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1.  Variability in Tuberculosis Granuloma T Cell Responses Exists, but a Balance of Pro- and Anti-inflammatory Cytokines Is Associated with Sterilization 
PLoS Pathogens  2015;11(1):e1004603.
Lung granulomas are the pathologic hallmark of tuberculosis (TB). T cells are a major cellular component of TB lung granulomas and are known to play an important role in containment of Mycobacterium tuberculosis (Mtb) infection. We used cynomolgus macaques, a non-human primate model that recapitulates human TB with clinically active disease, latent infection or early infection, to understand functional characteristics and dynamics of T cells in individual granulomas. We sought to correlate T cell cytokine response and bacterial burden of each granuloma, as well as granuloma and systemic responses in individual animals. Our results support that each granuloma within an individual host is independent with respect to total cell numbers, proportion of T cells, pattern of cytokine response, and bacterial burden. The spectrum of these components overlaps greatly amongst animals with different clinical status, indicating that a diversity of granulomas exists within an individual host. On average only about 8% of T cells from granulomas respond with cytokine production after stimulation with Mtb specific antigens, and few “multi-functional” T cells were observed. However, granulomas were found to be “multi-functional” with respect to the combinations of functional T cells that were identified among lesions from individual animals. Although the responses generally overlapped, sterile granulomas had modestly higher frequencies of T cells making IL-17, TNF and any of T-1 (IFN-γ, IL-2, or TNF) and/or T-17 (IL-17) cytokines than non-sterile granulomas. An inverse correlation was observed between bacterial burden with TNF and T-1/T-17 responses in individual granulomas, and a combinatorial analysis of pair-wise cytokine responses indicated that granulomas with T cells producing both pro- and anti-inflammatory cytokines (e.g. IL-10 and IL-17) were associated with clearance of Mtb. Preliminary evaluation suggests that systemic responses in the blood do not accurately reflect local T cell responses within granulomas.
Author Summary
The characteristic feature of Mycobacterium tuberculosis (Mtb) infection is the formation of lesions, which are organized structures of immune cells in the lungs called granulomas, which contain the bacteria. When the granuloma functions effectively, it can kill the bacteria. T cells (a type of immune cell, also present in granulomas) are known to play an important role in control of tuberculosis. However, functions of T cells at individual granuloma levels are unknown. Here, we studied the functional characteristics of T cells, which are defined by the production of chemical messengers (cytokines) at the granuloma level in a non-human primate model. We compared the relationship between cytokine response and the number of bacteria (Mtb) in each granuloma. Each granuloma was found to be unique, suggesting different types exist within an animal. Only a small proportion of T cells produced any cytokine, but different types of cytokines were observed within each granuloma. A balance between different types of cytokine was associated with more killing of bacteria in granulomas. Understanding how to improve the T cell responses to obtain killing of bacteria in the granuloma will be important for vaccine development.
doi:10.1371/journal.ppat.1004603
PMCID: PMC4303275  PMID: 25611466
2.  Failure or success of search strategies to identify adverse effects of medical devices: a feasibility study using a systematic review 
Systematic Reviews  2014;3:113.
Background
Research has indicated that adverse effects terms are increasingly prevalent in the title, abstract or indexing terms of articles that contain adverse drug effects data in MEDLINE and Embase. However, it is unknown whether adverse effects terms are present in the database records of articles that contain adverse effects data of medical devices, and thus, to what extent the development of an adverse effects search filter for medical devices may be feasible.
Methods
A case study systematic review of a medical device was selected. The included studies from a systematic review of the safety of recombinant human bone morphogenetic protein-2 (rhBMP-2) for spinal fusion were used in the analysis. For each included study, the corresponding database record on MEDLINE and Embase was assessed to measure the presence or absence of adverse effects terms in the title, abstract or indexing. The performance of each potential adverse effects search term was also measured and compared.
Results
There were 82 publications (49 studies) included in the systematic review with 51 of these indexed on MEDLINE and 55 on Embase. Ninety-four percent (48/51) of the records on MEDLINE and 95% (52/55) of the records on Embase contained at least one adverse effects related search term. The wide variety of adverse effects terms included in the title, abstract or indexing of bibliographic records, and the lack of any individual high-performing search terms suggests that a combination of terms in different fields is required to identify adverse effects of medical devices. In addition, the most successful search terms differed from the most successful terms for identifying adverse drug effects.
Conclusions
The search filters currently available for adverse drug effects are not necessarily useful for searching adverse effects data of medical devices. The presence of adverse effects terms in the bibliographic records of articles on medical devices, however, indicates that combinations of adverse effects search terms may be useful in search strategies in MEDLINE and Embase. The results, therefore, suggest that not only a search filter for the adverse effects of medical devices is feasible, but also that it should be a research priority.
doi:10.1186/2046-4053-3-113
PMCID: PMC4203467  PMID: 25312884
Adverse effects; Systematic reviews; Meta-analysis; Information storage and retrieval; Bibliographic databases
3.  A checklist designed to aid consistency and reproducibility of GRADE assessments: development and pilot validation 
Systematic Reviews  2014;3:82.
Background
The grading of recommendation, assessment, development and evaluation (GRADE) approach is widely implemented in health technology assessment and guideline development organisations throughout the world. GRADE provides a transparent approach to reaching judgements about the quality of evidence on the effects of a health care intervention, but is complex and therefore challenging to apply in a consistent manner.
Methods
We developed a checklist to guide the researcher to extract the data required to make a GRADE assessment. We applied the checklist to 29 meta-analyses of randomised controlled trials on the effectiveness of health care interventions. Two reviewers used the checklist for each paper and used these data to rate the quality of evidence for a particular outcome.
Results
For most (70%) checklist items, there was good agreement between reviewers. The main problems were for items relating to indirectness where considerable judgement is required.
Conclusions
There was consistent agreement between reviewers on most items in the checklist. The use of this checklist may be an aid to improving the consistency and reproducibility of GRADE assessments, particularly for inexperienced users or in rapid reviews without the resources to conduct assessments by two researchers independently.
doi:10.1186/2046-4053-3-82
PMCID: PMC4124503  PMID: 25056145
GRADE; Checklist; Quality assessment
4.  The Cellular Interactome of the Coronavirus Infectious Bronchitis Virus Nucleocapsid Protein and Functional Implications for Virus Biology 
Journal of Virology  2013;87(17):9486-9500.
The coronavirus nucleocapsid (N) protein plays a multifunctional role in the virus life cycle, from regulation of replication and transcription and genome packaging to modulation of host cell processes. These functions are likely to be facilitated by interactions with host cell proteins. The potential interactome of the infectious bronchitis virus (IBV) N protein was mapped using stable isotope labeling with amino acids in cell culture (SILAC) coupled to a green fluorescent protein-nanotrap pulldown methodology and liquid chromatography-tandem mass spectrometry. The addition of the SILAC label allowed discrimination of proteins that were likely to specifically bind to the N protein over background binding. Overall, 142 cellular proteins were selected as potentially binding to the N protein, many as part of larger possible complexes. These included ribosomal proteins, nucleolar proteins, translation initiation factors, helicases, and hnRNPs. The association of selected cellular proteins with IBV N protein was confirmed by immunoblotting, cosedimentation, and confocal microscopy. Further, the localization of selected proteins in IBV-infected cells as well as their activity during virus infection was assessed by small interfering RNA-mediated depletion, demonstrating the functional importance of cellular proteins in the biology of IBV. This interactome not only confirms previous observations made with other coronavirus and IBV N proteins with both overexpressed proteins and infectious virus but also provides novel data that can be exploited to understand the interaction between the virus and the host cell.
doi:10.1128/JVI.00321-13
PMCID: PMC3754094  PMID: 23637410
5.  Blastomyces dermatitidis Antigen Detection by Quantitative Enzyme Immunoassay 
The second-generation MVista Blastomyces antigen enzyme immunoassay was not quantitative; therefore, specimens obtained previously were tested in the same assay as new specimens to assess the change in antigen levels. Furthermore, the sensitivity in serum had not been fully evaluated. The purpose of this study was to evaluate a quantitative Blastomyces antigen assay and detection of antigen in serum. Calibrators containing known concentrations of Blastomyces galactomannan were used to quantify antigen in urine and serum from patients with proven blastomycosis and from controls. Paired current and previously obtained urine specimens were tested to determine if quantification eliminated the need for concurrent testing to assess change in antigen. Pretreatment of serum with EDTA at 104°C was evaluated to determine if dissociation of immune complexes improved detection of antigenemia. Antigenuria was detected in 89.9% of patients with culture- or histopathology-proven blastomycosis. Specificity was 99.0% in patients with nonfungal infections and healthy subjects, but cross-reactions occurred in 95.6% of patients with histoplasmosis. Change in antigen level categorized as increase, no change, or decrease based on antigen units determined in the same assay agreed closely with the category of change in ng/ml determined from different assays. Pretreatment increased the sensitivity of detection of antigenemia from 35.7% to 57.1%. Quantification eliminated the need for concurrent testing of current and previously obtained specimens for assessment of changes in antigen concentration. Pretreatment increased the sensitivity for detection of antigenemia. Differentiation of histoplasmosis and blastomycosis is not possible by antigen detection.
doi:10.1128/CVI.05248-11
PMCID: PMC3255946  PMID: 22116687
6.  The multistage vaccine H56 boosts the effects of BCG to protect cynomolgus macaques against active tuberculosis and reactivation of latent Mycobacterium tuberculosis infection  
It is estimated that one-third of the world’s population is infected with Mycobacterium tuberculosis. Infection typically remains latent, but it can reactivate to cause clinical disease. The only vaccine, Mycobacterium bovis bacillus Calmette-Guérin (BCG), is largely ineffective, and ways to enhance its efficacy are being developed. Of note, the candidate booster vaccines currently under clinical development have been designed to improve BCG efficacy but not prevent reactivation of latent infection. Here, we demonstrate that administering a multistage vaccine that we term H56 in the adjuvant IC31 as a boost to vaccination with BCG delays and reduces clinical disease in cynomolgus macaques challenged with M. tuberculosis and prevents reactivation of latent infection. H56 contains Ag85B and ESAT-6, which are two of the M. tuberculosis antigens secreted in the acute phase of infection, and the nutrient stress–induced antigen Rv2660c. Boosting with H56/IC31 resulted in efficient containment of M. tuberculosis infection and reduced rates of clinical disease, as measured by clinical parameters, inflammatory markers, and improved survival of the animals compared with BCG alone. Boosted animals showed reduced pulmonary pathology and extrapulmonary dissemination, and protection correlated with a strong recall response against ESAT-6 and Rv2660c. Importantly, BCG/H56-vaccinated monkeys did not reactivate latent infection after treatment with anti-TNF antibody. Our results indicate that H56/IC31 boosting is able to control late-stage infection with M. tuberculosis and contain latent tuberculosis, providing a rationale for the clinical development of H56.
doi:10.1172/JCI46252
PMCID: PMC3248283  PMID: 22133873
7.  Endometrial stromal sarcoma metastasis to the lumbar spine and sphenoid bone 
Rare Tumors  2011;3(3):e27.
Endometrial stromal sarcoma (ESS) is typically associated with metastasis to the abdomen, pelvis, and lung. We found three case reports of ESS metastasis to the bone (two to the thoracic spine, and one to the parietal bone). Our objective is to review the literature on ESS spinal and intracranial metastases and, report the first case of ESS metastatic to the lumbar paraspinal region and sphenoid bone. A 53-year-old female with ESS status-post radiation, chemotherapy, and pelvic exenteration surgery presented with right hip weakness, back pain, and radicular leg pain that were explained by chemotherapy-induced neuropathy, radiation-induced lumbosacral plexopathy, and femoral nerve and obturator nerve injury during pelvic exenteration surgery. During routine positron emission tomography, we found metastasis to the L3 lumbar spinal region. L3 laminectomy and subtotal resection of the mass was performed with tumor residual in the neuroforamina and pedicles. One month later, magnetic resonance imaging (MRI) performed for persistent headaches revealed a large lesion in the sphenoid bone that was biopsied transsphenoidally with the same diagnosis, but no further surgery was performed. She is intolerant of chemotherapy and currently undergoing whole brain radiation. Delay in the diagnosis and management of lumbar paraspinal and sphenoid bone metastasis of ESS likely occurred because of the uniqueness of the location and aggressiveness of ESS metastasis. Health care providers should be aware of potentially aggressive metastasis of ESS to bone, in particular the unusual locations of the lumbar paraspinal region and sphenoid bone.
doi:10.4081/rt.2011.e27
PMCID: PMC3208414  PMID: 22066034
endometrial stromal sarcoma; uterine sarcoma; lumbar spine; sphenoid bone; bone metastasis.
8.  Quantitative Comparison of Active and Latent Tuberculosis in the Cynomolgus Macaque Model▿ †  
Infection and Immunity  2009;77(10):4631-4642.
We previously described that low-dose Mycobacterium tuberculosis infection in cynomolgus macaques results in a spectrum of disease similar to that of human infection: primary disease, latent infection, and reactivation tuberculosis (S. V. Capuano III, D. A. Croix, S. Pawar, A. Zinovik, A. Myers, P. L. Lin, S. Bissel, C. Fuhrman, E. Klein, and J. L. Flynn, Infect. Immun. 71:5831-5844, 2003). This is the only established model of latent infection, and it provides a unique opportunity to understand host and pathogen differences across of range of disease states. Here, we provide a more extensive and detailed characterization of the gross pathology, microscopic histopathology, and immunologic characteristics of monkeys in each clinical disease category. The data underscore the similarities between human and nonhuman primate M. tuberculosis infection. Furthermore, we describe novel methods of quantifying gross pathology and bacterial burden that distinguish between active disease and latent infection, and we extend the usefulness of this model for comparative studies. Early in infection, an abnormal chest X ray, M. tuberculosis growth by gastric aspirate, and increased mycobacterium-specific gamma interferon (IFN-γ) in peripheral blood mononuclear cells (PBMCs) and bronchoalveolar lavage (BAL) cells were associated with the development of active disease. At necropsy, disease was quantified with respect to pathology and bacterial numbers. Microscopically, a spectrum of granuloma types are seen and differ with disease type. At necropsy, monkeys with active disease had more lung T cells and more IFN-γ from PBMC, BAL, and mediastinal lymph nodes than monkeys with latent infection. Finally, we have observed a spectrum of disease not only in monkeys with active disease but also in those with latent infection that provides insight into human latent tuberculosis.
doi:10.1128/IAI.00592-09
PMCID: PMC2747916  PMID: 19620341
9.  Assessment of the Effectiveness of Low-Pressure UV Light for Inactivation of Helicobacter pylori 
Three strains of Helicobacter pylori were exposed to UV light from a low-pressure source to determine log inactivation versus applied fluence. Results indicate that H. pylori is readily inactivated at UV fluences typically used in water treatment regimens. Greater than 4-log10 inactivation was demonstrated on all three strains at fluences of less than 8 mJ cm−2.
doi:10.1128/AEM.72.5.3763-3765.2006
PMCID: PMC1472312  PMID: 16672531
10.  Occurrence of Nontuberculous Mycobacteria in Environmental Samples 
Nontuberculous mycobacteria (NTM) are a major cause of opportunistic infection in immunocompromised hosts. Because there is no evidence of person-to-person transmission and NTM have been found in drinking water, the environment is considered a likely source of infection. In this study the widespread occurrence of NTM was examined in drinking water, bottled water, and ice samples. A total of 139 samples were examined for NTM by a membrane filtration culture technique followed by PCR amplification and 16S rRNA sequence determination to identify the isolates. NTM were not detected in bottled water or cisterns but were detected in 54% of the ice samples and 35% of the public drinking-water samples from 21 states. The most frequently occurring isolate was M. mucogenicum (formerly referred to as an M. chelonae-like organism).
PMCID: PMC91367  PMID: 10347032
11.  Reporting of industry funded study outcome data: comparison of confidential and published data on the safety and effectiveness of rhBMP-2 for spinal fusion 
Objective To investigate whether published results of industry funded trials of recombinant human bone morphogenetic protein 2 (rhBMP-2) in spinal fusion match underlying trial data by comparing three different data sources: individual participant data, internal industry reports, and publicly available journal publications and conference abstracts.
Data collection and synthesis The manufacturer of rhBMP-2 products (Medtronic; Minneapolis, MN) provided complete individual participant data and internal reports for all its studies of rhMBP-2 in spinal fusion. We identified publications and conference abstracts through comprehensive literature searches. We compared outcomes provided in the individual participant data against outcomes reported in publications. For effectiveness outcomes, we compared meta-analyses of randomised controlled trials based on each of the three data sources. For adverse events, meta-analysis of the published aggregate data was not possible and we compared the number and type of adverse events reported between data sources.
Results 32 publications reported outcomes from 11 of the 17 existing manufacturer sponsored studies. For individual randomised controlled trials, 56% (9/16) to 88% (15/17) of effectiveness outcomes known to have been collected were reported in the published literature. Meta-analyses of effectiveness data were almost identical for pain outcomes and similar for fusion across the three data sources. A minority of adverse event data known to have been collected were reported in the published literature. Several journal articles reported only “serious,” “related,” or “unanticipated” adverse events, without defining these terms. Others reported a small proportion of the collected adverse event categories. Around 23% (533/2302) of the total adverse events collected in published randomised controlled trials have been reported in the literature, with randomised controlled trials evaluating the licensed preparation (Infuse) reporting around 11% (122/1108) of collected adverse events.
Conclusions The published literature only partially represents the total data known to have been collected on the effects of rhBMP-2. This did not lead to substantially different results for meta-analysis of effectiveness outcomes. In contrast, reporting of adverse event data in trial publications was inadequate and inconsistent to the extent that any systematic review based solely on the publicly available data would not be able to properly evaluate the safety of rhBMP-2. Analysis of individual participant data enabled the most complete, detailed, and in-depth analysis and was not more resource intensive than extracting, collating, and analysing aggregate data from multiple trial publications and conference abstracts. Confidential internal reports presented considerably more adverse event data than publications, and in the absence of individual participant data access to these reports would support more accurate and reliable investigation, with less time and effort than relying on incomplete published data.
doi:10.1136/bmj.f3981
PMCID: PMC3687771  PMID: 23788229

Results 1-11 (11)