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Objective: LVADs are surgically implanted mechanical pumps that improve survival rates of individuals with advanced heart failure. LVAD therapy is associated with high morbidity, which can be partially attributed to challenges with detecting LVAD complications before adverse events occur. Current methods used to monitor for complications with LVAD support require frequent clinical assessments at specialized LVAD centers. Analysis of recorded precordial sounds may enable real-time, remote monitoring of device and cardiac function for early detection of LVAD complications. The dominance of LVAD sounds in the precordium limits the utility of routine cardiac auscultation of LVAD recipients. In this work, we develop a signal processing pipeline to mitigate sounds generated by the LVAD. Methods: We collected in vivo precordial sounds from 17 LVAD recipients, and contemporaneous echocardiograms from 12 of these individuals, to validate heart valve closure timings. Results: We characterized various acoustic signatures of heart sounds extracted from in vivo recordings, and report preliminary findings linking fundamental heart sound characteristics and level of LVAD support. Conclusion: Mitigation of LVAD sounds from precordial sound recordings of LVAD recipients enables analysis of intrinsic heart sounds. Significance: These findings provide proof-of-concept evidence of the clinical utility of heart sound analysis for bedside and remote monitoring of LVAD recipients.

Background Although prior studies have identified a low risk of venous thromboembolism (VTE) in rhinoplasty, these studies are limited by small samples and associated risk factors remain unknown. Objectives The aim of this study was to discern the incidence of VTE following rhinoplasty in a large patient population through analysis of a nationwide insurance claims database. Methods This study involved a population-based retrospective analysis of insurance claims made by patients who underwent rhinoplasty between 2007 and 2016. Established risk factors for VTE, demographic data, procedural details, and absolute incidence of VTE were collected. Results We identified a total of 55,287 patients who underwent rhinoplasty from 2007 to 2016. Mean age [standard error of the mean] was 38.74 [0.06] years (range, 18-74 years), and 54% were female. The overall incidence of VTE was 111, of which 70 were DVT and 41 were PE. From multivariate regression analysis, previous VTE (odds ratio [OR], 52.8; 95% confidence interval [CI], 35.2-78.6; P Conclusions We demonstrate a low overall incidence of VTE in rhinoplasty patients. Previous VTE, PICC/central line, advancing age, IBD, and intraoperative rib graft harvest were most strongly associated with VTE in this population cohort. Level of Evidence: 4

Background It would be useful if existing tools or outcomes measures could predict which patients are at greater risk of revision surgery following rhinoplasty. Objectives The authors sought to determine if a single question assessing nasal self-esteem could be utilized to predict which patients are at greatest risk of revision surgery following rhinoplasty. Methods The authors conducted a retrospective chart review of 148 patients who underwent cosmetic rhinoplasty. Results of pre- and postoperative Standardized Cosmesis and Health Nasal Outcomes Survey questionnaires and rates of revision or patient-initiated revision discussions (RD) were collected. Patients were stratified based on answers to Standardized Cosmesis and Health Nasal Outcomes Survey question 5 (SQ5), “Decreased mood and self-esteem due to my nose.” Results Of the 148 patients included in the analysis, 72.9% were women, and the mean age was 30.9 (15-59, standard deviation = 10.3) years. Those patients who selected 4 or 5 on SQ5 had an overall revision rate of 16.7% and 18.8%, respectively, and a RD rate of 27.8% and 31.25%, respectively. Those patients who selected 0 through 3 on SQ5 had an overall revision rate of 0% and an overall RD rate of 10.4%. Only SQ5 was predictive of revision and RD on logistic regression analysis (P = 0.0484 and P = 0.0257) after Bonferroni correction. Conclusions SQ5 appears to offer a useful adjunct to guide surgical management of the cosmetic rhinoplasty patient. Those patients who reported worse nasal self-esteem and associated mood preoperatively were more likely to request and undergo revision. Level of Evidence: 4

Importance: Although conventional hump resections are a hallmark of rhinoplasty, there has been a rekindled interest in dorsal preservation (DP) techniques as a means for addressing the dorsal hump, with claims of superior functional and aesthetic results. As such, an understanding of DP, including technical considerations and outcomes, is imperative. Observations: DP allows for mobilization of the osseocartilaginous nasal vault as a single unit and thereby prevents disruption of the natural keystone area. The osseous nasal vault is managed with a transverse osteotomy and either a bilateral single lateral osteotomy (pushdown procedure) or bilateral bony wedge resections (letdown procedure) to allow for descent of the nasal dorsum. A variety of approaches to the septum exist, each differentiated by the location of cartilage resection: subdorsal, high-septal, midseptal, or inferior septum. These techniques result in pleasing dorsal aesthetic lines but may be limited by a higher rate of dorsal hump recurrence. Patency of the internal nasal valve (INV) is theoretically improved with DP. Robust series with patient-reported outcomes are lacking, although several reports and early experience at our center with a newly described high-septal resection technique do suggest positive functional and cosmetic outcomes with DP. Conclusions and Relevance: With the recent revitalized interest in DP, an understanding of the potential benefits, techniques, and challenges associated with this surgery is helpful. Maintenance of the dorsum as a single unit has implications for maintaining structural integrity at the nasal keystone, pleasing dorsal aesthetic lines, and the patency of the INV. As surgeons continue to develop and employ these techniques, critical assessment of patient-reported outcomes and objective nasal measurements, with an emphasis on comparison with standard hump takedown techniques, will be valuable.

IMPORTANCE: In the last decade, there has been a significant increase in the number of practitioners administering botulinum toxin for facial synkinesis. However, there are few resources available to guide treatment patterns, and little is known about how these patterns are associated with functional outcomes and quality of life. OBJECTIVE: To evaluate botulinum treatment patterns, including the dosing and frequency of muscle targeting, for treatment of facial synkinesis and to quantify patient outcomes. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study of 99 patients treated for facial synkinesis was conducted from January 2016 through December 2018 at the Vanderbilt Bill Wilkerson Center in Nashville, Tennessee, a tertiary referral center. INTERVENTION: Onabotulinum toxin A treatment of facial synkinesis. MAIN OUTCOMES AND MEASURES: Patient-reported outcomes on the Synkinesis Assessment Questionnaire and botulinum treatment patterns, including the dosages and frequency of injection for each facial muscle, were compared at the initiation of treatment and at the end of recorded treatment. RESULTS: In total, 99 patients (80 female patients [81%]) underwent botulinum injections for treatment of facial synkinesis. The median (interquartile range) age was 54.0 (43.5-61.5) years, and the median (interquartile range) follow-up was 27.1 (8.9-59.7) months. Most patients underwent injections after receiving a diagnosis of Bell palsy (41 patients, 41%) or after resection of vestibular schwannoma (36 patients [36%]). The patients received a total of 441 treatment injections, and 369 pretreatment and posttreatment Synkinesis Assessment Questionnaire scores were analyzed. The mean botulinum dose was 2 to 3 U for each facial muscle and 9 to 10 U for the platysma muscle. The dose increased over time for the majority of all muscles, with steady state achieved after a median of 3 treatments (interquartile range, 2-3). Linear regression analysis for cluster data of the mean total questionnaire score difference was −14.2 (95% CI, −17.0 to −11.5; P

The left ventricular assist device (LVAD) has emerged as a bridge or alternative to heart transplant in individuals with advanced heart failure. However, the LVAD recipient population currently faces high rehospitalization rates. Remote analysis of precordial sounds in LVAD recipients may improve aftercare through early detection of complications. Prior work on analyses of precordial sounds in LVAD recipients focused on identifying pump thrombosis. Here, we focus on analyzing intrinsic precordial sounds to provide insight into intrinsic cardiac function. We analyzed a dataset of patient-acquired recordings of precordial sounds in LVAD recipients. We developed a signal processing pipeline to separate LVAD-generated sounds from other precordial sounds, making heart sound analysis in LVAD recipients feasible. Unsupervised clustering of features extracted from LVAD-mitigated sounds revealed subgroups of subjects possessing heart sounds with distinct frequency characteristics. The results provide preliminary evidence for the potential utility of exploring heart sound analysis in LVAD recipients for remote monitoring.

Introduction: Left ventricular assist device (LVAD) recipients experience variable improvements in quality of life (QoL). Methods for optimizing LVAD support to improve QoL are needed. Hypothesis: We hypothesized that acoustic signatures obtained from digital stethoscopes can predict patient-centered outcomes in LVAD recipients. Methods: Subjects were recruited from the LVAD clinic at Duke University Medical Center. Subjects were trained to use a digital stethoscope and recorded their precordial sounds weekly for 6 months. Subjects also completed a Kansas City Cardiomyopathy Questionnaire (KCCQ) weekly. The primary outcome for this study was QoL, as measured by the KCCQ summary score. Results: Twenty-four subjects, 8 supported by a HeartWare LVAD and 16 supported by a HeartMate3 (HM3) LVAD, were enrolled. We developed a novel algorithm to filter LVAD sounds from recordings. Unsupervised clustering of LVAD-mitigated sounds revealed discrete groups of acoustic features. Six out of 16 [38%] HM3 recipients made up a unique cluster and shared a common acoustic feature that we have termed the pulse synchronized sound (PSS) based on its temporal association to the artificial pulse of the HM3. Subjects with the PSS had significantly better KCCQ scores at baseline (median, 89.1 [IQR, 86.2-90.4] vs 66.1 [IQR, 31.1-73.7], P = 0.03) and over the 6 months of the study (mean = 79.67 [95% CI, 74.55 - 84.78] vs 60.57 [95% CI, 55.58 - 65.55], P < .001). Mechanistically, the PSS shares acoustic features with patient-derived intrinsic sounds. Because the PSS cannot be detected by routine auscultation, we developed a robust machine learning algorithm to detect the PSS in precordial sound recordings (AUC = 0.95 by leave-one-subject out cross-validation). Conclusions: We have identified a novel acoustic feature associated with better QoL in HM3 recipients. This novel biomarker is the first of its kind in LVAD recipients and may provide a method for assaying optimized LVAD support.

OBJECTIVE To compare presenting characteristics of patients with adductor spasmodic dysphonia (ADSD), ADSD with laryngeal tremor (ADSD + LT), and laryngeal tremor without ADSD (LT). DESIGN Cross-sectional analysis. METHODS Patients treated for laryngeal movement disorders (1990-2016) were included. Analysis of variance and chi square tests measured differences in patient characteristics across the three disease groups. Using ADSD as the referent, multivariable logistic regression models were used to determine whether potential risk factors including patient demographics, family history, presence of potential inciting events prior to disease onset, and coprevalent movement disorders were associated with ADSD + LT or LT. RESULTS In all, 652 patients with ADSD (n = 377), ADSD + LT (n = 98), and LT (n = 177) were included. ADSD patients were significantly younger than those with ADSD + LT and LT (52.5 ± 13.4, 63.9 ± 11.3, and 69.3 ± 10.5 years, respectively; P

More than 2,400 continuous-flow left ventricular assist devices (LVADs) are implanted each year in the United States alone. Both the number of patients living with LVADs and the life expectancy of these patients are increasing. As a result, patients with LVADs are increasingly encountered by non-LVAD specialists who do not have training in managing advanced heart failure for general medical care, cardiovascular procedures, and other subspecialty care. An understanding of the initial evaluation and management of patients with LVADs is now an essential skill for many health care providers. In this State-of-the-Art Review, we discuss current LVAD technology, summarize our clinical experience with LVADs, and review the current data for the medical management of patients living with LVADs.

AIMS Worsening heart failure (HF) is associated with shorter left ventricular systolic ejection time (SET), but there are limited data describing the relationship between SET and clinical outcomes. Thus, the objective was to describe the association between SET and clinical outcomes in an ambulatory HF population irrespective of ejection fraction (EF). METHODS AND RESULTS We identified ambulatory patients with HF with reduced EF (HFrEF) and HF with preserved EF (HFpEF) who had an outpatient transthoracic echocardiogram performed between August 2008 and July 2010 at a tertiary referral centre. Multivariable logistic regression was used to evaluate the association between SET and 1-year outcomes. A total of 545 HF patients (171 HFrEF, 374 HFpEF) met eligibility criteria. Compared with HFpEF, HFrEF patients were younger [median age 60 years (25th-75th percentiles 50-69) vs. 64 years (25th-75th percentiles 53-74], with fewer females (30% vs. 56%) and a similar percentage of African Americans (36% vs. 35%). Median (25th-75th percentiles) EF with HFrEF was 30% (25-35%) and with HFpEF was 54% (48-58%). Median SET was shorter (280 ms vs. 315 ms, P

Postoperative pulmonary complications (PPCs) are common following major surgical procedures. Risk stratification tools have been developed to identify patients at risk for PPCs. While otolaryngology cases were included in the development of common predictive tools, they comprised small percentages in each tool. It is unclear how these tools perform in patients undergoing major head and neck surgery with free flap reconstruction. This retrospective review studied all free flap reconstructions in head and neck surgery over a 12-year period at a single institution in the southeastern US. Baseline demographic and medical information were included for each case. All cases were reviewed for development of major PPCs, including pneumonia and respiratory failure. The cohort underwent risk stratification using the ARISCAT and Gupta pulmonary risk indices. Performance of these predictive models for head and neck surgery was determined through receiver-operator curve comparison. 794 patients were identified with a median age of 62 years (IQR 41–83). Sixty-five percent were male. Forty-three (5.4%) developed pneumonia, 23 patients developed respiratory failure (2.9%), and 38 patients developed both (4.8%), resulting in a total PPC proportion of 13.1% (n = 104). Both ARISCAT and Gupta pulmonary risk indices demonstrated low discrimination to predict PPCs in head and neck free flap reconstruction, with areas under the curve of 0.60 and 0.65, respectively. Two major indices for prediction of postoperative pulmonary complications do not accurately identify risk in patients undergoing major head and neck surgery. Further studies are needed to develop predictive tools for PPCs in this high-risk population.

Left ventricular assist devices (LVADs) are life-saving, surgically implanted mechanical heart pumps used to treat patients with advanced heart failure (HF). While life-saving, LVAD support is associated with a high incidence of complications, making early recognition and management of LVAD complications a critical need. Blood clot formation within the LVAD, known as LVAD thrombosis, is a catastrophic complication of LVAD therapy that often requires LVAD exchange due to delayed diagnosis and treatment. Using digital stethoscopes, we identified differences in acoustic spectra from two patients presenting with LVAD thrombosis compared with normally functioning LVAD pumps within the same patient. Importantly, these acoustic changes were present even in the absence of typical signs of HF that are often present in LVAD thrombosis patients. Our work suggests that acoustic spectral analysis of digital stethoscope signals could be used for early detection and mitigation of LVAD complications.

Background While there have been multiple studies published that have stressed the importance of restoring various different radiographic parameters to improve functional outcome scores, there is no consensus on the parameter that correlates most with patients’ functional outcomes. We hypothesize that obtaining near anatomical reduction of the palmar lunate facet is critical to improving functional outcome scores. The purpose of this study is to determine the effects of reduction and stabilization of the palmar lunate facet on functional outcomes in patients with intra-articular distal radius fracture. Materials and methods We prospectively collected clinical examination data, radiographic measurements, and functional outcome scores on 157 patients who were treated operatively for multifragmentary intra-articular fractures of the distal radius (AO Type C3) between 1996 and 2006. Prospective data were acquired at 3, 6 months, and 1 year postsurgical intervention in clinical follow-up. Based on radiographic measurements, patients were designated into a nondisplaced palmar lunate facet group and a displaced palmar lunate facet group. Clinical and functional outcomes were then compared between the groups. Results Patients without displacement had a significantly higher value of wrist extension and forearm supination when compared with the patients with displacement. In addition, the Gartland and Werley score was significantly higher in patients with displacement of the palmar lunate facet. Conclusion This study demonstrates that patients with near anatomical reduction of the palmar lunate facet after surgical treatment of an intra-articular distal radius fracture had improved range of motion and better functional outcome scores compared with patients with residual displacement of the palmar lunate facet. Richard MJ, Lampley AJ, Patel PD, Nomides REK, Mithani SK, Leversedge FJ, Ruch DS. The Importance of the Palmar Lunate Facet in the Treatment of Distal Radius Fractures. The Duke Orthop J 2016;6(1):56-60.

Background— Novel oral anticoagulants (NOACs) have been shown to be at least as good as warfarin for preventing stroke or transient ischemic attack in patients with atrial fibrillation, yet diffusion of these therapies and patterns of use among atrial fibrillation patients with ischemic stroke and transient ischemic attack have not been well characterized. Methods and Results— Using data from Get With The Guidelines-Stroke, we identified a cohort of 61 655 atrial fibrillation patients with ischemic stroke or transient ischemic attack hospitalized between October 2010 and September 2012 and discharged on warfarin or NOAC (either dabigatran or rivaroxaban). Multivariable logistic regression was used to identify factors associated with NOAC versus warfarin therapy. In our study population, warfarin was prescribed to 88.9%, dabigatran to 9.6%, and rivaroxaban to 1.5%. NOAC use increased from 0.04% to a 16% to 17% plateau during the study period, although anticoagulation rates among eligible patients did not change appreciably (93.7% versus 94.1% from first quarter 2011 to second quarter 2012), suggesting a trend of switching from warfarin to NOACs rather than increased rates of anticoagulation among eligible patients. Several bleeding risk factors and CHA 2 DS 2 -VASc scores were lower among those discharged on NOAC versus warfarin therapy (47.9% versus 40.9% with CHA 2 DS 2 -VASc ≤5, P 2 DS 2 -VASc). Conclusions— NOACs have had modest but growing uptake over time among atrial fibrillation patients hospitalized with stroke or transient ischemic attack and are prescribed to patients with lower stroke risk compared with warfarin.

The buccinator, despite being a prominent midface muscle, has been previously overlooked as a target in the treatment of facial synkinesis with botulinum toxin.To evaluate outcomes of patients treated with botulinum toxin to the buccinator muscle in the setting of facial synkinesis.Prospective cohort study of patients who underwent treatment for facial synkinesis with botulinum toxin over multiple treatment cycles during a 1-year period was carried out in a tertiary referral center.Botulinum toxin treatment of facial musculature, including treatment cycles with and without buccinator injections.Subjective outcomes were evaluated using the Synkinesis Assessment Questionnaire (SAQ) prior to injection of botulinum toxin and 2 weeks after treatment. Outcomes of SAQ preinjection and postinjection scores were compared in patients who had at least 1 treatment cycle with and without buccinator injections. Subanalysis was performed on SAQ questions specific to buccinator function (facial tightness and lip movement).Of 84 patients who received botulinum toxin injections for facial synkinesis, 33 received injections into the buccinator muscle. Of the 33, 23 met inclusion criteria (19 [82.6%] women; mean [SD] age, 46 [10] years). These patients presented for 82 treatment visits, of which 44 (53.6%) involved buccinator injections and 38 (46.4%) were without buccinator injections. The most common etiology of facial paralysis included vestibular schwannoma (10 [43.5%] participants) and Bell Palsy (9 [39.1%] participants). All patients had improved posttreatment SAQ scores compared with prebotulinum scores regardless of buccinator treatment. Compared with treatment cycles in which the buccinator was not addressed, buccinator injections resulted in lower total postinjection SAQ scores (45.9; 95% CI, 38.8-46.8; vs 42.8; 95% CI, 41.3-50.4; P = .43) and greater differences in prebotox and postbotox injection outcomes (18; 95% CI, 16.2-21.8; vs 19; 95% CI, 14.2-21.8; P = .73). Subanalysis of buccinator-specific scores revealed significantly improved postbotox injection scores with the addition of buccinator injections (5.7; 95% CI, 5.0-6.4; vs 4.1; 95% CI, 3.7-4.6; P = .004) and this corresponded to greater differences between prebotulinum and postbotulinum injection scores (3.3; 95% CI, 2.7-3.9; vs 2.0; 95% CI, 1.4-2.6; P = .02). The duration of botulinum toxin effect was similar both with and without buccinator treatment (66.8; 95% CI, 61.7-69.6; vs 65.7; 95% CI, 62.5-71.1; P = .72).The buccinator is a symptomatic muscle in the facial synkinesis population. Treatment with botulinum toxin is safe, effective and significantly improves patient symptoms.3.

Adenoid Cystic Carcinoma (ACC) is a salivary gland malignancy with unpredictable growth and poorly understood prognostic factors. A database search of patients treated at a single institution was used to identify patients with histologically confirmed ACC. Patient, tumor, and treatment characteristics were examined via review of medical records. Statistical analyses were performed to assess outcomes and associated prognostic factors. A total of 70 patients were identified with a median follow up of 3.5 years. Overall survival at 5, 10, and 15 years was 80.4%, 61.3%, and 29.4%, respectively. Disease recurrence was seen in 31.9%; of these, 72.7% developed distant metastasis. Older age, higher stage, skull base involvement, positive margins, and metastatic disease, but not local recurrence, predicted a worse overall survival. Higher stage and skull base disease were associated with shorter disease free survival. Higher T stage and perineural disease were associated with distant failure, whereas skull base involvement predicted higher local recurrence. While lung metastasis was the most common, vertebral metastasis was associated with poorer survival. In conclusion, disease stage, positive margins, skull base involvement, perineural invasion, time to recurrence, and location of metastasis, but not nodal involvement, could serve as poor prognostic factors in ACC.

To compare presenting characteristics of patients with adductor spasmodic dysphonia (ADSD), ADSD with laryngeal tremor (ADSD + LT), and laryngeal tremor without ADSD (LT).Cross-sectional analysis.Patients treated for laryngeal movement disorders (1990-2016) were included. Analysis of variance and chi square tests measured differences in patient characteristics across the three disease groups. Using ADSD as the referent, multivariable logistic regression models were used to determine whether potential risk factors including patient demographics, family history, presence of potential inciting events prior to disease onset, and coprevalent movement disorders were associated with ADSD + LT or LT.In all, 652 patients with ADSD (n = 377), ADSD + LT (n = 98), and LT (n = 177) were included. ADSD patients were significantly younger than those with ADSD + LT and LT (52.5 ± 13.4, 63.9 ± 11.3, and 69.3 ± 10.5 years, respectively; P 0.001). Coprevalent movement disorders were more common in ADSD + LT (38.7%) and LT (57.1%) groups than in the ADSD group (11.5%; P 0.001). Compared to ADSD, patients with ADSD + LT and LT were more likely to develop an additional movement disorder during follow-up. In multivariable analyses, increasing age, female gender, and having a movement disorder at presentation were associated with significantly greater odds of having ADSD + LT or LT when compared to ADSD.ADSD + LT patients demonstrate intermediate gender composition and age distributions between those with ADSD and LT. These findings suggest that ADSD + LT may be a distinct phenotype in the spectrum of laryngeal movement disorders.4 Laryngoscope, 129:170-176, 2019.

Anaplastic thyroid cancer (ATC) is characterized by very aggressive growth with undifferentiated features. Recently, it has been reported that the Notch1 signaling pathway, which affects thyrocyte proliferation and differentiation, is inactivated in ATC. However, it remains largely unknown whether using Notch1 activating compounds can be an effective therapeutic strategy in ATC. Therefore, in this study, we aimed to evaluate the drug effects of a potential Notch activator hesperetin on ATC cell. A unique ATC cell line HTh7 was used to evaluate the drug effects of hesperetin. The Notch1 activating function and cell proliferation were evaluated. The mechanism of growth regulation was investigated by the detection of apoptotic markers. The expression levels of thyrocyte-specific genes were quantified for ATC redifferentiation. Upregulated expression of Notch1 and its downstream effectors hairy and enhancer of split 1 (Hes1) and Hes1 related with YRPW motif was observed in hesperetin-treated ATC cells. The enhanced luciferase signal also confirmed the functional activity of hesperetin-induced Notch1 signaling. Hesperetin led to a time- and dose-dependent decrease in ATC cell proliferation. The cell-growth inhibition was mainly caused by apoptosis as evidenced by increased levels of cleaved poly ADP ribose polymerase and cleaved caspase-3 as well as decreased survivin. Additionally, hesperetin induced the expression levels of thyrocyte-specific genes including thyroid transcription factor 1 (TTF1), TTF2, paired box gene 8, thyroid stimulating hormone receptor, and sodium/iodide symporter. Hesperetin activates the Notch1 signaling cascade and suppresses ATC cell proliferation mainly via apoptosis. Hesperetin also induces cell redifferentiation of ATC, which could be useful clinically.

The seed storage glycoprotein Arachis hypogaea (Ara h) 1 is a major allergen found in peanuts. The biochemical resistance of food proteins to protease digestion contributes to their allergenicity. The rapid proteolysis of Ara h 1 under gastric conditions challenges this model. Biophysical and in vitro digestion experiments were carried out to identify how Ara h 1 epitopes might survive digestion, despite their facile degradation. The bicupin core of Ara h 1 can be unfolded at low pH and reversibly folded at higher pH. Additionally, peptide fragments from simulated gastric digestion predominantly form noncovalent aggregates when transferred to base. Disulfide cross-links within these aggregates occur as intermediates in relatively low amounts only at early times and play no role in shielding peptides from degradation. It is proposed that peptide fragments which survive gastric conditions form large aggregates in basic environments such as the small intestine, making epitopes available for triggering an allergic response.

The immune system is under strong circadian control, and circadian desynchrony is a risk factor for metabolic disorders, inflammatory responses and cancer. Signaling pathways that maintain circadian rhythms (CRs) in immune function in vivo, and the mechanisms by which circadian desynchrony impairs immune function, remain to be fully identified. These experiments tested the hypothesis that the hypothalamic circadian pacemaker in the suprachiasmatic nucleus (SCN) drives CRs in the immune system, using a non-invasive model of SCN circadian arrhythmia. Robust CRs in blood leukocyte trafficking, with a peak during the early light phase (ZT4) and nadir in the early dark phase (ZT18), were absent in arrhythmic hamsters, as were CRs in spleen clock gene (per1, bmal1) expression, indicating that a functional pacemaker in the SCN is required for the generation of CRs in leukocyte trafficking and for driving peripheral clocks in secondary lymphoid organs. Pinealectomy was without effect on CRs in leukocyte trafficking, but abolished CRs in spleen clock gene expression, indicating that nocturnal melatonin secretion is necessary for communicating circadian time information to the spleen. CRs in trafficking of antigen presenting cells (CD11c(+) dendritic cells) in the skin were abolished, and antigen-specific delayed-type hypersensitivity skin inflammatory responses were markedly impaired in arrhythmic hamsters. The SCN drives robust CRs in leukocyte trafficking and lymphoid clock gene expression; the latter of which is not expressed in the absence of melatonin. Robust entrainment of the circadian pacemaker provides a signal critical to diurnal rhythms in immunosurveilliance and optimal memory T-cell dependent immune responses.

Background— Diabetes mellitus, heart failure (HF), and chronic kidney disease are common comorbidities, but overall use and safety of antihyperglycemic medications (AHMs) among patients with these comorbidities are poorly understood. Methods and Results— Using Get With the Guidelines-Heart Failure and linked Medicare Part D data, we assessed AHM use within 90 days of hospital discharge among HF patients with diabetes mellitus discharged from Get With the Guidelines-Heart Failure hospitals between January 1, 2006, and October 1, 2011. We further summarized use by renal function and assessed renal contraindicated AHM use for patients with estimated glomerular filtration rate 2 . Among 8791 patients meeting inclusion criteria, the median age was 77 (interquartile range 71–83), 62.3% were female, median body mass index was 29.7 (interquartile range 25.5–35.3), median hemoglobin A1c was 6.8 (interquartile range 6.2–7.8), and 34% had ejection fraction 2 , 35.4% filled prescriptions for renal contraindicated AHMs per prescribing information, though there was a trend toward lower renal contraindicated AHM use over time (Cochran–Mantel–Haenszel row-mean score test P =0.048). Although use of other AHMs was low overall, thiazolidinediones were used in 6.6% of HF patients, and dipeptidyl peptidase-4 inhibitors were used in 5.1%, with trends for decreasing thiazolidinedione use and increased dipeptidyl peptidase-4 inhibitor use over time ( P Conclusions— Treatment of diabetes mellitus in patients with HF and chronic kidney disease is complex, and these patients are commonly treated with renal contraindicated AHMs, including over 6% receiving a thiazolidinedione, despite known concerns regarding HF. More research regarding safety and efficacy of various AHMs among HF patients is needed.

BACKGROUND: Anaplastic thyroid cancer (ATC) is a very aggressive thyroid gland malignancy with very poor prognosis. It is suspected that the Notch signaling pathway, which is not active in ATC, may have a tumor suppressor function in this neoplasm. However, it remains unknown whether activation of Notch can yield therapeutic efficacies in ATC. METHODS: The purpose of this study was to evaluate the effect of chrysin, a potential Notch inducer identified via high-throughput screening, on ATC both in vitro and in vivo. RESULTS: Chrysin treatment of ATC cells led to a dose-dependent inhibition of cellular growth. Protein and messenger RNA levels of Notch1 and Hes1 (hairy/enhancer of split 1), a downstream Notch1 effector, were both up-regulated with treatment. Luciferase reporter assays incorporating the C promoter-binding factor 1 (CBF1) binding site also confirmed the functional activity of chrysin-induced Notch1. Oral administration of chrysin suppressed the growth of ATC xenografts by an average of 59% compared with the vehicle control group (P = .002). In addition, calculated median time to tumor progression was 11 days for control mice and 21 days for the chrysin treatment group (P = .008). Analysis of chrysin-treated ATC tumors revealed an increase in the active intracellular domain of Notch1 protein. Activation of Notch1 in vivo was associated with the induction of cleaved Poly ADP ribose polymerase (PARP) protein, indicating that the growth inhibition was due to apoptosis. CONCLUSIONS: The novel Notch1 activator chrysin inhibits tumor growth in ATC both in vitro and in vivo. Chrysin could be a promising therapeutic candidate for ATC, and this justifies further clinical studies. Cancer 2013. © 2012 American Cancer Society.

Importance Essential vocal tremor (EVT) is a neurologic voice disorder characterized by periodic fluctuations in pitch and loudness that can hinder intelligibility. Defining the normative range of vocal tremor frequency may assist in diagnosis and provide insight into disease mechanisms. Objective To characterize the normative voice tremor frequency in EVT (in hertz). Design, Setting, and Participants Cross-sectional observational study of 160 patients with EVT. The setting was a tertiary voice center. Participants were identified from a database of consecutive patients diagnosed as having laryngeal movement disorders between January 1, 1990, and April 1, 2017. Main Outcomes and Measures The following 3 methods measured the frequency of tremor experienced by patients with EVT: perceptual method, computerized peak detection method, and laryngeal electromyography method. Within-person and population-level tremor frequencies were compared across modalities to assess measurement reliability and consistency and to characterize the normal distribution of tremor frequencies in this population. Results Among 160 participants (median age, 70 years; interquartile range [IQR], 64-77 years; 90.6% female [n = 145]), the median frequency of EVT was consistently between 4 and 5 Hz across all 3 methods (perceptual, 4.8 Hz [IQR, 4.4-5.5 Hz]; computerized peak detection, 4.6 Hz [IQR, 4.2-5.0 Hz]; and laryngeal electromyography, 4.3 Hz [IQR, 3.8-5.0 Hz]). The mean in-person differences between each measurement method were not clinically meaningful (range, 0.1-0.5 Hz). Including all interquartile ranges across measurement modalities, the normative tremor frequency range for EVT was 3.8 to 5.5 Hz. Conclusions and Relevance To our knowledge, this is the largest study to date to characterize the normal frequency of tremor in patients with EVT. The normative frequency of EVT (range, 3.8-5.5 Hz) falls within a much narrower range than previously reported. Those whose frequency is outside this range may still have EVT but should be carefully evaluated for potential other causes of vocal tremor. Defining characteristics of EVT may aid appropriate diagnosis and improve understanding of this disease.

Animals living in temperate climates with predictable seasonal changes in food availability may use seasonal information to engage different metabolic strategies. Siberian hamsters decrease costs of thermoregulation during winter by reducing food intake and body mass in response to decreasing or short-day lengths (SD). These experiments examined whether SD reduction in food intake in hamsters is driven, at least in part, by altered behavioral responses to ghrelin, a gut-derived orexigenic peptide which induces food intake via NPY-dependent mechanisms. Relative to hamsters housed in long-day (LD) photoperiods, SD hamsters consumed less food in response to i.p. treatment with ghrelin across a range of doses from 0.03 to 3 mg/kg. To determine whether changes in photoperiod alter behavioral responses to ghrelin-induced activation of NPY neurons, c-Fos and NPY expression were quantified in the arcuate nucleus (ARC) via double-label fluorescent immunocytochemistry following i.p. treatment with 0.3 mg/kg ghrelin or saline. Ghrelin induced c-Fos immunoreactivity (-ir) in a greater proportion of NPY-ir neurons of LD relative to SD hamsters. In addition, following ghrelin treatment, a greater proportion of ARC c-Fos-ir neurons were identifiable as NPY-ir in LD relative to SD hamsters. Changes in day length markedly alter the behavioral response to ghrelin. The data also identify photoperiod-induced changes in the ability of ghrelin to activate ARC NPY neurons as a possible mechanism by which changes in day length alter food intake.

Importance The relative outcomes of onabotulinum toxin A injections for treatment of adductor spasmodic dysphonia (ADSD), ADSD with lateral laryngeal tremor (ADSD+LT), and lateral LT without ADSD are unclear. Objective To compare the outcomes of onabotulinum toxin A treatment on ADSD, ADSD+LT, and lateral LT without ADSD. Design, Setting, and Participants A retrospective cohort study was conducted from January 1, 1990, to September 30, 2016, at a tertiary referral voice center. Participants included 817 patients treated with onabotulinum toxin A injections for diagnosis of ADSD, ADSD+LT, and lateral LT without ADSD. Exposure Injection of onabotulinum toxin A into the thyroarytenoid/lateral cricoarytenoid muscle complex. Main Outcomes and Measures Data from patient diaries were used to evaluate patient-perceived effectiveness of onabotulinum toxin A injection. Primary outcomes were (1) patient-reported good voice days (voice breaks or tremor minimized to patient satisfaction) and (2) percentage of injections in which maximal voice quality was reached (significant or complete reduction in vocal tremor or spasms during a treatment cycle). Multivariate analysis of variance tests compared differences in outcomes between groups. Subanalysis was performed to compare outcomes in patients with isolated LT with those who had mixed tremor (lateral with concomitant anterior-posterior and/or vertical components). Results Of 817 patients treated with onabotulinum toxin A injections for laryngeal movement disorders, 548 patients (12 771 injection sessions) met inclusion criteria (ADSD: n = 328, ADSD+LT: n = 77, lateral LT without ADSD: n = 143). Of these, 408 (80.8%) were women; mean (SD) age was 57.2 (13.7) years. Among patients with tremor, those with isolated LT had better outcomes than those with mixed tremor. In adjusted analysis, good voice days in patients with ADSD, ADSD+LT, and lateral LT without ADSD were 81.1, 75.4, and 71.3 days, respectively (partial η2, 0.05; 95% CI, 0.01-0.09). The percentage of maximally beneficial injections was 88.1% for ADSD, 83.4% for ADSD+LT, and 70.4% for LT without ADSD (partial η2, 0.12; 95% CI, 0.06-0.17). Conclusions and Relevance Onabotulinum toxin A injections into the thyroarytenoid/lateral cricoarytenoid muscle complex are an effective treatment for ADSD, ADSD+LT, and LT without ADSD; however, the greatest effectiveness was observed among patients with ADSD. Defining tremor directionality may help to prognosticate the effectiveness of onabotulinum toxin A injection among patients presenting with tremor components.

Background— Outcomes associated with episodes of hypotension while hospitalized with acute decompensated heart failure are not well understood. Methods and Results— Using data from Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF), we assessed factors associated with in-hospital hypotension and subsequent 30-day outcomes. Patients were classified as having symptomatic or asymptomatic hypotension. Multivariable logistic regression was used to determine factors associated with in-hospital hypotension, and Cox proportional hazards models were used to assess the association between hypotension and 30-day outcomes. We also tested for treatment interaction with nesiritide on 30-day outcomes and the association between in-hospital hypotension and renal function at hospital discharge. Overall, 1555 of 7141 (21.8%) patients had an episode of hypotension, of which 73.1% were asymptomatic and 26.9% were symptomatic. Factors strongly associated with in-hospital hypotension included randomization to nesiritide (odds ratio, 1.98; 95% confidence interval [CI], 1.76–2.23; P P P =0.001) or S3 gallop (odds ratio, 1.21; 95% CI, 1.06–1.40; P =0.006). In-hospital hypotension was associated with increased hazard of 30-day mortality (hazard ratio, 2.03; 95% CI, 1.57–2.61; P P P P =0.874 for death, P =0.908 for death/heart failure hospitalization, P =0.238 death/all-cause hospitalization). Conclusions— Hypotension while hospitalized for acute decompensated heart failure is an independent risk factor for adverse 30-day outcomes, and its occurrence highlights the need for modified treatment strategies. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00475852.

Emotional behaviors are influenced by the circadian timing system. Circadian disruptions are associated with depressive-like symptoms in clinical and preclinical populations. Circadian rhythm robustness declines markedly with aging and may contribute to susceptibility to emotional dysregulation in aged individuals. The present experiments used a model of chronic circadian arrhythmia generated noninvasively, via a series of circadian-disruptive light treatments, to investigate interactions between circadian desynchrony and aging on depressive- and anxiety-like behaviors, and on limbic neuroinflammatory gene expression that has been linked with emotionality. We also examined whether a social manipulation (group housing) would attenuate effects of arrhythmia on emotionality. In aged (14–18 months of age) male Siberian hamsters, circadian arrhythmia increased behavioral despair and decreased social motivation, but decreased exploratory anxiety. These effects were not evident in younger (5–9 months of age) hamsters. Social housing (3–5 hamsters/cage) abolished the effects of circadian arrhythmia on emotionality. Circadian arrhythmia alone was without effect on hippocampal or cortical interleukin-1β (IL-1β) and indoleamine 2,3-dioxygenase (Ido) mRNA expression in aged hamsters, but social housing decreased hippocampal IL-1β and Ido mRNAs. The data demonstrate that circadian disruption can negatively impact affective state, and that this effect is pronounced in older individuals. Although clear associations between circadian arrhythmia and constitutive limbic proinflammatory activity were not evident, the present data suggest that social housing markedly inhibits constitutive hippocampal IL-1β and Ido activity, which may contribute to the ameliorating effects of social housing on a number of emotional behaviors.

Anti-beta-1-adrenergic receptor antibodies (anti-β1AR Abs) have long been implicated in the pathogenesis of dilated cardiomyopathy (DCM). It is believed that these autoantibodies bind to and constitutively stimulate the β1AR to promote pathological cardiac remodelling and β1AR desensitization and downregulation. The prevalence of anti-β1AR Abs in patients with DCM ranges from 26% to 60%, and the presence of these autoantibodies correlates with a poor prognosis. Several small studies have shown improvements in functional status, haemodynamics, and biomarkers of heart failure upon removal or neutralization of these antibodies from the sera of affected patients. Traditionally, removal of anti-β1AR Abs required immunoadsorption therapy with apheresis columns directed against human immunoglobulins (Igs) and subsequent i.v. Ig infusion, thereby essentially performing a plasma exchange transfusion. However, recent advances have allowed the development of small peptides and nucleotide sequences that specifically target and neutralize anti-β1AR Abs, providing a hopeful avenue for future drug development to treat DCM. Herein, we briefly review the clinical literature of therapy directed against anti-β1AR Abs and highlight the opportunity for further research and development in this area.

Background: The FDA recently approved the direct thrombin inhibitor dabigatran (DTI) and factor Xa inhibitor rivaroxaban for atrial fibrillation (AF) stroke prophylaxis based on large randomized trials showing non-inferiority to warfarin for stroke prevention. However, real-world utilization patterns and predictors of use for these novel anticoagulants (NAC) remain poorly characterized. Methods: Using the AHA Get With The Guidelines Stroke Registry, we analyzed patients with AF who were hospitalized for ischemic stroke or transient ischemic attack (TIA) and discharged on warfarin or NAC. The first NAC approved by the FDA was dabigatran in 10/2010, so we chose a 2-year study period from 10/2010-9/2012. We excluded patients with contraindications for anticoagulation. Patient and hospital variables associated with discharge anticoagulant use were evaluated using Pearson chi-square and Wilcoxon tests. Results: Of 61,655 patients meeting inclusion criteria, 6,835 (11.1%) were discharged on NAC, of which 86.7% were prescribed DTI. Warfarin was prescribed in 54,820 (88.9%) patients. For patients discharged on NAC vs. warfarin, 51.8% vs. 53.3% (p=0.016) were female and median age was 77 [IQR 69-84] vs. 79 [IQR 70-85] (p Patients discharged on NAC vs. warfarin had less severe ischemic stroke (NIH stroke scale=3 [IQR 1-8] vs. 5 [IQR 2-11], p Conclusion: Among patients with AF and acute ischemic stroke or TIA discharged on oral anticoagulants, NAC use remains low and is prescribed to younger, more functional, and lower risk patients.

Production of T3 in the mediobasal hypothalamus is critical for regulation of seasonal reproductive physiology. Type 2 iodothyronine deiodinase (DIO2) and DIO3 enzymes catalyze the prohormone T4 into biologically-active T3 and biologically-inactive rT3, respectively. In several seasonally-breeding vertebrates, DIO2 and DIO3 expression is implicated in photoperiod signal transduction in adulthood. These experiments tested the hypothesis that juvenile Siberian hamsters, which are highly responsive to photoperiod at weaning (postnatal day [PND]18), exhibit rapid and sustained changes in hypothalamic dio3 mRNA expression during photoperiod-induced and photoperiod-inhibited puberty. Hypothalamic dio2 and dio3 expression was measured via quantitative PCR in hamsters born and reared in a long-day photoperiod (15L:9D) and weaned on PND18 into short-day photoperiods (9L:15D). In SD males, hypothalamic dio3 mRNA was elevated 2.5-fold within 3 days (PND21) and continued to increase (>20-fold) through PND32; changes in dio3 mRNA preceded inhibition of gonadotropin (FSH) secretion and gonadal regression in SD. Females exhibited comparable dio3 responses to SD. In LD males, dio3 remained low and invariant from PND18–PND32. In contrast, dio2 mRNA rose conspicuously on PND21, independent of photoperiod, returning to basal levels thereafter. In LD, a single afternoon melatonin (MEL) injection on PND18 or PND20 was sufficient to increase hypothalamic dio3 mRNA, and dio3 increased in proportion to the number of successive days of MEL treatment. SD photoperiods and MEL exert rapid, sustained, and additive effects on hypothalamic dio3 mRNA, which may play a central role in inhibiting maturation of the peripubertal hypothalamo-pituitary-gonadal axis.

Left ventricular assist devices (LVAD) are used to support cardiac function in patients with advanced heart failure, however device-related adverse events remain common. Cardiac computed tomography angiography (CCTA) has the potential to provide unique information on cardio-mechanical complications

Anaplastic thyroid cancer (ATC) is a very aggressive thyroid gland malignancy with very poor prognosis. It is suspected that the Notch signaling pathway, which is not active in ATC, may have a tumor suppressor function in this neoplasm. However, it remains unknown whether activation of Notch can yield therapeutic efficacies in ATC.The purpose of this study was to evaluate the effect of chrysin, a potential Notch inducer identified via high-throughput screening, on ATC both in vitro and in vivo.Chrysin treatment of ATC cells led to a dose-dependent inhibition of cellular growth. Protein and messenger RNA levels of Notch1 and Hes1 (hairy/enhancer of split 1), a downstream Notch1 effector, were both up-regulated with treatment. Luciferase reporter assays incorporating the C promoter-binding factor 1 (CBF1) binding site also confirmed the functional activity of chrysin-induced Notch1. Oral administration of chrysin suppressed the growth of ATC xenografts by an average of 59% compared with the vehicle control group (P = .002). In addition, calculated median time to tumor progression was 11 days for control mice and 21 days for the chrysin treatment group (P = .008). Analysis of chrysin-treated ATC tumors revealed an increase in the active intracellular domain of Notch1 protein. Activation of Notch1 in vivo was associated with the induction of cleaved Poly ADP ribose polymerase (PARP) protein, indicating that the growth inhibition was due to apoptosis.The novel Notch1 activator chrysin inhibits tumor growth in ATC both in vitro and in vivo. Chrysin could be a promising therapeutic candidate for ATC, and this justifies further clinical studies.

Cancer, in addition to many other chronic diseases, is associated with serious and problematic behavioral symptoms, including cognitive impairments. In humans, various factors likely contribute to cancer-associated cognitive deficits including disease awareness and chemotherapy; however, the endogenous biological factors arising from tumor development may also play a causal role. In the present study, rats with mammary tumors exhibited impaired spatial reference memory on a radial arm maze and amnesia for familiar objects in an object recognition memory test. In contrast, their performance in the Morris water maze and in fear conditioning tests was comparable to that of controls. These select cognitive impairments were accompanied by elevations in hippocampal interleukin-1beta mRNA expression, but were not associated with decreases in hippocampal brain-derived neurotrophic factor gene expression. Together the results indicate that peripheral tumors alone are sufficient to induce increases in hippocampal cytokine expression and select deficits in hippocampal-dependent memory tasks.

beta1-Adrenergic receptor (beta1AR) stimulation confers cardioprotection via beta-arrestin-de pend ent transactivation of epidermal growth factor receptors (EGFRs), however, the precise mechanism for this salutary process is unknown. We tested the hypothesis that the beta1AR and EGFR form a complex that differentially directs intracellular signaling pathways. beta1AR stimulation and EGF ligand can each induce equivalent EGFR phosphorylation, internalization, and downstream activation of ERK1/2, but only EGF ligand causes translocation of activated ERK to the nucleus, whereas beta1AR-stimulated/EGFR-transactivated ERK is restricted to the cytoplasm. beta1AR and EGFR are shown to interact as a receptor complex both in cell culture and endogenously in human heart, an interaction that is selective and undergoes dynamic regulation by ligand stimulation. Although catecholamine stimulation mediates the retention of beta1AR-EGFR interaction throughout receptor internalization, direct EGF ligand stimulation initiates the internalization of EGFR alone. Continued interaction of beta1AR with EGFR following activation is dependent upon C-terminal tail GRK phosphorylation sites of the beta1AR and recruitment of beta-arrestin. These data reveal a new signaling paradigm in which beta-arrestin is required for the maintenance of a beta1AR-EGFR interaction that can direct cytosolic targeting of ERK in response to catecholamine stimulation.

Beta-arrestin is a multifunctional adapter protein well known for its role in G-protein-coupled receptor (GPCR) desensitization. Exciting new evidence indicates that beta-arrestin is also a signaling molecule capable of initiating its own G-protein-independent signaling at GPCRs. One of the best-studied beta-arrestin signaling pathways is the one involving beta-arrestin-dependent activation of a mitogen-activated protein kinase cascade, the extracellular regulated kinase (ERK). ERK signaling, which is classically activated by agonist stimulation of the epidermal growth factor receptor (EGFR), can be activated by a number of GPCRs in a beta-arrestin-dependent manner. Recent work in animal models of heart failure suggests that beta-arrestin-dependent activation of EGFR/ERK signaling by the beta-1-adrenergic receptor, and possibly the angiotensin II Type 1A receptor, are cardioprotective. Hence, a new model of signaling at cardiac GPCRs has emerged and implicates classical G-protein-mediated signaling with promoting harmful remodeling in heart failure, while concurrently linking beta-arrestin-dependent, G-protein-independent signaling with cardioprotective effects. Based on this paradigm, a new class of drugs could be identified, termed "biased ligands", which simultaneously block harmful G-protein signaling, while also promoting cardioprotective beta-arrestin-dependent signaling, leading to a potential breakthrough in the treatment of chronic cardiac disease.

Adverse cardiovascular events such as myocardial infarction, stroke, arrhythmias, and sudden cardiac death are well known to follow a circadian pattern, peaking in the morning hours of 6 AM to 12 PM. Many physiologic factors have been shown to follow a circadian pattern and together may create an environment that promotes intraluminal thrombi formation. Blood pressure follows this pattern with a "dip" at night and an increase on awakening. This morning surge may lead to hemodynamic forces that predispose patients to plaque rupture. The clinical impression of these known physiologic patterns associated with adverse cardiovascular events suggests that a strict treatment schedule targeting this phenomenon is needed. The goal of this review is to provide clinicians with an overview, allowing for informed decisions about chronotherapeutic formulations tailored to provide blood pressure control throughout the day and night.

Diabetes (DM) and chronic kidney disease (CKD) are common co-morbidities in patients with heart failure (HF). However, there is uncertainty on optimal DM management with these co-morbidities, and usage patterns of anti-hyperglycemic medications (AHM) among these complex patients are poorly

Plant pathogenic Pseudomonas syringae deliver type III effector proteins into the host cell, where they function to manipulate host defense and metabolism to benefit the extracellular bacterial colony. The activity of these virulence factors can be monitored by plant disease resistance proteins deployed to “guard” the targeted host proteins. The Arabidopsis RIN4 protein is targeted by three different type III effectors. Specific manipulation of RIN4 by each of them leads to activation of either the RPM1 or RPS2 disease resistance proteins. The type III effector AvrRpt2 is a cysteine protease that is autoprocessed inside the host cell where it activates RPS2 by causing RIN4 disappearance. RIN4 contains two sites related to the AvrRpt2 cleavage site (RCS1 and RCS2). We demonstrate that AvrRpt2-dependent cleavage of RIN4 at RCS2 is functionally critical in vivo . This event leads to proteasome-mediated elimination of all but a membrane-embedded ≈6.4-kDa C-terminal fragment of RIN4. One or more of three consecutive cysteines in this C-terminal fragment are required for RIN4 localization; these are likely to be palmitoylation and/or prenylation sites. AvrRpt2-dependent cleavage at RCS2, and release of the remainder of RIN4 from the membrane, consequently prevents RPM1 activation by AvrRpm1 or AvrB. RCS2 is contained within the smallest tested fragment of RIN4 that binds AvrB in vitro . Thus, at least two bacterial virulence factors target the same domain of RIN4, a ≈30-aa plant-specific signature sequence found in a small Arabidopsis protein family that may be additional targets for these bacterial virulence factors.

Many studies have been developed to characterize the mechanical behavior of the intervertebral disc specifically for the lumbar spine and there have been limited studies done on the cervical spine with the goal to evaluate the strength of the cervical spine under compression without any information on the bulging of the intervertebral discs. The goal of the current study is to examine the deformation response of the cervical intervertebral disc classified with grade III or greater degeneration and analyze the relationship between axial deformation and anterior and posterior bulge under compression up to 550 N.Each specimen was compressed for 3 cycles to a maximum load of 550N in steps of 50 N. The bulge was measured using Linear Variable Differential Transformers (LVDTs on an intact spinal segment, spinal segment with post laminectomy, and spinal segment post facetectomy.The anterior budge for an intact spinal segment shows a change of slope at loads of 262N±66N. For a physiological load of 250N the vertical displacement or spine segment height was reduced by 10.1% for an intact segment and 8.78% for the laminectomy and facetectomy configurations with F = 0.159 (Fcrit = 3.89) with no statistical difference observed. For the post laminectomy there was a decrease of 35% in anterior bulge compared to the intact specimen.Our results show that for grade III disc degeneration the cervical segments bulging for both the laminectomy and facetectomy procedures are not significantly different. In post laminectomy the average anterior and posterior bulges are similar to the average anterior and posterior bulge post facetectomy.

The prognostic significance of transient hypotension during hospitalization for acute decompensated heart failure (ADHF) is uncertain. We evaluated factors associated with hypotension and its relationship with 30-day (30d) outcomes in the ASCEND-HF trial (which randomized patients without baseline

The association between breast cancer and modifiable health behaviors is well supported. At least one-half of all cancers are suggested to have a dietary component. It is not surprising therefore that many of the dietary agents and natural health products that have attracted the attentions of scientists and practitioners are now moving into clinical trials. In this report, we review 65 clinical intervention trials evaluating over 30 dietary supplements and natural health products for use in breast cancer. The products being tested in these trials fall broadly into the following categories: (i) vitamins, minerals, cofactors; (ii) herbal extracts; (iii) amino acids; (iv) fatty acids; (v) animal products; (vi) probiotics; (vii) phytochemicals; and (viii) combination formulations. Trial outcome measures include risk modification, efficacy testing (with dietary supplements alone or dietary supplement-anticancer drug combinations), toxicity reduction, biomarker identification, symptom management, and quality of life parameters. The wide range of interests in natural product testing at the clinical trial level supports the potential utility of these agents in the breast cancer prevention, treatment, and management regimens of the future.