Source-sink connectivity: a novel interictal EEG marker for seizure localization.

Over 15 million epilepsy patients worldwide have drug-resistant epilepsy. Successful surgery is a standard of care treatment but can only be achieved through complete resection or disconnection of the epileptogenic zone, the brain region(s) where seizures originate. Surgical success rates vary between 20% and 80%, because no clinically validated biological markers of the epileptogenic zone exist. Localizing the epileptogenic zone is a costly and time-consuming process, which often requires days to weeks of intracranial EEG (iEEG) monitoring. Clinicians visually inspect iEEG data to identify abnormal activity on individual channels occurring immediately before seizures or spikes that occur interictally (i.e. between seizures). In the end, the clinical standard mainly relies on a small proportion of the iEEG data captured to assist in epileptogenic zone localization (minutes of seizure data versus days of recordings), missing opportunities to leverage these largely ignored interictal data to better diagnose and treat patients. IEEG offers a unique opportunity to observe epileptic cortical network dynamics but waiting for seizures increases patient risks associated with invasive monitoring. In this study, we aimed to leverage interictal iEEG data by developing a new network-based interictal iEEG marker of the epileptogenic zone. We hypothesized that when a patient is not clinically seizing, it is because the epileptogenic zone is inhibited by other regions. We developed an algorithm that identifies two groups of nodes from the interictal iEEG network: those that are continuously inhibiting a set of neighbouring nodes ('sources') and the inhibited nodes themselves ('sinks'). Specifically, patient-specific dynamical network models were estimated from minutes of iEEG and their connectivity properties revealed top sources and sinks in the network, with each node being quantified by source-sink metrics. We validated the algorithm in a retrospective analysis of 65 patients. The source-sink metrics identified epileptogenic regions with 73% accuracy and clinicians agreed with the algorithm in 93% of seizure-free patients. The algorithm was further validated by using the metrics of the annotated epileptogenic zone to predict surgical outcomes. The source-sink metrics predicted outcomes with an accuracy of 79% compared to an accuracy of 43% for clinicians' predictions (surgical success rate of this dataset). In failed outcomes, we identified brain regions with high metrics that were untreated. When compared with high frequency oscillations, the most commonly proposed interictal iEEG feature for epileptogenic zone localization, source-sink metrics outperformed in predictive power (by a factor of 1.2), suggesting they may be an interictal iEEG fingerprint of the epileptogenic zone.

Vaccination in pediatric solid organ transplant: A primer for the immunizing clinician.

Pediatric solid organ transplant (SOT) recipients are at a uniquely elevated risk for vaccine preventable illness (VPI) secondary to a multitude of factors including incomplete immunization at the time of transplant, inadequate response to vaccines with immunosuppression, waning antibody titers observed post-SOT, and uncertainty among providers on the correct immunization schedule to utilize post-SOT. Multiple guidelines are in existence from the Infectious Diseases Society of America and the American Society of Transplantation, which require use in adjunct with additional published references. We summarize the present state of SOT vaccine recommendations from relevant resources in tandem with the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices guidance utilizing both routine and rapid catch-up schedules. The purpose of this all-inclusive review is to provide improved clarity on the most optimal pre- and post-transplant vaccine management within a one-stop-shop for the immunizing clinician.

Efficacy of Ultrasound-Guided Glenohumeral Joint Injections of Leukocyte-Poor Platelet-Rich Plasma Versus Hyaluronic Acid in the Treatment of Glenohumeral Osteoarthritis: A Randomized, Double-Blind Controlled Trial.

OBJECTIVE: To compare the efficacy of ultrasound-guided hyaluronic acid (HA) versus leukocyte-poor platelet-rich plasma (LP-PRP) injection in the treatment of glenohumeral osteoarthritis. DESIGN: Double-blind randomized controlled trial. SETTING: Academic institution. PATIENTS: Seventy patients with chronic glenohumeral osteoarthritis were randomly assigned to receive a single injection of HA (n = 36) or LP-PRP (n = 34). INTERVENTIONS: Leukocyte-poor platelet-rich plasma was processed using Harvest/TerumoBCT Clear PRP kits. Ultrasound-guided injections of 6 mL HA or 6 mL LP-PRP into the glenohumeral joint were performed. Patients, the injecting physician, and outcomes assessor were blinded to treatment assignments. MAIN OUTCOME MEASURES: Shoulder Pain and Disability Index (SPADI), American Shoulder and Elbow Surgeons (ASES) score, current/average numerical rating scale (NRS) pain scores, satisfaction, and side effects were assessed at the 5 follow-up time points over 12 months. RESULTS: Baseline characteristics were similar between groups. There were no significant between-group differences regarding SPADI, ASES, and current/average NRS pain scores at any time point up to 12 months postinjection ( P > 0.05). However, significant improvements in SPADI, ASES, and current/average NRS pain scores were observed in both groups starting at 1 or 2 months ( P < 0.01, P < 0.01, P < 0.001, and P < 0.01, respectively). These improvements were observed regardless of osteoarthritis severity. For patients who received LP-PRP, there was no effect of platelet yield on outcomes. Side effect and satisfaction rates were similar between groups. CONCLUSIONS: There were no differences in pain and functional outcomes after a single injection of LP-PRP versus HA. However, significant improvements in pain and function were observed after both treatments in patients with glenohumeral osteoarthritis.

Clinical outcomes following intradiscal injections of higher-concentration platelet-rich plasma in patients with chronic lumbar discogenic pain.

PURPOSE: This study aimed to assess clinical outcomes following intradiscal injections of higher-concentration (> 10 ×) platelet-rich plasma (PRP) in patients with chronic lumbar discogenic pain and to compare outcomes with a historical cohort. METHODS: This retrospective study included 37 patients who received intradiscal injections of higher-concentration (> 10 ×) PRP and had post-procedure outcomes data (visual numerical scale pain score, Functional Rating Index [FRI], and NASS Patient Satisfaction Index). Outcomes were compared to a historical cohort of 29 patients who received intradiscal injections of < 5X PRP. RESULTS: Pain and FRI scores significantly improved by 3.4 ± 2.5 and 46.4 ± 27.6, respectively, at 18.3 ± 13.3 months following intradiscal injections of > 10 × PRP (p < 0.001). These improvements were greater than those reported by the historical cohort (1.7 ± 1.6 and 33.7 ± 12.3; p = 0.004 and 0.016, respectively). Additionally, the satisfaction rate was higher in patients receiving > 10 × PRP compared to those receiving < 5 × PRP (81% vs. 55%; p = 0.032). CONCLUSIONS: Findings from this study suggest that clinical outcomes can be optimized by using PRP preparations that contain a higher concentration of platelets. Further research is needed to continue to optimize the composition of PRP used to treat patients with lumbar disc disease.

Multisystem Inflammatory Syndrome in Children Associated With Coronavirus Disease 2019 in a Children's Hospital in New York City: Patient Characteristics and an Institutional Protocol for Evaluation, Management, and Follow-Up.

OBJECTIVES: The disease caused by severe acute respiratory syndrome coronavirus 2, known as coronavirus disease 2019, has resulted in a global pandemic. Reports are emerging of a new severe hyperinflammatory syndrome related to coronavirus disease 2019 in children and adolescents. The Centers for Disease Control and Prevention has designated this disease multisystem inflammatory syndrome in children. Our objective was to develop a clinical inpatient protocol for the evaluation, management, and follow-up of patients with this syndrome. DATA SOURCES: The protocol was developed by a multidisciplinary team based on relevant literature related to coronavirus disease 2019, multisystem inflammatory syndrome in children, and related inflammatory syndromes, as well as our experience caring for children with multisystem inflammatory syndrome in children. Data were obtained on patients with multisystem inflammatory syndrome in children at our institution from the pre-protocol and post-protocol periods. DATA SYNTHESIS: Our protocol was developed in order to identify cases of multisystem inflammatory syndrome in children with high sensitivity, stratify risk to guide treatment, recognize co-infectious or co-inflammatory processes, mitigate coronary artery abnormalities, and manage hyperinflammatory shock. Key elements of evaluation include case identification using broad clinical characteristics and comprehensive laboratory and imaging investigations. Treatment centers around glucocorticoids and IV immunoglobulin with biologic immunomodulators as adjuncts. Multidisciplinary follow-up after discharge is indicated to manage continued outpatient therapy and evaluate for disease sequelae. In nearly 2 months, we admitted 54 patients with multisystem inflammatory syndrome in children, all of whom survived without the need for invasive ventilatory or mechanical circulatory support. After institution of this protocol, patients received earlier treatment and had shorter lengths of hospital stay. CONCLUSIONS: This report provides guidance to clinicians on evaluation, management, and follow-up of patients with a novel hyperinflammatory syndrome related to coronavirus disease 2019 known as multisystem inflammatory syndrome in children. It is based on the relevant literature and our experience. Instituting such a protocol during a global pandemic is feasible and is associated with patients receiving treatment and returning home more quickly.

Prevalence of Lumbosacral Transitional Vertebrae in Patients With Symptomatic Femoroacetabular Impingement Requiring Hip Arthroscopy.

PURPOSE: The primary aim of this study was to determine the prevalence of lumbosacral transitional vertebrae (LSTVs) in patients with symptomatic femoroacetabular impingement (FAI) requiring hip arthroscopy. The secondary aim was to determine whether there is an association between LSTV anatomy and patient-reported outcomes. METHODS: This retrospective study included patients aged 18 to 45 years with symptomatic FAI who underwent arthroscopy between March 2010 and March 2016 and had anteroposterior pelvic radiographs. The exclusion criteria included lack of an FAI diagnosis, hip osteoarthritis (Tönnis grade ≥ 2), prior spinal fusion surgery, prior total hip arthroplasty, indications for total hip arthroplasty, and revision surgery on the affected hip. All radiographs were assessed by an interventional spine and sports fellow. The primary outcome was the prevalence of LSTVs, classified using the criteria of Castellvi et al. Secondary outcomes included the modified Harris Hip Score, Hip Outcome Score, and International Hip Outcome Tool 33 score. RESULTS: A total of 1,880 patients were included. Review of the patients' radiographs yielded 262 LSTVs, for an overall prevalence of 13.9% (type IA in 104 [5.5%], type IB in 53 [2.8%], type IIA in 60 [3.2%], type IIB in 25 [1.3%], type IIIA in 8 [0.4%], type IIIB in 0 [0%], and type IV in 12 [0.64%]). The prevalence of type II, III, and IV LSTVs was 5.6% (n = 105). Unilateral LSTV sidedness did not correlate with symptom laterality (κ = 0.07). There were no differences in patient-reported outcomes between patients with LSTV anatomy and those without it. CONCLUSIONS: In this large cohort of 1,880 patients with symptomatic FAI, the prevalence of LSTVs was 13.9%. There was no correlation between sidedness of unilateral LSTVs and the symptomatic hip. Furthermore, there was no association between LSTV anatomy and patient-reported outcomes. The prevalence of LSTVs in this cohort was similar to the prevalence rates previously reported in patients with low-back pain. LEVEL OF EVIDENCE: Level IV, case series.

Evaluation of an interprofessional care coordination model: Benefits to health professions students and the community served.

BACKGROUND/PURPOSE: An innovative care coordination program was developed to enhance wellness among low-income older adults living in subsidized apartment buildings and to provide rich interprofessional education experiences for health professions students. METHODS: Program effectiveness for the residents was measured through an evaluation of participation, services used, and healthcare utilization. Educational effectiveness was measured through a change in health concepts and perceptions of interprofessional practice. FINDINGS: Health care utilization among participating residents showed an 8.6% reduction in emergency department visits and 9.8% reduction in hospital admissions. Students demonstrated improved knowledge in motivational interviewing (p = .02); diabetes (p = .02); hypertension (p≤.01); and frailty (p≤.01). Changes in students perception of interprofessional practice were significant in two areas; Teamwork and Collaboration (p≥.00); and Person Centeredness (p = .00). DISCUSSION: This care coordination model may be an effective approach to reduce care resource utilization among medically complex lower income older adults and provides a rich interprofessional learning experience for students.

Psychosocial, behavioral and clinical correlates of children with overweight and obesity.

BACKGROUND: Psychological and behavioral correlates are considered important in the development and persistence of obesity in both adults and youth. This study aimed to identify such features in youth with severe obesity (BMI ≥ 120% of 95thpercentile of sex-specific BMI-for-age) compared to those with overweight or non-severe obesity. METHODS: Youth with BMI ≥ 85th percentile were invited to participate in a prospective research registry where data was collected on attributes such as family characteristics, eating behaviors, dietary intake, physical activity, perception of health and mental well-being, and cardiometabolic parameters. RESULTS: In a racially/ethnically diverse cohort of 105 youth (65% female, median age 16.1 years, range 4.62-25.5), 51% had severe obesity. The body fat percent increased with the higher levels of obesity. There were no differences in the self-reported frequency of intake of sugar sweetened beverages or fresh produce across the weight categories. However, the participants with severe obesity reported higher levels of emotional eating and eating when bored (p = 0.022), levels of stress (p = 0.013), engaged in fewer sports or organized activities (p = 0.044), and had suboptimal perception of health (p = 0.053). Asthma, depression and obstructive sleep apnea were more frequently reported in youth with severe obesity. The presence of abnormal HDL-C, HOMA-IR, hs-CRP and multiple cardiometabolic risk factors were more common among youth with severe obesity. CONCLUSIONS: Youth with severe obesity have identifiable differences in psychosocial and behavioral attributes that can be used to develop targeted intervention strategies to improve their health.

Women Are at Higher Risk for Concussions Due to Ball or Equipment Contact in Soccer and Lacrosse.

BACKGROUND: There is ample evidence to suggest sex- and gender-based differences in the incidence of sports-related concussions. The mechanisms of concussion may vary between male and female athletes and contribute to this observed difference. Understanding the underlying etiology by pooling data from primary studies across different settings and sport types will inform interventions that can reduce concussion rates. QUESTIONS/PURPOSES: Specifically, we asked: (1) In which sports are female athletes less likely to experience concussions from player contact? (2) In which sports are female athletes more likely to experience concussions because of ball or equipment contact? METHODS: PubMed, EMBASE, and Cochrane Library databases were searched to identify articles published from January 2000 to December 2018. Ten studies met the inclusion criteria, which were studies that reported concussion incidence by mechanism for both male and female athletes. Exclusion criteria included non-English studies, conference abstracts, and studies on non-sports related concussions. The sports represented by the 10 studies included ice hockey (n = 4), soccer (n = 5), basketball (n = 4), baseball/softball (n = 4), and lacrosse (n = 5). The rate ratio was calculated as the incidence rate in female athletes/male athletes for each concussion mechanism or activity. Data were pooled using the DerSimonian-Laird random-effects model. Study quality was assessed with the Newcastle-Ottawa Scale. RESULTS: Female athletes were at lower risk of player-contact-induced concussions in lacrosse (pooled rate ratio 0.33 [95% CI 0.25 to 0.43]; p < 0.001), basketball (pooled rate ratio 0.86 [95% CI 0.76 to 0.97]; p = 0.01), ice hockey (pooled rate ratio 0.64 [95% CI 0.56 to 0.73]; p < 0.001), soccer (pooled rate ratio 0.70 [95% CI 0.66 to 0.75]; p < 0.001), and soccer heading (pooled rate ratio 0.80 [95% CI 0.72 to 0.90]; p < 0.001); in these sports, men were at higher risk of concussions from player contact. Female athletes were more likely to experience concussions because of ball or equipment contact in lacrosse (pooled rate ratio 3.24 [95% CI 2.10 to 4.99]; p < 0.001), soccer (pooled rate ratio 2.04 [95% CI 1.67 to 2.49]; p < 0.001), and soccer heading (pooled rate ratio 2.63 [95% CI 1.84 to 3.77]; p < 0.001). CONCLUSIONS: The mechanism or activity underlying concussions differs between male and female athletes across different sports. This finding remains the same regardless of whether there are rule differences between the men's and women's games. The implementation of other interventions are required to further ensure player safety, including protective head equipment, concussion prevention training, or rules limiting player contact in the men's game. LEVEL OF EVIDENCE: Level III, retrospective study.

Fluoroscopically guided caudal epidural steroid injections for axial low back pain associated with central disc protrusions: a prospective outcome study.

PURPOSE: To determine if axial low back pain (LBP) associated with central disc protrusions can be improved by caudal epidural steroid injections (ESIs). METHODS: Adults with chronic (> 3 months) moderate-to-severe axial LBP with L4-5 and/or L5-S1 central disc protrusions were enrolled in this prospective study. Participants underwent caudal ESIs under standard-of-care practice. The numerical rating scale (NRS) pain score, modified North American Spine Society satisfaction, and Roland Morris Disability Questionnaire (RMDQ) were collected at one week, one month, three months, six months, and one year post-injection. Pre-injection magnetic resonance images were assessed by a musculoskeletal radiologist. RESULTS: Sixty-eight participants (42 males, 26 females) were analyzed. There were statistically significant improvements in all outcome measures at all follow-up time points, with the exception of NRS best pain at six months. Clinically significant improvements in outcomes were observed at various time points: at three months and one year for current pain; at one week, one month, three months, six months, and one year for worst pain; and at one month and one year for RMDQ. The proportion of satisfied participants ranged from 57 to 69% throughout the study. No adverse events were observed. CONCLUSIONS: This study demonstrated significant improvements in pain and function following caudal ESIs in a cohort of axial LBP with associated central disc protrusions. Further studies, including the use of randomized controlled trials, are needed to determine the ideal subset of candidates for this treatment and to explore additional applications that caudal ESIs may have for chronic LBP.

Contribution of alveolar type II cell-derived cyclooxygenase-2 to basal airway function, lung inflammation, and lung fibrosis.

Cyclooxygenase (COX)-2 has been shown to be involved in regulating basal airway function, bacterial LPS-induced airway hyperresponsiveness (AHR) and lung inflammation, and bleomycin-induced lung fibrosis; however, the cellular source of COX-2 that underlies these effects is unknown. We generated mice with alveolar type II (ATII) cell-specific knockdown of COX-2 (AT2CC(-/-)), to examine the role of ATII cell-derived prostaglandins (PGs) in these processes. Specific knockdown of COX-2 was confirmed by real-time RT-PCR and Western blot analyses. LC/MS/MS analysis showed that ATII cells produced PGs. Basal airway responsiveness of AT2CC(-/-) mice was decreased compared to that of wild-type (WT) mice. LPS-induced hypothermic response, infiltration of inflammatory cells into the airway, and lung inflammation were enhanced in AT2CC(-/-) mice relative to WT controls; however, LPS-induced AHR and proinflammatory cytokine and chemokine expression were similar between the genotypes. After 21 d of bleomycin administration, AT2CC(-/-) mice behaved in a manner similar to WT mice. Thus, ATII cell-derived COX-2 plays an important role in regulating basal airway function and LPS-induced lung inflammation, but does not play a role in bleomycin-induced fibrosis. These findings provide insight into the cellular source of COX-2 related to these lung phenotypes.

Perineural dexamethasone with subsartorial saphenous nerve blocks in ACL reconstruction.

PURPOSE: Subsartorial saphenous nerve blockade (SSNB) is an effective analgesic alternative to femoral nerve blockade after anterior cruciate ligament (ACL) reconstruction with bone-tendon-bone (BTB) autograft. It was hypothesized that dexamethasone in a SSNB will prolong analgesia, improve pain and satisfaction, and reduce postoperative opioid requirements and side effects. METHODS: One hundred ninety-five patients undergoing ACL reconstruction with BTB autograft (ages 16-65) were enrolled. Subjects received SSNB with 13 ml of 0.5 % bupivacaine (control group), 1 mg preservative-free dexamethasone +0.5 % bupivacaine (treatment group I), or 4 mg preservative-free dexamethasone +0.5 % bupivacaine (treatment group II). Subjects received identical perioperative management. On postoperative days 1 and 2, subjects reported perceived block duration, pain scores, satisfaction, opioid use, and side effects. Cox-proportional hazards modelling was used to compare block duration, adjusting for body mass index, age, sex, tourniquet time, American Society of Anesthesiologists classification, and intravenous dexamethasone dose. RESULTS: Patient-perceived block duration was significantly increased in treatment group I [hazard ratio (95 % confidence interval [CI]) 0.48 (0.31-0.75); P = 0.001] and treatment group II (hazard ratio (95 % CI): 0.52 (0.33-0.81); P = 0.004) compared to control. The block was extended from a median (95 % CI) of 33.1 (28.4-37.3) to 41.2 (32.4-50.9) and 46.5 (35.8-48.9) hours, respectively. Additionally, patients in treatment group II reported increased time that block provided pain relief, higher patient satisfaction, lower pain scores at rest, and decreased drowsiness and confusion. CONCLUSION: The addition of 1 and 4 mg of dexamethasone to the block injectate significantly increased SSNB duration by 8-13 h compared to control. LEVEL OF EVIDENCE: Therapeutic study, level 1.

Mechanisms of deep brain stimulation.

Deep brain stimulation (DBS) is widely used for the treatment of movement disorders including Parkinson's disease, essential tremor, and dystonia and, to a lesser extent, certain treatment-resistant neuropsychiatric disorders including obsessive-compulsive disorder. Rather than a single unifying mechanism, DBS likely acts via several, nonexclusive mechanisms including local and network-wide electrical and neurochemical effects of stimulation, modulation of oscillatory activity, synaptic plasticity, and, potentially, neuroprotection and neurogenesis. These different mechanisms vary in importance depending on the condition being treated and the target being stimulated. Here we review each of these in turn and illustrate how an understanding of these mechanisms is inspiring next-generation approaches to DBS.

Vascular characterization of mice with endothelial expression of cytochrome P450 4F2.

Cytochrome P450 (CYP) 4A and 4F enzymes metabolize arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE). Although CYP4A-derived 20-HETE is known to have prohypertensive and proangiogenic properties, the effects of CYP4F-derived metabolites are not well characterized. To investigate the role of CYP4F2 in vascular disease, we generated mice with endothelial expression of human CYP4F2 (Tie2-CYP4F2-Tr). LC/MS/MS analysis revealed 2-foldincreases in 20-HETE levels in tissues and endothelial cells (ECs), relative to wild-type (WT) controls. Tie2-CYP4F2-Tr ECs demonstrated increases in growth (267.1 ± 33.4 vs. 205.0 ± 13% at 48 h) and tube formation (7.7 ± 1.1 vs. 1.6 ± 0.5 tubes/field) that were 20-HETE dependent and associated with up-regulation of prooxidant NADPH oxidase and proangiogenic VEGF. Increases in VEGF and NADPH oxidase levels were abrogated by inhibitors of NADPH oxidase and MAPK, respectively, suggesting the possibility of crosstalk between pathways. Interestingly, IL-6 levels in Tie2-CYP4F2-Tr mice (18.6 ± 2.7 vs. 7.9 ± 2.7 pg/ml) were up-regulated via NADPH oxidase- and 20-HETE-dependent mechanisms. Although Tie2-CYP4F2-Tr aortas displayed increased vasoconstriction, vasorelaxation and blood pressure were unchanged. Our findings indicate that human CYP4F2 significantly increases 20-HETE production, CYP4F2-derived 20-HETE mediates EC proliferation and angiogenesis via VEGF- and NADPH oxidase-dependent manners, and the Tie2-CYP4F2-Tr mouse is a novel model for examining the pathophysiological effects of CYP4F2-derived 20-HETE in the vasculature.-Cheng, J., Edin, M. L., Hoopes, S. L., Li, H., Bradbury, J. A., Graves, J. P., DeGraff, L. M., Lih, F. B., Garcia, V., Shaik, J. S. B., Tomer, K. B., Flake, G. P., Falck, J. R., Lee, C. R., Poloyac, S. M., Schwartzman, M. L., Zeldin, D. C. Vascular characterization of mice with endothelial expression of cytochrome P450 4F2.

ß-Arrestin-2 deficiency attenuates abdominal aortic aneurysm formation in mice.

RATIONALE: Abdominal aortic aneurysms (AAAs) are a chronic inflammatory vascular disease for which pharmacological treatments are not available. A mouse model of AAA formation involves chronic infusion of angiotensin II (AngII), and previous studies indicated a primary role for the AngII type 1a receptor in AAA formation. ß-arrestin (ßarr)-2 is a multifunctional scaffolding protein that binds G-protein-coupled receptors such as AngII type 1a and regulates numerous signaling pathways and pathophysiological processes. However, a role for ßarr2 in AngII-induced AAA formation is currently unknown. OBJECTIVE: To determine whether ßarr2 played a role in AngII-induced AAA formation in mice. METHODS AND RESULTS: Treatment of ßarr2(+/+) and ßarr2(-/-) mice on the hyperlipidemic apolipoprotein E-deficient (apoE(-/-)) background or on normolipidemic C57BL/6 background with AngII for 28 days indicated that ßarr2 deficiency significantly attenuated AAA formation. ßarr2 deficiency attenuated AngII-induced expression of cyclooxygenase-2, monocyte chemoattractant protein-1, macrophage inflammatory protein 1α, and macrophage infiltration. AngII also increased the levels of phosphorylated extracellular signal-regulated kinase 1/2 in apoE(-/-)/ßarr2(+/+) aortas, whereas ßarr2 deficiency diminished this increase. Furthermore, inhibition of extracellular signal-regulated kinase 1/2 activation with CI1040 (100 mg/kg per day) reduced the level of AngII-induced cyclooxygenase-2 expression in apoE(-/-)/ßarr2(+/+) mice to the level observed in apoE(-/-)/ßarr2(-/-) mice. AngII treatment also increased matrix metalloproteinase expression and disruption of the elastic layer in apoE(-/-)/ßarr2(+/+) aortas, and ßarr2 deficiency reduced these effects. CONCLUSIONS: ßarr2 contributes to AngII-induced AAA formation in mice by phosphorylated extracellular signal-regulated kinase 1/2-mediated cyclooxygenase-2 induction and increased inflammation. These studies suggest that for the AngII type 1a receptor, G-protein-independent, ßarr2-dependent signaling plays a major role in AngII-induced AAA formation.

Androgen-induced hypertension in angiotensinogen deficient mice: role of 20-HETE and EETS.

20-HETE is a potent inducer of endothelial ACE in vitro and administration of lisinopril or losartan attenuates blood pressure in models of 20-HETE-dependent hypertension. The present study was undertaken to further define the relationship between 20-HETE and the renin-angiotensin system in hypertension using an angiotensinogen-deficient mouse (Agt+/-). Treatment of male AGT+/- with 5α-dihydrotestosterone (DHT) increased systolic BP from 102±2 to 125±3mmHg; in comparison, the same treatment raised BP in wild type (WT) from 110±2 to 138±2mmHg. DHT increased vascular 20-HETE levels in AGT+/- and WT from 1.5±0.7 and 2.1±0.6 to 13.0±2.0 and 15.8±4.0ng/mg, respectively. Concurrent treatment with the 20-HETE antagonist, 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (20-HEDE) prevented the increases in BP in both AGT+/- and WT mice. Administration of 20-HEDE at the peak of the DHT-induced BP increase (12 days) reduced BP to basal levels after 48h. Interestingly, basal levels of renal microvascular EETs were higher in AGT+/- compared to WT (55.2±9.7 vs 20.0±4.1ng/mg) and treatment of AGT+/- with DHT decreased the levels of EETs (28.4±5.1ng/mg). DHT-mediated changes in vascular EET level were not observed in WT mice. Vascular Cyp4a12 and ACE protein levels were increased in both AGT+/- and WT by 30-40% and decreased with concomitant administration of 20-HEDE. Lisinopril was as effective as 20-HEDE in preventing DHT-mediated increases in BP in both AGT+/- and WT mice. This study substantiates our previous findings that the RAS plays an important role in 20-HETE-mediated hypertension. It also proposes a novel interaction between 20-HETE and EETs.

Phase II/III trial of a pre-transplant farnesyl transferase inhibitor in juvenile myelomonocytic leukemia: a report from the Children's Oncology Group.

BACKGROUND: Juvenile myelomonocytic leukemia (JMML) is not durably responsive to chemotherapy, and approximately 50% of patients relapse after hematopoietic stem cell transplant (HSCT). Here we report the activity and acute toxicity of the farnesyl transferase inhibitor tipifarnib, the response rate to 13-cis retinoic acid (CRA) in combination with cytoreductive chemotherapy, and survival following HSCT in children with JMML. PROCEDURE: Eighty-five patients with newly diagnosed JMML were enrolled on AAML0122 between 2001 and 2006. Forty-seven consented to receive tipifarnib in a phase II window before proceeding to a phase III trial of CRA in combination with fludarabine and cytarabine followed by HSCT and maintenance CRA. Thirty-eight patients enrolled only in the phase III trial. RESULTS: Overall response rate was 51% after tipifarnib and 68% after fludarabine/cytarabine/CRA. Tipifarnib did not increase pre-transplant toxicities. Forty-six percent of the 44 patients who received protocol compliant HSCT relapsed. Five-year overall survival was 55 ± 11% and event-free survival was 41 ± 11%, with no significant difference between patients who did or did not receive tipifarnib. CONCLUSIONS: Administration of tipifarnib in the window setting followed by HSCT in patients with newly diagnosed JMML was safe and yielded a 51% initial response rate as a single agent, but failed to reduce relapse rates or improve long-term overall survival.

Postoperative symptoms of psychosis after deep brain stimulation in patients with Parkinson's disease.

OBJECT: Cases of postoperative psychosis in Parkinson's disease patients receiving deep brain stimulation (DBS) treatment have previously been published. However, the magnitude of symptom incidence and the clinical risk factors are currently unknown. This retrospective study sheds light on these issues by investigating psychosis in a group of 128 Parkinson's disease patients who received DBS implants. METHODS: A retrospective chart review was performed to obtain surgery dates, follow-up clinic visit dates, and associated stimulation parameter settings (contacts in use and the polarity of each along with stimulation voltage, frequency, and pulse width) for each patient. Unified Parkinson's Disease Rating Scale II Thought Disorder scores, used as a clinical assessment tool to evaluate the presence of psychosis at each visit, were also collected. The data were compiled into a database and analyzed. RESULTS: The lifetime incidence of psychosis in this cohort of patients was 28.1%. The data suggest that risk of psychosis remains fairly constant throughout the first 5 years after implantation of a DBS system and that patients older at the time of receiving the first DBS implant are not only more likely to develop psychosis, but also to develop symptoms sooner than their younger counterparts. Further analysis provides evidence that psychosis is largely independent of the clinically used electrode contact and of stimulation parameters prior to psychosis onset. CONCLUSIONS: Although symptoms of psychosis are widely seen in patients with Parkinson's disease in the years following stimulator placement, results of the present suggest that most psychoses occurring postoperatively are likely independent of implantation and stimulation settings.

Cyclooxygenase-2 inhibits T helper cell type 9 differentiation during allergic lung inflammation via down-regulation of IL-17RB.

RATIONALE: Helper CD4(+) T cell subsets, including IL-9- and IL-10-producing T helper cell type 9 (Th9) cells, exist under certain inflammatory conditions. Cyclooxygenase (COX)-1 and COX-2 play important roles in allergic lung inflammation and asthma. It is unknown whether COX-derived eicosanoids regulate Th9 cells during allergic lung inflammation. OBJECTIVES: To determine the role of COX metabolites in regulating Th9 cell differentiation and function during allergic lung inflammation. METHODS: COX-1(-/-), COX-2(-/-), and wild-type (WT) mice were studied in an in vivo model of ovalbumin-induced allergic inflammation and an in vitro model of Th9 differentiation using flow cytometry, cytokine assays, confocal microscopy, real-time PCR, and immunoblotting. In addition, the role of specific eicosanoids and their receptors was examined using synthetic prostaglandins (PGs), selective inhibitors, and siRNA knockdown. MEASUREMENTS AND MAIN RESULTS: Experimental endpoints were not different between COX-1(-/-) and WT mice; however, the percentage of IL-9(+) CD4(+) T cells was increased in lung, bronchoalveolar lavage fluid, lymph nodes, and blood of allergic COX-2(-/-) mice relative to WT. Bronchoalveolar lavage fluid IL-9 and IL-10, serum IL-9, and lung IL-17RB levels were significantly increased in allergic COX-2(-/-) mice or in WT mice treated with COX-2 inhibitors. IL-9, IL-10, and IL-17RB expression in vivo was inhibited by PGD2 and PGE2, which also reduced Th9 cell differentiation of murine and human naive CD4(+) T cells in vitro. Inhibition of protein kinase A significantly increased Th9 cell differentiation of naive CD4(+) T cells isolated from WT mice in vitro. CONCLUSIONS: COX-2-derived PGD2 and PGE2 regulate Th9 cell differentiation by suppressing IL-17RB expression via a protein kinase A-dependent mechanism.