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Infected abdominal aortic aneurysms (AAAs) make up a small minority of AAAs yet are characterized by a high fatality rate, largely attributed to their increased risk of aneurysm rupture. This case details a rare presentation of a 56-year-old man that developed Proteus mirabilis bacteremia secondary to a perineal abscess and subsequently experienced a 3 cm growth of his previously stable AAA over an 8 day period. This case underscores the importance of maintaining a heightened suspicion for infected aortic aneurysms in sick patients and highlights the critical role of surgical management in achieving source control.
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In the list of top 10 causes of death worldwide in 2019, stroke ranks number two, with a recent uptick in incidence involving younger adults. While common risk factors like tobacco use, hypertension, diabetes, and atrial fibrillation have been well studied, recent reports have also linked paroxysmal supraventricular tachycardia (PSVT) with strokes. This case highlights a rare presentation of a 25-year-old female who suffered an ischemic stroke shortly after undergoing chemical cardioversion for sustained SVT. To date, there are only three documented cases reporting an ischemic event following shortly after cardioversion of SVT, all confined to the pediatric population. Currently, there is limited evidence to guide the management of these complex patients. This case presents a valuable discussion regarding the futility or efficacy of imaging prior to cardioversion of SVT as well as furthers the conversation behind the theorized mechanisms linking PSVT and strokes.
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Nuclear factor-erythroid 2-related factor 2 (Nrf2), a transcription factor, controls the expression of more than 1000 genes that can be clustered into different categories with distinct functions ranging from redox balance and metabolism to protein quality control in the cell. The biological consequence of Nrf2 activation can be either protective or detrimental in a context-dependent manner. In the cardiovascular system, most studies have focused on the protective properties of Nrf2, mainly as a key transcription factor of antioxidant defense. However, emerging evidence revealed an unexpected role of Nrf2 in mediating cardiovascular maladaptive remodeling and dysfunction in certain disease settings. Herein we review the role of Nrf2 in cardiovascular diseases with a focus on vascular disease. We discuss the negative effect of Nrf2 on the vasculature as well as the potential underlying mechanisms. We also discuss the clinical relevance of targeting Nrf2 pathways for the treatment of cardiovascular and other diseases.
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Antioxidantes , Factor 2 Relacionado con NF-E2 , Antioxidantes/metabolismo , Células Cultivadas , Miocitos del Músculo Liso/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Transducción de Señal/fisiologíaRESUMEN
BACKGROUND: Management of bladder cancer (BLCA) has not changed significantly in the past few decades, with platinum agent chemotherapy being used in most cases. Chemotherapy reduces tumor recurrence after resection, but debilitating toxicities render a large percentage of patients ineligible. Recently approved immunotherapy can improve outcomes in only a third of metastatic BLCA patients. Therefore, more options for therapy are needed. In this study, we explored the efficacy of PARP inhibitors (PARPi) as single agents or as combinations with platinum therapy. METHODS: We treated BLCA cells with PARPi (olaparib, niraparib, rucaparib, veliparib, or talazoparib) alone or as the combination of cisplatin with PARPi. We then measured their survival, proliferation, apoptosis, as well as their ability to form colonies. BLCA xenografts in male SCID mice were treated similarly, followed by the assessment of their growth, proliferation, and apoptosis. RESULTS: PARPi niraparib and talazoparib were effective in reducing BLCA cell survival as single agents. Combinations of Cisplatin with talazoparib and niraparib effectively reduced the survival of BLCA cells, while veliparib was not effective even at high concentrations. In vivo, the combinations of cisplatin with niraparib, rucaparib, or talazoparib reduced BLCA xenograft growth significantly. CONCLUSIONS: We provide evidence that PARPi can be effective against BLCA as single agents or as combinatorial therapy with cisplatin.
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Inhibidores de Poli(ADP-Ribosa) Polimerasas , Neoplasias de la Vejiga Urinaria , Animales , Supervivencia Celular , Cisplatino/farmacología , Cisplatino/uso terapéutico , Humanos , Masculino , Ratones , Ratones SCID , Recurrencia Local de Neoplasia/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológicoRESUMEN
The bacterial pathogen Staphylococcus aureus is capable of infecting a broad spectrum of host tissues, in part due to flexibility of metabolic programs. S. aureus, like all organisms, requires essential biosynthetic intermediates to synthesize macromolecules. We therefore sought to determine the metabolic pathways contributing to synthesis of essential precursors during invasive S. aureus infection. We focused specifically on staphylococcal infection of bone, one of the most common sites of invasive S. aureus infection and a unique environment characterized by dynamic substrate accessibility, infection-induced hypoxia, and a metabolic profile skewed toward aerobic glycolysis. Using a murine model of osteomyelitis, we examined survival of S. aureus mutants deficient in central metabolic pathways, including glycolysis, gluconeogenesis, the tricarboxylic acid (TCA) cycle, and amino acid synthesis/catabolism. Despite the high glycolytic demand of skeletal cells, we discovered that S. aureus requires glycolysis for survival in bone. Furthermore, the TCA cycle is dispensable for survival during osteomyelitis, and S. aureus instead has a critical need for anaplerosis. Bacterial synthesis of aspartate in particular is absolutely essential for staphylococcal survival in bone, despite the presence of an aspartate transporter, which we identified as GltT and confirmed biochemically. This dependence on endogenous aspartate synthesis derives from the presence of excess glutamate in infected tissue, which inhibits aspartate acquisition by S. aureus Together, these data elucidate the metabolic pathways required for staphylococcal infection within bone and demonstrate that the host nutrient milieu can determine essentiality of bacterial nutrient biosynthesis pathways despite the presence of dedicated transporters.
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Ácido Aspártico/biosíntesis , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/metabolismo , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , Ratones , Ratones Endogámicos C57BL , Nutrientes/metabolismo , Osteomielitis/metabolismo , Osteomielitis/microbiología , Infecciones Estafilocócicas/metabolismo , Staphylococcus aureus/genéticaRESUMEN
Staphylococcus aureus is able to infect virtually all organ systems and is a frequently isolated etiologic agent of osteomyelitis, a common and debilitating invasive infection of bone. Treatment of osteomyelitis requires invasive surgical procedures and prolonged antibiotic therapy, yet is frequently unsuccessful due to extensive pathogen-induced bone damage that can limit antibiotic penetration and immune cell influx to the infectious focus. We previously established that S. aureus triggers profound alterations in bone remodeling in a murine model of osteomyelitis, in part through the production of osteolytic toxins. However, staphylococcal strains lacking osteolytic toxins still incite significant bone destruction, suggesting that host immune responses are also major drivers of pathologic bone remodeling during osteomyelitis. The objective of this study was to identify host immune pathways that contribute to antibacterial immunity during S. aureus osteomyelitis, and to define how these immune responses alter bone homeostasis and contribute to bone destruction. We specifically focused on the interleukin-1 receptor (IL-1R) and downstream adapter protein MyD88 given the prominent role of this signaling pathway in both antibacterial immunity and osteo-immunologic crosstalk. We discovered that while IL-1R signaling is necessary for local control of bacterial replication during osteomyelitis, it also contributes to bone loss during infection. Mechanistically, we demonstrate that S. aureus enhances osteoclastogenesis of myeloid precursors in vitro, and increases the abundance of osteoclasts residing on bone surfaces in vivo. This enhanced osteoclast abundance translates to trabecular bone loss, and is dependent on intact IL-1R signaling. Collectively, these data define IL-1R signaling as a critical component of the host response to S. aureus osteomyelitis, but also demonstrate that IL-1R-dependent immune responses trigger collateral bone damage through activation of osteoclast-mediated bone resorption.
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Resorción Ósea/inmunología , Factor 88 de Diferenciación Mieloide/fisiología , Osteoclastos/inmunología , Osteomielitis/inmunología , Receptores Tipo I de Interleucina-1/fisiología , Infecciones Estafilocócicas/inmunología , Staphylococcus aureus/inmunología , Animales , Resorción Ósea/metabolismo , Resorción Ósea/microbiología , Diferenciación Celular , Células Cultivadas , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Osteoclastos/metabolismo , Osteoclastos/microbiología , Osteomielitis/metabolismo , Osteomielitis/microbiología , Transducción de Señal , Infecciones Estafilocócicas/metabolismo , Infecciones Estafilocócicas/microbiologíaRESUMEN
Objective: We present a technical protocol for rigorous assessment of patient-reported outcomes and psychophysical testing relevant to lumbar sympathetic blocks for the treatment of postamputation pain (PAP). This description is intended to inform future prospective investigation. Design: Series of four participants from a blinded randomized sham-controlled trial. Setting: Tertiary, urban, academic pain medicine center. Subjects: Four participants with a single lower limb amputation and associated chronic PAP. Methods: Participants were randomized to receive a lumbar sympathetic block with 0.25% bupivacaine or sham needle placement. Patient-rated outcome measures included the numerical rating scale (NRS) for pain, the McGill Pain Questionnaire-Short Form, Center for Epidemiological Studies Depression Scale, Pain and Anxiety Symptoms Scale-short version, and Pain Disability Index (PDI). Psychophysical and biometric testing was also performed, which included vibration sensation testing, pinprick sensation testing, brush sensation testing, Von Frey repeated weighted pinprick sensation, and thermal quantitative sensory testing. Results: In the four described cases, treatment of PAP with a single lumbar sympathetic block but not sham intervention resulted in reduction of both residual limb pain and phantom limb pain as well as perceived disability on the PDI at three-month follow-up. Conclusions: An appropriately powered randomized controlled study using this methodology may not only aid in determining the possible clinical efficacy of lumbar sympathetic block in PAP, but could also improve our understanding of underlying pathophysiologic mechanisms of PAP.
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Amputación Quirúrgica , Bupivacaína/uso terapéutico , Dolor de la Región Lumbar/terapia , Miembro Fantasma/terapia , Amputación Quirúrgica/métodos , Bloqueo Nervioso Autónomo/métodos , Femenino , Humanos , Dolor de la Región Lumbar/diagnóstico , Masculino , Dimensión del Dolor/métodos , Miembro Fantasma/diagnóstico , Estudios Prospectivos , Resultado del TratamientoRESUMEN
Staphylococcus aureus osteomyelitis is a common and debilitating invasive infection of bone. Treatment of osteomyelitis is confounded by widespread antimicrobial resistance and the propensity of bacteria to trigger pathological changes in bone remodeling that limit antimicrobial penetration to the infectious focus. Adjunctive therapies that limit pathogen-induced bone destruction could therefore limit morbidity and enhance traditional antimicrobial therapies. In this study, we evaluate the efficacy of the U.S. Food and Drug Administration-approved, nonsteroidal anti-inflammatory (NSAID) compound diflunisal in limiting S. aureus cytotoxicity toward skeletal cells and in preventing bone destruction during staphylococcal osteomyelitis. Diflunisal is known to inhibit S. aureus virulence factor production by the accessory gene regulator (agr) locus, and we have previously demonstrated that the Agr system plays a substantial role in pathological bone remodeling during staphylococcal osteomyelitis. Consistent with these observations, we find that diflunisal potently inhibits osteoblast cytotoxicity caused by S. aureus secreted toxins independently of effects on bacterial growth. Compared to commonly used NSAIDs, diflunisal is uniquely potent in the inhibition of skeletal cell death in vitro Moreover, local delivery of diflunisal by means of a drug-eluting, bioresorbable foam significantly limits bone destruction during S. aureus osteomyelitis in vivo Collectively, these data demonstrate that diflunisal potently inhibits skeletal cell death and bone destruction associated with S. aureus infection and may therefore be a useful adjunctive therapy for osteomyelitis.