Standard and modified glabellar flap for medial canthus reconstruction following mass removal in three dogs and two cats.

PURPOSE: To describe the surgical technique and clinical outcomes of the glabellar flap and its modification for the reconstruction of the medial canthus following resection of tumors in three dogs and two cats. METHODS: Three dogs (7-, 7-, and 12.5-year-old mixed breeds) and two cats (10- and 14-year-old Domestic shorthair) presented with a 7-13 mm tumor affecting the eyelid and/or conjunctiva in the medial canthal region. Following en bloc mass excision, an inverted V-shaped skin incision was made in the glabellar region (i.e., the area between the eyebrows in humans). The apex of the inverted V-shaped flap was rotated in three cases, whereas a horizontal sliding movement was performed in the other two cases to better cover the surgical wound. The surgical flap was then trimmed to fit the surgical wound and sutured in place in two layers (subcutaneous and cutaneous). RESULTS: Tumors were diagnosed as mast cell tumors (n = 3), amelanotic conjunctival melanoma (n = 1), and apocrine ductal adenoma (n = 1). No recurrence was noted in a follow-up time of 146 ± 84 days. Satisfactory cosmetic outcome with normal eyelids closure was achieved in all cases. Mild trichiasis was present in all patients and mild epiphora was noted in 2/5 patients, but there were no associated clinical signs such as discomfort or keratitis. CONCLUSIONS: The glabellar flap was easy to perform and provided a good outcome in terms of cosmetic, eyelid function, and corneal health. Postoperative complications from trichiasis appear to be minimized by the presence of the third eyelid in this region.

Concurrence of High Fat Diet and APOE Gene Induces Allele Specific Metabolic and Mental Stress Changes in a Mouse Model of Alzheimer's Disease.

Aging is the main risk factor for neurodegenerative diseases, including Alzheimer's disease (AD). However, evidence indicates that the pathological process begins long before actual cognitive or pathological symptoms are apparent. The long asymptomatic phase and complex integration between genetic, environmental and metabolic factors make it one of the most challenging diseases to understand and cure. In the present study, we asked whether an environmental factor such as high-fat (HF) diet would synergize with a genetic factor to affect the metabolic and cognitive state in the Apolipoprotein E (ApoE4) mouse model of AD. Our data suggest that a HF diet induces diabetes mellitus (DM)-like metabolism in ApoE4 mice, as well as changes in ß-site amyloid precursor protein-cleaving enzyme 1 (BACE1) protein levels between the two ApoE strains. Furthermore, HF diet induces anxiety in this AD mouse model. Our results suggest that young ApoE4 carriers are prone to psychological stress and metabolic abnormalities related to AD, which can easily be triggered via HF nutrition.

PKR Inhibition Rescues Memory Deficit and ATF4 Overexpression in ApoE ε4 Human Replacement Mice.

Sporadic Alzheimer's disease (AD) is an incurable neurodegenerative disease with clear pathological hallmarks, brain dysfunction, and unknown etiology. Here, we tested the hypothesis that there is a link between genetic risk factors for AD, cellular metabolic stress, and transcription/translation regulation. In addition, we aimed at reversing the memory impairment observed in a mouse model of sporadic AD. We have previously demonstrated that the most prevalent genetic risk factor for AD, the ApoE4 allele, is correlated with increased phosphorylation of the translation factor eIF2α. In the present study, we tested the possible involvement of additional members of the eIF2α pathway and identified increased mRNA expression of negative transcription factor ATF4 (aka CREB2) both in human and a mouse model expressing the human ApoE4 allele. Furthermore, injection of a PKR inhibitor rescued memory impairment and attenuated ATF4 mRNA increased expression in the ApoE4 mice. The results propose a new mechanism by which ApoE4 affects brain function and further suggest that inhibition of PKR is a way to restore ATF4 overexpression and memory impairment in early stages of sporadic AD. Significance statement: ATF4 mRNA relative quantities are elevated in ApoE4 allele carriers compared with noncarrier controls. This is true also for the ApoE ε4 human replacement mice. ApoE4 mice injected with PKR inhibitor (PKRi) demonstrate a significant reduction in ATF4 expression levels 3 h after one injection of PKRi. Treatment of ApoE4 human replacement mice with the PKRi before learning rescues the memory impairment of the ApoE4 AD model mice. We think that these results propose a new mechanism by which ApoE4 affects brain function and suggest that inhibition of PKR is a way to restore memory impairment in early stages of sporadic AD.

ApoE ε4 is associated with eIF2α phosphorylation and impaired learning in young mice.

Protein translation is regulated during both initiation and elongation phases to enable cells to accommodate for ever-changing environmental and internal states. Eukaryotic initiation factor-2 (eIF2)α, a major signaling pathway for responses to metabolic stress, controls translation initiation in various cells, including neurons, and affects cognitive functions. The main risk factor for sporadic Alzheimer's disease (SAD) is aging, and the main genetic risk factor reducing the age of SAD onset is the expression of apolipoprotein E (ApoE)4. We tested the hypothesis that both genetic and aging risk factors converge on the eIF2α pathway. Aged rodents showed increased eIF2α phosphorylation in the brain, indicating a shift in the rate of translation initiation with increasing age. Interestingly, mice overexpressing human ApoE4 already, at an early age, exhibited increased eIF2α phosphorylation together with mild impairment in cognitive tasks, compared with ApoE3 mice. These results suggest that the eIF2α pathway is linked to SAD, possibly via genetic as well as prolonged metabolic stress, and these findings position it as a new and important target for treatment of the currently incurable Alzheimer's disease.

Two faces of chondroitin sulfate proteoglycan in spinal cord repair: a role in microglia/macrophage activation.

BACKGROUND: Chondroitin sulfate proteoglycan (CSPG) is a major component of the glial scar. It is considered to be a major obstacle for central nervous system (CNS) recovery after injury, especially in light of its well-known activity in limiting axonal growth. Therefore, its degradation has become a key therapeutic goal in the field of CNS regeneration. Yet, the abundant de novo synthesis of CSPG in response to CNS injury is puzzling. This apparent dichotomy led us to hypothesize that CSPG plays a beneficial role in the repair process, which might have been previously overlooked because of nonoptimal regulation of its levels. This hypothesis is tested in the present study. METHODS AND FINDINGS: We inflicted spinal cord injury in adult mice and examined the effects of CSPG on the recovery process. We used xyloside to inhibit CSPG formation at different time points after the injury and analyzed the phenotype acquired by the microglia/macrophages in the lesion site. To distinguish between the resident microglia and infiltrating monocytes, we used chimeric mice whose bone marrow-derived myeloid cells expressed GFP. We found that CSPG plays a key role during the acute recovery stage after spinal cord injury in mice. Inhibition of CSPG synthesis immediately after injury impaired functional motor recovery and increased tissue loss. Using the chimeric mice we found that the immediate inhibition of CSPG production caused a dramatic effect on the spatial organization of the infiltrating myeloid cells around the lesion site, decreased insulin-like growth factor 1 (IGF-1) production by microglia/macrophages, and increased tumor necrosis factor alpha (TNF-alpha) levels. In contrast, delayed inhibition, allowing CSPG synthesis during the first 2 d following injury, with subsequent inhibition, improved recovery. Using in vitro studies, we showed that CSPG directly activated microglia/macrophages via the CD44 receptor and modulated neurotrophic factor secretion by these cells. CONCLUSIONS: Our results show that CSPG plays a pivotal role in the repair of injured spinal cord and in the recovery of motor function during the acute phase after the injury; CSPG spatially and temporally controls activity of infiltrating blood-borne monocytes and resident microglia. The distinction made in this study between the beneficial role of CSPG during the acute stage and its deleterious effect at later stages emphasizes the need to retain the endogenous potential of this molecule in repair by controlling its levels at different stages of post-injury repair.