The Impact of Muscarinic Antagonism on Psychosis-Relevant Behaviors and Striatal [11C] Raclopride Binding in Tau Mouse Models of Alzheimer's Disease.

Psychosis that occurs over the course of Alzheimer's disease (AD) is associated with increased caregiver burden and a more rapid cognitive and functional decline. To find new treatment targets, studies modeling psychotic conditions traditionally employ agents known to induce psychosis, utilizing outcomes with cross-species relevance, such as locomotive activity and sensorimotor gating, in rodents. In AD, increased burdens of tau pathology (a diagnostic hallmark of the disease) and treatment with anticholinergic medications have, separately, been reported to increase the risk of psychosis. Recent evidence suggests that muscarinic antagonists may increase extracellular tau. Preclinical studies in AD models have not previously utilized muscarinic cholinergic antagonists as psychotomimetic agents. In this report, we utilize a human-mutant-tau model (P301L/COMTKO) and an over-expressed non-mutant human tau model (htau) in order to compare the impact of antimuscarinic (scopolamine 10 mg/kg/day) treatment with dopaminergic (reboxetine 20 mg/kg/day) treatment, for 7 days, on locomotion and sensorimotor gating. Scopolamine increased spontaneous locomotion, while reboxetine reduced it; neither treatment impacted sensorimotor gating. In the P301L/COMTKO, scopolamine treatment was associated with decreased muscarinic M4 receptor expression, as quantified with RNA-seq, as well as increased dopamine receptor D2 signaling, as estimated with Micro-PET [11C] raclopride binding. Scopolamine also increased soluble tau in the striatum, an effect that partially mediated the observed increases in locomotion. Studies of muscarinic agonists in preclinical tau models are warranted to determine the impact of treatment-on both tau and behavior-that may have relevance to AD and other tauopathies.

Carbon Dioxide Pyelography: A Convenient and Safe Alternative to Both Room Air and Iodinated Contrast Pyelography During Endourologic Procedures.

Introduction/Background: There are increasing reports of serious complications related to the air pyelography technique, which raise concerns about the safety of room air (RA) injection into the renal collecting system. Carbon dioxide (CO2) is much more soluble in blood than nitrogen and oxygen and thus considerably less likely to cause gas emboli. Iodinated contrast medium (ICM) is expensive, and supplies may not be as reliable as previously assumed. CO2 pyelography (CO2-P) techniques using standard fluoroscopy and digital subtraction fluoroscopy (CO2 digital subtraction pyelography [CO2-DSP]) are described. Materials and Methods: During the endourologic stone cases, 15 to 20 mL of CO2 gas was typically injected into the renal pelvis through a catheter or sheath. Imaging was usually obtained with endovascular CO2 digital subtraction angiography settings using either a traditional fluoroscopy system (TFS) or robotic arm multiplanar fluoroscopy system (RMPFS) (Artis Zeego Care+Clear®; Siemens). Results: CO2-P was performed in 22 endoscopic stone treatment cases between March 2021 and August 2022, primarily using digital subtraction settings in 20 cases. CO2-DSP overall provided higher quality images of the renal pelvis and collecting system than CO2-P, but with a relatively higher radiation dose. Following a quality intervention, fluoroscopy doses for CO2-DSP cases were decreased by 81% overall. The use of CO2-P avoided fluoroscopic or intraoperative CT (ICT) artifacts seen with intraluminal ICM. Conclusions: CO2-P allows the urologist to obtain imaging of the renal collecting system without ICM and with much lower risk of air embolism compared with RA pyelography. CO2 is a nearly cost-free alternative to ICM. Because CO2 is widely available and the technique is easy to perform, we propose that CO2-P should be favored over traditional air pyelography to improve patient safety.

Comparison Study of Iliac Branch Endoprosthesis when Used on and off Label.

BACKGROUND: The aim of this study is to compare how instructions for use (IFU) affected perioperative and intermediate term outcomes for common iliac artery aneurysms (CIAA) treated with the Gore Excluder iliac branch endoprosthesis (IBE). METHODS: A retrospective analysis was performed of all patients treated at two affiliated academic centers from September 2016 to May 2020. Outcomes were compared between IFU and nonIFU IBE cases. Criteria for nonIFU included: (1) use with a nonGore aortic endoprosthesis (n = 10), (2) isolated IBE (n = 3), and (3) requiring nondedicated covered stents for additional extension into a more suitable landing zone in the ipsilateral internal iliac artery or one of its branches (n = 11). Perioperative and intermediate term data were collected for both groups. The primary end points were free from the major adverse event (MAE) at 30 days and primary effectiveness at 1 year. RESULTS: A total of 51 CIAA (39 patients) were treated with an IBE. Overall, 15 patients were treated under IFU and 24 under nonIFU. The IFU group mean age was older (72 vs. 67 years, P = 0.03), and males (97%) were primarily treated. Comorbidities were similar except nonIFU had more patients with previous endovascular abdominal aortic aneurysm repair on presentation (0 vs. 4 cases, P = 0.04). Procedure (178 vs. 264 min, P = 0.02) and fluoroscopy (52 vs. 74 min, P = 0.04) times were longer in the nonIFU group. Technical success was 100% for both groups, and there was no difference in device related reintervention at 30 days (0 vs. 1, P = 0.44). There was no MAE in either group at 30 days. Intervention for any endoleak was similar between the groups (2 vs. 3, P = 0.94). Percent CIAA sac regression was similar between the groups (19% vs. 18%, P = 0.21). There was no difference for primary effectiveness at 1 year (93% vs. 92%, P = 0.85). There was one death per group at one year not related to an aortic or iliac cause. CONCLUSIONS: In properly selected patients with complex anatomy, IBE can be used with nondedicated aortic and internal iliac components with good early term outcomes.

Anesthesia promotes acute expression of genes related to Alzheimer's disease and latent tau aggregation in transgenic mouse models of tauopathy.

BACKGROUND: Exposure to anesthesia in the elderly might increase the risk of dementia. Although the mechanism underlying the association is uncertain, anesthesia has been shown to induce acute tau hyperphosphorylation in preclinical models. We sought to investigate the impact of anesthesia on gene expression and on acute and long-term changes in tau biochemistry in transgenic models of tauopathy in order to better understand how anesthesia influences the pathophysiology of dementia. METHODS: We exposed mice with over-expressed human mutant tau (P301L and hyperdopaminergic COMTKO/P301L) to two hours of isoflurane and compared anesthetized mice to controls at several time points. We evaluated tau hyperphosphorylation with quantitative high-sensitivity enzyme-linked immunosorbent assay and performed differential expression and functional transcriptome analyses following bulk mRNA-sequencing. RESULTS: Anesthesia induced acute hyperphosphorylation of tau at epitopes related to Alzheimer's disease (AD) in both P301L-based models. Anesthesia was associated with differential expression of genes in the neurodegenerative pathways (e.g., AD-risk genes ApoE and Trem2) and thermogenesis pathway, which is related to both mammalian hibernation and tau phosphorylation. One and three months after anesthesia, hyperphosphorylated tau aggregates were increased in the anesthetized mice. CONCLUSIONS: Anesthesia may influence the expression of AD-risk genes and induce biochemical changes in tau that promote aggregation even after single exposure. Further preclinical and human studies are necessary to establish the relevance of our transcriptomic and biochemical findings in these preclinical models to the pathogenesis of dementia following anesthesia. TRIAL REGISTRATION: Not applicable.

The impact of pimavanserin on psychotic phenotypes and tau phosphorylation in the P301L/COMT- and rTg(P301L)4510 mouse models of Alzheimer's disease.

INTRODUCTION: Psychosis in Alzheimer's disease (AD) is associated with grave clinical consequences including a precipitous cognitive decline and a hastened demise. These outcomes are aggravated by use of existing antipsychotic medications, which are also associated with cognitive decline and increased mortality; preclinical models that would develop new therapeutic approaches are desperately needed. The current report evaluates the ability of the neoteric antipsychotic, pimavanserin, to normalize hyperkinesis and sensorimotor gating in the novel catechol-O-methyltransferase (COMT) deleted P301L/COMT- and rTg(P301L)4510 models of psychotic AD, and the impact of pimavanserin on tau pathology. METHODS: Female P301L/COMT- mice were behaviorally characterized for abnormalities of locomotion and sensorimotor gating, and biochemically characterized for patterns of tau phosphorylation relative to relevant controls utilizing high-sensitivity tau enzyme-linked immunosorbent assay (ELISA). Female P301L/COMT- and rTg(P301L)4510 mice were randomized to pimavanserin or vehicle treatment to study the ability of pimavanserin to normalize locomotion and rescue sensorimotor gating. Additionally, high-sensitivity tau ELISA was used to investigate the impact of treatment on tau phosphorylation. RESULTS: P301L/COMT- mice evidenced a hyperlocomotive phenotype and deficits of sensorimotor gating relative to wild-type mice on the same background, and increased tau phosphorylation relative to COMT-competent P301L mice. Pimavanserin normalized the hyperkinetic phenotype in both the P301L/COMT- and rTg(P301L)4510 mice but had no impact on sensorimotor gating in either model. Pimavanserin treatment had little impact on tau phosphorylation patterns. DISCUSSION: These data suggest that pimavanserin ameliorates tau-driven excessive locomotion. Given the morbidity associated with aberrant motor behaviors such as pacing in AD and lack of effective treatments, future studies of the impact of pimavanserin on actigraphy in patients with this syndrome may be warranted.

A Systematic Review of Interventions to Improve Initiation of Mental Health Care Among Racial-Ethnic Minority Groups.

OBJECTIVE: The objective of this systematic review was to identify interventions to improve the initiation of mental health care among racial-ethnic minority groups. METHODS: The authors searched three electronic databases in February 2016 and independently assessed eligibility of 2,065 titles and abstracts on the basis of three criteria: the study design included an intervention, the participants were members of racial-ethnic minority groups and lived in the United States, and the outcome measures included initial access to or attitudes toward mental health care. The qualitative synthesis involved 29 studies. RESULTS: Interventions identified included collaborative care (N=10), psychoeducation (N=7), case management (N=5), colocation of mental health services within existing services (N=4), screening and referral (N=2), and a change in Medicare medication reimbursement policy that served as a natural experiment (N=1). Reduction of disparities in the initiation of antidepressants or psychotherapy was noted in seven interventions (four involving collaborative care, two involving colocation of mental health services, and one involving screening and referral). Five of these disparities-reducing interventions were tested among older adults only. Most (N=23) interventions incorporated adaptations designed to address social or cultural barriers to care. CONCLUSIONS: Interventions that used a model of integrated care reduced racial-ethnic disparities in the initiation of mental health care.

Parenting style and mental disorders in a nationally representative sample of US adolescents.

PURPOSE: We examined associations between parenting style and past-year mental disorders in a nationally representative cross-sectional survey of US adolescents and whether the associations differed by adolescent demographic characteristics. METHODS: The sample included 6483 adolescents aged 13-18 years who were interviewed for a full range of DSM-IV mental disorders. Parenting style was assessed by adolescent-reported maternal and paternal care and control using items from the Parental Bonding Instrument. We controlled for socio-demographics, parental history of mental disorders, stressful life events, sexual violence, inter-parental conflict, and household composition. We also tested for two-way interactions between parental care and control and adolescent age, sex, and race/ethnicity. RESULTS: In adjusted models, high maternal care was associated with lower odds of depressive, eating, and behavioral disorders, and high maternal control was associated with greater odds of depressive, anxiety, eating, and behavioral disorders. High paternal care was associated with lower odds of social phobia and alcohol abuse/dependence. High paternal control was associated with greater odds of agoraphobia and alcohol abuse/dependence but with lower odds of attention-deficit/hyperactivity disorder. Associations of maternal and paternal control with anxiety disorders and substance abuse/dependence differed by sex. High paternal care was associated with lower odds of anxiety disorders only among Hispanics and non-Hispanic blacks. CONCLUSIONS: Perceived parental care and control were associated with adolescent mental disorders after controlling for multiple potential confounders. Differential patterns of association were found according to adolescent sex and race/ethnicity. Findings have implications for prevention and intervention programs that incorporate familial contextual factors.

Morbidity of endovascular abdominal aortic aneurysm repair is directly related to diameter.

OBJECTIVE: Previous randomized controlled trials have defined specific size thresholds to guide surgical decision-making in patients presenting with an abdominal aortic aneurysm (AAA). With recent advances in endovascular techniques, the anatomic considerations of AAA repair are rapidly changing. Our specific aims were to evaluate the most recent national population data to compare anatomic differences and perioperative outcomes in patients with AAA. METHODS: The American College of Surgeons National Surgical Quality Improvement Program was queried from 2011 to 2015 using the targeted vascular public use file. Patients with AAA undergoing elective open or endovascular repair were included. Risk factors and outcomes were stratified by size and divided into quartiles for categorical comparison. A logistic regression model was used to compare the impact of size on morbidity and mortality with each technique. A risk adjustment model used all preoperative criteria to generate observed and expected values for open and endovascular repair. RESULTS: There were 10,026 patients who underwent elective AAA repair, 8182 (81.6%) endovascular and 1844 (18.4%) open. Repairs were divided into density quartiles for a logistic analysis: smallest quartile, 3.5 to 5 cm; second quartile, 5.01 to 5.5 cm; third quartile, 5.51 to 6.2 cm; and largest quartile, >6.2 cm. Patients with larger aneurysms (>6.2 cm) were more likely to be male, to have a dependent functional status, and to have increased blood urea nitrogen concentration and American Society of Anesthesiologists score (P < .05). Larger aneurysms had longer operative time (162 vs 135 minutes) and greater extension toward the renal and iliac vessels (all P < .05). Risk adjustment revealed an observed/expected morbidity plot that favored endovascular repair throughout the size range but confirmed lack of size effect within the open repair category. The adjusted increase in morbidity with endovascular repair is 9.7% per centimeter increase in size of AAA. These trends remained true with an infrarenal subgroup analysis. CONCLUSIONS: Patients with a larger AAA have comorbidities and anatomic factors associated with a more difficult repair. The higher morbidity seen with larger aneurysms represents both anatomic and patient factors but seems to have a greater impact on endovascular repairs. However, endovascular repair still results in fewer near-term complications than open repair across all size strata.

Nonatherosclerotic limb ischemia: Prompt evaluation and diagnosis.

Limb ischemia is most often associated with atherosclerosis and older age. When a younger patient without risk factors for atherosclerosis presents with symptoms of limb ischemia, vascular occlusion may not be suspected initially, thus delaying diagnosis and treatment. Delayed diagnosis can lead to a poor outcome. Here, we describe several uncommon causes of limb ischemia and their initial presentations, workup, and treatment to help guide the practitioner in making a timely diagnosis in this unusual patient population.

Measures to reduce unplanned readmissions after vascular surgery.

Hospital readmissions are increasingly utilized as a measure of health care quality. Unplanned readmissions in surgical patients are viewed as a marker of poor care quality, and are associated with significant expense both to the health care system and to the patient. Interventions aimed at reducing readmissions have been the focus of several prospective randomized trials addressing medical conditions like congestive heart failure, but few data exist on efforts to reduce readmissions in surgical patients. Vascular surgery patients have been found to be at a particularly high risk for readmission, and a number of groups have reported on the risk factors for readmission in these patients. However, measures to reduce unplanned readmissions after vascular surgery have not be thoroughly investigated. Here, we summarize the existing data on risk factors for readmission in vascular surgery patients, review interventional studies in medical patients aimed at reducing readmissions, and suggest interventions that may be helpful in reducing readmissions in vascular patients. Further investigative work is needed to ascertain practical approaches to reducing unplanned readmissions in vascular surgery patients and thus improve the quality of care they receive.

Vascular injury is associated with increased mortality in winter sports trauma.

BACKGROUND: Trauma is the leading cause of injury and death for individuals aged 1-44 years. Up to 8% of the US population participates in winter sports, and although vascular injuries are uncommon in these activities, little is published in this area. We sought to identify the incidence, injury patterns, and outcomes of vascular injuries resulting from winter sports trauma. METHODS: Patients with winter sports trauma and the subset with vascular injuries were identified by accessing the National Trauma Data Bank querying years 2007-2010. Patients with and without vascular injuries were then compared. Admission variables included transport time, emergency department hypotension (systolic blood pressure < 90), Glasgow Coma Scale ≤ 8, Injury Severity Score ≥ 25, fractures, solid organ injury, and vascular injury. Outcomes were analyzed and associations with vascular injuries were determined. RESULTS: A total of 2,298 patients were identified with winter sports-related trauma and 28 (1.2%) had associated vascular injuries. Overall, the top 3 injuries were head trauma (16.7%), thoracic vertebral fractures (5.5%), and lumbar vertebral fractures (5.1%). The most common associated vascular injures were to the popliteal artery (17.7%), splenic artery (14.7%), and brachial blood vessels (14.7%). In the entire cohort, 1 patient (0.04%) suffered an amputation and 15 patients (0.7%) died. There were no amputations in the vascular injury group. Mortality was 0.6% in patients without a vascular injury compared with 7.1% of those with a vascular injury (P = 0.01). CONCLUSIONS: Although vascular injury is an uncommon associated finding in winter sports trauma, it is associated with a significant increase in mortality. These findings highlight the need for rapid identification of traumatic vascular injuries, which predicts worse overall outcomes in this patient population.

The 5-lipoxygenase pathway is required for acute lung injury following hemorrhagic shock.

The cellular and biochemical mechanisms leading to acute lung injury (ALI) and subsequent multiple organ failure are only partially understood. To study the potential role of eicosanoids, particularly leukotrienes, as possible mediators of ALI, we used a murine experimental model of ALI induced by hemorrhagic shock after blood removal via cardiac puncture. Neutrophil sequestration, as shown by immunofluorescence and protein leakage into the alveolar space were measured as markers of injury. We used liquid chromatography coupled to tandem mass spectrometry to unequivocally identify several eicosanoids in the bronchoalveolar lavage fluid of experimental animals. MK886, a specific inhibitor of the 5-lipoxygenase (5-LO) pathway, and transgenic mice deficient in 5-LO were used to determine the role of this enzymatic pathway in this model. Leukotriene B4 and leukotriene C4 were consistently elevated in shock-treated mice compared with sham-treated mice. MK886 attenuated neutrophil infiltration and protein extravasation induced by hemorrhagic shock. 5-Lipoxygenase-deficient mice showed reduced neutrophil infiltration and protein extravasation after shock treatment, indicating greatly reduced lung injury. These results support the hypothesis that 5-LO, most likely through the generation of leukotrienes, plays an important role in the pathogenesis of ALI induced by hemorrhagic shock in mice. This pathway could represent a new target for pharmacological intervention to reduce lung damage following severe primary injury.

Cross-transfusion of postshock mesenteric lymph provokes acute lung injury.

OBJECTIVE: Substantial investigation has implicated mesenteric lymph as the mechanistic link between gut ischemia/reperfusion (I/R) and distant organ injury. Specifically, lymph diversion prevents acute lung injury (ALI) in vitro, and bioactive lipids and proteins isolated from postshock mesenteric lymph (PSML) maintain bioactivity in vitro. However, Koch's postulates remain to be satisfied via direct cross-transfusion into a naïve animal. We therefore hypothesized that real time cross-transfusion of postshock mesenteric lymph provokes acute lung injury. METHODS: One set of Sprague-Dawley rats (lymph donors) was anesthetized, with the mesenteric lymph ducts cannulated and exteriorized to drain freely into a siliconates plastic cup; concurrently, a second group of rats ( lymph recipients) was anesthetized, with a cannula inserted into the animal's right internal jugular vein. Blood was removed from the donor rats to induce hemorrhagic shock (MAP of 35 mmHg × 45 min). The recipient rats were positioned 10 cm below the plastic cup, which emptied into the jugular vein cannula. Thus, mesenteric lymph from the shocked donor rat was delivered to the recipient rat at the rate generated during shock and the subsequent 3 h of resuscitation. RESULTS: Neutrophil (PMN) accumulation in the lungs was substantially elevated in the postshock lymph cross-transfusion group compared to both sham lymph cross-transfusion and instrumented control (MPO: 9.42 ± 1.55 versus 2.81 ± 0.82 U/mg lung tissue in postshock versus sham lymph cross-transfusion, n = 6 in each group, P = 0.02). Additionally, cross-transfusion of PSML induced oxidative stress in the lung (0.21 ± 0.03 versus 0.10 ± 0.01 micromoles MDA per mg lung tissue in lymph cross-transfusion versus instrumented control, n = 6 in each group, P = 0.046). Furthermore, transfusion of PSML provoked lung injury (BAL protein 0.77 ± 0.18 versus 0.15 ± 0.02 mg/mL protein in BALF, postshock versus sham lymph cross-transfusion, n = 6 in each group, P = 0.004). CONCLUSION: Cross-transfusion of PSML into a naïve animal leads to PMN accumulation and provokes ALI. These data provide evidence that postshock agents released into mesenteric lymph are capable of provoking distant organ injury.

Leukotriene b4 and its metabolites prime the neutrophil oxidase and induce proinflammatory activation of human pulmonary microvascular endothelial cells.

Leukotrienes are proinflammatory lipid mediators, derived from arachidonic acid via 5-lipoxygenase (5-LO). Leukotriene B4 (LTB4) is an effective polymorphonuclear neutrophil (PMN) chemoattractant, as well as being a major product of PMN priming. Leukotriene B4 is rapidly metabolized into products that are thought to be inactive, and little is known about the effects of LTB4 on the pulmonary endothelium. We hypothesize that LTB4 and its metabolites are effective PMN priming agents and cause proinflammatory activation of pulmonary endothelial cells. Isolated PMNs were primed (5 min, 37°C) with serial concentrations 10 to 10 M of LTB4 and its metabolites: 6-trans-LTB4, 20-OH-LTB4, and 20-COOH-LTB4, and then activated with fMLP. Primary human pulmonary microvascular endothelial cells (HMVECs) were incubated with these lipids (6 h, 37°C, 5% CO2), and intercellular adhesion molecule 1 was measured by flow cytometry. Polymorphonuclear neutrophil adhesion was measured by myeloperoxidase assays, and to ensure that these reactions were specific to the LTB4 receptors, BLT1 and BLT2 were antagonized with CP105,696 (BLT1) or silenced with siRNA (BLT1 and BLT2). Leukotriene B4 and its metabolites primed PMNs over a wide range of concentrations, depending on the specific metabolite. In addition, at high concentrations these lipids also caused increases in the surface expression of intercellular adhesion molecule 1 on HMVECs and induced HMVEC-mediated adhesion of PMNs. Silencing of BLT2 abrogated HMVEC activation, and blockade of BLT1 inhibited the observed PMN priming activity. We conclude that LTB4 and its ω-oxidation and nonenzymatic metabolites prime PMNs over a range of concentrations and activate HMVECs. These data have expanded the repertoire of causative agents in acute lung injury and postinjury multiple organ failure.

Proteome and system ontology of hemorrhagic shock: exploring early constitutive changes in postshock mesenteric lymph.

BACKGROUND: Postshock mesenteric lymph (PSML) is the mechanistic link between splanchnic ischemia reperfusion (IR) and remote organ injury. We hypothesize that an unbiased inspection of the proteome of PSML will reveal previously unrecognized aberrations in systems biology provoked by hemorrhage-induced mesenteric IR injury in vivo. METHODS: Shock was induced in male Sprague-Dawley rats by controlled hemorrhage, and the mesenteric duct was cannulated for lymph collection. Preshock and postshock lymph were collected for differential in-gel electrophoresis (DIGE)-based proteomics. Proteins that increased or decreased in relative concentration > or =1.5-fold were selected for trypsin digestion and analysis by mass spectrometry (MS). RESULTS: Evidence of tissue injury was detected by an increase in cell/tissue proteins in PSML. Components of coagulation were depleted, whereas products of hemolysis were increased. Haptoglobin was decreased, which supports an early postshock hemolytic process. Interestingly, several protective protease inhibitors were decreased in PSML. The unexpected findings were an increase in alpha-enolase (a key glycolitic enzyme and cell-surface plasminogen binding receptor, +2.4-fold change) and increased major urinary protein (MUP, a sex-specific lipid-binding protein, +17.1-fold change) in PSML. CONCLUSION: A proteomic evaluation of PSML revealed evidence of several shock-associated processes: protein release from tissue injury, depletion of coagulation factors and evidence of hemolysis, depletion of protective protease inhibitors, and an increase in abundance of lipid carriers. These results suggest that constitutive changes in the proteome of PSML may provide novel insights into the complex pathophysiology of postshock systems biology.