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Traumatic brain injury (TBI) is a disabling neurotraumatic condition and the leading cause of injury-related deaths and disability in the United States. Attenuation of neuroinflammation early after TBI is considered an important treatment target; however, while these inflammatory responses can induce secondary brain injury, they are also involved in the repair of the nervous system. Pioglitazone, which activates peroxisome proliferator-activated receptor gamma, has been shown to decrease inflammation acutely after TBI, but the long-term consequences of its use remain unknown. For this reason, the impacts of treatment with pioglitazone during the acute/subacute phase (30â¯min after injury and each subsequent 24â¯h for 5â¯days) after TBI were interrogated during the chronic phase (30- and 274-days post-injury (DPI)) in mice using the controlled cortical impact model of experimental TBI. Acute/subacute pioglitazone treatment after TBI results in long-term deleterious consequences, including disruption of tau homeostasis, chronic glial cell activation, neuronal pathology, and worsened injury severity particularly at 274â¯DPI, with male mice being more susceptible than female mice. Further, male pioglitazone-treated TBI mice exhibited increased dominant and offensive-like behavior while having a decreased non-social exploring behavior at 274â¯DPI. After TBI, both sexes exhibited glial activation at 30â¯DPI when treated with pioglitazone; however, while injury severity was increased in females it was not impacted in male mice. This work reveals that although pioglitazone has been shown to lead to attenuated TBI outcomes acutely, sex-based differences, timing and long-term consequences of treatment with glitazones must be considered and further studied prior to their clinical use for TBI therapy.
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BACKGROUND: Though the proportion of women in medical schools has increased, gender disparities among those who pursue research careers still exists. In this study, we seek to better understand the main factors contributing to the existing gender disparities among medical students choosing to pursue careers in medical research. METHODS: A secondary cross-sectional cohort analysis of previously published data was conducted using a 70-item survey that was sent to 16,418 medical students at 32 academic medical centers, and was IRB exempt from the need for ethical approval at the University of Illinois at Chicago and the University of Pennsylvania. Data was collected from September 2012 to December 2014. Survey results were analyzed using chi-square tests and Cramer's V to determine gender differences in demographic characteristics (training stage, race/ethnicity, marital status, parental status, financial support, and parental career background), career sector choice, career content choice, specialty choice, foreseeable career obstacles, and perceptions about medical research careers. RESULTS: Female respondents were more likely to be enrolled in MD-only programs, while male respondents were more likely to be enrolled in MD/PhD programs. More male students selected academia as their first-choice career sector, while more female respondents selected hospitalist as their first-choice career sector. More female respondents identified patient care and opportunities for community service as their top career selection factors, while more male respondents identified research and teaching as their top career selection factors. Student loan burden, future compensation, and work/life balance were the most reported obstacles to pursuing a career in medical research. CONCLUSIONS: There are many factors from a medical student's perspective that may contribute to the existing gender disparities in pursuing a career in medical research. While much progress has been made in attracting nearly equal numbers of men and women to the field of medicine, active efforts to bridge the gap between men and women in medical research careers are needed.
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Pesquisa Biomédica , Estudantes de Medicina , Escolha da Profissão , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Masculino , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Reactive oxidative stress is a critical player in the amyloid beta (Aß) toxicity that contributes to neurodegeneration in Alzheimer's disease (AD). Damaged mitochondria are one of the main sources of reactive oxygen species and accumulate in Aß plaque-associated dystrophic neurites in the AD brain. Although Aß causes neuronal mitochondria reactive oxidative stress in vitro, this has never been directly observed in vivo in the living mouse brain. Here, we tested for the first time whether Aß plaques and soluble Aß oligomers induce mitochondrial oxidative stress in surrounding neurons in vivo, and whether this neurotoxic effect can be abrogated using mitochondrial-targeted antioxidants. METHODS: We expressed a genetically encoded fluorescent ratiometric mitochondria-targeted reporter of oxidative stress in mouse models of the disease and performed intravital multiphoton microscopy of neuronal mitochondria and Aß plaques. RESULTS: For the first time, we demonstrated by direct observation in the living mouse brain exacerbated mitochondrial oxidative stress in neurons after both Aß plaque deposition and direct application of soluble oligomeric Aß onto the brain, and determined the most likely pathological sequence of events leading to oxidative stress in vivo. Oxidative stress could be inhibited by both blocking calcium influx into mitochondria and treating with the mitochondria-targeted antioxidant SS31. Remarkably, the latter ameliorated plaque-associated dystrophic neurites without impacting Aß plaque burden. CONCLUSIONS: Considering these results, combination of mitochondria-targeted compounds with other anti-amyloid beta or anti-tau therapies hold promise as neuroprotective drugs for the prevention and/or treatment of AD.
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Doença de Alzheimer , Peptídeos beta-Amiloides , Camundongos , Animais , Peptídeos beta-Amiloides/metabolismo , Doença de Alzheimer/metabolismo , Estresse Oxidativo/fisiologia , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Oxirredução , Mitocôndrias/metabolismo , Modelos Animais de DoençasRESUMO
Objective: To determine trends in internet search volume for elective surgery terms during the first peak of the coronavirus disease 2019 (COVID-19) pandemic using Google Trends data. Background: Postponement of much-needed elective and urgent oncologic surgeries takes a toll on patients and the health care system. The COVID-19 pandemic has led to a decline in elective surgery volume, partially due to the cancellation of elective surgeries at the start of the pandemic. Methods: We performed a cross-sectional analysis of internet search volume trends for elective surgery terms during the first peak of the COVID-19 pandemic using Google Trends data and compared to a control group of terms representing common urgent and oncologic surgeries. Results: Search volume for elective surgery terms ("knee replacement," "spinal fusion," "hip replacement," "laminectomy," "cataract surgery") revealed a decrease of up to 54% compared to the prepandemic period, a significantly greater decrease than search volume for urgent and oncologic surgery terms ("C-section," "cholecystectomy," "CABG," "colectomy," "lobectomy," and "mastectomy"). Conclusions: The first phase of the COVID-19 pandemic led to sharp declines in search volume for essential elective surgical procedures, which may have been partially due to the cancellation of elective surgeries, but patient factors such as a temporary decline in interest in elective surgery might have also played a role. Attention to internet search volume may be used during future public health crises to monitor public engagement and interest in important health topics, including preventive health measures such as cancer screening.
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RATIONALE AND OBJECTIVES: To ascertain the perceived obstacles that medical students and Interventional Radiology (IR) residents face performing IR research during training and incorporating research into their future careers. MATERIALS AND METHODS: The study was reviewed and exempt from Institutional Review Board review. Participants' attitudes and perceived barriers toward performing IR research, and experience with mentorship in IR were assessed using a 27-item survey sent to all members of the Society of Interventional Radiology Resident, Fellow and Student (SIR-RFS, n = 445), and Medical Student Council (SIR-MSC, n = 267) sections between July and September 2020. Descriptive statistics were computed for all assessed categorical variables. Fisher's exact tests were performed to measure the significance of association between categorical variables. RESULTS: Of the 712 students and residents surveyed, 151 (â¼21%) responded. Of respondents, 100% reported that conducting research is important to advancing the field of IR. The highest ranked factors and obstacles to performing IR research were increased clinical demands (67.9%), lack of time (46.2%), lack of institutional support (41.5%), and lack of research experience (35.8%). Interestingly, those with a mentor were more likely to report an interest in pursuing a career in IR compared to those without a mentor (98.6% vs 41.0%, p < 0.0001). Furthermore, those with a mentor were more likely to report an interest in pursuing IR research compared to those without a mentor (32.5% vs 14.4%, p < 0.0001). CONCLUSION: There are many obstacles to performing IR research. Strong mentorship is an avenue to address these deterrents. The deployment of mentorship programs in IR is needed to ensure trainees can overcome the barriers outlined in this study and successfully pursue research careers in IR.
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Internato e Residência , Estudantes de Medicina , Escolha da Profissão , Humanos , Mentores , Radiologia Intervencionista/educação , Inquéritos e QuestionáriosRESUMO
The COVID-19 pandemic has led to delays in cancer diagnosis, in part due to postponement of cancer screening. We used Google Trends data to assess public attention to cancer screening during the first peak of the COVID-19 pandemic. Search volume for terms related to established cancer screening tests ("colonoscopy," "mammogram," "lung cancer screening," and "pap smear") showed a marked decrease of up to 76% compared to the pre-pandemic period, a significantly greater drop than for search volume for terms denoting common chronic diseases. Maintaining awareness of cancer screening during future public health crises may decrease delays in cancer diagnosis.
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COVID-19 , Detecção Precoce de Câncer , Comportamento de Busca de Informação , Armazenamento e Recuperação da Informação/tendências , Ferramenta de Busca/tendências , Neoplasias da Mama/diagnóstico por imagem , Colonoscopia/tendências , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Masculino , Mamografia/tendências , Ferramenta de Busca/estatística & dados numéricos , Esfregaço Vaginal/tendênciasRESUMO
Paravascular drainage of solutes, including ß-amyloid (Aß), appears to be an important process in brain health and diseases such as Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). However, the major driving force for clearance remains largely unknown. Here we used in vivo two-photon microscopy in awake head-fixed mice to assess the role of spontaneous vasomotion in paravascular clearance. Vasomotion correlated with paravascular clearance of fluorescent dextran from the interstitial fluid. Increasing the amplitude of vasomotion by means of visually evoked vascular responses resulted in increased clearance rates in the visual cortex of awake mice. Evoked vascular reactivity was impaired in mice with CAA, which corresponded to slower clearance rates. Our findings suggest that low-frequency arteriolar oscillations drive drainage of solutes. Targeting naturally occurring vasomotion in patients with CAA or AD may be a promising early therapeutic option for prevention of Aß accumulation in the brain.
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Encéfalo/irrigação sanguínea , Encéfalo/metabolismo , Músculo Liso Vascular/irrigação sanguínea , Músculo Liso Vascular/metabolismo , Vigília/fisiologia , Peptídeos beta-Amiloides/metabolismo , Animais , Capilares/metabolismo , Líquido Extracelular/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Estimulação Luminosa/métodos , Sistema Vasomotor/metabolismo , Córtex Visual/irrigação sanguínea , Córtex Visual/metabolismoRESUMO
Mitochondria contribute to shape intraneuronal Ca2+ signals. Excessive Ca2+ taken up by mitochondria could lead to cell death. Amyloid beta (Aß) causes cytosolic Ca2+ overload, but the effects of Aß on mitochondrial Ca2+ levels in Alzheimer's disease (AD) remain unclear. Using a ratiometric Ca2+ indicator targeted to neuronal mitochondria and intravital multiphoton microscopy, we find increased mitochondrial Ca2+ levels associated with plaque deposition and neuronal death in a transgenic mouse model of cerebral ß-amyloidosis. Naturally secreted soluble Aß applied onto the healthy brain increases Ca2+ concentration in mitochondria, which is prevented by blockage of the mitochondrial calcium uniporter. RNA-sequencing from post-mortem AD human brains shows downregulation in the expression of mitochondrial influx Ca2+ transporter genes, but upregulation in the genes related to mitochondrial Ca2+ efflux pathways, suggesting a counteracting effect to avoid Ca2+ overload. We propose lowering neuronal mitochondrial Ca2+ by inhibiting the mitochondrial Ca2+ uniporter as a novel potential therapeutic target against AD.
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Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Cálcio/metabolismo , Mitocôndrias/metabolismo , Doenças Neurodegenerativas/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Animais , Western Blotting , Células Cultivadas , Citosol/metabolismo , Imuno-Histoquímica , Masculino , Potencial da Membrana Mitocondrial/fisiologia , Camundongos , Camundongos Endogâmicos C57BLRESUMO
The detection of amyloid beta deposits and neurofibrillary tangles, both hallmarks of Alzheimer's disease (AD), is key to understanding the mechanisms underlying these pathologies. Luminescent conjugated oligothiophenes (LCOs) enable fluorescence imaging of these protein aggregates. Using LCOs and multiphoton microscopy, individual tangles and amyloid beta deposits were labeled in vivo and imaged longitudinally in a mouse model of tauopathy and cerebral amyloidosis, respectively. Importantly, LCO HS-84, whose emission falls in the green region of the spectrum, allowed for the first time longitudinal imaging of tangle dynamics following a single intravenous injection. In addition, LCO HS-169, whose emission falls in the red region of the spectrum, successfully labeled amyloid beta deposits, allowing multiplexing with other reporters whose emission falls in the green region of the spectrum. In conclusion, this method can provide a new approach for longitudinal in vivo imaging using multiphoton microscopy of AD pathologies as well as other neurodegenerative diseases associated with protein aggregation in mouse models.