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1.
J Agric Food Chem ; 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32138511

RESUMO

Wheat-based thin stillage (W-TS) is a liquid co-product of wheat fermentation for ethanol production that typically contains substantial amounts of glycerol. Two-stage fermentation (TSF), via endemic microorganisms, can be used in processes to convert this compound to more valuable products and simplify the enrichment process through the clarification of the medium and concentration of particles as a protein rich concentrate. We recultured bacteria 90 times (72 h at 37 C) on fresh W-TS to determine the stability of the culture and metabolic processes. Next-generation sequencing of W-TS revealed the presence of a predominant lactobacilli community that rapidly displaced competing microorganisms (e.g. Pediococcus) in subsequent fermentations. These organisms produced bacteriocins (e.g. helveticin J; interpreted through the presence of bacteriocin genes), and acidified the fermentation broth (through production of succinic; 1.7 g/L, lactic; 1.8 g/L, and acetic; 4.1 g/L, acids). Furthermore, the microbial community produced cobalamin (inferred through sequencing) and converted glycerol (10 g/L reduced to 3.5 g/L after 72 h) to 1,3-propanediol (6.1 g/L after 72 h). Altogether, lactobacilli were identified as the predominant endemic microorganisms in W-TS after the first ten cultures. The community was stable and provided a novel approach to increase the value of organic solutes in W-TS.

2.
Comp Med ; 70(2): 131-139, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32156324

RESUMO

To facilitate rational experimental design and fulfill the NIH requirement of including sex as a biologic variable, we examined the influences of genetic background and sex on responses to intervertebral disc (IVD) injury in the mouse tail. The goal of this study was to compare gene expression and histologic changes in response to a tail IVD injury (needle puncture) in male and female mice on the DBA and C57BL/6 (B6) backgrounds. We hypothesized that extracellular matrix gene expression in response to IVD injury differs between mice of different genetic backgrounds and sex. Consistent changes were detected in gene expression and histologic features after IVD injury in mice on both genetic backgrounds and sexes. In particular, expression of col1a1 and adam8 was higher in the injured IVD of DBA mice than B6 mice. Conversely, col2a1 expression was higher in B6 mice than DBA mice. Sex-associated differences were significant only in B6 mice, in which col2a1 expression was greater in male mice than in female. Histologic differences in response to injury were not apparent between DBA and B6 mice or between males and females. In conclusion, mouse tail IVD showed sex- and strain-related changes in gene expression and histology after needle puncture. The magnitude of change in gene expression differed with regard to genetic background and, to a lesser degree, sex.

3.
Theranostics ; 10(4): 1910-1922, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32042344

RESUMO

Tumor normalization strategies aim to improve tumor blood vessel functionality (i.e., perfusion) by reducing the hyper-permeability of tumor vessels or restoring compressed vessels. Despite progress in strategies to normalize the tumor microenvironment (TME), their combinatorial antitumor effects with nanomedicine and immunotherapy remain unexplored. Methods: Here, we re-purposed the TGF-ß inhibitor tranilast, an approved anti-fibrotic and antihistamine drug, and combined it with Doxil nanomedicine to normalize the TME, increase perfusion and oxygenation, and enhance anti-tumor immunity. Specifically, we employed two triple-negative breast cancer (TNBC) mouse models to primarily evaluate the therapeutic and normalization effects of tranilast combined with doxorubicin and Doxil. We demonstrated the optimized normalization effects of tranilast combined with Doxil and extended our analysis to investigate the effect of TME normalization to the efficacy of immune checkpoint inhibitors. Results: Combination of tranilast with Doxil caused a pronounced reduction in extracellular matrix components and an increase in the intratumoral vessel diameter and pericyte coverage, indicators of TME normalization. These modifications resulted in a significant increase in tumor perfusion and oxygenation and enhanced treatment efficacy as indicated by the notable reduction in tumor size. Tranilast further normalized the immune TME by restoring the infiltration of T cells and increasing the fraction of T cells that migrate away from immunosuppressive cancer-associated fibroblasts. Furthermore, we found that combining tranilast with Doxil nanomedicine, significantly improved immunostimulatory M1 macrophage content in the tumorigenic tissue and improved the efficacy of the immune checkpoint blocking antibodies anti-PD-1/anti-CTLA-4. Conclusion: Combinatorial treatment of tranilast with Doxil optimizes TME normalization, improves immunostimulation and enhances the efficacy of immunotherapy.

4.
Nat Rev Clin Oncol ; 17(4): 251-266, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32034288

RESUMO

Multiple nanotherapeutics have been approved for patients with cancer, but their effects on survival have been modest and, in some examples, less than those of other approved therapies. At the same time, the clinical successes achieved with immunotherapy have revolutionized the treatment of multiple advanced-stage malignancies. However, the majority of patients do not benefit from the currently available immunotherapies and many develop immune-related adverse events. By contrast, nanomedicines can reduce - but do not eliminate - the risk of certain life-threatening toxicities. Thus, the combination of these therapeutic classes is of intense research interest. The tumour microenvironment (TME) is a major cause of the failure of both nanomedicines and immunotherapies that not only limits delivery, but also can compromise efficacy, even when agents accumulate in the TME. Coincidentally, the same TME features that impair nanomedicine delivery can also cause immunosuppression. In this Perspective, we describe TME normalization strategies that have the potential to simultaneously promote the delivery of nanomedicines and reduce immunosuppression in the TME. Then, we discuss the potential of a combined nanomedicine-based TME normalization and immunotherapeutic strategy designed to overcome each step of the cancer-immunity cycle and propose a broadly applicable 'minimal combination' of therapies designed to increase the number of patients with cancer who are able to benefit from immunotherapy.

5.
J Vasc Res ; 57(2): 65-75, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32036370

RESUMO

AIMS: Percutaneous coronary intervention is routinely performed to treat occlusive coronary artery disease. Coronary perforation is a potential complication and can be treated with a stent graft. Current stent grafts are associated with high restenosis rates. We tested the safety and feasibility of biodegradable stent grafts in pig and rabbit models. METHODS AND RESULTS: Stent grafts were examined in pig coronaries with repeated OCT imaging for 42 days. Novel biodegradable coatings were applied on a bare metal stent by either an electrospinning (ES) or dip coating (DC) method. A completely biodegradable system was made by ES coating a magnesium-based stent. A commercially available stent graft served as a control. ES devices showed less restenosis (44.3 ± 8.8 vs. 59.1 ± 11.1% in controls, p < 0.05) and smaller reduction in minimum lumen area (44.3 ± 13.4 vs. 64.4 ± 13.6% in controls, p < 0.05) at day 42. DC devices occluded during follow-up. ES devices showed recanalization through the graft wall at day 42. Feasibility of the ES and DC devices was evaluated in pig coronary aneurysms and rabbit aortic perforation models and sealed aneurysms and perforations without complications. CONCLUSIONS: Recanalization of the graft wall improves biocompatibility. Biodegradable stent grafts may present an alternative to permanent implants by showing reduced restenosis at day 42.

6.
Perm J ; 242020.
Artigo em Inglês | MEDLINE | ID: mdl-31905333

RESUMO

The term polypharmacy in older adults is generally used in a pejorative context in the medical literature. Because of its link to geriatric syndromes and disability, the avoidance of polypharmacy is usually recommended in older adults as a strategy to optimize functional status. However, there are many polypharmacy regimens based on high-quality trials that clearly reduce the risk of disability in older adults. Other guidelines for older adults recommend the use of additional medications that may or may not be evidence based and that may or may not reduce disability. Therefore, we propose that, in the geriatric literature, polypharmacy now be categorized as "necessary polypharmacy," "unnecessary polypharmacy," or "polypharmacy of unclear benefit." In this article, we discuss the 3 categories of polypharmacy and give examples on each polypharmacy regimen and its potential relationship to disability in older adults.

7.
Sci Transl Med ; 12(528)2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31996462

RESUMO

One quarter of the world's population is infected with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). Although most infected individuals successfully control or clear the infection, some individuals will progress to TB disease. Immune correlates identified using animal models are not always effectively translated to human TB, thus resulting in a slow pace of translational discoveries from animal models to human TB for many platforms including vaccines, therapeutics, biomarkers, and diagnostic discovery. Therefore, it is critical to improve our poor understanding of immune correlates of disease and protection that are shared across animal TB models and human TB. In this study, we have provided an in-depth identification of the conserved and diversified gene/immune pathways in TB models of nonhuman primate and diversity outbred mouse and human TB. Our results show that prominent differentially expressed genes/pathways induced during TB disease progression are conserved in genetically diverse mice, macaques, and humans. In addition, using gene-deficient inbred mouse models, we have addressed the functional role of individual genes comprising the gene signature of disease progression seen in humans with Mtb infection. We show that genes representing specific immune pathways can be protective, detrimental, or redundant in controlling Mtb infection and translate into identifying immune pathways that mediate TB immunopathology in humans. Together, our cross-species findings provide insights into modeling TB disease and the immunological basis of TB disease progression.

8.
J Arthroplasty ; 35(2): 508-512, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31662280

RESUMO

BACKGROUND: Revision of monoblock metal-on-metal (MoM) total hip arthroplasty (THA) is associated with high complication rates. Limited revision by conversion to a dual mobility (DM) without acetabular component extraction may mitigate these complications. However, the concern for polyethylene wear and osteolysis remains unsettled. This study investigates the results of DM conversion of monoblock MoM THA compared to formal acetabular revision. METHODS: One hundred forty-three revisions of monoblock MoM THA were reviewed. Twenty-nine were revisions to a DM construct, and 114 were complete revisions of the acetabular component. Mean patient age was 61, 54% were women. Components used, acetabular cup position, radiographic outcomes, serum metal ion levels, and HOOS Jr clinical outcome scores were investigated. RESULTS: At 3.9 years of follow-up (range 2-5), there were 2 revisions (6.9%) in the DM cohort, 1 for instability and another for periprosthetic fracture. Among the formal acetabular revision group there was a 20% major complication rate (23/114) and 16% underwent revision surgery (18/114) for aseptic loosening of the acetabular component (6%), deep infection (6%), dislocation (4%), acetabular fracture (3%), or delayed wound healing (6%). In the DM cohort, there were no radiographic signs of aseptic loosening, component migration, or polyethylene wear. One DM patient had a small posterior metadiaphyseal femur lesion that will require close monitoring. There were no other radiographic signs of osteolysis. There were no clinically significant elevations of serum metal ion levels. HOOS Jr scores were favorable. CONCLUSION: Limited revision with conversion to DM is a viable treatment option for failed monoblock MoM THA with lower complication rates than formal revision. Limited revision to DM appears to be a safe option for revision of monoblock MoM THA with a cup in good position and an internal geometry free of sharp edges or articular surface damage. Longer follow-up is needed to demonstrate any potential wear implications of these articulations.

9.
Arch Pathol Lab Med ; 144(2): 189-195, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31246113

RESUMO

CONTEXT.­: Preanalytic errors, including specimen labeling errors and specimen loss, occur frequently during specimen collection, transit, and accessioning. Radio-frequency identification tags can decrease specimen identification and tracking errors through continuous and automated tracking of specimens. OBJECTIVE.­: To implement a specimen tracking infrastructure to reduce preanalytic errors (specimen mislabeling or loss) between specimen collection and laboratory accessioning. Specific goals were to decrease preanalytic errors by at least 70% and to simultaneously decrease employee effort dedicated to resolving preanalytic errors or investigating lost specimens. DESIGN.­: A radio-frequency identification specimen-tracking system was developed. Major features included integral radio-frequency identification labels (radio-frequency identification tags and traditional bar codes in a single printed label) printed by point-of-care printers in collection suites; dispersed radio-frequency identification readers at major transit points; and systems integration of the electronic health record, laboratory information system, and radio-frequency identification tracking system to allow for computerized physician order entry driven label generation, specimen transit time tracking, interval-based alarms, and automated accessioning. RESULTS.­: In the 6-month postimplementation period, 6 mislabeling events occurred in collection areas using the radio-frequency identification system, compared with 24 events in the 6-month preimplementation period (75% decrease; P = .001). In addition, the system led to the timely recovery of 3 lost specimens. Labeling expenses were decreased substantially in the transition from high-frequency to ultrahigh frequency radio-frequency identification tags. CONCLUSIONS.­: Radio-frequency identification specimen tracking prevented several potential specimen-loss events, decreased specimen recovery time, and decreased specimen labeling errors. Increases in labeling/tracking expenses for the system were more than offset by time savings and loss avoidance through error mitigation.

10.
Liver Transpl ; 26(1): 100-112, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31742878

RESUMO

Biliary complications (strictures and leaks) represent major limitations in living donor liver transplantation. Mesenchymal stem cells (MSCs) are a promising modality to prevent biliary complications because of immunosuppressive and angiogenic properties. Our goal was to evaluate the safety of adipose-derived MSC delivery to biliary anastomoses in a porcine model. Secondary objectives were defining the optimal method of delivery (intraluminal versus extraluminal) and to investigate MSC engraftment, angiogenesis, and fibrosis. Pigs were divided into 3 groups. Animals underwent adipose collection, MSC isolation, and expansion. Two weeks later, animals underwent bile duct transection, reanastomosis, and stent insertion. Group 1 received plastic stents wrapped in unseeded Vicryl mesh. Group 2 received stents wrapped in MSC-seeded mesh. Group 3 received unwrapped stents with the anastomosis immersed in an MSC suspension. Animals were killed 1 month after stent insertion when cholangiograms and biliary tissue were obtained. Serum was collected for liver biochemistries. Tissue was used for hematoxylin-eosin and trichrome staining and immunohistochemistry for MSC markers (CD44 and CD34) and for a marker of neoangiogenesis (CD31). There were no intraoperative complications. One pig died on postoperative day 3 due to acute cholangitis. All others recovered without complications. Cholangiography demonstrated no biliary leaks and minimal luminal narrowing. Surviving animals exhibited no symptoms, abnormal liver biochemistries, or clinically significant biliary stricturing. Group 3 showed significantly greater CD44 and CD34 staining, indicating MSC engraftment. Fibrosis was reduced at the anastomotic site in group 3 based on trichrome stain. CD31 staining of group 3 was more pronounced, supporting enhanced neoangiogenesis. In conclusion, adipose-derived MSCs were safely applied to biliary anastomoses. MSCs were locally engrafted within the bile duct and may have beneficial effects in terms of fibrosis and angiogenesis.

11.
Surg Endosc ; 34(2): 806-813, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31139990

RESUMO

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is technically challenging in Roux-en-Y gastric bypass (RYGB). Current approaches either have high failure rate, are resource intensive, or invasive. OBJECTIVE: To describe successful adoption of an old technique for performance of ERCP in patients with RYGB anatomy employing enteroscopy with the assistance of a percutaneously placed guidewire, which facilitates both reaching and cannulating the major papilla. METHOD: A retrospective cohort study in a tertiary-care center. We included patients with RYGB from 2015 to 2017 who underwent ERCP. We compared success rate and adverse events between rendezvous guidewire-assisted (RGA) and balloon-assisted enteroscopy (BAE) ERCP techniques. RESULTS: Thirty patients with RYGB underwent 62 ERCPs. The mean age was 62.2 ± 11 years with female predominance 83.3%. The procedures were performed using BAE 43/62 (69.3%), RGA 13/62 (21%), gastrostomy tube 5/62 (8.1%), and colonoscope 1/62 (1.6%). In patients with a native papilla (n = 37 ERCPs), clinical success rate with BAE was 36.8% compared to 100% with RGA (P < 0.001). There was no significant difference in bleeding (P = 0.17), post-ERCP pancreatitis (P = 0.4), or luminal perforation (P = not estimated) between the two techniques in native papilla. The mean procedure time with the RGA was significantly shorter than successful BAE with mean difference: 33 min (95% CI 8-57 min, P = 0.01). Twenty-five ERCPs were performed in eight patients with non-native papilla. BAE success rate in non-native papilla was 95.8%. The mean procedure time of the BAE in non-native papilla was 111 ± 60 min. Native papillae were associated with a significantly higher BAE failure rate compared to non-native papillae (OR: 12; 95% CI 1.44-99.7, P = 0.02). CONCLUSION: In patients with RYGB, RGA appears to be highly successful and safe in achieving clinical success for patients with native papilla as compared to BAE.

13.
J Arthroplasty ; 35(4): 1069-1073, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31870582

RESUMO

BACKGROUND: Extensive femoral bone loss poses a challenge in revision total hip arthroplasty (rTHA). Many techniques have been developed to address this problem including fully porous cylindrical stems, impaction bone grafting, and cementation of long stems, which have had varied success. Modular tapered fluted femoral stems (MTFS) show favorable results. We sought to determine the minimum 2-year radiographic and clinical performance of MTFS in rTHA in a population with extensive proximal femoral bone loss. METHODS: Our clinical database was queried retrospectively for all patients who underwent rTHA with an MTFS. We included patients with Paprosky 3 and 4 femoral bone loss and patients with Vancouver B2 and B3 periprosthetic femur fractures. Patients without 2-year follow-up were invited to return to clinic for X-ray evaluation and to complete clinical questionnaires. We assessed distance of stem subsidence and presence of stem fixation on final X-ray. We recorded all-cause revision and survival of the stem at final follow-up. RESULTS: One hundred twenty-nine patients were available for follow-up. Average follow-up time was 3.75 years. One hundred twenty-two stems (95%) remained in place at final follow-up. Median subsidence was 1.4 mm (range 0-21). All-cause revision rate was 16.3% (21 patients). Of the hips revised, 10 were for instability, 6 for infection, 1 for aseptic loosening, and 1 for periprosthetic femur fracture. Three were revised for other reasons. The stem was revised in 7 patients (5.4%), and the most common reason for stem revision was infection (5 patients). The other 2 stems were revised for aseptic loosening in a Paprosky 4 femur and periprosthetic femur fracture. Survival of tapered modular fluted stems with aseptic failure as an endpoint was 98.4%. The mean Hip disability and Osteoarthritis Outcome Score, Joint Replacement score at final follow-up was 73, and mean Veterans Rand 12 item health survey physical and mental scores were 32.8 and 52.2, respectively. CONCLUSION: In patients with Paprosky 3, 4 femoral defects or Vancouver type B2, B3 fractures, modular tapered fluted stems for femoral revision show excellent outcomes at minimum 2-year follow-up.

14.
J Infect Dis ; 2019 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-31832640

RESUMO

Specific spatial organization of granulomas within the lungs is crucial for protective anti-tuberculosis (TB) immune responses. However, only large animal models such as macaques are thought to reproduce the morphological hallmarks of human TB granulomas. In this study, we show that infection of mice with clinical "hypervirulent" Mycobacterium tuberculosis (Mtb) HN878 induces human-like granulomas composed of bacilli-loaded macrophages surrounded by lymphocytes and organized localization of germinal centers and B cell follicles. Conversely, infection with lab-adapted Mtb H37Rv resulted in granulomas that are characterized by unorganized clusters of macrophages scattered between lymphocytes. An in-depth exploration of the functions of B cells within these follicles suggested diverse roles and the activation of signaling pathways associated with antigen presentation and immune cell recruitment. These findings support the use of clinical Mtb HN878 strain for infection in mice as an appropriate model to study immune parameters associated with human TB granulomas.

15.
Sci Rep ; 9(1): 19521, 2019 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-31863009

RESUMO

Filarial nematode infections cause a substantial global disease burden. Genomic studies of filarial worms can improve our understanding of their biology and epidemiology. However, genomic information from field isolates is limited and available reference genomes are often discontinuous. Single molecule sequencing technologies can reduce the cost of genome sequencing and long reads produced from these devices can improve the contiguity and completeness of genome assemblies. In addition, these new technologies can make generation and analysis of large numbers of field isolates feasible. In this study, we assessed the performance of the Oxford Nanopore Technologies MinION for sequencing and assembling the genome of Brugia malayi, a human parasite widely used in filariasis research. Using data from a single MinION flowcell, a 90.3 Mb nuclear genome was assembled into 202 contigs with an N50 of 2.4 Mb. This assembly covered 96.9% of the well-defined B. malayi reference genome with 99.2% identity. The complete mitochondrial genome was obtained with individual reads and the nearly complete genome of the endosymbiotic bacteria Wolbachia was assembled alongside the nuclear genome. Long-read data from the MinION produced an assembly that approached the quality of a well-established reference genome using comparably fewer resources.

16.
J Infect Dis ; 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31844885

RESUMO

Schistosoma infection has been associated with altered immune function, including hyporesponsiveness. S. haematobium-infected schoolchildren were studied before and after praziquantel treatment and compared to uninfected controls. Cellular responses were characterised by cytokine production and flow cytometry, and in a subset of children RNA-Seq transcriptome profiling performed. Removal of S. haematobium infection resulted in increased schistosome-specific cytokine responses which were negatively associated with CD4+CD25+FOXP3+ T cells and accompanied by increased frequency of effector memory T cells. Innate responses to TLR ligation decreased with treatment and showed positive association with CD4+CD25+FOXP3+ T cells. At the transcriptome level, schistosome infection was associated with enrichment in cell adhesion, while parasite removal with a more quiescent profile. Further analysis indicated alteration in cellular energy metabolism to be associated with S. haematobium infection and that EGR2 and EGR3, transcription factors which negatively regulate T cell activation, may play a role in adaptive immune hyporesponsiveness.

17.
HPB (Oxford) ; 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31685380

RESUMO

BACKGROUND: Select patients with acute cholecystitis (AC) are not candidates for index cholecystectomy. We compared the influence of ERCP-guided transpapillary gallbladder drainage (ERGD) versus percutaneous cholecystostomy (PC) on delayed cholecystectomy outcomes. METHODS: Consecutive patients undergoing ERGD or PC for AC from January 2007 to October 2018 were included. Primary outcome was the rate of conversion to open cholecystectomy and perioperative complications in groups. RESULTS: The study included 52 patients with ERGD and 140 with PC prior to cholecystectomy (median 68 days [IQR: 47-105.5]). Technical success was higher in the PC group (100% vs 91%; P = 0.0004). There was a nonsignificant trend to lower postoperative complications with ERGD (30.7% vs 43.5%; P = 0.07). No difference in conversion to open cholecystectomy OR: 1.5 (95% CI: 0.68-3.65; P = 0.28) or severity of complications (Clavien-Dindo grade >2) OR: 0.60, (95% CI: 0.19-1.87; P = 0.38) was noted between the ERGD and PC groups. PC was associated with higher rates of unplanned repeat intervention (16.4% vs 7.7%; P = 0.02). CONCLUSION: ERGD is suitable for patients with AC who is candidates for delayed cholecystectomy and should be considered for gallbladder drainage in patients with concomitant choledocholithiasis or cholangitis who require ERCP.

18.
Zootaxa ; 4661(1): zootaxa.4661.1.3, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31716717

RESUMO

The crane fly genus Rhabdomastix Skuse, 1890 is briefly introduced, the four species hitherto known from Australia are reviewed. The male of R. tonnoirana Alexander, 1934 and the female of R. wilsoniana Alexander, 1934 are described for the first time and R. minima Alexander, 1926 is considered as nomen dubium. A further eight Australian species are described as new, their affinities and distributions are discussed. They are R. borroloola sp. nov., R. dobrotworskyi sp. nov., R. dooragana sp. nov., R. hirsuta sp. nov., R. nivalis sp. nov., R. ponticulus sp. nov., R. collessiana sp. nov., R. rosae sp. nov.  A key to the males of Australian Rhabdomastix is presented.


Assuntos
Dípteros , Distribuição Animal , Estruturas Animais , Animais , Austrália , Feminino , Masculino , Nematóceros
19.
PLoS Negl Trop Dis ; 13(11): e0007825, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31756188

RESUMO

BACKGROUND: Enterotoxigenic Escherichia coli (ETEC) cause significant diarrheal morbidity and mortality in children of resource-limited regions, warranting development of effective vaccine strategies. Genetic diversity of the ETEC pathovar has impeded development of broadly protective vaccines centered on the classical canonical antigens, the colonization factors and heat-labile toxin. Two non-canonical ETEC antigens, the EtpA adhesin, and the EatA mucinase are immunogenic in humans and protective in animal models. To foster rational vaccine design that complements existing strategies, we examined the distribution and molecular conservation of these antigens in a diverse population of ETEC isolates. METHODS: Geographically diverse ETEC isolates (n = 1159) were interrogated by PCR, immunoblotting, and/or whole genome sequencing (n = 46) to examine antigen conservation. The most divergent proteins were purified and their core functions assessed in vitro. RESULTS: EatA and EtpA or their coding sequences were present in 57.0% and 51.5% of the ETEC isolates overall, respectively; and were globally dispersed without significant regional differences in antigen distribution. These antigens also exhibited >93% amino acid sequence identity with even the most divergent proteins retaining the core adhesin and mucinase activity assigned to the prototype molecules. CONCLUSIONS: EtpA and EatA are well-conserved molecules in the ETEC pathovar, suggesting that they serve important roles in virulence and that they could be exploited for rational vaccine design.


Assuntos
Antígenos de Bactérias/genética , Escherichia coli Enterotoxigênica/genética , Infecções por Escherichia coli/microbiologia , Proteínas de Escherichia coli/genética , Variação Genética , Glicoproteínas de Membrana/genética , Peptídeo Hidrolases/genética , Antígenos de Bactérias/análise , Escherichia coli Enterotoxigênica/química , Escherichia coli Enterotoxigênica/classificação , Escherichia coli Enterotoxigênica/isolamento & purificação , Infecções por Escherichia coli/imunologia , Proteínas de Escherichia coli/análise , Saúde Global , Humanos , Immunoblotting , Glicoproteínas de Membrana/análise , Peptídeo Hidrolases/análise , Reação em Cadeia da Polimerase , Sequenciamento Completo do Genoma
20.
Dig Dis Sci ; 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31571103

RESUMO

BACKGROUND AND AIMS: Single-operator cholangioscopy (SOC) has been suggested to be a cost-effective strategy for the detection of cholangiocarcinoma (CCA). The aim of this study is to compare the performance characteristics of SOC-guided biopsies and transpapillary biopsies with standard sampling techniques for the detection of CCA. METHODS: A retrospective cohort study of patients undergoing SOC between 1/2007 and 10/2018 at a single academic center was performed. Demographic, procedural, and outcomes data were recorded and analyzed using STATA 14.0. Sensitivity comparison between diagnostic tests was performed using exact McNemar test exclusively among patients with CCA. Two-sided p value < 0.05 was considered statistically significant. RESULTS: Ninety-two patients were included; 36 (39.1%) with primary sclerosing cholangitis (PSC), 41 (44.6%) with CCA, and median follow-up was 15.1 months. In the overall cohort, brush cytology demonstrated a sensitivity of 44.7% and increased with the addition of FISH (56.8%; p = 0.12), FISH with SOC-guided biopsy (71.4%; p = 0.03), and FISH with transpapillary biopsy (64.5%; p = 0.01). However, in patients with PSC, there was no significant improvement in sensitivity with the addition of SOC-guided biopsy or transpapillary biopsy in addition to FISH when compared to brush cytology. There was no difference in the rates of overall adverse events (14% vs. 23.2%; p = 0.27) or infection (3% vs. 4%; p = 0.83) in patients with and without PSC. CONCLUSIONS: SOC-guided and transpapillary biopsies improve sensitivity for the detection of cholangiocarcinoma in combination with other ERCP-based techniques compared to brush cytology alone. However, while safe, these modalities do not significantly improve the sensitivity for the detection of malignancy in PSC patients.

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