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1.
Clin Infect Dis ; 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31323088

RESUMO

BACKGROUND: The optimal antibiotic regimen for Pseudomonas aeruginosa bacteremia is controversial. Though beta-lactam monotherapy is common, data to guide the choice between antibiotics are scarce. We aimed to compare ceftazidime, carbapenems, and piperacillin-tazobactam as definitive monotherapy. METHODS: A multinational retrospective study (9 countries, 25 centers), including hospitalized patients with P . aeruginosa bacteremia treated with beta-lactam monotherapy during 2009-2015. The primary outcome was 30-day all-cause mortality. Univariate and multivariate analyses, including propensity adjusted analysis, were conducted introducing monotherapy type as an independent variable. RESULTS: We included 767 patients. Thirty-day mortality was 37/213 (17.4%) in the ceftazidime group; 42/210 (20%) in the carbapenem group, and 55/344 (16%) in the piperacillin-tazobactam group. Type of monotherapy was not significantly associated with mortality in either univariate, multivariate or propensity adjusted analyses (odds ratio [OR] 1.14, 95% confidence interval [CI] 0.52-2.46 for ceftazidime, OR 1.3, 95% CI 0.67-2.51 for piperacillin-tazobactam with carbapenems as reference in propensity adjusted multivariate analysis, 542 patients). No significant difference between antibiotics was demonstrated for clinical failure, microbiological failure, or adverse events. Isolation of P. aeruginosa with new resistance to antipseudomonal drugs was significantly more frequently with carbapenems (36/206, 17.5% versus ceftazidime 25/201, 12.4% and piperacillin-tazobactam 28/332, 8.4%, p=0.007). CONCLUSIONS: No significant difference in mortality, clinical, and microbiological outcomes or adverse events was demonstrated between ceftazidime, carbapenems and piperacillin-tazobactam as definitive treatment of P. aeruginosa bacteremia. Higher rates of resistant P. aeruginosa after patients were treated with carbapenems, along with the general preference for carbapenem-sparing regimens, suggests using ceftazidime or piperacillin-tazobactam for treating susceptible infection.

2.
Arthritis Res Ther ; 21(1): 47, 2019 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-30728072

RESUMO

OBJECTIVE: We applied systems biology approaches to investigate circadian rhythmicity in rheumatoid arthritis (RA). METHODS: We recruited adults (age 16-80 years old) with a clinical diagnosis of RA (active disease [DAS28 > 3.2]). Sleep profiles were determined before inpatient measurements of saliva, serum, and peripheral blood mononuclear leukocytes (PBML). Transcriptome and proteome analyses were carried out by RNA-SEQ and LC-MS/MS. Serum samples were analysed by targeted lipidomics, along with serum from mouse collagen induced-arthritis (CIA). Bioinformatic analysis identified RA-specific gene networks and rhythmic processes differing between healthy and RA. RESULTS: RA caused greater time-of-day variation in PBML gene expression, and ex vivo stimulation identified a time-of-day-specific RA transcriptome. We found increased phospho-STAT3 in RA patients, and some targets, including phospho-ATF2, acquired time-of-day variation in RA. Serum ceramides also gained circadian rhythmicity in RA, which was also seen in mouse experimental arthritis, resulting from gain in circadian rhythmicity of hepatic ceramide synthases. CONCLUSION: RA drives a gain in circadian rhythmicity, both in immune cells, and systemically. The coupling of distant timing information to ceramide synthesis and joint inflammation points to a systemic re-wiring of the circadian repertoire. Circadian reprogramming in response to chronic inflammation has implications for inflammatory co-morbidities and time-of-day therapeutics.

3.
FASEB J ; 33(5): 6226-6238, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30794439

RESUMO

Pulmonary airway epithelial cells (AECs) form a critical interface between host and environment. We investigated the role of the circadian clock using mice bearing targeted deletion of the circadian gene brain and muscle ARNT-like 1 (Bmal1) in AECs. Pulmonary neutrophil infiltration, biomechanical function, and responses to influenza infection were all disrupted. A circadian time-series RNA sequencing study of laser-captured AECs revealed widespread disruption in genes of the core circadian clock and output pathways regulating cell metabolism (lipids and xenobiotics), extracellular matrix, and chemokine signaling, but strikingly also the gain of a novel rhythmic transcriptome in Bmal1-targeted cells. Many of the rhythmic components were replicated in primary AECs cultured in air-liquid interface, indicating significant cell autonomy for control of pulmonary circadian physiology. Finally, we found that metabolic cues dictate phasing of the pulmonary clock and circadian responses to immunologic challenges. Thus, the local circadian clock in AECs is vital in lung health by coordinating major cell processes such as metabolism and immunity.-Zhang, Z. Hunter, L., Wu, G., Maidstone, R., Mizoro, Y., Vonslow, R., Fife, M., Hopwood, T., Begley, N., Saer, B., Wang, P., Cunningham, P., Baxter, M., Durrington, H., Blaikley, J. F., Hussell, T., Rattray, M., Hogenesch, J. B., Gibbs, J., Ray, D. W., Loudon, A. S. I. Genome-wide effect of pulmonary airway epithelial cell-specific Bmal1 deletion.

4.
Arthritis Res Ther ; 21(1): 5, 2019 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-30612576

RESUMO

BACKGROUND: The circadian clock plays a crucial role in regulating physiology and is important for maintaining immune homeostasis and responses to inflammatory stimuli. Inflammatory arthritis often shows diurnal variation in disease symptoms and disease markers, and it is now established that cellular clocks regulate joint inflammation. The clock gene Bmal1 is critical for maintenance of 24-h rhythms and plays a key role in regulating immune responses, as well as in aging-related processes. Fibroblast-like synoviocytes (FLS) are circadian rhythmic joint mesenchymal cells which are important for maintenance of joint health and play a crucial role in the development of inflammatory arthritis. The aim of this study was to investigate the importance of the joint mesenchymal cell circadian clock in health and disease. METHODS: Mice were generated which lack Bmal1 in Col6a1-expressing cells, targeting mesenchymal cells in the ankle joints. Joints of these animals were assessed by X-ray imaging, whole-mount staining and histology, and the composition of the synovium was assessed by flow cytometry. Arthritis was induced using collagen antibodies. RESULTS: Bmal1 deletion in joint mesenchymal cells rendered the FLS and articular cartilage cells arrhythmic. Targeted mice exhibited significant changes in the architecture of the joints, including chondroid metaplasia (suggesting a switch of connective tissue stem cells towards a chondroid phenotype), reductions in resident synovial macrophages and changes in the basal pro-inflammatory activity of FLS. Loss of Bmal1 in FLS rendered these resident immune cells more pro-inflammatory in response to challenge, leading to increased paw swelling, localised infiltration of mononuclear cells and enhanced cytokine production in a model of arthritis. CONCLUSIONS: This study demonstrates the importance of Bmal1 in joint mesenchymal cells in regulating FLS and chondrocyte development. Additionally, we have identified a role for this core clock component for restraining local responses to inflammation and highlight a role for the circadian clock in regulating inflammatory arthritis.

5.
Thorax ; 2018 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-30301818

RESUMO

The importance of circadian factors in managing patients is poorly understood. We present two retrospective cohort studies showing that lungs reperfused between 4 and 8 AM have a higher incidence (OR 1.12; 95% CI 1.03 to 1.21; p=0.01) of primary graft dysfunction (PGD) in the first 72 hours after transplantation. Cooling of the donor lung, occurring during organ preservation, shifts the donor circadian clock causing desynchrony with the recipient. The clock protein REV-ERBα directly regulates PGD biomarkers explaining this circadian regulation while also allowing them to be manipulated with synthetic REV-ERB ligands.

7.
Semin Cutan Med Surg ; 37(2): 88-100, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30040085

RESUMO

Recent advances in techniques for pathologic evaluation of melanocytic neoplasms, updates in staging, and novel treatment and prognostic assays have brought pathologists to the forefront of the care of the melanoma patient. Specimen procurement, handling, and evaluation are all key to the production of a pathology report that guides the clinician to the proper treatment of the patient. Recent, relevant changes in the pathologic analysis of melanocytic neoplasms, highlighting the AJCC 8th edition guidelines, and pathologic changes related to therapy are discussed herein. Also included is a discussion of molecular assays used to aid in diagnosis of challenging lesions, predict clinical outcome, and predict response to targeted therapy.

8.
FASEB J ; : fj201800026RR, 2018 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-29965797

RESUMO

The circadian clock is a critical regulator of immune function. We recently highlighted a role for the circadian clock in a mouse model of pulmonary inflammation. The epithelial clock protein Bmal1 was required to regulate neutrophil recruitment in response to inflammatory challenge. Bmal1 regulated glucocorticoid receptor (GR) recruitment to the neutrophil chemokine, CXC chemokine ligand 5 (CXCL5), providing a candidate mechanism. We now show that clock control of pulmonary neutrophilia persists without rhythmic glucocorticoid availability. Epithelial GR-null mice had elevated expression of proinflammatory chemokines in the lung under homeostatic conditions. However, deletion of GR in the bronchial epithelium blocked rhythmic CXCL5 production, identifying GR as required to confer circadian control to CXCL5. Surprisingly, rhythmic pulmonary neutrophilia persisted, despite nonrhythmic CXCL5 responses, indicating additional circadian control mechanisms. Deletion of GR in myeloid cells alone did not prevent circadian variation in pulmonary neutrophilia and showed reduced neutrophilic inflammation in response to dexamethasone treatment. These new data show GR is required to confer circadian control to some inflammatory chemokines, but that this alone is insufficient to prevent circadian control of neutrophilic inflammation in response to inhaled LPS, with additional control mechanisms arising in the myeloid cell lineage.-Ince, L. M., Zhang, Z., Beesley, S., Vonslow, R. M., Saer, B. R., Matthews, L. C., Begley, N., Gibbs, J. E., Ray, D. W., Loudon, A. S. I. Circadian variation in pulmonary inflammatory responses is independent of rhythmic glucocorticoid signaling in airway epithelial cells.

9.
Anticancer Res ; 38(5): 2989-2994, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29715129

RESUMO

AIM: The objective of this study was to define the rates of discrepancy between outside pathological diagnoses and secondary reviews. MATERIALS AND METHODS: We assessed the rates of discordance between outside diagnoses and secondary reviews, categorizing by organ site and minor or major (affecting patient care) discordances. RESULTS: A total of 9,289 consecutive surgical pathology (SP) and cytopathology (CP) cases reviewed in 2015 were identified. For 8,191 outside SP cases reviewed, the overall discordance rate (DR) was 14.2% (2.2% major, 12.0% minor). Specifically, neuropathology had the highest DR (10.9%), cutaneous and breast the lowest (1.1% each). Among 1,098 CP cases, the total DR was 13.7% (3.0% major, 10.7% minor). The majority of CP cases (1,066) were non-gynecological and had a total DR of 13.4% (2.7% major, 10.7% minor). CONCLUSION: While major DR was low, certain subspecialties had high DRs. This project can help identify areas where focused education could help improve pathological diagnostic accuracy for cancer.


Assuntos
Oncologia/normas , Neoplasias/diagnóstico , Patologia Cirúrgica/normas , Encaminhamento e Consulta , Humanos
10.
BMJ Open ; 8(4): e020251, 2018 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-29654026

RESUMO

OBJECTIVE: Complicated urinary tract infections (cUTIs) impose a high burden on healthcare systems and are a frequent cause of hospitalisation. The aims of this paper are to estimate the cost per episode of patients hospitalised due to cUTI and to explore the factors associated with cUTI-related healthcare costs in eight countries with high prevalence of multidrug resistance (MDR). DESIGN: This is a multinational observational, retrospective study. The mean cost per episode was computed by multiplying the volume of healthcare use for each patient by the unit cost of each item of care and summing across all components. Costs were measured from the hospital perspective. Patient-level regression analyses were used to identify the factors explaining variation in cUTI-related costs. SETTING: The study was conducted in 20 hospitals in eight countries with high prevalence of multidrug resistant Gram-negative bacteria (Bulgaria, Greece, Hungary, Israel, Italy, Romania, Spain and Turkey). PARTICIPANTS: Data were obtained from 644 episodes of patients hospitalised due to cUTI. RESULTS: The mean cost per case was €5700, with considerable variation between countries (largest value €7740 in Turkey; lowest value €4028 in Israel), mainly due to differences in length of hospital stay. Factors associated with higher costs per patient were: type of admission, infection source, infection severity, the Charlson comorbidity index and presence of MDR. CONCLUSIONS: The mean cost per hospitalised case of cUTI was substantial and varied significantly between countries. A better knowledge of the reasons for variations in length of stays could facilitate a better standardised quality of care for patients with cUTI and allow a more efficient allocation of healthcare resources. Urgent admissions, infections due to an indwelling urinary catheterisation, resulting in septic shock or severe sepsis, in patients with comorbidities and presenting MDR were related to a higher cost.

11.
Nat Rev Immunol ; 18(7): 423-437, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29662121

RESUMO

Circadian rhythms are a ubiquitous feature of virtually all living organisms, regulating a wide diversity of physiological systems. It has long been established that the circadian clockwork plays a key role in innate immune responses, and recent studies reveal that several aspects of adaptive immunity are also under circadian control. We discuss the latest insights into the genetic and biochemical mechanisms linking immunity to the core circadian clock of the cell and hypothesize as to why the immune system is so tightly controlled by circadian oscillations. Finally, we consider implications for human health, including vaccination strategies and the emerging field of chrono-immunotherapy.

12.
J Clin Invest ; 128(6): 2281-2296, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29533925

RESUMO

Recent studies reveal that airway epithelial cells are critical pulmonary circadian pacemaker cells, mediating rhythmic inflammatory responses. Using mouse models, we now identify the rhythmic circadian repressor REV-ERBα as essential to the mechanism coupling the pulmonary clock to innate immunity, involving both myeloid and bronchial epithelial cells in temporal gating and determining amplitude of response to inhaled endotoxin. Dual mutation of REV-ERBα and its paralog REV-ERBß in bronchial epithelia further augmented inflammatory responses and chemokine activation, but also initiated a basal inflammatory state, revealing a critical homeostatic role for REV-ERB proteins in the suppression of the endogenous proinflammatory mechanism in unchallenged cells. However, REV-ERBα plays the dominant role, as deletion of REV-ERBß alone had no impact on inflammatory responses. In turn, inflammatory challenges cause striking changes in stability and degradation of REV-ERBα protein, driven by SUMOylation and ubiquitination. We developed a novel selective oxazole-based inverse agonist of REV-ERB, which protects REV-ERBα protein from degradation, and used this to reveal how proinflammatory cytokines trigger rapid degradation of REV-ERBα in the elaboration of an inflammatory response. Thus, dynamic changes in stability of REV-ERBα protein couple the core clock to innate immunity.

13.
Sci Rep ; 8(1): 3782, 2018 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-29491349

RESUMO

Resistance to the intestinal parasitic helminth Trichuris muris requires T-helper 2 (TH2) cellular and associated IgG1 responses, with expulsion typically taking up to 4 weeks in mice. Here, we show that the time-of-day of the initial infection affects efficiency of worm expulsion, with strong TH2 bias and early expulsion in morning-infected mice. Conversely, mice infected at the start of the night show delayed resistance to infection, and this is associated with feeding-driven metabolic cues, such that feeding restriction to the day-time in normally nocturnal-feeding mice disrupts parasitic expulsion kinetics. We deleted the circadian regulator BMAL1 in antigen-presenting dendritic cells (DCs) in vivo and found a loss of time-of-day dependency of helminth expulsion. RNAseq analyses revealed that IL-12 responses to worm antigen by circadian-synchronised DCs were dependent on BMAL1. Therefore, we find that circadian machinery in DCs contributes to the TH1/TH2 balance, and that environmental, or genetic perturbation of the DC clock results in altered parasite expulsion kinetics.

14.
Clin Case Rep ; 5(9): 1482-1485, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28878909

RESUMO

Extramedullary plasmacytomas, Epstein-Bar virus (EBV) associated, are rarely encountered and usually have a fairly good clinical outcome. EBV+ plasmacytoma may cause a diagnostic dilemma as it phenotypically resembles an aggressive plasmablastic lymphoma (PBL). Herein, we report a unique case with maxillary EBV+ plasmacytoma from a 76-year-old immunocompetent individual.

15.
Cancer Control ; 24(1): 83-88, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28178719

RESUMO

Endometriosis is a common gynecological disorder most often involving the pelvic region. Although it is rare, endometriosis occurring outside of the peritoneal cavity most commonly occurs within scars of the abdominal wall, but it has been reported in the lungs, pleura, kidneys, brain, and the extremities. Herein, we present 2 cases of endometriosis, including 1 case of endometriosis of the wrist that clinically mimicked a soft-tissue neoplasm and 1 case of right-groin endometriosis mimicking synovial sarcoma during the initial pathological interpretation of findings on fine needle aspiration. We also report on a third patient with synovial sarcoma to demonstrate a diagnostic pitfall. To our knowledge, endometriosis within the skeletal muscle of the wrist has not been previously reported in the literature. A literature review was performed, and we discuss how this diagnostic pitfall may be avoided. We review the techniques for diagnosing synovial sarcoma and the importance of a high index of suspicion for endometriosis when investigating any soft-tissue mass in a female patient of reproductive age. Adequate pathological evaluation in conjunction with the correlating clinical and radiological information should help facilitate an accurate diagnosis.


Assuntos
Endometriose/diagnóstico , Sarcoma Sinovial/diagnóstico , Neoplasias de Tecidos Moles/diagnóstico , Adulto , Diagnóstico Diferencial , Endometriose/cirurgia , Feminino , Humanos , Prognóstico , Sarcoma Sinovial/cirurgia , Neoplasias de Tecidos Moles/cirurgia , Adulto Jovem
16.
FASEB J ; 30(11): 3759-3770, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27488122

RESUMO

There is strong diurnal variation in the symptoms and severity of chronic inflammatory diseases, such as rheumatoid arthritis. In addition, disruption of the circadian clock is an aggravating factor associated with a range of human inflammatory diseases. To investigate mechanistic links between the biological clock and pathways underlying inflammatory arthritis, mice were administered collagen (or saline as a control) to induce arthritis. The treatment provoked an inflammatory response within the limbs, which showed robust daily variation in paw swelling and inflammatory cytokine expression. Inflammatory markers were significantly repressed during the dark phase. Further work demonstrated an active molecular clock within the inflamed limbs and highlighted the resident inflammatory cells, fibroblast-like synoviocytes (FLSs), as a potential source of the rhythmic inflammatory signal. Exposure of mice to constant light disrupted the clock in peripheral tissues, causing loss of the nighttime repression of local inflammation. Finally, the results show that the core clock proteins cryptochrome (CRY) 1 and 2 repressed inflammation within the FLSs, and provide novel evidence that a CRY activator has anti-inflammatory properties in human cells. We conclude that under chronic inflammatory conditions, the clock actively represses inflammatory pathways during the dark phase. This interaction has exciting potential as a therapeutic avenue for treatment of inflammatory disease.-Hand, L. E., Hopwood, T. W., Dickson, S. H., Walker, A. L., Loudon, A. S. I., Ray, D. W., Bechtold, D. A., Gibbs, J. E. The circadian clock regulates inflammatory arthritis.


Assuntos
Artrite Reumatoide/metabolismo , Proteínas CLOCK/metabolismo , Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Animais , Artrite Reumatoide/terapia , Proteínas CLOCK/genética , Modelos Animais de Doenças , Humanos , Inflamação/genética , Inflamação/metabolismo , Inflamação/terapia , Masculino , Camundongos
17.
Surg Clin North Am ; 96(5): 915-62, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27542635

RESUMO

Soft tissue and bone tumors are a heterogeneous group of tumors most often classified according to the type of tissue they most closely histologically resemble. Although sarcomas are rare, greater than 100 histologic subtypes of benign and malignant soft tissue and bone tumors are currently recognized. In this article, the authors review the current pathologic definitions, the classification and grading systems, supportive ancillary techniques, and the prognostic implications for some of the more common soft tissue and bone tumors.


Assuntos
Neoplasias Ósseas/patologia , Estadiamento de Neoplasias , Neoplasias de Tecidos Moles/patologia , Humanos , Prognóstico
18.
Arch Pathol Lab Med ; 140(7): 694-7, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27116087

RESUMO

CONTEXT: -Despite great interest in using whole slide imaging (WSI) in pathology practice and education, few pathology journals have published WSI pertinent to articles within their pages or as supplemental materials. OBJECTIVE: -To evaluate whether there is measurable added educational value of including WSI in publications. DESIGN: -Thirty-seven participants, 16 (43.3%), 15 (40.5%), and 6 (16.2%) junior pathology residents (postgraduate year 1-2), senior pathology residents (postgraduate year 3-4), and board-certified pathologists, respectively, read a sequence of 10 journal articles on a wide range of pathology topics. A randomized subgroup also reviewed the WSI published with the articles. Both groups completed a survey tool assessing recall of text-based content and of image-based material pertinent to the diseases but not present in the fixed published images. RESULTS: -The group examining WSI had higher performance scores in 72% of image-based questions (36 of 50 questions) as compared with the non-WSI group. As an internal study control, the WSI group had higher performance scores in only 40% of text-based questions (6 of 15 questions). The WSI group had significantly better performance than the non-WSI group for image-based questions compared with text-based questions (P < .05, Fisher exact test). CONCLUSION: -Our study provides supporting evidence that WSI offers enhanced value to the learner beyond the text and fixed images selected by the author. We strongly encourage more journals to incorporate WSI into their publications.


Assuntos
Patologia/educação , Publicações Periódicas como Assunto , Telepatologia , Humanos , Internato e Residência , Manejo de Espécimes , Fluxo de Trabalho
19.
J Leukoc Biol ; 99(4): 549-60, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26856993

RESUMO

Circadian rhythms regulate changes in physiology, allowing organisms to respond to predictable environmental demands varying over a 24 h period. A growing body of evidence supports a key role for the circadian clock in the regulation of immune functions and inflammatory responses, which influence the understanding of infections and inflammatory diseases and their treatment. A variety of experimental methods have been used to assess the complex bidirectional crosstalk between the circadian clock and inflammation. In this review, we summarize the organization of the molecular clock, experimental methods used to study circadian rhythms, and both the inflammatory and immune consequences of circadian disturbance.


Assuntos
Relógios Circadianos/imunologia , Modelos Animais de Doenças , Animais , Humanos , Inflamação/imunologia , Inflamação/patologia
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