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1.
Nat Immunol ; 13(9): 888-99, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22797772

ABSTRACT

Although much progress has been made in the understanding of the ontogeny and function of dendritic cells (DCs), the transcriptional regulation of the lineage commitment and functional specialization of DCs in vivo remains poorly understood. We made a comprehensive comparative analysis of CD8(+), CD103(+), CD11b(+) and plasmacytoid DC subsets, as well as macrophage DC precursors and common DC precursors, across the entire immune system. Here we characterized candidate transcriptional activators involved in the commitment of myeloid progenitor cells to the DC lineage and predicted regulators of DC functional diversity in tissues. We identified a molecular signature that distinguished tissue DCs from macrophages. We also identified a transcriptional program expressed specifically during the steady-state migration of tissue DCs to the draining lymph nodes that may control tolerance to self tissue antigens.


Subject(s)
Cell Differentiation/immunology , Cell Lineage/immunology , Dendritic Cells/immunology , Transcription, Genetic , Cell Differentiation/genetics , Dendritic Cells/cytology , Gene Expression Profiling , Humans
2.
Pain Manag Nurs ; 24(5): 558-566, 2023 10.
Article in English | MEDLINE | ID: mdl-37455185

ABSTRACT

BACKGROUND: Substance use disorders (SUDs) are highly prevalent among adults with persistent pain. Yet, standard competencies for integrating pain and SUD content are lacking across health science student curricula. Additionally, pharmacotherapies to treat SUDs are underutilized. AIM: To address these gaps, a team of health science faculty created an interprofessional simulation activity using a standardized patient and evaluated learner outcomes related to assessment and treatment of comorbid persistent pain and substance use. METHODS: A total of 304 health science students representing nursing, medicine, pharmacy, and social work programs attended virtual learning sessions. Interprofessional student teams developed a team-based care plan for an adult with musculoskeletal pain who takes prescribed opioids while using alcohol. Pre- and post-activity surveys assessing knowledge and confidence were matched for 198 students. Descriptive statistics summarized survey data with inferential analysis of paired data. RESULTS: The largest significant improvements between pre- and post-activity knowledge were observed in items specific to pharmacotherapy options for alcohol and opioid use disorders. Similar gains were noted in students' confidence regarding pharmacotherapies. No significant differences were noted on pre-post-activity knowledge scores between the three main profession groups (medicine, nursing, and pharmacy). CONCLUSIONS: Students attending this interprofessional simulation demonstrated improved knowledge and confidence, particularly in pharmacotherapies for alcohol and opioid use disorders. Replication of such programs can be used to provide consistent content across health science disciplines to heighten awareness and receptivity to medications available to treat SUDs in people treated for persistent pain. The curriculum is freely available from the corresponding author.


Subject(s)
Interprofessional Education , Opioid-Related Disorders , Humans , Adult , Program Evaluation , Curriculum , Pain
3.
Curr Cardiol Rep ; 23(1): 1, 2020 11 20.
Article in English | MEDLINE | ID: mdl-33216256

ABSTRACT

PURPOSE OF REVIEW: Despite the promise of remote patient monitoring (RPM), this technology remained underutilized secondary to a lack of data transparency and systems issues until the COVID-19 pandemic ushered in a new era of telehealth and virtual solutions out of necessity. This review will explore the data supporting the use of RPM via both implantable and wearable devices in the field of cardiology and the role of home monitoring using RPM in the era of COVID-19. RECENT FINDINGS: RPM using implantable cardiac devices is a safe alternative to in-person only visits which leads to enhanced patient satisfaction and improved clinical outcomes. Consumer-grade wearable sensors have drastically expanded RPM capabilities from just the sickest cardiac patients to the entire population aiding in early diagnosis and real-time disease management. Home monitoring enabled by automated alert systems tailored specifically to the needs of the patient by the provider will be the cornerstone of a more continuous, patent-centric healthcare model.


Subject(s)
COVID-19 , Defibrillators, Implantable , Telemedicine , Humans , Pandemics , SARS-CoV-2
4.
J Immunol ; 189(5): 2488-501, 2012 Sep 01.
Article in English | MEDLINE | ID: mdl-22851707

ABSTRACT

Localized elevation in type I IFN has been uniquely linked to the severe Lyme arthritis that develops in C3H mice infected with the spirochete Borrelia burgdorferi. In this study, the dynamic interactions that result in generation of these responses were further examined in C3H mice carrying the type I IFN receptor gene ablation, which effectively blocks all autocrine/paracrine signaling crucial to induction of downstream effectors. Reciprocal radiation chimeras between C3H and IFNAR1Ć¢ĀĀ»/Ć¢ĀĀ» mice implicated both radiation-sensitive and radiation-resistant cells of the joint tissue in the proarthritic induction of type I IFN. Ex vivo analysis of cells from the naive joint revealed CD45Ć¢ĀĀŗ cells residing in the tissue to be uniquely capable of initiating the type I IFN response to B. burgdorferi. Type I IFN responses were analyzed in real time by lineage sorting of cells from infected joint tissue. This demonstrated that myeloid cells, endothelial cells, and fibroblasts were responsible for propagating the robust IFN response, which peaked at day 7 postinfection and rapidly resolved. Endothelial cells and fibroblasts were the dominant sources of IFN signature transcripts in the joint tissue. Fibroblasts were also the major early source of chemokines associated with polymorphonuclear leukocyte and monocyte/macrophage infiltration, thus providing a focal point for arthritis development. These findings suggest joint-localized interactions among related and unrelated stromal, endothelial, and myeloid cell lineages that may be broadly applicable to understanding the pathogeneses of diseases associated with type I IFN signature, including systemic lupus erythematosus and some rheumatoid arthritides.


Subject(s)
Arthritis, Experimental/immunology , Fibroblasts/immunology , Interferon Type I/biosynthesis , Lyme Disease/immunology , Myeloid Cells/immunology , Up-Regulation/immunology , Animals , Ankle Joint/immunology , Ankle Joint/microbiology , Ankle Joint/pathology , Arthritis, Experimental/metabolism , Arthritis, Experimental/pathology , Borrelia burgdorferi/immunology , Borrelia burgdorferi/pathogenicity , Cells, Cultured , Chemokines/biosynthesis , Chemokines/genetics , Fibroblasts/metabolism , Fibroblasts/pathology , Interferon Type I/deficiency , Interferon Type I/genetics , Lyme Disease/metabolism , Lyme Disease/pathology , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Mice, Knockout , Myeloid Cells/metabolism , Myeloid Cells/pathology , Severity of Illness Index , Signal Transduction/immunology , Transcription, Genetic/immunology , Up-Regulation/genetics
5.
Neurocrit Care ; 21(1): 20-6, 2014 Aug.
Article in English | MEDLINE | ID: mdl-23839704

ABSTRACT

BACKGROUND: Severe middle cerebral artery stroke (MCA) is associated with a high rate of morbidity and mortality. We assessed the hypothesis that patient-specific variables may be associated with outcomes. We also sought to describe under-recognized patient-centered outcomes. METHODS: A consecutive, multi-institution, retrospective cohort of adult patients (≤70 years) was established from 2009 to 2011. We included patients with NIHSS score ≥15 and infarct volume ≥60 mL measured within 48 h of symptom onset. Malignant edema was defined as the development of midline brain shift of ≥5 mm in the first 5 days. Exclusion criterion was enrollment in any experimental trial. A univariate and multivariate logistic regression analysis was performed to model and predict the factors related to outcomes. RESULTS: 46 patients (29 female, 17 male; mean age 57.3 Ā± 1.5 years) met study criteria. The mortality rate was 28% (n = 13). In a multivariate analysis, only concurrent anterior cerebral artery (ACA) involvement was associated with mortality (OR 9.78, 95% CI 1.15, 82.8, p = 0.04). In the malignant edema subgroup (n = 23, 58%), 4 died (17%), 7 underwent decompressive craniectomy (30%), 7 underwent tracheostomy (30%), and 15 underwent gastrostomy (65%). CONCLUSIONS: Adverse outcomes after severe stroke are common. Concurrent ACA involvement predicts mortality in severe MCA stroke. It is useful to understand the incidence of life-sustaining procedures, such as tracheostomy and gastrostomy, as well as factors that contribute to their necessity.


Subject(s)
Brain Edema/mortality , Infarction, Anterior Cerebral Artery/mortality , Infarction, Middle Cerebral Artery/mortality , Patient Outcome Assessment , Brain Edema/surgery , Female , Humans , Infarction, Anterior Cerebral Artery/pathology , Infarction, Middle Cerebral Artery/pathology , Infarction, Middle Cerebral Artery/therapy , Male , Middle Aged , Severity of Illness Index
6.
Am J Pharm Educ ; 88(9): 101252, 2024 Sep.
Article in English | MEDLINE | ID: mdl-39053812

ABSTRACT

OBJECTIVE: To evaluate experiential pharmacy preceptor perceptions of student pharmacists' ability to administer pediatric immunizations. METHODS: Semi-structured, qualitative key informant interviews using the Outcomes Evaluation Framework were conducted with 10 pharmacist preceptors in outpatient community pharmacies where pediatric immunizations were provided. Interviews were audio-recorded, transcribed, and deidentified prior to analysis by the research team. Qualitative analysis and thematic coding procedures were used to identify relevant themes. RESULTS: Saturation was met after 10 pharmacists participated. All stated that it was beneficial for student pharmacists to administer pediatric vaccines if trained in proper technique. Participants acknowledged that the training students currently receive in immunization administration within the PharmD curriculum is valuable but did identify general confidence and child-comforting techniques during and after vaccination as areas of improvement for students. Just-in-time training, preceptor coaching, and hands-on practice outside of the didactic curriculum were utilized to help build confidence. Barriers to the implementation or expansion of pediatric immunization delivered by students in community pharmacies were identified as competing priorities, time, and reimbursement. CONCLUSION: Student pharmacists can be helpful in easing the challenges of incorporating pediatric immunization services into the community pharmacy setting. Results demonstrate that the integration of student pharmacists into these services is beneficial. Pediatric immunizations are still relatively new to many pharmacists and specific training for pediatric immunization administration may not be integrated into all Doctor of Pharmacy curricula but the experiential education of pediatric immunization training can be beneficial to help prepare student pharmacists for hands-on practice.


Subject(s)
Immunization , Preceptorship , Students, Pharmacy , Humans , Community Pharmacy Services , Pharmacists , Curriculum , Feedback , Education, Pharmacy/methods , Clinical Competence , Female , Male , Child
7.
Front Psychol ; 15: 1348119, 2024.
Article in English | MEDLINE | ID: mdl-38689722

ABSTRACT

Introduction: Group living skills (GLS), that is, being tidy and considerate of others, are an important skillset for teams who live and work together. However, this construct does not have a validated measure to enable an understanding of how group living skills influence team dynamics over time. We developed and validated a short measure of group living skills for teams living in extreme work environments. Methods: We collected data from 83 individuals in 24 teams living and working in space and spaceflight analog environments on missions of 45-240 days. Results: We provide evidence of reliability and validity for the GLS Survey over time and identify a two-factor structure. We also demonstrate its use as a measure of team-level dynamics and its utility as a sociometric measure to identify a person's degree of group living skills. Discussion: We outline recommendations for using this new measure in future research and applied settings to understand this unique aspect of teams living and working together.

8.
Clinicoecon Outcomes Res ; 16: 233-246, 2024.
Article in English | MEDLINE | ID: mdl-38716161

ABSTRACT

Introduction: As the shortage of primary care providers widens nationwide, access to care utilizing non-physician providers is one strategy to ensure equitable access to care. This study aimed to compare community pharmacist-provided care for minor ailments to care provided at three traditional sites of care: primary care, urgent care, and emergency department, to determine if care provided by pharmacists improved access with comparable quality and reduced financial strain on the healthcare system. Methods: Pharmacy data was provided from 46 pharmacies and 175 pharmacists who participated across five pharmacy corporations over a 3-year period (2016-2019). Data for non-pharmacy sites of care was provided by a large health plan, matching episodes of care for conditions seen in the community pharmacy. Cost-of-care analysis was conducted using superiority study design and revisit data analysis was conducted using noninferiority study design. Results: Median cost-of-care across traditional sites of care was $277.78 higher than care provided at the pharmacies, showing superiority. Noninferiority was demonstrated for revisit care when the initial visit was conducted by a pharmacist compared to traditional sites. Discussion: The authors conclude community pharmacist-provided care for minor ailments improved cost-effective access for patients with comparable quality and reduced financial strains on the healthcare system.

9.
Microorganisms ; 12(9)2024 Aug 26.
Article in English | MEDLINE | ID: mdl-39338441

ABSTRACT

Borrelia burgdorferi, the bacterium responsible for Lyme disease, has been shown to form antimicrobial-tolerant biofilms, which protect it from unfavorable conditions. Bacterial biofilms are known to significantly contribute to severe inflammation, such as carditis, a common manifestation of Lyme disease. However, the role of B. burgdorferi biofilms in the development of Lyme carditis has not been thoroughly investigated due to the absence of an appropriate model system. In this study, we examined heart tissues from mice infected with B. burgdorferi for the presence of biofilms and inflammatory markers using immunohistochemistry (IHC), combined fluorescence in situ hybridization FISH/IHC, 3D microscopy, and atomic force microscopy techniques. Our results reveal that B. burgdorferi spirochetes form aggregates with a known biofilm marker (alginate) in mouse heart tissues. Furthermore, these biofilms induce inflammation, as indicated by elevated levels of murine C-reactive protein near the biofilms. This research provides evidence that B. burgdorferi can form biofilms in mouse heart tissue and trigger inflammatory processes, suggesting that the mouse model is a valuable tool for future studies on B. burgdorferi biofilms.

10.
Cell Chem Biol ; 31(3): 465-476.e12, 2024 Mar 21.
Article in English | MEDLINE | ID: mdl-37918401

ABSTRACT

Conventional antimicrobial discovery relies on targeting essential enzymes in pathogenic organisms, contributing to a paucity of new antibiotics to address resistant strains. Here, by targeting a non-essential enzyme, Borrelia burgdorferi HtpG, to deliver lethal payloads, we expand what can be considered druggable within any pathogen. We synthesized HS-291, an HtpG inhibitor tethered to the photoactive toxin verteporfin. Reactive oxygen species, generated by light, enables HS-291 to sterilize Borrelia cultures by causing oxidation of HtpG, and a discrete subset of proteins in proximity to the chaperone. This caused irreversible nucleoid collapse and membrane blebbing. Tethering verteporfin to the HtpG inhibitor was essential, since free verteporfin was not retained by Borrelia in contrast to HS-291. For this reason, we liken HS-291 to a berserker, wreaking havoc upon the pathogen's biology once selectively absorbed and activated. This strategy expands the druggable pathogenic genome and offsets antibiotic resistance by targeting non-essential proteins.


Subject(s)
Borrelia burgdorferi , Borrelia burgdorferi/genetics , Borrelia burgdorferi/metabolism , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Verteporfin/metabolism , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/metabolism , Molecular Chaperones/metabolism
11.
Physiol Meas ; 44(3)2023 03 01.
Article in English | MEDLINE | ID: mdl-36753767

ABSTRACT

Objective.Children with heart failure have higher rates of emergency department utilization, health care expenditure, and hospitalization. Therefore, a need exists for a simple, non-invasive, and inexpensive method of screening for left ventricular (LV) dysfunction. We recently demonstrated the practicality and reliability of a wireless smartphone-based handheld device in capturing carotid pressure waveforms and deriving cardiovascular intrinsic frequencies (IFs) in children with normal LV function. Our goal in this study was to demonstrate that an IF-based machine learning method (IF-ML) applied to noninvasive carotid pressure waveforms can distinguish between normal and abnormal LV ejection fraction (LVEF) in pediatric patients.Approach. Fifty patients ages 0 to 21 years underwent LVEF measurement by echocardiogram or cardiac magnetic resonance imaging. On the same day, patients had carotid waveforms recorded using Vivio. The exclusion criterion was known vascular disease that would interfere with obtaining a carotid artery pulse. We adopted a hybrid IF- Machine Learning (IF-ML) method by applying physiologically relevant IF parameters as inputs to Decision Tree classifiers. The threshold for low LVEF was chosen as <50%.Main results.The proposed IF-ML method was able to detect an abnormal LVEF with an accuracy of 92% (sensitivity = 100%, specificity = 89%, area under the curve (AUC) = 0.95). Consistent with previous clinical studies, the IF parameterω1was elevated among patients with reduced LVEF.Significance.A hybrid IF-ML method applied on a carotid waveform recorded by a hand-held smartphone-based device can differentiate between normal and abnormal LV systolic function in children with normal cardiac anatomy.


Subject(s)
Smartphone , Ventricular Dysfunction, Left , Humans , Child , Infant, Newborn , Infant , Child, Preschool , Adolescent , Young Adult , Adult , Reproducibility of Results , Ventricular Dysfunction, Left/diagnosis , Ventricular Function, Left , Stroke Volume , Carotid Arteries/diagnostic imaging
12.
PLoS One ; 18(11): e0291382, 2023.
Article in English | MEDLINE | ID: mdl-37939060

ABSTRACT

Lyme disease, caused by vector-borne Borrelia bacteria, can present with diverse multi-system symptoms that resemble other conditions. The objective of this study was to evaluate disease presentations and Borrelia seroreactivity in individuals experiencing a spectrum of chronic and complex illnesses. We recruited 157 participants from Eastern Canada who reported one or more diagnoses of Lyme disease, neurological, rheumatic, autoimmune, inflammatory, gastrointestinal, or cardiovascular illnesses, or were asymptomatic and presumed healthy. Intake categories were used to classify participants based on their perceived proximity to Lyme disease, distinguishing between those with a disclosed history of Borrelia infection, those with lookalike conditions (e.g. fibromyalgia syndrome), and those with unrelated ailments (e.g. intestinal polyps). Participants completed three questionnaires, the SF-36 v1, SIQR, and HMQ, to capture symptoms and functional burden, and provided blood serum for analysis at an accredited diagnostic lab. Two-tiered IgG and IgM serological assessments (whole cell ELISA and Western blot) were performed in a blinded fashion on all samples. The pattern of symptoms and functional burden were similarly profound in the presumptive Lyme and Lyme-like disease categories. Borrelia seroprevalence across the study cohort was 10% for each of IgG and IgM, and occurred within and beyond the Lyme disease intake category. Western blot positivity in the absence of reactive ELISA was also substantial. Fibromyalgia was the most common individual diagnostic tag disclosed by two-tier IgG-positive participants who did not report a history of Lyme disease. Within the IgG seropositive cohort, the presence of antibodies against the 31 kDa Outer Surface Protein A (OspA) was associated with significantly better health outcomes. Previously, this marker has been linked to treatment-refractory Lyme arthritis. Overall, our findings support prior observations of phenotypic overlap between Lyme and other diseases. Seropositivity associated with non-specific symptoms and functional impairment warrants further mechanistic investigation and therapeutic optimization.


Subject(s)
Borrelia burgdorferi , Borrelia , Fibromyalgia , Lyme Disease , Humans , Fibromyalgia/epidemiology , Seroepidemiologic Studies , Canada/epidemiology , Lyme Disease/diagnosis , Lyme Disease/epidemiology , Chronic Disease , Antibodies, Bacterial , Immunoglobulin G , Immunoglobulin M
13.
Curr Pharm Teach Learn ; 14(4): 507-513, 2022 04.
Article in English | MEDLINE | ID: mdl-35483818

ABSTRACT

BACKGROUND AND PURPOSE: To describe the implementation of a pediatric vaccination training for student pharmacists and to assess student confidence in providing pediatric vaccinations after taking part in a mixed media, traditional lecture, and active learning, formatted training course. EDUCATIONAL ACTIVITY AND SETTING: Student pharmacists were trained with a two-hour pediatric immunization training module which consisted of materials to detail administration techniques. Students were assessed using a live skills assessment and a multiple-choice knowledge examination. To assess student confidence in these skills, the students were given a pre- and post-instruction survey which was analyzed using the Mann-Whitney U test. FINDINGS: All 170 students enrolled successfully completed the knowledge assessment with an average score of 87% (SD 10%). The skills assessment items most commonly needing remediation were verifying that caregivers received the Vaccine Information Sheet (24%) and reviewing comfort measures and after care instructions with the caregiver (24%). The pre-course survey was completed by 169 out of 170 student pharmacists (99.4%) while the post-course survey was completed by 164 student pharmacists (96.4%) with each item showing a statistically significant increase in perceived confidence in vaccine administration. SUMMARY: Pediatric vaccination training was integrated into a doctor of pharmacy curriculum with the goals of increasing student knowledge and confidence in giving pediatric immunizations. Upon course completion, there was a statistically significant increase in student-perceived knowledge and confidence when administering pediatric immunizations. By expanding access to pediatric immunizers, pharmacists can aid in increasing immunization rates improving public health in their communities.


Subject(s)
Education, Pharmacy , Students, Pharmacy , Vaccines , Child , Education, Pharmacy/methods , Humans , Immunization , Pharmacists
14.
JACC Case Rep ; 4(10): 613-616, 2022 May 18.
Article in English | MEDLINE | ID: mdl-35615211

ABSTRACT

Early recognition of Lyme carditis is critical to preventing unnecessary pacemaker implantation for conduction abnormalities associated with this tick-born infection. Patients who do receive a pacemaker should be considered for device extraction after the completion of their antibiotic therapy if they recover normal atrioventricular node conduction. (Level of Difficulty: Intermediate.).

15.
Blood ; 114(9): 1913-8, 2009 Aug 27.
Article in English | MEDLINE | ID: mdl-19587376

ABSTRACT

Hepcidin is the major regulator of systemic iron homeostasis in mammals. Hepcidin is produced mainly by the liver and is increased by inflammation, leading to hypoferremia. We measured serum levels of bioactive hepcidin and its effects on serum iron levels in mice infected with Borrelia burgdorferi. Bioactive hepcidin was elevated in the serum of mice resulting in hypoferremia. Infected mice produced hepcidin in both liver and spleen. Both intact and sonicated B burgdorferi induced hepcidin expression in cultured mouse bone marrrow macrophages. Hepcidin production by cultured macrophages represents a primary transcriptional response stimulated by B burgdorferi and not a secondary consequence of cytokine elaboration. Hepcidin expression induced by B burgdorferi was mediated primarily by activation of Toll-like receptor 2.


Subject(s)
Antimicrobial Cationic Peptides/metabolism , Borrelia burgdorferi/metabolism , Toll-Like Receptor 2/metabolism , Toll-Like Receptors/metabolism , Animals , Bone Marrow Cells/cytology , Cytokines/metabolism , Green Fluorescent Proteins/metabolism , Hepcidins , Humans , Inflammation , Macrophages/metabolism , Mice , Mice, Inbred C57BL , Mice, Transgenic , Models, Biological
16.
Pathogens ; 10(11)2021 Nov 11.
Article in English | MEDLINE | ID: mdl-34832618

ABSTRACT

We describe the development, optimization, and validation of a multiplex droplet digital PCR (ddPCR) assay for the simultaneous detection of Babesia, Bartonella, and Borrelia spp. DNA from several sample matrices, including clinical blood samples from animals and humans, vectors, in-vitro infected human and animal cell lines, and tissues obtained from animal models (infected with Bartonella and/or B. burgdorferi). The multiplex ddPCR assay was able to detect 31 Bartonella, 13 Borrelia, and 24 Babesia species, including Theileria equi, T. cervi, and Cytauxzoon felis. No amplification of Treponema or Leptospira spp. was observed. Sensitivity of 0.2-5 genome equivalent DNA copies per microliter was achieved for different members of the Bartonella and Borrelia genus, depending on the species or matrix type (water or spiked blood DNA) tested. The ddPCR assay facilitated the simultaneous detection of co-infections with two and three vector-borne pathogens comprising four different genera (Babesia, Bartonella, Borrelia, and Theileria) from clinical and other sample sources.

17.
Pathogens ; 10(3)2021 Mar 10.
Article in English | MEDLINE | ID: mdl-33802018

ABSTRACT

Bartonella bacilliformis (B. bacilliformis), Bartonella henselae (B. henselae), and Bartonella quintana (B. quintana) are bacteria known to cause verruga peruana or bacillary angiomatosis, vascular endothelial growth factor (VEGF)-dependent cutaneous lesions in humans. Given the bacteria's association with the dermal niche and clinical suspicion of occult infection by a dermatologist, we determined if patients with melanoma had evidence of Bartonella spp. infection. Within a one-month period, eight patients previously diagnosed with melanoma volunteered to be tested for evidence of Bartonella spp. exposure/infection. Subsequently, confocal immunohistochemistry and PCR for Bartonella spp. were used to study melanoma tissues from two patients. Blood from seven of the eight patients was either seroreactive, PCR positive, or positive by both modalities for Bartonella spp. exposure. Subsequently, Bartonella organisms that co-localized with VEGFC immunoreactivity were visualized using multi-immunostaining confocal microscopy of thick skin sections from two patients. Using a co-culture model, B. henselae was observed to enter melanoma cell cytoplasm and resulted in increased vascular endothelial growth factor C (VEGFC) and interleukin 8 (IL-8) production. Findings from this small number of patients support the need for future investigations to determine the extent to which Bartonella spp. are a component of the melanoma pathobiome.

18.
Infect Immun ; 78(7): 3144-53, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20404081

ABSTRACT

We recently discovered a critical role for type I interferon (IFN) in the development of murine Lyme arthritis. Borrelia burgdorferi-mediated induction of IFN-responsive genes by bone marrow-derived macrophages (BMDMs) was dependent upon a functional type I IFN receptor but independent of Toll-like receptor 2 (TLR2), TLR4, TLR9, and the adapter molecule MyD88. We now demonstrate that induction of the IFN transcriptional profile in B. burgdorferi-stimulated BMDMs occurs independently of the adapter TRIF and of the cytoplasmic sensor NOD2. In contrast, B. burgdorferi-induced transcription of these genes was dependent upon a rapid STAT1 feedback amplification pathway. IFN profile gene transcription was IRF3 dependent but did not utilize B. burgdorferi-derived DNA or DNase-sensitive ligands. Instead, IFN-responsive gene expression could be induced by B. burgdorferi-derived RNA. Interferon regulatory factor 3 (IRF3)-dependent IFN profile gene transcription was also induced by sonicated bacteria, by the lipoprotein OspA, and by factors released into the BSKII medium during culture of B. burgdorferi. The IFN-stimulatory activity of B. burgdorferi culture supernatants was not destroyed by nuclease treatment. Nuclease digestion also had no effect on IFN profile induction mediated by sonicated B. burgdorferi. Thus, B. burgdorferi-derived RNA, OspA, and non-nucleic acid ligands present in both sonicated bacteria and B. burgdorferi culture medium contribute to type I IFN-responsive gene induction. These findings suggest that B. burgdorferi invasion of joint tissue and the resultant type I IFN induction associated with Lyme arthritis development may involve multiple triggering ligands.


Subject(s)
Borrelia burgdorferi/physiology , Interferon Regulatory Factor-3/physiology , Interferon Type I/biosynthesis , Lyme Disease/microbiology , Animals , Borrelia burgdorferi/genetics , Gene Expression Regulation, Bacterial/physiology , Genes, Bacterial/genetics , Genes, Bacterial/physiology , Interferon Type I/physiology , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Nod2 Signaling Adaptor Protein/physiology , Reverse Transcriptase Polymerase Chain Reaction , STAT1 Transcription Factor/immunology , STAT1 Transcription Factor/physiology , Transcription, Genetic/genetics , Transcription, Genetic/physiology
19.
J Immunol ; 181(12): 8492-503, 2008 Dec 15.
Article in English | MEDLINE | ID: mdl-19050267

ABSTRACT

Gene expression analysis previously revealed a robust IFN-responsive gene induction profile that was selectively up-regulated in Borrelia burgdorferi-infected C3H mice at 1 wk postinfection. This profile was correlated with arthritis development, as it was absent from infected, mildly arthritic C57BL/6 mice. In this report we now demonstrate that profile induction in infected C3H scid mice occurs independently of B or T lymphocyte infiltration in the joint tissue. Additionally, type I IFN receptor-blocking Abs, but not anti-IFN-gamma Abs, dramatically reduced arthritis, revealing a critical but previously unappreciated role for type I IFN in Lyme arthritis development. Certain examined IFN-inducible transcripts were also significantly diminished within joint tissue of mice treated with anti-IFNAR1, whereas expression of other IFN-responsive genes was more markedly altered by anti-IFN-gamma treatment. These data indicate that induction of the entire IFN profile is not necessary for arthritis development. These findings further tie early type I IFN induction to Lyme arthritis development, a connection not previously made. Bone marrow-derived macrophages readily induced IFN-responsive genes following B. burgdorferi stimulation, and this expression required a functional type I IFN receptor. Strikingly, induction of these genes was independent of TLRs 2,4, and 9 and of the adapter molecule MyD88. These data demonstrate that the extracellular pathogen B. burgdorferi uses a previously unidentified receptor and a pathway traditionally associated with viruses and intracellular bacteria to initiate transcription of type I IFN and IFN-responsive genes and to initiate arthritis development.


Subject(s)
Borrelia burgdorferi/immunology , Interferon Type I/physiology , Lyme Disease/immunology , Lyme Disease/microbiology , Animals , Antibodies, Blocking/administration & dosage , Cells, Cultured , Dendritic Cells/immunology , Dendritic Cells/pathology , Female , Gene Expression Profiling , Immunity, Innate/genetics , Interferon Type I/biosynthesis , Interferon Type I/deficiency , Lyme Disease/metabolism , Lyme Disease/therapy , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Mice, Knockout , Mice, SCID , Receptor, Interferon alpha-beta/antagonists & inhibitors , Receptor, Interferon alpha-beta/immunology , Signal Transduction/genetics , Signal Transduction/immunology
20.
Cardiovasc Digit Health J ; 1(3): 149-159, 2020.
Article in English | MEDLINE | ID: mdl-33043314

ABSTRACT

In December 2019, the novel COVID-19 virus spread from a cluster of pneumonia cases in Wuhan, China, to every corner of the globe, creating a worldwide pandemic pushing hospital systems past capacity and bringing economies worldwide to a halt. The COVID-19 pandemic is unique in comparison to prior coronavirus epidemics in its superior ability to be spread by asymptomatic and presymptomatic patients, allowing the virus to silently evade traditional symptoms-based screening approaches. Countries have implemented cutting-edge digital solutions to enhance traditional contact-tracing methodologies in combination with novel testing strategies to combat the virus, with variable levels of success. Despite having one of the most advanced and expensive health care systems in the world, the United States (U.S.) response is arguably one of the world's largest failures, as it leads the globe in case number as well as deaths. Until a successful vaccine can be broadly distributed, it is imperative that the U.S. curb the viral spread by rapidly developing a framework implementing both enhanced tracing and testing strategies balancing the needs of public health while respecting individual liberties. This review will explore the role of technology-augmented contact-based surveillance in tracking the outbreak in select countries in comparison to the current U.S. approach. It will evaluate barriers in the U.S. to implementing similar technologies, focusing on privacy concerns and a lack of unified testing and tracing strategy. Finally, it will explore strategies for rapidly scaling testing in a cost-effective manner.

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