Last data update: Oct 28, 2024. (Total: 48004 publications since 2009)
Records 1-30 (of 38 Records) |
Query Trace: Mukherjee I[original query] |
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COVID-19 Across Pandemic Variant Periods: The Severe Acute Respiratory Infection-Preparedness (SARI-PREP) Study
Mukherjee V , Postelnicu R , Parker C , Rivers PS , Anesi GL , Andrews A , Ables E , Morrell ED , Brett-Major DM , Broadhurst MJ , Cobb JP , Irwin A , Kratochvil CJ , Krolikowski K , Kumar VK , Landsittel DP , Lee RA , Liebler JM , Segal LN , Sevransky JE , Srivastava A , Uyeki TM , Wurfel MM , Wyles D , Evans LE , Lutrick K , Bhatraju PK . Crit Care Explor 2024 6 (7) e1122 IMPORTANCE: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has evolved through multiple phases in the United States, with significant differences in patient centered outcomes with improvements in hospital strain, medical countermeasures, and overall understanding of the disease. We describe how patient characteristics changed and care progressed over the various pandemic phases; we also emphasize the need for an ongoing clinical network to improve the understanding of known and novel respiratory viral diseases. OBJECTIVES: To describe how patient characteristics and care evolved across the various COVID-19 pandemic periods in those hospitalized with viral severe acute respiratory infection (SARI). DESIGN: Severe Acute Respiratory Infection-Preparedness (SARI-PREP) is a Centers for Disease Control and Prevention Foundation-funded, Society of Critical Care Medicine Discovery-housed, longitudinal multicenter cohort study of viral pneumonia. We defined SARI patients as those hospitalized with laboratory-confirmed respiratory viral infection and an acute syndrome of fever, cough, and radiographic infiltrates or hypoxemia. We collected patient-level data including demographic characteristics, comorbidities, acute physiologic measures, serum and respiratory specimens, therapeutics, and outcomes. Outcomes were described across four pandemic variant periods based on a SARS-CoV-2 sequenced subsample: pre-Delta, Delta, Omicron BA.1, and Omicron post-BA.1. SETTING: Multicenter cohort of adult patients admitted to an acute care ward or ICU from seven hospitals representing diverse geographic regions across the United States. PARTICIPANTS: Patients with SARI caused by infection with respiratory viruses. MAIN OUTCOMES AND RESULTS: Eight hundred seventy-four adult patients with SARI were enrolled at seven study hospitals between March 2020 and April 2023. Most patients (780, 89%) had SARS-CoV-2 infection. Across the COVID-19 cohort, median age was 60 years (interquartile range, 48.0-71.0 yr) and 66% were male. Almost half (430, 49%) of the study population belonged to underserved communities. Most patients (76.5%) were admitted to the ICU, 52.5% received mechanical ventilation, and observed hospital mortality was 25.5%. As the pandemic progressed, we observed decreases in ICU utilization (94% to 58%), hospital length of stay (median, 26.0 to 8.5 d), and hospital mortality (32% to 12%), while the number of comorbid conditions increased. CONCLUSIONS AND RELEVANCE: We describe increasing comorbidities but improved outcomes across pandemic variant periods, in the setting of multiple factors, including evolving care delivery, countermeasures, and viral variants. An understanding of patient-level factors may inform treatment options for subsequent variants and future novel pathogens. |
Impaired immune responses in the airways are associated with poor outcome in critically ill COVID-19 patients
Barnett CR , Krolikowski K , Postelnicu R , Mukherjee V , Sulaiman I , Chung M , Angel L , Tsay JJ , Wu BG , Yeung ST , Duerr R , Desvignes L , Khanna K , Li Y , Schluger R , Rafeq S , Collazo D , Kyeremateng Y , Amoroso N , Pradhan D , Das S , Evans L , Uyeki TM , Ghedin E , Silverman GJ , Segal LN , Brosnahan SB . ERJ Open Res 2024 10 (4) INTRODUCTION: Mounting evidence indicates that an individual's humoral adaptive immune response plays a critical role in the setting of SARS-CoV-2 infection, and that the efficiency of the response correlates with disease severity. The relationship between the adaptive immune dynamics in the lower airways with those in the systemic circulation, and how these relate to an individual's clinical response to SARS-CoV-2 infection, are less understood and are the focus of this study. MATERIAL AND METHODS: We investigated the adaptive immune response to SARS-CoV-2 in paired samples from the lower airways and blood from 27 critically ill patients during the first wave of the pandemic (median time from symptom onset to intubation 11 days). Measurements included clinical outcomes (mortality), bronchoalveolar lavage fluid (BALF) and blood specimen antibody levels, and BALF viral load. RESULTS: While there was heterogeneity in the levels of the SARS-CoV-2-specific antibodies, we unexpectedly found that some BALF specimens displayed higher levels than the paired concurrent plasma samples, despite the known dilutional effects common in BALF samples. We found that survivors had higher levels of anti-spike, anti-spike-N-terminal domain and anti-spike-receptor-binding domain IgG antibodies in their BALF (p<0.05), while there was no such association with antibody levels in the systemic circulation. DISCUSSION: Our data highlight the critical role of local adaptive immunity in the airways as a key defence mechanism against primary SARS-CoV-2 infection. |
Distinct features of ribonucleotides within genomic DNA in Aicardi-Goutières syndrome ortholog mutants of Saccharomyces cerevisiae
Kundnani DL , Yang T , Gombolay AL , Mukherjee K , Newnam G , Meers C , Verma I , Chhatlani K , Mehta ZH , Mouawad C , Storici F . iScience 2024 27 (6) Ribonucleoside monophosphates (rNMPs) are abundantly found within genomic DNA of cells. The embedded rNMPs alter DNA properties and impact genome stability. Mutations in ribonuclease (RNase) H2, a key enzyme for rNMP removal, are associated with the Aicardi-Goutières syndrome (AGS), a severe neurological disorder. Here, we engineered orthologs of the human RNASEH2A-G37S and RNASEH2C-R69W AGS mutations in yeast Saccharomyces cerevisiae: rnh201-G42S and rnh203-K46W. Using the ribose-seq technique and the Ribose-Map bioinformatics toolkit, we unveiled rNMP abundance, composition, hotspots, and sequence context in these AGS-ortholog mutants. We found a high rNMP presence in the nuclear genome of rnh201-G42S-mutant cells, and an elevated rCMP content in both mutants, reflecting preferential cleavage of RNase H2 at rGMP. We discovered unique rNMP patterns in each mutant, showing differential activity of the AGS mutants on the leading or lagging replication strands. This study guides future research on rNMP characteristics in human genomes with AGS mutations. © 2024 The Authors |
Genomic analysis of azithromycin-resistant Salmonella from food animals at slaughter and processing, and retail meats, 2011-2021, United States
Ge B , Mukherjee S , Li C , Harrison LB , Hsu CH , Tran TT , Whichard JM , Dessai U , Singh R , Gilbert JM , Strain EA , McDermott PF , Zhao S . Microbiol Spectr 2023 e0348523 Macrolides of different ring sizes are critically important antimicrobials for human medicine and veterinary medicine, though the widely used 15-membered ring azithromycin in humans is not approved for use in veterinary medicine. We document here the emergence of azithromycin-resistant Salmonella among the NARMS culture collections between 2011 and 2021 in food animals and retail meats, some with co-resistance to ceftriaxone or decreased susceptibility to ciprofloxacin. We also provide insights into the underlying genetic mechanisms and genomic contexts, including the first report of a novel combination of azithromycin resistance determinants and the characterization of multidrug-resistant plasmids. Further, we highlight the emergence of a multidrug-resistant Salmonella Newport clone in food animals (mainly cattle) with both azithromycin resistance and decreased susceptibility to ciprofloxacin. These findings contribute to a better understating of azithromycin resistance mechanisms in Salmonella and warrant further investigations on the drivers behind the emergence of resistant clones. |
Disease severity of respiratory syncytial virus compared with COVID-19 and influenza among hospitalized adults aged ≥60 years - IVY Network, 20 U.S. States, February 2022-May 2023
Surie D , Yuengling KA , DeCuir J , Zhu Y , Gaglani M , Ginde AA , Talbot HK , Casey JD , Mohr NM , Ghamande S , Gibbs KW , Files DC , Hager DN , Ali H , Prekker ME , Gong MN , Mohamed A , Johnson NJ , Steingrub JS , Peltan ID , Brown SM , Leis AM , Khan A , Hough CL , Bender WS , Duggal A , Wilson JG , Qadir N , Chang SY , Mallow C , Kwon JH , Exline MC , Lauring AS , Shapiro NI , Columbus C , Vaughn IA , Ramesh M , Safdar B , Halasa N , Chappell JD , Grijalva CG , Baughman A , Rice TW , Womack KN , Han JH , Swan SA , Mukherjee I , Lewis NM , Ellington S , McMorrow ML , Martin ET , Self WH . MMWR Morb Mortal Wkly Rep 2023 72 (40) 1083-1088 On June 21, 2023, CDC's Advisory Committee on Immunization Practices recommended respiratory syncytial virus (RSV) vaccination for adults aged ≥60 years, offered to individual adults using shared clinical decision-making. Informed use of these vaccines requires an understanding of RSV disease severity. To characterize RSV-associated severity, 5,784 adults aged ≥60 years hospitalized with acute respiratory illness and laboratory-confirmed RSV, SARS-CoV-2, or influenza infection were prospectively enrolled from 25 hospitals in 20 U.S. states during February 1, 2022-May 31, 2023. Multivariable logistic regression was used to compare RSV disease severity with COVID-19 and influenza severity on the basis of the following outcomes: 1) standard flow (<30 L/minute) oxygen therapy, 2) high-flow nasal cannula (HFNC) or noninvasive ventilation (NIV), 3) intensive care unit (ICU) admission, and 4) invasive mechanical ventilation (IMV) or death. Overall, 304 (5.3%) enrolled adults were hospitalized with RSV, 4,734 (81.8%) with COVID-19 and 746 (12.9%) with influenza. Patients hospitalized with RSV were more likely to receive standard flow oxygen, HFNC or NIV, and ICU admission than were those hospitalized with COVID-19 or influenza. Patients hospitalized with RSV were more likely to receive IMV or die compared with patients hospitalized with influenza (adjusted odds ratio = 2.08; 95% CI = 1.33-3.26). Among hospitalized older adults, RSV was less common, but was associated with more severe disease than COVID-19 or influenza. High disease severity in older adults hospitalized with RSV is important to consider in shared clinical decision-making regarding RSV vaccination. |
Per- and polyfluoroalkyl substances (PFAS) and lipid trajectories in women 45-56 years of age: The study of women's health across the nation
Kang H , Ding N , Karvonen-Gutierrez CA , Mukherjee B , Calafat AM , Park SK . Environ Health Perspect 2023 131 (8) 87004 BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are associated with less favorable blood lipid profiles in epidemiological studies. However, little is known about the potential role of PFAS in longitudinal changes in lipids among midlife women even though women become more susceptible to metabolic alterations during the menopausal transition. OBJECTIVES: To examine associations of serum PFAS concentrations with longitudinal trajectories of blood total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides in midlife women undergoing menopausal transition. METHODS: The sample included 1,130 women from the Study of Women's Health Across the Nation 45-56 y of age at baseline (1999-2000). We measured serum PFAS concentrations including linear perfluorooctanoic acid (n-PFOA), perfluorononanoic acid (PFNA), linear and branched perfluorooctanesulfonic acid (n-PFOS and Sm-PFOS, respectively), and perfluorohexanesulfonic acid (PFHxS) at baseline. We used k-means clustering to identify subgroups with different patterns of PFAS mixture. Blood lipids were measured annually or biannually through 2016 with an average follow-up of 14.8 y. We identified longitudinal trajectories of each lipid using latent class growth models. We used multinomial log-linear models adjusted for covariates to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of lipid trajectory classes by PFAS and their mixtures. RESULTS: Three distinct trajectories (low, middle, high) of total, LDL, and HDL cholesterol and two distinct trajectories (low and high) of triglycerides were identified. n-PFOS, Sm-PFOS, and PFHxS were positively associated with total and LDL cholesterol trajectories. n-PFOS was inversely associated with triglycerides trajectories. PFAS mixtures (high vs. low) showed positive associations with total and LDL cholesterol trajectories (high vs. low), showing ORs (95% CIs) of 1.69 (95% CI: 1.36, 2.12) and 1.79 (95% CI: 1.44, 2.22), respectively. DISCUSSION: Concentrations of serum PFAS were positively associated with trajectories of total and LDL cholesterol, providing a line of evidence supporting adverse effects of PFAS on lipid homeostasis. https://doi.org/10.1289/EHP12351. |
Microbial signatures in the lower airways of mechanically ventilated COVID19 patients associated with poor clinical outcome (preprint)
Sulaiman I , Chung M , Angel L , Koralov S , Wu B , Yeung S , Krolikowski K , Li Y , Duerr R , Schluger R , Thannickal S , Koide A , Rafeq S , Barnett C , Postelnicu R , Wang C , Banakis S , Perez-Perez L , Jour G , Shen G , Meyn P , Carpenito J , Liu X , Ji K , Collazo D , Labarbiera A , Amoroso N , Brosnahan S , Mukherjee V , Kaufman D , Bakker J , Lubinsky A , Pradhan D , Sterman D , Heguy A , Uyeki T , Clemente J , de Wit E , Schmidt AM , Shopsin B , Desvignes L , Wang C , Li H , Zhang B , Forst C , Koide S , Stapleford K , Khanna K , Ghedin E , Weiden M , Segal L . Res Sq 2021 Mortality among patients with COVID-19 and respiratory failure is high and there are no known lower airway biomarkers that predict clinical outcome. We investigated whether bacterial respiratory infections and viral load were associated with poor clinical outcome and host immune tone. We obtained bacterial and fungal culture data from 589 critically ill subjects with COVID-19 requiring mechanical ventilation. On a subset of the subjects that underwent bronchoscopy, we also quantified SARS-CoV-2 viral load, analyzed the microbiome of the lower airways by metagenome and metatranscriptome analyses and profiled the host immune response. We found that isolation of a hospital-acquired respiratory pathogen was not associated with fatal outcome. However, poor clinical outcome was associated with enrichment of the lower airway microbiota with an oral commensal ( Mycoplasma salivarium ), while high SARS-CoV-2 viral burden, poor anti-SARS-CoV-2 antibody response, together with a unique host transcriptome profile of the lower airways were most predictive of mortality. Collectively, these data support the hypothesis that 1) the extent of viral infectivity drives mortality in severe COVID-19, and therefore 2) clinical management strategies targeting viral replication and host responses to SARS-CoV-2 should be prioritized. |
Microbial signatures in the lower airways of mechanically ventilated COVID19 patients associated with poor clinical outcome (preprint)
Sulaiman I , Chung M , Angel L , Tsay JJ , Wu BG , Yeung ST , Krolikowski K , Li Y , Duerr R , Schluger R , Thannickal SA , Koide A , Rafeq S , Barnett C , Postelnicu R , Wang C , Banakis S , Perez-Perez L , Jour G , Shen G , Meyn P , Carpenito J , Liu X , Ji K , Collazo D , Labarbiera A , Amoroso N , Brosnahan S , Mukherjee V , Kaufman D , Bakker J , Lubinsky A , Pradhan D , Sterman DH , Weiden M , Hegu A , Evans L , Uyeki TM , Clemente JC , De Wit E , Schmidt AM , Shopsin B , Desvignes L , Wang C , Li H , Zhang B , Forst CV , Koide S , Stapleford KA , Khanna KM , Ghedin E , Segal LN . medRxiv 2021 Mortality among patients with COVID-19 and respiratory failure is high and there are no known lower airway biomarkers that predict clinical outcome. We investigated whether bacterial respiratory infections and viral load were associated with poor clinical outcome and host immune tone. We obtained bacterial and fungal culture data from 589 critically ill subjects with COVID-19 requiring mechanical ventilation. On a subset of the subjects that underwent bronchoscopy, we also quantified SARS-CoV-2 viral load, analyzed the microbiome of the lower airways by metagenome and metatranscriptome analyses and profiled the host immune response. We found that isolation of a hospital-acquired respiratory pathogen was not associated with fatal outcome. However, poor clinical outcome was associated with enrichment of the lower airway microbiota with an oral commensal ( Mycoplasma salivarium ), while high SARS-CoV-2 viral burden, poor anti-SARS-CoV-2 antibody response, together with a unique host transcriptome profile of the lower airways were most predictive of mortality. Collectively, these data support the hypothesis that 1) the extent of viral infectivity drives mortality in severe COVID-19, and therefore 2) clinical management strategies targeting viral replication and host responses to SARS-CoV-2 should be prioritized. |
Perceived Hospital Stress, Severe Acute Respiratory Syndrome Coronavirus 2 Activity, and Care Process Temporal Variance During the COVID-19 Pandemic.
Anesi GL , Andrews A , Bai HJ , Bhatraju PK , Brett-Major DM , Broadhurst MJ , Campbell ES , Cobb JP , Gonzalez M , Homami S , Hypes CD , Irwin A , Kratochvil CJ , Krolikowski K , Kumar VK , Landsittel DP , Lee RA , Liebler JM , Lutrick K , Marts LT , Mosier JM , Mukherjee V , Postelnicu R , Rodina V , Segal LN , Sevransky JE , Spainhour C , Srivastava A , Uyeki TM , Wurfel MM , Wyles D , Evans L . Crit Care Med 2023 51 (4) 445-459 OBJECTIVES: The COVID-19 pandemic threatened standard hospital operations. We sought to understand how this stress was perceived and manifested within individual hospitals and in relation to local viral activity. DESIGN: Prospective weekly hospital stress survey, November 2020-June 2022. SETTING: Society of Critical Care Medicine's Discovery Severe Acute Respiratory Infection-Preparedness multicenter cohort study. SUBJECTS: Thirteen hospitals across seven U.S. health systems. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed 839 hospital-weeks of data over 85 pandemic weeks and five viral surges. Perceived overall hospital, ICU, and emergency department (ED) stress due to severe acute respiratory infection patients during the pandemic were reported by a mean of 43% (sd, 36%), 32% (30%), and 14% (22%) of hospitals per week, respectively, and perceived care deviations in a mean of 36% (33%). Overall hospital stress was highly correlated with ICU stress (ρ = 0.82; p < 0.0001) but only moderately correlated with ED stress (ρ = 0.52; p < 0.0001). A county increase in 10 severe acute respiratory syndrome coronavirus 2 cases per 100,000 residents was associated with an increase in the odds of overall hospital, ICU, and ED stress by 9% (95% CI, 5-12%), 7% (3-10%), and 4% (2-6%), respectively. During the Delta variant surge, overall hospital stress persisted for a median of 11.5 weeks (interquartile range, 9-14 wk) after local case peak. ICU stress had a similar pattern of resolution (median 11 wk [6-14 wk] after local case peak; p = 0.59) while the resolution of ED stress (median 6 wk [5-6 wk] after local case peak; p = 0.003) was earlier. There was a similar but attenuated pattern during the Omicron BA.1 subvariant surge. CONCLUSIONS: During the COVID-19 pandemic, perceived care deviations were common and potentially avoidable patient harm was rare. Perceived hospital stress persisted for weeks after surges peaked. |
Angiopoietin-Like4 Is a Novel Marker of COVID-19 Severity.
Bhatraju PK , Morrell ED , Stanaway IB , Sathe NA , Srivastava A , Postelnicu R , Green R , Andrews A , Gonzalez M , Kratochvil CJ , Kumar VK , Hsiang TY , Gale M Jr , Anesi GL , Wyles D , Broadhurst MJ , Brett-Major D , Mukherjee V , Sevransky JE , Landsittel D , Hung C , Altemeier WA , Gharib SA , Uyeki TM , Cobb JP , Liebler JM , Crosslin DR , Jarvik GP , Segal LN , Evans L , Mikacenic C , Wurfel MM . Crit Care Explor 2023 5 (1) e0827 Vascular dysfunction and capillary leak are common in critically ill COVID-19 patients, but identification of endothelial pathways involved in COVID-19 pathogenesis has been limited. Angiopoietin-like 4 (ANGPTL4) is a protein secreted in response to hypoxic and nutrient-poor conditions that has a variety of biological effects including vascular injury and capillary leak. OBJECTIVES: To assess the role of ANGPTL4 in COVID-19-related outcomes. DESIGN SETTING AND PARTICIPANTS: Two hundred twenty-five COVID-19 ICU patients were enrolled from April 2020 to May 2021 in a prospective, multicenter cohort study from three different medical centers, University of Washington, University of Southern California and New York University. MAIN OUTCOMES AND MEASURES: Plasma ANGPTL4 was measured on days 1, 7, and 14 after ICU admission. We used previously published tissue proteomic data and lung single nucleus RNA (snRNA) sequencing data from specimens collected from COVID-19 patients to determine the tissues and cells that produce ANGPTL4. RESULTS: Higher plasma ANGPTL4 concentrations were significantly associated with worse hospital mortality (adjusted odds ratio per log(2) increase, 1.53; 95% CI, 1.17-2.00; p = 0.002). Higher ANGPTL4 concentrations were also associated with higher proportions of venous thromboembolism and acute respiratory distress syndrome. Longitudinal ANGPTL4 concentrations were significantly different during the first 2 weeks of hospitalization in patients who subsequently died compared with survivors (p for interaction = 8.1 × 10(-5)). Proteomics analysis demonstrated abundance of ANGPTL4 in lung tissue compared with other organs in COVID-19. ANGPTL4 single-nuclear RNA gene expression was significantly increased in pulmonary alveolar type 2 epithelial cells and fibroblasts in COVID-19 lung tissue compared with controls. CONCLUSIONS AND RELEVANCE: ANGPTL4 is expressed in pulmonary epithelial cells and fibroblasts and is associated with clinical prognosis in critically ill COVID-19 patients. |
Severe Acute Respiratory Infection-Preparedness: Protocol for a Multicenter Prospective Cohort Study of Viral Respiratory Infections.
Postelnicu R , Srivastava A , Bhatraju PK , Wurfelc MM , Anesi GL , Gonzalez M , Andrews A , Lutrick K , Kumar VK , Uyeki TM , Cobb PJ , Segal LN , Brett-Major D , Liebler JM , Kratochvil CJ , Mukherjee V , Broadhurst MJ , Lee R , Wyles D , Sevransky JE , Evans L , Landsittel D . Crit Care Explor 2022 4 (10) e0773 Respiratory virus infections cause significant morbidity and mortality ranging from mild uncomplicated acute respiratory illness to severe complications, such as acute respiratory distress syndrome, multiple organ failure, and death during epidemics and pandemics. We present a protocol to systematically study patients with severe acute respiratory infection (SARI), including severe acute respiratory syndrome coronavirus 2, due to respiratory viral pathogens to evaluate the natural history, prognostic biomarkers, and characteristics, including hospital stress, associated with clinical outcomes and severity. DESIGN: Prospective cohort study. SETTING: Multicenter cohort of patients admitted to an acute care ward or ICU from at least 15 hospitals representing diverse geographic regions across the United States. PATIENTS: Patients with SARI caused by infection with respiratory viruses that can cause outbreaks, epidemics, and pandemics. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Measurements include patient demographics, signs, symptoms, and medications; microbiology, imaging, and associated tests; mechanical ventilation, hospital procedures, and other interventions; and clinical outcomes and hospital stress, with specimens collected on days 0, 3, and 7-14 after enrollment and at discharge. The primary outcome measure is the number of consecutive days alive and free of mechanical ventilation (VFD) in the first 30 days after hospital admission. Important secondary outcomes include organ failure-free days before acute kidney injury, shock, hepatic failure, disseminated intravascular coagulation, 28-day mortality, adaptive immunity, as well as immunologic and microbiologic outcomes. CONCLUSIONS: SARI-Preparedness is a multicenter study under the collaboration of the Society of Critical Care Medicine Discovery, Resilience Intelligence Network, and National Emerging Special Pathogen Training and Education Center, which seeks to improve understanding of prognostic factors associated with worse outcomes and increased resource utilization. This can lead to interventions to mitigate the clinical impact of respiratory virus infections associated with SARI. |
Per- and polyfluoroalkyl substances and incident hypertension in multi-racial/ethnic women: The Study of Women's Health Across the Nation
Ding N , Karvonen-Gutierrez CA , Mukherjee B , Calafat AM , Harlow SD , Park SK . Hypertension 2022 79 (8) 101161hypertensionaha12118809 BACKGROUND: Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are ubiquitous synthetic chemicals that may disrupt blood pressure controls; however, human evidence to support this hypothesis is scant. We examined the association between serum concentrations of PFAS and risks of developing hypertension. METHODS: This study included 1058 midlife women initially free of hypertension from the multiracial and multiethnic SWAN (Study of Women's Health Across the Nation) with annual follow-up visits between 1999 and 2017. Hypertension was defined as blood pressure ≥140 mm Hg systolic or ≥90 mm Hg diastolic or receiving antihypertensive treatment. Cox proportional hazards models were utilized to calculate hazard ratios and 95% CIs. Quantile g-computation was implemented to evaluate the joint effect of PFAS mixtures. RESULTS: During 11 722 person-years of follow-up, 470 participants developed incident hypertension (40.1 cases per 1000 person-years). Compared with the lowest tertile, women in the highest tertile of baseline serum concentrations had adjusted hazard ratios of 1.42 (95% CI, 1.19-1.68) for perfluorooctane sulfonate (P trend=0.01), 1.47 (95% CI, 1.24-1.75) for linear perfluorooctanoate (P trend=0.01), and 1.42 (95% CI, 1.19-1.70) for 2-(N-ethyl-perfluorooctane sulfonamido) acetate (P trend=0.01). No significant associations were observed for perfluorononanoate and perfluorohexane sulfonate. In the mixture analysis, women in the highest tertile of overall PFAS concentrations had a hazard ratio of 1.71 (95% CI, 1.15-2.54; P trend=0.008), compared with those in the lowest tertile. CONCLUSIONS: Several PFAS showed positive associations with incident hypertension. These findings suggest that PFAS might be an underappreciated contributing factor to women's cardiovascular disease risk. |
Per- and polyfluoroalkyl substances and incident diabetes in midlife women: the Study of Women's Health Across the Nation (SWAN)
Park SK , Wang X , Ding N , Karvonen-Gutierrez CA , Calafat AM , Herman WH , Mukherjee B , Harlow SD . Diabetologia 2022 65 (7) 1157-1168 AIMS/HYPOTHESIS: Diabetogenic effects of per- and polyfluoroalkyl substances (PFAS) have been suggested. However, evidence based on prospective cohort studies is limited. We examined the association between serum PFAS concentrations and incident diabetes in the Study of Women's Health Across the Nation Multi-Pollutant Study (SWAN-MPS). METHODS: We included 1237 diabetes-free women aged 45-56 years at baseline (1999-2000) who were followed up to 2017. At each follow-up visit, women with incident diabetes were identified by the presence of one or more of the following conditions: (1) use of a glucose-lowering medication at any visit; (2) fasting glucose ≥7 mmol/l on two consecutive visits while not on steroids; and (3) any two visits with self-reported diabetes and at least one visit with fasting blood glucose ≥7 mmol/l. Serum concentrations of 11 PFAS were quantified by online solid-phase extraction-HPLC-isotope dilution-tandem MS. Seven PFAS with high detection rates (>96%) (n-perfluorooctanoic acid [n-PFOA], perfluorononanoic acid [PFNA], perfluorohexane sulfonic acid [PFHxS], n-perfluorooctane sulfonic acid [n-PFOS], sum of perfluoromethylheptane sulfonic acid isomers [Sm-PFOS], 2-[N-methyl-perfluorooctane sulfonamido] acetic acid [MeFOSAA] and 2-[N-ethyl-perfluorooctane sulfonamido] acetic acid) were included in data analysis. Cox proportional hazards models were used to compute HRs and 95% CIs. Quantile-based g-computation was used to evaluate the joint effects of PFAS mixtures. RESULTS: After adjustment for race/ethnicity, site, education, smoking status, alcohol consumption, total energy intake, physical activity, menopausal status and BMI, the HR (95% CI) comparing the lowest with the highest tertile was 1.67 (1.21, 2.31) for n-PFOA (p(trend) = 0.001), 1.58 (1.13, 2.21) for PFHxS (p(trend) = 0.003), 1.36 (0.97, 1.90) for Sm-PFOS (p(trend) = 0.05), 1.85 (1.28, 2.67) for MeFOSAA (p(trend) = 0.0004) and 1.64 (1.17, 2.31) for the sum of four common PFAS (n-PFOA, PFNA, PFHxS and total PFOS) (p(trend) = 0.002). Exposure to seven PFAS as mixtures was associated with an HR of 2.62 (95% CI 1.12, 6.20), comparing the top with the bottom tertiles for all seven PFAS. CONCLUSIONS/INTERPRETATION: This study suggests that PFAS may increase diabetes risk in midlife women. Reduced exposure to these 'forever and everywhere chemicals' may be an important preventative approach to lowering population-wide diabetes risk. |
Microbial signatures in the lower airways of mechanically ventilated COVID-19 patients associated with poor clinical outcome.
Sulaiman I , Chung M , Angel L , Tsay JJ , Wu BG , Yeung ST , Krolikowski K , Li Y , Duerr R , Schluger R , Thannickal SA , Koide A , Rafeq S , Barnett C , Postelnicu R , Wang C , Banakis S , Pérez-Pérez L , Shen G , Jour G , Meyn P , Carpenito J , Liu X , Ji K , Collazo D , Labarbiera A , Amoroso N , Brosnahan S , Mukherjee V , Kaufman D , Bakker J , Lubinsky A , Pradhan D , Sterman DH , Weiden M , Heguy A , Evans L , Uyeki TM , Clemente JC , de Wit E , Schmidt AM , Shopsin B , Desvignes L , Wang C , Li H , Zhang B , Forst CV , Koide S , Stapleford KA , Khanna KM , Ghedin E , Segal LN . Nat Microbiol 2021 6 (10) 1245-1258 Respiratory failure is associated with increased mortality in COVID-19 patients. There are no validated lower airway biomarkers to predict clinical outcome. We investigated whether bacterial respiratory infections were associated with poor clinical outcome of COVID-19 in a prospective, observational cohort of 589 critically ill adults, all of whom required mechanical ventilation. For a subset of 142 patients who underwent bronchoscopy, we quantified SARS-CoV-2 viral load, analysed the lower respiratory tract microbiome using metagenomics and metatranscriptomics and profiled the host immune response. Acquisition of a hospital-acquired respiratory pathogen was not associated with fatal outcome. Poor clinical outcome was associated with lower airway enrichment with an oral commensal (Mycoplasma salivarium). Increased SARS-CoV-2 abundance, low anti-SARS-CoV-2 antibody response and a distinct host transcriptome profile of the lower airways were most predictive of mortality. Our data provide evidence that secondary respiratory infections do not drive mortality in COVID-19 and clinical management strategies should prioritize reducing viral replication and maximizing host responses to SARS-CoV-2. |
Per- and Polyfluoroalkyl Substances (PFAS) and Hormone Levels during the Menopausal Transition
Harlow SD , Hood MM , Ding N , Mukherjee B , Calafat AM , Randolph JF , Gold EB , Park SK . J Clin Endocrinol Metab 2021 106 (11) e4427-e4437 CONTEXT: Per- and polyfluoroalkyl substances (PFAS) are widespread chemicals that may affect sex hormones and accelerate reproductive aging in midlife women. OBJECTIVE: To examine associations between serum PFAS concentrations at baseline (1999-2000) and longitudinal serum concentrations of follicle stimulating hormone (FSH), estradiol, testosterone, and sex hormone-binding globulin (SHBG) at baseline and through 2015-2016. DESIGN: Prospective cohort. SETTING: General community. PARTICIPANTS: 1,371 midlife women aged 45-56 years at baseline in the Study of Women's Health Across the Nation (SWAN). MAIN OUTCOME MEASURE(S): FSH, estradiol, testosterone, SHBG. RESULTS: In linear mixed models fitted with log-transformed hormones and log-transformed PFAS adjusting for age, site, race/ethnicity, smoking status, menopausal status, parity and body mass index, FSH was positively associated with linear perfluorooctanoate (n-PFOA) (3.12% (95% CI: 0.37%, 5.95%) increase for a doubling in serum concentration), linear perfluorooctane sulfonate (n-PFOS) (2.88% (0.21%, 5.63%)), branched perfluorooctane sulfonate (Sm-PFOS) (2.25% (0.02%, 4.54%)), total PFOS (3.03% (0.37%, 5.76%)), and 2-(N-ethyl-perfluorooctane sulfonamido) acetate (EtFOSAA) (1.70% (0.01%, 3.42%)). Estradiol was inversely associated with perfluorononanoate (PFNA) (-2.47% (-4.82%, -0.05%)) and n-PFOA (-2.43% (-4.97%, 0.18%)). Significant linear trends were observed in the associations between PFOS and EtFOSAA with SHBG across parity (Ps-trend≤0.01), with generally inverse associations among nulliparous women but positive associations among women with 3+ births. No significant associations were observed between PFAS and testosterone. CONCLUSIONS: This study observed positive associations of PFOA and PFOS with FSH and inverse associations of PFNA and PFOA with estradiol in midlife women during the menopausal transition, consistent with findings that PFAS affect reproductive aging. |
Associations of perfluoroalkyl and polyfluoroalkyl substances (PFAS) and PFAS mixtures with adipokines in midlife women
Ding N , Karvonen-Gutierrez CA , Herman WH , Calafat AM , Mukherjee B , Park SK . Int J Hyg Environ Health 2021 235 113777 BACKGROUND: Perfluoroalkyl and polyfluoroalkyl substances (PFAS) exposure have been associated with obesity and related comorbidities, possibly through disrupting signaling pathways of adipokines. Both leptin and adiponectin can modulate metabolic processes. However, the effects of PFAS on adipokines are not well understood. OBJECTIVE: We determined if serum PFAS concentrations were associated with adipokine profiles in midlife women. METHODS: We examined 1245 women aged 45-56 years from the Study of Women's Health Across the Nation. Concentrations of 11 PFAS were quantified in baseline serum samples collected in 1999-2000. Linear and branched perfluorooctane sulfonic acid isomers (n-PFOS and Sm-PFOS) and their sum (PFOS), linear perfluorooctanoic acid (n-PFOA), perfluorononanoic acid (PFNA), perfluorohexane sulfonic acid (PFHxS), 2-(N-methyl-perfluorooctane sulfonamido) acetic acid (MeFOSAA), and 2-(N-ethyl-perfluorooctane sulfonamido) acetic acid (EtFOSAA) with detection frequencies >60% were included in the analysis. Adipokines including leptin, soluble leptin receptor (sOB-R), free leptin index (FLI, the ratio of leptin to sOB-R), total and high molecular weight (HMW) adiponectin were assessed in 2002-2003. We utilized multivariable linear regressions and Bayesian kernel machine regression (BKMR) to assess individual and overall joint effects of PFAS on adipokines with adjustment for age, race/ethnicity, study site, education, smoking status, physical activity, menopausal status, and waist circumference. RESULTS: A doubling of PFAS concentrations was associated with 7.8% (95% CI: 2.5%, 13.4%) higher FLI for PFOS, 9.4% (95% CI: 3.7%, 15.3%) for n-PFOA, 5.5% (95% CI: 2.2%, 9.0%) for EtFOSAA and 7.4% (95% CI: 2.8%, 12.2%) for MeFOSAA. Similar associations were found for leptin. Only EtFOSAA was associated with lower sOB-R concentrations (-1.4%, 95% CI: -2.7%, -0.1%). Results remained in women with overweight or obesity but not those with normal weight or underweight. No statistically significant associations were observed with total or HMW adiponectin, except for PFNA with total and HMW adiponectin observed in women with normal weight or underweight. In BKMR analysis, women with PFAS concentrations at the median and the 90th percentile had 30.9% (95% CI: 15.6%, 48.3%) and 52.1% (95% CI: 27.9%, 81.0%) higher FLI, respectively, compared with those with concentrations fixed at the 10th percentile. CONCLUSION: Some PFAS may alter circulating levels of leptin. Understanding associations between PFAS and adipokines may help elucidate whether PFAS can influence obesity and metabolic disease. |
Perfluoroalkyl and polyfluoroalkyl substances and body size and composition trajectories in midlife women: the Study of Women's Health Across the Nation 1999-2018
Ding N , Karvonen-Gutierrez CA , Herman WH , Calafat AM , Mukherjee B , Park SK . Int J Obes (Lond) 2021 45 (9) 1937-1948 BACKGROUND/OBJECTIVES: Perfluoroalkyl and polyfluoroalkyl substances (PFAS) have been suggested as obesogens but epidemiologic evidence is limited. We examined associations of serum PFAS concentrations with longitudinal trajectories of weight, waist circumference (WC), fat mass, and proportion fat in midlife women. SUBJECTS/METHODS: This study included 1,381 midlife women, with a total of 15,000 repeated measures from the multi-racial/ethnic Study of Women's Health Across the Nation between 1999 and 2018. The average follow-up was 14.9 (range: 0-18.6) years. Body size (objectively measured weight and WC) and body composition from dual-energy X-ray absorptiometry were assessed at near-annual visits. Linear mixed models with piecewise linear splines were utilized to model non-linear trajectories of body size and composition. RESULTS: After multivariable adjustment, PFAS concentrations were positively associated with weight, WC, fat mass, and proportion fat at baseline and during follow-up. Comparing the highest to the lowest tertiles of PFAS concentrations, adjusted geometric mean weight was 73.9 kg vs. 69.6 kg for PFOS (P < 0.0001), and 74.0 vs. 69.4 kg for linear PFOA (P < 0.0001) at baseline. Women with the highest tertile of PFOS had an annual increase rate of 0.33% (95% CI: 0.27%, 0.40%) in weight, compared to the lowest tertile with 0.10% (95% CI: 0.04%, 0.17%) (P < 0.0001). PFOS was also significantly related to higher increase rates in WC (difference = 0.12% per year, P = 0.002) and fat mass (difference = 0.25% per year, P = 0.0002). EtFOSAA and MeFOSAA showed similar effects to PFOS. Although PFHxS was not related to body size or fat at baseline, PFHxS was significantly associated with accelerated increases in weight (P < 0.0001), WC (P = 0.003), fat mass (P < 0.0001), and proportion fat (P = 0.0009). No significant results were found for PFNA. CONCLUSIONS: Certain PFAS were positively associated with greater body size and body fat, and higher rates of change over time. PFAS may be an underappreciated contributing factor to obesity risk. |
Multi-walled carbon nanotubes elicit concordant changes in DNA methylation and gene expression following long-term pulmonary exposure in mice
Scala G , Delaval MN , Mukherjee SP , Federico A , Khaliullin TO , Yanamala N , Fatkhutdinova LM , Kisin ER , Greco D , Fadeel B , Shvedova AA . Carbon N Y 2021 178 563-572 Pulmonary exposure to multi-walled carbon nanotubes (MWCNTs) causes inflammation and fibrosis. Our previous work has shown that industrially produced MWCNTs trigger specific changes in gene expression in the lungs of exposed animals. To elucidate whether epigenetic effects play a role for these gene expression changes, we performed whole genome bisulphite sequencing to assess DNA methylation patterns in the lungs 56 days after exposure to MWCNTs. Lung tissues were also evaluated with respect to histopathological changes and cytokine profiling of bronchoalveolar lavage (BAL) fluid was conducted using a multi-plex array. Integrated analysis of transcriptomics data and DNA methylation data revealed concordant changes in gene expression. Functional analysis showed that the muscle contraction, immune system/inflammation, and extracellular matrix pathways were the most affected pathways. Taken together, the present study revealed that MWCNTs exert epigenetic effects in the lungs of exposed animals, potentially driving the subsequent gene expression changes. © 2021 The Authors |
Associations of perfluoroalkyl substances with incident natural menopause: the Study of Women's Health Across the Nation
Ding N , Harlow SD , Randolph JF , Calafat AM , Mukherjee B , Batterman S , Gold EB , Park SK . J Clin Endocrinol Metab 2020 105 (9) e3169-82 CONTEXT: Previous epidemiologic studies of per- and polyfluoroalkyl substances (PFAS) and menopausal timing conducted in cross-sectional settings were limited by reverse causation because PFAS serum concentrations increase after menopause. OBJECTIVES: To investigate associations between perfluoroalkyl substances and incident natural menopause. DESIGN AND SETTING: A prospective cohort of midlife women, the Study of Women's Health Across the Nation, 1999-2017. PARTICIPANTS: 1120 multi-racial/ethnic premenopausal women aged 45-56 years. METHODS: Serum concentrations of perfluoroalkyls were quantified by high performance liquid chromatography-isotope dilution-tandem mass spectrometry. Natural menopause was defined as the bleeding episode prior to at least 12 months of amenorrhea not due to surgery or hormone use. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Participants contributed 5466 person-years of follow-up, and 578 had incident natural menopause. Compared to the lowest tertile, women at the highest tertile of baseline serum concentrations had adjusted HR for natural menopause of 1.26 (95%CI: 1.02-1.57) for n-perfluorooctane sulfonic acid (n-PFOS) (Ptrend=0.03), 1.27 (95%CI: 1.01-1.59) for branched-PFOS (Ptrend=0.03), and 1.31 (95%CI: 1.04-1.65) for n-perfluorooctanoic acid (Ptrend=0.01). Women were classified into four clusters based on their overall PFAS concentrations as mixtures: low, low-medium, medium-high, and high. Compared to the low cluster, the high cluster had a HR of 1.63 (95% CI: 1.08-2.45), which is equivalent to 2.0 years earlier median time to natural menopause. CONCLUSION: This study suggests that select PFAS serum concentrations are associated with earlier natural menopause, a risk factor for adverse health outcomes in later life. |
Immunologic timeline of Ebola virus disease and recovery in humans
McElroy AK , Akondy RS , McLlwain DR , Chen H , Bjornson-Hooper Z , Mukherjee N , Mehta AK , Nolan G , Nichol ST , Spiropoulou CF . JCI Insight 2020 5 (10) A complete understanding of human immune responses to Ebola virus infection is limited by the availability of specimens and the requirement for biosafety level 4 (BSL-4) containment. In an effort to bridge this gap, we evaluated cryopreserved PBMCs from 4 patients who survived Ebola virus disease (EVD) using an established mass cytometry antibody panel to characterize various cell populations during both the acute and convalescent phases. Acute loss of nonclassical monocytes and myeloid DCs, especially CD1c+ DCs, was noted. Classical monocyte proliferation and CD38 upregulation on plasmacytoid DCs coincided with declining viral load. Unsupervised analysis of cell abundance demonstrated acute declines in monocytic, NK, and T cell populations, but some populations, many of myeloid origin, increased in abundance during the acute phase, suggesting emergency hematopoiesis. Despite cell losses during the acute phase, upregulation of Ki-67 correlated with recovery of cell populations over time. These data provide insights into the human immune response during EVD. |
A repeated measures study of phenol, paraben and triclocarban urinary biomarkers and circulating maternal hormones during gestation in the Puerto Rico PROTECT cohort
Aker AM , Ferguson KK , Rosario ZY , Mukherjee B , Alshawabkeh AN , Calafat AM , Cordero JF , Meeker JD . Environ Health 2019 18 (1) 28 INTRODUCTION: Prenatal exposure to some phenols and parabens has been associated with adverse birth outcomes. Hormones may play an intermediate role between phenols and adverse outcomes. We examined the associations of phenol and paraben exposures with maternal reproductive and thyroid hormones in 602 pregnant women in Puerto Rico. Urinary triclocarban, phenol and paraben biomarkers, and serum hormones (estriol, progesterone, testosterone, sex-hormone-binding globulin (SHBG), corticotropin-releasing hormone (CRH), total triiodothyronine (T3), total thyroxine (T4), free thyroxine (FT4) and thyroid-stimulating hormone (TSH)) were measured at two visits during pregnancy. METHODS: Linear mixed models with a random intercept were constructed to examine the associations between hormones and urinary biomarkers. Results were additionally stratified by study visit. Results were transformed to hormone percent changes for an inter-quartile-range difference in exposure biomarker concentrations (%Delta). RESULTS: Bisphenol-S was associated with a decrease in CRH [(%Delta -11.35; 95% CI: -18.71, - 3.33), and bisphenol-F was associated with an increase in FT4 (%Delta: 2.76; 95% CI: 0.29, 5.22). Butyl-, methyl- and propylparaben were associated with decreases in SHBG [(%Delta: -5.27; 95% CI: -9.4, - 1.14); (%Delta: -3.53; 95% CI: -7.37, 0.31); (%Delta: -3.74; 95% CI: -7.76, 0.27)]. Triclocarban was positively associated with T3 (%Delta: 4.08; 95% CI: 1.18, 6.98) and T3/T4 ratio (%Delta: 4.67; 95% CI: -1.37, 6.65), and suggestively negatively associated with TSH (%Delta: -10.12; 95% CI: -19.47, 0.32). There was evidence of susceptible windows of vulnerability for some associations. At 24-28 weeks gestation, there was a positive association between 2,4-dichlorophenol and CRH (%Delta: 9.66; 95% CI: 0.67, 19.45) and between triclosan and estriol (%Delta: 13.17; 95% CI: 2.34, 25.2); and a negative association between triclocarban and SHBG (%Delta: -9.71; 95% CI:-19.1, - 0.27) and between bisphenol A and testosterone (%Delta: -17.37; 95% CI: -26.7, - 6.87). CONCLUSION: Phenols and parabens are associated with hormone levels during pregnancy. Further studies are required to substantiate these findings. |
CDK5 inhibition resolves PKA/cAMP-independent activation of CREB1 signaling in glioma stem cells
Mukherjee S , Tucker-Burden C , Kaissi E , Newsam A , Duggireddy H , Chau M , Zhang C , Diwedi B , Rupji M , Seby S , Kowalski J , Kong J , Read R , Brat DJ . Cell Rep 2018 23 (6) 1651-1664 Cancer stem cells promote neoplastic growth, in part by deregulating asymmetric cell division and enhancing self-renewal. To uncover mechanisms and potential therapeutic targets in glioma stem cell (GSC) self-renewal, we performed a genetic suppressor screen for kinases to reverse the tumor phenotype of our Drosophila brain tumor model and identified dCdk5 as a critical regulator. CDK5, the human ortholog of dCdk5 (79% identity), is aberrantly activated in GBMs and tightly aligned with both chromosome 7 gains and stem cell markers affecting tumor-propagation. Our investigation revealed that pharmaceutical inhibition of CDK5 prevents GSC self-renewal in vitro and in xenografted tumors, at least partially by suppressing CREB1 activation independently of PKA/cAMP. Finally, our TCGA GBM data analysis revealed that CDK5, stem cell, and asymmetric cell division markers segregate within non-mesenchymal patient clusters, which may indicate preferential dependence on CDK5 signaling and sensitivity to its inhibition in this group. |
Macrophage sensing of single-walled carbon nanotubes via Toll-like receptors
Mukherjee SP , Bondarenko O , Kohonen P , Andon FT , Brzicova T , Gessner I , Mathur S , Bottini M , Calligari P , Stella L , Kisin E , Shvedova A , Autio R , Salminen-Mankonen H , Lahesmaa R , Fadeel B . Sci Rep 2018 8 (1) 1115 Carbon-based nanomaterials including carbon nanotubes (CNTs) have been shown to trigger inflammation. However, how these materials are 'sensed' by immune cells is not known. Here we compared the effects of two carbon-based nanomaterials, single-walled CNTs (SWCNTs) and graphene oxide (GO), on primary human monocyte-derived macrophages. Genome-wide transcriptomics assessment was performed at sub-cytotoxic doses. Pathway analysis of the microarray data revealed pronounced effects on chemokine-encoding genes in macrophages exposed to SWCNTs, but not in response to GO, and these results were validated by multiplex array-based cytokine and chemokine profiling. Conditioned medium from SWCNT-exposed cells acted as a chemoattractant for dendritic cells. Chemokine secretion was reduced upon inhibition of NF-kappaB, as predicted by upstream regulator analysis of the transcriptomics data, and Toll-like receptors (TLRs) and their adaptor molecule, MyD88 were shown to be important for CCL5 secretion. Moreover, a specific role for TLR2/4 was confirmed by using reporter cell lines. Computational studies to elucidate how SWCNTs may interact with TLR4 in the absence of a protein corona suggested that binding is guided mainly by hydrophobic interactions. Taken together, these results imply that CNTs may be 'sensed' as pathogens by immune cells. |
Engineering Botulinum Neurotoxin C1 as a Molecular Vehicle for Intra-Neuronal Drug Delivery.
Vazquez-Cintron EJ , Beske PH , Tenezaca L , Tran BQ , Oyler JM , Glotfelty EJ , Angeles CA , Syngkon A , Mukherjee J , Kalb SR , Band PA , McNutt PM , Shoemaker CB , Ichtchenko K . Sci Rep 2017 7 42923 Botulinum neurotoxin (BoNT) binds to and internalizes its light chain into presynaptic compartments with exquisite specificity. While the native toxin is extremely lethal, bioengineering of BoNT has the potential to eliminate toxicity without disrupting neuron-specific targeting, thereby creating a molecular vehicle capable of delivering therapeutic cargo into the neuronal cytosol. Building upon previous work, we have developed an atoxic derivative (ad) of BoNT/C1 through rationally designed amino acid substitutions in the metalloprotease domain of wild type (wt) BoNT/C1. To test if BoNT/C1 ad retains neuron-specific targeting without concomitant toxic host responses, we evaluated the localization, activity, and toxicity of BoNT/C1 ad in vitro and in vivo. In neuronal cultures, BoNT/C1 ad light chain is rapidly internalized into presynaptic compartments, but does not cleave SNARE proteins nor impair spontaneous neurotransmitter release. In mice, systemic administration resulted in the specific co-localization of BoNT/C1 ad with diaphragmatic motor nerve terminals. The mouse LD50 of BoNT/C1 ad is 5 mg/kg, with transient neurological symptoms emerging at sub-lethal doses. Given the low toxicity and highly specific neuron-targeting properties of BoNT/C1 ad, these data suggest that BoNT/C1 ad can be useful as a molecular vehicle for drug delivery to the neuronal cytoplasm. |
Hollow carbon spheres trigger inflammasome-dependent IL-1beta secretion in macrophages
Andon FT , Mukherjee SP , Gessner I , Wortmann L , Xiao L , Hultenby K , Shvedova AA , Mathur S , Fadeel B . Carbon N Y 2017 113 243-251 It is disputed whether inflammasome activation leading to secretion of pro-inflammatory interleukin (IL)-1beta in macrophages transpires independently of cell death or whether the two processes are linked. Here, we synthesized hollow carbon spheres (HCS) and investigated their effects on primary human monocyte-derived macrophages (HMDM); short (500 nm) non-functionalized single-walled carbon nanotubes (SWCNT) were included for comparison. HCS (250 nm) were readily taken up by HMDM and induced ROS production, but did not trigger a loss of cell viability. However, a dose- and time-dependent release of IL-1beta was detected in lipopolysaccharide (LPS)-primed macrophages upon exposure to HCS, while SWCNT-induced secretion of IL-1β was less pronounced. HCS-triggered IL-1beta secretion was cathepsin B- and caspase-1-dependent, and was accompanied by a reduction in intracellular K+. Furthermore, cytokine secretion was reduced following treatment with the antioxidant, N-acetylcysteine, and cytochalasin D, an inhibitor of actin polymerization. HCS also triggered IL-1beta release in LPS-primed THP.1 cells, but not in THP.1 cells with silencing of ASC, NLRP3, or caspase-1 expression, providing evidence that IL-1beta was elicited through NLRP3 inflammasome activation. These studies shed light on the effects of HCS on primary macrophages, and show that spherical carbon-based nanoparticles are potent inflammasome activators. |
MRSA and multidrug-resistant Staphylococcus aureus in U.S. retail meats, 2010–2011
Ge B , Mukherjee S , Hsu CH , Davis JA , Tran TTT , Yang Q , Abbott JW , Ayers SL , Young SR , Crarey ET , Womack NA , Zhao S , McDermott PF . Food Microbiol 2017 62 289-297 Methicillin-resistant Staphylococcus aureus (MRSA) has been detected in retail meats, although large-scale studies are scarce. We conducted a one-year survey in 2010–2011 within the framework of the National Antimicrobial Resistance Monitoring System. Among 3520 retail meats collected from eight U.S. states, 982 (27.9%) contained S. aureus and 66 (1.9%) were positive for MRSA. Approximately 10.4% (107/1032) of S. aureus isolates, including 37.2% (29/78) of MRSA, were multidrug-resistant (MDRSA). Turkey had the highest MRSA prevalence (3.5%), followed by pork (1.9%), beef (1.7%), and chicken (0.3%). Whole-genome sequencing was performed for all 66 non-redundant MRSA. Among five multilocus sequence types identified, ST8 (72.7%) and ST5 (22.7%) were most common and livestock-associated MRSA ST398 was assigned to one pork isolate. Eleven spa types were represented, predominately t008 (43.9%) and t2031 (22.7%). All four types of meats harbored t008, whereas t2031 was recovered from turkey only. The majority of MRSA (84.8%) possessed SCCmec IV and 62.1% harbored Panton-Valentine leukocidin. Pulsed-field gel electrophoresis showed that all ST8 MRSA belonged to the predominant human epidemic clone USA300, and others included USA100 and USA200. We conclude that a diverse MRSA population was present in U.S. retail meats, albeit at low prevalence. |
Whole Genome Sequencing Analysis Accurately Predicts Antimicrobial Resistance Phenotypes in Campylobacter.
Zhao S , Tyson GH , Chen Y , Li C , Mukherjee S , Young S , Lam C , Folster JP , Whichard JM , McDermott PF . Appl Environ Microbiol 2015 82 (2) 459-66 OBJECTIVES: The objectives of this study were to identify antimicrobial resistance genotypes for Campylobacter and to evaluate the correlation between resistance phenotypes and genotypes using in vitro antimicrobial susceptibility testing and whole-genome sequencing (WGS). METHODS: One hundred-fourteen Campylobacter sp. (82 C. coli and 32 C. jejuni) isolated from 2000-2013 from ill humans, retails meats and cecal samples from food production animals in the United States as part of the National Antimicrobial Resistance Monitoring System were selected for study. Resistance phenotypes were determined using broth micro-dilution of nine antimicrobials. Genomic DNA was sequenced using the Illumina MiSeq platform, and resistance genotypes were identified using assembled WGS sequences through BLASTx analysis. RESULTS: Eighteen resistance genes, including tetO, blaOXA-61, catA, lnuC, aph(2' ')-Ib, aph(2' ')-Ic, aph(2')-If, aph(2' ')-Ig, aph(2' ')-Ih, aac(6')-Ie/aph(2' ')-Ia, aac(6')-Ie/aph(2' ')-If, aac(6')-Im, aadE, sat4, ant(6'), aad9, aph(3')-Ic, aph(3')-IIIa, and mutations in two house-keeping genes (gyrA and 23S rRNA) were identified. There was a high degree of correlation between phenotypic resistance to a given drug and the presence of one or more corresponding resistance genes. Phenotypic and genotypic correlation was 100% for tetracycline, ciprofloxacin/nalidixic acid, and erythromycin and ranged from 95.4% to 98.7% for gentamicin, azithromycin, clindamycin, and telithromycin. All isolates were susceptible to florfenicol, and no genes associated with florfenicol resistance were detected. CONCLUSIONS: There was a strong correlation (99.2%) between resistance genotypes and phenotypes, suggesting that WGS is a reliable indicator of resistance to the nine antimicrobial agents assayed in this study. WGS has the potential to be a powerful tool for antimicrobial resistance surveillance programs. |
The movement of multidrug-resistant tuberculosis across borders in East Africa needs a regional and global solution
Cain KP , Marano N , Kamene M , Sitienei J , Mukherjee S , Galev A , Burton J , Nasibov O , Kioko J , De Cock KM . PLoS Med 2015 12 (2) e1001791 Kevin Cain and colleagues reflect on the cross border movement of people from Somalia with MDR-TB and the implications for MDR-TB programs in East Africa. |
Novel gentamicin resistance genes in Campylobacter isolated from humans and retail meats in the USA.
Zhao S , Mukherjee S , Chen Y , Li C , Young S , Warren M , Abbott J , Friedman S , Kabera C , Karlsson M , McDermott PF . J Antimicrob Chemother 2015 70 (5) 1314-21 OBJECTIVES: To understand the molecular epidemiology of gentamicin-resistant Campylobacter and investigate aminoglycoside resistance mechanisms. METHODS: One-hundred-and-fifty-one gentamicin-resistant Campylobacter isolates from humans (n = 38 Campylobacter jejuni; n = 41, Campylobacter coli) and retail chickens (n = 72 C. coli), were screened for the presence of gentamicin resistance genes by PCR and subtyped using PFGE. A subset of the isolates (n = 41) was analysed using WGS. RESULTS: Nine variants of gentamicin resistance genes were identified: aph(2'')-Ib, Ic, Ig, If, If1, If3, Ih, aac(6')-Ie/aph(2'')-Ia and aac(6')-Ie/aph(2'')-If2. The aph(2'')-Ib, Ic, If1, If3, Ih and aac(6')-Ie/aph(2'')-If2 variants were identified for the first time in Campylobacter. Human isolates showed more diverse aminoglycoside resistance genes than did retail chicken isolates, in which only aph(2'')-Ic and -Ig were identified. The aph(2'')-Ig gene was only gene shared by C. coli isolates from human (n = 27) and retail chicken (n = 69). These isolates displayed the same resistance profile and similar PFGE patterns, suggesting that contaminated retail chicken was probably the source of human C. coli infections. Human isolates were genetically diverse and generally more resistant than the retail chicken isolates. The most frequent co-resistance was to tetracycline (78/79, 98.7%), followed by ciprofloxacin/nalidixic acid (46/79, 58.2%), erythromycin and azithromycin (36/79, 45.6%), telithromycin (32/79, 40.5%) and clindamycin (18/79, 22.8%). All human and retail meat isolates were susceptible to florfenicol. CONCLUSIONS: This study demonstrated that several new aminoglycoside resistance genes underlie the recent emergence of gentamicin-resistant Campylobacter, and that, in addition to contaminated retail chicken, other sources have also contributed to gentamicin-resistant Campylobacter infections in humans. |
Urinary phthalate metabolite associations with biomarkers of inflammation and oxidative stress across pregnancy in Puerto Rico
Ferguson KK , Cantonwine DE , Rivera-Gonzalez LO , Loch-Caruso R , Mukherjee B , Anzalota Del Toro LV , Jimenez-Velez B , Calafat AM , Ye X , Alshawabkeh AN , Cordero JF , Meeker JD . Environ Sci Technol 2014 48 (12) 7018-25 Phthalate exposure during pregnancy has been linked to adverse birth outcomes such as preterm birth, and inflammation and oxidative stress may mediate these relationships. In a prospective cohort study of pregnant women recruited early in gestation in Northern Puerto Rico, we investigated the associations between urinary phthalate metabolites and biomarkers of inflammation, including C-reactive protein, IL-1beta, IL-6, IL-10, and TNF-alpha, and oxidative stress, including 8-hydroxydeoxyguanosine (OHdG) and 8-isoprostane. Inflammation biomarkers were measured in plasma twice during pregnancy (N = 215 measurements, N = 120 subjects), and oxidative stress biomarkers in urine were measured three times (N = 148 measurements, N = 54 subjects) per woman. In adjusted linear mixed models, metabolites of di-2-ethylhexyl phthalate (DEHP) were associated with increased IL-6 and IL-10 but relationships were generally not statistically significant. All phthalates were associated with increases in oxidative stress markers. Relationships with OHdG were significant for DEHP metabolites as well as mono-n-butyl phthalate (MBP) and monoiso-butyl phthalate (MiBP). For 8-isoprostane, associations with nearly all phthalates were statistically significant and the largest effect estimates were observed for MBP and MiBP (49-50% increase in 8-isoprostane with an interquartile range increase in metabolite concentration). These relationships suggest a possible mechanism for phthalate action that may be relevant to a number of adverse health outcomes. |
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