Comparative Quantification of Diffusion Tensor Tractography Using Automated Whole Brain MRI Tractography for Intracranial Tumor Surgery: Technical Note.

With the improvement of diffusion tensor imaging (DTI) and algorithms, diffusion tensor tractography (DTT) may provide quantitative information on white matter tracts (WMT) that may help quantitatively assess WMT integrity and distortion, which may help with correlations of neurologic function or prognosis. This manuscript is the first to describe a technical method for quantitative analysis of clinically relevant white matter tracts during intracranial tumor surgery. The authors quantitatively analyzed relevant proximal WMT, pre and postoperatively, in a patient undergoing cranial surgery using DTT software to evaluate fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AD), geodesic anisotropy (GA), tract count, and tract volume. A method was then established to formulate quantitative comparisons between pre and postoperative WMT. Quantitative assessment of the corticospinal and optic radiation tracts revealed significant increases in the FA, GA, and tract count in the corticospinal and optic radiations postoperatively (p<.0001). MD, RD, and AD were found to be significantly diminished postoperatively (p<.0001). The postoperative optic radiations showed diminished volume as a result of damage to the tract pathway. To conclude, the utilization of white matter tractography provides a technical advancement that allows for quantitative comparative assessments of white matter tracts, which could assess the degree of brain changes following tumor surgery.

Surgical Considerations in Endoscopic Pituitary Dissection for the Neurosurgeon.

Many surgical considerations exist for an endoscopic approach for pituitary surgery for a neurosurgeon. The neurosurgical approach to endoscopic pituitary dissection requires proper surgical planning and identification of relevant anatomic structures. With the introduction of endoscopic transsphenoidal pituitary surgery, better visualization and more intricate surgical resections are achieved. Whether performing this surgery solo or with an otolaryngologist, the neurosurgeon must consider multiple aspects for this surgical approach. This article focuses on the surgical considerations involving the anatomic regions of the sphenoid sinus and sellar region for endoscopic pituitary dissections.

Meningiomas in the elderly.

Meningiomas are benign tumors that arise from the meningo-epithelial cells of the arachnoid dura and account for approximately one-third of all adult intracranial tumors. With the evolution of diagnostic imaging and the average life span increasing, meningiomas are being detected more frequently in an older population. In the elderly population, defined by patients aged 60 years or older, meningiomas are the most incidentally detected benign primary brain tumor. As a patient ages, the rate of growth of the meningioma decreases, while comorbidities increase, making the elderly population a unique group when it comes to decision-making for treatment. Treatment options for intracranial meningiomas in the elderly include surgery, radiosurgery, or observation. Although age may have some part in treatment considerations, comorbidities, overall state of health, and tumor characteristics play a more significant role in patient outcome. This chapter will investigate the incidence, evaluation, treatment, and outcomes of intracranial meningiomas in the elderly population.

Comparative Cost Analysis of Endoscopic versus Microscopic Endonasal Transsphenoidal Surgery for Pituitary Adenomas.

Objective This study presents a comparative analysis of cost efficacy between the microscopic and endoscopic transsphenoidal approaches, evaluating neurological outcome, extent of resection (EOR), and inpatient hospital costs. Design This study was a retrospective chart review. Setting This study was conducted at a tertiary care center. Participants The study group consisted of 68 patients with transsphenoidal surgeries between January 2007 and January 2014. Main Outcome Measures Two-sample t -tests and Pearson's chi-square test evaluated inpatient costs, quality-adjusted life years (QALYs), volumetric EOR, and neurological outcomes. Results Total inpatient costs per patient was $22,853 in the microscopic group and less ($19,736) in the endoscopic group ( p = 0.049). Operating room costs were $5,974 in the microscopic group and lower in the endoscopic group ($5,045; p = 0.038). Operative time was 203.6 minutes in the microscopic group and 166.3 minutes in the endoscopic group ( p = 0.032). The QALY score, length of hospital stay, and postoperative outcomes were found to be similar between the two cohorts. Multivariate linear regression modeling suggested that length of stay ( p < 0.001) and operative time ( p = 0.008) were important factors that influenced total inpatient costs following transsphenoidal surgery. Conclusion This study shows that transsphenoidal surgery is more cost effective with the endoscopic approach than with the microscopic approach and depends on efficiency in the operating room as well as reduction in the length of hospitalization.

Three-Hand Endoscopic Endonasal Transsphenoidal Surgery: Experience With an Anatomy-Preserving Mononostril Approach Technique.

BACKGROUND: Variations on the endoscopic transsphenoidal approach present unique surgical techniques that have unique effects on surgical outcomes, extent of resection (EOR), and anatomical complications. OBJECTIVE: To analyze the learning curve and perioperative outcomes of the 3-hand endoscopic endonasal mononostril transsphenoidal technique. METHODS: Prospective case series and retrospective data analysis of patients who were treated with the 3-hand transsphenoidal technique between January 2007 and May 2015 by a single neurosurgeon. Patient characteristics, preoperative presentation, tumor characteristics, operative times, learning curve, and postoperative outcomes were analyzed. Volumetric EOR was evaluated, and a logistic regression analysis was used to assess predictors of EOR. RESULTS: Two hundred seventy-five patients underwent an endoscopic transsphenoidal surgery using the 3-hand technique. One hundred eighteen patients in the early group had surgery between 2007 and 2010, while 157 patients in the late group had surgery between 2011 and 2015. Operative time was significantly shorter in the late group (161.6 min) compared to the early group (211.3 min, P = .001). Both cohorts had similar EOR (early group 84.6% vs late group 85.5%, P = .846) and postoperative outcomes. The learning curve showed that it took 54 cases to achieve operative proficiency with the 3-handed technique. Multivariate modeling suggested that prior resections and preoperative tumor size are important predictors for EOR. CONCLUSION: We describe a 3-hand, mononostril endoscopic transsphenoidal technique performed by a single neurosurgeon that has minimal anatomic distortion and postoperative complications. During the learning curve of this technique, operative time can significantly decrease, while EOR, postoperative outcomes, and complications are not jeopardized.

Intraoperative Seizures in Awake Craniotomy for Perirolandic Glioma Resections That Undergo Cortical Mapping.

BACKGROUND: Perirolandic motor area gliomas present invasive eloquent region tumors within the precentral gyrus that are difficult to resect without causing neurologic deficits. STUDY AIMS: This study evaluates the role of awake craniotomy and motor mapping on neurologic outcome and extent of resection (EOR) of tumor in the perirolandic motor region. It also analyzes preoperative risk factors for intraoperative seizures. METHODS: We evaluated 57 patients who underwent an awake craniotomy for a perirolandic motor area eloquent region glioma. Patients who had positive mapping (PM) or intraoperative identification of motor regions in the cortex using direct cortical stimulation were compared with patients with no positive motor mapping following direct cortical stimulation and negative mapping (NM). Preoperative risks, intraoperative seizures, perioperative outcomes, tumor characteristics, and EOR were also compared. A logistic regression model was used to evaluate the predictors for intraoperative seizures in this patient cohort. RESULTS: Overall, 33 patients were in the PM cohort; 24 were in the NM cohort. Our study showed an 8.8% incidence of intraoperative seizures during cortical and subcortical mapping for awake craniotomies in the perirolandic motor area, none of which aborted the case. PM patients had significantly more intraoperative and postoperative seizures (15.5% and 30.3%, respectively) compared with the NM patients (0% and 8.3%, respectively; p = 0.046 and 0.044). New transient postoperative motor deficits were found more often in the PM group (51.5%) versus the NM group (12.5%; p = 0.002). A univariate logistic regression showed that PM (odds ratio [OR]: 1.16; 95% confidence interval [CI], 1.01-1.34; p = 0.035) and preoperative tumor volume (OR: 0.998; 95% CI, 0.996-0.999; p = 0.049) were significant predictors for intraoperative seizures in patients with perirolandic gliomas. CONCLUSION: Awake craniotomies in the perirolandic motor region can be safely performed with a similar incidence of intraoperative seizures as reported for the language cortex. PM in this region may increase the likelihood of perioperative seizures or motor deficits compared with NM. Craniotomies that minimize cortical exposure for perirolandic gliomas that may not localize motor regions can still allow for extensive tumor resection with a good postoperative outcome.

Comparative analysis of monotherapy versus duotherapy antiseizure drug management for postoperative seizure control in patients undergoing an awake craniotomy.

OBJECTIVE Postoperative seizures are a common complication in patients undergoing an awake craniotomy, given the cortical manipulation during tumor resection and the electrical cortical stimulation for brain mapping. However, little evidence exists about the efficacy of postoperative seizure prophylaxis. This study aims to determine the most appropriate antiseizure drug (ASD) management regimen following an awake craniotomy. METHODS The authors performed a retrospective analysis of data pertaining to patients who underwent an awake craniotomy for brain tumor from 2007 to 2015 performed by a single surgeon. Patients were divided into 2 groups, those who received a single ASD (the monotherapy group) and those who received 2 types of ASDs (the duotherapy group). Patient demographics, symptoms, tumor characteristics, hospitalization details, and seizure outcome were evaluated. Multivariable logistic regression was used to evaluate numerous clinical variables associated with postoperative seizures. RESULTS A total of 81 patients underwent an awake craniotomy for tumor resection of an eloquent brain lesion. Preoperative baseline characteristics were comparable between the 2 groups. The postoperative seizure rate was 21.7% in the monotherapy group and 5.7% in the duotherapy group (p = 0.044). Seizure outcome at 6 months' follow-up was assessed with the Engel classification scale. The duotherapy group had a significantly higher proportion of seizure-free (Engel Class I) patients than the monotherapy group (90% vs 60%, p = 0.027). The length of stay was similar, 4.02 days in the monotherapy group and 4.51 days in the duotherapy group (p = 0.193). The 90-day readmission rate was higher for the monotherapy group (26.1% vs 8.5% in the duotherapy group, p = 0.044). Multivariate logistic regression showed that preoperative seizure history was a significant predictor for postoperative seizures following an awake craniotomy (OR 2.08, 95% CI 0.56-0.90, p < 0.001). CONCLUSIONS Patients with a preoperative seizure history may be at a higher risk for postoperative seizures following an awake craniotomy and may benefit from better postoperative seizure control with postoperative ASD duotherapy.

Comparative volumetric analysis of the extent of resection of molecularly and histologically distinct low grade gliomas and its role on survival.

The authors investigate the role of extent of resection (EOR) and genetic markers on patient outcome and survival for LGGs. We conducted a retrospective cohort between 2005 and 2015, of 109 adult patients who underwent surgery for a LGG by a single surgeon. Volumetric computations of MRI studies were conducted to evaluate the EOR, and genetic markers (IDH1, 1p/19q co-deletion, and p53) were assessed and their effects on survival and neurological outcome were evaluated. The median EOR was 88.1%. Permanent postoperative neurological deficits were seen in 4.6% of patients. EOR was a significant predictor for both overall survival (OS) (hazard ratio [HR] = 0.979, 95% CI 0.961-0.980, p = 0.029) and progression free survival (PFS) (HR = 0.982, 95% CI 0.968-0.997, p = 0.018). Malignant progression free survival (MPFS) was predicted by the 1p/19q co-deletion (HR = 0.148, 95% CI 0.019-1.148, p = 0.048). Patients with EOR of 100% had a significantly better OS than EOR less than 90% (p = 0.038). Patients with an EOR of at least 76% had a better OS than EOR less than 76% (p = 0.025). Patients with an EOR of at least 71% had a better PFS than EOR less than 71% (p = 0.030). Preoperative tumor volume was found to have significant association with EOR (R2 = 0.049, p = 0.031). Increased EOR is associated with improved OS and PFS survival outcomes, while 1p/19q co-deletion provides improved MPFS. Understanding both surgical resections and molecular markers of the tumor are important for effective management of LGG patients.

Awake Craniotomy Anesthesia: A Comparison of the Monitored Anesthesia Care and Asleep-Awake-Asleep Techniques.

BACKGROUND: Commonly used sedation techniques for an awake craniotomy include monitored anesthesia care (MAC), using an unprotected airway, and the asleep-awake-asleep (AAA) technique, using a partially or totally protected airway. We present a comparative analysis of the MAC and AAA techniques, evaluating anesthetic management, perioperative outcomes, and complications in a consecutive series of patients undergoing the removal of an eloquent brain lesion. METHODS: Eighty-one patients underwent awake craniotomy for an intracranial lesion over a 9-year period performed by a single-surgeon and a team of anesthesiologists. Fifty patients were treated using the MAC technique, and 31 were treated using the AAA technique. A retrospective analysis evaluated anesthetic management, intraoperative complications, postoperative outcomes, pain management, and complications. RESULTS: The MAC and AAA groups had similar preoperative patient and tumor characteristics. Mean operative time was shorter in the MAC group (283.5 minutes vs. 313.3 minutes; P = 0.038). Hypertension was the most common intraoperative complication seen (8% in the MAC group vs. 9.7% in the AAA group; P = 0.794). Intraoperative seizure occurred at a rate of 4% in the MAC group and 3.2% in the AAA group (P = 0.858). Awake cases were converted to general anesthesia in no patients in the MAC group and in 1 patient (3.2%) in the AAA group (P = 0.201). No cases were aborted in either group. The mean hospital length of stay was 3.98 days in the MAC group and 3.84 days in the AAA group (P = 0.833). CONCLUSIONS: Both the MAC and AAA sedation techniques provide an efficacious and safe method for managing awake craniotomy cases and produce similar perioperative outcomes, with the MAC technique associated with shorter operative time.

Volumetric Analysis of Extent of Resection, Survival, and Surgical Outcomes for Insular Gliomas.

BACKGROUND: Insular gliomas are challenging tumors to surgically resect owing to the anatomy surrounding them. This study evaluates the role of extent of resection (EOR) and molecular markers in surgical outcome and survival for insular gliomas. METHODS: Seventy-four patients who had undergone initial resection for insular glioma by the same surgeon between 2006 and 2016 were analyzed. Low-grade gliomas (LGGs) (grade II) and high-grade gliomas (HGGs) (grade III/IV) were analyzed for the prognostic role of volumetric EOR and molecular markers in patient survival outcomes. RESULTS: The cohort included 25 patients with LGGs (33.8%) and 49 patients with HGGs (66.2%). Median EOR was 91.7% (range, 10%-100%). New permanent postoperative deficits were found in 2.7% of patients. Patients with LGGs with ≥90% EOR had 5-year survival of 100%, and patients with <90% EOR had 5-year survival of 80%. Patients with HGGs with ≥90% EOR had 2-year survival of 83.7%, and patients with <90% EOR had 2-year survival of 43.8%. For LGGs, EOR was predictive of overall survival (P = 0.017), progression-free survival (PFS) (P = 0.039), and malignant PFS (P = 0.014), whereas 1p/19q codeletion was predictive of PFS (P = 0.014). For HGGs, EOR was predictive of overall survival (P = 0.020) and PFS (P = 0.024). Preoperative tumor volume most significantly affected EOR for insular gliomas (R2 = 0.053, P = 0.048). CONCLUSIONS: Extensive resections of insular gliomas can be achieved with low morbidity and can improve overall survival and PFS. In this series of LGGs, EOR was associated with longer malignant PFS, and 1p/19q codeletion was predictive of PFS.

Awake Craniotomy vs Craniotomy Under General Anesthesia for Perirolandic Gliomas: Evaluating Perioperative Complications and Extent of Resection.

BACKGROUND: A craniotomy with direct cortical/subcortical stimulation either awake or under general anesthesia (GA) present 2 approaches for removing eloquent region tumors. With a reported higher prevalence of intraoperative seizures occurring during awake resections of perirolandic lesions, oftentimes, surgery under GA is chosen for these lesions. OBJECTIVE: To evaluate a single-surgeon's experience with awake craniotomies (AC) vs surgery under GA for resecting perirolandic, eloquent, motor-region gliomas. METHODS: Between 2005 and 2015, a retrospective analysis of 27 patients with perirolandic, eloquent, motor-area gliomas that underwent an AC were case-control matched with 31 patients who underwent surgery under GA for gliomas in the same location. All patients underwent direct brain stimulation with neuromonitoring and perioperative risk factors, extent of resection, complications, and discharge status were assessed. RESULTS: The postoperative Karnofsky Performance Score (KPS) was significantly lower for the GA patients at 81.1 compared to the AC patients at 93.3 ( P = .040). The extent of resection for GA patients was 79.6% while the AC patients had an 86.3% resection ( P = .136). There were significantly more 100% total resections in the AC patients 25.9% compared to the GA group (6.5%; P = .041). Patients in the GA group had a longer mean length of hospitalization of 7.9 days compared to the AC group at 4.2 days ( P = .049). CONCLUSION: We show that AC can be performed with more frequent total resections, better postoperative KPS, shorter hospitalizations, as well as similar perioperative complication rates compared to surgery under GA for perirolandic, eloquent motor-region glioma.

The Cost of Brain Surgery: Awake vs Asleep Craniotomy for Perirolandic Region Tumors.

BACKGROUND: Cost effectiveness has become an important factor in the health care system, requiring surgeons to improve efficacy of procedures while reducing costs. An awake craniotomy (AC) with direct cortical stimulation (DCS) presents one method to resect eloquent region tumors; however, some authors assert that this procedure is an expensive alternative to surgery under general anesthesia (GA) with neuromonitoring. OBJECTIVE: To evaluate the cost effectiveness and clinical outcomes between AC and GA patients. METHODS: Retrospective analysis of a cohort of 17 patients with perirolandic gliomas who underwent an AC with DCS were case-control matched with 23 patients with perirolandic gliomas who underwent surgery under GA with neuromonitoring (ie, motor-evoked potentials, somatosensory-evoked potentials, phase reversal). Inpatient costs, quality-adjusted life years (QALY), extent of resection, and neurological outcome were compared between the groups. RESULTS: Total inpatient expense per patient was $34 804 in the AC group and $46 798 in the GA group ( P = .046). QALY score for the AC group was 0.97 and 0.47 for the GA group ( P = .041). The incremental cost per QALY for the AC group was $82 720 less than the GA group. Postoperative Karnofsky performance status was 91.8 in the AC group and 81.3 in the GA group (P = .047). Length of hospitalization was 4.12 days in the AC group and 7.61 days in the GA group ( P = .049). CONCLUSION: The total inpatient costs for awake craniotomies were lower than surgery under GA. This study suggests better cost effectiveness and neurological outcome with awake craniotomies for perirolandic gliomas.

Endoscopic Versus Microscopic Transsphenoidal Approach for Pituitary Adenomas: Comparison of Outcomes During the Transition of Methods of a Single Surgeon.

OBJECTIVE: The transition from microscopic to fully endoscopic transsphenoidal surgery requires a surgeon to assess how the change in technique will affect the extent of tumor resection (EOR), outcomes, and complications. We compared a single surgeon's experience transitioning from one technique to the other and examined the operative outcomes and EOR between microscopic versus endoscopic transsphenoidal surgery. METHODS: Retrospective data analysis of adult patients who were treated surgically for a pituitary adenoma between August 2005 and May 2015 by a single neurosurgeon, who was originally trained and practiced in the microscopic transsphenoidal approach. Patient demographics, perioperative conditions, tumor characteristics, operative times, volumetric EOR, postoperative outcome, and the endoscopic learning curve were evaluated. RESULTS: One hundred and nine patients underwent microscopic transsphenoidal surgery and 275 patients underwent a fully endoscopic approach. The patient characteristics were similar in the 2 groups. Operative room time was significantly shorter in the endoscopic group than in the microscopic group (180.2 vs. 215.6 minutes; P < 0.001). The endoscopic and microscopic groups had similar volumetric EOR (85.1% vs. 82.8%; P = 0.371) as well as residual tumor volume (1.06 cm3 vs. 1.15 cm3; P = 0.765). The mean length of hospital stay was 2.4 days in the endoscopic group and 3.2 days in the microscopic group (P = 0.03). CONCLUSIONS: During the transition from the microscopic to the endoscopic approach, similar surgical outcomes and EOR were achieved in the 2 cohorts. In our experience, the endoscopic approach offers the advantage of shorter operative times and lengths of hospital stays after the surgeon has developed more experience with the technique.

Postoperative Cerebral Vasospasm Following Transsphenoidal Pituitary Adenoma Surgery.

PURPOSE: Cerebral vasospasm following a transsphenoidal resection of a pituitary adenoma is a devastating occurrence that can lead to delayed cerebral ischemia and poor neurologic outcome if not diagnosed and treated in a timely manner. The etiology of this condition is not well understood but can lead to significant arterial vasospasm that causes severe ischemic insults. In this paper, we identify common presenting symptoms and essential management strategies to treat this harmful disease. METHODS: A retrospective case report and literature review of presentation, treatment, and outcome of cerebral vasospasm following transsphenoidal surgery. RESULTS: We present 1 case and review 12 known cases in the literature on vasospasm following transsphenoidal surgery. Mean age was 48 (±13.8) years. There were 46.2% male patients. Factors associated with vasospasm, such as cerebral spinal fluid leaks following surgery, were seen in 38.5% of cases, and postoperative subarachnoid hemorrhage (SAH) was seen in 84.6% of cases. Hemiparesis was the presenting symptom of delayed cerebral ischemia in 61.5% of cases. For management, maintaining at least a euvolemic volume status was used in 76.9%, induced hypertension was used in 61.5%, and nimodipine was administered in 46.2% of cases. Patients returned to their neurologic baseline in 61.5% of cases, had new permanent deficits in 7.7% of cases, and died in 30.8% of cases. CONCLUSION: Cerebral vasospasm following transsphenoidal surgery is a dangerous disease that can lead to a high likelihood of mortality if not identified and treated. Early postoperative events, such as peritumoral subarachnoid hemorrhage and hemiparesis, may be factors associated with post-transsphenoidal surgery vasospasm. Effective treatment options used in patients that regained complete neurologic recovery were by inducing hypertension, maintaining euvolemia, and administering nimodipine.

Early Surgical Intervention for a Large Newborn Cephalohematoma.

Cephalohematomas in newborns are often managed nonsurgically and resolve within the first month of life. In cases of large hematomas (>7 cm) with delayed resorption and persistence over 4 weeks, these masses can often lead to complications of calcification, infection, or hyperbilirubinemia. We report a case of a 14-day-old child with a persistent, large, noncalcified cephalohematoma. After observation alone showed that the cephalohematoma increased in size, 100 ml of old blood was surgically evacuated on day 15 of life. The procedure required a small 1-cm incision and, unlike most large cephalohematomas evacuated after 1 month of observation, there were no signs of skull-deforming calcification observed. This case report presents the earliest evacuation of large noncalcified cephalohematomas in newborns ever reported in the literature, and suggests benefits of early surgical evacuation before 1 month of life.

Reduced CSF leak in complete calvarial reconstructions of microvascular decompression craniectomies using calcium phosphate cement.

OBJECT: Calcium phosphate cement provides a biomaterial that can be used for calvarial reconstruction in a retrosigmoid craniectomy for microvascular decompression (MVD). This study evaluates the outcomes of postoperative CSF leak and wound infection for patients undergoing a complete cranioplasty using calcium phosphate cement versus incomplete cranioplasty using polyethylene titanium mesh following a retrosigmoid craniectomy for MVD. METHODS: The authors evaluated 211 cases involving patients who underwent first-time retrosigmoid craniectomies performed by a single attending surgeon fortrigeminal neuralgia from October 2008 to June 2014. From this patient population, 111 patients underwent calvarial reconstruction after retrosigmoid craniectomy using polyethylene titanium mesh, and 100 patients had reconstructions using calcium phosphate cement. A Pearson's chi-square test was used to compare postoperative complications of CSF leak and wound infection in these 2 types of cranioplasties. RESULTS: The polyethylene titanium mesh group included 5 patients (4.5%) with postoperative CSF leak or pseudomeningocele and 3 patients (2.7%) with wound infections. In the calcium phosphate cement group, no patients had a CSF leak, and 2 patients (2%) had wound infections. This represented a statistically significant reduction of postoperative CSF leak in patients who underwent calcium phosphate reconstructions of their calvarial defect compared with those who underwent polyethylene titanium mesh reconstructions (p = 0.03). No significant difference was seen between the 2 groups in the number of patients with postoperative wound infections. CONCLUSIONS: Calcium phosphate cement provides a viable alternative biomaterial for calvarial reconstruction of retrosigmoid craniectomy defects in patients who have an MVD. The application of this material provides a biocompatible barrier that reduces the incidence of postoperative CSF leaks.

Endothelial cells expressing low levels of CD143 (ACE) exhibit enhanced sprouting and potency in relieving tissue ischemia.

The sprouting of endothelial cells from pre-existing blood vessels represents a critical event in the angiogenesis cascade. However, only a fraction of cultured or transplanted endothelial cells form new vessels. Moreover, it is unclear whether this results from a stochastic process or instead relates to certain endothelial cells having a greater angiogenic potential. This study investigated whether there exists a sub-population of cultured endothelial cells with enhanced angiogenic potency in vitro and in vivo. First, endothelial cells that participated in sprouting, and non-sprouting cells, were separately isolated from a 3D fibrin gel sprouting assay. Interestingly, the sprouting cells, when placed back into the same assay, displayed a sevenfold increase in the number of sprouts, as compared to control cells. Angiotensin-converting enzyme (CD143) was significantly down regulated on sprouting cells, as compared to regular endothelial cells. A subset of endothelial cells with low CD143 expression was then prospectively isolated from an endothelial cell culture. Finally, these cells were found to have greater potency in alleviating local ischemia, and restoring regional blood perfusion when transplanted into ischemic hindlimbs, as compared to unsorted endothelial cells. In summary, this study indicates that low expression of CD143 can be used as a biomarker to identify an endothelial cell sub-population that is more capable to drive neovascularization.

Suppressors of cytokine-signaling proteins induce insulin resistance in the retina and promote survival of retinal cells.

OBJECTIVE: Suppressors of cytokine signaling (SOCS) are implicated in the etiology of diabetes, obesity, and metabolic syndrome. Here, we show that some SOCS members are induced, while others are constitutively expressed, in retina and examine whether persistent elevation of SOCS levels in retina by chronic inflammation or cellular stress predisposes to developing insulin resistance in retina, a condition implicated in diabetic retinopathy. RESEARCH DESIGN AND METHODS: SOCS-mediated insulin resistance and neuroprotection in retina were investigated in 1) an experimental uveitis model, 2) SOCS1 transgenic rats, 3) insulin-deficient diabetic rats, 4) retinal cells depleted of SOCS6 or overexpressing SOCS1/SOCS3, and 5) oxidative stress and light-induced retinal degeneration models. RESULTS: We show that constitutive expression of SOCS6 protein in retinal neurons may improve glucose metabolism, while elevated SOCS1/SOCS3 expression during uveitis induces insulin resistance in neuroretina. SOCS-mediated insulin resistance, as indicated by its inhibition of basally active phosphoinositide 3-kinase/AKT signaling in retina, is validated in retina-specific SOCS1 transgenic rats and retinal cells overexpressing SOCS1/SOCS3. We further show that the SOCS3 level is elevated in retina by oxidative stress, metabolic stress of insulin-deficient diabetes, or light-induced retinal damage and protects ganglion cells from apoptosis, suggesting that upregulation of SOCS3 may be a common physiologic response of neuroretinal cells to cellular stress. CONCLUSIONS: Our data suggest two-sided roles of SOCS proteins in retina. Whereas SOCS proteins may improve glucose metabolism, mitigate deleterious effects of inflammation, and promote neuroprotection, persistent SOCS3 expression caused by chronic inflammation or cellular stress can induce insulin resistance and inhibit neurotrophic factors, such as ciliary neurotrophic factor, leukemia inhibitory factor, and insulin, that are essential for retinal cell survival.