Extracellular Alpha-Synuclein Promotes a Neuroinhibitory Secretory Phenotype in Astrocytes.

Multiple system atrophy (MSA) and dementia with Lewy bodies (DLB) are α-synucleinopathies that exhibit widespread astrogliosis as a component of the neuroinflammatory response. Munc18, a protein critical to vesicle exocytosis, was previously found to strongly mark morphologically activated astrocytes in brain tissue of MSA patients. Immunofluorescence of MSA, DLB and normal brain tissue sections was combined with cell culture and co-culture experiments to investigate the relationship between extracellular α-synuclein and the transition to a secretory astrocyte phenotype. Increased Munc18-positive vesicles were resolved in activated astrocytes in MSA and DLB tissue compared to controls, and they were also significantly upregulated in the human 1321N1 astrocytoma cell line upon treatment with α-synuclein, with parallel increases in GFAP expression and IL-6 secretion. In co-culture experiments, rat primary astrocytes pretreated with α-synuclein inhibited the growth of neurites of co-cultured primary rat neurons and upregulated chondroitin sulphate proteoglycan. Taken together, these results indicate that the secretory machinery is significantly upregulated in the astrocyte response to extracellular α-synuclein and may participate in the release of neuroinhibitory and proinflammatory factors in α-synucleinopathies.

Ageing as a risk factor for cerebral ischemia: Underlying mechanisms and therapy in animal models and in the clinic.

Age is the only one non-modifiable risk of cerebral ischemia. Advances in stroke medicine and behavioral adaptation to stroke risk factors and comorbidities was successful in decreasing stroke incidence and increasing the number of stroke survivors in western societies. Comorbidities aggravates the outcome after cerebral ischemia. However, due to the increased in number of elderly, the incidence of stroke has increased again paralleled by an increase in the number of stroke survivors, many with severe disabilities, that has led to an increased economic and social burden in society. Animal models of stroke often ignore age and comorbidities frequently associated with senescence. This might explain why drugs working nicely in animal models fail to show efficacy in stroke survivors. Since stroke afflicts mostly the elderly comorbid patients, it is highly desirable to test the efficacy of stroke therapies in an appropriate animal stroke model. Therefore, in this review, we make parallels between animal models of stroke und clinical data and summarize the impact of ageing and age-related comorbidities on stroke outcome.

3D printing strategies for peripheral nerve regeneration.

After many decades of biomaterials research for peripheral nerve regeneration, a clinical product (the nerve guide), is emerging as a proven alternative for relatively short injury gaps. This review identifies aspects where 3D printing can assist in improving long-distance nerve guide regeneration strategies. These include (1) 3D printing of the customizable nerve guides, (2) fabrication of scaffolds that fill nerve guides, (3) 3D bioprinting of cells within a matrix/bioink into the nerve guide lumen and the (4) establishment of growth factor gradients along the length a nerve guide. The improving resolution of 3D printing technologies will be an important factor for peripheral nerve regeneration, as fascicular-like guiding structures provide one path to improved nerve guidance. The capability of 3D printing to manufacture complex structures from patient data based on existing medical imaging technologies is an exciting aspect that could eventually be applied to treating peripheral nerve injury. Ultimately, the goal of 3D printing in peripheral nerve regeneration is the automated fabrication, potentially customized for the patient, of structures within the nerve guide that significantly outperform the nerve autograft over large gap injuries.

Photochemically Induced Crosslinking of Tarsal Collagen as a Treatment for Eyelid Laxity: Assessing Potentiality in Animal Tissue.

PURPOSE: An experimental study to demonstrate in animal eyelids that the controlled exposure of excised tarsal plate to ultraviolet-A radiation can induce a rigidification effect due to photochemical crosslinking of the constitutive collagen. METHODS: Excised strips of sheep tarsus were irradiated with ultraviolet-A rays (wavelength 365 nm) at low and high irradiances, in the presence of riboflavin as a photosensitizer, using radiation sources available for corneal collagen crosslinking procedure. The tensile strength and Young's modulus (stiffness) of irradiated and control samples were measured in a mechanical tester and analyzed statistically. Histologic examination of the specimens was carried out to evaluate the effect of radiation on the meibomian glands and collagen organization. RESULTS: Mechanical evaluation showed that irradiation induced both stiffening and strengthening of the tarsal plate specimens, and this effect was enhanced at the higher levels of irradiance. The changes in mechanical properties can be attributed to a process of photochemically induced crosslinking of tarsal collagen. Histology revealed no changes in the meibomian glands or in the fibrous collagen system of the tarsus. CONCLUSIONS: These findings indicate that irradiation of tarsal collagen leading to tissue stiffening could be a safe procedure for treating lax eyelid conditions in human patients.

Standardization of negative controls in diagnostic immunohistochemistry: recommendations from the international ad hoc expert panel.

Standardization of controls, both positive and negative controls, is needed for diagnostic immunohistochemistry (dIHC). The use of IHC-negative controls, irrespective of type, although well established, is not standardized. As such, the relevance and applicability of negative controls continues to challenge both pathologists and laboratory budgets. Despite the clear theoretical notion that appropriate controls serve to demonstrate the sensitivity and specificity of the dIHC test, it remains unclear which types of positive and negative controls are applicable and/or useful in day-to-day clinical practice. There is a perceived need to provide "best practice recommendations" for the use of negative controls. This perception is driven not only by logistics and cost issues, but also by increased pressure for accurate IHC testing, especially when IHC is performed for predictive markers, the number of which is rising as personalized medicine continues to develop. Herein, an international ad hoc expert panel reviews classification of negative controls relevant to clinical practice, proposes standard terminology for negative controls, considers the total evidence of IHC specificity that is available to pathologists, and develops a set of recommendations for the use of negative controls in dIHC based on "fit-for-use" principles.

Dental implant placement with bone augmentation in a patient who received intravenous bisphosphonate treatment for osteoporosis.

Intravenous (IV) administration of bisphosphonates has been considered an absolute contraindication for placement of dental implants, because of the increased risk of bisphosphonate-related osteonecrosis of the jaw (BRONJ). However, the evidence regarding this association originates from patients being treated for various forms of metastatic cancer. In the case reported here, a patient received a dental implant while undergoing IV treatment with zoledronic acid for osteoporosis. The authors discuss the current evidence regarding the risks of dental procedures in patients receiving IV bisphosphonates for this indication. They also evaluate important risk factors and the decision-making pathway in such cases. On the basis of existing evidence, receipt of a single IV infusion of zoledronic acid for the treatment of osteoporosis does not appear to be an absolute contraindication to implant placement.

Bisphosphonate-related osteonecrosis of jaw (BRONJ): diagnostic criteria and possible pathogenic mechanisms of an unexpected anti-angiogenic side effect.

Recently, bisphosphonates (BPs) have been widely used in medical practice as anti-resorptive agents owing to their anti-osteoclatic action. In addition, these compounds are also used for their analgesic action and their potential anti-tumour effect. Patients treated with BPs may subsequently develop osteonecrosis of the jaw or maxillary bone after minor local trauma including dental work, recently labelled as bisphosphonate osteonecrosis of jaw (BRONJ). However, the etiopathogenic mechanisms of this pathological condition are poorly understood. Although, several pathways have been proposed for BRONJ occurrence, no single model can explain all morphological changes observed at the macro- and microscopic level. Recent research suggests that BPs may promote an anti-angiogenic effect which contributes directly to the clinical features associated with BRONJ. Remarkably, the anti-angiogenic effect promoting BRONJ might be in keeping with the anti-neoplastic action of BPs. The current review, presents clinical diagnostic criteria. In addition, based on our own experience we describe the histopathological criteria for diagnosis of BRONJ and the possible pathways which may lead to this frustrating pathological condition.

Bisphosphonate-related osteonecrosis of jaw (BRONJ): an anti-angiogenic side-effect?

Bisphosphonates are recommended in the treatment of osteoporosis and some cancers, in which case they prevent the appearance of bone metastasis. The patients taking bisphosphonates are at increased risk of developing bisphosphonate-related osteonecrosis of jaw (BRONJ) which is characterised by the presence of an un-healing wound after dental surgery. BRONJ might represent an anti-angiogenic side effect. However, the real number of patients with BRONJ might be higher than currently recorded. Considering the differential diagnosis which includes various primary and secondary cancers, a correct histopathological diagnosis is very important. The morphological criteria for diagnosis of BRONJ are highlighted in this material.

Angiogenesis in old-aged subjects after ischemic stroke: a cautionary note for investigators.

Angiogenesis represents a form of neovascularisation of exceptional importance in numerous pathological conditions including stroke. In this context it is directly related to neuroregeneration which is seen in close proximity. However, numerous experimental data have been drawn from studies that have ignored the age criterion. This is extremely important as angiogenesis is different in young versus old subjects. Extrapolating data obtained from studies performed in young subjects or "in vitro" to old-age patients could lead to inexact conclusions since the dynamics of angiogenesis is age-dependent.The current review covers the key features of brain senescence including morphological and functional changes related to the brain parenchyma, its vascular network and blood flow which could possibly influence the process of angiogenesis. This is followed by a description of post-stroke angiogenesis and its relationship to neuroregeneration and its modulation by vascular endothelial growth factor (VEGF) and insulin-like growth factor 1 (IGF 1), the most important factors active in old brain after ischemic injury.

Placental calcium pump: clinical-based evidence.

Placenta can be considered as a pump of calcium necessary for the normal development of the fetus. We believe that the location of this pump is in the placental basement membrane. The calcification of this membrane has been described only in cases of in utero fetal death. In this study we describe for the first time a case of placental calcification in a living fetus. The fetus of a normal 21-year-old pregnant woman showed heart abnormalities but the genetic analysis showed a normal male karyotype. The histology of the placenta demonstrated multiple intravillous linear and granular calcific incrustations The hemtoxylin/eosin stain of the sections revealed basement membrane calcific incrustations and intravillous calcium deposits. We postulate that the fetal circulation in the villi was impaired and the calcium that reached the villi from the mother was deposited at this level.