Attenuation of Corpus Callosum Axon Myelination and Remyelination in the Absence of Circulating Sex Hormones

Sex differences in the structure and organization of the corpus callosum (CC) can be attributed to genetic, hormonal or environmental effects, or a combination of these factors. To address the role of gonadal hormones on axon myelination, functional axon conduction and immunohistochemistry analysis of the CC in intact, gonadectomized and hormone‐replaced gonadectomized animals were used. These groups were subjected to cuprizone diet‐induced demyelination followed by remyelination. The myelinated component of callosal compound action potential was significantly decreased in ovariectomized and castrated animals under normal myelinating condition. Compared to gonadally intact cohorts, both gonadectomized groups displayed more severe demyelination and inhibited remyelination. Castration in males was more deleterious than ovariectomy in females. Callosal conduction in estradiol‐supplemented ovariectomized females was significantly increased during normal myelination, less attenuated during demyelination, and increased beyond placebo‐treated ovariectomized or intact female levels during remyelination. In castrated males, the non‐aromatizing steroid dihydrotestosterone was less efficient than testosterone and estradiol in restoring normal myelination/axon conduction and remyelination to levels of intact males. Furthermore, in both sexes, estradiol supplementation in gonadectomized groups increased the number of oligodendrocytes. These studies suggest an essential role of estradiol to promote efficient CC myelination and axon conduction in both sexes.     

Combined MEK Inhibition and BMP2 Treatment Promotes Osteoblast Differentiation and Bone Healing in Nf1Osx−/− Mice

Neurofibromatosis type I (NF1) is an autosomal dominant disease with an incidence of 1/3000, caused by mutations in the NF1 gene, which encodes the RAS/GTPase‐activating protein neurofibromin. Non‐bone union after fracture (pseudarthrosis) in children with NF1 remains a challenging orthopedic condition to treat. Recent progress in understanding the biology of neurofibromin suggested that NF1 pseudarthrosis stems primarily from defects in the bone mesenchymal lineage and hypersensitivity of hematopoietic cells to TGFβ. However, clinically relevant pharmacological approaches to augment bone union in these patients remain limited. In this study, we report the generation of a novel conditional mutant mouse line used to model NF1 pseudoarthrosis, in which Nf1 can be ablated in an inducible fashion in osteoprogenitors of postnatal mice, thus circumventing the dwarfism associated with previous mouse models where Nf1 is ablated in embryonic mesenchymal cell lineages. An ex vivo–based cell culture approach based on the use of Nf1^flox/flox bone marrow stromal cells showed that loss of Nf1 impairs osteoprogenitor cell differentiation in a cell‐autonomous manner, independent of developmental growth plate–derived or paracrine/hormonal influences. In addition, in vitro gene expression and differentiation assays indicated that chronic ERK activation in Nf1‐deficient osteoprogenitors blunts the pro‐osteogenic property of BMP2, based on the observation that only combination treatment with BMP2 and MEK inhibition promoted the differentiation of Nf1‐deficient osteoprogenitors. The in vivo preclinical relevance of these findings was confirmed by the improved bone healing and callus strength observed in Nf1_osx^?/? mice receiving Trametinib (a MEK inhibitor) and BMP2 released locally at the fracture site via a novel nanoparticle and polyglycidol‐based delivery method. Collectively, these results provide novel evidence for a cell‐autonomous role of neurofibromin in osteoprogenitor cells and insights about a novel targeted approach for the treatment of NF1 pseudoarthrosis. © 2014 American Society for Bone and Mineral Research.     

Gamma Knife radiosurgery in the management of brainstem metastases

Background

Metastases to the brainstem portend a poor prognosis and present a challenge in clinical management. Surgical resection is rarely a viable option.

Methods

Post-treatment MRI scans of patients with brainstem metastases treated with radiosurgery were used to determine local control and disease progression. Median survival was calculated using Kaplan–Meier analysis. Univariate and multivariate analyses were performed using log-rank test and Cox proportional hazards model, respectively.

Results

Thirty-two consecutive patients with brainstem metastasis underwent Gamma Knife radiosurgery. Median age was 50 years. Median tumor volume was 0.71 cm³ and median tumor margin dose was 13 Gy. Seventeen of 32 patients received WBRT prior to stereotactic radiosurgery. Median survival was 5.2 months. There was a statistically significant difference in survival based on RTOG recursive partition analysis (RPA) class. Median survival of patients categorized as RPA class I was 19.2 months, RPA class II was 8.4 months, and RPA class III was 1.9 months. The overall local tumor control rate was 87.5%. There were no acute complications following stereotactic radiosurgery and no evidence of radiation necrosis noted on post-treatment MRI scans.

Conclusion

Stereotactic radiosurgery is an effective treatment for brainstem metastases and should be considered especially for patients with good performance status.     

Genetics of coronary artery disease – A clinician's perspective

Coronary artery disease (CAD) is the major cause of fatality and disability among all cardiovascular diseases (CVD). Intricate interactions of genes and environment dictate the outcomes of CAD. Technological advances in the different fields of genetics including linkage studies (LS), candidate gene studies (CGS) and genome-wide association studies (GWA studies) have augmented the knowledge of pathogenesis of CAD. LS were more successful in identifying genetic variants among monogenic disease. GWA studies were relatively popular in identification of variation in polygenic disease. Until now, GWA studies recognized about 50 loci determining around 6% of the heritability in CAD. Clinical utility of the above knowledge would result in better CAD management, but validation of the variants in native population is warranted for active adoption into the clinic. The major aim of this review is to provide an adequate perspective of our current understanding and advances of genetics in CAD.     

Aspirin and clopidogrel drug response in patients undergoing percutaneous coronary intervention: the role of dual drug resistance.

We evaluated the response to clopidogrel among aspirin-resistant versus aspirin-sensitive patients undergoing elective coronary stenting. Patients (n = 150) treated with aspirin but not clopidogrel had blood samples drawn at baseline and 24 h after clopidogrel loading. Depending on the definition used, 9% to 15% were resistant to aspirin and 24% to clopidogrel. About half of the aspirin-resistant patients were also resistant to clopidogrel. As a group, aspirin-resistant patients had lower response to clopidogrel (assessed by platelet aggregation and activation markers) than aspirin-sensitive patients. Both aspirin- and clopidogrel-resistant patients had higher incidence of creatine kinase-MB elevation than the respective sensitive patients. OBJECTIVES: We sought to evaluate the response to clopidogrel among aspirin-resistant versus aspirin-sensitive patients undergoing percutaneous coronary intervention (PCI). BACKGROUND: Wide variability has been reported in response to aspirin and clopidogrel. There are limited data on the simultaneous responses to both drugs. METHODS: Elective PCI patients (n = 150) who received aspirin for > or = 1 week but not clopidogrel were included. All patients received bivalirudin during PCI. Blood samples were drawn at baseline and 20 to 24 h after a 300-mg clopidogrel dose. Aspirin resistance was defined by > or = 2 of 3 criteria: rapid platelet function analyzer-ASA score > or = 550, 5 micromol/l adenosine diphosphate (ADP)-induced aggregation > or = 70%, and 0.5 mg/ml arachidonic acid-induced aggregation > or = 20%. Clopidogrel resistance was defined as baseline minus post-treatment aggregation < or = 10% in response to 5 and 20 micromol/l ADP. RESULTS: Nineteen (12.7%) patients were resistant to aspirin and 36 (24%) to clopidogrel. Nine (47.4%) of the aspirin-resistant patients were also clopidogrel resistant. Aspirin-resistant patients were more likely to be women and have diabetes than were aspirin-sensitive patients. They also had lower response to clopidogrel, assessed by platelet aggregation and activation markers (flow cytometry-determined PAC-1 binding and P-selectin expression). Elevation of creatine kinase-myocardial band after stenting occurred more frequently in aspirin-resistant versus aspirin-sensitive patients (38.9% vs. 18.3%; p = 0.04) and in clopidogrel-resistant versus clopidogrel-sensitive patients (32.4% vs. 17.3%; p = 0.06). CONCLUSIONS: Aspirin-resistant patients as a group have reduced response to clopidogrel. Furthermore, we have identified a unique group of dual drug-resistant patients who may be at increased risk for thrombotic complications after PCI.     

Biomechanical properties of high-density polyethylene for pterional prosthesis

The pterional approach is the most popular surgical technique in aneurysm and skull base tumor removal. Reconstruction of the temporal contour deformity due to craniotomy requires graft implantation. Porous high-density polyethylene (PHDPE) as a craniofacial and pterional implant material recently became available. However, material properties of the pterional implant are not yet known. In order to measure the biomechanical properties of PHDPE, we implemented the tensile test, the three-point bending test and the water displacement method for density measurement. Elastic modulus varies from 227 to 307MPa. Density range is 0.68 and 0.7 depending on the size of pores. The data can be used to study the character of the porous high-density polyethylene implant, how it resists stress or fatigue in combination with conventional plating systems.