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1.
Nat Commun ; 10(1): 3067, 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31296851

RESUMO

WalKR (YycFG) is the only essential two-component regulator in the human pathogen Staphylococcus aureus. WalKR regulates peptidoglycan synthesis, but this function alone does not explain its essentiality. Here, to further understand WalKR function, we investigate a suppressor mutant that arose when WalKR activity was impaired; a histidine to tyrosine substitution (H271Y) in the cytoplasmic Per-Arnt-Sim (PASCYT) domain of the histidine kinase WalK. Introducing the WalKH271Y mutation into wild-type S. aureus activates the WalKR regulon. Structural analyses of the WalK PASCYT domain reveal a metal-binding site, in which a zinc ion (Zn2+) is tetrahedrally-coordinated by four amino acids including H271. The WalKH271Y mutation abrogates metal binding, increasing WalK kinase activity and WalR phosphorylation. Thus, Zn2+-binding negatively regulates WalKR. Promoter-reporter experiments using S. aureus confirm Zn2+ sensing by this system. Identification of a metal ligand recognized by the WalKR system broadens our understanding of this critical S. aureus regulon.

2.
Mol Microbiol ; 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31283061

RESUMO

Capsular polysaccharide (CP) biosynthesis in Staphylococcus aureus is tightly controlled resulting in a heterogeneous phenotype within a population and CP being mainly detectable in nongrowing cells. Expression of the corresponding biosynthesis gene cluster is driven by one promoter element (Pcap ). Here, we demonstrate that Pcap contains a main SigB-dependent promoter. The SigB consensus motif overlaps with a previously described inverted repeat (IR) that is crucial for cap expression. The essentiality of the IR is derived from this region acting as a SigB binding site rather than as an operator site for the proposed cap activators RbsR and MsaB. Furthermore, Pcap contains an extensive upstream region harboring a weak SigA-dependent promoter and binding sites for cap repressors such as SaeR, CodY and Rot. Heterogeneous CP synthesis is determined by SigB activity and repressor binding to the upstream region. SigB dependency and regulation by the upstream repressors are also sufficient to explain the temporal gene expression pattern at the transcriptional level. However, CP synthesis remains growth phase-dependent even when transcription is rendered constitutive, suggesting additional posttranscriptional regulatory circuits. Thus, the interference of multiple repressors with SigB-dependent promoter activity as well as post-transcriptional mechanisms ensure the appropriate regulation of CP synthesis.

3.
Clin Pharmacol Ther ; 2019 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-31102467

RESUMO

Using positron emission tomography imaging, we determined the hepatic concentrations and hepatobiliary transport of [11 C]rosuvastatin (RSV; i.v. injection) in the absence (n = 6) and presence (n = 4 of 6) of cyclosporin A (CsA; i.v. infusion) following a therapeutic dose of unlabeled RSV (5 mg, p.o.) in healthy human volunteers. The sinusoidal uptake, sinusoidal efflux, and biliary efflux clearance (CL; mL/minute) of [11 C]RSV, estimated through compartment modeling were 1,205.6 ± 384.8, 16.2 ± 11.2, and 5.1 ± 1.8, respectively (n = 6). CsA (blood concentration: 2.77 ± 0.24 µM), an organic-anion-transporting polypeptide, Na+ -taurocholate cotransporting polypeptide, and breast cancer resistance protein inhibitor increased [11 C]RSV systemic blood exposure (45%; P < 0.05), reduced its biliary efflux CL (52%; P < 0.05) and hepatic uptake (25%; P > 0.05) but did not affect its distribution into the kidneys. CsA increased plasma concentrations of coproporphyrin I and III and total bilirubin by 297 ± 69%, 384 ± 102%, and 81 ± 39%, respectively (P < 0.05). These data can be used in the future to verify predictions of hepatic concentrations and hepatobiliary transport of RSV.

4.
Nat Commun ; 10(1): 1404, 2019 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-30926919

RESUMO

The Gram-positive cell wall consists of peptidoglycan functionalized with anionic glycopolymers, such as wall teichoic acid and capsular polysaccharide (CP). How the different cell wall polymers are assembled in a coordinated fashion is not fully understood. Here, we reconstitute Staphylococcus aureus CP biosynthesis and elucidate its interplay with the cell wall biosynthetic machinery. We show that the CapAB tyrosine kinase complex controls multiple enzymatic checkpoints through reversible phosphorylation to modulate the consumption of essential precursors that are also used in peptidoglycan biosynthesis. In addition, the CapA1 activator protein interacts with and cleaves lipid-linked CP precursors, releasing the essential lipid carrier undecaprenyl-phosphate. We further provide biochemical evidence that the subsequent attachment of CP is achieved by LcpC, a member of the LytR-CpsA-Psr protein family, using the peptidoglycan precursor native lipid II as acceptor substrate. The Ser/Thr kinase PknB, which can sense cellular lipid II levels, negatively controls CP synthesis. Our work sheds light on the integration of CP biosynthesis into the multi-component Gram-positive cell wall.


Assuntos
Cápsulas Bacterianas/metabolismo , Parede Celular/metabolismo , Staphylococcus aureus/metabolismo , Proteínas de Bactérias/metabolismo , Biocatálise , Lipídeos/biossíntese , Modelos Biológicos , Peptidoglicano/metabolismo , Fosforilação , Fosfotirosina/metabolismo , Polissacarídeos Bacterianos/biossíntese
5.
Intern Med J ; 49(3): 388-391, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30897671

RESUMO

The natural history of a systemic right ventricle after an atrial switch procedure has yet to be fully characterised. We describe the case of the longest surviving patient at our institution who underwent a Mustard Baffle correction for dextro-transposition of great arteries in childhood. Over following decades he was reviewed regularly with deteriorating systemic right ventricle function. At around 50 years of age he developed worsening heart failure on maximal medical therapy. He was subsequently assessed for cardiac transplantation which he underwent successfully at the age of 55 years.

7.
JMIR Mhealth Uhealth ; 7(1): e12041, 2019 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-30664473

RESUMO

BACKGROUND: With the emergence of mobile devices, mobile electronic health record (mEHR) systems have been utilized by health care professionals (HCPs), including doctors, nurses, and other practitioners, to improve efficiency at the point of care. Although several studies on mEHR systems were conducted, including those analyzing their effects and HCPs' usage frequency, only a few considered the specific workflows of doctors based on their specialties in which the work process differs greatly. OBJECTIVE: This study aimed to investigate the differences in mEHR usage paths across clinical specialties. METHODS: We collected the log data of 974 doctors who worked from August 2016 to August 2017 and used the mEHR system at the Samsung Medical Center, one of the biggest hospitals in South Korea. The doctors were classified into 3 groups based on their specialty: the physician, the surgeon, and other hospital-based physician (OHBP) groups. We used various descriptive and visualization methods to understand and compare doctors' usage paths of mEHRs. First, the average numbers of log-ins per day and features used per log-in were examined over different specialties and positions. Second, the number of features used by each doctor was visualized via a heat map to provide an overview of mEHR usage across feature types and doctors' specialties. Third, we conducted a path analysis via a Sankey diagram to describe main usage paths and association rule mining to find frequent paths in mEHR usage. RESULTS: The physician group logged on most frequently, whereas the OHBP group logged on least frequently. In fact, the number of log-ins per day of residents in the physician group was 4.4 times higher than that of staff members in the other groups. The heat map visualization showed a visible difference among specialty groups. The physician group used more consultation-related features, whereas the surgeon group used more surgery-related features. Generally, 50% of the doctors spent about 15 seconds at a time when using mEHRs. In the Sankey diagram, the physician group showed diverse usage patterns with higher complexity compared with the other 2 groups; in particular, their paths contained more loops, which reflected repetitive checks on multiple patients. The most frequent path included inpatient summary, which means that most users stopped at the point of summary and did not proceed to view more details. CONCLUSIONS: The usage paths of mEHRs showed considerable differences among the specialty groups. Such differences can be accommodated into an mEHR design to enhance the efficiency of care.

8.
J Nucl Med ; 2018 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-30361381

RESUMO

Calibration and reproducibility of quantitative 18F-fluorodeoxyglucose (FDG) PET measures are essential for adopting integral FDG-PET/CT biomarkers and response measures in multicenter clinical trials. We implemented a multicenter qualification process using NIST-traceable reference sources for scanners and dose calibrators, and similar patient and imaging protocols. We then assessed standardized uptake value (SUV) in patient test-retest studies. Methods: Five FDG-PET/CT scanners from 4 institutions (2 in a NCI-designated Comprehensive Cancer Center, 3 in a community-based network) were qualified for study use. Patients were scanned twice within 15 days, on the same scanner (n = 10); different but same model scanners within an institution (n = 2); or different model scanners at different institutions (n = 11). SUVmax values were recorded for lesions, and SUVmean for normal liver uptake. Linear mixed models with random intercept were fitted to evaluate test-retest differences in multiple lesions per patient and to estimate the concordance correlation coefficient (CCC). Bland-Altman plots and repeatability coefficients were also produced. Results: 162 lesions (82 bone, 80 soft tissue) were assessed in patients with breast cancer (n = 17) or other cancers (n = 6). Repeat scans within the same institution, using the same scanner or two scanners of the same model, had an average percent difference in SUVmax of 8% (95% CI 6%-10%). For test-retest on different scanners at different sites, the average percent difference in lesion SUVmax was 18% (95% CI 13%-24%). Normal liver uptake (SUVmean) showed an average percent difference of 5% (95% CI 3%-10%) for the same scanner model/institution and 6% (95% CI 3%-11%) for different scanners from different institutions. Protocol adherence was good; the median difference in injection-to-acquisition time was 2 minutes (range 0-11 minutes). Test-retest SUVmax variability was not explained by available information regarding protocol deviations or patient/lesion characteristics. Conclusion: FDG-PET/CT scanner qualification and calibration can yield highly reproducible test-retest tumor SUV measurements. Our data support use of different qualified scanners of the same model for serial studies. Test-retest differences from different scanner models were greater; more resolution-dependent harmonization of scanner protocols and reconstruction algorithms may be capable of reducing these differences to values closer to same-scanner results.

9.
JMIR Mhealth Uhealth ; 6(9): e11187, 2018 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-30249577

RESUMO

BACKGROUND: Improved medical practice efficiency has been demonstrated by physicians using mobile device (mobile phones, tablets) electronic medical record (EMR) systems. However, the quantitative effects of these systems have not been adequately measured. OBJECTIVE: This study aimed to determine the effectiveness of near-field communication (NFC) integrated with a mobile EMR system regarding physician turnaround time in a hospital emergency department (ED). METHODS: A simulation study was performed in a hospital ED. Twenty-five physicians working in the ED participated in 2 scenarios, using either a mobile device or personal computer (PC). Scenario A involved randomly locating designated patients in the ED. Scenario B consisted of accessing laboratory results of an ED patient at the bedside. After completing the scenarios, participants responded to 10 questions that were scored using a system usability scale (SUS). The primary metric was the turnaround time for each scenario. The secondary metric was the usability of the system, graded by the study participants. RESULTS: Locating patients from the ED entrance took a mean of 93.0 seconds (SD 34.4) using the mobile scenario. In contrast, it only required a mean of 57.3 seconds (SD 10.5) using the PC scenario (P<.001). Searching for laboratory results of the patients at the bedside required a mean of only 25.2 seconds (SD 5.3) with the mobile scenario, and a mean of 61.5 seconds (SD 11.6) using the PC scenario (P<.001). Sensitivity analysis comparing only the time for login and accessing the relevant information also determined mobile devices to be significantly faster. The mean SUS score of NFC-mobile EMR was 71.90 points. CONCLUSIONS: NFC integrated with mobile EMR provided for a more efficient physician practice with good usability.

10.
Nat Microbiol ; 3(10): 1175-1185, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30177740

RESUMO

Staphylococcus epidermidis is a conspicuous member of the human microbiome, widely present on healthy skin. Here we show that S. epidermidis has also evolved to become a formidable nosocomial pathogen. Using genomics, we reveal that three multidrug-resistant, hospital-adapted lineages of S. epidermidis (two ST2 and one ST23) have emerged in recent decades and spread globally. These lineages are resistant to rifampicin through acquisition of specific rpoB mutations that have become fixed in the populations. Analysis of isolates from 96 institutions in 24 countries identified dual D471E and I527M RpoB substitutions to be the most common cause of rifampicin resistance in S. epidermidis, accounting for 86.6% of mutations. Furthermore, we reveal that the D471E and I527M combination occurs almost exclusively in isolates from the ST2 and ST23 lineages. By breaching lineage-specific DNA methylation restriction modification barriers and then performing site-specific mutagenesis, we show that these rpoB mutations not only confer rifampicin resistance, but also reduce susceptibility to the last-line glycopeptide antibiotics, vancomycin and teicoplanin. Our study has uncovered the previously unrecognized international spread of a near pan-drug-resistant opportunistic pathogen, identifiable by a rifampicin-resistant phenotype. It is possible that hospital practices, such as antibiotic monotherapy utilizing rifampicin-impregnated medical devices, have driven the evolution of this organism, once trivialized as a contaminant, towards potentially incurable infections.

11.
Free Radic Biol Med ; 126: 221-234, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30118828

RESUMO

Among the various causative factors involved in the pathogenesis of Alzheimer's disease (AD), oxidative stress has emerged as an important factor. Phloroglucinol is a polyphenol component of phlorotannin, which is found at sufficient levels in Ecklonia cava (E. cava). Phloroglucinol has been reported to exert antioxidant activities in various tissues. Previously, we reported that the stereotaxic injection of phloroglucinol regulated synaptic plasticity in an AD mouse model. In this study, we aimed to investigate the effects of oral administration of phloroglucinol in AD. The oral administration of phloroglucinol for 2 months attenuated the impairments in cognitive function observed in 6-month-old 5X familial AD (5XFAD) mice, as assessed with the T-maze and Y-maze tests. The administration of phloroglucinol for 2 months in 5XFAD mice caused a reduction in the number of amyloid plaques and in the protein level of BACE1, a major amyloid precursor protein cleavage enzyme, together with γ-secretase. Phloroglucinol also restored the reduction in dendritic spine density and the number of mature spines in the hippocampi of 5XFAD mice. In addition, phloroglucinol-administered 5XFAD mice displayed lower protein levels of GFAP and Iba-1 and mRNA levels of TNF-α and IL-6 compared with vehicle-administered 5XFAD mice. These results demonstrated that phloroglucinol alleviated the neuropathological features and behavioral phenotypes in the 5XFAD mouse model. Taken together, our results suggest that phloroglucinol has therapeutic potential for AD treatment.

12.
Sci Transl Med ; 10(452)2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30068573

RESUMO

Alcohol-based disinfectants and particularly hand rubs are a key way to control hospital infections worldwide. Such disinfectants restrict transmission of pathogens, such as multidrug-resistant Staphylococcus aureus and Enterococcus faecium Despite this success, health care infections caused by E. faecium are increasing. We tested alcohol tolerance of 139 hospital isolates of E. faecium obtained between 1997 and 2015 and found that E. faecium isolates after 2010 were 10-fold more tolerant to killing by alcohol than were older isolates. Using a mouse gut colonization model of E. faecium transmission, we showed that alcohol-tolerant E. faecium resisted standard 70% isopropanol surface disinfection, resulting in greater mouse gut colonization compared to alcohol-sensitive E. faecium We next looked for bacterial genomic signatures of adaptation. Alcohol-tolerant E. faecium accumulated mutations in genes involved in carbohydrate uptake and metabolism. Mutagenesis confirmed the roles of these genes in the tolerance of E. faecium to isopropanol. These findings suggest that bacterial adaptation is complicating infection control recommendations, necessitating additional procedures to prevent E. faecium from spreading in hospital settings.

13.
Artigo em Inglês | MEDLINE | ID: mdl-30150477

RESUMO

Coagulase-negative staphylococci (CoNS), such as Staphylococcus capitis, are major causes of bloodstream infections in neonatal intensive care units (NICUs). Recently, a distinct clone of S. capitis (designated S. capitis NRCS-A) has emerged as an important pathogen in NICUs internationally. Here, 122 S. capitis isolates from New Zealand (NZ) underwent whole-genome sequencing (WGS), and these data were supplemented with publicly available S. capitis sequence reads. Phylogenetic and comparative genomic analyses were performed, as were phenotypic assessments of antimicrobial resistance, biofilm formation, and plasmid segregational stability on representative isolates. A distinct lineage of S. capitis was identified in NZ associated with neonates and the NICU environment. Isolates from this lineage produced increased levels of biofilm, displayed higher levels of tolerance to chlorhexidine, and were multidrug resistant. Although similar to globally circulating NICU-associated S. capitis strains at a core-genome level, NZ NICU S. capitis isolates carried a novel stably maintained multidrug-resistant plasmid that was not present in non-NICU isolates. Neonatal blood culture isolates were indistinguishable from environmental S. capitis isolates found on fomites, such as stethoscopes and neonatal incubators, but were generally distinct from those isolates carried by NICU staff. This work implicates the NICU environment as a potential reservoir for neonatal sepsis caused by S. capitis and highlights the capacity of genomics-based tracking and surveillance to inform future hospital infection control practices aimed at containing the spread of this important neonatal pathogen.

14.
Radiology ; 289(2): 443-454, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30015591

RESUMO

Purpose To investigate performance in detectability of small (≤1 cm) low-contrast hypoattenuating focal lesions by using filtered back projection (FBP) and iterative reconstruction (IR) algorithms from two major CT vendors across a range of 11 radiation exposures. Materials and Methods A low-contrast detectability phantom consisting of 21 low-contrast hypoattenuating focal objects (seven sizes between 2.4 and 10.0 mm, three contrast levels) embedded into a liver-equivalent background was scanned at 11 radiation exposures (volume CT dose index range, 0.5-18.0 mGy; size-specific dose estimate [SSDE] range, 0.8-30.6 mGy) with four high-end CT platforms. Data sets were reconstructed by using FBP and varied strengths of image-based, model-based, and hybrid IRs. Sixteen observers evaluated all data sets for lesion detectability by using a two-alternative-forced-choice (2AFC) paradigm. Diagnostic performances were evaluated by calculating area under the receiver operating characteristic curve (AUC) and by performing noninferiority analyses. Results At benchmark exposure, FBP yielded a mean AUC of 0.79 ± 0.09 (standard deviation) across all platforms which, on average, was approximately 2% lower than that observed with the different IR algorithms, which showed an average AUC of 0.81 ± 0.09 (P = .12). Radiation decreases of 30%, 50%, and 80% resulted in similar declines of observer detectability with FBP (mean AUC decrease, -0.02 ± 0.05, -0.03 ± 0.05, and -0.05 ± 0.05, respectively) and all IR methods investigated (mean AUC decrease, -0.00 ± 0.05, -0.04 ± 0.05, and -0.04 ± 0.05, respectively). For each radiation level and CT platform, variance in performance across observers was greater than that across reconstruction algorithms (P = .03). Conclusion Iterative reconstruction algorithms have limited radiation optimization potential in detectability of small low-contrast hypoattenuating focal lesions. This task may be further complicated by a high degree of variation in radiologists' performances, seemingly exceeding real performance differences among reconstruction algorithms. © RSNA, 2018 Online supplemental material is available for this article.

15.
Pediatr Surg Int ; 34(8): 891-895, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29968096

RESUMO

PURPOSE: In resource-limited settings, up to two-thirds of surgical patients develop surgical site infections (SSIs). Our aim was to implement a multimodal protocol including an occlusive dressing and parental engagement to achieve low SSI rates in patients undergoing elective ambulatory pediatric surgery at a tertiary center in Haiti. METHODS: An observational retrospective review of pediatric patients who underwent elective ambulatory procedures from August 2015 to May 2016 following the implementation of a multimodal protocol consisting of: washing and prepping the operative site with chlorhexidine; review of the surgical safety checklist; one dose of cefazolin before incision; after wound closure application of steri strips, gauze, and tegaderm; and with parental engagement maintenance of the dressing until the follow-up visit. RESULTS: We performed 119 procedures in 99 patients. Mean age was 6.2 years. The most common procedure was inguinal hernia repair (66%); 89% of parents returned to clinic with their children for the follow-up visit, which occurred on average on day 7.6 (range 3-40 days). The SSI rate was 1% (CI 0.00-0.03). CONCLUSION: Implementing a multimodal protocol including an occlusive dressing and parental engagement led to a 1% SSI rate in a resource-constrained setting.


Assuntos
Procedimentos Cirúrgicos Ambulatórios/efeitos adversos , Procedimentos Cirúrgicos Eletivos/efeitos adversos , Hérnia Inguinal/cirurgia , Curativos Oclusivos , Infecção da Ferida Cirúrgica/prevenção & controle , Centros de Atenção Terciária , Criança , Feminino , Haiti/epidemiologia , Humanos , Incidência , Masculino , Estudos Retrospectivos , Infecção da Ferida Cirúrgica/epidemiologia
16.
Stem Cell Res Ther ; 9(1): 154, 2018 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-29895321

RESUMO

Neural stem cells (NSCs) play vital roles in brain homeostasis and exhibit a broad repertoire of potentially therapeutic actions following neurovascular injury. One such injury is stroke, a worldwide leading cause of death and disability. Clinically, extensive injury from ischemic stroke results from ischemia-reperfusion (IR), which is accompanied by inflammation, blood-brain barrier (BBB) damage, neural cell death, and extensive tissue loss. Tissue plasminogen activator (tPA) is still the only US Food and Drug Administration-approved clot-lysing agent. Whereas the thrombolytic role of tPA within the vasculature is beneficial, the effects of tPA (in a non-thrombolytic role) within the brain parenchyma have been reported as harmful. Thus, new therapies are needed to reduce the deleterious side effects of tPA and quickly facilitate vascular repair following stroke. The Stroke Treatment Academic Industry Roundtable (STAIR) recommends that stroke therapies "focus on drugs/devices/treatments with multiple mechanisms of action and that target multiple pathways". Thus, based on multifactorial ischemic cascades in various stroke stages, effective stroke therapies need to focus on targeting and ameliorating early IR injury as well as facilitating angiogenesis, neurogenesis, and neurorestorative mechanisms following stroke. This review will discuss the preclinical perspectives of NSC transplantation as a promising treatment for neurovascular injury and will emphasize both the subacute and chronic phase of ischemic stroke.

17.
J Nucl Med ; 59(12): 1823-1830, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29748233

RESUMO

Assessing therapy response of breast cancer bone metastases is challenging. In retrospective studies, serial 18F-FDG PET was predictive of time to skeletal-related events (tSRE) and time to progression (TTP). 18F-NaF PET improves bone metastasis detection compared with bone scanning. We prospectively tested 18F-FDG PET and 18F-NaF PET to predict tSRE, TTP, and overall survival (OS) in patients with bone-dominant metastatic breast cancer (MBC). Methods: Patients with bone-dominant MBC were imaged with 18F-FDG PET and 18F-NaF PET before starting new therapy (scan1) and again at a range of times centered around approximately 4 mo later (scan2). Maximum standardized uptake value (SUVmax) and lean body mass adjusted standardized uptake (SULpeak) were recorded for a single index lesion and up to 5 most dominant lesions for each scan. tSRE, TTP, and OS were assessed exclusive of the PET images. Univariate Cox regression was performed to test the association between clinical endpoints and 18F-FDG PET and 18F-NaF PET measures. mPERCIST (Modified PET Response Criteria in Solid Tumors) were also applied. Survival curves for mPERCIST compared response categories of complete response+partial response+stable disease versus progressive disease for tSRE, TTP, and OS. Results: Twenty-eight patients were evaluated. Higher 18F-FDG SULpeak at scan2 predicted shorter time to tSRE (P = <0.001) and TTP (P = 0.044). Higher 18F-FDG SUVmax at scan2 predicted a shorter time to tSRE (P = <0.001). A multivariable model using 18F-FDG SUVmax of the index lesion at scan1 plus the difference in SUVmax of up to 5 lesions between scans was predictive for tSRE and TTP. Among 24 patients evaluable by 18F-FDG PET mPERCIST, tSRE and TTP were longer in responders (complete response, partial response, or stable disease) than in nonresponders (progressive disease) (P = 0.007, 0.028, respectively), with a trend toward improved survival (P = 0.1). An increase in the uptake between scans of up to 5 lesions by 18F-NaF PET was associated with longer OS (P = 0.027). Conclusion: Changes in 18F-FDG PET parameters during therapy are predictive of tSRE and TTP, but not OS. mPERCIST evaluation in bone lesions may be useful in assessing response to therapy and is worthy of evaluation in multicenter, prospective trials. Serial 18F-NaF PET was associated with OS but was not useful for predicting TTP or tSRE in bone-dominant MBC.

18.
Nat Commun ; 9(1): 1379, 2018 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-29643357

RESUMO

Secretion of extracellular vesicles (EVs), a process common to eukaryotes, archae, and bacteria, represents a secretory pathway that allows cell-free intercellular communication. Microbial EVs package diverse proteins and influence the host-pathogen interaction, but the mechanisms underlying EV production in Gram-positive bacteria are poorly understood. Here we show that EVs purified from community-associated methicillin-resistant Staphylococcus aureus package cytosolic, surface, and secreted proteins, including cytolysins. Staphylococcal alpha-type phenol-soluble modulins promote EV biogenesis by disrupting the cytoplasmic membrane; whereas, peptidoglycan cross-linking and autolysin activity modulate EV production by altering the permeability of the cell wall. We demonstrate that EVs purified from a S. aureus mutant that is genetically engineered to express detoxified cytolysins are immunogenic in mice, elicit cytolysin-neutralizing antibodies, and protect the animals in a lethal sepsis model. Our study reveals mechanisms underlying S. aureus EV production and highlights the usefulness of EVs as a S. aureus vaccine platform.


Assuntos
Anticorpos Neutralizantes/biossíntese , Citotoxinas/administração & dosagem , Vesículas Extracelulares/imunologia , Sepse/prevenção & controle , Infecções Estafilocócicas/prevenção & controle , Vacinas Antiestafilocócicas/administração & dosagem , Animais , Parede Celular/química , Parede Celular/imunologia , Citotoxinas/metabolismo , Vesículas Extracelulares/química , Feminino , Engenharia Genética/métodos , Staphylococcus aureus Resistente à Meticilina/química , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/imunologia , Staphylococcus aureus Resistente à Meticilina/patogenicidade , Camundongos , Peptidoglicano/química , Peptidoglicano/imunologia , Sepse/imunologia , Sepse/microbiologia , Sepse/mortalidade , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/mortalidade , Vacinas Antiestafilocócicas/genética , Vacinas Antiestafilocócicas/imunologia , Análise de Sobrevida , Vacinação
19.
Diagnostics (Basel) ; 8(2)2018 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-29673157

RESUMO

The rapid evolution of antibiotic resistance in bacterial pathogens is driving the development of innovative, rapid antibiotic susceptibility testing (AST) tools as a way to provide more targeted and timely antibiotic treatment. We have previously presented a stress-based microfluidic method for the rapid determination of antibiotic susceptibility in methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA). In this method, stress is used to potentiate the action of antibiotics, and cell death is measured as a proxy for susceptibility. The method allows antibiotic susceptibility to be determined within an hour from the start of the antibiotic introduction. However, the relatively low dynamic range of the signal (2–10% cell response) even with high antibiotic concentrations (10–50 µg/mL) left room for the method’s optimization. We have conducted studies in which we varied the flow patterns, the media composition, and the antibiotic concentration to increase the cell death response and concordantly decrease the required antibiotic concentration down to 1–3 µg/mL, in accordance with the Clinical and Laboratory Standards Institute’s (CLSI) guidelines for AST breakpoint concentrations.

20.
Am J Physiol Heart Circ Physiol ; 314(6): H1137-H1152, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29350999

RESUMO

Abdominal aortic aneurysm (AAA) is a vascular disorder with a high case fatality rate in the instance of rupture. AAA is a multifactorial disease, and the etiology is still not fully understood. AAA is more likely to occur in men, but women have a greater risk of rupture and worse prognosis. Women are reportedly protected against AAA possibly by premenopausal levels of estrogen and are, on average, diagnosed at older ages than men. Here, we review the present body of research on AAA pathophysiology in humans, animal models, and cultured cells, with an emphasis on sex differences and sex steroid hormone signaling.

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