Motor stereotypies occurring in early-onset neuropsychiatric diseases are associated with dysregulated basal ganglia direct-pathway activity. Disruptions in network connectivity through impaired neuronal structure have been implicated in both rodents and humans. However, the neurobiological mechanisms leading to direct-pathway neuron disconnectivity in stereotypy remain poorly understood. We have a mouse line with Tropomyosin receptor kinase B (TrkB) receptor deletion from D1-expressing cells (D1-Cre-flTrkB) in which a subset of animals shows repetitive rotations and head tics with juvenile onset. Here we demonstrate these behaviors may be associated with abnormal direct-pathway activity by reducing rotations using chemogenetic inhibition of dorsal striatum D1-medium spiny neurons (D1-MSNs) in both juvenile and young adult mice. Taking advantage of phenotypical differences in animals with similar genotype, we then interrogated the D1-MSN specific translatome associated with repetitive behavior by using RNA-sequencing of ribosome-associated mRNA. Detailed translatome analysis followed by multiplexed gene expression assessment revealed profound alterations in neuronal projection and synaptic structure related genes in stereotypy mice. Examination of neuronal morphology demonstrated dendritic atrophy and dendritic spine loss in dorsal striatum D1-MSNs from mice with repetitive behavior. Together, our results uncover phenotype-specific molecular alterations in D1-MSNs that relate to morphological adaptations in mice displaying stereotypy behavior.
Background: Preoperative depression and anxiety in patients undergoing surgery have been shown to be associated with increased postoperative complications, decreased functional improvement, and longterm dissatisfaction. The purpose of this prospective study was to measure the relationship between a diagnosis of depression or anxiety and Patient-Reported Outcomes Measurement Information System (PROMIS) domains, as well as determine which preoperative factors are associated with depression or anxiety in patients undergoing knee surgery. We hypothesized that preoperative depression and/or anxiety would be associated with worse preoperative pain, function, and general health status. Methods: Three-hundred and eighty-six patients undergoing knee surgery between 2015 and 2017 were administered health-related quality of life measures preoperatively, and their medical records were reviewed for relevant medical history. A propensity matched analysis was performed to determine clinical factors independently associated with preoperative depression and/or anxiety. Results: The overall study population consisted of 216 males and 170 females, with a mean age of 39.4 ± 16.2 years. From this overall cohort, 43 (11.1%) patients had a positive preoperative diagnosis of depression and/or anxiety. After controlling for covariate imbalances, preoperative depression/anxiety was independently associated with PROMIS Anxiety (p ¼ 0.018), PROMIS Depression (p < 0.019), and Tegner pre-injury (p ¼ 0.013) scores. Regression analysis also determined that preoperative depression/anxiety was independently associated with arthroscopic anterior cruciate ligament reconstruction (ACLR) (p ¼ 0.004), total knee arthroplasty (TKA) (p ¼ 0.019), and uni-compartmental knee arthroplasty (p < 0.05). Conclusion:The results support our hypothesis that preoperative depression/anxiety is associated with worse preoperative pain, function, and general health status. Furthermore, PROMIS Anxiety and Depression tools offer a reliable means of measuring psychological distress in the orthopaedic knee population. Similar to other studies, we also noted psychological comorbidity to be independently associated with ACLR and TKA.
Introduction. Novel urinary biomarkers, including Tissue Inhibitor Metallo-protease-2 and Insulin-like Growth Factor Binding Protein 7 ([TIMP-2]*[IGFBP7]), have been developed to identify patients at risk for acute kidney injury (AKI). We investigated the “real world” clinical utility of [TIMP-2]*[IGFBP7] in preventing AKI. Methods. We performed a prospective single-center quality improvement study of intensive care unit (ICU) patients at risk for severe (KDIGO stage 2 or 3) AKI. In the prospective cohort, ICU providers were allowed to order [TIMP-2]*[IGFBP7] for patients at their discretion, then offered AKI practice recommendations based on the result. Outcomes were compared to a historical cohort in which biomarker values were not reported to clinical teams. Results. There was no difference in 7-day progression to severe AKI between the prospective (n=116) and historical cohorts (n=63) when [TIMP-2]*[IGFBP7] ≥0.3 (24(28%) vs 8(21%), p=0.38) despite more stage 1 AKI at time of biomarker measurement in the prospective cohort (58(67%) vs 9(23%), p<0.001). In the prospective cohort, patients with higher [TIMP-2]*[IGFBP7] values were more likely to receive a nephrology consult. Early consultation (within 24 hours of biomarker measurement, n=20) had a nonsignificant trends towards net negative volume balance (-1787mL(6716mL) vs +4974mL(15540mL)) and more diuretic use (19(95%) vs 8(80%)), and was associated with less severe AKI (9(45%) vs 10(100%), p=0.004) and inpatient dialysis (2(10%) vs 7(70%), p=0.002) compared to delayed consultation (n=10). Discussion/Conclusions. Despite the prospective cohort having more preexisting stage 1 AKI, there were equal rates of progression to severe AKI in the prospective and historical cohorts. In the setting of [TIMP-2]*[IGFBP7] reporting, there were more nephrology consults in response to elevated biomarker levels. Early nephrology consultation resulted in improved volume balance and favorable outcomes compared to delayed consultation.
This is an Early Access article. Please select the PDF button, above, to view it. Be sure to also read the PRO: 10.34067/KID.0004872021 and the COMMENTARY 10.34067/KID.0005562021
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