Search

Combining our data with these prior reports, focusing on WHO grade 1 meningiomas only, Clark et al. found I TRAF7 i co-mutations in 50/68 I AKT1 i -mutant intracranial meningiomas (15 were I AKT1 i "isolated", and 3 were co-mutant for I AKT1/NF2 i ), while we observed only 1 of 15 co-mutant tumors. In contrast to I AKT1 i -mutant intracranial meningiomas, where I TRAF7 i mutations are found to co-occur very frequently [[5]], we observed only a single I AKT1 i -mutant SM case with a I TRAF7 i co-mutation. Subsequently, Sahm et al. screened 1437 tumors for I AKT1 i mutations and found 65 mutant cases, including 6 I AKT1 i -mutant cases in 57 SMs [[10]], and described a strong association between I AKT1 i SP I E17K i sp mutations and spinal tumor localization. [Extracted from the article]

Treatment of osteoporosis with medications like teriparatide, a parathyroid hormone, is known to improve bone density and reduce the risk of osteoporotic vertebral fractures. Anecdotal and limited surgical series have described the utility of this treatment for osteoporotic patients prior to spinal fusion surgery, but there is variability in adoption of this strategy as well as consensus regarding optimal treatment duration before and after surgery. In this study, the clinical results of the use of teriparatide for this application are reviewed and critically examined. We conducted a systematic review of electronic databases using different MeSH terms from 1980 to 2020. Pooled and subgroup analyses were performed using fixed and random effect models based upon the heterogeneity (I2). The results were reported as either mean difference (MD) or odds ratio (OR) with 95% confidence interval (CI). A total of 771 patients from 12 studies were identified. Three hundred seventy-seven patients (90.8% females) were treated with teriparatide. Lumbar spinal fusion rates were significantly higher among patients who received teriparatide compared to the non-teriparatide group (OR 2.15, 95%CI 1.56–2.97, p < 0.00001). Subgroup analysis revealed that patients receiving teriparatide demonstrated 2.12-fold and 2.23-fold higher likelihood of fusion compared to those in the bisphosphonate (OR 2.12, 95%CI 1.45–3.11, p = 0.0001) and placebo (OR 2.23, 95%CI 1.22–4.08, p = 0.009) cohorts, respectively. The treatment effect of teriparatide was associated with significantly reduced subsequent vertebral fractures (OR 0.16, 95%CI 0.06–0.41, p = 0.0002), sagittal malalignment (MD − 3.85, 95%CI: −6.49 to − 1.21, p = 0.004), limb visual analogue score (VAS) (MD − 0.36, 95%CI − 0.64 to − 0.09, p = 0.008), and spinal VAS (MD − 0.24, 95%CI − 0.44 to − 0.04, p = 0.02) compared to the non-teriparatide group. Patients using teriparatide had 30% less likelihood of screw loosening at last follow-up compared to the non-teriparatide group; however, this was not statistically significant (OR 0.70, 95%CI 0.43–1.14, p = 0.15). There did not exist any statistically significant difference between the two comparative groups in terms of pseudoarthrosis (OR 0.54, 95%CI 0.24–1.21, p = 0.13), cage subsidence (OR 1.30, 95%CI 0.38–4.52, p = 0.68), and bone mineral density (MD 0.04, 95%CI − 0.19–0.29, p = 0.74) at last follow-up examination. This meta-analysis corroborates the effectiveness of teriparatide resulting in higher fusion rates. Further study is required to determine the optimal duration of treatment and timing of surgery. [ABSTRACT FROM AUTHOR]

Tranexamic acid (TXA) is an effective and commonly used hemostatic agent for perioperative blood loss in various surgical specialties. It is being increasingly used in spinal deformity surgery. We aimed to evaluate the safety and efficacy of topical TXA (tTXA) compared to both placebo and/or intravenous (IV) TXA in patients undergoing spinal deformity surgery. We conducted a systematic review of the electronic databases using different MeSH terms from January 1970 to August 2019. Pooled and subgroup analysis was performed using fixed and random-effect model based upon the heterogeneity (I2). A total of 609 patients (tTXA: n = 258, 42.4%) from 8 studies were included. We found that there was a statistically significant difference in terms of (i) postoperative blood loss [mean difference (MD) − 147.1, 95% CI − 189.5 to − 104.8, p < 0.00001], (ii) postoperative hemoglobin level (MD 1.09, 95% CI 0.45 to 1.72, p = 0.0008), (iii) operative time (MD 7.47, 95% CI 2.94 to 12.00, p < 0.00001), (iv) postoperative transfusion rate [odds ratio (OR) 0.39, 95% CI 0.20 to 0.78, p = 0.007], postoperative drain output (MD, − 184.0, 95% CI − 222.03 to − 146.04, p < 0.00001), and (v) duration of hospital stay (MD − 1.14, 95% CI − 1.44 to − 0.85, p < 0.00001) in patients treated with tTXA compared to the control group. However, there was no significant difference in terms of intraoperative blood loss (p = 0.13) and complications (p = 0.23) between the two comparative groups. Furthermore, low-dose (250–500 mg) tTXA (p < 0.00001) reduced postoperative blood loss more effectively compared to high-dose tTXA (1–3 g) (p = 0.001). Our meta-analysis corroborates the effectiveness and safety of tTXA in spinal deformity surgery. [ABSTRACT FROM AUTHOR]

Papillary meningioma (PM) is a World Health Organization (WHO) grade III tumor defined histologically by a perivascular pseudopapillary growth pattern across most of the tumor (> 50%) [[10]]. Our findings suggest that I BAP1 i mutations tend to occur in rhabdoid meningiomas whereas I PBRM1 i mutations tend to occur in papillary meningiomas, although genetic and histologic overlap is noted. Although our findings suggest that I PBRM1 i mutation is uncommon in meningioma, the inclusion of patients with this defined genetic subtype of meningioma in similar trials may reveal new therapeutic approaches. In conclusion, we identify the tumor suppressor gene I PBRM1 i as a recurrently altered gene in meningiomas with papillary histomorphology. [Extracted from the article]

Progressive meningiomas that have failed surgery and radiation have a poor prognosis and no standard therapy. While meningiomas are more common in females overall, progressive meningiomas are enriched in males. We performed a comprehensive molecular characterization of 169 meningiomas from 53 patients with progressive/high-grade tumors, including matched primary and recurrent samples. Exome sequencing in an initial cohort (n = 24) detected frequent alterations in genes residing on the X chromosome, with somatic intragenic deletions of the dystrophin-encoding and muscular dystrophy-associated DMD gene as the most common alteration (n = 5, 20.8%), along with alterations of other known X-linked cancer-related genes KDM6A (n =2, 8.3%), DDX3X, RBM10 and STAG2 (n = 1, 4.1% each). DMD inactivation (by genomic deletion or loss of protein expression) was ultimately detected in 17/53 progressive meningioma patients (32%). Importantly, patients with tumors harboring DMD inactivation had a shorter overall survival (OS) than their wild-type counterparts [5.1 years (95% CI 1.3-9.0) vs. median not reached (95% CI 2.9-not reached, p = 0.006)]. Given the known poor prognostic association of TERT alterations in these tumors, we also assessed for these events, and found seven patients with TERT promoter mutations and three with TERT rearrangements in this cohort (n = 10, 18.8%), including a recurrent novel RETREG1-TERT rearrangement that was present in two patients. In a multivariate model, DMD inactivation (p = 0.033, HR = 2.6, 95% CI 1.0-6.6) and TERT alterations (p = 0.005, HR = 3.8, 95% CI 1.5-9.9) were mutually independent in predicting unfavorable outcomes. Thus, DMD alterations identify a subset of progressive/high-grade meningiomas with worse outcomes. [ABSTRACT FROM AUTHOR]

The article discusses a study related to supratentorial gliomas which reveals discrete genomic alterations to discriminate discriminate pilocytic astrocytomas, diffuse gliomas, and glioblastoma. Topics discussed includes co-deletion of chromosomes not revealed by loss of heterozygosity analysis for variant allele frequency, assess for the changes by transcriptional analysis of spinal cord astrocytomas, and success in BRAF-mutant cancer types with the BRAFâ€MEK inhibitors.

Purpose: Despite the popularity and an increased use of bone morphogenetic protein to improve bone healing in patients with congenital pseudoarthrosis of the tibia (CPT), no previous study has compared its efficacy against any other procedure. Methods: We randomised 20 consecutive patients (mean age 4.1 years) with CPT (Crawford type IV) associated with neurofibromatosis type 1(NF1) and no previous history of surgery into two groups. Group 1 received recombinant human bone morphogenetic protein-7 (rhBMP-7) along with intramedullary Kirschner (K)-wire fixation and autologous bone grafting; group 2 received only K wire and grafting. Outcome measures were time to achieve union, Johnston grade, tibial length and the American Orthopaedic Foot and Ankle Society (AOFAS) score, which were evaluated preoperatively and at five year follow-up. Results: Study results showed that patients in group 1 achieved primary bone union at a mean of 14.5 months [standard error (SE) 5.2], whereas group 2 took a mean of 17.11 months (SE 5.0). However, the log-rank test showed no difference in healing times between groups at all time points ( P = 0.636). There was a statistically significant pre- to post operative improvement ( P < 0.05) within groups for the other outcome measures. Conclusion: In a five year follow-up, these results suggest that rh-BMP-7 and autologous bone grafting is no better than autologous grafting alone. [ABSTRACT FROM AUTHOR]

In this paper, a typical 3-degree of freedom (3-DOF) translational parallel kinematic machine (PKM) is studied and analyzed whose tool platform has only translations along X-, Y- and Z-axes. It consists of three limbs, each of which have arm and forearm with prismatic-revolute-revolute-revolute (PRRR) joints. Inverse kinematics analysis is carried out to find the slider coordinates and joint angles for a given position of tool platform. Stiffness modeling is done based on the compliance matrices of arm and forearm of each limb. Using the stiffness modeling the variations of minimum and maximum translational stiffness in the workspace are analyzed. For various architectural parameters of the 3-DOF PKM the tendency of variations on the minimum and maximum stiffness over the entire workspace is studied; and also the deflections of the tool platform along X, Y, and Z directions with respect to various forces are presented. [ABSTRACT FROM AUTHOR]

In this paper, error modeling and analysis of a typical 3-degree of freedom translational Parallel Kinematic Machine is presented. This mechanism provides translational motion along the Cartesian X-, Y- and Z-axes. It consists of three limbs each having an arm and forearm with prismatic-revolute-revolute-revolute joints. The moving or tool platform maintains same orientation in the entire workspace due to its joint arrangement. From inverse kinematics, the joint angles for a given position of tool platform necessary for the error modeling and analysis are obtained. Error modeling is done based on the differentiation of the inverse kinematic equations. Variation of pose errors along X, Y and Z directions for a set of dimensions of the parallel kinematic machine is presented. A non-dimensional performance index, namely, global error transformation index is used to study the influence of dimensions and its corresponding global maximum pose error is reported. An attempt is made to find the optimal dimensions of the Parallel Kinematic Machine using Genetic Algorithms in MATLAB. The methodology presented and the results obtained are useful for predicting the performance capability of the Parallel Kinematic Machine under study. [ABSTRACT FROM AUTHOR]

Purpose: Primary intraosseous spinal malignant peripheral nerve sheath tumor (MPNST) is exceedingly rare. MPNST with multifocal origin has been described to occur in the extremities. Such a lesion has not been described to occur in the spine. We describe a case of multifocal spinal MPNST and to review the literature relevant to this rare entity and its management. Methods: A 40-year-old immunodeficient patient presented with rapidly progressive paraparesis and mid back ache. Results: Despite aggressive surgical decompression, he developed multiple metastases 3 months after surgery. However, he remained stable for 1 year without any adjuvant therapy. Presently, he has received palliative radiotherapy for spinal recurrence and cerebral metastasis. Conclusion: Multifocal spinal MPNST is a rare lesion. In this instance, the multifocality of the disease and its odd location could be attributed to the immunodeficiency state. The prolonged survival could be due to an improvement in his immune status due to HAART. [ABSTRACT FROM AUTHOR]

Presence of single umbilical persistent vitelline artery distinguishes sirenomelia from caudal regression syndrome. We report a case of a12 - year - old boy who had bilateral umbilical arteries presented with fusion of both legs in the lower one third of leg. Both feet were rudimentary. The right foot had a valgus rocker - bottom deformity. All toes were present but rudimentary. The left foot showed absence of all toes. Physical examination showed left tibia vara. The chest evaluation in sitting revealed pigeon chest and elevated right shoulder. Posterior examination of the trunk showed thoracic scoliosis with convexity to right. The patient was operated and at 1 year followup the boy had two separate legs with a good aesthetic and functional results. [ABSTRACT FROM AUTHOR]

Alzheimer's disease constitutes a rising threat to public health. Despite extensive research in cellular and animal models, identifying the pathogenic agent present in the human brain and showing that it confers key features of Alzheimer's disease has not been achieved. We extracted soluble amyloid-β protein (Aβ) oligomers directly from the cerebral cortex of subjects with Alzheimer's disease. The oligomers potently inhibited long-term potentiation (LTP), enhanced long-term depression (LTD) and reduced dendritic spine density in normal rodent hippocampus. Soluble Aβ from Alzheimer's disease brain also disrupted the memory of a learned behavior in normal rats. These various effects were specifically attributable to Aβ dimers. Mechanistically, metabotropic glutamate receptors were required for the LTD enhancement, and N-methyl D-aspartate receptors were required for the spine loss. Co-administering antibodies to the Aβ N-terminus prevented the LTP and LTD deficits, whereas antibodies to the midregion or C-terminus were less effective. Insoluble amyloid plaque cores from Alzheimer's disease cortex did not impair LTP unless they were first solubilized to release Aβ dimers, suggesting that plaque cores are largely inactive but sequester Aβ dimers that are synaptotoxic. We conclude that soluble Aβ oligomers extracted from Alzheimer's disease brains potently impair synapse structure and function and that dimers are the smallest synaptotoxic species. [ABSTRACT FROM AUTHOR]

One of the most clinically advanced forms of experimental disease-modifying treatment for Alzheimer disease is immunization against the amyloidßprotein (Aß), but how this may prevent cognitive impairment is unclear. We hypothesized that antibodies to Aßcould exert a beneficial action by directly neutralizing potentially synaptotoxic soluble Aßspecies in the brain. Intracerebroventricular injection of naturally secreted human Aßinhibited long-term potentiation (LTP), a correlate of learning and memory, in rat hippocampus in vivo but a monoclonal antibody to Aßcompletely prevented the inhibition of LTP when injected after Aß. Size fractionation showed that Aßoligomers, not monomers or fibrils, were responsible for inhibiting LTP, and an Aßantibody again prevented such inhibition. Active immunization against Aßwas partially effective, and the effects correlated positively with levels of antibodies to Aßoligomers. The ability of exogenous and endogenous antibodies to rapidly neutralize soluble Aßoligomers that disrupt synaptic plasticity in vivo suggests that treatment with such antibodies might show reversible cognitive deficits in early Alzheimer disease. [ABSTRACT FROM AUTHOR]

A central unresolved problem in research on Alzheimer disease is the nature of the molecular entity causing dementia. Here we provide the first direct experimental evidence that a defined molecular species of the amyloid-ßprotein interferes with cognitive function. Soluble oligomeric forms of amyloid-ß, including trimers and dimers, were both necessary and sufficient to disrupt learned behavior in a manner that was rapid, potent and transient; they produced impaired cognitive function without inducing permanent neurological deficits. Althoughß-amyloidosis has long been hypothesized to affect cognition, the abnormally folded protein species associated with this or any other neurodegenerative disease has not previously been isolated, defined biochemically and then specifically characterized with regard to its effects on cognitive function. The biochemical isolation of discrete amyloid-ßmoieties with pathophysiological properties sets the stage for a new approach to studying the molecular mechanisms of cognitive impairment in Alzheimer disease and related neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Hemangioblastomas consist of 10-20% neoplastic “stromal” cells within a vascular tumor cell mass of reactive pericytes, endothelium and lymphocytes. Familial cases of central nervous system hemangioblastoma uniformly result from mutations in the Von Hippel-Lindau (VHL) gene. In contrast, inactivation of VHL has been previously observed in only a minority of sporadic hemangioblastomas, suggesting an alternative genetic etiology. We performed deep-coverage DNA sequencing on 32 sporadic hemangioblastomas (whole exome discovery cohort n = 10, validation n = 22), followed by analysis of clonality, copy number alteration, and somatic mutation. We identified somatic mutation, loss of heterozygosity and/or deletion of VHL in 8 of 10 discovery cohort tumors. VHL inactivating events were ultimately detected in 78% (25/32) of cases. No other gene was significantly mutated. Overall, deep-coverage sequence analysis techniques uncovered VHL alterations within the neoplastic fraction of these tumors at higher frequencies than previously reported. Our findings support the central role of VHL inactivation in the molecular pathogenesis of both familial and sporadic hemangioblastomas.