beta expression; however, the HIV-1 LTR was not maximally stimulated and NF-kappaB was not activated. Maximal HIV-1 LTR stimulation required both lymphocyte derived soluble factors and cross-linking of macrophage expressed co-stimulatory molecules. These results demonstrate that neither contact nor soluble factor(s) are sufficient to maximally enhance HIV-1 LTR activity in macrophages. Contact between activated lymphocytes and macrophages is necessary to downregulate inhibitory C/EBP beta, thereby derepressing the HIV-1 LTR. Lymphocyte derived soluble factor(s) activate NF-kappaB, further enhancing the HIV-1 LTR
— id: 78806, year: 2004, vol: 79, page: 659, stat: Journal Article,

Vascular endothelial growth factor blockade reduces serum cytokines in a murine model of polymicrobial sepsis
Nolan A; Thurston G; Weiden MD; Gold JA
2004 ;169:A118-A118, American journal of respiratory & critical care medicine
— id: 101400, year: 2004, vol: 169, page: A118, stat: Journal Article,

Cd40 but not CD154 knockout mice have reduced inflammatory response in polymicrobial sepsis: a potential role for Escherichia coli heat shock protein 70 in CD40-mediated inflammation in vivo
Nolan, Anna; Weiden, Michael D; Hoshino, Yoshihiko; Gold, Jeffrey A
2004 Dec;22(6):538-542, Shock
The CD40-CD154 system controls various aspects of the host inflammatory response in models of cellular and humoral immunity. Recently, we described a role for CD40 in the innate immune response in polymicrobial sepsis. However, recent data suggests that CD40 maybe activated by CD154 or directly via bacterial heat shock protein (HSP) 70. Therefore, we decided to test the mechanism of CD40 activation in murine polymicrobial sepsis. Wild-type (WT), CD40, and CD154 underwent cecal ligation and puncture (CLP). Compared with WT mice, CD40 had improved survival in association with attenuated production of IL-12, TNF-alpha, and IL-6. In contrast, CD154 mice behaved similar to WT mice with regard to mortality and cytokine production. The differential response of CD40 and CD154 mice to CLP was not due to a general attenuated response to inflammatory stimuli, as all three strains had similar survival after LPS administration, and CD40 macrophages had normal production of IL-12 in response to lipopolysaccharide. In contrast, CD40 macrophages had attenuated IL-12 production in response to Escherichia coli HSP70 (DnaK). Furthermore, intraperitoneal administration of DnaK resulted in a 4-fold increase in IL-12 in WT mice, which was absent in CD40 mice. This data demonstrates CD154-independent CD40 activation in polymicrobial sepsis and suggests that bacterial HSP70 is capable of stimulating CD40 in vitro and in vivo
— id: 55783, year: 2004, vol: 22, page: 538, stat: Journal Article,

Vascular endothelial growth factor blockade reduces plasma cytokines in a murine model of polymicrobial sepsis
Nolan, Anna; Weiden, Michael D; Thurston, Gavin; Gold, Jeffrey A
2004 Oct;28(5):271-278, Inflammation
Numerous cytokines, including vascular endothelial growth factor (VEGF), are implicated in the pathogenesis of sepsis. While overexpression of VEGF produces pulmonary capillary leak, the role of VEGF in sepsis is less clear. We investigated VEGF in sepsis, utilizing a VEGF trap (VEGF(T)). Polymicrobial sepsis was induced in C57BL/6 mice by cecal ligation and puncture (CLP) and resulted in significantly increased plasma VEGF levels (234 vs. 46 pg/mL; p = 0.03). Inhibition of VEGF had no effect on mortality or lung leak but did attenuate plasma IL-6 (120 vs. 236 ng/mL; p = 0.02) and IL-10 (16 vs. 41 ng/mL; p = 0.03). These alterations in inflammatory cytokines were associated with increased levels of the dominant negative inhibitory C/EBPbeta. In vitro, VEGF stimulated IL-6, IL-10 and reduced the inhibitory isoform of C/EBPbeta in cultured macrophages. Together these data suggest VEGF can regulate inflammatory cytokine production in murine polymicrobial sepsis, via regulation of C/EBPbeta
— id: 58737, year: 2004, vol: 28, page: 271, stat: Journal Article,

Posttranscriptional inhibition of gene expression by Mycobacterium tuberculosis offsets transcriptional synergism with IFN-gamma and posttranscriptional up-regulation by IFN-gamma
Qiao, Yaming; Prabhakar, Savita; Canova, Antony; Hoshino, Yoshihiko; Weiden, Michael; Pine, Richard
2004 Mar 1;172(5):2935-2943, Journal of immunology
Host defense against Mycobacterium tuberculosis requires the cytokine IFN-gamma and IFN regulatory factor 1 (IRF-1), a transcription factor that is induced to high levels by IFN-gamma. Therefore, we chose to study regulation of IRF-1 expression as a model for effects of M. tuberculosis on response to IFN-gamma. We found that IRF-1 mRNA abundance increased far more than transcription rate in human monocytic THP-1 cells stimulated by IFN-gamma, but less than transcription rate in cells infected by M. tuberculosis. IFN-gamma stimulation of infected cells caused a synergistic increase in IRF-1 transcription, yet IRF-1 mRNA abundance was similar in uninfected and infected cells stimulated by IFN-gamma, as was the IRF-1 protein level. Comparable infection by Mycobacterium bovis bacillus Calmette-Guerin failed to induce IRF-1 expression and had no effect on the response to IFN-gamma. We also examined the kinetics of transcription, the mRNA t(1/2), and the distribution of IRF-1 transcripts among total nuclear RNA, poly(A) nuclear RNA, and poly(A) cytoplasmic RNA pools in cells that were infected by M. tuberculosis and/or stimulated by IFN-gamma. Our data suggest that infection by M. tuberculosis inhibits RNA export from the nucleus. Moreover, the results indicate that regulated entry of nascent transcripts into the pool of total nuclear RNA affects IRF-1 expression and that this process is stimulated by IFN-gamma and inhibited by M. tuberculosis. The ability of infection by M. tuberculosis to limit the increase in IRF-1 mRNA expression that typically follows transcriptional synergism may contribute to the pathogenicity of M. tuberculosis
— id: 42259, year: 2004, vol: 172, page: 2935, stat: Journal Article,

Aerosolized gamma interferon (IFN-gamma) induces expression of the genes encoding the IFN-gamma-inducible 10-kilodalton protein but not inducible nitric oxide synthase in the lung during tuberculosis
Raju, Bindu; Hoshino, Yoshihiko; Kuwabara, Kenichi; Belitskaya, Ilana; Prabhakar, Savita; Canova, Antony; Gold, Jeffrey A; Condos, Rany; Pine, Richard I; Brown, Stuart; Rom, William N; Weiden, Michael D
2004 Mar;72(3):1275-1283, Infection & immunity
Gamma interferon (IFN-gamma) is critical in the immune response against Mycobacterium tuberculosis. In an ongoing trial of aerosol IFN-gamma in conjunction with standard drug therapy, we have observed activation of IFN signaling in bronchoalveolar lavage (BAL) cells from tuberculosis (TB) patients. We hypothesized that aerosol IFN-gamma treatment of pulmonary TB would increase expression of genes important for the control of TB. We investigated the expression of downstream genes by measuring inducible nitric oxide synthase (iNOS) and the chemokine IFN-inducible 10-kDa protein (IP-10) by real-time quantitative reverse transcription-PCR. In vitro, M. tuberculosis induced IP-10, and IFN-gamma stimulated this further, with no effect on iNOS expression. We studied 21 patients with pulmonary TB and 7 healthy subjects. Similar to the in vitro model, IP-10 mRNA was increased in BAL cells from TB patients and was augmented after treatment with aerosolized IFN-gamma. TB was also associated with elevated iNOS mRNA, but aerosolized IFN-gamma did not further enhance expression. Genomic analysis identified 1,300 of 4,058 genes expressed in BAL cells from six TB patients before and after 1 month of therapy, including aerosolized IFN-gamma. However, only 15 genes were differentially regulated by IFN-gamma. We conclude that iNOS and IP-10 mRNA expression is increased in TB but that aerosol IFN-gamma treatment increases expression of few genes in the human lung
— id: 42241, year: 2004, vol: 72, page: 1275, stat: Journal Article,

Role of CD 40 ligand in early sepsis
Shih PH; Nolan A; Tse D; Doshi AM; Weiden MD; Gold JA
2004 ;169:A635-A635, American journal of respiratory & critical care medicine
— id: 101402, year: 2004, vol: 169, page: A635, stat: Journal Article,

Persistent hyperreactivity and reactive airway dysfunction in firefighters at the World Trade Center
Banauch, Gisela I; Alleyne, Dawn; Sanchez, Raoul; Olender, Kattia; Cohen, Hillel W; Weiden, Michael; Kelly, Kerry J; Prezant, David J
2003 Jul 1;168(1):54-62, American journal of respiratory & critical care medicine
New York City Fire Department rescue workers experienced massive exposure to airborne particulates at the World Trade Center site. Aims of this longitudinal study were to (1) determine if bronchial hyperreactivity was present, persistent, and independently associated with exposure intensity, (2) identify objective measures shortly after the collapse that would predict persistent hyperreactivity and a diagnosis of reactive airways dysfunction 6 months post-collapse. A representative sample of 179 rescue workers stratified by exposure intensity (high, moderate, and control) without current smoking or prior respiratory disease was enrolled. Highly exposed workers arrived within 2 hours of collapse, moderately exposed workers arrived later on Days 1-2; control subjects were not exposed. Hyperreactivity at 1, 3, and 6 months post-collapse was associated with exposure intensity, independent of ex-smoking and airflow obstruction. Six months post-collapse, highly exposed workers were 6.8 times more likely than moderately exposed workers and control subjects to be hyperreactive (95% confidence interval, 1.8-25.2; p = 0.004), and hyperreactivity persisted in 55% of those hyperreactive at 1 and/or 3 months. In highly exposed subjects, hyperreactivity 1 or 3 months post-collapse was the sole predictor for reactive airways dysfunction (p = 0.021). In conclusion, development and persistence of hyperreactivity and reactive airways dysfunction were strongly and independently associated with exposure intensity. Hyperreactivity shortly post-collapse predicted reactive airways dysfunction at 6 months in highly exposed workers; this has important implications for disaster management
— id: 42261, year: 2003, vol: 168, page: 54, stat: Journal Article,

Recombinant gamma interferon stimulates signal transduction and gene expression in alveolar macrophages in vitro and in tuberculosis patients
Condos, Rany; Raju, Bindu; Canova, Antony; Zhao, Ben-Yang; Weiden, Michael; Rom, William N; Pine, Richard
2003 Apr;71(4):2058-2064, Infection & immunity
Tuberculosis is the seventh leading cause of morbidity and mortality in the world, with eight million cases per year. Animal and human studies demonstrate an enrichment of CD4 cells at sites of disease, with a more favorable clinical course when there is a Th1 response with the presence of gamma interferon (IFN-gamma). We previously treated patients who had multidrug-resistant tuberculosis with recombinant IFN-gamma (rIFN-gamma) in aerosol form and were able to convert smear-positive cases to smear negative with 12 treatments over 1 month. We hypothesized that rIFN-gamma would induce signal transducer and activator of transcription (STAT) and interferon regulatory factor (IRF) binding activity in alveolar macrophages (AM). AM treated in vitro showed clear upregulation of STAT-1 and IRF-1 by rIFN-gamma. STAT-1 was not activated and IRF-1 was only weakly induced after 1 day of infection by Mycobacterium tuberculosis TN913. In bronchoalveolar lavage (BAL) cells obtained from 10 of 10 tuberculosis patients 10 +/- 2 days post-antituberculosis treatment, there was no detectable STAT-1 or IRF-1 DNA-binding activity. After 4 weeks of treatment with rIFN-gamma aerosol in addition to the antituberculosis drugs, 10 of 10 patients had increased STAT-1, IRF-1, and/or IRF-9 DNA-binding activity in BAL cells from lung segments shown radiographically to be involved and in those shown to be uninvolved. Symptoms and chest radiographs improved, and amounts of macrophage inflammatory cytokines and human immunodeficiency virus type 1 (HIV-1) viral loads (in five of five HIV-1-coinfected patients) declined in the second BAL specimens. rIFN-gamma aerosol induces signal transduction and gene expression in BAL cells and should be evaluated for efficacy in a randomized, controlled clinical trial
— id: 44958, year: 2003, vol: 71, page: 2058, stat: Journal Article,

CD40 contributes to lethality in acute sepsis: in vivo role for CD40 in innate immunity
Gold, Jeffrey A; Parsey, Merdad; Hoshino, Yoshihiko; Hoshino, Satomi; Nolan, Anna; Yee, Herman; Tse, Doris B; Weiden, Michael D
2003 Jun;71(6):3521-3528, Infection & immunity
Sepsis induces an early inflammatory cascade initiated by the innate immune response. This often results in the development of multisystem organ failure. We examined the role of CD40, a costimulatory molecule that is integral in adaptive immunity, by using a murine model of polymicrobial sepsis. CD40 knockout (KO) mice had delayed death and improved survival after cecal ligation and puncture (CLP). In addition, they had less remote organ injury as manifested by reduced pulmonary capillary leakage. The improvements in survival and remote organ dysfunction in CD40 KO mice were associated with reduced interleukin-6 (IL-6) and IL-10 levels in serum and bronchoalveolar lavage fluid compared to the levels in wild-type (WT) controls. Furthermore, in contrast to WT mice, CD40 KO mice had no induction of the Th1 cytokines IL-12 and gamma interferon in serum or lungs after CLP. The alterations in cytokine production in CD40 KO mice were associated with similar changes in transcription factor activity. After CLP, CD40 KO mice had attenuated activation of nuclear factor kappaB and signal transducer and activator of transcription 3 in both the lung and the liver. Finally, WT mice had increased expression of CD40 on their alveolar macrophages. These data highlight the importance of CD40 activation in the innate immune response during polymicrobial sepsis and the subsequent development of remote organ dysfunction
— id: 39222, year: 2003, vol: 71, page: 3521, stat: Journal Article,

CD40 is integral to the innate immune response during polymicrobial sepsis
Nolan A; Parsey M; Hoshino Y; Yee H; Tse DT; Weiden MD; Gold JA
2003 ;167:A556-A556, American journal of respiratory & critical care medicine
— id: 101404, year: 2003, vol: 167, page: A556, stat: Journal Article,

Inhibition of response to alpha interferon by Mycobacterium tuberculosis
Prabhakar, Savita; Qiao, Yaming; Hoshino, Yoshihiko; Weiden, Michael; Canova, Antony; Giacomini, Elena; Coccia, Eliana; Pine, Richard
2003 May;71(5):2487-2497, Infection & immunity
We previously reported that infection by Mycobacterium tuberculosis, the causative agent of tuberculosis, leads to secretion of alpha/beta interferon (IFN-alpha/beta). While IFN-alpha/beta ordinarily stimulates formation of signal transducer and stimulator of transcription-1 (STAT-1) homodimers and IFN-stimulated gene factor-3 (ISGF-3), only ISGF-3 is found in infected human monocytes and macrophages. We have now investigated the basis for this unusual profile of transcription factor activation and its consequences for regulation of transcription, as well as the impact of infection on response to IFN-alpha. After infection, IFN-alpha stimulation of STAT-1 homodimers is inhibited in monocytes and macrophages, while stimulation of ISGF-3 increases in monocytes but tends to decline in macrophages. Effects of infection on the abundance of ISGF-3 subunits, STAT-1, STAT-2, and interferon regulatory factor 9, and on tyrosine phosphorylation of STAT-1 and STAT-2 explain the observed changes in DNA-binding activity, which correlate with increased or inhibited transcription of genes regulated by ISGF-3 and STAT-1. Infection by Mycobacterium bovis BCG does not inhibit IFN-alpha-stimulated tyrosine phosphorylation of STAT-1, formation of homodimers, or transcription of genes regulated by STAT-1 homodimers, suggesting that inhibition of the response to IFN-alpha/beta by M. tuberculosis is an aspect of pathogenicity. Thus, this well-known feature of infection by pathogenic viruses may also be a strategy employed by pathogenic bacteria
— id: 42260, year: 2003, vol: 71, page: 2487, stat: Journal Article,

Maximal HIV-1 replication in alveolar macrophages during tuberculosis requires both lymphocyte contact and cytokines
Hoshino, Yoshihiko; Nakata, Koh; Hoshino, Satomi; Honda, Yoshihiro; Tse, Doris B; Shioda, Tatsuo; Rom, William N; Weiden, Michael
2002 Feb 18;195(4):495-505, Journal of experimental medicine
HIV-1 replication is markedly upregulated in alveolar macrophages (AM) during pulmonary tuberculosis (TB). This is associated with loss of an inhibitory CCAAT enhancer binding protein beta (C/EBPbeta) transcription factor and activation of nuclear factor (NF)-kappaB. Since the cellular immune response in pulmonary TB requires lymphocyte--macrophage interaction, a model system was developed in which lymphocytes were added to AM. Contact between lymphocytes and AM reduced inhibitory C/EBPbeta, activated NF-kappaB, and enhanced HIV-1 replication. If contact between lymphocytes and macrophages was prevented, inhibitory C/EBPbeta expression was maintained and the HIV-1 long terminal repeat (LTR) was not maximally stimulated although NF-kappaB was activated. Antibodies that cross-linked macrophage expressed B-7, and vascular cell adhesion molecule and CD40 were used to mimic lymphocyte contact. All three cross-linking antibodies were required to abolish inhibitory C/EBPbeta expression. However, the HIV-1 LTR was not maximally stimulated and NF-kappaB was not activated. Maximal HIV-1--LTR stimulation required both lymphocyte-derived soluble factors, and cross-linking of macrophage expressed costimulatory molecules. High level HIV-1--LTR stimulation was also achieved when IL-1beta, IL-6, and TNF-beta were added to macrophages with cross-linked costimulatory molecules. Contact between activated lymphocytes and macrophages is necessary to down-regulate inhibitory C/EBPbeta, thereby derepressing the HIV-1 LTR. Lymphocyte-derived cytokines activate NF-kappaB, further enhancing the HIV-1 LTR
— id: 39706, year: 2002, vol: 195, page: 495, stat: Journal Article,

Oligoclonal T cell expansions in pulmonary lymphoproliferative disorders: demonstration of the frequent occurrence of oligoclonal T cells in human immunodeficiency virus-related lymphoid interstitial pneumonia
Kurosu, Katsushi; Yumoto, Norio; Rom, William N; Takiguchi, Yuichi; Jaishree, Jagirdai; Nakata, Koh; Tatsumi, Koichiro; Mikata, Aatsuo; Kuriyama, Takatyuki; Weiden, Michael D
2002 Jan 15;165(2):254-259, American journal of respiratory & critical care medicine
We used a denaturing gradient gel electrophoresis (DGGE) procedure with 40-nucleotide guanine- and cytosine-rich sequences in the polymerase chain reaction (PCR) and sequencing analysis to analyze the T cell antigen receptor (TCR)-Vgamma gene repertoire of infiltrating T lymphocytes in pulmonary lymphoproliferative disorders. Six of 15 low-grade mucosa-associated lymphoid tissue (MALT) lymphomas and 8 of 15 cases of lymphocytic interstitial pneumonia (LIP) showed some oligoclonal bands for TCR-Vgamma genes on DGGE. Sequencing analysis demonstrated plural oligoclonal TCR-Vgamma clones among the oligoclonal PCR products on DGGE, leading to the conclusion that conventional antigen-specific oligoclonal expansions may play some role in the pathogenesis of pulmonary lymphoproliferative disorders. The frequency of oligoclonal infiltrating T cell expansions in human immunodeficiency virus (HIV)-related LIP (100%) was significantly higher than in low-grade pulmonary MALT lymphomas (40%) or in HIV-negative LIP (30%). Because recent evidence demonstrates that the V3 loop in the proviral amino acid sequences of mononuclear cells from bronchoalveolar lavage is more homogeneous than those from peripheral blood, this homogeneity might result in oligoclonal expansions of infiltrating T lymphocytes as a consequence of ongoing reactions against lung-specific viral strains
— id: 42264, year: 2002, vol: 165, page: 254, stat: Journal Article,

Cough and bronchial responsiveness in firefighters at the World Trade Center site
Prezant, David J; Weiden, Michael; Banauch, Gisela I; McGuinness, Georgeann; Rom, William N; Aldrich, Thomas K; Kelly, Kerry J
2002 Sep 12;347(11):806-815, New England journal of medicine
BACKGROUND: Workers from the Fire Department of New York City were exposed to a variety of inhaled materials during and after the collapse of the World Trade Center. We evaluated clinical features in a series of 332 firefighters in whom severe cough developed after exposure and the prevalence and severity of bronchial hyperreactivity in firefighters without severe cough classified according to the level of exposure. METHODS: 'World Trade Center cough' was defined as a persistent cough that developed after exposure to the site and was accompanied by respiratory symptoms severe enough to require medical leave for at least four weeks. Evaluation of exposed firefighters included completion of a standard questionnaire, spirometry, airway-responsiveness testing, and chest imaging. RESULTS: In the first six months after September 11, 2001, World Trade Center cough occurred in 128 of 1636 firefighters with a high level of exposure (8 percent), 187 of 6958 with a moderate level of exposure (3 percent), and 17 of 1320 with a low level of exposure (1 percent). In addition, 95 percent had symptoms of dyspnea, 87 percent had gastroesophageal reflux disease, and 54 percent had nasal congestion. Of those tested before treatment of World Trade Center cough, 63 percent of firefighters (149 of 237) had a response to a bronchodilator and 24 percent (9 of 37) had bronchial hyperreactivity. Chest radiographs were unchanged from precollapse findings in 319 of the 332 with World Trade Center cough. Among the cohort without severe cough, bronchial hyperreactivity was present in 77 firefighters with a high level of exposure (23 percent) and 26 with a moderate level of exposure (8 percent). CONCLUSIONS: Intense, short-term exposure to materials generated during the collapse of the World Trade Center was associated with bronchial responsiveness and the development of cough. Clinical and physiological severity was related to the intensity of exposure
— id: 42262, year: 2002, vol: 347, page: 806, stat: Journal Article,

Host defense responses to infection by Mycobacterium tuberculosis. Induction of IRF-1 and a serine protease inhibitor
Qiao, Yaming; Prabhakar, Savita; Coccia, Eliana M; Weiden, Michael; Canova, Antony; Giacomini, Elena; Pine, Richard
2002 Jun 21;277(25):22377-22385, Journal of biological chemistry
Alveolar macrophages and newly recruited monocytes are targets of infection by Mycobacterium tuberculosis. Therefore, we examined the expression of interferon regulatory factor 1 (IRF-1), which plays an important role in host defense against M. tuberculosis, in undifferentiated and differentiated cells. Infection induced IRF-1 in both. IRF-1 from undifferentiated, uninfected monocytic cell lines was modified during extraction to produce specific species that were apparently smaller than intact IRF-1. After infection by M. tuberculosis or differentiation, intact IRF-1 was recovered. Subcellular fractions were assayed for the ability to modify IRF-1 or inhibit its modification. A serine protease on the cytoplasmic surface of an organelle or vesicle in the 'lysosomal/mitochondrial' fraction from undifferentiated cells was responsible for the modification of IRF-1. Thus, the simplest explanation of the modification is cleavage of IRF-1 by the serine protease. Recovery of intact IRF-1 correlated with induction of a serine protease inhibitor that was able to significantly reduce the modification of IRF-1. The inhibitor was present in the cytoplasm of M. tuberculosis-infected or -differentiated cells. It is likely that induction of both IRF-1 and the serine protease inhibitor in response to infection by M. tuberculosis represent host defense mechanisms
— id: 69401, year: 2002, vol: 277, page: 22377, stat: Journal Article,

Acute eosinophilic pneumonia in a New York City firefighter exposed to World Trade Center dust
Rom, William N; Weiden, Michael; Garcia, Roberto; Yie, Ting An; Vathesatogkit, Pratan; Tse, Doris B; McGuinness, Georgeann; Roggli, Victor; Prezant, David
2002 Sep 15;166(6):797-800, American journal of respiratory & critical care medicine
We report a sentinel case of acute eosinophilic pneumonia in a firefighter exposed to high concentrations of World Trade Center dust during the rescue effort from September 11 to 24. The firefighter presented with a Pa(O2) of 53 mm Hg and responded to oxygen and corticosteroids. Computed tomography scan showed patchy ground glass density, thickened bronchial walls, and bilateral pleural effusions. Bronchoalveolar lavage recovered 70% eosinophils, with only 1% eosinophils in peripheral blood. Eosinophils were not degranulated and increased levels of interleukin-5 were measured in bronchoalveolar lavage and serum. Mineralogic analysis counted 305 commercial asbestos fibers/10(6) macrophages including those with high aspect ratios, and significant quantities of fly ash and degraded fibrous glass. Acute eosinophilic pneumonia is a rare consequence of acute high dust exposure. World Trade Center dust consists of large particle-size silicates, but fly ash and asbestos fibers may be found in bronchoalveolar lavage cells
— id: 39593, year: 2002, vol: 166, page: 797, stat: Journal Article,

Lung-specific immune response in tuberculosis
Condos R; Rom WN; Weiden M
2000 Feb;4(2 Suppl 1):S11-S17, International journal of tuberculosis & lung disease
— id: 11825, year: 2000, vol: 4, page: S11, stat: Journal Article,

Aberrant expression of immunoglobulin heavy chain genes in Epstein-Barr virus-negative, human immunodeficiency virus-related lymphoid interstitial pneumonia.[In Process Citation]
Kurosu K; Yumoto N; Rom WN; Jaishree J; Nakata K; Kuriyama T; Mikata A; Weiden MD
2000 Dec;80(12):1891-1903, Laboratory investigation
The two-step polymerase chain reaction (PCR) and sequencing analysis was used to analyze the immunoglobulin heavy chain variable (Ig V(H)) genes of open-chest biopsy or autopsy samples from five patients with Epstein-Barr virus-negative human immunodeficiency virus (HIV)-related lymphoid interstitial pneumonia (LIP), and the results were compared with those for Ig V(H) genes from five HIV-negative LIP patients. The findings of this study are consistent with the different immunological situations of HIV-related and HIV-negative LIP. (a) The Ig V(H)3 subgroup was underexpressed in three of five cases of HIV-related LIP. In contrast, none of the HIV-negative cases showed this abnormality. Because the Ig V(H)3 subgroup encodes the largest portion of Ig V(H) genes, a depletion of B cells expressing Ig V(H)3 genes reflects a major alteration in the B-cell compartment. (b) All HIV-related LIP cases demonstrated two or three oligoclonal populations. HIV-negative cases showed minor monoclonal or polyclonal populations, but not oligoclonal ones. These oligoclonal populations suggest the coexistence of several occult clonal B-cell populations in HIV-related LIP. (c) Some oligoclonal clones in HIV-related LIP showed mutated framework regions not demonstrated in HIV-negative clones. This degree of variation exceeds the usual mutation rate for frameworks, suggesting a role for framework residues in antigen binding. (d) The frequency of D-D fusions of minor oligoclonal clones (HIV-related LIP) is higher than that of minor monoclonal clones (HIV-negative LIP). Such D-D fusions may enhance the probability of expression of antibodies capable of binding HIV glycoproteins
— id: 15395, year: 2000, vol: 80, page: 1891, stat: Journal Article,

Differentiation of monocytes to macrophages switches the Mycobacterium tuberculosis effect on HIV-1 replication from stimulation to inhibition: modulation of interferon response and CCAAT/enhancer binding protein beta expression
Weiden M; Tanaka N; Qiao Y; Zhao BY; Honda Y; Nakata K; Canova A; Levy DE; Rom WN; Pine R
2000 Aug 15;165(4):2028-2039, Journal of immunology
HIV-1 replication is inhibited in uninflamed lung macrophages and is stimulated during tuberculosis. Attempts to recapitulate activation of HIV-1 replication in primary monocytes and macrophages ex vivo and in the untreated and PMA-treated THP-1 cell line model in vitro have produced opposite results depending on the state of differentiation of the cells. After infection with Mycobacterium tuberculosis, monocytes enhanced HIV-1 replication and produced a stimulatory 37-kDa CCAAT/enhancer binding protein beta (C/EBPbeta) transcription factor, whereas macrophages suppressed HIV-1 replication and produced an inhibitory 16-kDa C/EBPbeta transcription factor. IFN-beta induced inhibitory 16-kDa C/EBPbeta in macrophages, but had no effect on C/EBPbeta expression in monocytes. Macrophages, but not monocytes, were able to activate IFN-stimulated gene factor-3 (ISGF-3), a transcription factor composed of STAT-1, STAT-2, and IFN regulatory factor (IRF)-9, after infection with M. tuberculosis or stimulation with type I IFN. Macrophages expressed IRF-9 DNA-binding activity, but monocytes did not, and addition of the IRF-9 component reconstituted ISGF-3 in extracts of IFN-treated monocytes. Modulation of IFN responsiveness upon differentiation occurred at least in part through a post-transcriptionally regulated increase in IRF-9 expression. Both monocytes and macrophages maintained IFN responsiveness, activating STAT-1 homodimer formation and transcription of the STAT-1 gene after IFN stimulation. In addition, both monocytes and macrophages were able to activate NF-kappaB upon infection with M. tuberculosis. These results show that induction of ISGF-3, expression of the inhibitory 16-kDa C/EBPbeta, and suppression of HIV-1 replication via a transcriptional mechanism are macrophage-specific responses to infection with M. tuberculosis
— id: 11568, year: 2000, vol: 165, page: 2028, stat: Journal Article,

Aberrant expression of immunoglobulin genes in human immunodeficiency virus lymphoid interstitial pneumonia (LIP)
Kurosu, K; Yumoto, N; Jaqirdar, J; Nakata, K; Tanaka, N; Mikata, A; Kuriyama, T; Rom, WN; Weiden, M
1999 MAR ;159(3):A393-A393, American journal of respiratory & critical care medicine
— id: 53880, year: 1999, vol: 159, page: A393, stat: Journal Article,

Effects of fire fighting uniform (modern, modified modern, and traditional) design changes on exercise duration in New York City Firefighters
Malley KS; Goldstein AM; Aldrich TK; Kelly KJ; Weiden M; Coplan N; Karwa ML; Prezant DJ
1999 Dec;41(12):1104-1115, Journal of occupational & environmental medicine
Fire departments have replaced traditional uniforms with modern, more thermal protective gear. Although the new uniforms afford superior burn protection, they may reduce work time. Our purpose was to determine if exercise time was (1) reduced by wearing the modern versus traditional uniform, and (2) increased by a design change to a modified modern uniform (T-shirt and short pants rather than a shirt and long pants under the outer uniform). Male firefighters (n = 23; age 27 to 59) performed a maximum exercise test in gym clothes (maximal oxygen consumption = 46 +/- 9 ml/kg/min) and then returned on separate days to exercise using a moderately high intensity, constant work rate treadmill protocol while wearing fire fighting breathing apparatus and each of three uniforms. Firefighters exceeded anaerobic threshold by 1 minute and eventually reached or exceeded maximum heart rate and maximal oxygen consumption. Exercise time in modern (15 +/- 3 min) was significantly less than in traditional (18 +/- 5 min) uniform. Exercise time in modified modern (17 +/- 5 min) was significantly greater than in modern and not significantly different than in traditional uniforms. The rate of change in oxygen consumption and water loss were significantly affected by uniform type, with faster rates in modern compared with modified modern or traditional uniforms. These findings show the impact that design changes have on energy demands and exercise duration
— id: 42263, year: 1999, vol: 41, page: 1104, stat: Journal Article,

Type I interferon induces inhibitory 16-kD CCAAT/ enhancer binding protein (C/EBP)beta, repressing the HIV-1 long terminal repeat in macrophages: pulmonary tuberculosis alters C/EBP expression, enhancing HIV-1 replication
Honda Y; Rogers L; Nakata K; Zhao BY; Pine R; Nakai Y; Kurosu K; Rom WN; Weiden M
1998 Oct 5;188(7):1255-1265, Journal of experimental medicine
We have previously observed that HIV-1 replication is suppressed in uninflamed lung and increased during tuberculosis. In vitro THP-1 cell-derived macrophages inhibited HIV-1 replication after infection with Mycobacterium tuberculosis. Suppression of HIV-1 replication was associated with inhibition of the HIV-1 long terminal repeat (LTR) and induction of ISGF-3, a type I interferon (IFN)-specific transcription factor. Repression of the HIV-1 LTR required intact CCAAT/enhancer binding protein (C/EBP) sites. THP-1 cell-derived macrophages infected with M. tuberculosis, lipopolysaccharide, or IFN-beta induced the 16-kD inhibitory C/EBPbeta isoform and coincidentally repressed HIV-1 LTR transcription. C/EBPbeta was the predominant C/EBP family member produced in THP-1 macrophages during HIV-1 LTR repression. In vivo, alveolar macrophages from uninflamed lung strongly expressed inhibitory 16-kD C/EBPbeta, but pulmonary tuberculosis abolished inhibitory C/EBPbeta expression and induced a novel C/EBP DNA binding protein. Therefore, in vitro, proinflammatory stimulation produces an IFN response inhibiting viral replication by induction of a C/EBPbeta transcriptional repressor. THP-1 cell-derived macrophages stimulated with type I IFN are similar to alveolar macrophages in the uninflamed lung in vivo. In contrast, the cellular immune response in active pulmonary tuberculosis disrupts this innate immunity, switching C/EBP expression and allowing high level viral replication
— id: 8036, year: 1998, vol: 188, page: 1255, stat: Journal Article,

Mycobacterium tuberculosis enhances human immunodeficiency virus-1 replication in the lung
Nakata K; Rom WN; Honda Y; Condos R; Kanegasaki S; Cao Y; Weiden M
1997 Mar;155(3):996-1003, American journal of respiratory & critical care medicine
We investigated the in vivo effect of coinfection of Mycobacterium tuberculosis on human immunodeficiency virus type 1 (HIV-1) replication using bronchoalveolar lavage (BAL) of 11 HIV-1-infected patients with pulmonary tuberculosis and 10 patients with no lung disease. Lung segments involved with pulmonary tuberculosis had significantly elevated HIV-1 branched DNA (bDNA) levels and p24 in BAL compared with lung segments uninvolved with tuberculosis or with BAL from patients with no lung disease. The BAL viral burden was higher than plasma HIV-1 in tuberculosis patients, indicating local production of virus. BAL HIV-1 bDNA declined over the course of treatment for tuberculosis in three patients who underwent serial bronchoscopies. Tumor necrosis factor-alpha (TNF-alpha) and HIV-1 bDNA particles were strongly correlated (r2 = 0.9, p < 0.01) in lung segments involved with tuberculosis. The deduced amino acid sequence of HIV-1 gp120 V3 region from involved segments of three patients with pulmonary tuberculosis showed basic substitutions associated with altered viral phenotype. Phylogenetic analysis of V3 sequences demonstrated that BAL HIV-1 RNA had diverged from plasma. These data support the conclusion that pulmonary tuberculosis enhances local HIV-1 replication in vivo
— id: 12363, year: 1997, vol: 155, page: 996, stat: Journal Article,

Increased release of interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha by bronchoalveolar cells lavaged from involved sites in pulmonary tuberculosis
Law K; Weiden M; Harkin T; Tchou-Wong K; Chi C; Rom WN
1996 Feb;153(2):799-804, American journal of respiratory & critical care medicine
Mycobacterium tuberculosis and its components have been shown to stimulate mononuclear phagocytes in vitro to release interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6). Animal models of tuberculosis (TB) also demonstrate the presence of cytokines in granulomas. We hypothesized that bronchoalveolar lavage (BAL) cells from patients with pulmonary TB would have increased spontaneous release of IL-1 beta, IL-6, and TNF-alpha and would have a concomitant alveolitis. We performed BAL on 26 patients with active TB and on six normal volunteers. BAL fluid from radiographically involved and uninvolved sites was evaluated separately for cell types and the spontaneous release of cytokines. The alveolar inflammation in involved sites was characterized by an increase in lymphocytes (miliary TB, 38 +/- 10%; involved sites, 22 +/- 4%; uninvolved sites, 13 +/- 2%; normal, 5 +/- 2%) and neutrophils (involved sites, 21 +/- 7%; uninvolved sites, 3 +/- 2%). There was a significant increase in the spontaneous release of IL-1 beta (501 +/- 280 pg/ml), TNF-alpha (782 +/- 165 pg/ml), and IL-6 (473 +/- 157 pg/ml) from involved sites of TB patients that was 5- to 20-fold greater than uninvolved sites, normal controls, or miliary TB. Northern analysis revealed increased gene expression of IL-1 beta, TNF-alpha, and IL-6 from the involved sites from two patients with TB compared with two negative controls. We conclude that BAL cells, especially alveolar macrophages, are activated in the alveolar inflammation of active TB and spontaneously release increased quantities of IL-1 beta, IL-6, and TNF-alpha, and that these cytokines are likely to be involved in directing granuloma formation and control of M. tuberculosis infection
— id: 8003, year: 1996, vol: 153, page: 799, stat: Journal Article,

Tuberculosis in HIV-positive patients: cellular response and immune activation in the lung
Law KF; Jagirdar J; Weiden MD; Bodkin M; Rom WN
1996 Apr;153(4 Pt 1):1377-1384, American journal of respiratory & critical care medicine
The host response to Mycobacterium tuberculosis is dependent on the accumulation and activation of cytotoxic and memory CD4+ T cells, resulting in granuloma formation and delayed type hypersensitivity. We characterized the cellular response of radiographically involved lung segments from 17 HIV-positive and 11 HIV-negative patients with acute tuberculosis (TB) using bronchoalveolar lavage (BAL) and compared the response to uninvolved segments, normal control subjects and peripheral blood. In both HIV-positive and HIV-negative patients, radiographically involved segments had significantly increased numbers of total cells per milliliter, percent of neutrophils recovered, and percent of lymphocytes recovered compared with uninvolved segments or normal control subjects, but HIV-positive patients had a lower proportion of lymphocytes in the involved segments than HIV-negative patients with tuberculosis (19 +/- 5% versus 33 +/- 5%; p < 0.05). Lymphocyte subset analysis demonstrated that HIV-positive patients had markedly reduced percentages of CD4+ lymphocytes (CD4+ lymphocytes in HIV-positive TB involved site 25 +/- 6%; HIV-negative TB involved site 73 +/- 2%; p < 0.01) and an increase in the percentage of CD8+ lymphocytes (HIV positive involved site 61 +/- 6% versus HIV negative involved site 19 +/- 3%; p < 0.01). Immunohistochemistry of lung biopsy tissue in five HIV-negative patients showed similar lymphocyte subset profiles as BAL, indicating that BAL reflects cell populations in tissue granulomas. BAL lymphocytes from four HIV-positive and four HIV-negative tuberculosis patients demonstrated immune activation by staining with a murine antibody to TIA-1, a cytoplasmic protein associated with cytotoxicity and apoptosis (HIV positive 48 +/- 6%, HIV negative 31 +/- 7%, normals 11 +/- 5%). Steady state mRNA for gamma-interferon was decreased in four HIV-positive patients when compared with four HIV-negative patients. IL-8 production was comparable in HIV-negative and HIV-positive patients with focal disease but reduced in two patients with miliary tuberculosis. We conclude that HIV-positive patients with+ tuberculosis have a reduced enrichment and activation of immune cells in the lung, and this failure of a CD4+ alveolitis limits an effective immune response
— id: 6926, year: 1996, vol: 153, page: 1377, stat: Journal Article,

Streptomycin, other aminoglycosides, and capreomycin
Law, Kevin F; Weiden, Michael
Tuberculosis Boston : Little Brown, 1996,
— id: 4857, year: 1996, vol: , page: ?, stat: Chapter,

Genetics of M. tuberculosis
Weiden, Michael; Tchou-Wong, Kam-Meng
Tuberculosis Boston : Little Brown, 1996,
— id: 4830, year: 1996, vol: , page: ?, stat: Chapter,

Low copy number and limited variability of proviral DNA in alveolar macrophages from HIV-1-infected patients: evidence for genetic differences in HIV-1 between lung and blood macrophage populations
Nakata K; Weiden M; Harkin T; Ho D; Rom WN
1995 Nov;1(7):744-757, Molecular medicine
BACKGROUND: We investigated the human immunodeficiency virus (HIV) proviral DNA sequence and copy number in alveolar macrophages (AM) and peripheral blood monocytes (PBM) from 10 HIV-positive patients without any active concurrent pulmonary disease to understand the nature of HIV-1 infection in vivo in the lung microenvironment. MATERIALS AND METHODS: The 10 seropositive patients without active pulmonary disease were selected based on chest roentegenography and pathological/cytological test of bronchoalveolar (BAL) fluid. In order to determine accurate proviral copy numbers, AM and PBM were isolated to 99 and 94% purity, respectively, and quantitative polymerase chain reaction (PCR), with a sensitivity to detect three copies of HIV proviral DNA per 10(5) cells, was applied. For analysis of genetic variation in HIV-1, PCR-amplified HIV-1 DNA from AM and PBM of five patients were subcloned and 2-12 clones from each sample underwent DNA sequence analysis of HIV-1 gp120 V3-V5. Heteroduplex mobility assays were performed to confirm the results of the sequence analysis. RESULTS: The proviral copy number in AM or PBM were less than 20 copies/10(5) cells in all patients, and five patients had less than the detection limit. There was no significant difference in HIV copy number between AM and PBM. No correlation was found between PBM/AM HIV copy number and CD4+ lymphocyte count in the peripheral blood. Sequence analysis revealed that the mean intrapatient genetic similarity in AM was 97.5 +/- 0.18% (n = 107), which was significantly higher than that in PBM (96.2 +/- 0.26% (n = 94), p < 0.001), suggesting that variability of HIV-1 DNA in AM was relatively limited. Divergence occurred when AM derived HIV-1 sequence was compared with PBM derived sequence from the same patient (95.8 +/- 0.17% (n = 223) p < 0.001). Phylogenetic analysis of DNA sequence demonstrated complete separation of HIV lineages from lung and blood in four of five patients. CONCLUSIONS: The results suggest the HIV-1 infection in AM is restricted in vivo with low viral burden and homogenous genotype. We propose that the pulmonary microenvironment may limit the extent of HIV-1 infection
— id: 7024, year: 1995, vol: 1, page: 744, stat: Journal Article,

LIMITED VARIABILITY AND COPY NUMBER OF HIV-1 IN HUMAN ALVEOLAR MACROPHAGES
NAKATA, K; WEIDEN, M; HARKIN, T; HO, D; ROM, WN
1995 APR 2 ;54(3):241-241, Journal of cellular biochemistry
— id: 87325, year: 1995, vol: 54, page: 241, stat: Journal Article,

Human host response to Mycobacterium tuberculosis
Rom WN; Schluger N; Law K; Condos R; Zhang Y; Weiden M; Harkin T; Tchou-Wong KM
1995 Nov 11;125(45):2178-2185, Schweizerische medizinische wochenschrift = Journal suisse de medecine
Despite the importance of tuberculosis as the leading cause of death due to infectious disease in the world, it has only been recently that an understanding of the human host response in this infection has begun to emerge. The key components of this response are cytokines and components of cellular immunity, predominantly T-lymphocytes and macrophages. Though the relationships among the components of the immune response are complex, it seems likely that in response to mycobacterial infection associated with active disease, cytokines such as TNF-alpha and IL-1 beta are produced; these cytokines serve to recruit more lymphocytes, generally of the T(H) (T helper) phenotype, which then produces substances such as the macrophage activating factor interferon-gamma. Macrophages activated by IFN-gamma ar thus stimulating to enhance intracellular killing of mycobacteria. The role of other cytokines, such as IL-6 and IL-8, both of which are induced by M. tuberculosis or its cell was components, is less clear. Further elucidation of the human host response to tuberculosis should help in the development of new vaccines and treatment strategies
— id: 12714, year: 1995, vol: 125, page: 2178, stat: Journal Article,

Mycobacterium tuberculosis enhances human immunodeficiency virus-1 replication by transcriptional activation at the long terminal repeat
Zhang Y; Nakata K; Weiden M; Rom WN
1995 May;95(5):2324-2331, Journal of clinical investigation
Tuberculosis has emerged as an epidemic fueled by the large number of individuals infected with the human immunodeficiency virus, especially those who are injecting drug users. We found a striking increase from 4- to 208-fold in p24 levels in bronchoalveolar lavage fluid from involved sites of Mycobacterium tuberculosis infection vs uninvolved sites in three HIV+ patients. We used an in vitro cell culture model to determine if tuberculosis could activate replication of HIV-1. Mononuclear phagocyte cell lines U937 and THP-1 infected with HIV-1JR-CSF, in vitro and stimulated with live M. tuberculosis H37Ra, had a threefold increase in p24 in culture supernatants. Using the HIV-1 long terminal repeat with a chloramphenicol acetyltransferase (CAT) reporter construct, live M. tuberculosis increased transcription 20-fold in THP-1 cells, and cell wall components stimulated CAT expression to a lesser extent. The nuclear factor-kappa B enhancer element was responsible for the majority of the increased CAT activity although two upstream nuclear factor-IL6 sites may also contribute to enhanced transcription. Antibodies to TNF-alpha and IL-1 inhibited the increase in CAT activity of the HIV-1 long terminal repeat by M. tuberculosis from 21-fold to 8-fold. Stimulation of HIV-1 replication by M. tuberculosis may exacerbate dysfunction of the host immune response in dually infected individuals
— id: 6794, year: 1995, vol: 95, page: 2324, stat: Journal Article,

Deletion of the E4 region of the genome produces adenovirus DNA concatemers
Weiden MD; Ginsberg HS
1994 Jan 4;91(1):153-157, Proceedings of the National Academy of Sciences of the United States of America
Two mutants containing large deletions in the E4 region of the adenovirus genome H5dl366 (91.9-98.3 map units) and H2dl808 (93.0-97.1 map units) were used to investigate the role of E4 genes in adenovirus DNA synthesis. Infection of KB human epidermoid carcinoma cells with either mutant resulted in production of large concatemers of viral DNA. Only monomer viral genome forms were produced, however, when mutants infected W162 cells, a monkey kidney cell line transformed with and expressing the E4 genes. Diffusible E4 gene products, therefore, complement the E4 mutant phenotype. The viral DNA concatemers produced in dl366- and dl808-infected KB cells did not have any specific orientation of monomer joining: the junctions consisted of head-to-head, head-to-tail, and tail-to-tail joints. The junctions were covalently linked molecules, but molecules were not precisely joined, and restriction enzyme maps revealed a heterogeneous size distribution of junction fragments. A series of mutants that disrupted single E4 open reading frames (ORFs) was also studied: none showed phenotypes similar to that of dl366 or dl808. Mutants containing defects in both ORF3 and ORF6, however, manifested the concatemer phenotype, indicating redundancy in genes preventing concatemer formation. These data suggest that the E4 ORFs 3 and 6 express functions critical for regulation of viral DNA replication and that concatemer intermediates may exist during adenovirus DNA synthesis
— id: 42265, year: 1994, vol: 91, page: 153, stat: Journal Article,

Rhodococcus equi endobronchial mass with lung abscess in a patient with AIDS
Shapiro JM; Romney BM; Weiden MD; White CS; O'Toole KM
1992 Jan;47(1):62-63, Thorax
An endobronchial lesion with lung abscess in a patient with AIDS was due to Rhodococcus equi. The patient responded to triple chemotherapy
— id: 42266, year: 1992, vol: 47, page: 62, stat: Journal Article,

Chromosome structure: DNA nucleotide sequence elements of a subset of the minichromosomes of the protozoan Trypanosoma brucei
Weiden M; Osheim YN; Beyer AL; Van der Ploeg LH
1991 Aug;11(8):3823-3834, Molecular & cellular biology
The genome of the protozoan Trypanosoma brucei contains a set of about 100 minichromosomes of about 50 to 150 kb in size. The small size of these chromosomes, their involvement in antigenic variation, and their mitotic stability make them ideal candidates for a structural analysis of protozoan chromosomes and their telomeres. We show that a subset of the minichromosomes is composed predominantly of simple-sequence DNA, with over 90% of the length of the minichromosome consisting of a tandem array of 177-bp repeats, indicating that these molecules have limited protein-coding capacity. Proceeding from the tip of the telomere to a chromosome internal position, a subset of the minichromosomes contained the GGGTTA telomere repeat, a 29-bp telomere-derived repeat, a region containing 74-bp G + C-rich direct repeats separated by approximately 155 bp of A + T-rich DNA that has a bent character, and 50 to 150 kb of the 177-bp repeat. Several of the minichromosome-derived telomeres did not encode protein-coding genes, indicating that the repertoire of telomeric variant cell surface glycoprotein genes is restricted to some telomeres only. The telomere organization in trypanosomes shares striking similarities to the organization of telomeres and subtelomeres in humans, yeasts, and plasmodia. An electron microscopic analysis of the minichromosomes showed that they are linear molecules without abnormal structures in the main body of the chromosome. The structure of replicating molecules indicated that minichromosomes probably have a single bidirectional origin of replication located in the body of the chromosome. We propose a model for the structure of the trypanosome minichromosomes
— id: 42267, year: 1991, vol: 11, page: 3823, stat: Journal Article,