R-spondins (RSPOs) are secreted cysteine-rich glycoproteins that belong to a superfamily of thrombospondin type 1 repeat-containing proteins. RSPOs together with WNT proteins potentiate canonical ...WNT/β-catenin signaling activity. Over the last several years, the understanding of the regulatory mechanisms and functional roles of RSPOs in many biological contexts has increased. Particularly, because a leucine-rich repeat containing G protein-coupled receptor 5 (LGR5), a stem cell marker originally identified as a marker for intestinal stem cells, and two closely related proteins, LGR4 and LGR6, were identified as cognate receptors for RSPOs, significant research progress has been made in understanding the functional roles of RSPO/LGR signaling in stem cell biology. Given the crucial roles of canonical WNT signaling in self-renewal and differentiation of various types of stem cells, examination of RSPO function and underlying mechanism in these stem cells has provided new insight into the regulatory roles of WNT signaling in stem cell behavior. In this review, we summarize and discuss recent advances in the understanding of the signaling mechanism and roles of RSPOs in different stem cell contexts.
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The lung has a vital function in gas exchange between the blood and the external atmosphere. It also has a critical role in the immune defense against external pathogens and environmental factors. ...While the lung is classified as a relatively quiescent organ with little homeostatic turnover, it shows robust regenerative capacity in response to injury, mediated by the resident stem/progenitor cells. During regeneration, regionally distinct epithelial cell populations with specific functions are generated from several different types of stem/progenitor cells localized within four histologically distinguished regions: trachea, bronchi, bronchioles, and alveoli. WNT signaling is one of the key signaling pathways involved in regulating many types of stem/progenitor cells in various organs. In addition to its developmental role in the embryonic and fetal lung, WNT signaling is critical for lung homeostasis and regeneration. In this minireview, we summarize and discuss recent advances in the understanding of the role of WNT signaling in lung regeneration with an emphasis on stem/progenitor cells.
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In this prospective study the authors' objective was to evaluate the accuracy of deep brain stimulation (DBS) electrode placement using image guidance for direct anatomical targeting with ...intraoperative CT.
Preoperative 3-T MR images were merged with intraoperative CT images for planning. Electrode targets were anatomical, based on the MR images. A skull-mounted NexFrame system was used for electrode placement, and all procedures were performed under general anesthesia. After electrode placement, intraoperative CT images were merged with trajectory planning images to calculate accuracy. Accuracy was assessed by both vector error and deviation off the planned trajectory.
Sixty patients (33 with Parkinson disease, 26 with essential tremor, and 1 with dystonia) underwent the procedure. Patient's mean age was 64 ± 9.5 years. Over an 18-month period, 119 electrodes were placed (all bilateral, except one). Electrode implant locations were the ventral intermediate nucleus (VIM), globus pallidus internus (GPI), and subthalamic nucleus (STN) in 25, 23, and 12 patients, respectively. Target accuracy measurements were as follows: mean vector error 1.59 ± 1.11 mm and mean deviation off trajectory 1.24 ± 0.87 mm. There was no statistically significant difference between the accuracy of left and right brain electrodes. There was a statistically significant (negative) correlation between the distance of the closest approach of the electrode trajectory to the ventricular wall of the lateral ventricle and vector error (r(2) = -0.339, p < 0.05, n = 76), and the deviation from the planned trajectory (r(2) = -0.325, p < 0.05, n = 77). Furthermore, when the distance from the electrode trajectory and the ventricular wall was < 4 mm, the correlation of the ventricular distance to the deviation from the planned trajectory was stronger (r(2) = -0.419, p = 0.05, n = 19). Electrodes placed in the GPI were significantly more accurate than those placed in the VIM (p < 0.05). Only 1 of 119 electrodes required intraoperative replacement due to a vector error > 3 mm. In this series there was one infection and no intraparenchymal hemorrhages.
Placement of DBS electrodes using an intraoperative CT scanner and the NexFrame achieves an accuracy that is at least comparable to other methods.
OBJECT Trigeminal neuralgia (TN) occurs and recurs in the absence of neurovascular compression (NVC). While microvascular decompression (MVD) is the most effective treatment for TN, it is not ...possible when NVC is not present. Therefore, the authors sought to evaluate the safety, efficacy, and durability of internal neurolysis (IN), or "nerve combing," as a treatment for TN without NVC. METHODS This was a retrospective review of all cases of Type 1 TN involving all patients 18 years of age or older who underwent evaluation (and surgery when appropriate) at Oregon Health & Science University between July 2006 and February 2013. Chart reviews and telephone interviews were conducted to assess patient outcomes. Pain intensity was evaluated with the Barrow Neurological Institute (BNI) Pain Intensity scale, and the Brief Pain Inventory-Facial (BPI-Facial) was used to assess general and face-specific activity. Pain-free survival and durability of successful pain relief (BNI pain scores of 1 or 2) were statistically evaluated with Kaplan-Meier analysis. Prognostic factors were identified and analyzed using Cox proportional hazards regression. RESULTS A total of 177 patients with Type 1 TN were identified. A subgroup of 27 was found to have no NVC on high-resolution MRI/MR angiography or at surgery. These patients were significantly younger than patients with classic Type 1 TN. Long-term follow-up was available for 26 of 27 patients, and 23 responded to the telephone survey. The median follow-up duration was 43.4 months. Immediate postoperative results were comparable to MVD, with 85% of patients pain free and 96% of patients with successful pain relief. At 1 year and 5 years, the rate of pain-free survival was 58% and 47%, respectively. Successful pain relief at those intervals was maintained in 77% and 72% of patients. Almost all patients experienced some degree of numbness or hypesthesia (96%), but in patients with successful pain relief, this numbness did not significantly impact their quality of life. There was 1 patient with a CSF leak and 1 patient with anesthesia dolorosa. Previous treatment for TN was identified as a poor prognostic factor for successful outcome. CONCLUSIONS This is the first report of IN with meaningful outcomes data. This study demonstrated that IN is a safe, effective, and durable treatment for TN in the absence of NVC. Pain-free outcomes with IN appeared to be more durable than radiofrequency gangliolysis, and IN appears to be more effective than stereotactic radiosurgery, 2 alternatives to posterior fossa exploration in cases of TN without NVC. Given the younger age distribution of patients in this group, consideration should be given to performing IN as an initial treatment. Accrual of further outcomes data is warranted.
Pain surgery is one of the historic foundations of neurological surgery. The authors present a review of contemporary concepts in surgical pain management, with reference to past successes and ...failures, what has been learned as a subspecialty over the past 50 years, as well as a vision for current and future practice. This subspecialty confronts problems of cancer pain, nociceptive pain, and neuropathic pain. For noncancer pain, ablative procedures such as dorsal root entry zone lesions and rhizolysis for trigeminal neuralgia (TN) should continue to be practiced. Other procedures, such as medial thalamotomy, have not been proven effective and require continued study. Dorsal rhizotomy, dorsal root ganglionectomy, and neurotomy should probably be abandoned. For cancer pain, cordotomy is an important and underutilized method for pain control. Intrathecal opiate administration via an implantable system remains an important option for cancer pain management. While there are encouraging results in small case series, cingulotomy, hypophysectomy, and mesencephalotomy deserve further detailed analysis. Electrical neuromodulation is a rapidly changing discipline, and new methods such as high-frequency spinal cord stimulation (SCS), burst SCS, and dorsal root ganglion stimulation may or may not prove to be more effective than conventional SCS. Despite a history of failure, deep brain stimulation for pain may yet prove to be an effective therapy for specific pain conditions. Peripheral nerve stimulation for conditions such as occipital neuralgia and trigeminal neuropathic pain remains an option, although the quality of outcomes data is a challenge to these applications. Based on the evidence, motor cortex stimulation should be abandoned. TN is a mainstay of the surgical treatment of pain, particularly as new evidence and insights into TN emerge. Pain surgery will continue to build on this heritage, and restorative procedures will likely find a role in the armamentarium. The challenge for the future will be to acquire higher-level evidence to support the practice of surgical pain management.
When used to treat craniofacial pain, CT-guided trigeminal tractotomy-nucleotomy (TR-NC) is usually performed with local anesthesia. Unfortunately, local anesthesia is insufficient for patients with ...such severe pain that they cannot tolerate the required head positioning while awake. This study aimed to contextualize previous findings associated with TR-NC performed under general anesthesia. The authors examined clinical and operative factors that could impact postoperative pain outcomes.
This is a retrospective single-institution cohort study of patients who underwent a percutaneous CT-guided TR-NC under general anesthesia at a single institution between 2012 and 2019. Outcome data were analyzed.
Twenty-five patients underwent CT-guided TR-NC procedures under general anesthesia; 23 met the inclusion criteria and underwent a total of 31 procedures. The procedure success rate was 74% (23/31). Approximately 50% and 40% of procedures provided pain relief for at least 6 and 12 months, respectively. The median duration of pain relief was 153 days. Adverse events, all minor and transient, occurred following 6/31 (19%) of procedures. Patients with a body mass index > 25 were less likely to experience a successful TR-NC (p = 0.045). Higher electrode ablation temperatures (p = 0.033) and more medial entry trajectories relative to the midsagittal plane (p = 0.029) characterized successful procedures.
These results suggest that CT-guided TR-NC performed under general anesthesia is safe and effective. Postoperative outcomes were found to be associated with a number of clinical and operative factors. Such associations should be further explored and evaluated in the context of future, better-powered analyses.
Vascular compression of the trigeminal nerve is the most common factor associated with the etiology of trigeminal neuralgia (TN). Microvascular decompression (MVD) has proven to be the most ...successful and durable surgical approach for this disorder. However, not all patients with TN manifest unequivocal neurovascular compression (NVC). Furthermore, over time patients with an initially successful MVD manifest a relentless rate of TN recurrence.
The authors performed a retrospective review of cases of TN Type 1 (TN1) or Type 2 (TN2) involving patients 18 years or older who underwent evaluation (and surgery when indicated) at Oregon Health & Science University between July 2006 and February 2013. Surgical and imaging findings were correlated.
The review identified a total of 257 patients with TN (219 with TN1 and 38 with TN2) who underwent high-resolution MRI and MR angiography with 3D reconstruction of combined images using OsiriX. Imaging data revealed that the occurrence of TN1 and TN2 without NVC was 28.8% and 18.4%, respectively. A subgroup of 184 patients underwent surgical exploration. Imaging findings were highly correlated with surgical findings, with a sensitivity of 96% for TN1 and TN2 and a specificity of 90% for TN1 and 66% for TN2.
Magnetic resonance imaging detects NVC with a high degree of sensitivity. However, despite a diagnosis of TN1 or TN2, a significant number of patients have no NVC. Trigeminal neuralgia clearly occurs and recurs in the absence of NVC.
•Lung mesenchymal cells are highly heterogeneous.•Mesenchymal cells are key to lung repair and fibrosis.•Collagen-producing mesenchymal cells are drivers of pulmonary fibrosis.
Mesenchymal cells in ...the lung are crucial during development, but also contribute to the pathogenesis of fibrotic disorders, including idiopathic pulmonary fibrosis (IPF), the most common and deadly form of fibrotic interstitial lung diseases. Originally thought to behave as supporting cells for the lung epithelium and endothelium with a singular function of producing basement membrane, mesenchymal cells encompass a variety of cell types, including resident fibroblasts, lipofibroblasts, myofibroblasts, smooth muscle cells, and pericytes, which all occupy different anatomic locations and exhibit diverse homeostatic functions in the lung. During injury, each of these subtypes demonstrate remarkable plasticity and undergo varying capacity to proliferate and differentiate into activated myofibroblasts. Therefore, these cells secrete high levels of extracellular matrix (ECM) proteins and inflammatory cytokines, which contribute to tissue repair, or in pathologic situations, scarring and fibrosis. Whereas epithelial damage is considered the initial trigger that leads to lung injury, lung mesenchymal cells are recognized as the ultimate effector of fibrosis and attempts to better understand the different functions and actions of each mesenchymal cell subtype will lead to a better understanding of why fibrosis develops and how to better target it for future therapy. This review summarizes current findings related to various lung mesenchymal cells as well as signaling pathways, and their contribution to the pathogenesis of pulmonary fibrosis.
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Pain relief following microvascular decompression (MVD) for trigeminal neuralgia (TN) may be related to pain type, degree of neurovascular conflict, arterial compression, and location of compression. ...The objective of this study was to construct a predictive pain-free scoring system based on clinical and radiographic factors that can be used to preoperatively prognosticate long-term outcomes for TN patients following surgical intervention (MVD or internal neurolysis IN). It was hypothesized that contributing factors would include pain type, presence of an artery or vein, neurovascular conflict severity, and compression location (root entry zone).
At the authors' institution 275 patients with type 1 or type 2 TN (TN1 or TN2) underwent MVD or IN following preoperative high-resolution brain MRI studies. Outcome data were obtained retrospectively by chart review and/or phone follow-up. Characteristics of neurovascular conflict were obtained from preoperative MRI studies. Factors that resulted in a probability value of < 0.05 on univariate logistic regression analyses were entered into a multivariate Cox regression analysis in a backward stepwise fashion. For the multivariate analysis, significance at the 0.15 level was used. A prognostic system was then devised with 4 possible scores (0, 1, 2, or 3) and pain-free survival analyses conducted.
Univariate predictors of pain-free survival were pain type (p = 0.013), presence of any vessel (p = 0.042), and neurovascular compression severity (p = 0.038). Scores of 0, 1, 2, and 3 were found to be significantly different in regard to pain-free survival (log rank, p = 0.005). At 5 and 10 years there were 36%, 43%, 61%, and 69%, and 36%, 43%, 56%, and 67% pain-free survival rates in groups 0, 1, 2, and 3, respectively. While TN2 patients had worse outcomes regardless of score, a subgroup analysis of TN1 patients with higher neurovascular conflict (score of 3) had significantly better outcomes than TN1 patients without severe neurovascular conflict (score of 1) (log rank, p = 0.005). Regardless of pain type, those patients with severe neurovascular conflict were more likely to have arterial compression (99%) compared to those with low neurovascular conflict (p < 0.001).
Pain-free survival was predicted by a scoring system based on preoperative clinical and radiographic findings. Higher scores predicted significantly better pain relief than lower scores. TN1 patients with severe neurovascular conflict had the best long-term pain-free outcome.
The lungs have a remarkable ability to regenerate damaged tissues caused by acute injury. Many lung diseases, especially chronic lung diseases, are associated with a reduced or disrupted regeneration ...potential of the lungs. Therefore, understanding the underlying mechanisms of the regenerative capacity of the lungs offers the potential to identify novel therapeutic targets for these diseases. R-spondin2, a co-activator of WNT/β-catenin signaling, plays an important role in embryonic murine lung development. However, the role of
in adult lung homeostasis and regeneration remains unknown. The aim of this study is to determine
function in distal lung stem/progenitor cells and adult lung regeneration. In this study, we found that robust
expression was detected in different epithelial cells, including airway club cells and alveolar type 2 (AT2) cells in the adult lungs. However,
expression significantly decreased during the first week after naphthalene-induced airway injury and was restored by day 14 post-injury. In ex vivo 3D organoid culture, recombinant RSPO2 promoted the colony formation and differentiation of both club and AT2 cells through the activation of canonical WNT signaling. In contrast,
ablation in club and AT2 cells significantly disrupted their expansion capacity in the ex vivo 3D organoid culture. Furthermore, mice lacking
showed significant defects in airway regeneration after naphthalene-induced injury. Our results strongly suggest that RSPO2 plays a key role in the adult lung epithelial stem/progenitor cells during homeostasis and regeneration, and therefore, it may be a potential therapeutic target for chronic lung diseases with reduced regenerative capability.
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