Prenatal Cannabinoid Exposure Elicits Memory Deficits Associated with Reduced PSA-NCAM Expression, Altered Glutamatergic Signaling, and Adaptations in Hippocampal Synaptic Plasticity.

Cannabis is now one of the most commonly used illicit substances among pregnant women. This is particularly concerning since developmental exposure to cannabinoids can elicit enduring neurofunctional and cognitive alterations. This study investigates the mechanisms of learning and memory deficits resulting from prenatal cannabinoid exposure (PCE) in adolescent offspring. The synthetic cannabinoid agonist WIN55,212-2 was administered to pregnant rats, and a series of behavioral, electrophysiological, and immunochemical studies were performed to identify potential mechanisms of memory deficits in the adolescent offspring. Hippocampal-dependent memory deficits in adolescent PCE animals were associated with decreased long-term potentiation (LTP) and enhanced long-term depression (LTD) at hippocampal Schaffer collateral-CA1 synapses, as well as an imbalance between GluN2A- and GluN2B-mediated signaling. Moreover, PCE reduced gene and protein expression of neural cell adhesion molecule (NCAM) and polysialylated-NCAM (PSA-NCAM), which are critical for GluN2A and GluN2B signaling balance. Administration of exogenous PSA abrogated the LTP deficits observed in PCE animals, suggesting PSA mediated alterations in GluN2A- and GluN2B- signaling pathways may be responsible for the impaired hippocampal synaptic plasticity resulting from PCE. These findings enhance our current understanding of how PCE affects memory and how this process can be manipulated for future therapeutic purposes.

Aneurysm extent-based mortality differences in complex endovascular repair of thoracoabdominal aneurysms in the Vascular Quality Initiative and the United States Aortic Research Consortium.

BACKGROUND: Endovascular management of thoracoabdominal aneurysms (TAAA) is becoming more common. Technological advances including custom devices under the Physician-Sponsored Investigational Device Exemption (PS-IDE), physician-modified endografts (PMEG), and parallel stenting techniques have expanded the extent of disease that is amenable to endovascular treatment. Patients within the PS-IDE studies are a highly selected group of patients, whereas patients treated with PMEG as captured within the Society for Vascular Surgery Vascular Quality Initiative (SVS VQI) represent a real-world experience. Research within both the SVS VQI on PMEG and the US Aortic Research Consortium (US-ARC) has demonstrated a relationship between extent of aneurysmal disease and mortality after complex endovascular TAAA repair, but no direct comparison of these cohorts has been conducted. In this study, we sought to compare outcomes of custom PS-IDE devices with off-label uses of commercially available devices for the endovascular management of TAAAs. METHODS: A retrospective review of patients presenting for elective endovascular TAAA repair for asymptomatic disease between 2011 and 2019 was conducted within both the SVS VQI registry and the US-ARC. Patients within the SVS VQI registry were treated with either PMEG or with parallel stenting techniques. Patients within the US-ARC were treated with PS-IDE custom devices. The extent of aneurysm disease was defined by the deployment zones documented for the devices entered in the registry using Crawford extents I to V. Primary outcomes were 30-day and 1-year mortality rates. RESULTS: A total of 3212 patients were included in the study: 1571 PMEG/parallel stenting within the VQI registry and 1641 with PS-IDE within the US-ARC database. The majority of patients presented with extent IV aneurysms (n = 1827 [57%]), with extent IV aneurysms being slightly more prevalent within the US-ARC cohort. Maximal aneurysm diameter within each extent did not vary between the US-ARC and VQI cohorts. Across all patients, the 30-day mortality was 4.4% and the 1-year mortality was 12.2%. Unadjusted mortality at 30-days was 6.7% within the VQI, and 2.2% in the US-ARC (P < .001). The unadjusted 1-year mortality was 14.3% within the VQI and 10.2% within the US-ARC (P < .001). When adjusted for aneurysm extent, similar differences in 30-day and 1-year survivals were identified. CONCLUSIONS: Patients treated in PS-IDE studies had better 30-day and 1-year survival rates compared with those treated with a similar extent of disease using off-label approaches in a real-world registry. These differences are complex and likely associated with a number of factors, including arterial anatomy, patient comorbidities, device construct, and volume outcomes, as well as complex and unmeasurable surgeon- and patient-specific factors.

Association between thoracoabdominal aneurysm extent and mortality after complex endovascular repair.

OBJECTIVE: Traditional open surgical repair of thoracoabdominal aortic aneurysms (TAAAs) has historically resulted in 30-day mortality rates ranging from 6% to 20%, depending on the Crawford anatomic extent. Although short-term survival is important, long-term survival is essential for patients to benefit from these often elective and potentially morbid procedures. The aneurysm extent affects the long-term survival after open repair; however, effect on endovascular repair is unknown and could influence the decision process for repair. We evaluated the association between aneurysm extent and survival and identified patient and perioperative factors associated with mortality after endovascular repair. METHODS: A retrospective cohort of patients treated for TAAAs recorded in the Society for Vascular Surgery Vascular Quality Initiative thoracic and complex endovascular aneurysm repair registry were evaluated. All patients treated for asymptomatic degenerative aneurysms from 2010 to 2019 were included. Crawford extent I to V was defined according to the proximal and distal landing zones documented in the registry. Patients without extension into the visceral aorta were used for comparison and categorized as having extent 0a or 0b, depending on the distal landing zone in the thoracic aorta. Kaplan-Meier plots were used to estimate survival, and Cox proportional hazard regression models were created to identify the predictors of mortality. RESULTS: From 2010 to 2019, 15,333 patients were entered into the registry, of whom 2062 met the inclusion criteria. The Crawford extent was 0a for 379, 0b for 848, I for 81, II for 98, III for 130, IV for 454, and V for 72. Three groups were created in accordance with the similar outcomes noted on a preliminary analysis: (1) extent 0a and 0b; (2) extent I, II, and III; and (3) extent IV and V. The mean survival time for the extent 0a and 0b group was 70.7 ± 1.43 months and was 48.6 ± 1.65 months for the extent I, II, and III group and 57.6 ± 1.24 months for the extent IV and V group. The corresponding 1-year mortality was 8.4%, 18.4%, and 7.8%. Cox regression analysis identified the following preoperative factors were associated with mortality: chronic obstructive pulmonary disease (odds ratio [OR], 1.70; P < .001), Crawford extent I to III (OR, 1.64; P = .015), preexisting chronic kidney disease (OR, 1.37; P = .024), and age per year (OR, 1.03; P < .001). A number of postoperative factors were also associated with mortality. CONCLUSIONS: Similar to open TAAA repair, patients with more extensive aortic disease treated with endovascular repair had worse 1-year and long-term survival. The extent of aortic disease and anticipated postoperative survival should factor prominently into the surgical decision-making process for elective endovascular TAAA repair.

Neuronal CXCL10/CXCR3 Axis Mediates the Induction of Cerebral Hyperexcitability by Peripheral Viral Challenge.

Peripheral infections can potently exacerbate neuropathological conditions, though the underlying mechanisms are poorly understood. We have previously demonstrated that intraperitoneal (i.p.) injection of a viral mimetic, polyinosinic-polycytidylic acid (PIC) induces a robust generation of CXCL10 chemokine in the hippocampus. The hippocampus also features hyperexcitability of neuronal circuits following PIC challenge. The present study was undertaken to determine the role of CXCL10 in mediating the development of hyperexcitability in response to PIC challenge. Briefly, young female C57BL/6 mice were i.p. injected with PIC, and after 24 h, the brains were analyzed by confocal microscopy. CXCL10 staining of neuronal perikarya and a less intense staining of the neuropil was observed in the hippocampus and cortex. CXCL10 staining was also evident in a subpopulation of astrocytes, whereas microglia were CXCL10 negative. CXCR3, the cognate receptor of CXCL10 was present exclusively on neurons, indicating that the CXCL10/CXCR3 axis operates through an autocrine/paracrine neuronal signaling. Blocking cerebral CXCR3 through intracerebroventricular injection of a specific inhibitor, AMG487, abrogated PIC challenge-induced increase in basal synaptic transmission and long-term potentiation (LTP), as well as the reduction of paired-pulse facilitation (PPF), in the hippocampus. The PIC-mediated abolishment of hippocampal long-term depression (LTD) was also restored after administration of AMG487. Moreover, CXCR3 inhibition attenuated seizure hypersensitivity induced by PIC challenge. The efficacy of AMG487 strongly strengthens the notion that CXCL10/CXCR3 axis mediates the induction of cerebral hyperexcitability by PIC challenge.

Using Enzyme-based Biosensors to Measure Tonic and Phasic Glutamate in Alzheimer's Mouse Models.

Neurotransmitter disruption is often a key component of diseases of the central nervous system (CNS), playing a role in the pathology underlying Alzheimer's disease, Parkinson's disease, depression, and anxiety. Traditionally, microdialysis has been the most common (lauded) technique to examine neurotransmitter changes that occur in these disorders. But because microdialysis has the ability to measure slow 1-20 minute changes across large areas of tissue, it has the disadvantage of invasiveness, potentially destroying intrinsic connections within the brain and a slow sampling capability. A relatively newer technique, the microelectrode array (MEA), has numerous advantages for measuring specific neurotransmitter changes within discrete brain regions as they occur, making for a spatially and temporally precise approach. In addition, using MEAs is minimally invasive, allowing for measurement of neurotransmitter alterations in vivo. In our laboratory, we have been specifically interested in changes in the neurotransmitter, glutamate, related to Alzheimer's disease pathology. As such, the method described here has been used to assess potential hippocampal disruptions in glutamate in a transgenic mouse model of Alzheimer's disease. Briefly, the method used involves coating a multi-site microelectrode with an enzyme very selective for the neurotransmitter of interest and using self-referencing sites to subtract out background noise and interferents. After plating and calibration, the MEA can be constructed with a micropipette and lowered into the brain region of interest using a stereotaxic device. Here, the method described involves anesthetizing rTg(TauP301L)4510 mice and using a stereotaxic device to precisely target sub-regions (DG, CA1, and CA3) of the hippocampus.

A 100% departmental mortality review improves observed-to-expected mortality ratios and University HealthSystem Consortium rankings.

BACKGROUND: Public reporting of mortality, Patient Safety Indicators (PSI) and hospital-acquired conditions (HACs) is the reality of quality measurement. A review of our department's data identified opportunities for improvement. We began a surgeon-led 100% review of mortality, PSIs, and HACs to improve patient care and surgeon awareness of these metrics. STUDY DESIGN: From December 2012 through August 2013, there were 11,899 patients cared for on 12 surgical services. A surgeon from each service led monthly reviews of all mortality, PSIs, or HACs with central reporting of preventability and coding accuracy. We compared the University HealthSystem Consortium observed-to-expected (OE) mortality ratios (mean <1 fewer observed than expected deaths) and University HealthSystem Consortium relative rankings (lower number is better) before and after implementation. Statistical significance was p < 0.05 by Poisson regression. RESULTS: Of the 11,899 patients in the study period, there were 235 deaths, 290 PSIs, and 26 HACs identified and reviewed. The most common PSIs were postoperative deep vein thrombosis/pulmonary thromboembolism (n = 75), respiratory failure (n = 61), hemorrhage/hematoma (n = 33), and accidental puncture/laceration (n = 33). Before December 20, 2012, the OE ratio for mortality was consistently >1, then fell and remained <1 during the study period (p < 0.05). The OE mortality ratio in the fourth quarter of 2012 was 1.14 and fell to 0.88, 0.91, and 0.75 in the first, second, and third quarters of calendar year 2013 (p < 0.05). The overall Inpatient Quality Indicators #90 (composite postoperative mortality rank) rankings increased from 109 of 118 in the third quarter of 2012 to 47 of 119 in the third quarter of 2013. CONCLUSIONS: A surgeon-led systematic review of mortality, PSIs, and HACs improved our OE ratio and University HealthSystem Consortium postsurgical relative rankings. Surgeon engagement and ownership is critical for success.