Background and Aims Loss-of-function variants in protein tyrosine phosphatase non-receptor type-2 (PTPN2) promote susceptibility to inflammatory bowel diseases (IBD). PTPN2 regulates Janus-kinase (JAK) and signal transducer and activator of transcription (STAT) signaling, while protecting the intestinal epithelium from inflammation-induced barrier disruption. The pan-JAK inhibitor, tofacitinib, is approved to treat ulcerative colitis but its effects on intestinal epithelial cell–macrophage interactions and on barrier properties are unknown. We aimed to determine if tofacitinib can rescue disrupted epithelial-macrophage interaction and barrier function upon loss of PTPN2. Methods Human Caco-2BBe intestinal epithelial cells (IECs) and THP-1 macrophages expressing control or PTPN2-specific shRNA were co-cultured with tofacitinib or vehicle. Transepithelial electrical resistance and 4 kDa fluorescein-dextran flux were measured to assess barrier function. Ptpn2fl/fl and Ptpn2-LysMCre mice, which lack Ptpn2 in myeloid cells, were treated orally with tofacitinib citrate twice daily to assess the in vivo effect on the intestinal epithelial barrier. Colitis was induced via administration of 1.5% DSS in drinking water. Results Tofacitinib corrected compromised barrier function upon PTPN2 loss in macrophages and/or IECs via normalization of (i) tight junction protein expression, (ii) excessive STAT3 signaling, and (iii) IL-6 and IL-22 secretion. In Ptpn2-LysMCre mice, tofacitinib reduced colonic pro-inflammatory macrophages, corrected underlying permeability, and prevented the increased susceptibility to DSS colitis. Conclusions PTPN2 loss in IECs or macrophages compromises IEC-macrophage interactions and reduces epithelial barrier integrity. Both of these events were corrected by tofacitinib in vitro and in vivo. Tofacitinib may have greater therapeutic efficacy in IBD patients harboring PTPN2 loss-of-function mutations.
Hemangioblastomas are rare and benign tumors accounting for less than 2% of all central nervous system (CNS) tumors. The vast majority of hemangioblastomas occur sporadically, whereas a small number of cases, especially in younger patients, are associated with Von Hippel–Lindau (VHL) syndrome. It is thought that loss of tumor suppressor function of the VHL gene results in stabilization of hypoxia-inducible factor alpha with downstream activation of cellular proliferative and angiogenic genes that promote tumorigenesis. VHL-related hemangioblastomas predominantly occur in the cerebellum and spine. Lesions are often diagnosed on contrast-enhanced craniospinal MRIs, and the diagnosis of VHL occurs through assessment for germline VHL mutations. Surgical resection remains the primary treatment modality for symptomatic or worrisome lesions, with excellent local control rates and neurological outcomes. Stereotactic radiotherapy can be employed in patients who are deemed high risk for surgery, have multiple lesions, or have non-resectable lesions. Given the tendency for development of either new or multiple lesions, close radiographic surveillance is often recommended for asymptomatic lesions.
The surgical repair of atlantoaxial instabilities (AAI) presents complex and unique challenges, originating from abnormalities and/or trauma within the junction regions of the C1-C2 atlas-axis, to surgeons. When this region is destabilized, surgical fusion becomes of key importance in order to prevent spinal cord injury. Several techniques can be utilized to provide for the adequate fusion of the atlantoaxial construct. Nevertheless, many individuals have less than ideal rates of fusion, below 35%-40%, which also involves the C2 nerve root being sacrificed. This suboptimal and unavoidable iatrogenic complication results in the elevated probability of complications typically composed of vertebral artery injury. This review is a retrospective analysis of 87 patients from Cedars Sinai Medical Center in Los Angeles, California, who had the C1-C2 surgical fusion procedure performed within the time frame from 2001 to 2008, with a mean follow-up period of three years. These patients had presented with typical AAI symptoms of fatigability, limited mobility, and clumsiness. Diagnosis of C1-C2 instability was documented via radiographic studies, typically utilizing computed tomography (CT) scans or x-rays. All patients had bilateral C1 lateral masses and C2 pedicle screws. In addition, the C1-C2 joint was accessed by retracting the C2 nerve root superiorly and exposing the joint by utilizing a high-speed burr. The cavity that is developed within the joint is packed with local autologous bone from the cephalad resection of the C2 laminae. Fusion of the C1-C2 joint was achieved in all patients and a final follow-up was conducted approximately three years postoperative. Of the 87 patients, two presented with occipital headaches resulting from the C1 screws impinging on the C2 nerve root. The issue was rectified by removing instrumentation in both patients after documenting complete fusion via radiographic studies, with complete resolution of symptoms. No vertebral artery or spinal cord injuries were reported as a result of the minor complication. Overall, we aim to describe a safe and reliable alternative technique to fuse C1-C2 instability by focusing on intra-articular arthrodesis complementing instrumentation fixation. This methodology is advantageous from a biomechanical standpoint secondary to axial loading, as well as the large surface area available for arthrodesis. Additionally, this technique does not involve the resection of the C2 nerve root, resulting in low risk for vertebral artery or spinal cord injury.
Traumatic brain injury (TBI) also known as intracranial injury is the result of a lesion within the brain due to an external force. Common forms of TBI result from falls, violence, and/or vehicle crashes; the classification of this pathology is dependent on the severity of the lesion as well as the mechanism of trauma to the head. One of the most common onsets of traumatic brain injuries result from mild to severe lesions to the white matter tracts of the brain called diffuse axonal injury (DAI); however, additional forms of TBI's can present in non-penetrating forms. Penetrating forms of TBI's such as trauma to the head via a foreign object do also contribute to the many millions of TBI cases per year, but we will not discuss these traumatic injuries as in depth within this chapter. The onset of diffuse axonal injury will vary on a per-patient basis from mild to severe, based on a standardized neurological examination rated on the Glasgow Coma Scale (GCS), which indicates the severity of brain damage present. While there is a spectrum of severity for DAI patients, a concussion is typically observed within a larger majority of patients in addition to other overwhelming trauma.
Traumatic brain injury (TBI) is the result of an external force acting upon the head, causing damage to the brain. The severity of injury, mechanism by which the injury occurs, and the frequency of the high-force impact all play a role in the determination of a TBI. TBI describes a wide range of traumatic pathologies which is comprised of damage done to a multitude of cranial central nervous system components. TBI patients typically present with a series of symptoms are correlated with the presence of an intracranial injury, such as physical/cognitive difficulties. A major concern associated with intracranial injuries is the management of intracranial pressure (ICP), a resulting factor of a TBI which facilitates into intracranial hematoma and/or cerebral edema. These conditions have adverse effects on one's brain, and the immediate management and relief of intracranial pressure are crucial in avoiding hydrocephalus and brain herniation, conditions which lead to sensory loss and even death. In this chapter, we will begin by thoroughly understanding what a TBI is, its clinical presentation, and the first-tier examination to determine severity. Then, we will progress into the anatomy of the brain, followed by a thorough investigation into intracranial pressure management strategies and prognosis.
Polyostotic fibrous dysplasia (FD) is a rare pathology characterized by the abnormal and gradual replacement of normal bone (calcium hydroxylapatite of osteoid matrix) with fibrous connective tissue. Aneurysmal bone cyst (ABC) is a tumor-like benign lesion with blood-filled cavities that can affect virtually any bone in the body. We report on a 20-year-old male presenting with an extremely rare pathology of FD with ABC formation of the skull, fourth rib and humerus. Our case report represents a novel literary addition to rare FD with ABC pathologies. Optimal diagnosis of this rare pathology can be achieved by a full body evaluation for clinical and radiographic FD with or without ABC, and optimal treatment for this rare pathology is the maximum surgical excision of the tumor and/or soft tissue.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.