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We report a dengue outbreak in Key Largo, Florida, USA, from February through August 2020, during the COVID-19 pandemic. Successful community engagement resulted in 61% of case-patients self-reporting. We also describe COVID-19 pandemic effects on the dengue outbreak investigation and the need to increase clinician awareness of dengue testing recommendations.
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COVID-19 , Dengue , Humanos , COVID-19/epidemiologia , Dengue/epidemiologia , Florida/epidemiologia , Pandemias , Surtos de DoençasRESUMO
Prostate cancer (PCa) is the second most commonly diagnosed cancer worldwide. Radiotherapy remains one of the first-line treatments in localised disease and may be used as monotherapy or in combination with other treatments such as androgen deprivation therapy or radical prostatectomy. Despite advancements in delivery methods and techniques, radiotherapy has been unable to totally overcome radioresistance resulting in treatment failure or recurrence of previously treated PCa. Various factors have been linked to the development of tumour radioresistance including abnormal tumour vasculature, oxygen depletion, glucose and energy deprivation, changes in gene expression and proteome alterations. Understanding the biological mechanisms behind radioresistance is essential in the development of therapies that are able to produce both initial and sustained response to radiotherapy. This review will investigate the different biological mechanisms utilised by PCa tumours to drive radioresistance.
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Evidence to support the effectiveness of ß3-adrenoceptor agonist mirabegron and anti-muscarinic solifenacin in the management of bladder dysfunction caused by psychological stress is lacking. This study investigates whether mirabegron or solifenacin reduces the bladder overactivity caused by water avoidance stress (WAS) in mice. Female mice were exposed to WAS for 1 h/day for 10 days and received either placebo, solifenacin or mirabegron in drinking water. Controls were age-matched without stress exposure. Voiding behaviour and functional isolated whole bladder responses during distension and in response to pharmacological agents and electrical field stimulation was investigated. Urinary frequency was significantly increased following stress. Mice treated with mirabegron or solifenacin displayed significantly fewer voiding events compared to the stressed mice, and voiding frequency in drug-treated animals was comparable to unstressed controls. The maximal contractile responses of bladders to carbachol were significantly enhanced by stress and reduced by mirabegron but not solifenacin. The frequency of phasic bladder contractions following stimulation with carbachol was significantly enhanced following stress and remained elevated in the mirabegron treated group. However, treatment with solifenacin significantly reduced the frequency of phasic contractions to unstressed control levels. Solifenacin and mirabegron are beneficial in reducing the overall voiding dysfunction caused by WAS in mice.
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Succinato de Solifenacina , Bexiga Urinária Hiperativa , Acetanilidas/farmacologia , Animais , Carbacol , Feminino , Camundongos , Antagonistas Muscarínicos/uso terapêutico , Succinato de Solifenacina/farmacologia , Succinato de Solifenacina/uso terapêutico , Estresse Psicológico , Tiazóis , Resultado do TratamentoRESUMO
Psychological stress causes bladder dysfunction in humans and in rodent models, with increased urinary frequency and altered contractile responses evident following repeated environmental stress exposure. However, whether these changes persist after removal of the stressor is unknown, and the aim of this study was to determine if stress-induced changes in voiding behaviour and bladder function recover following removal of the stressor. Adult female mice were allocated to three groups: Unstressed, Stressed or Stressed + Recovery. Animals in the stressed groups were exposed to water avoidance stress for 1h/day for 10-days, with unstressed animals age-matched and housed under normal conditions. For recovery studies, animals were housed without stress exposure for an additional 10-days. Voiding behaviour was assessed periodically and animals sacrificed on day 10 (Unstressed and Stressed) or day 20 (Unstressed and Stressed + Recovery). Isolated whole bladder studies were used to assess compliance, urothelial mediator release and contractile responses. Exposure to stress increased plasma corticosterone levels almost three-fold (P<0.05) but this returned to baseline during the recovery period. Contractile responses of the bladder to carbachol and KCl were also increased following stress, and again fully recovered after a 10-day stress-free period. In contrast, stress increased urinary frequency four-fold (P<0.001), but this did not return fully to baseline during the recovery period. Bladder compliance was unchanged by stress; however, it was increased in the stressed + recovery group (P<0.05). Thus, following a stress-free period there is partial recovery of voiding behaviour, with an increase in bladder compliance possibly contributing to the compensatory mechanisms.
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Bexiga Urinária , Micção , Animais , Carbacol , Corticosterona , Feminino , Camundongos , Estresse Psicológico , Micção/fisiologiaRESUMO
In popular media, autistic subjectivity is most often produced through the lens of the neurotypical gaze. Dominant understandings of autism therefore tend to focus on perceived deficits in social communication and relationships. Accordingly, this article has two primary concerns. First, it uses the Danish/Swedish television series The Bridge (Bron/Broen, 2011-2018) and critical responses to the series as examples of how the neurotypical gaze operates, concentrating on the pleasures derived from looking at autism, how autism is 'fixed' (Frantz Fanon, 1986) as a socially undesirable subject position, and the self-interested focus of the gaze. Second, it analyses key scenes from the series to expose and challenge the dominance of the neurotypical perspective in scholarly accounts of autistic sexuality and relationality. Using Lauren Berlant's (2012) work on love, I argue that the non-normative ways of being constructed by the series do not fit easily within neuroconventional frameworks of love and desire. Consequently, autistic expressions of love are rendered both undesirable and illegible to the neurotypical gaze. The article therefore offers a flexible framework for understanding how the neurotypical gaze functions across cultural and academic spheres and gives vital insight into how autistic love and relationships are narratively constructed.
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Transtorno Autístico , Comunicação , Humanos , Amor , Comportamento SexualRESUMO
Many postsecondary institutions have begun their own Autism-Specific College Support Programs (ASPs) to integrate the emergence of autistic students into college and offer supports aiding their success (Longtin in J Postsecond Educ Disabil 27(1):63-72, 2014), yet little is known about these programs. We conducted an exhaustive, year-long search of all postsecondary institutions in the United States to identify all ASPs. Although we identified a total of 74 programs located in 29 states, our analyses suggest these are unavailable to students in large portions of the country. When they are available, these programs appear to be disproportionately located at 4-year institutions, public institutions, and in the Mid-East. Our study highlights inequities based on institutional type and geography, as well as offers a complete public list of ASPs.
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Transtorno do Espectro Autista , Transtorno Autístico , Logro , Transtorno do Espectro Autista/epidemiologia , Transtorno Autístico/epidemiologia , Geografia , Humanos , Estudantes , Estados Unidos , UniversidadesRESUMO
Psychological stress has been linked to the development and exacerbation of overactive bladder symptoms, as well as afferent sensitisation in other organ systems. Therefore, we aimed to investigate the effects of water avoidance stress on bladder afferent nerve activity in response to bladder filling and pharmaceutical stimulation with carbachol and ATP in mice. Adult female C57BL/6J mice were exposed to either water avoidance stress (WAS) for 1 h/day for 10 days or normal housing conditions. Voiding behaviour was measured before starting and 24-h after final stress exposure and then animals were euthanised to measure afferent nerve activity in association with bladder compliance, spontaneous phasic activity, contractile responses, as well as release of urothelial mediators. WAS caused increased urinary frequency without affecting urine production. The afferent nerve activity at low bladder pressures (4-7 mmHg), relevant to normal physiological filling, was significantly increased after stress. Both low and high threshold nerves demonstrated enhanced activity at physiological bladder pressures. Urothelial ATP and acetylcholine release and bladder compliance were unaffected by stress as was the detrusor response to ATP (1 mM) and carbachol (1 µM). WAS caused enhanced activity of individual afferent nerve fibres in response bladder distension. The enhanced activity was seen in both low and high threshold nerves suggesting that stressed animals may experience enhanced bladder filling sensations at lower bladder volumes as well as increased pain sensations, both potentially contributing to the increased urinary frequency seen after stress.
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Vias Aferentes/fisiopatologia , Neurônios Aferentes/patologia , Estresse Psicológico/complicações , Bexiga Urinária Hiperativa/patologia , Animais , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Bexiga Urinária Hiperativa/etiologiaRESUMO
It is well established that lower urinary tract symptoms (LUTS), particularly urinary urgency and incontinence, cause stress and anxiety for patients. However, there is mounting evidence that the relationship between these two factors is bidirectional and that chronic psychological stress itself can result in the development of symptoms such as urinary frequency, urgency, incontinence, and pelvic pain. This review considers the evidence that such a relationship exists and reviews the literature from clinical and animal studies to identify some of the mechanisms that might be involved. Inflammatory responses induced by chronic stress appear to offer the strongest link to bladder dysfunction. There is overwhelming evidence, both in patients and animal models, for a release of pro-inflammatory cytokines and chemokines during periods of chronic stress. Furthermore, cytokines have been shown to cause bladder dysfunction and pain via actions in the central nervous system and locally in the bladder. In the brain and spinal cord, pro-inflammatory cytokines influence the regulation of micturition pathways by corticotropin-releasing factor (CRF) and its receptors, while peripherally cytokines affect bladder function, directly causing detrusor hypertrophy and afferent nerve hypersensitivity. There is little information on which treatments may have most benefit for stressed/anxious patients with LUTS, but animal studies suggest traditional drugs for overactive bladder (solifenacin, mirabegron) are more effective on LUTS than anxiolytic drugs (fluoxetine, imipramine). The preliminary preclinical data for CRF receptor antagonists is not consistent. A clearer understanding of the mechanisms involved in stress-induced LUTS should provide a basis for improved treatment of this condition.
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Sintomas do Trato Urinário Inferior , Bexiga Urinária Hiperativa , Incontinência Urinária , Animais , Humanos , Sintomas do Trato Urinário Inferior/tratamento farmacológico , Sintomas do Trato Urinário Inferior/etiologia , Estresse Psicológico/complicações , Bexiga Urinária Hiperativa/tratamento farmacológico , Bexiga Urinária Hiperativa/etiologiaRESUMO
AIMS: To determine if treatment with the selective serotonin reuptake inhibitor (SSRI) sertraline reduces the bladder dysfunction caused by water avoidance stress in mice. MAIN METHODS: Adult female mice were randomly allocated to (1) Unstressed, (2) Stressed or (3) Stress + Sertraline experimental groups. Stressed mice were subjected to water avoidance for 1 h/day for 10 days and received sertraline or vehicle in drinking water, starting 10-days prior to the first stress exposure. Age matched control/unstressed mice were house under normal conditions without stress exposure. Voiding behaviour was assessed throughout the experimental protocol. After the final stress exposure, a blood sample was taken to measure plasma corticosterone levels and bladders were removed, catheterised and intravesical pressure responses recorded during distension and in response to pharmacological agents. KEY FINDINGS: Plasma corticosterone levels in sertraline-treated animals were equivalent to unstressed controls and significantly decreased compared to the stressed group. Voiding frequency was significantly increased in the stressed group, and treatment with sertraline significantly decreased voiding frequency, however, this remained elevated compared to unstressed control animals. Bladders from stressed mice displayed enhanced maximal contractile response to the muscarinic agonist carbachol and greater release of ACh in the serosal fluid, which was reduced to control levels by sertraline treatment. Spontaneous phasic contractions were not altered by stress but were significantly reduced in bladders from sertraline treated animals, relative to controls. SIGNIFICANCE: These results indicate that management of voiding dysfunction caused by psychological stress may be aided by the addition of an SSRI such as sertraline.
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Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Sertralina/uso terapêutico , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/fisiopatologia , Bexiga Urinária/efeitos dos fármacos , Animais , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Bexiga Urinária/fisiopatologia , Micção/efeitos dos fármacosRESUMO
INTRODUCTION: Public health responses often lack the infrastructure to capture the impact of public health emergencies on pregnant women and infants, with limited mechanisms for linking pregnant women with their infants nationally to monitor long-term effects. In 2019, the Centers for Disease Control and Prevention (CDC), in close collaboration with state, local, and territorial health departments, began a 5-year initiative to establish population-based mother-baby linked longitudinal surveillance, the Surveillance for Emerging Threats to Mothers and Babies Network (SET-NET). OBJECTIVES: The objective of this report is to describe an expanded surveillance approach that leverages and modernizes existing surveillance systems to address the impact of emerging health threats during pregnancy on pregnant women and their infants. METHODS: Mother-baby pairs are identified through prospective identification during pregnancy and/or identification of an infant with retrospective linking to maternal information. All data are obtained from existing data sources (e.g., electronic medical records, vital statistics, laboratory reports, and health department investigations and case reporting). RESULTS: Variables were selected for inclusion to address key surveillance questions proposed by CDC and health department subject matter experts. General variables include maternal demographics and health history, pregnancy and infant outcomes, maternal and infant laboratory results, and child health outcomes up to the second birthday. Exposure-specific modular variables are included for hepatitis C, syphilis, and Coronavirus Disease 2019 (COVID-19). The system is structured into four relational datasets (maternal, pregnancy outcomes and birth, infant/child follow-up, and laboratory testing). DISCUSSION: SET-NET provides a population-based mother-baby linked longitudinal surveillance approach and has already demonstrated rapid adaptation to COVID-19. This innovative approach leverages existing data sources and rapidly collects data and informs clinical guidance and practice. These data can help to reduce exposure risk and adverse outcomes among pregnant women and their infants, direct public health action, and strengthen public health systems.
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Defesa Civil/métodos , Relações Mãe-Filho , Vigilância da População/métodos , Adulto , COVID-19/complicações , COVID-19/diagnóstico , Defesa Civil/instrumentação , Feminino , Hepatite C/complicações , Hepatite C/diagnóstico , Humanos , Recém-Nascido , Programas de Rastreamento/métodos , Gravidez , Sífilis/complicações , Sífilis/diagnósticoRESUMO
AIMS: To investigates the effects of water avoidance stress on voiding behaviour and functional bladder responses in mice. MAIN METHODS: Mice in the Stress group were exposed to water avoidance stress (WAS) for 1 h/day for 10 days, Controls were age-matched and housed normally. Voiding behaviour was measured periodically throughout the stress protocol and bladders were isolated 24-h after final stress exposure to measure bladder compliance, spontaneous phasic activity, contractile responses, and release of urothelial mediators. KEY FINDINGS: Repeated stress exposure induced a significant increase in plasma corticosterone levels in the WAS group compared to control. An overactive bladder phenotype was observed in WAS mice, causing a significant increase in the number of voiding events observed from as early as day-3, and a 7-fold increase following 10-days' stress. This increase in voiding frequency was associated with a significant decrease in void size, an increase in the number of small voids, but no change in total voided volume. Bladders from stressed mice showed a significant increase in the maximum responses to the muscarinic agonist carbachol (p < 0.01), in addition to enhanced pressure responses to the purinergic agonists ATP (p < 0.05) and αß-mATP (p < 0.05), and non-receptor mediated contractions to KCl (p < 0.05) compared to controls. Nerve-mediated bladder contractions to electric field stimulation were not significantly affected by stress, nor were spontaneous phasic contractions or release of urothelial ATP and acetylcholine. SIGNIFICANCE: Repeated exposure to water avoidance stress produced an overactive bladder phenotype, confirmed by increased voiding frequency, and associated with enhanced bladder contractile responses.
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Contração Muscular/fisiologia , Estresse Psicológico/metabolismo , Bexiga Urinária Hiperativa/fisiopatologia , Acetilcolina , Animais , Carbacol/farmacologia , Corticosterona , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Agonistas Muscarínicos/farmacologia , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Cloreto de Potássio/farmacologia , Agonistas Purinérgicos/farmacologia , Estresse Psicológico/fisiopatologia , Bexiga Urinária/patologia , Bexiga Urinária Hiperativa/metabolismo , Micção/efeitos dos fármacosRESUMO
Drug repurposing has been increasingly used by both researchers and clinicians to identify new cancer treatments. The alpha-1 adrenoreceptor blockers are a class of drugs that have been used for many years in the treatment of hypertension and benign prostatic hyperplasia. Some of the drugs in this class, notably the quinazoline derivatives, have been found to display cytotoxic properties, identifying them as potential options in the treatment of cancer. This review will examine the currently available evidence that investigates the cytotoxic and anti-cancer properties of these agents, the mechanisms behind these properties and how the alpha-1 blockers fit within current cancer therapies. It aims to answer the question of whether these agents can go from the laboratory bench top into cancer clinics.
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Antagonistas de Receptores Adrenérgicos alfa 1/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Quinazolinas/uso terapêutico , Receptores Adrenérgicos alfa 1/metabolismo , Pesquisa Translacional Biomédica , Antagonistas de Receptores Adrenérgicos alfa 1/efeitos adversos , Animais , Antineoplásicos/efeitos adversos , Reposicionamento de Medicamentos , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Quinazolinas/efeitos adversos , Transdução de SinaisRESUMO
The cytotoxic drugs cyclophosphamide (CPO) and ifosfamide (IFO) cause toxic urological effects due to the production of urinary metabolites that cause bladder inflammation. This study aimed to identify changes in the bladder afferent system following treatment with these drugs that might explain reported urological adverse effects. Intravesical pressure and afferent nerve activity were recorded during bladder distension and drug administration in isolated bladders from mice, 24 h after intraperitoneal treatment with cyclophosphamide (100 mg/kg), ifosphamide (200 mg/kg) or saline (control). In isolated bladders, total afferent nerve activity at maximum bladder distension was increased from 182 ± 13 imp/s in control animals, to 230 ± 14 imp/s in CPO-treated (p < 0.05) and 226 ± 17 imp/s in IFO-treated (p < 0.001) mice. Single fibre analysis revealed the increase resulted from an enhanced activity in low threshold, wide dynamic range fibres (23.3 ± 1.9 imp/s/fibre in controls to 31.5 ± 2.5 (p < 0.01) in CPO and 29.9 ± 2.0 imp/s/fibre (p < 0.05) in IFO treated). CPO treatment was accompanied by an increase in urinary frequency in vivo, but was not associated with increases in urothelial release of ATP or acetylcholine, bladder compliance or spontaneous muscle activity. Also, CPO-treatment did not affect afferent nerve responses or pressure responses to purinergic, muscarinic or nicotinic agonists. This is the first report of CPO and IFO-induced changes in specific populations of bladder afferents, namely an increase in low threshold, wide dynamic range fibres. These effects appear to be direct and not secondary to increases in smooth muscle activity or the release of urothelial mediators.
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Antineoplásicos Alquilantes/toxicidade , Ciclofosfamida/toxicidade , Ifosfamida/toxicidade , Células Receptoras Sensoriais/efeitos dos fármacos , Doenças da Bexiga Urinária/induzido quimicamente , Bexiga Urinária/inervação , Urodinâmica/efeitos dos fármacos , Animais , Masculino , Mecanotransdução Celular , Camundongos Endogâmicos C57BL , Pressão , Doenças da Bexiga Urinária/fisiopatologiaRESUMO
While alpha-blockers are commonly used to reduce lower urinary tract symptoms in prostate cancer patients receiving radiotherapy, their impact on response to radiotherapy remains unknown. Therefore, this pilot study aimed to retrospectively determine if alpha-blockers use, influenced response to radiotherapy for localised prostate cancer. In total, 303 prostate cancer patients were included, consisting of 84 control (alpha-blocker naïve), 72 tamsulosin and 147 prazosin patients. The main outcomes measured were relapse rates (%), time to biochemical relapse (months) and PSA velocity (ng/mL/year). Recurrence free survival was calculated using Kaplan-Meier analysis. Prazosin significantly reduced biochemical relapse at both two and five-years (2.72%, 8.84%) compared to control (22.61%, 34.52%). Recurrence free survival was also significantly higher in the prazosin group. This remained after multivariable analysis (HR: 0.09, 95% CI: 0.04-0.26, p < 0.001). Patients receiving prazosin had a 3.9 times lower relative risk of biochemical relapse compared to control. Although not statistically significant, tamsulosin and prazosin extended recurrence free survival by 13.15 and 9.21 months respectively. We show for the first time that prazosin may reduce risk of prostate cancer recurrence and delay time to biochemical relapse and provides justification for prospective studies to examine its potential as an adjunct treatment option for localised prostate cancer.
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Antagonistas Adrenérgicos alfa/farmacologia , Neoplasias da Próstata/radioterapia , Idoso , Intervalo Livre de Doença , Humanos , Masculino , Projetos Piloto , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Recidiva , Estudos RetrospectivosRESUMO
Psychological stress is associated with bladder dysfunction, however, the local bladder mechanisms affected are not well understood. This study aimed to determine how psychological stress, caused by social defeat or witness trauma, affects voiding behavior and bladder function. Pairs of male C57Bl/6J mice were placed in a custom-made plexiglass chamber with an aggressor ARC(S) mouse for 1 h/day for 10 days. The social defeat mouse was in physical contact with the aggressor, while the witness was physically separated but could observe interactions between its cage-mate and the aggressor. Age matched control pairs were used for comparison. Voiding analysis was conducted periodically over the 10 days. An ex vivo whole bladder preparation was used to assess functional changes after the period of stress. Plasma corticosterone levels were significantly increased by both social defeat and witness trauma stress when compared to unstressed controls. Voiding analysis revealed a significant decrease in voiding frequency in the social defeat group compared to control animals, indicating an altered voiding phenotype. Witness trauma did not alter voiding behavior. Bladder contractile responses to cholinergic stimulation were not significantly altered in either stress group, nor was relaxation to the beta-adrenoceptor agonist isoprenaline. However, nerve evoked contractile responses were significantly increased at all frequencies in bladders from social defeat but not witness trauma mice. Purinergic contractile responses were also significantly enhanced in this group. Social defeat also resulted in increased urothelial acetylcholine release during bladder distension, with no change in ATP release. In conclusion, functional bladder changes are dependent upon stressor type. Enhanced urothelial acetylcholine may desensitize bladder sensory nerves, which, coupled with more efficient voiding contractions due to enhanced nerve-mediated and purinergic detrusor responses, may account for the altered voiding phenotype observed. This study reports a male model of social defeat stress with reduced urinary frequency, with no voiding changes observed in the witness.
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It is widely accepted that the hypoxic nature of solid tumors contribute to their resistance to radiation therapy. There is increasing evidence that cyclooxygenase-2 (COX-2) contributes to increased resistance of tumors to radiation therapy. Several studies demonstrate that combination of COX-2 selective inhibitors with radiation therapy selectively enhances radio responsiveness of tumor cells. However, the majority of these studies utilised suprapharmacological concentrations under normoxic conditions only. Furthermore, the mechanism by which these agents act remain largely unclear. Therefore, the aim of this study was to determine the impact of COX-2 selective inhibitors on both normoxic and hypoxic radiosensitivity in vitro and the mechanisms underlying this. Because of the close, reciprocal relationship between COX-2 and p53 we investigated their contribution to radioresistance. To achieve this we exposed HeLa, MCF-7 and MeWo cells to the COX-2 selective inhibitor, NS398 (10µM). NS398 (10µM) selectively sensitized hypoxic HeLa and MCF-7 but not MeWo cells to ionising radiation (5 Gy). Furthermore, while knockdown of COX-2 with siRNA did not affect either normoxic radiosensitivity in HeLa cells, the radiosensitisation observed with NS398 was lost suggesting both COX-2 dependent and independent mechanisms. We also show that ionising radiation at 5 Gy results in phosphorylation of p53 at serine 15, a key phosphorylation site for p53-mediated apoptosis, and that hypoxia attenuates this phosphorylation. Attenuated phosphorylation of p53 under hypoxic conditions may therefore contribute to hypoxic radioresistance. We also show that NS398 selectively phosphorylates p53 under hypoxic conditions following irradiation at 5 Gy. p53 phosphorylation could be an underlying mechanism by which this agent and other COX-2 inhibitors sensitize tumors to radiation therapy.
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Ciclo-Oxigenase 2/química , Nitrobenzenos/farmacologia , Tolerância a Radiação/efeitos dos fármacos , Sulfonamidas/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Neoplasias do Colo do Útero/radioterapia , Anti-Inflamatórios não Esteroides/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Ciclo-Oxigenase 2/metabolismo , Feminino , Células HeLa , Humanos , Hipóxia/fisiopatologia , Fosforilação , Radiação Ionizante , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologiaRESUMO
The clinical use of cyclophosphamide and ifosfamide is limited by a resultant bladder toxicity which has been attributed to the metabolite acrolein. Another metabolite chloroacetaldehyde (CAA) associated with nephrotoxicity, has not been investigated for toxicity in the bladder and this study investigates the effects of acrolein and CAA on human urothelial cells in vitro. Human urothelial cells (RT4 and T24) were treated with acrolein or CAA and changes in cell viability, reactive oxygen species, caspase-3 activity and release of urothelial mediators ATP, acetylcholine, PGE2 were measured. The protective effects of N-acetyl cysteine (NAC) were also assessed. Both metabolites were toxic to human urothelial cells, however, CAA significantly decreased cell viability at a ten-fold lower concentration (10 µM) than acrolein (100 µM). This was associated with increased ROS production and caspase-3 activity. NAC protected cells from these changes. In RT4 cells 100 µM acrolein caused a significant increase in basal and stretch-induced ATP, Ach and PGE2 release. In T24 cells chloroacetaldehyde (10 µM) increased basal and stimulated ATP and PGE2 levels. Again, NAC protected against changes in urothelial mediator release following acrolein or CAA. This study is the first to report that CAA in addition to acrolein contributes to the urotoxicity of cyclophosphamide and ifosfamide. Both metabolites altered urothelial mediator levels which could contribute to the sensory and functional bladder changes experienced by patients after treatment with cyclophosphamide or ifosfamide. Alterations in urothelial cell viability and mediator release may be causally linked to oxidative stress, with NAC providing protection against these changes.
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Acetaldeído/análogos & derivados , Acroleína/toxicidade , Antineoplásicos Alquilantes/toxicidade , Ciclofosfamida/toxicidade , Células Epiteliais/efeitos dos fármacos , Bexiga Urinária/efeitos dos fármacos , Urotélio/efeitos dos fármacos , Acetaldeído/metabolismo , Acetaldeído/toxicidade , Acroleína/metabolismo , Antineoplásicos Alquilantes/metabolismo , Técnicas de Cultura de Células , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ciclofosfamida/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Humanos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Bexiga Urinária/metabolismo , Bexiga Urinária/patologia , Urotélio/metabolismo , Urotélio/patologiaRESUMO
Intravesical treatment of superficial bladder cancer with epirubicin is associated with local urological adverse effects, the causes of which are unknown. Our aim was to investigate the effects of epirubicin on the release of urothelial mediators and inflammatory cytokines. UROtsa cells were treated with epirubicin for 1â¯hâ¯at 37⯰C. Release of urothelial transmitters and inflammatory cytokines was examined immediately, 24â¯h and 7 days following treatment. Release of ATP and nitric oxide were increased transiently after treatment with epirubicin (0.01â¯mg/ml), but this was not evident one-week after treatment. Basal prostaglandin E2 release was decreased at 24â¯h but not at 7 days. An increase in basal acetylcholine release and decrease in stretch-induced acetylcholine release were observed 24-h after treatment (0.01â¯mg/ml). One week following epirubicin treatment (0.001â¯mg/ml), stretch-induced, but not basal acetylcholine release, was observed. Secretion of interleukin-6 and interleukin-8 was increased 70-fold and 5-fold respectively, at 24â¯h (0.01â¯mg/ml). This was sustained and one week after epirubicin treatment (0.001â¯mg/ml), the increase in the secretion of both inflammatory cytokines was still evident. Epirubicin treatment induces several transient changes in urothelial function. However, the increased secretion of inflammatory cytokines (IL-6 and IL-8) is sustained and these mediators may be involved in the pathophysiology of bladder toxicity following intravesical epirubicin treatment.
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Epirubicina/farmacologia , Mediadores da Inflamação/metabolismo , Urotélio/efeitos dos fármacos , Urotélio/metabolismo , Linhagem Celular , Citocinas/metabolismo , Humanos , Óxido Nítrico/metabolismo , Fatores de Tempo , Urotélio/citologiaRESUMO
As health systems are adapting to increased accountability for quality outcomes, population health, and collaborative care, medical schools are adapting curricula to better prepare physicians to function in health systems. Two components of this educational transformation are (1) increasing physician competence in Health Systems Science, including quality, population health, social determinants of health, and interprofessional collaboration, and (2) providing roles for students to act as change agents while adding value to the health system. The authors, three medical students who served as patient navigators during their first year of medical school, provide perspectives regarding their clinical systems learning roles, which spanned the levels of individual patients, clinic operations, and the health system. Specifically, authors describe working with a struggling patient, developing an intake assessment tool to aid clinical operations, and creating a directory of community-based resources. Authors discuss educational benefits, including understanding social determinants of health, barriers to care, and inefficiencies within the healthcare system. Several challenges are explored, including the importance of student initiative and concerns about traditional curricular outcomes. Through early experiences, students describe developing a professional identity as a change agent, while also learning key competencies required for clinical practice.
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Gestão de Mudança , Faculdades de Medicina/organização & administração , Estudantes de Medicina , Currículo , Feminino , Humanos , Navegação de Pacientes/organização & administraçãoRESUMO
The current study replicates and expands prior work on children's ownership intuitions and explores whether variability in theory of mind and linguistic ability predicts patterns in children's understanding of ownership. We tested children ages 4 to 6 and found age-related differences in ownership intuitions, but those differences were not significantly predicted by variability in theory of mind or linguistic ability. This report is the first to specifically investigate the cognitive competencies that contribute to the development of mature ownership concepts, and to replicate many of the core findings in the literature.