No Detectable Effect on Visual Responses Using Functional MRI in a Rodent Model of α-Synuclein Expression.

Parkinson's disease (PD) is a progressive neurodegenerative disease that is typically diagnosed late in its progression. There is a need for biomarkers suitable for monitoring the disease progression at earlier stages to guide the development of novel neuroprotective therapies. One potential biomarker, α-synuclein, has been found in both the familial cases of PD, as well as the sporadic cases and is considered a key feature of PD. α-synuclein is naturally present in the retina, and it has been suggested that early symptoms of the visual system may be used as a biomarker for PD. Here, we use a viral vector to induce a unilateral expression of human wild-type α-synuclein in rats as a mechanistic model of protein aggregation in PD. We employed functional magnetic resonance imaging (fMRI) to investigate whether adeno-associated virus (AAV) mediated expression of human wild-type α-synuclein alter functional activity in the visual system. A total of 16 rats were injected with either AAV-α-synuclein (n = 7) or AAV-null (n = 9) in the substantia nigra pars compacta (SNc) of the left hemisphere. The expression of α-synuclein was validated by a motor assay and postmortem immunohistochemistry. Five months after the introduction of the AAV-vector, fMRI showed robust blood oxygen level-dependent (BOLD) responses to light stimulation in the visual systems of both control and AAV-α-synuclein animals. However, our results demonstrate that the expression of AAV-α-synuclein does not affect functional activation of the visual system. This negative finding suggests that fMRI-based read-outs of visual responses may not be a sensitive biomarker for PD.

Classification of α-synuclein-induced changes in the AAV α-synuclein rat model of Parkinson's disease using electrophysiological measurements of visual processing.

Biomarkers suitable for early diagnosis and monitoring disease progression are the cornerstone of developing disease-modifying treatments for neurodegenerative diseases such as Parkinson's disease (PD). Besides motor complications, PD is also characterized by deficits in visual processing. Here, we investigate how virally-mediated overexpression of α-synuclein in the substantia nigra pars compacta impacts visual processing in a well-established rodent model of PD. After a unilateral injection of vector, human α-synuclein was detected in the striatum and superior colliculus (SC). In parallel, there was a significant delay in the latency of the transient VEPs from the affected side of the SC in late stages of the disease. Inhibition of leucine-rich repeat kinase using PFE360 failed to rescue the VEP delay and instead increased the latency of the VEP waveform. A support vector machine classifier accurately classified rats according to their `disease state' using frequency-domain data from steady-state visual evoked potentials (SSVEP). Overall, these findings indicate that the latency of the rodent VEP is sensitive to changes mediated by the increased expression of α-synuclein and especially when full overexpression is obtained, whereas the SSVEP facilitated detection of α-synuclein across reflects all stages of PD model progression.

Positional Scanning MUC1 Glycopeptide Library Reveals the Importance of PDTR Epitope Glycosylation for Lectin Binding.

One of the main barriers to explaining the functional significance of glycan-based changes in cancer is the natural epitope heterogeneity found on the surface of cancer cells. To help address this knowledge gap, we focused on designing synthetic tools to explore the role of tumor-associated glycans of MUC1 in the formation of metastasis via association with lectins. In this study, we have synthesized for the first time a MUC1-derived positional scanning synthetic glycopeptide combinatorial library (PS-SGCL) that vary in number and location of cancer-associated Tn antigen using the "tea bag" approach. The determination of the isokinetic ratios necessary for the equimolar incorporation of (glyco)amino acids mixtures to resin-bound amino acid was determined, along with developing an efficient protocol for on resin deprotection of O-acetyl groups. Enzyme-linked lectin assay was used to screen PS-SGCL against two plant lectins, Glycine max soybean agglutinin and Vicia villosa. The results revealed a carbohydrate density-dependent affinity trend and site-specific glycosylation requirements for high affinity binding to these lectins. Hence, PS-SGCLs provide a platform to systematically elucidate MUC1-lectin binding specificities, which in the long term may provide a rational design for novel inhibitors of MUC1-lectin interactions involved in tumor spread and glycopeptide-based cancer vaccines.

Predictors of outpatient resource utilization following ventral and incisional hernia repair.

INTRODUCTION: Little is known about the predictors of increased ambulatory costs following open ventral and incisional hernia repair (VIHR); however, postoperative complications would be expected to be associated with an increased burden on outpatient resources. The purpose of this study is to evaluate the impact of perioperative factors on outpatient resource utilization following VIHR. METHODS: With IRB approval, the surgery scheduling system was queried to identify all cases of VIHR done at our institution over 3 years. Cases with other procedures done at time of VIHR were excluded. National Surgical Quality Improvement Program clinical data, physician billing data which included market and payor across cases, and medical record review data were combined and evaluated in order to quantify care and predictors of usage during the 6 months postoperatively. RESULTS: Data were analyzed for 308 patients. Median patient age was 52 years (SD = 13.3), and over half were female. The number of outpatient visits to the surgical office varied from 0 to 18 [median = 2; interquartile range (IQR) = 1-3]. CDC Wound Class >1 was associated with increase of mean 1.4 visits (IQR: 0.5-2.3); p = 0.003. Component separation, longer duration of operation, and increased mesh size were also predictive of increased number of office visits (p < 0.01). Postoperative infected seroma/seroma requiring drainage added a mean 2.3 visits (IQR: 1.3-3.3), (p < 0.001); and deep wound infection added a mean 3.9 visits (IQR: 1.9-5.9) (p < 0.001). CONCLUSIONS: Postoperative complications confer a significant burden for patients and to the outpatient surgical office. In an era in which improved quality and cost-efficiency has become imperative, measures to decrease risk of postoperative complications particularly for more complex VIHR would be expected to decrease resource utilization and increase value of care.

Concomitant open ventral hernia repair: what is the financial impact of performing open ventral hernia with other abdominal procedures concomitantly?

BACKGROUND: Open ventral hernia repair (VHR) is often performed in conjunction with other abdominal procedures. Clinical outcomes and financial implications of VHR are becoming better understood; however, financial implications of concomitant VHR during other abdominal procedures are unknown. This study aimed to evaluate the financial implications of adding VHR to open abdominal procedures. METHODS: This IRB-approved study retrospectively reviewed hospital costs to 180-day post-discharge of standalone VHRs, isolated open abdominal surgeries (bowel resection or stoma closure, removal of infected mesh, hysterectomy or oophorectomy, panniculectomy or abdominoplasty, open appendectomy or cholecystectomy), performed at our institution from October 1, 2011 to September 30, 2014. The perioperative risk data were obtained from the local National Surgery Quality Improvement Program (NSQIP) database, and resource utilization data were obtained from the hospital cost accounting system. RESULTS: 345 VHRs, 1389 open abdominal procedures as described, and 104 concomitant open abdominal and VHR cases were analyzed. The VHR-only group had lower ASA Class, shorter operative duration, and a higher percentage of hernias repaired via separation of components than the concomitant group (p < 0.001). The median hospital cost for VHR-alone was $12,900 (IQR: $9500-$20,700). There were significant increases to in-hospital costs when VHR was combined with removing an infected mesh (63%) or with bowel resections or stoma closures (0.7%). The addition of VHR did not cause a significant change in 180-day post-discharge costs for any of the procedures. CONCLUSIONS: This study noted decreased costs when combining VHR with panniculectomy or abdominoplasty and hysterectomy or oophorectomy. For removal of infected mesh and bowel resection or stoma closure, waiting, when feasible, is recommended. Given the impending changes in financial reimbursements in healthcare in the United States, it is prudent that future studies evaluate further the clinical and fiscal benefit of concomitant procedures.

A lack of experience-dependent plasticity after more than a decade of recovered sight.

In 2000, monocular vision was restored to M. M., who had been blind between the ages of 3 and 46 years. Tests carried out over 2 years following the surgery revealed impairments of 3-D form, object, and face processing and an absence of object- and face-selective blood-oxygen-level-dependent responses in ventral visual cortex. In the present research, we reexamined M. M. to test for experience-dependent recovery of visual function. Behaviorally, M. M. remains impaired in 3-D form, object, and face processing. Accordingly, we found little to no evidence of the category-selective organization within ventral visual cortex typically associated with face, body, scene, or object processing. We did observe remarkably normal object selectivity within lateral occipital cortex, consistent with M. M.'s previously reported shape-discrimination performance. Together, these findings provide little evidence for recovery of high-level visual function after more than a decade of visual experience in adulthood.