RESUMEN
Patients who recover from pneumonia subsequently have elevated rates of death after hospital discharge as a result of secondary organ damage, the causes of which are unknown. We used the bacterium Pseudomonas aeruginosa, a common cause of hospital-acquired pneumonia, as a model for investigating this phenomenon. We show that infection of pulmonary endothelial cells by P. aeruginosa induces production and release of a cytotoxic amyloid molecule with prion characteristics, including resistance to various nucleases and proteases. This cytotoxin was self-propagating, was neutralized by anti-amyloid Abs, and induced death of endothelial cells and neurons. Moreover, the cytotoxin induced edema in isolated lungs. Endothelial cells and isolated lungs were protected from cytotoxin-induced death by stimulation of signal transduction pathways that are linked to prion protein. Analysis of bronchoalveolar lavage fluid collected from human patients with P. aeruginosa pneumonia demonstrated cytotoxic activity, and lavage fluid contained amyloid molecules, including oligomeric τ and Aß. Demonstration of long-lived cytotoxic agents after Pseudomonas infection may establish a molecular link to the high rates of death as a result of end-organ damage in the months after recovery from pneumonia, and modulation of signal transduction pathways that have been linked to prion protein may provide a mechanism for intervention.-Balczon, R., Morrow, K. A., Zhou, C., Edmonds, B., Alexeyev, M., Pittet, J.-F., Wagener, B. M., Moser, S. A., Leavesley, S., Zha, X., Frank, D. W., Stevens, T. Pseudomonas aeruginosa infection liberates transmissible, cytotoxic prion amyloids.
Asunto(s)
Citotoxinas/metabolismo , Proteínas Priónicas/toxicidad , Infecciones por Pseudomonas/metabolismo , Pseudomonas aeruginosa , Animales , Edema , Células Endoteliales/microbiología , Humanos , Ratones , Neuronas/microbiología , Neumonía Bacteriana/microbiología , Neumonía Bacteriana/patología , Proteínas Priónicas/metabolismo , Infecciones por Pseudomonas/patología , RatasRESUMEN
Exoenzyme Y (ExoY) was identified as a component of the Pseudomonas aeruginosa type 3 secretion system secretome in 1998. It is a common contributor to the arsenal of type 3 secretion system effectors, as it is present in approximately 90% of Pseudomonas isolates. ExoY has adenylyl cyclase activity that is dependent upon its association with a host cell cofactor. However, recent evidence indicates that ExoY is not just an adenylyl cyclase; rather, it is a promiscuous cyclase capable of generating purine and pyrimidine cyclic nucleotide monophosphates. ExoY's enzymatic activity causes a characteristic rounding of mammalian cells, due to microtubule breakdown. In endothelium, this cell rounding disrupts cell-to-cell junctions, leading to loss of barrier integrity and an increase in tissue edema. Microtubule breakdown seems to depend upon tau phosphorylation, where the elevation of cyclic nucleotide monophosphates activates protein kinases A and G and causes phosphorylation of endothelial microtubule associated protein tau. Phosphorylation is a stimulus for tau release from microtubules, leading to microtubule instability. Phosphorylated tau accumulates inside endothelium as a high molecular weight, oligomeric form, and is then released from the cell. Extracellular high molecular weight tau causes a transmissible cytotoxicity that significantly hinders cellular repair following infection. Thus, ExoY may contribute to bacterial virulence in at least two ways; first, by microtubule breakdown leading to loss of endothelial cell barrier integrity, and second, by promoting release of a high molecular weight tau cytotoxin that impairs cellular recovery following infection.
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Proteínas Bacterianas/metabolismo , Glucosiltransferasas/metabolismo , Infecciones por Pseudomonas/enzimología , Pseudomonas aeruginosa/enzimología , Adenilil Ciclasas/metabolismo , Animales , Permeabilidad Capilar , Citoesqueleto/enzimología , Citoesqueleto/microbiología , Células Endoteliales/enzimología , Células Endoteliales/microbiología , Guanilato Ciclasa/metabolismo , Interacciones Huésped-Patógeno , Humanos , Fosforilación , Pseudomonas aeruginosa/patogenicidad , Sistemas de Mensajero Secundario , Virulencia , Proteínas tau/metabolismoRESUMEN
We tested the hypothesis that Pseudomonas aeruginosa type 3 secretion system effectors exoenzymes Y and U (ExoY and ExoU) induce release of a high-molecular-weight endothelial tau, causing transmissible cell injury characteristic of an infectious proteinopathy. Both the bacterial delivery of ExoY and ExoU and the conditional expression of an activity-attenuated ExoU induced time-dependent pulmonary microvascular endothelial cell gap formation that was paralleled by the loss of intracellular tau and the concomitant appearance of high-molecular-weight extracellular tau. Transfer of the high-molecular-weight tau in filtered supernatant to naïve endothelial cells resulted in intracellular accumulation of tau clusters, which was accompanied by cell injury, interendothelial gap formation, decreased endothelial network stability in Matrigel, and increased lung permeability. Tau oligomer monoclonal antibodies captured monomeric tau from filtered supernatant but did not retrieve higher-molecular-weight endothelial tau and did not rescue the injurious effects of tau. Enrichment and transfer of high-molecular-weight tau to naïve cells was sufficient to cause injury. Thus we provide the first evidence for a pathophysiological stimulus that induces release and transmissibility of high-molecular-weight endothelial tau characteristic of an endothelial proteinopathy.
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Células Endoteliales/microbiología , Infecciones por Pseudomonas/transmisión , Pseudomonas aeruginosa/enzimología , Animales , AMP Cíclico/metabolismo , Células Endoteliales/metabolismo , Pulmón/enzimología , Pulmón/microbiología , Microvasos/metabolismo , Infecciones por Pseudomonas/microbiología , RatasRESUMEN
Here, we tested the hypothesis that a promiscuous bacterial cyclase synthesizes purine and pyrimidine cyclic nucleotides in the pulmonary endothelium. To test this hypothesis, pulmonary endothelial cells were infected with a strain of the Gram-negative bacterium Pseudomonas aeruginosa that introduces only exoenzyme Y (PA103 ΔexoUexoT::Tc pUCPexoY; ExoY(+)) via a type III secretion system. Purine and pyrimidine cyclic nucleotides were simultaneously detected using mass spectrometry. Pulmonary artery (PAECs) and pulmonary microvascular (PMVECs) endothelial cells both possess basal levels of four different cyclic nucleotides in the following rank order: cAMP > cUMP ≈ cGMP ≈ cCMP. Endothelial gap formation was induced in a time-dependent manner following ExoY(+) intoxication. In PAECs, intercellular gaps formed within 2 h and progressively increased in size up to 6 h, when the experiment was terminated. cGMP concentrations increased within 1 h postinfection, whereas cAMP and cUMP concentrations increased within 3 h, and cCMP concentrations increased within 4 h postinfection. In PMVECs, intercellular gaps did not form until 4 h postinfection. Only cGMP and cUMP concentrations increased at 3 and 6 h postinfection, respectively. PAECs generated higher cyclic nucleotide levels than PMVECs, and the cyclic nucleotide levels increased earlier in response to ExoY(+) intoxication. Heterogeneity of the cyclic nucleotide signature in response to P. aeruginosa infection exists between PAECs and PMVECs, suggesting the intracellular milieu in PAECs is more conducive to cNMP generation.
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Células Endoteliales/metabolismo , Nucleótidos Cíclicos/fisiología , Pseudomonas aeruginosa/enzimología , Permeabilidad Capilar , Células Cultivadas , Células Endoteliales/microbiología , Interacciones Huésped-Patógeno , Microvasos/citología , Arteria Pulmonar/citologíaRESUMEN
Exoenzyme Y (ExoY) is a Pseudomonas aeruginosa toxin that is introduced into host cells through the type 3 secretion system (T3SS). Once inside the host cell cytoplasm, ExoY generates cyclic nucleotides that cause tau phosphorylation and microtubule breakdown. Microtubule breakdown causes interendothelial cell gap formation and tissue edema. Although ExoY transiently induces interendothelial cell gap formation, it remains unclear whether ExoY prevents repair of the endothelial cell barrier. Here, we test the hypothesis that ExoY intoxication impairs recovery of the endothelial cell barrier following gap formation, decreasing migration, proliferation, and lung repair. Pulmonary microvascular endothelial cells (PMVECs) were infected with P. aeruginosa strains for 6 h, including one possessing an active ExoY (PA103 exoUexoT::Tc pUCPexoY; ExoY(+)), one with an inactive ExoY (PA103ΔexoUexoT::Tc pUCPexoY(K81M); ExoY(K81M)), and one that lacks PcrV required for a functional T3SS (ΔPcrV). ExoY(+) induced interendothelial cell gaps, whereas ExoY(K81M) and ΔPcrV did not promote gap formation. Following gap formation, bacteria were removed and endothelial cell repair was examined. PMVECs were unable to repair gaps even 3-5 days after infection. Serum-stimulated growth was greatly diminished following ExoY intoxication. Intratracheal inoculation of ExoY(+) and ExoY(K81M) caused severe pneumonia and acute lung injury. However, whereas the pulmonary endothelial cell barrier was functionally improved 1 wk following ExoY(K81M) infection, pulmonary endothelium was unable to restrict the hyperpermeability response to elevated hydrostatic pressure following ExoY(+) infection. In conclusion, ExoY is an edema factor that chronically impairs endothelial cell barrier integrity following lung injury.
Asunto(s)
Proteínas Bacterianas/fisiología , Proliferación Celular , Células Endoteliales/microbiología , Glucosiltransferasas/fisiología , Neumonía Bacteriana/inmunología , Infecciones por Pseudomonas/inmunología , Pseudomonas aeruginosa/enzimología , Animales , AMP Cíclico/metabolismo , Edema/inmunología , Edema/microbiología , Células Endoteliales/inmunología , Células Endoteliales/fisiología , Interacciones Huésped-Patógeno , Pulmón/irrigación sanguínea , Pulmón/inmunología , Pulmón/microbiología , Lesión Pulmonar/inmunología , Lesión Pulmonar/microbiología , Masculino , Microvasos/patología , Microvasos/fisiopatología , Neumonía Bacteriana/microbiología , Neumonía Bacteriana/patología , Infecciones por Pseudomonas/microbiología , Infecciones por Pseudomonas/patología , Pseudomonas aeruginosa/inmunología , Pseudomonas aeruginosa/fisiología , RatasRESUMEN
A foodborne outbreak with 49 cases (22 culture positive for Campylobacter sp.) following a wedding party in the East of England was investigated. A retrospective cohort study identified an association between consumption of chicken liver pâté and infection with Campylobacter jejuni/coli. There was a statistically significant association between dose (amount of chicken liver pâté eaten) and the risk of disease ['tasted': odds ratio (OR) 1·5, 95% confidence interval (CI) 0·04-∞; 'partly eaten': OR 8·4, 95% CI 1·4-87·5; 'most or all eaten': OR 36·1, 95% CI 3·3-2119). The local authority found evidence that the preparation of chicken livers breached Food Standards Agency's guidelines. This epidemiological investigation established a clear dose-response relationship between consumption of chicken liver pâté and the risk of infection with Campylobacter. The continuing need to raise public awareness of the risk to human health posed by undercooked chicken liver is evident.
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Infecciones por Campylobacter/epidemiología , Brotes de Enfermedades/estadística & datos numéricos , Enfermedades Transmitidas por los Alimentos/epidemiología , Adulto , Animales , Campylobacter , Infecciones por Campylobacter/etiología , Infecciones por Campylobacter/microbiología , Pollos/microbiología , Inglaterra/epidemiología , Femenino , Enfermedades Transmitidas por los Alimentos/etiología , Gastroenteritis/epidemiología , Gastroenteritis/etiología , Humanos , Hígado , Masculino , Carne/efectos adversos , Carne/microbiología , Persona de Mediana EdadRESUMEN
INTRODUCTION: Radiographers are responsible for protecting foetuses against ionising radiation and must screen all individuals for pregnancy prior to a pelvic X-ray examination following new guidance from the Society of Radiographers. This includes male, female, transgender, non-binary and intersex patients. Student diagnostic radiographers learn to undertake this screening so this project was designed to understand their attitudes towards doing so. METHOD: A qualitative study was conducted with third-year students on the BSc Diagnostic Radiography programme at a University in the North West of England. Following ethical approval, focus groups were conducted using open-ended questions to gain insight into how comfortably students conduct Inclusive Pregnancy Status (IPS) checks at seven National Health Service (NHS) Trust clinical placement sites. Students were also asked about their attitudes towards IPS checks. These data were analysed using Clarke and Braun's thematic analysis model. RESULTS: The analysis of seven focus groups with nineteen participants yielded four themes: education, standardisation, fear of reaction, and placement involvement. Barriers to conducting IPS checks include a lack of staff encouragement as guidance is enforced at the employers' discretion, and a lack of awareness around transgender, non-binary and intersex (TNBI) inclusivity. Students showed a willingness to conduct IPS checks despite this. CONCLUSION: Age and experience range of participants were limiting factors in this study. Students who had the opportunity to practice and were encouraged to conduct IPS checks on placement felt confident in doing so. IMPLICATIONS FOR PRACTICE: More training and awareness should be provided surrounding LGBTQ + issues in healthcare. IPS checks should be standardised across placement sites to ensure equal learning opportunities.
Asunto(s)
Actitud del Personal de Salud , Grupos Focales , Investigación Cualitativa , Humanos , Femenino , Masculino , Embarazo , Inglaterra , AdultoRESUMEN
BACKGROUND: Bacterial pneumonia and sepsis are both common causes of end-organ dysfunction, especially in immunocompromised and critically ill patients. Pre-clinical data demonstrate that bacterial pneumonia and sepsis elicit the production of cytotoxic tau and amyloids from pulmonary endothelial cells, which cause lung and brain injury in naïve animal subjects, independent of the primary infection. The contribution of infection-elicited cytotoxic tau and amyloids to end-organ dysfunction has not been examined in the clinical setting. We hypothesized that cytotoxic tau and amyloids are present in the bronchoalveolar lavage fluid of critically ill patients with bacterial pneumonia and that these tau/amyloids are associated with end-organ dysfunction. METHODS: Bacterial culture-positive and culture-negative mechanically ventilated patients were recruited into a prospective, exploratory observational study. Levels of tau and Aß42 in, and cytotoxicity of, the bronchoalveolar lavage fluid were measured. Cytotoxic tau and amyloid concentrations were examined in comparison with patient clinical characteristics, including measures of end-organ dysfunction. RESULTS: Tau and Aß42 were increased in culture-positive patients (n = 49) compared to culture-negative patients (n = 50), independent of the causative bacterial organism. The mean age of patients was 52.1 ± 16.72 years old in the culture-positive group and 52.78 ± 18.18 years old in the culture-negative group. Males comprised 65.3% of the culture-positive group and 56% of the culture-negative group. Caucasian culture-positive patients had increased tau, boiled tau, and Aß42 compared to both Caucasian and minority culture-negative patients. The increase in cytotoxins was most evident in males of all ages, and their presence was associated with end-organ dysfunction. CONCLUSIONS: Bacterial infection promotes the generation of cytotoxic tau and Aß42 within the lung, and these cytotoxins contribute to end-organ dysfunction among critically ill patients. This work illuminates an unappreciated mechanism of injury in critical illness.
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Neumonía Bacteriana , Sepsis , Masculino , Animales , Humanos , Adulto , Persona de Mediana Edad , Anciano , Femenino , Estudios Prospectivos , Enfermedad Crítica , Células Endoteliales , Insuficiencia Multiorgánica , Irrigación Terapéutica , Líquido del Lavado Bronquioalveolar/microbiología , Neumonía Bacteriana/microbiología , Amiloide , Citotoxinas , Péptidos beta-Amiloides , Proteínas tauRESUMEN
Neurofibromatosis type 2 (NF2), characterized by tumors of the nervous system, is a result of functional loss of the NF2 gene. The NF2 gene encodes Merlin (moesin-ezrin-radixin-like protein), an ERM (Ezrin, Radixin, Moesin) protein family member. Merlin functions as a tumor suppressor through impacting mechanisms related to proliferation, apoptosis, survival, motility, adhesion, and invasion. Several studies have summarized the tumor intrinsic mutations in Merlin. Given the fact that tumor cells are not in isolation, but rather in an intricate, mutually sustaining synergy with their surrounding stroma, the dialog between the tumor cells and the stroma can potentially impact the molecular homeostasis and promote evolution of the malignant phenotype. This review summarizes the epigenetic modifications, transcript stability, and post-translational modifications that impact Merlin. We have reviewed the role of extrinsic factors originating from the tumor milieu that influence the availability of Merlin inside the cell. Information regarding Merlin regulation could lead to novel therapeutics by stabilizing Merlin protein in tumors that have reduced Merlin protein expression without displaying any NF2 genetic alterations.
Asunto(s)
Neurofibromina 2/fisiología , Proteínas Supresoras de Tumor/fisiología , Animales , Epigénesis Genética , Humanos , Neurofibromina 2/química , Proteínas Proto-Oncogénicas c-akt/fisiología , Estabilidad del ARNRESUMEN
The objectives of this study were to: (a) estimate the costs of providing a single-session HIV prevention intervention and a multi-session intervention, and (b) estimate the number of HIV transmissions that would need to be prevented for the intervention to be cost-saving or cost-effective (threshold analysis). Project START was evaluated with 522 young men aged 18-29 years released from eight prisons located in California, Mississippi, Rhode Island, and Wisconsin. Cost data were collected prospectively. Costs per participant were $689 for the single-session comparison intervention, and ranged from $1,823 to 1,836 for the Project START multi-session intervention. From the incremental threshold analysis, the multi-session intervention would be cost-effective if it prevented one HIV transmission for every 753 participants compared to the single-session intervention. Costs are comparable with other HIV prevention programs. Program managers can use these data to gauge costs of initiating these HIV prevention programs in correctional facilities.
Asunto(s)
Seropositividad para VIH/economía , Hepatitis/economía , Servicios Preventivos de Salud/economía , Prisioneros/estadística & datos numéricos , Enfermedades de Transmisión Sexual/economía , Enfermedades de Transmisión Sexual/prevención & control , Adolescente , Adulto , California/epidemiología , Análisis Costo-Beneficio , Seropositividad para VIH/epidemiología , Seropositividad para VIH/transmisión , Hepatitis/epidemiología , Hepatitis/prevención & control , Humanos , Masculino , Mississippi/epidemiología , Estudios Prospectivos , Rhode Island/epidemiología , Enfermedades de Transmisión Sexual/epidemiología , Wisconsin/epidemiologíaRESUMEN
Unlike malignancies of the nervous system, there have been no mutations identified in Merlin in breast cancer. As such, the role of the tumor suppressor, Merlin, has not been investigated in breast cancer. We assessed Merlin expression in breast cancer tissues by immunohistochemistry and by real-time PCR. The expression of Merlin protein (assessed immunohistochemically) was significantly decreased in breast cancer tissues (although the transcript levels were comparable) simultaneous with increased expression of the tumor-promoting protein, osteopontin (OPN). We further demonstrate that the loss of Merlin in breast cancer is brought about, in part, due to OPN-initiated Akt-mediated phosphorylation of Merlin leading to its proteasomal degradation. Restoring expression of Merlin resulted in reduced malignant attributes of breast cancer, characterized by reduced invasion, migration, motility, and impeded tumor (xenograft) growth in immunocompromised mice. The possibility of developing a model using the relationship between OPN and Merlin was tested with a logistic regression model applied to immunohistochemistry data. This identified consistent loss of immunohistochemical expression of Merlin in breast tumor tissues. Thus, we demonstrate for the first time a role for Merlin in impeding breast malignancy, identify a novel mechanism for the loss of Merlin protein in breast cancer, and have developed a discriminatory model using Merlin and OPN expression in breast tumor tissues.
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Neoplasias de la Mama/metabolismo , Regulación Neoplásica de la Expresión Génica , Modelos Biológicos , Neurofibromina 2/metabolismo , Procesamiento Proteico-Postraduccional , Proteolisis , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Movimiento Celular , Femenino , Humanos , Ratones , Ratones Desnudos , Invasividad Neoplásica , Trasplante de Neoplasias , Neurofibromina 2/genética , Osteopontina/genética , Osteopontina/metabolismo , Fosforilación/genética , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Trasplante HeterólogoRESUMEN
High rates of HIV, STD and hepatitis and associated risk behaviors have been documented among persons entering correctional facilities. However, there is a paucity of data on risk behaviors after release from custody. This study documents risk behaviors and informs intervention development targeting young men leaving incarcerated settings. We enrolled and interviewed 106 men from five prisons up to 60 days prior to their release from prison and interviewed them again four times after their release (at 1-week, 1-, 3- and 6-months). At enrollment, men were 18-29 years of age. Nearly 54% identified as African American, while 27% identified as White, 10% identified as Hispanic/Latino and 10% identified as "other". Approximately 83% had been incarcerated multiple times, 37% reported a prior STD diagnosis and their mean lifetime number of sex partners was 36 (median = 20). Many reported multiple sex partners and inconsistent condom use after release. A significant decrease in condom use during vaginal sex with primary committed female partners and in oral sex with both committed and casual female partners after release from prison were reported from 1-6 months. These young men are at sexual risk of HIV, STD and hepatitis infection after release from prison. Interventions are needed to prevent this population from acquiring and transmitting HIV, STD and hepatitis.
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Prisioneros/estadística & datos numéricos , Enfermedades de Transmisión Sexual/prevención & control , Enfermedades de Transmisión Sexual/psicología , Sexo Inseguro/psicología , Adolescente , Adulto , Condones/estadística & datos numéricos , Infecciones por VIH/prevención & control , Infecciones por VIH/psicología , Hepatitis Viral Humana/prevención & control , Hepatitis Viral Humana/psicología , Homosexualidad Masculina , Humanos , Masculino , Factores de Riesgo , Parejas Sexuales , Estados Unidos , Adulto JovenRESUMEN
To gain insight into practices that may inform formulation and use of rectal microbicides, in-depth interviews were conducted with an ethnically diverse sample of 28 women who engage in anal intercourse. Microbicides are compounds under development to decrease sexually transmitted infections. Most women practiced anal sex in conjunction with vaginal intercourse. Anal sex typically was not preplanned, and few women reported preparation. Condom use was rare. Most women relied on saliva, vaginal fluids, prelubricated condoms, or used no lubrication at last intercourse. Women were uncertain about the amount of lubricant used during sex, with typical estimates of 1 to 2 teaspoons. This may prove challenging to the formulation and promotion of rectal microbicides, as substantially higher amounts may be required. Additional challenges include infrequent use of packaged lubricants, and typical male lubricant application, which may make women's control of rectal microbicides more difficult. Women overwhelmingly expressed interest in rectal microbicides.
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Antiinfecciosos Locales/uso terapéutico , Conocimientos, Actitudes y Práctica en Salud , Lubricantes/uso terapéutico , Conducta Sexual , Adolescente , Adulto , Boston , Estudios de Cohortes , Femenino , Humanos , Entrevistas como Asunto , Persona de Mediana Edad , EspermicidasRESUMEN
In this review, we describe recent advances in antibody processing technology including: (1) development of proprietary cell lines; (2) improved expression systems optimized by selective technologies to boost underperformers; (3) improved protein-free and serum-free culture media; and (4) attention to glycosylation and other post-translational modifications. Advances in computer technology and sophisticated redesign of bioreactors have been major contributors to the dramatic improvements in antibody yields that have been documented in the last decade. Disposable bioreactor components are now widespread, resulting in improved yields, better quality product and lower costs for producers. Downstream innovations include (1) disposable devices for clarification and purification, (2) improved resins and ligands, and (3) new designs of hardware for improved performance. While there are numerous factors contributing to the increased yields that have been obtained, the most sustained of these is the introduction of disposable technologies on both the upstream and the downstream ends of the process. With the continuing introduction of improved computer technology and technological innovation, there is every reason to believe that quality and quantity of antibody products will continue to improve in the coming years, and supply will be adequate to meet the forthcoming needs of the industry.
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Anticuerpos/genética , Células Productoras de Anticuerpos/fisiología , Fenómenos Fisiológicos Celulares , Industria Farmacéutica/métodos , Ingeniería de Proteínas/métodos , Animales , Anticuerpos/inmunología , Humanos , MamíferosRESUMEN
Nanomedicine is a global business enterprise. Industry and governments clearly are beginning to envision nanomedicine's enormous potential. A clear definition of nanotechnology is an issue that requires urgent attention. This problem exists because nanotechnology represents a cluster of technologies, each of which may have different characteristics and applications. Although numerous novel nanomedicine-related applications are under development or nearing commercialization, the process of converting basic research in nanomedicine into commercially viable products will be long and difficult. Although realization of the full potential of nanomedicine may be years or decades away, recent advances in nanotechnology-related drug delivery, diagnosis, and drug development are beginning to change the landscape of medicine. Site-specific targeted drug delivery and personalized medicine are just a few concepts that are on the horizon.
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Nanomedicina/tendencias , Animales , Investigación Biomédica , Humanos , Nanomedicina/legislación & jurisprudencia , Nanoestructuras/uso terapéutico , Patentes como AsuntoRESUMEN
OBJECTIVES: To assess progress of neonatal intensive care units (NICUs) participating in the Vermont Oxford Network iNICQ 2015: Alarm Safety Collaborative in achieving Joint Commission 2014 alarm safety goals with respect to oximeters, and to compare patient-level oxygen saturation (SpO2) and oximeter alarm data to local policies. STUDY DESIGN: Prospective multicenter audits in February and August 2015 assessed implementation of policies addressing Joint Commission 2014 Alarm Safety goals, and ascertained SpO2 targets, oximeter alarm settings and compliance with policy-specified SpO2 targets and alarms. RESULTS: Eighty-six NICUs completed both audits. Of 13 policies addressing mandated goals, median (interquartile range) 8 (5, 9) policies were implemented at audit 1 and 9 (6, 11) at audit 2 (P=0.004). At audit 1, 28 NICUs had implemented ⩾9 policies versus 47 at audit 2. For 794 infants <31 weeks gestation, <36 weeks postmenstrual age, and on supplemental oxygen, median SpO2 target lower limit was 88% (interquartile range 87%, 90%; range 75% to 94%), upper limit 95% (interquartile range 94%, 96%; range 85% to 100%). High oximeter alarm was set according to local policy for 63% of infants, for whom SpO2 >97% was less frequent than when high alarm was not set to policy (10.1% vs 21.5%, P=0.006). CONCLUSIONS: Participating NICUs showed significant progress between audits in their implementation of Joint Commission Alarm Safety goals for oximeter monitoring. Oximeter high alarm not set per local policy is associated with increased hyperoxemia in preterm infants. Recommendations to standardize oxygen saturation targets for infants at risk for oxygenation-related outcomes have not been widely adopted.
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Alarmas Clínicas/normas , Recien Nacido Prematuro/sangre , Unidades de Cuidado Intensivo Neonatal/normas , Oxígeno/sangre , Seguridad del Paciente , Edad Gestacional , Humanos , Hiperoxia/prevención & control , Hipoxia/prevención & control , Recién Nacido , Modelos Logísticos , Monitoreo Fisiológico , Oximetría/métodos , Estudios Prospectivos , VermontRESUMEN
The gamma-irradiation of normal cells causes an increased synthesis of specific proteins. However, few studies have described the effects of high doses of irradiation on the expression of cell surface antigens in tumor cells. This study analyzed the effects of high doses of gamma-irradiation on the surface antigen expression of Major Histocompatability Complex (MHC) class I/II and intercellular adhesion molecule-1 (ICAM-I) in human multiple myeloma (MM) cell lines ARP-1, ARK-RS, and 10 MM primary tumors. The expression of surface antigens was evaluated by fluorescence-activated cell sorter analysis at different time points, following the exposure to high doses of gamma-irradiation. Doses of 10,000 and 15,000 cGy were not sufficient to totally block cell replication in both cell lines and primary tumors; cell replication was able to be inhibited completely only at 18,000 cGy. Lower doses (10,000 cGy) and lethal doses of irradiation (i.e., 15,000 and 18,000 cGy) increased the expression of all surface antigens present on the cells before irradiation. Essentially, such upregulation was shown to be dose dependent, with higher radiation doses resulting in higher antigen expression. Furthermore, when the kinetics of this upregulation were studied 3 and 6 d after irradiation, there was a constant increase in antigen expression in MM cells. These findings suggest that upregulation of costimulatory molecules, such as of MHC class I/II antigens and ICAM-I molecules in MM patients treated by gamma-radiation, can increase the immunogenicity of the tumor cells. In light of these findings, radiotherapy combined with immunotherapy might be considered in relapsing patients after receiving the standard treatment.
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Rayos gamma , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Genes MHC Clase II , Genes MHC Clase I , Molécula 1 de Adhesión Intercelular/metabolismo , Mieloma Múltiple/inmunología , Mieloma Múltiple/radioterapia , Antígenos de Neoplasias/metabolismo , Antígenos de Superficie/metabolismo , Línea Celular Tumoral , Citometría de Flujo , Antígenos HLA , Humanos , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patologíaRESUMEN
PURPOSE: The present study investigated the extent of cortical activity during overt picture naming using functional magnetic resonance imaging (fMRI). METHOD: Participants comprised 20 healthy, adult participants with ages ranging from 20 to 82 years. While undergoing fMRI, participants completed a picture-naming task consisting of 60 high-frequency nouns. RESULTS: Linear regression analysis revealed a positive relationship between age and cortical activation intensity in Broca's and Wernicke's areas as well as the right-hemisphere homologue of Broca's area. In contrast, neural activity in the anterior cingulate gyrus, an area thought to be involved in attentional processing, did not increase as a function of age. CONCLUSIONS: These findings suggest age-related increases in cortical activation during simple language tasks, such as picture naming, in brain areas typically associated with language processing.
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Envejecimiento/fisiología , Percepción Auditiva/fisiología , Corteza Cerebral/fisiología , Lenguaje , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Modelos Lineales , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Análisis MultivarianteRESUMEN
UNLABELLED: Spaced retrieval (SR) has recently been modified to target anomia in persons with aphasia (PWA). It relies on a strict management of the inter-stimulus interval (ISI) where the time between stimulus presentations is doubled or halved based on response accuracy. Although SR is successful in treating anomia, it remains to be studied whether the strict ISI management is necessary. The present study compared fixed-interval spaced retrieval (FISR) to randomized-interval spaced retrieval (RISR) in anomia treatment. Using alternating treatments single subject design, three PWA were trained to name 30 target items. Although both treatments were successful, the present data did not reveal one approach as superior even though fewer FISR sessions were needed and more FISR items were maintained on the post-treatment probes. This difference was only minimal suggesting that a less stringent stimulus schedule, as used in RISR, is sufficient for successful treatment outcome. LEARNING OUTCOMES: Readers will be able to describe the spaced retrieval treatment approach using both fixed- and randomized-interval stimulus schedules, as well as applications of this technique in the treatment of anomia in aphasia.