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The American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) staging for all cancer sites has been periodically updated as a published manual for many years. The last update, the eighth edition AJCC Cancer Staging Manual went into use on January 1, 2018. The AJCC has since restructured and updated its processes, and all AJCC staging-related data are now housed on its new application programming interface. Consequently, the next AJCC TNM staging update, AJCC version 9 TNM staging, will be published electronically and will be released chapter by chapter. The first chapter of version 9 AJCC TNM staging is the updated cervical cancer staging, which is now published. This article highlights the changes to the AJCC TNM cervical cancer staging; these changes align with the International Federation of Gynecology and Obstetrics staging. The most important of the changes are: 1) the incorporation of imaging and surgical findings, 2) the elimination of lateral spread from T1a, 3) the addition of a subcategory to T1b (T1b3), and 4) histopathology is updated to reflect human papillomavirus-associated and human papillomavirus-independent carcinomas.
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Estadificación de Neoplasias/normas , Neoplasias del Cuello Uterino/patología , Comités Consultivos , Femenino , Humanos , Ganglios Linfáticos/patología , Metástasis Linfática/patología , Guías de Práctica Clínica como Asunto , Pronóstico , Estados UnidosRESUMEN
Until recently, cancer registries have only collected cancer clinical stage at diagnosis, before any therapy, and pathological stage after surgical resection, provided no treatment has been given before the surgery, but they have not collected stage data after neoadjuvant therapy (NAT). Because NAT is increasingly being used to treat a variety of tumors, it has become important to make the distinction between both the clinical and the pathological assessment without NAT and the assessment after NAT to avoid any misunderstanding of the significance of the clinical and pathological findings. It also is important that cancer registries collect data after NAT to assess response and effectiveness of this treatment approach on a population basis. The prefix y is used to denote stage after NAT. Currently, cancer registries of the American College of Surgeons' Commission on Cancer only partially collect y stage data, and data on the clinical response to NAT (yc or posttherapy clinical information) are not collected or recorded in a standardized fashion. In addition to NAT, nonoperative management after radiation and chemotherapy is being used with increasing frequency in rectal cancer and may be expanded to other treatment sites. Using examples from breast, rectal, and esophageal cancers, the pathological and imaging changes seen after NAT are reviewed to demonstrate appropriate staging.
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Neoplasias de la Mama/diagnóstico , Neoplasias Esofágicas/diagnóstico , Terapia Neoadyuvante , Estadificación de Neoplasias/métodos , Neoplasias del Recto/diagnóstico , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/terapia , Femenino , Humanos , Masculino , Estadificación de Neoplasias/estadística & datos numéricos , Neoplasias del Recto/patología , Neoplasias del Recto/terapia , Sistema de Registros/estadística & datos numéricos , Resultado del Tratamiento , Estados UnidosRESUMEN
Microphysiological systems (MPS) are comprised of one or multiple cell types of human or animal origins that mimic the biochemical/electrical/mechanical responses and blood-tissue barrier properties of the cells observed within a complex organ. The goal of incorporating these in vitro systems is to expedite and advance the drug discovery and development paradigm with improved predictive and translational capabilities. Considering the industry need for improved efficiency and the broad challenges of model qualification and acceptance, the International Consortium for Innovation and Quality (IQ) founded an IQ MPS working group in 2014 and Affiliate in 2018. This group connects thought leaders and end users, provides a forum for crosspharma collaboration, and engages with regulators to qualify translationally relevant MPS models. To understand how pharmaceutical companies are using MPS, the IQ MPS Affiliate conducted two surveys in 2019, survey 1, and 2021, survey 2, which differed slightly in the scope of definition of the complex in vitro models under question. The surveys captured demographics, resourcing, rank order for organs of interest, compound modalities tested, and MPS organ-specific questions, including nonclinical species needs and cell types. The major focus of this manuscript is on results from survey 2, where we specifically highlight the context of use for MPS within safety, pharmacology, or absorption, disposition, metabolism, and excretion and discuss considerations for including MPS data in regulatory submissions. In summary, these data provide valuable insights for developers, regulators, and pharma, offering a view into current industry practices and future considerations while highlighting key challenges impacting MPS adoption. SIGNIFICANCE STATEMENT: The application of microphysiological systems (MPS) represents a growing area of interest in the drug discovery and development framework. This study surveyed 20+ pharma companies to understand resourcing, current areas of application, and the key challenges and barriers to internal MPS adoption. These results will provide regulators, tech providers, and pharma industry leaders a starting point to assess the current state of MPS applications along with key learnings to effectively realize the potential of MPS as an emerging technology.
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Industria Farmacéutica , Sistemas Microfisiológicos , Animales , Humanos , Descubrimiento de DrogasRESUMEN
Recent studies have focused on the contribution of capillary endothelial TRPV4 channels to pulmonary pathologies, including lung edema and lung injury. However, in pulmonary hypertension (PH), small pulmonary arteries are the focus of the pathology, and endothelial TRPV4 channels in this crucial anatomy remain unexplored in PH. Here, we provide evidence that TRPV4 channels in endothelial cell caveolae maintain a low pulmonary arterial pressure under normal conditions. Moreover, the activity of caveolar TRPV4 channels is impaired in pulmonary arteries from mouse models of PH and PH patients. In PH, up-regulation of iNOS and NOX1 enzymes at endothelial cell caveolae results in the formation of the oxidant molecule peroxynitrite. Peroxynitrite, in turn, targets the structural protein caveolin-1 to reduce the activity of TRPV4 channels. These results suggest that endothelial caveolin-1-TRPV4 channel signaling lowers pulmonary arterial pressure, and impairment of endothelial caveolin-1-TRPV4 channel signaling contributes to elevated pulmonary arterial pressure in PH. Thus, inhibiting NOX1 or iNOS activity, or lowering endothelial peroxynitrite levels, may represent strategies for restoring vasodilation and pulmonary arterial pressure in PH.
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Caveolas/metabolismo , Endotelio Vascular/metabolismo , Ácido Peroxinitroso/metabolismo , Hipertensión Arterial Pulmonar/etiología , Canales Catiónicos TRPV/metabolismo , Animales , Presión Arterial , Humanos , Ratones Noqueados , NADPH Oxidasa 1/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Proteína Quinasa C/metabolismo , Hipertensión Arterial Pulmonar/metabolismo , Canales Catiónicos TRPV/genéticaRESUMEN
PURPOSE: Emerging evidence indicates that incarcerated populations' perceptions of dehumanization by officers are prevalent, yet measures of it are few, and to our knowledge, no self-report measure of dehumanization from officers exists. To fill this gap, we have developed the Perceived Dehumanization from Officers Scale (PDOS), which is designed as a brief measure to assess perception of officer treatment as dehumanizing. METHODS: In this article, we provide preliminary evidence from two studies examining the reliability and validity of the PDOS. In study 1, a jail sample (n = 411), we analyzed the exploratory factor structure, internal consistency, and discriminant validity (in relation to procedural justice [PJ]) of the PDOS. Additionally, using a cross-sectional ordinary least squares (OLS) regression analysis, we related independent variables with the PDOS, the dependent variable. In Study 2, a prison sample (n = 2993), we confirmed the findings from study 1. RESULTS: The PDOS appears to be a psychometrically sound measure of perceived dehumanization from officers with strong association between perceptions of PJ and perceived dehumanization from officers. CONCLUSIONS: The PDOS provides opportunity for future research, intervention through rehumanization efforts, and signals the important officer treatment. Importantly We close by discussing implications of these studies, limitations, and future research directions to further develop and test the PDOS.
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Deshumanización , Prisiones , Humanos , Autoinforme , Reproducibilidad de los Resultados , Estudios TransversalesRESUMEN
BACKGROUND: Ca2+ signals in smooth muscle cells (SMCs) contribute to vascular resistance and control blood pressure. Increased vascular resistance in hypertension has been attributed to impaired SMC Ca2+ signaling mechanisms. In this regard, transient receptor potential vanilloid 4 (TRPV4SMC) ion channels are a crucial Ca2+ entry pathway in SMCs. However, their role in blood pressure regulation has not been identified. METHODS: We used SMC-specific TRPV4-/- (TRPV4SMC-/-) mice to assess the role of TRPV4SMC channels in blood pressure regulation. We determined the contribution of TRPV4SMC channels to the constrictor effect of α1 adrenergic receptor (α1AR) stimulation and elevated intraluminal pressure: 2 main physiologic stimuli that constrict resistance-sized arteries. The contribution of spatially separated TRPV4SMC channel subpopulations to elevated blood pressure in hypertension was evaluated in angiotensin II-infused mice and patients with hypertension. RESULTS: We provide first evidence that TRPV4SMC channel activity elevates resting blood pressure in normal mice. α1AR stimulation activated TRPV4SMC channels through PKCα (protein kinase Cα) signaling, which contributed significantly to vasoconstriction and blood pressure elevation. Intraluminal pressure-induced TRPV4SMC channel activity opposed vasoconstriction through activation of Ca2+-sensitive K+ (BK) channels, indicating functionally opposite pools of TRPV4SMC channels. Superresolution imaging of SMCs revealed spatially separated α1AR:TRPV4 and TRPV4:BK nanodomains in SMCs. These data suggest that spatially separated α1AR-TRPV4SMC and intraluminal pressure-TRPV4SMC-BK channel signaling have opposite effects on blood pressure, with α1AR-TRPV4SMC signaling dominating under resting conditions. Furthermore, in patients with hypertension and a mouse model of hypertension, constrictor α1AR-PKCα-TRPV4 signaling was upregulated, whereas dilator pressure-TRPV4-BK channel signaling was disrupted, thereby increasing vasoconstriction and elevating blood pressure. CONCLUSIONS: Our data identify novel smooth muscle Ca2+-signaling nanodomains that regulate blood pressure and demonstrate their impairment in hypertension.
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Hipertensión , Canales Catiónicos TRPV , Animales , Presión Sanguínea/fisiología , Señalización del Calcio , Canales de Potasio de Gran Conductancia Activados por el Calcio/metabolismo , Ratones , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Proteína Quinasa C-alfa/genética , Proteína Quinasa C-alfa/metabolismo , Proteína Quinasa C-alfa/farmacología , Canales Catiónicos TRPV/genética , Canales Catiónicos TRPV/metabolismoRESUMEN
BACKGROUND: Post-procedural coronary aneurysms can have high morbidity and mortality. Although found more commonly on ultrasound or computed tomography imaging, if large enough, they may appear on chest x-ray studies. CASE REPORTS: We present two cases of coronary artery aneurysm visible on chest x-ray study-one originating from a saphenous vein graft and the other a left anterior descending artery pseudoaneurysm 1 week post heart catheterization. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: It is important for emergency physicians to recognize abnormal chest x-ray studies and to look for post-procedural complications, such as coronary artery aneurysm. Coronary artery aneurysm can be a potentially life-threatening condition requiring prompt recognition and surgical consultation.
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Aneurisma Falso , Aneurisma Coronario , Humanos , Vasos Coronarios , Puente de Arteria Coronaria/efectos adversos , Rayos X , Aneurisma Coronario/complicaciones , Aneurisma Falso/etiología , Vena Safena/trasplanteRESUMEN
INTRODUCTION: Studies in Cx40-GCaMP2 mice, which express calcium biosensor GCaMP2 in the endothelium under connexin 40 promoter, have identified the unique properties of endothelial calcium signals. However, Cx40-GCaMP2 mouse is associated with a narrow dynamic range and lack of signal in the venous endothelium. Recent studies have proposed many GCaMPs (GCaMP5/6/7/8) with improved properties although their performance in endothelium-specific calcium studies is not known. METHODS: We characterized a newly developed mouse line that constitutively expresses GCaMP8 in the endothelium under the VE-cadherin (Cdh5-GCaMP8) promoter. Calcium signals through endothelial IP3 receptors and TRP vanilloid 4 (TRPV4) ion channels were recorded in mesenteric arteries (MAs) and veins from Cdh5-GCaMP8 and Cx40-GCaMP2 mice. RESULTS: Cdh5-GCaMP8 mice showed lower baseline fluorescence intensity, higher dynamic range, and higher amplitudes of individual calcium signals than Cx40-GCaMP2 mice. Importantly, Cdh5-GCaMP8 mice enabled the first recordings of discrete calcium signals in the intact venous endothelium and revealed striking differences in IP3 receptor and TRPV4 channel calcium signals between MAs and mesenteric veins. CONCLUSION: Our findings suggest that Cdh5-GCaMP8 mice represent significant improvements in dynamic range, sensitivity for low-intensity signals, and the ability to record calcium signals in venous endothelium.
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Antígenos CD/metabolismo , Cadherinas/metabolismo , Señalización del Calcio , Proteínas de Unión al Calcio/metabolismo , Calcio/metabolismo , Conexinas/metabolismo , Células Endoteliales/metabolismo , Proteínas Fluorescentes Verdes/metabolismo , Animales , Antígenos CD/genética , Técnicas Biosensibles , Cadherinas/genética , Proteínas de Unión al Calcio/genética , Conexinas/genética , Proteínas Fluorescentes Verdes/genética , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Arterias Mesentéricas/citología , Arterias Mesentéricas/metabolismo , Venas Mesentéricas/citología , Venas Mesentéricas/metabolismo , Ratones Endogámicos C57BL , Ratones Transgénicos , Microscopía Fluorescente , Regiones Promotoras Genéticas , Canales Catiónicos TRPV/metabolismo , Proteína alfa-5 de Unión ComunicanteRESUMEN
Recent experimental data on Bose-Einstein condensation of magnons in the spin-gap compound Yb_{2}Si_{2}O_{7} revealed an asymmetric Bose-Einstein condensation dome [G. Hester et al., Phys. Rev. Lett. 123, 027201 (2019)PRLTAO0031-900710.1103/PhysRevLett.123.027201]. We examine modifications to the Heisenberg model on a breathing honeycomb lattice, showing that this physics can be explained by competing anisotropic perturbations. We employ a gamut of analytical and numerical techniques to show that the anisotropy yields a field driven phase transition from a state with broken Ising symmetry to a phase that breaks no symmetries and crosses over to the polarized limit.
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The current project is to explore feasibility of direct intra-renal injection of human bone marrow derived mesenchymal stem cells (hMSC) for treatment of lupus nephritis in mice. The treatment protocol involved aged male BXSB (20 weeks) injected with 1 × 106 hMSC unilaterally under the renal capsule. Mice were harvested after 10 weeks follow-up for postmortem exam. Controls included untreated age matched male BXSB and healthy C57Bl/6. At the end of follow-up period, the survival of treated BXSB was 10 folds higher at 62.5% compared to survival of untreated control at 6.3%. The survival of C57Bl/6 remained at 100% with or without similar treatment. The renal pathology review was most significant for decreased tissue inflammation in treated BXSB compared to untreated controls. Renal tissue expression of IL-1b, IL17 were decreased and CTLA-4 was increased by RT PCR among treated compared to untreated BXSB. Thus, direct delivery of hMSC by intrarenal injection is a promising route for treatment of lupus nephritis as shown in this xenogeneic model. Further studies -using expanded numbers of mice to include other lupus strains- are warranted to investigate the mechanisms involved and to optimize treatment protocol for safety and efficacy.
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Riñón/patología , Nefritis Lúpica/terapia , Trasplante de Células Madre Mesenquimatosas/métodos , Animales , Creatinina/orina , Citocinas/sangre , Modelos Animales de Enfermedad , Humanos , Inyecciones , Nefritis Lúpica/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Proyectos Piloto , Albúmina Sérica/análisisRESUMEN
Treprostinil palmitil (TP) is a prodrug of treprostinil (TRE), a pulmonary vasodilator that has been previously formulated for inhaled administration via a nebulizer. TP demonstrates a sustained presence in the lungs with reduced systemic exposure and prolonged inhibition of hypoxia-induced pulmonary vasoconstriction in vivo. Here, we report on re-formulation efforts to develop a more convenient solution-based metered-dose inhaler (MDI) formulation of TP, a treprostinil palmitil inhalation aerosol (TPIA) that matches the pharmacokinetic (PK) and efficacy profile of a nebulized TP formulation, treprostinil palmitil inhalation suspension (TPIS). MDI canisters were manufactured using a two-stage filling method. Aerosol performance, formulation solubility, and chemical stability assays were utilized for in vitro evaluation. For in vivo studies, TPIA formulations were delivered to rodents using an inhalation tower modified for MDI delivery. Using an iterative process involving evaluation of formulation performance in vitro (TP and excipient solubility, chemical stability, physical stability, and aerosol properties) and confirmatory testing in vivo (rat PK and efficacy, guinea pig cough), a promising formulation was identified. The optimized formulation, TPIA-W, demonstrates uniform in vitro drug delivery, a PK profile suitable for a once-daily administration, efficacy lasting at least 12 h in a hypoxic challenge model, and a significantly higher cough threshold than the parent drug treprostinil.
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Aerosoles/farmacología , Epoprostenol/análogos & derivados , Profármacos/farmacología , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Administración por Inhalación , Animales , Modelos Animales de Enfermedad , Composición de Medicamentos , Epoprostenol/química , Epoprostenol/farmacología , Cobayas , Humanos , Nanopartículas/química , Profármacos/química , Hipertensión Arterial Pulmonar/patología , Ratas , Vasoconstricción/efectos de los fármacos , Vasodilatadores/química , Vasodilatadores/farmacologíaRESUMEN
Using a sample of 3,041 incarcerated men and women, this study examines the impact of being incarcerated for a sex offense and individuals' in-prison experiences on their concerns about reentry into society. Bivariate analyses suggest that being incarcerated for a sex offense is related to greater concerns about housing and fewer concerns about recidivism compared with individuals incarcerated for nonsex offenses. A sex offense conviction is also associated with weaker social bonds, greater relational difficulties, and greater fear of victimization while incarcerated. Multiple regression models indicate that, after controlling for in-prison experiences, being incarcerated for a sex offense increases reentry concerns related to employment and housing, though may reduce them for recidivism. In-prison experiences mediate the relationship between being incarcerated for a sex offense and reentry concerns. Policy implications of these findings are discussed.
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Prisioneros/psicología , Prisiones , Delitos Sexuales , Interacción Social , Adulto , Empleo , Femenino , Vivienda , Humanos , Masculino , Análisis de Mediación , Persona de Mediana Edad , ReincidenciaRESUMEN
Two odorant receptors (ORs), OnubOR3 and OnubOR6, in the sex pheromone communication systems of E- and Z-strain European corn borers, Ostrinia nubilalis, were broadly receptive to analogs of their pheromone components. In addition to responding to their natural 14-carbon pheromone components, (Z)-11- and (E)-11-tetradecenyl acetates (Z11- and E11-14:OAc), these pheromone ORs responded to the longer-chain compounds, (Z)-11- and (E)-11-hexadecenyl acetate (Z11- and E11-16:OAc). Z11-16:OAc is a pheromone gland constituent of E-strain O. nubilalis females in Europe but has not previously been shown to have behavioral activity to males. Here, we demonstrate that Z11-16:OAc evokes high levels of upwind flight and source location in E-strain males when substituted for Z11-14:OAc (minor component) in the E-strain blend. Since Z11-16:OAc is found in the gland and has behavioral activity when Z11-14:OAc is missing, then it should be classified as a cryptic, redundant minor pheromone component in E-strain O. nubilalis. The opposite geometric isomer, E11-16:OAc, also functions in Z-strain O. nubilalis, substituting behaviorally for the E11-14:OAc minor component, but has not been found in Z-strain female glands. Single-sensillum recordings showed that sensory neurons of E- and Z-strain male antennae expressing OnubOR3 and OnubOR6 produced responses to these hexadecenyl acetates similar to those evoked by the natural (tetradecenyl acetate) pheromone components. We postulate that the wide responsiveness of these two ORs to the 16-carbon acetates could be a preadaptation for O. nubilalis to use these compounds as minor components in lieu of the respective 14-carbon acetates. Alternatively, the responsiveness of OnubOR3 to E11-16:OAc and OnubOR6 to Z11-16:OAc could represent a vestigial state of these receptors, with the 16-carbon acetates having previously acted as functional minor components in an ancestral blend.
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Quimiotaxis , Mariposas Nocturnas/fisiología , Receptores Odorantes/fisiología , Atractivos Sexuales/fisiología , Acetatos/metabolismo , Animales , Ácidos Grasos Monoinsaturados/metabolismo , Masculino , Especificidad de la EspecieRESUMEN
Sulfur is an underused by-product of the petrochemicals industry. Recent research into inverse vulcanization has shown how this excess sulfur can be transformed into functional polymers, by stabilization with organic crosslinkers. For these interesting new materials to realize their potential for applications, more understanding and control of their physical properties is needed. Here we report four new terpolymers prepared from sulfur and two distinct alkene monomers that can be predictively tuned in glass transition, molecular weight, solubility, mechanical properties, and color.
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The study of false memory has had a profound impact on our understanding of how and what we remember, as shown by the misinformation paradigm [Loftus, E. F. (2005). Planting misinformation in the human mind: A 30-year investigation of the malleability of memory. Learning & Memory, 12(4), 361-366. doi: 10.1101/lm.94705 ]. Though misinformation effects have been demonstrated extensively within visual tasks, they have not yet been explored in the realm of non-visual auditory stimuli. Thus, the present study aimed to investigate whether post-event information can create false memories of music listening episodes. In addition, we explored individual difference factors potentially associated with false memory susceptibility in music, including age, suggestibility, personality, and musical training. In two music recognition tasks, participants (N = 151) listened to an initial music track, which unbeknownst to them was missing an instrument. They were then presented with post-event information which either suggested the presence of the missing instrument or did not. The presence of misinformation resulted in significantly poorer performance on the music recognition tasks (d = .43), suggesting the existence of false musical memories. A random forest analysis indicated that none of the individual difference factors assessed were significantly associated with misinformation susceptibility. These findings support previous research on the fallibility of human memory and demonstrate, to some extent, the generality of the misinformation effect to a non-visual auditory domain.
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Comunicación , Individualidad , Memoria , Música , Represión Psicológica , Estimulación Acústica , Adolescente , Adulto , Factores de Edad , Percepción Auditiva , Femenino , Humanos , Masculino , Persona de Mediana Edad , Personalidad , Reconocimiento en Psicología , Sugestión , Adulto JovenRESUMEN
BACKGROUND: Goodpasture syndrome (GP) is a pulmonary-renal syndrome characterized by autoantibodies directed against the NC1 domains of collagen IV in the glomerular and alveolar basement membranes. Exposure of the cryptic epitope is thought to occur via disruption of sulfilimine crosslinks in the NC1 domain that are formed by peroxidasin-dependent production of hypobromous acid. Peroxidasin, a heme peroxidase, has significant structural overlap with myeloperoxidase (MPO), and MPO-ANCA is present both before and at GP diagnosis in some patients. We determined whether autoantibodies directed against peroxidasin are also detected in GP. METHODS: We used ELISA and competitive binding assays to assess the presence and specificity of autoantibodies in serum from patients with GP and healthy controls. Peroxidasin activity was fluorometrically measured in the presence of partially purified IgG from patients or controls. Clinical disease severity was gauged by Birmingham Vasculitis Activity Score. RESULTS: We detected anti-peroxidasin autoantibodies in the serum of patients with GP before and at clinical presentation. Enriched anti-peroxidasin antibodies inhibited peroxidasin-mediated hypobromous acid production in vitro. The anti-peroxidasin antibodies recognized peroxidasin but not soluble MPO. However, these antibodies did crossreact with MPO coated on the polystyrene plates used for ELISAs. Finally, peroxidasin-specific antibodies were also found in serum from patients with anti-MPO vasculitis and were associated with significantly more active clinical disease. CONCLUSIONS: Anti-peroxidasin antibodies, which would previously have been mischaracterized, are associated with pulmonary-renal syndromes, both before and during active disease, and may be involved in disease activity and pathogenesis in some patients.
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Enfermedad por Anticuerpos Antimembrana Basal Glomerular/inmunología , Autoanticuerpos/sangre , Proteínas de la Matriz Extracelular/inmunología , Glomerulonefritis/inmunología , Hemorragia/inmunología , Enfermedades Pulmonares/inmunología , Peroxidasa/inmunología , Peroxidasas/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad por Anticuerpos Antimembrana Basal Glomerular/etiología , Anticuerpos Anticitoplasma de Neutrófilos/sangre , Especificidad de Anticuerpos , Autoantígenos/inmunología , Niño , Estudios de Cohortes , Colágeno Tipo IV/inmunología , Proteínas de la Matriz Extracelular/antagonistas & inhibidores , Femenino , Glomerulonefritis/etiología , Hemorragia/etiología , Humanos , Enfermedades Pulmonares/etiología , Masculino , Persona de Mediana Edad , Modelos Inmunológicos , Peroxidasa/antagonistas & inhibidores , Peroxidasas/antagonistas & inhibidores , Adulto Joven , PeroxidasinaRESUMEN
Background: Bacteremia caused by extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae (ESBL-E) is associated with inadequate empirical therapy and substantial mortality in neutropenic patients. Strategies are needed to identify neutropenic patients at high risk of these infections. Methods: From April 2014 to September 2016, we collected perianal swabs, both at admission and weekly thereafter, from patients undergoing hematopoietic stem cell transplantation (HSCT). Patients received prophylactic levofloxacin while neutropenic. Swabs were plated onto selective agar, colonies were identified and underwent antimicrobial susceptibility testing, and phenotypic ESBL testing and polymerase chain reaction for ß-lactamase genes were performed on ceftriaxone-resistant Enterobacteriaceae. We then determined the prevalence of pre-transplant ESBL-E colonization and risk of ESBL-E bacteremia. Colonizing and bloodstream isolates from patients with ESBL-E bacteremia underwent multilocus sequence typing and pulsed-field gel electrophoresis. Results: We analyzed 312 patients, including 212 allogeneic and 100 autologous HSCT recipients. Ten percent (31/312) of patients had pre-transplant ESBL-E colonization. Susceptibility rates of colonizing ESBL-E were: levofloxacin, 25%; cefepime, 9%; piperacillin-tazobactam, 84%; and meropenem, 97%. Of 31 patients colonized with ESBL-E pre-transplant, 10 (32%) developed ESBL-E bacteremia during their transplant admission, compared to 1 (0.4%) of 281 patients not colonized with ESBL-E (P < .001). All bloodstream ESBL-E were levofloxacin-resistant and colonizing and bloodstream isolates from individual patients had identical genotypic profiles. Conclusions: HSCT recipients who are colonized with levofloxacin-resistant ESBL-E pre-transplant and receive levofloxacin prophylaxis have high rates of bacteremia from their colonizing strain during neutropenia. Assessing for ESBL-E colonization in neutropenic patients could lead to optimization of empirical antibacterial therapy.
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Antibacterianos/uso terapéutico , Infecciones por Enterobacteriaceae/complicaciones , Enterobacteriaceae/aislamiento & purificación , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Levofloxacino/uso terapéutico , Neutropenia/complicaciones , Adulto , Anciano , Bacteriemia/complicaciones , Bacteriemia/prevención & control , Técnicas de Tipificación Bacteriana , Farmacorresistencia Bacteriana , Electroforesis en Gel de Campo Pulsado , Enterobacteriaceae/enzimología , Infecciones por Enterobacteriaceae/prevención & control , Femenino , Tracto Gastrointestinal/microbiología , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Tipificación de Secuencias Multilocus , Neutropenia/microbiología , Estudios Prospectivos , Factores de Riesgo , beta-LactamasasRESUMEN
Gas-chromatography-electroantennographic detection (GC-EAD) is a technique used in the identification of volatile organic compounds (VOCs), such as pheromones and plant host odors, which are physiologically relevant to insects. Although pheromones often elicit large EAD responses, other behaviorally relevant odors may elicit responses that are difficult to discern from noise. Lock-in amplification has long been used to reduce noise in a wide range of applications. Its utility when incorporated with GC-EAD was demonstrated previosuly by chopping (or pulsing) effluent-laden air that flowed over an insect antenna. This method had the disadvantage that it stimulated noise-inducing mechanoreceptors and, in some cases, disturbed the electrochemical interfaces in a preparation, limiting its performance. Here, the chopping function necessary for lock-in amplification was implemented directly on the GC effluent using a simple Deans switch. The technique was applied to excised antennae from female Heliothis virescens responding to phenethyl alcohol, a common VOC emitted by plants. Phenethyl alcohol was always visible and quantifiable on the flame ionization detector (FID) chromatogram, allowing the timing and amount of stimulus delivered to the antennal preparation to be measured. In our new chopper EAG configuration, the antennal preparation was shielded from air currents in the room, further reducing noise. A dose-response model in combination with a Markov-chain monte-carlo (MCMC) method for Bayesian inference was used to estimate and compare performance in terms of error rates involved in the detection of insect responses to GC peaks visible on an FID detector. Our experiments showed that the predicted single-trial phenethyl alcohol detection limit on female H. virescens antennae (at a 5.0% expected error rate) was 140,330 pg using traditional EAG recording methods, compared to 2.6-6.3 pg (5th to the 95th percentile) using Deans switch-enabled lock-in amplification, corresponding to a 10.4-12.7 dB increase in signal-to-noise ratio.
Asunto(s)
Antenas de Artrópodos/fisiología , Cromatografía de Gases/instrumentación , Mariposas Nocturnas/fisiología , Alcohol Feniletílico/metabolismo , Compuestos Orgánicos Volátiles/metabolismo , Animales , Teorema de Bayes , Cromatografía de Gases/métodos , Electrofisiología/instrumentación , Electrofisiología/métodos , Diseño de Equipo , Femenino , Ionización de Llama/instrumentación , Ionización de Llama/métodos , Método de Montecarlo , Alcohol Feniletílico/análisis , Relación Señal-Ruido , Compuestos Orgánicos Volátiles/análisisRESUMEN
We performed single-sensillum recordings from male and female antennae of the Asian longhorned beetle, Anoplophora glabripennis, that included as stimuli the two components of this species' aggregation-sex pheromone in addition to various general odorants. We compared the aggregation-sex-pheromone-component responses of olfactory sensory neurons (OSNs) to those of OSNs that responded to a variety of plant-related odorants. In the smooth-tipped, tapered, trichoid sensilla on the most distal antennal flagellomeres nos. 10 or 11 of both males and females, we found OSNs with high-amplitude action potentials that were tuned to the aldehyde and alcohol pheromone components and that did not respond to various plant-related volatiles. Because this OSN type responded to both the alcohol and aldehyde components it cannot be considered to be specifically tuned to either component. These large-spiking OSNs were co-compartmentalized in these sensilla with a second, smaller-spiking OSN responding to plant-related volatiles such as geraniol, citronellal, limonene, 1-octanol, nerol and citral. The large-spiking OSNs thus appear to be a type that will be involved in aggregation-sex pheromone pathways targeting a specific glomerulus in the antennal lobe and in generating pheromone-related behavioral responses in A. glabripennis. In other sensilla located in these distal antennal flagellomeres as well as those located more proximally, i.e., mid-length along the antenna on flagellomere nos. 4-7, we found OSNs in blunt-tipped basiconic sensilla that were responsive to other plant-related volatiles, especially the terpenoids, (E,E)-alpha farnesene, (E)-ß-farnesene, ß-caryophyllene, and eugenol. Some of these terpenoids have been implicated in improving attraction to pheromone-baited traps. Some of these same OSNs responded additionally to either of the two sex pheromone components, but because these OSNs also responded to some of the above plant volatiles as shown by cross-adaptation experiments, these OSNs will not be the types that convey sex-pheromone-specific information to the antennal lobe.