State of the field: cellular and exosomal therapeutic approaches in vascular regeneration.

Pathologies of the vasculature including the microvasculature are often complex in nature, leading to loss of physiological homeostatic regulation of patency and adequate perfusion to match tissue metabolic demands. Microvascular dysfunction is a key underlying element in the majority of pathologies of failing organs and tissues. Contributing pathological factors to this dysfunction include oxidative stress, mitochondrial dysfunction, endoplasmic reticular (ER) stress, endothelial dysfunction, loss of angiogenic potential and vascular density, and greater senescence and apoptosis. In many clinical settings, current pharmacologic strategies use a single or narrow targeted approach to address symptoms of pathology rather than a comprehensive and multifaceted approach to address their root cause. To address this, efforts have been heavily focused on cellular therapies and cell-free therapies (e.g., exosomes) that can tackle the multifaceted etiology of vascular and microvascular dysfunction. In this review, we discuss 1) the state of the field in terms of common therapeutic cell population isolation techniques, their unique characteristics, and their advantages and disadvantages, 2) common molecular mechanisms of cell therapies to restore vascularization and/or vascular function, 3) arguments for and against allogeneic versus autologous applications of cell therapies, 4) emerging strategies to optimize and enhance cell therapies through priming and preconditioning, and, finally, 5) emerging strategies to bolster therapeutic effect. Relevant and recent clinical and animal studies using cellular therapies to restore vascular function or pathologic tissue health by way of improved vascularization are highlighted throughout these sections.

Inflammatory blockade prevents injury to the developing pulmonary gas exchange surface in preterm primates.

Perinatal inflammatory stress is associated with early life morbidity and lifelong consequences for pulmonary health. Chorioamnionitis, an inflammatory condition affecting the placenta and fluid surrounding the developing fetus, affects 25 to 40% of preterm births. Severe chorioamnionitis with preterm birth is associated with significantly increased risk of pulmonary disease and secondary infections in childhood, suggesting that fetal inflammation may markedly alter the development of the lung. Here, we used intra-amniotic lipopolysaccharide (LPS) challenge to induce experimental chorioamnionitis in a prenatal rhesus macaque (Macaca mulatta) model that mirrors structural and temporal aspects of human lung development. Inflammatory injury directly disrupted the developing gas exchange surface of the primate lung, with extensive damage to alveolar structure, particularly the close association and coordinated differentiation of alveolar type 1 pneumocytes and specialized alveolar capillary endothelium. Single-cell RNA sequencing analysis defined a multicellular alveolar signaling niche driving alveologenesis that was extensively disrupted by perinatal inflammation, leading to a loss of gas exchange surface and alveolar simplification, with notable resemblance to chronic lung disease in newborns. Blockade of the inflammatory cytokines interleukin-1ß and tumor necrosis factor-α ameliorated LPS-induced inflammatory lung injury by blunting stromal responses to inflammation and modulating innate immune activation in myeloid cells, restoring structural integrity and key signaling networks in the developing alveolus. These data provide new insight into the pathophysiology of developmental lung injury and suggest that modulating inflammation is a promising therapeutic approach to prevent fetal consequences of chorioamnionitis.

Anterior Cruciate Ligament Reconstruction Using Bone-Patellar Tendon-Bone Autograft With Suture Tape Augmentation.

The anterior cruciate ligament (ACL) is the most commonly injured ligament in the knee, with injury usually occurring as a result of multidirectional sports. The incidence of ACL injury has continued to increase, with most patients opting for surgery to improve stability as well as permit a return to sport. Traditional methods of ACL reconstruction can achieve this but are not without their problems, including graft rupture, residual laxity, and donor-site morbidity. There is therefore a requirement for further research into newer, innovative surgical techniques to help improve complication rates. This article describes, with video illustration, ACL reconstruction using a reduced-size bone-patellar tendon-bone autograft with suture tape augmentation. The augmentation acts as a stabilizer during the early stages of graft incorporation while resisting against reinjury during an accelerated recovery. The ability to use a reduced-size graft decreases the donor-site burden, and retention of residual native ACL tissue, when possible, may help with proprioception.

Efforts to Improve Appropriate Trauma Activation for Patients Transferred to a Level 1 Trauma Center From Outside Hospitals.

Trauma centers monitor under- and overtriage rates to comply with American College of Surgeons Committee on Trauma verification requirements. Efforts to maintain acceptable rates are often undertaken as part of quality assurance. The purpose of this project was to improve the institutional undertriage rate by focusing on appropriately triaging patients transferred from outside hospitals (OSHs). Trauma physicians received education and pocket cards outlining injury severity score (ISS) calculation to aid in prospectively estimating ISS for patients transferred from OSHs, and activate the trauma response expected for that score. Under- and overtriage rates before and after the intervention were compared. The postintervention period saw a significant decrease in overall overtriage rate, with simultaneous trend toward lower overall undertriage rate, attributable to the significant reduction in undertriage rate of patients transferred from OSHs. Prospectively estimating ISS to assist in determining trauma activation level shows promise in managing appropriate patient triage. However, questions arose regarding the necessity for full trauma activation for transferred patients, regardless of ISS. It may be necessary to reconsider how patients transferred from OSHs are evaluated. Full trauma activation can be a financial and resource burden, and should not be taken lightly.

Anterior Talofibular Ligament Repair With Suture Tape Augmentation.

The most common injury sustained to the ankle ligaments is a result of inversion of the foot. This mechanism results in injury to the anterior talofibular ligament alone or in conjunction with the calcaneofibular ligament and posterior talofibular ligament. Patients experiencing recurrent ankle sprains despite nonoperative measures often require surgical management. Recent focus has been on augmentation procedures to improve the stability of a lateral ankle ligament repair by protecting it during the healing phase and supporting early mobilization. This article describes, with video illustration, anterior talofibular ligament repair with suture tape augmentation.

Biochemical and Epigenetic Insights into L-2-Hydroxyglutarate, a Potential Therapeutic Target in Renal Cancer.

PURPOSE: Elevation of L-2-hydroxylgutarate (L-2-HG) in renal cell carcinoma (RCC) is due in part to reduced expression of L-2-HG dehydrogenase (L2HGDH). However, the contribution of L-2-HG to renal carcinogenesis and insight into the biochemistry and targets of this small molecule remains to be elucidated. EXPERIMENTAL DESIGN: Genetic and pharmacologic approaches to modulate L-2-HG levels were assessed for effects on in vitro and in vivo phenotypes. Metabolomics was used to dissect the biochemical mechanisms that promote L-2-HG accumulation in RCC cells. Transcriptomic analysis was utilized to identify relevant targets of L-2-HG. Finally, bioinformatic and metabolomic analyses were used to assess the L-2-HG/L2HGDH axis as a function of patient outcome and cancer progression. RESULTS: L2HGDH suppresses both in vitro cell migration and in vivo tumor growth and these effects are mediated by L2HGDH's catalytic activity. Biochemical studies indicate that glutamine is the predominant carbon source for L-2-HG via the activity of malate dehydrogenase 2 (MDH2). Inhibition of the glutamine-MDH2 axis suppresses in vitro phenotypes in an L-2-HG-dependent manner. Moreover, in vivo growth of RCC cells with basal elevation of L-2-HG is suppressed by glutaminase inhibition. Transcriptomic and functional analyses demonstrate that the histone demethylase KDM6A is a target of L-2-HG in RCC. Finally, increased L-2-HG levels, L2HGDH copy loss, and lower L2HGDH expression are associated with tumor progression and/or worsened prognosis in patients with RCC. CONCLUSIONS: Collectively, our studies provide biochemical and mechanistic insight into the biology of this small molecule and provide new opportunities for treating L-2-HG-driven kidney cancers.

Feasibility of Intracorporeal Robotic-Assisted Laparoscopic Appendiceal Interposition for Ureteral Stricture Disease: A Case Report.

OBJECTIVE: To describe a robotic-assisted laparoscopic (RAL) technique for using the appendix to repair ureteral stricture disease MATERIALS AND METHODS: A case of a patient presenting with a 5-cm obliterative right ureteral stricture was reviewed, and surgical technique, complications, and outcomes were reported. RESULTS: Our patient developed a right-sided 5-cm obliterative ureteral stricture secondary to recurrent stone disease and pyelonephritis. He underwent an uncomplicated RAL repair of his stricture with interposition of the appendix between the 2 segments of ureter. Operative time was just over 6 hours, blood loss was minimal, and there were no complications. A 10-month follow-up showed resolution of hydronephrosis with no flank pain. CONCLUSION: We report our initial experience with this procedure and believe that RAL appendiceal interposition for ureteral stricture disease presents an excellent option for reconstruction.

Three- to six-year follow-up of stand-alone BAK cages implanted by a single surgeon.

BACKGROUND CONTEXT: Multiple studies involving the outcomes of anterior interbody cages have been published, but the majority were by authors who designed the cage. No outcome studies with Bagby and Kuslich (BAK) cages implanted by a single-surgeon have either 3 years of follow-up or at least 25 patients. PURPOSE: To determine the 3- to 6-year clinical outcomes, including fusion rate, revision rate, complications and functional status of patients who underwent placement of anterior, stand-alone BAK cages by a single surgeon. STUDY DESIGN: This is a retrospective cohort study of patients who underwent anterior, stand-alone BAK cage placement by a single surgeon with a minimum of 3 years of follow-up. PATIENT SAMPLE: A total of 46 consecutive patients who underwent placement of anterior BAK cages from 1997 to 1999 were the study group. OUTCOME MEASURES: Complications, fusion rate, revision rate, Prolo scores, Oswestry scores, pain scores, patient satisfaction. METHODS: A retrospective review of charts of patients undergoing anterior stand-alone placement of BAK cages over the study period were reviewed. Demographic data were collected, and postoperative radiographs and clinic notes were reviewed. Patients were then contacted to complete a survey to determine Prolo and Oswestry scores, workers' compensation status and general satisfaction with the procedure. Patients were also asked to undergo repeat radiographs of their lumbar spine to determine if the operative levels had fused. RESULTS: Follow-up was available on 33 of 46 patients (72%). At least 10 patients (22%) required revision surgery. Ten patients (22%) had 14 total complications not requiring revision surgery. Seventy percent of patients had a fair or poor outcome as assessed by the Prolo rating system, and 58% of patients had at least "severe disability" according to the Oswestry outcome scale. Fifty percent of patients were satisfied with their surgery. CONCLUSIONS: This single-surgeon series of stand-alone BAK cages demonstrates significantly worse clinical outcomes than has been previously reported. The use of stand-alone BAK cages for degenerative disc disease should be reconsidered given the large number of patients with unacceptable outcomes.

The intriguing encounters of Pavlov and Cushing.

Ivan Petrovich Pavlov and Harvey William Cushing were two of the most prominent neuroscientists of the early 20th century. Their contributions helped advance the understanding of the brain and its disorders, and propelled neuroscience into a new era of research and treatment. Although separated geographically and culturally, Pavlov and Cushing exchanged letters and followed one another's careers from afar. They met only a few times, during international scientific gatherings in the US and abroad. These encounters were captured in journal entries, letters, and photographs, and provide a glimpse into the lives of these two great men and the history of neuroscience at the turn of the last century.

L-2-Hydroxyglutarate: an epigenetic modifier and putative oncometabolite in renal cancer.

UNLABELLED: Through unbiased metabolomics, we identified elevations of the metabolite 2-hydroxyglutarate (2HG) in renal cell carcinoma (RCC). 2HG can inhibit 2-oxoglutaratre (2-OG)-dependent dioxygenases that mediate epigenetic events, including DNA and histone demethylation. 2HG accumulation, specifically the d enantiomer, can result from gain-of-function mutations of isocitrate dehydrogenase (IDH1, IDH2) found in several different tumors. In contrast, kidney tumors demonstrate elevations of the l enantiomer of 2HG (l-2HG). High-2HG tumors demonstrate reduced DNA levels of 5-hydroxymethylcytosine (5hmC), consistent with 2HG-mediated inhibition of ten-eleven translocation (TET) enzymes, which convert 5-methylcytosine (5mC) to 5hmC. l-2HG elevation is mediated in part by reduced expression of l-2HG dehydrogenase (L2HGDH). L2HGDH reconstitution in RCC cells lowers l-2HG and promotes 5hmC accumulation. In addition, L2HGDH expression in RCC cells reduces histone methylation and suppresses in vitro tumor phenotypes. Our report identifies l-2HG as an epigenetic modifier and putative oncometabolite in kidney cancer. SIGNIFICANCE: Here, we report elevations of the putative oncometabolite l-2HG in the most common subtype of kidney cancer and describe a novel mechanism for the regulation of DNA 5hmC levels. Our findings provide new insight into the metabolic basis for the epigenetic landscape of renal cancer.

Coccygectomy for chronic refractory coccygodynia: clinical case series and literature review.

OBJECT: Coccygodynia is disabling pain in the coccyx and is usually provoked by sitting or rising from sitting. The diagnosis can be missed by neurosurgeons likely to encounter the disorder, and surgical treatment for coccygodynia has historically been viewed with caution. The authors conducted a retrospective review of 62 successive coccygectomy surgeries for coccygodynia performed at their institution. METHODS: Sixty-two consecutive cases of coccygectomy for coccygodynia in 61 unique patients were identified from the surgical database; they had been treated between 1997 and 2009. The authors succeeded in contacting 26 patients for follow-up (42.6%). A retrospective chart review was performed, and a telephone questionnaire was administered to these patients. Data collected included cause, pre- and postoperative visual analog scale, a graded outcome measure, and patient satisfaction. The median follow-up time was 37 months (range 2-133 months). RESULTS: The clinical results among the 26 patients with follow-up were as follows: 13 excellent, 9 good, 2 fair, and 2 poor. The overall favorable (excellent and good) outcome after coccygectomy was 84.6%. There were 3 wound infections (11.5%). There were no rectal injuries. An overwhelming majority of patients were satisfied with the procedure. CONCLUSIONS: The authors report the results of their clinical case series, which to date is the largest in North America. The results closely concur with previously published case series from Europe. Coccygectomy for chronic intractable coccygodynia is simple and effective, with a low complication rate. A comprehensive literature review and discussion of coccygectomy is provided.

Thoracic vertebral body exostosis as a cause of myelopathy in a patient with hereditary multiple exostoses.

The posterior thoracic vertebral body appears to be a novel origin for an exostosis causing myelopathy. A patient with hereditary multiple exostoses and myelopathy caused by an exostosis originating from the posterior aspect of the T5 vertebral body was treated with a staged anterior decompression/corpectomy and posterior spinal fusion. The patient had near-complete resolution of his myelopathy immediately after undergoing removal of the exostosis through a right-sided lateral thoracotomy approach. This was a unique origin for an exostosis causing spinal cord compression in a patient with hereditary multiple exostoses. The delivery of the exostosis was performed en bloc during the anterior decompression and corpectomy portion of the surgery. This resulted in the expected favorable outcome.

Efficacy of osteogenic protein-1 in a challenging multilevel fusion model.

STUDY DESIGN: A therapeutic study compared the influence of osteogenic protein-1 to autograft and collagen carrier in multilevel sheep spine fusions. OBJECTIVE: To evaluate the efficacy of osteogenic protein-1 compared to autograft and collagen carrier in achieving fusion in a challenging multilevel lumbar spine ovine model. SUMMARY OF BACKGROUND DATA: Bone morphogenetic proteins can successfully augment spinal fusion. To date, all the preclinical and clinical studies using bone morphogenetic proteins have evaluated single-level fusion. In practice, multiple level fusions are commonly required for various conditions, like spinal deformity. METHODS: Eighteen sheep underwent three-level spine fusion. Six sheep were treated with osteogenic protein-1 and its carrier, autograft, or with the carrier alone. Specimens were analyzed for evidence of fusion by palpation, radiographic and histologic analysis, and biomechanical testing. RESULTS: Manual palpation testing for the presence of fusion showed none of the specimens fused all three levels or fused at the lumbosacral junction. No statistically significant difference was found between the osteogenic protein-1 and autograft groups' fusion rates based on radiographic grading (P = 0.65) or biomechanical testing. Histologic analysis showed no qualitative difference in bone morphology or cellularity of fusion masses when comparing the autograft and osteogenic protein-1 specimens. CONCLUSIONS: No model before this exists that tests the efficacy of bone morphogenic proteins in as challenging an environment. Extrapolation of single-level preclinical and clinical studies with bone morphogenic proteins for use in multilevel fusion requires careful review. Autograft and osteogenic protein-1 had similar rates of fusion. A high rate of nonunion is seen with this multiple level fusion to the sacrum using autograft or osteogenic protein-1. The biologic enhancement with osteogenic protein-1 is not able to overcome this mechanically rigorous model.