ABSTRACT
Bladder rupture is an uncommon injury that leads to significant morbidity and mortality. Though occurring mostly due to trauma, this life-threatening pathology may also occur spontaneously or after a procedure such as transurethral resection of bladder tumor (TURBT). Computed tomography (CT) cystography is the standard imaging modality for diagnosis. However, this test is unlikely to be ordered in a patient with undifferentiated abdominal pain unless there is specific suspicion for this diagnosis. In our emergency department, a 48 year-old male with history of bladder cancer and TURBT two weeks prior to arrival presented with severe abdominal pain and difficulty urinating for 3 days. Point of care ultrasound (POCUS) revealed an irregularly shaped bladder, likely site of bladder rupture, and large amount of abdominal free fluid with sediment. These findings prompted an expedited diagnostic CT scan with cystography. Emergent exploratory laparotomy ultimately confirmed a small bladder defect with 2.5 L of urinary ascites. The diagnosis of non-traumatic bladder rupture can be overlooked in patients presenting with a peritonitic abdominen. The typically ordered test for such patients is standard CT, which carries a high false-negative rate for bladder rupture. This case highlights the utility of POCUS in facilitating a rapid diagnosis.
ABSTRACT
TAM tyrosine kinases play multiple functional roles, including regulation of the target genes important in homeostatic regulation of cytokine receptors or TLR-mediated signal transduction pathways. In this study, we show that TAM receptors affect adult hippocampal neurogenesis and loss of TAM receptors impairs hippocampal neurogenesis, largely attributed to exaggerated inflammatory responses by microglia characterized by increased MAPK and NF-κB activation and elevated production of proinflammatory cytokines that are detrimental to neuron stem cell proliferation and neuronal differentiation. Injection of LPS causes even more severe inhibition of BrdU incorporation in the Tyro3(-/-)Axl(-/-)Mertk(-/-) triple-knockout (TKO) brains, consistent with the LPS-elicited enhanced expression of proinflammatory mediators, for example, IL-1ß, IL-6, TNF-α, and inducible NO synthase, and this effect is antagonized by coinjection of the anti-inflammatory drug indomethacin in wild-type but not TKO brains. Conditioned medium from TKO microglia cultures inhibits neuron stem cell proliferation and neuronal differentiation. IL-6 knockout in Axl(-/-)Mertk(-/-) double-knockout mice overcomes the inflammatory inhibition of neurogenesis, suggesting that IL-6 is a major downstream neurotoxic mediator under homeostatic regulation by TAM receptors in microglia. Additionally, autonomous trophic function of the TAM receptors on the proliferating neuronal progenitors may also promote progenitor differentiation into immature neurons.
Subject(s)
Dentate Gyrus/pathology , Microglia/physiology , Neurogenesis/physiology , Proto-Oncogene Proteins/physiology , Receptor Protein-Tyrosine Kinases/physiology , Animals , Astrocytes/metabolism , Cells, Cultured , Culture Media, Conditioned/pharmacology , Cytokines/biosynthesis , Cytokines/genetics , DNA Replication , Encephalitis/immunology , Encephalitis/pathology , Gene Expression Regulation , Indomethacin/pharmacology , Interleukin-6/antagonists & inhibitors , Interleukin-6/deficiency , Interleukin-6/genetics , Interleukin-6/physiology , Lipopolysaccharides/toxicity , MAP Kinase Signaling System , Mice , Mice, Inbred C57BL , Mice, Knockout , Microglia/immunology , NF-kappa B/metabolism , Neural Stem Cells/drug effects , Neural Stem Cells/metabolism , Neurogenesis/genetics , Nitric Oxide Synthase Type II/biosynthesis , Nitric Oxide Synthase Type II/genetics , Proto-Oncogene Proteins/deficiency , Proto-Oncogene Proteins/genetics , Receptor Protein-Tyrosine Kinases/deficiency , Receptor Protein-Tyrosine Kinases/genetics , Toll-Like Receptors/immunology , c-Mer Tyrosine Kinase , Axl Receptor Tyrosine KinaseABSTRACT
14-3-3σ plays a regulatory role in epidermal epithelial differentiation and loss of 14-3-3σ leads to increased proliferation and impaired differentiation. A tumor suppressor function for 14-3-3σ has been proposed based on the fact that some epithelial-derived tumors lose 14-3-3σ expression. p63, a p53 family member, is a master regulator of epidermal epithelial proliferation and differentiation and is necessary for the epidermal development. The function of p63 in tumorigenesis is still controversial and poorly defined as multiple isoforms have been found to play either collaborative or opposing roles. By using 'repeated epilation' heterozygous (Er/+) mice containing a dominant-negative 14-3-3σ mutation, the functional relationship of p63 with 14-3-3σ in epidermal proliferation, differentiation and tumorigenesis was investigated. It was found that p63, particularly the ΔNp63α isoform, was strongly expressed in 14-3-3σ-deficient keratinocytes and knockdown of p63 remarkably inhibited proliferation in these cells. To study the functional roles of 14-3-3σ and p63 in epidermal tumorigenesis, we adopted a 7,12-dimethylbenzanthracene/12-O-tetradecanoyl-phorbol-13-acetate (DMBA/TPA) two-stage tumorigenesis procedure to induce formation of skin papillomas and squamous cell carcinomas in Er/+ mice and identified strong p63 expression in resultant tumors. The loss of one allele of p63 caused by the generation of Er/+/p63(+/-) double compound mice decreased the sensitivity to DMBA-/TPA-induced tumorigenesis as compared with Er/+ mice. This study shows that p63 and 14-3-3σ play opposing roles in the development of skin tumors and that the accumulation of p63 is essential for Ras/14-3-3σ mutation-induced papilloma formation and squamous cell carcinoma carcinogenesis.
