Protein Binding Partners of Dysregulated miRNAs in Parkinson's Disease Serum.

Accumulating evidence suggests that microRNAs (miRNAs) are a contributing factor to neurodegenerative diseases. Although altered miRNA profiles in serum or plasma have been reported for several neurodegenerative diseases, little is known about the interaction between dysregulated miRNAs and their protein binding partners. We found significant alterations of the miRNA abundance pattern in serum and in isolated serum-derived extracellular vesicles of Parkinson's disease (PD) patients. The differential expression of miRNA in PD patients was more robust in serum than in isolated extracellular vesicles and could separate PD patients from healthy controls in an unsupervised approach to a high degree. We identified a novel protein interaction partner for the strongly dysregulated hsa-mir-4745-5p. Our study provides further evidence for the involvement of miRNAs and HNF4a in PD. The demonstration that miRNA-protein binding might mediate the pathologic effects of HNF4a both by direct binding to it and by binding to proteins regulated by it suggests a complex role for miRNAs in pathology beyond the dysregulation of transcription.

Inflammatory dysregulation of blood monocytes in Parkinson's disease patients.

Despite extensive effort on studying inflammatory processes in the CNS of Parkinson's disease (PD) patients, implications of peripheral monocytes are still poorly understood. Here, we set out to obtain a comprehensive picture of circulating myeloid cells in PD patients. We applied a human primary monocyte culture system and flow cytometry-based techniques to determine the state of monocytes from PD patients during disease. We found that the classical monocytes are enriched in the blood of PD patients along with an increase in the monocyte-recruiting chemoattractant protein CCL2. Moreover, we found that monocytes from PD patients display a pathological hyperactivity in response to LPS stimulation that correlates with disease severity. Inflammatory pre-conditioning was also reflected on the transcriptome in PD monocytes using next-generation sequencing. Further, we identified the CD95/CD95L as a key regulator for the PD-associated alteration of circulating monocytes. Pharmacological neutralization of CD95L reverses the dysregulation of monocytic subpopulations in favor of non-classical monocytes. Our results suggest that PD monocytes are in an inflammatory predisposition responding with hyperactivation to a "second hit". These results provide the first direct evidence that circulating human peripheral blood monocytes are altered in terms of their function and composition in PD patients. This study provides insights into monocyte biology in PD and establishes a basis for future studies on peripheral inflammation.

Stimulating angiogenesis by hyperbaric oxygen in an isolated tissue construct.

BACKGROUND: Hyperbaric oxygen (HBO2) treatment has been shown to stimulate angiogenesis in prefabricated myocutaneous flaps. We conducted the current study to determine optimal HBO2 treatment intervals for peak angiogenesis. METHODS: Lewis rats were implanted subcutaneously with silicone molds in the inguinal region. Molds contained inguinal fat, a vascular pedicle and Matrigel plug. Thirty-two animals were randomized into four groups: HBO2 Treatment (2.5 atm of 100% oxygen, 90 minutes, 2x/day)--Group 1 (seven days) or--Group 2 (14 days); and Control Treatment (room air at atmospheric pressure)--Group 1 (seven days) or--Group 2(14 days). Implants were harvested, processed for H&E staining, and imaged digitally; angiogenesis was assessed by grade of vascularization at the Matrigel/fat boundary. Intergroup grading differences were assessed statistically. RESULTS: Vascularization in seven-day HBO2-treated implants was significantly increased compared to seven-day controls (p = 0.008). Vascularization in 14-day HBO2-treated implants was significantly decreased compared to 14-day controls (p = 0.012). There was no significant difference between seven-day HBO-treated implants and 14-day controls (p > 0.05). CONCLUSIONS: Short-term HBO2 exposure appears to increase angiogenesis in isolated tissue constructs. Prolonged HBO2 exposure may lead to vascular pruning. Short-term HBO2 exposure appears to expedite the natural vascularization process, resulting in equivalent vascularization in a shorter time.

Association of third-year medical students' first clerkship with overall clerkship performance and examination scores.

CONTEXT: Anecdotal experience has suggested that third-year medical students whose first clerkship is internal medicine may have superior performance throughout the academic year. OBJECTIVE: To determine whether the order of clerkships by specialty is associated with student performance. DESIGN, SETTING, AND PARTICIPANTS: Clerkship performance records of medical students at all 4 campuses of the University of Illinois College of Medicine who completed their third-year core clerkships from July 2000 through June 2008 (N = 2236) were reviewed. MAIN OUTCOME MEASURES: Analysis of covariance was used to test for between-group differences (by first clerkship) in mean National Board of Medical Examiners subject examination scores (range, 0-100), preceptor ratings of clerkship clinical performances (range, 12-30), total overall clerkship grades (range, 12-30), and United States Medical Licensing Examination (USMLE) Step 2 scores, adjusted for sex, campus, and USMLE Step 1 score. RESULTS: First clerkship specialty was significantly associated with mean subject examination scores (family medicine, 71.96 [95% confidence interval {CI}, 70.90-72.98], internal medicine, 73.86 [95% CI, 73.33-74.39], obstetrics/gynecology, 72.36 [95% CI, 71.64-73.04], pediatrics, 73.11 [95% CI, 72.38-73.84], psychiatry, 72.17 [95% CI, 71.52-72.81], surgery, 72.37 [95% CI, 71.73-73.02]; P < .001) and overall clerkship grades (family medicine, 24.20 [95% CI, 23.90-24.90], internal medicine, 25.33 [95% CI, 25.07-25.60], obstetrics/gynecology, 24.68 [95% CI, 24.32-25.05], pediatrics, 24.92 [95% CI, 24.59-25.27], psychiatry, 24.61 [95% CI, 24.33-25.01], surgery 24.97 [95% CI, 24.64-25.30]; P = .01). There was no significant association with preceptor ratings or USMLE Step 2 scores. Pairwise comparisons for mean total overall clerkship grades showed a significant difference for students taking internal medicine first compared with obstetrics/gynecology (mean difference, 0.65; 95% CI, 0.18-1.12), psychiatry (mean difference, 0.66; 95% CI, 0.20-1.12), and family medicine (mean difference, 0.93; 95% CI, 0.37-1.50). CONCLUSION: Among students at 4 campuses of a US medical school, clerkship order was significantly associated with performance on clerkship subject examinations and overall grades but not with clerkship clinical performance or USMLE Step 2 scores.