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Glioblastoma (GBM) is the most common primary brain cancer in adults where tumor cell heterogeneity and sex differences influence clinical outcomes. Here, we functionally characterize three male and three female patient-derived GBM cell lines, identify protumorigenic BTICs, and create novel male and female preclinical models of GBM. Cell lines were evaluated on the following features: proliferation, stemness, migration, tumorigenesis, clinical characteristics, and sensitivity to radiation, TMZ, rhTNFSF10 (rhTRAIL), and rhBMP4. All cell lines were classified as GBM according to epigenetic subtyping, were heterogenous and functionally distinct from one another, and re-capitulated features of the original patient tumor. In establishing male and female preclinical models, it was found that two male-derived GBM cell lines (QNS108 and QNS120) and one female-derived GBM cell line (QNS315) grew at a faster rate in female mice brains. One male-derived GBM cell line (QNS108) decreased survival in female mice in comparison with male mice. However, no survival differences were observed for mice injected with a female-derived cell line (QNS315). In summary, a panel of six GBM patient-derived cell lines were functionally characterized, and it was shown that BTIC lines can be used to construct sex-specific models with differential phenotypes for additional studies.

Objective Neurosurgical patients are at a higher risk of having a severe course of coronavirus disease 2019 (COVID-19). The objective of this study was to determine morbidity, hospital course, and mortality of neurosurgical patients during the coronavirus disease 2019 (COVID-19) pandemic in a multicenter health care system. Methods A retrospective observational study was conducted to identify all hospitalized neurosurgical patients positive for COVID-19 from March 11, 2020 to November 2, 2020 at Mayo Clinic and the Mayo Clinic Health System. Results Eleven hospitalized neurosurgical patients (0.68%) were positive for COVID-19. Four patients (36.6%) were men and 7 (63.3%) were women. The mean age was 65.7 years (range, 35–81 years). All patients had comorbidities. The mean length of stay was 13.4 days (range, 4–30 days). Seven patients had a central nervous system malignancy (4 metastases, 1 meningioma, 1 glioblastoma, and 1 schwannoma). Three patients presented with cerebrovascular complications, comprising 2 spontaneous intraparenchymal hemorrhages and 1 ischemic large-vessel stroke. One patient presented with an unstable traumatic spinal burst fracture. Four patients underwent neurosurgical/neuroendovascular interventions. Discharge disposition was to home in 5 patients, rehabilitation facility in 3, and hospice in 3. Five patients had died at follow-up, 3 within 30 days from COVID-19 complications and 2 from progression of their metastatic cancer. Conclusions COVID-19 is rare among the inpatient neurosurgical population. In all cases, patients had multiple comorbidities. All symptomatic patients from the respiratory standpoint had complications during their hospitalization. Deaths of 3 patients who died within 30 days of hospitalization were all related to COVID-19 complications. Neurosurgical procedures were performed only if deemed emergent.

Chordoma is a rare but devastating tumor that arises in the cranial skull base or spine. There are currently no US Food and Drug Administration-approved targeted therapies for chordoma, and little understanding of whether using more than one therapy has benefit over monotherapy. The objective of this study was to systematically review the current status of clinical trials completed for patients with chordoma to determine if multimodal therapy offers a benefit in progression-free survival over monomodal therapy. We performed a systematic review of the literature according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines to review the available clinical trials of targeted therapy for chordoma. We compiled the clinical data to determine if there is a benefit of multimodal therapy over monotherapy. Our search resulted in 11 clinical trials including 270 patients with advanced chordoma who were treated with targeted therapies. The most commonly employed targeted therapies acted within the following pathways: platelet-derived growth factor receptor (187 patients), vascular endothelial growth factor (66 patients), and mammalian target of rapamycin (43 patients). Reported progression-free survival for included studies ranged from 2.5 to 58 months, with the longest progression-free survival in a trial that included a platelet-derived growth factor receptor inhibitor, nilotinib, and concurrent radiotherapy (58.2 months). There was a higher range of progression-free survival for trials treating patients with multimodal therapy (10.2–14 months vs 2.5–9.2 months, except for a monotherapy trial published in 2020 with a progression-free survival of 18 months), and those published in 2018 or later (14–58.2 months vs 2.5–10.2 months). Only 23% of patients with chordoma in published clinical trials have been treated with multimodal therapy. Progression-free survival may be enhanced by the use of targeted therapy with concurrent radiotherapy, use of multimodal therapy, and use of newer targeted therapy. Future clinical trials should consider use of concurrent radiotherapy and multimodal therapy for patients with advanced chordoma.

Background The primary goal of brain tumor surgery is maximal safe resection while avoiding iatrogenic injury. As surgical technology increases, it is becoming more possible to resect these lesions using minimally invasive approaches. While keyhole surgeries are being advocated, the lower limit of these approaches is unclear. Bur hole–based approaches may represent a standardized minimally invasive approach. The exoscope may provide increased visualization over standard microscopic visualization, making this approach possible. This approach has yet to be described strictly for intra-axial brain tumors.Material and Methods All patients who underwent a bur hole–based surgery of an intra-axial tumor with exoscopic visualization by the senior author from January 2018 to December 2019 were prospectively identified and patient information and outcomes were collected.Results Fifteen consecutive patients underwent surgical resection of an intrinsic brain tumor using a bur hole–based approach with exoscopic visualization. The average ± standard deviation age was 57.9 ± 24.2 years. The pathology was a metastatic brain tumor in eight patients (53%), low-grade glioma in four patients (27%), and high-grade glioma in three patients (20%). The average percent resection was 100 ± 1%, where 14 (93%) underwent gross total resection. Following surgery, the median (interquartile range) Karnofsky performance scale (KPS) score was 90 (90–90), where 11 (73%) and four patients (27%) had improved and stable KPS, respectively. Zero patients had complications. The average length of stay following surgery was 1.4 ± 0.5 days, where nine patients (60%) were discharged on postoperative day 1.Conclusion This study shows that intra-axial tumors can be resected through a bur hole–based approach with exoscopic visualization with extensive resection, minimal morbidity, and early discharge rates.

Background Awake craniotomy (AC) with brain mapping has been successfully used for the resection of lesions located in or near eloquent areas of the brain. The selection process includes a thorough presurgical evaluation to determine candidates suitable for the procedure. Psychiatric disorders including post-traumatic stress disorder (PTSD) are considered potential contraindications for this type of surgery because these patients may be less cooperative to tolerate AC. Here we present the management of a patient with PTSD who underwent an AC using a multidisciplinary team for removal of a dominant hemisphere low-grade insular glioma with speech, motor, and cognitive mapping. Case Description A 34-year-old right-handed male military veteran with a previous history of PTSD was scheduled for a left AC for resection of a low-grade insular glioma. He underwent preoperative neurocognitive assessment with a neuropsychologist and clinic visit with a neurosurgeon to characterize his PTSD and potential triggers, explain the procedure in a stepwise fashion, and address any concerns. The intraoperative environment was modified to minimize triggering stimuli, and an asleep-awake-asleep anesthetic protocol was followed. The patient tolerated the procedure well without any postoperative neurologic deficits including cognitive deficits. At 1-month follow-up, he denied any worsening of his PTSD symptoms and recalls the AC as a positive experience. Conclusions With a multidisciplinary team, adequate preoperative education, detailed clinical interview to identify triggers, and a controlled intraoperative environment, awake surgery can be carried out safely in a patient with PTSD.

Acquired Reactive Perforating Collagenosis (ARPC) is a rare condition that belongs to a larger group of diseases: The Perforating Dermatoses (1). ARPC is usually refractory to treatment; thus, many treatments have been reported, including topical and systemic corticosteroids, retinoids, doxycycline, allopurinol and narrowband ultraviolet B (NBUVB) phototherapy (1). The aim of this manuscript is to present a case successfully treated with NBUVB phototherapy after 96 sessions and describe the treatment protocol used, as well as the utilized in currently reports as well.

Background: Obesity is common among children and teenagers and is associated with cardiometabolic risk factors in the adult age. The objective of this paper was to evaluate the association between the percentage of body fat and cardiometabolic risk factors in children and adolescents in the city of Bucaramanga, Colombia. Material and Methods: About 494 children and adolescents aged 10–20 years were studied. Laboratory tests were made for analyzing cardiovascular risk factors and anthropometric measurements. Percentage body fat was determined with Slaughter equation. Lineal regression analyses were conducted to evaluate the association between cardiometabolic risk factors and the percentage body fat. Results: Prevalence of percentage body fat (>26%) was 46.1%. Variables associated with percentage body fat were HOMA-IR – insulin resistance, HDL, LDL, triglycerides, and total cholesterol levels, and high blood pressure. Conclusions: Increase in percentage body fat is significantly associated with cardiometabolic risk factors in children and adolescents in Bucaramanga. Early identification and intervention of this population at risk is fundamental. Keywords: Skinfold thickness, Risk factors, Cardiovascular disease, Insulin resistance

Spinal Cord Injury (SCI) is a devastating disease that causes disruption of sensorimotor function below the site of injury. Current management is based on surgical decompression of the neural tissue and pharmacotherapy; however, there is no gold standard treatment readily available for patients in the clinic. This indicates that novel therapeutic strategies for the treatment are still needed in the clinical setting. There are several alternatives that are currently under investigation for the treatment of this disease, with increasing focus in regenerative medicine treatments. Mesenchymal stem cells (MSCs) are one of the most promising candidates for stem cell therapy in SCI, as they are easily obtained, have high safety profiles, and help with neural regeneration in SCI mainly via release of trophic factors, neovascularization, and immunomodulation. In this work, authors provide an insight of the available MSC for neural regeneration, their therapeutic role, and the potential MSC-based therapies for SCI.

Glioblastoma (GBM) is the most common and devastating primary cancer of the central nervous system in adults. High grade gliomas are able to modify and respond to the brain microenvironment. When GBM tumors infiltrate the Subventricular zone (SVZ) they have a more aggressive clinical presentation than SVZ-distal tumors. We suggest that cerebrospinal fluid (CSF) contact contributes to enhance GBM malignant characteristics in these tumors. We evaluated the impact of human CSF on GBM, performing a transcriptome analysis on human primary GBM cells exposed to CSF to measure changes in gene expression profile and their clinical relevance on disease outcome. In addition we evaluated the proliferation and migration changes of CSF-exposed GBM cells in vitro and in vivo. CSF induced transcriptomic changes in pathways promoting cell malignancy, such as apoptosis, survival, cell motility, angiogenesis, inflammation, and glucose metabolism. A genetic signature extracted from the identified transcriptional changes in response to CSF proved to be predictive of GBM patient survival using the TCGA database. Furthermore, CSF induced an increase in viability, proliferation rate, and self-renewing capacity, as well as the migratory capabilities of GBM cells in vitro. In vivo, GBM cells co-injected with human CSF generated larger and more proliferative tumors compared to controls. Taken together, these results provide direct evidence that CSF is a key player in determining tumor growth and invasion through the activation of complex gene expression patterns characteristic of a malignant phenotype. These findings have diagnostic and therapeutic implications for GBM patients. The changes induced by CSF contact might play a role in the increased malignancy of SVZ-proximal GBM.

We appreciate the opportunity to respond to the letter published by Batchu S., regarding our work titled “In Vitro Effect of Dovitinib (TKI258), a Multi-target Angiokinase Inhibitor on Aggressive M...

White matter changes (WMC) are frequently observed in clinical practice, but their clinical relevance is often obscured by radiology reports that do not clearly convey a likely diagnosis. In this regard, two attitudes contribute to diagnostic confusion: a tendency to dismiss findings as trivial (i.e., using vague characterizations such as “non-specific” or “normal for age”), and a gratuitous dilatation of the differential diagnosis (i.e., routinely adding rare diseases to the list, such as vasculitis). Very often, the finding of WMC presents physicians with a very practical problem, which is to determine whether the underlying etiology is an autoimmune demyelinating disease such as multiple sclerosis (MS), or a vasculopathy such as small vessel cerebrovascular disease (SVCVD). The implications of this distinction are great, because the treatment and prognosis of these two syndromes are very different. Here, we describe the challenging case of a relatively young woman with dementia due to a combination of MS and cerebrovascular disease.

Intraoperative stimulation (IS) mapping has become the preferred standard treatment for eloquent tumors as it permits a more accurate identification of functional areas, allowing surgeons to achieve higher extents of resection (EOR) and decrease postoperative morbidity. For lesions adjacent to the perirolandic area and descending motor tracts, mapping can be done with both awake craniotomy (AC) and under general anesthesia (GA). We aimed to determine which anesthetic protocol—AC vs. GA—provides better patient outcomes by comparing EOR and postoperative morbidity for surgeries using IS mapping in gliomas located near or in motor areas of the brain. A systematic literature search was carried out to identify relevant studies from 1983 to 2019. Seven databases were screened. A total of 2351 glioma patients from 17 studies were analyzed. A random-effects meta-analysis revealed a trend towards a higher mean EOR in AC [90.1% (95% C.I. 85.8–93.8)] than with GA [81.7% (95% C.I. 72.4–89.7)] (p = 0.06). Neurological deficits were divided by timing and severity for analysis. There was no significant difference in early neurological deficits [20.9% (95% C.I. 4.1–45.0) vs. 25.4% (95% C.I. 13.6–39.2)] (p = 0.74), late neurological deficits [17.1% (95% C.I. 0.0–50.0) vs. 3.8% (95% C.I. 1.1–7.6)] (p = 0.06), or in non-severe [28.4% (95% C.I. 0.0–88.5) vs. 20.1% (95% C.I. 7.1–32.2)] (p = 0.72), and severe morbidity [2.6% (95% C.I. 0.0–15.5) vs. 4.5% (95% C.I. 1.1–9.6)] (p = 0.89) between patients who underwent AC versus GA, respectively. Mapping during resection of gliomas located in or near the perirolandic area and descending motor tracts can be safely carried out with both AC and GA.

Background Mycetoma is a neglected tropical disease characterized by nodules, scars, abscesses, and fistulae that drain serous or purulent material containing the etiological agent. Mycetoma may be caused by true fungi (eumycetoma) or filamentous aerobic bacteria (actinomycetoma). Mycetoma is more frequent in the so-called mycetoma belt (latitude 15° south and 30° north around the Tropic of Cancer), especially in Sudan, Nigeria, Somalia, India, Mexico, and Venezuela. The introduction of new antibiotics with fewer side effects, broader susceptibility profiles, and different administration routes has made information on actinomycetoma treatment and outcomes necessary. The objective of this report was to provide an update on clinical, therapeutic, and outcome data for patients with actinomycetoma attending a reference center in northeast Mexico. Methodology/principal findings This was a retrospective, cross-sectional, descriptive study of 31 patients (male to female ratio 3.4:1) diagnosed with actinomycetoma by direct grain examination, histopathology, culture, or serology from January 2009 to September 2018. Most lesions were caused by Nocardia brasiliensis (83.9%) followed by Actinomadura madurae (12.9%) and Actinomadura pelletieri (3.2%). About 50% of patients had bone involvement, and the right leg was the most commonly affected region in 38.7% of cases. Farmers/agriculture workers were most commonly affected, representing 41.9% of patients. The most commonly used treatment regimen was the Welsh regimen (35.5% of cases), a combination of trimethoprim/sulfamethoxazole (TMP/SMX) plus amikacin, which had a 90% cure rate, followed by TMP/SMX plus amoxicillin/clavulanic acid in 19.4% of cases with a cure rate of 100%. In our setting, 28 (90.3%) patients were completely cured and three (9.7%) were lost to follow-up. Four patients required multiple antibiotic regimens due to recurrences and adverse effects. Conclusions/significance In our sample, actinomycetoma was predominantly caused by N. brasiliensis. Most cases responded well to therapy with a combination of TMP/SMX with amikacin or TMP/SMX and amoxicillin/clavulanic acid. Four patients required multiple antibiotics and intrahospital care., Author summary Mycetoma is a chronic skin disease that can invade bone or underlying organs. Inadequate treatment may lead to long-lasting disability. Information about treatment is scarce. We report the outcomes of 31 patients with a diagnosis of bacterial actinomycetoma attending a tertiary care hospital in northeast Mexico. Most cases were treated with a combination of antibiotics including TMP/SMX plus amikacin or TMP/SMX plus amoxicillin/clavulanic acid. Cure was achieved in 90% of patients and only one required surgery.

Objective To compare outcomes between patients who underwent mechanical thrombectomy for large vessel occlusion based on platelet count: low versus normal. Methods Three studies were included with a pooled cohort of 1125 patients. Data points were collected and pooled by meta-analysis of proportions via a logit transformation to provide a summary statistic. Both fixed-effect and random-effects models were recruited for the analysis. In this meta-analysis, risk of developing symptomatic intracranial hemorrhage, unfavorable clinical outcomes (modified Rankin Scale score >3), and mortality of patients with low platelet counts were compared with patients with normal platelet counts according to the criteria for inclusion used by each study. Results Of patients, 50 (4.7%) had low platelet count, and 1075 (95.3%) had normal platelet count. Patients in the low platelet count group had a substantially higher risk of mortality (risk ratio 1.93, 95% confidence interval 1.43–2.60, P Conclusions Patients with low platelet counts had increased mortality compared with patients with normal platelet counts following mechanical thrombectomy for large vessel occlusion.

Glioblastoma (GBM) is the most common form of malignant primary brain cancer in adults with a median survival of only 15 months. Therefore, new therapies to suppress malignant brain cancer are needed. Brain Tumor Initiating Cells (BTICs) are a GBM subpopulation of cells with a highly glycolytic profile that are thought to be responsible of the resistance of GBM to treatments. Metabolic reprogramming allows tumor cells to survive in unsupportive microenvironments. Manipulating tumor metabolism to counteract GBM resistance arises as a powerful approach with minimum effects in normal counterparts. At pharmacological concentrations, melatonin displays oncostatic properties. This is thought to be due to an increase in mitochondrial oxidative phosphorylation through the effects of melatonin in mitochondria, key organelle in metabolic homeostasis. We hypothesize that melatonin could alter BTIC metabolism, by inducing an anti-Warburg effect and as consequence, melatonin will decrease the viability of GBM cells and tumor growth. We found that treatment of GBM cell lines with 3mM melatonin significantly altered tumor cell metabolism. We observed that melatonin downregulated the lactate symporter MCT4 (p

Despite aggressive treatment with chemoradiotherapy and maximum surgical resection, survival in patients with glioblastoma (GBM) remains poor. Ongoing efforts are aiming to prolong the lifespan of these patients; however, disparities exist in reported survival values with lack of clear evidence that objectively examines GBM survival trends. We aim to describe the current status and advances in the survival of patients with GBM, by analyzing median overall survival through time and between treatment modalities. A systematic review was conducted according to PRISMA guidelines to identify articles of newly diagnosed glioblastoma from 1978 to 2018. Full-text glioblastoma papers with human subjects, ≥ 18 years old, and n ≥ 25, were included for evaluation. The central tendency of median overall survival (MOS) was 13.5 months (2.3–29.6) and cumulative 5-year survival was 5.8% (0.01%–29.1%), with a significant difference in survival between studies that predate versus postdate the implementation of temozolomide and radiation, [12.5 (2.3–28) vs 15.6 (3.8–29.6) months, P

Gliomas are molecularly complex neoplasms and require a multidisciplinary approach to treatment. Maximal safe resection is often the initial goal of treatment and extent of resection (EOR) is an important prognostic factor correlating with both progression-free-survival (PFS) and overall survival (OS). Postoperative patient outcome is also a critical and independent prognosticator and high EOR must not be achieved at the expense of good functional outcome. Several intraoperative adjuvant techniques have been developed to help the surgeon push the boundaries of EOR while maintaining safety. Fluorescence-guided surgery for brain tumors is a contemporary adjuvant technique that allows for intraoperative delineation of diseased and normal brain thus improving maximal safe resection. The most extensively used fluorophores are 5-aminolevulinic acid (5-ALA) and sodium fluorescein (SFL). These fluorophores have different spectrophotometric properties, mechanisms of action and considerations for use. Both have demonstrated utility in neurosurgical oncology. They are safe and both are FDA approved for use as surgical adjuncts during resection of primary CNS neoplasms although they have been used with varying success for other tumor types. When combined with other surgical adjuvant strategies such as neuronavigation, intraoperative ultrasound, intraoperative MRI, awake resection and/or electrophysiological mapping/monitoring, fluorescence-guided resection appears to further improve resection quality in regard to EOR and safety. In this article, we review the current knowledge related to both fluorophores for brain tumor resection, their benefits, and pitfalls, as well as the major advantages associated with their use. We also briefly review additional fluorophores in early clinical development. Fluorescence-guided surgery is a novel surgical adjuvant which allows for real-time delineation of neoplastic tissues. The most widely used fluorophores are 5-ALA and SFL. They are safe compounds and there is a large body of evidence suggesting improvement in EOR when these are employed. There are nuances to the use of each; the fluorescence intensity is dose-dependent in either case and the sensitivity and specificity for various tumors vary widely. Additional prospective studies will be necessary to parse the impact of this technique and these fluorophores on survival metrics.

INTRODUCTION The management of glioblastoma (GBM) has changed over time and varies based on geographic location. Despite its universally fatal prognoses, it is unclear if GBM outcomes have changed over time, if they vary by geographic location, and differ based on type of intervention. As a result, we conducted a systematic review of the literature to identify the average survival differences of GBM patients across time, between different continents, and among various treatments. METHODS The systematic review of PubMed included glioblastoma, GBM, and survival. Inclusion criteria consisted of full-text titles with human subjects, GBM/Grade IV astrocytoma, age >18 years old, and with available survival data. RESULTS 9,162 articles were screened for survival data, 1728 were eligible, 405 complied with the inclusion criteria. Of the 405 studies, 179 (44.2%) were conducted in Europe, 151 (37.3%) in the Americas, 61 (15.1%) in Asia, 9 (2.2%) in Oceania, and 1 (0.2%) in Africa. Leading countries are the United States (33.1%), Germany (12.3%), and Italy (11.1%). Asia had the highest median survival (14.9 months), followed by Europe (13.2 months), and the United States (12.9 months) (P=0.003). Regarding treatment, survival was significantly higher after the introduction of the Stupp protocol (P< 0.001). Post-Stupp Studies had longer survival estimates (15.3 months, range: 3.8–29.6) than Pre-Stupp Studies (12.2 months, range: 2.3–28). In the included clinical trials (182), radiation (43.4%), temozolomide (25.3%), or other chemotherapies (24.2%) were the most common interventions. Clinical trial median survival estimates were significantly higher than all other studies (P< 0.017). Bevacizumab (19.3 months) and Temozolomide (15.9 months) had the longest recorded median survival estimates; while radiation (14 months), other chemotherapies, and carmustine (13.2 months) had the shortest (P=0.009). CONCLUSION This epidemiological study describes the current global state of GBM. Important differences regarding survival and treatment of patients with GBM were found.

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. Currently, treatment is focused on achieving maximal safe resection, followed by chemo- and radiotherapy. Although surgery remains the most important therapeutic component, complete surgical resection is virtually impossible, as GBM cells readily infiltrate the adjacent brain parenchyma. One fundamental mechanism for GBM cell migration is the ability of these cells to use cell volume regulation as a driving force of cell infiltration and potentially interfering with apoptosis and cell cycle progression. In this work, we targeted the master regulators of cell volume, the kinases STE20/SPS1-Related Proline-Alanine-Rich Protein Kinase (SPAK) and Oxidative stress-responsive kinase-1) (OSR1) by using a novel proprietary small molecule inhibitor. In order to study the effects of inhibiting SPAK and OSR1, we analyzed cell proliferation and migration. First, we determined the IC50 using six different patient-derived GBM cell lines; we found IC50 values ranging from 0.2–2μM. Next, cell proliferation was determined by cell cycle analysis through Edu labeling. We found a significant decrease in S phase and cell cycle arrest in G2M (p= 0.001, n=6). In addition, cell migration was determined using boyden chamber assay. We found a dose-dependent reduction in cell migration (p=0.001, n=3). These results correlated with the phenomenon observed in an orthotopic murine model of GBM, in which the inhibitor showed a decrease in tumor growth (p=0.0026, n=4) and greater survival rates in vivo (p=0.0046, n=8). When used in combination with radiation therapy, this small molecule inhibitor was capable of radio-sensitizing GBM cells decreasing clonogenicity (p=0.01, n=3) were observed in vitro. In summary, by targeting the SPAK/OSR1 kinases with a small molecule inhibitor, GBM cells become less aggressive, mainly by interfering with cell migration and proliferation and becoming more sensitive to radiation.

Glioblastoma (GBM), also known as grade IV astrocytoma, is the most common and devastating primary cancer of the central nervous system in adults. Despite the most advanced therapeutic strategies combining surgery, chemotherapy, and radiation, survival expectancy of GBM patients averages 14 months, with a recurrence rate of almost 100%. Remarkably, tumor location has great implications in the prognosis of GBM. Approximately 50-60% of GBM tumors infiltrates or contacts the subventricular zone (SVZ). These patients have significantly worse outcomes, in terms of median overall survival, time to progression and reoccurrence. The reason for the worse prognosis of SVZ-infiltrating tumors is unknown. The SVZ is the largest neurogenic niche in the adult brain, here the differentiation and migration of SVZ cells is regulated by direct contact with the cerebrospinal fluid (CSF). We suggest that CSF contribute to enhance GBM malignant characteristics in SVZ-infiltrating tumors. This study evaluated the impact of CSF exposure on GBM cells proliferation, migration in vitro and in vivo, as well as changes in gene expression profile. We demonstrated that CSF affects the malignancy of GBM cells by increasing their ability to proliferate and migrate. GBM cells stimulated with cancer CSF, non-cancer CSF, or control conditions at different time points (24-72 hrs) were evaluated for viability (by Alamar Blue assay) and proliferation rate (Ki67+ immunostaining), as well as for migratory capabilities (by means of transwell assay and time-lapse microscopy). We recapitulated these CSF effects in vivo using an in vivo model in which both female and male nude mice were implanted with GBM cells in suspension with human cancer or non-cancer CSF in an hydrogel as vehicle (n=8 mice per group). Tumor growth was followed via IVIS imaging and then studied by measuring tumor area on H&E slides and immunohistochemistry staining for Ki67, 21 days after tumor implantation. Animals receiving cancer CSF presented with greater tumor size and Ki67 proliferation index. To further dissect the mechanisms behind these observations, we performed a transcriptome analysis of CSF-treated GBM cells. At the molecular level we observed that cancer CSF induced changes in pathways regulating apoptosis, survival, integrins signaling, angiogenesis, glucose metabolism and response to inflammatory stimuli, all of which might be responsible for the increase in GBM malignancy. Taken together, this study provides direct evidence that CSF is an important player in determining tumor growth and invasion through the activation of complex gene expression patterns characteristic of a malignant phenotype. Understanding the interaction of brain tumors and CSF may lead to new therapeutic strategies that will target the CSF components in GBM patients. Citation Format: Anna Carrano, Jordan Phillipps, Montserrat Lara-Velazquez, Natanael Zarco, Paola Suarez-Meade, Kaisorn Chaichana, Alfredo Quinones-Hinojosa, Yan Asmann, Hugo Guerrero-Cázares. The role of human cerebrospinal fluid in glioblastoma malignancy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1574.

Background Mycetoma is a chronic, granulomatous infection of subcutaneous tissue, that may involve deep structures and bone. It can be caused by bacteria (actinomycetoma) or fungi (eumycetoma). There is an epidemiological association between mycetoma and the environment, including rainfall, temperature and humidity but there are still many knowledge gaps in the identification of the natural habitat of actinomycetes, their primary reservoir, and their precise geographical distribution. Knowing the potential distribution of this infection and its ecological niche in endemic areas is relevant to determine disease management strategies and etiological agent habitat or reservoirs. Methodology/principal findings This was an ambispective descriptive study of 31 patients with actinomycetoma. We determined the biophysical characteristics including temperature, precipitation, soil type, vegetation, etiological agents, and mapped actinomycetoma cases in Northeast Mexico. We identified two disease cluster areas. One in Nuevo Leon, with a predominantly kastanozems soil type, with a mean annual temperature of 22°, and a mean annual precipitation of 585.2 mm. Herein, mycetoma cases were produced by Actinomadura pelletieri, Actinomadura madurae, Nocardia brasiliensis, and Nocardia spp. The second cluster was in San Luis Potosi, where lithosols soil type predominates, with a mean annual temperature of 23.5° and a mean annual precipitation of 635.4 mm. In this area, all the cases were caused by N. brasiliensis. A. madurae cases were identified in rendzinas, kastanozems, vertisols, and lithosols soils, and A. pelletieri cases in xerosols, kastanozems, and rendzinas soils. Previous thorn trauma with Acacia or Prosopis plants was referred by 35.4% of subjects. In these states, the presence of thorny plants, such as Acacia spp., Prosopis spp., Senegalia greggi, Vachellia farnesiana and Vachellia rigidula, are common. Conclusions/significance Mapping this neglected tropical infection aids in the detection of disease cluster areas, the development of public health strategies for early diagnosis and disease prediction models; this paves the way for more ecological niche etiological agent research.

BackgroundIdentification of a safe and effective medical therapy for abdominal aortic aneurysm (AAA) disease remains a significant unmet medical need. Recent small cohort studies indicate that metformin, the world's most commonly prescribed oral hypoglycemic agent, may limit AAA enlargement. We sought to validate these preliminary observations in a larger cohort.MethodsAll patients with asymptomatic AAA disease managed in the Veterans Affairs Health Care System between 2003 and 2013 were identified by International Classification of Diseases, Ninth Revision codes. Those with a concomitant diagnosis of diabetes mellitus who also received two or more abdominal imaging studies (computed tomography, magnetic resonance imaging, or ultrasound) documenting the presence and size of an AAA, separated by at least 1year, were included for review. Maximal AAA diameters were determined from radiologic reports. Further data acquisition was censored after surgical AAA repair, when performed. Comorbidities, active smoking status, and outpatient medication records (within 6months of AAA diagnosis) were also queried. Yearly AAA enlargement rates, as a function of metformin treatment status, were compared using two statistical models expressed in millimeters per year: a multivariate linear regression (model 1) and a multivariate mixed-effects model with random intercept and random slope (model 2).ResultsA total of 13,834 patients with 58,833 radiographic records were included in the analysis, with radiology imaging follow-up of 4.2± 2.6years (mean± standard deviation). The average age of the patients at AAA diagnosis was 69.8± 7.8years, and 39.7% had a metformin prescription within±6months of AAA. The mean growth rate for AAAs in the entire cohort was 1.4± 2.0mm/y by model 1 analysis and 1.3± 1.6mm/y by model 2 analysis. The unadjusted mean rate of AAA growth was 1.2± 1.9mm/y for patients prescribed metformin compared with 1.5± 2.2mm/y for those without (P< .001), a 20% decrease. This effect remained significant when adjusted for variables relevant on AAA progression: metformin prescription was associated with a reduction in yearly AAA growth rate of-0.23mm (95% confidence interval,-0.35 to-0.16; P< .001) by model 1 analysis and 0.20mm/y (95% confidence interval,-0.26 to-0.14; P< .001) by model 2 analysis. A subset analysis of 7462 patients with baseline AAA size of 35 to 49mm showed a similar inhibitory effect (1.4± 2.0mm/y to 1.7± 2.2mm/y; P< .001). Patients' factors associated with an increased yearly AAA growth rate were baseline AAA size, metastatic solid tumors, active smoking, chronic obstructive pulmonary disease, and chronic renal disease. Factors associated with decreased yearly AAA growth rates included prescriptions for angiotensin II type 1 receptor blockers or sulfonylureas and the presence of diabetes-related complications.ConclusionsIn a nationwide analysis of diabetic Veterans Affairs patients, prescription for metformin was associated with decreased AAA enlargement. These findings provide further support for the conduct of prospective clinical trials to test the ability of metformin to limit progression of early AAA disease.

Periarterial sympathectomy is a treatment option for patients with systemic sclerosis (SSc) suffering from digital vasculopathy. Despite potential benefits of ulcer healing, pain improvement, and amputation prevention, this operation appears to be infrequently performed. The aims of our study are as follows: (1) to assess national digital sympathectomy rates in patients with SSc and (2) to improve our understanding of referring physicians' perceptions of operative management and access to hand surgeons. Our hypothesis is that rheumatologists' practices largely influence their referral patterns for digital sympathectomy.To determine the rates and demographics of hospitalized patients with SSc who had undergone digital sympathectomy, we queried the Nationwide Inpatient Sample from 2006 to 2010. Additionally, we mailed a self-administered survey to a national sample of 500 board-certified rheumatologists to elicit their practice patterns and perceptions of digital sympathectomy. Using logistic regression, we analyzed potential predictor variables associated with rheumatologists performing the following: (1) routinely counseling patients about digital sympathectomy and (2) expressing the desire to refer these patients for operative evaluation.Of 348,539 hospitalizations associated with a diagnosis of SSc, only 0.2% were for digital sympathectomy. Our questionnaire revealed that only 50% of rheumatologists routinely counseled, whereas 67% expressed the desire to refer. Factors associated with increased rheumatologists' interest in surgical management for patients with SSc included positive perception of the operation's efficacy, comfort with postoperative management, and interdisciplinary relationship with a hand surgeon.Critical components to increasing appropriate utilization of digital sympathectomy include enhancing rheumatologists' understanding of the operation, comfort with postoperative management, and promoting strong, interdisciplinary relationships with hand surgeons. Increasing education and awareness, as well as establishing a solid referral network of hand surgeons may thereby improve patient access to digital sympathectomy.

Survey. To determine whether upper extremity reconstruction in patients with tetraplegia is underutilized internationally and, if so, what are the barriers to care. International—attendees of a meeting in Paris, France. One hundred and seventy attendees at the Tetrahand meeting in Paris in 2010 were sent a 13-question survey to determine the access and utilization of upper limb reconstruction in tetraplegic patients in their practice. Respondents ranged the globe including North America, South America, Europe, Asia and Australia. Fifty-nine percent of respondents had been practicing for more than 10 years. Sixty-four percent of respondents felt that at least 25% of people with tetraplegia would be candidates for surgery. Yet the majority of respondents found that

Objective Socio-cultural factors obscure diagnostic specificity for neurodegenerative disorders, particularly among minority or foreign-born patients with limited access to education. Our objective with the following case presentation is to illustrate the utility of a Socially Responsible Neuropsychology (SRN) model in guiding clinical practice through the comprehensive incorporation of significant, yet common, socio-cultural factors throughout the neuropsychological assessment. Method The present case involved a 79-year-old Spanish-speaking Mexican woman with two years of education, who underwent two serial neuropsychological assessments, as well as, structural/functional neuroimaging to monitor acute onset of telegraphic speech following the kidnapping of her husband. The SRN model guided clinical decision-making in understanding the onset and progression of symptoms within the context of medical-psychiatric comorbidities intertwined with socio-cultural and educational factors. Results Mild vascular neurocognitive disorder and complicated grief were the initial diagnostic impressions as supported by structural neuroimaging. Neuropsychological assessment over time, however, revealed progressive global cognitive decline whereas psychiatric symptomatology remained stable. In the presence of equivocal converging evidence from available neuroimaging studies (PET vs MRI), strong suspicion for the language variant of frontotemporal neurocognitive disorder was considered given the onset and progressive decline of expressive/receptive language, executive and memory abilities, and qualitative evidence for progressive behavioral disihibition. Conclusion Telegraphic speech in an elderly Latina woman that initially appeared most consistent with vascular neurocognitive disorder in the context of complex trauma with possible conversion disorder, was deemed most consistent with a neurodegenerative process after careful consideration of the time course and evolution of the neurocognitive profile over time within an SRN model.

Background Immunization with neural derived peptides (INDP) as well as scar removal—separately—have shown to induce morphological and functional improvement after spinal cord injury (SCI). In the present study, we compared the effect of INDP alone versus INDP with scar removal on motor recovery, regeneration-associated and cytokine gene expression, and axonal regeneration after chronic SCI. Scar removal was conducted through a single incision with a double-bladed scalpel along the stump, and scar renewal was halted by adding α,α′-dipyridyl. Results During the chronic injury stage, two experiments were undertaken. The first experiment was aimed at testing the therapeutic effect of INDP combined with scar removal. Sixty days after therapeutic intervention, the expression of genes encoding for TNFα, IFNγ, IL4, TGFβ, BDNF, IGF1, and GAP43 was evaluated at the site of injury. Tyrosine hydroxylase and 5-hydroxytryptamine positive fibers were also studied. Locomotor evaluations showed a significant recovery in the group treated with scar removal + INDP. Moreover; this group presented a significant increase in IL4, TGFβ, BDNF, IGF1, and GAP43 expression, but a decrease of TNFα and IFNγ. Also, the spinal cord of animals receiving both treatments presented a significant increase of serotonergic and catecholaminergic fibers as compared to other the groups. The second experiment compared the results of the combined approach versus INDP alone. Rats receiving INDP likewise showed improved motor recovery, although on a lesser scale than those who received the combined treatment. An increase in inflammation and regeneration-associated gene expression, as well as in the percentage of serotonergic and catecholaminergic fibers was observed in INDP-treated rats to a lesser degree than those in the combined therapy group. Conclusions These findings suggest that INDP, both alone and in combination with scar removal, could modify the non-permissive microenvironment prevailing at the chronic phase of SCI, providing the opportunity of improving motor recovery.

Spinal cord injury (SCI) is a phenomenon characterized by damage to the spinal cord and nerve roots, resulting in loss of physiological activity below the lesion. Injury to the spinal cord activates a cascade of cellular and molecular reactions in which the immune system plays an essential role, as there is an uncontrolled immune response that endows further damage to neural tissue. However, the activity of immune system at the site of injury can be modified in order to obtain a neuroprotective environment and promote SCI recovery. This strategy has been designed under the light of the innovative concept “protective autoimmunity” (PA) and can be stimulated with the use of altered peptide ligands (APL). Adequate immunomodulation with APL can be obtained with the peptide A91, which is a safe synthetic peptide derived from the myelin basic protein (MBP) that has proven to be effective in preclinical research. Immunization with A91 is carried out with the objective of preventing further damage and promoting neuropro‐ tection. This peptide has direct influence over SCI secondary mechanisms such as inflammation, lipid peroxidation, and apoptosis. Preclinical results suggest that immunization with A91 could be an effective treatment in the clinical field, providing a better quality of life to SCI patients.

Methamphetamine (meth) abuse is increasingly of public health concern and has been associated with neurocognitive dysfunction. Some previous studies have been hampered by background differences between meth users and comparison subjects, as well as unknown HIV and hepatitis C (HCV) status, which can also affect brain functioning. We compared the neurocognitive functioning of 54 meth dependent (METH+) study participants who had been abstinent for an average of 129 days, to that of 46 demographically comparable control subjects (METH-) with similar level of education and reading ability. All participants were free of HIV and HCV infection. The METH+ group exhibited higher rates of neuropsychological impairment in most areas tested. Among meth users, neuropsychologically normal (n=32) and impaired (n=22) subjects did not differ with respect to self-reported age at first use, total years of use, route of consumption, or length of abstinence. Those with motor impairment had significantly greater meth use in the past year, but impairment in cognitive domains was unrelated to meth exposure. The apparent lack of correspondence between substance use parameters and cognitive impairment suggests the need for further study of individual differences in vulnerability to the neurotoxic effects of methamphetamine.

Background The purpose of the study was to examine the relationship between age and plasma viral load in HIV-1-infected individuals. Design The experimental method was to recruit older (> 50 years of age) and younger (18-39 years of age) HIV-1-infected individuals. The plasma viral load was measured using the Roche Molecular Systems UltraSensitive Roche HIV-1 Monitor test reflexively with the standard Amplicor HIV Monitor test to quantify viral load in the range of 50-750,000 copies of HIV-1 RNA/ml plasma. Subjects A total of 135 HIV-1-seropositive individuals (at Centers for Disease Control and Prevention early symptomatic stage B or late symptomatic stage/AIDS C) were enrolled as part of a larger cohort also consisting of HIV-1-seronegative individuals. Results A generalized linear models statistical analysis was conducted in order to evaluate age category as a predictor of plasma viral load. The result was a significant effect of age category, with older age associated with a lower plasma viral load. The association held controlling for antiretroviral therapy usage, disease stage, antiretroviral medication adherence, HIV-1 serostatus duration, alcohol and substance use, recent sexually transmitted disease, and sociodemographics (except income). Conclusion Older age was associated with lower levels of HIV-1 replication in this sample, independent of antiretroviral therapy usage, regimen adherence, and disease stage. It is suggested that the effect may be caused by changes in viral evolution or immunological monitoring specific to older individuals with HIV-1 infection.

Older HIV-1-seropositive individuals largely have not been investigated with respect to their psychosocial characteristics. In this article, the authors review research reported to date regarding the psychosocial context of this growing subgroup of HIV-1-infected individuals. Specifically, the authors consider the characteristics of mood state, life stressor burden, social support network, and coping strategies that individuals older than 50 years are more likely to adopt in adjusting to HIV-1 infection. The authors also separately consider issues of caregiving burden. Data supporting a theoretically based stressor-support-coping model are presented and related to targeting psychotherapeutic interventions for this age group.

Spinal cord (SC) injury is a neurological emergency that results in complications increasing in number and severity according to the level of the injury. Systemic response after SC injury may alter hematological and biochemical parameters. The present study was designed to investigate the effect of the lesion depending on its level and severity in order to provide a prognosis during its acute (24 hours post injury) and subacute (15 days post injury) phases. We hypothesized that hematologic and biochemical parameters will depend directly on the site, severity and phase of the lesion. Rats were subjected to T1 (high) or T11 (low) severe or moderate SC injury. Rats that were anesthetized but did not receive surgical procedure were used as controls. Blood samples were obtained 24 hours and 15 days post injury for acute and subacute analysis respectively. Results show that in both acute and subacute phases, the level of injury is not related to hematological alterations, in contrast, severity interferes with the normal blood cell count, hematocrit and hemoglobin concentrations. Regarding biochemical values, neither level, nor severity of injury are related to changes. It is worth mentioning that on the subacute phase almost all of the altered variables, that appeared during the acute stage of injury, tend to return to their normal values. The variation on both hematological and biochemical parameters may also be caused by hemorrhage, liver damage and inflammatory responses due to secondary mechanisms inflicted by SC injury. These findings help to understand the pathophysiology observed after injury and provide data that contribute to improve the initial management and the design of future therapies after SC injury.

Objective To assess the risks associated with surgical and nonsurgical care of femur fractures in people with spinal cord injury (SCI). Design Retrospective cohort study; an analysis of Veterans Affairs (VA) data from the National Patient Care Database. Setting Administrative data from database. Participants The cohort was identified by searching the administrative data from fiscal years 2001 to 2006 for veterans with a femur fracture diagnosis using the International Classification of Diseases, 9th Revision, Clinical Modification codes. This group was subdivided into those with (n=396) and without (n=13,350) SCI and those treated with and without surgical intervention. Interventions Not applicable. Main Outcome Measures Rates of mortality and adverse events. Results The SCI group was younger with more distal fractures than the non-SCI group. In the non-SCI population, 78% of patients had associated surgical codes compared with 37% in the SCI population. There was higher mortality in the non-SCI group treated nonoperatively. In the SCI population, there was no difference in mortality between patients treated nonoperatively and operatively. Overall adverse events were similar between groups except for pressure sores in the SCI population, of which the nonoperative group had 20% and the operative had 7%. Rates of surgical interventions for those with SCI varied greatly among VA institutions. Conclusions We found lower rates of surgical intervention in the SCI population. Those with SCI who had surgery did not have increased mortality or adverse events. Surgical treatment minimizes the risks of immobilization and should be considered in appropriate SCI patients.

Carpal tunnel syndrome (CTS) is a common disorder among individuals with spinal cord injury (SCI). Although carpal tunnel release is highly effective, the procedure may be under-utilized in this population. This study attempts to identify if CTS is under-treated in Veterans with SCI.The Veterans Affairs (VA) National Patient Care Database was used for data compilation within fiscal years 2007 and 2008. Using ICD-9-CM diagnoses codes, individuals with SCIs were identified, including those diagnosed with CTS. Current procedural terminology (CPT) codes further showed those who had undergone surgical intervention including open and endoscopic release of the transverse carpal ligament. The VA SCI cohort was compared to the general VA population with regard to demographics, diagnosis, surgical intervention, and treatment location.A total of 19 296 veterans with SCI were identified within the 2-year period. The prevalence of CTS within this cohort was 3.5%, compared to 2.1% in the general VA population. The rate of transverse carpal ligament release was similar between the VA SCI cohort and general population (0.24 and 0.17%, respectively). The majority of surgical treatment (89%) occurred within the VA 'hub-and-spoke' system of SCI care.CTS appears to be under-diagnosed and under-treated in veterans with SCI.

In young adults, a major neurologic complication of HIV-1 infection is cognitive motor impairment. Epidemiologic findings suggest that increasing age is a significant risk factor for HIV-1-associated dementia as the AIDS-defining illness. Findings from the few studies that have directly measured cognition in younger and older HIV-1-infected adults, however, have been mixed, in part, because of small sample sizes and other methodologic differences between studies. The authors present preliminary findings on cognitive functioning in symptomatic HIV-1-infected younger (aged 20-39 years) and older (aged 50 years or older) adults. Independent of age, HIV-1 infection was accompanied by learning and memory retrieval deficits, which were significantly associated with high plasma viral loads in the young adults. Relative to the younger and older HIV-1-negative (HIV-1-) groups, only the younger HIV-1-positive (HIV-1+) group had significantly longer reaction times (RTs). Within the older HIV-1+ group, however, longer simple and choice RTs were significantly correlated with higher viral loads and lower CD4 cell counts. Although HIV-1 infection affects cognition independent of age, longitudinal studies involving large numbers of older individuals are needed to determine whether there are age differences in the prevalence, nature, and severity of HIV-1-associated cognitive dysfunction.

Cerebrovascular diseases are considered to be amongst the most serious public health issues, since they are the third leading cause of death (WHO, 2014) and the most common cause of disability worldwide. Its monetary significance is evidenced by the economic burden imposed on health care systems, given that the cost of medical care for a patient that has suffered a stroke is around $25,741 US dollars every 5 years (Luengo-Fernandez et al., 2012). A stroke occurs as a result of a disturbance or interruption of cerebral blood flow that significantly reduces the supply of oxygen and glucose to the neural tissue. Consequently, several cell death mechanisms (secondary lesion mechanisms) such as necrosis, excitotoxicity, free radical production and inflammation are triggered (Castillo, 2000). Over the last decades, a variety of therapies with thrombolytic, neuroprotective, and restorative properties have been investigated. However, the results of these studies appear to be limited. That is the case of the tissue plasminogen activator (tPA) – the first line of treatment for decades – which is associated with low rates of recanalization and high rates of morbidity. Also, endovascular intervention, particularly mechanical thrombectomy, has been proposed as a promising therapeutic adjunct to tPA for the treatment of stroke; however, until recently, the efficacy of this therapeutic approach has been controversial (Ding, 2015). Innovative theurapeutic options are currently being developed in order to restore affected neuronal circuits following a cerebral ischemic event. Some of these innovative therapeutic approaches are based on stem cell transplantation and/or induction of neurogenesis.