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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

This study evaluates the impact of different hump takedown techniques, namely the conventional hump resection with midvault reconstruction, the push-down (PD) and the let-down (LD) procedures, on the INV dimensions.In this cadaveric study, six heads were divided randomly into either the conventional hump resection technique (Group A; n = 6 sides) or DPR techniques (n = 6 sides). This latter group was subdivided such that initially a PD procedure was performed (Group B; n = 6 sides), followed by a LD procedure on the same heads (Group C; n = 6 sides). A validated radiological method was used to measure the INV angle and cross-sectional area (CSA) in a modified coronal plane both pre- and post-procedurally.Group A did not show significant reduction in the INV angle nor in CSA (p = 0.068 and p = 0.156, respectively). In the push-down group (B), we observed a mean change of 2.05° in the angles and 0.3 cmNeither the conventional hump resection nor the LD DPR technique reduced the INV dimensions. However, the PD preservation technique significantly reduced the INV dimensions.This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Introduction Heart failure (HF) is the number one discharge diagnosis at most hospitals in America. The impact of newly added heart failure providers on the care of heart failure patients is unclear. We reviewed the impact of creating a new HF practice on clinical care and readmissions at a large, tertiary care health system. Methods In December 2017, a new heart failure practice was established at a large, 3 hospital system. The practice included 1.5 physicians and 1 advanced practice provider and developed both an inpatient consultative service and an outpatient practice including availability of same day IV diuretic therapy. We reviewed the 2018-2019 readmission rate of patients seen versus not seen by the HF practice in either the inpatient or outpatient setting. Results A total of 2597 patients were discharged with a primary diagnosis of HF and 372 (14.3%) were readmitted within 1 month. Table 1 shows quarterly clinic volumes. Due to challenges with referral volumes, guidelines for referral were developed and included patients with new diagnosis of heart failure, readmissions within 6 months, or BNP > 1000. Readmission rates by provider type are shown in Table 2. There was a substantial reduction in readmissions when the HF team was involved in care. Additionally, 30 patients were referred for heart transplantation and 21 for LVAD therapy. Conclusion Establishing a HF practice is associated with a reduction in readmissions for patients managed by the HF practice, but not for the overall hospital. Careful consideration of appropriate referrals and strategies to increase “patient touches” should be performed when establishing a new heart failure practice.

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.

To assess current management strategies for advanced heart failure in adults with congenital heart disease, including heart transplantation and mechanical circulatory support. Current data demonstrate that adults with CHD generally experience higher short-term mortality after heart transplantation and MCS implantation, but enjoy superior long-term survival. Such patients are nonetheless less likely to receive a transplant than non-ACHD peers due to a variety of factors, including lack of applicability of current listing criteria to HF in ACHD. MCS is underutilized in ACHD, but provides similar quality of life benefits for ACHD and non-ACHD patients alike. Heart failure in ACHD is complex and difficult to treat, and both heart transplantation and mechanical circulatory support are often challenging to implement in this patient population. However, long-term results are encouraging, and existing data supports increasing use of MCS and transplant earlier in their disease course. Multidisciplinary care is critical to success in these complex patients.

Objective To determine if immediate postoperative uncuffed tracheostomy placement following oral cavity or oropharyngeal head and neck free flap reconstruction is associated with shorter hospital length of stay and higher inpatient decannulation rates without an increase in respiratory complications, as compared with immediate placement of cuffed tracheostomy. Study Design Retrospective cohort. Setting Tertiary referral center. Subjects and Methods Patients were included if they underwent free flap reconstruction for oral cavity or oropharyngeal squamous cell carcinoma and had an intraoperative tracheostomy placed between 2005 and 2016. In 2012, head and neck surgeons changed from routine placement of cuffed to uncuffed tracheostomy tubes immediately after free flap reconstruction. This study compares length of hospital stay, inpatient decannulation rates, and respiratory complications between patients who had cuffed and uncuffed tracheostomies. Analysis of variance and chi-square test were used to examine continuous and categorical variables, respectively. Multivariable regression analyses were performed to determine whether cuff status was independently associated with primary outcomes of length of hospital stay, decannulation, and respiratory complications. Results Of 752 patients who underwent free flap reconstruction, 493 patients met inclusion criteria (cuffed, n = 366; uncuffed, n = 127). Patient variables (ie, age, sex, body mass index, prior chemoradiation) and tumor characteristics (ie, location, stage) did not differ significantly between groups. Adjusted analysis showed that an uncuffed tracheostomy (vs a cuffed tracheostomy) was associated with shorter length of stay (7.7 vs 9.7 days, P < .001) and did not increase the rate of respiratory complications. Conclusion Immediate placement of a uncuffed tracheostomy after oral cavity or oropharyngeal free flap reconstruction is associated with shorter hospital stays without an increase in respiratory complications.

Objective To determine the factors associated with intra- and postoperative cerebrospinal fluid (CSF) leaks in setting of endoscopic transsphenoidal sellar surgery. Study Design Retrospective cohort. Setting Tertiary referral center. Subjects and Methods This study included 806 patients who underwent endoscopic transsphenoidal sellar surgery between 2004 and 2016. The associations between CSF leaks (intra- and postoperative) and patient demographics, medical history, tumor characteristics, and intraoperative repair techniques were analyzed. Results In sum, 205 (25.4%) patients had a CSF leak: 188 (23.3%) intraoperative leaks and 38 (4.7%) postoperative leaks. Twenty-one (2.6%) patients had postoperative leaks after having repair of an intraoperative leak; 55% of patients with a postoperative leak had an intraoperative leak repaired. On multivariate analysis, body mass index (BMI), hydrocephalus, suprasellar extension, and craniopharyngioma significantly predicted intraoperative CSF leaks, while only BMI and hydrocephalus predicted postoperative CSF leaks. Patients having septal flap repairs of CSF leaks had a higher postoperative leak rate relative to other repair techniques (odds ratio, 6.37; P = .013). Rigid reconstruction did not correlate with leaks. Conclusion For this large cohort of patients undergoing endoscopic transsphenoidal sellar surgery, BMI and hydrocephalus were identified as predictors of postoperative CSF leaks, including those occurring after repair of intraoperative leak. These variables may put stress on the surgical repair of sellar defects, and consideration of these risk factors may help counsel patients and guide perioperative decision making in regard to repair strategies and CSF diversion techniques.

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.

Nasopharyngeal carcinoma (NPC) is a rare malignancy of epidermoid origin, one that is especially uncommon in children in low risk areas such as the United States. The relative rarity in children makes the diagnosis of this malignancy difficult, and therefore childhood nasopharyngeal carcinoma is associated with advanced locoregional disease and higher prevalence of distant metastasis. A case of pediatric nasopharyngeal carcinoma is described here to highlight a possible presentation of this uncommon pediatric disease and reasons for delayed diagnosis. This is followed by a brief discussion of epidemiology, diagnosis, treatment, and outcomes for this malignancy in children.

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.

To report on the post-tonsillectomy bleeding outcomes and factors associated with hemorrhage among children with pre- or post-operatively diagnosed bleeding disorders treated with an institutional protocol.Retrospective cohort study of patients with hematologic disorders who underwent tonsillectomy between 2003 and 2016 and were treated with perioperative desmopressin or factor replacement and/or aminocaproic acid. Postoperative outcomes were compared to controls matched for age, sex, and indication for surgery. Analysis of factors associated with hemorrhage was performed in patients with bleeding disorders using Mann-Whitney U or chi-squared tests.45 patients with hematologic disorders met inclusion criteria. Platelet dysfunction, including von Willebrand Disease (vWD), was the most common diagnosis (77.8%). Most patients had a preoperative diagnosis of a bleeding disorder and received perioperative hematologic medications (86.7%). Compared to matched controls, patients with hematologic disorders experienced more postoperative bleeding (15.5%; 12 bleeds, 7 patients vs. 1.7%; 1 bleed, 1 patient, p = 0.05) and had longer postoperative stays (1.3 days vs. 0.4 days, p 0.001). Among the patients with hematologic disorders, patients who experienced a postoperative bleed were significantly more likely to have a factor deficiency (e.g. Hemophilia over vWD) and have a postoperative diagnosis (compared to preoperative diagnosis) for which they did not receive perioperative hematologic medication. Of patients with a postoperative bleed, all those diagnosed postoperatively required at least one surgical intervention to control bleeding compared to 33% of patients with a preoperative diagnosis. A history of post-surgical bleeding, male sex, age at surgery, and pharyngitis as surgical indication were not associated with higher hemorrhage rates in this group.This study suggests a clinically important magnitude of increased bleeding risk in patients with hematologic disease. This risk appears to decrease with the use of an institutional protocol consisting of desmopressin or factor replacement and an antifibrinolytic agent extending through postoperative day 10.

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.

Scaphoid fractures are very common in young, active individuals. Most fractures are nondisplaced and can be treated with cast immobilization; however, there is a strong demand to return to function as early as possible. Scaphoid fractures with displacement >1 mm can lead to nonunion and late carpal osteoarthritis. Displaced scaphoid fractures require anatomic reduction and rigid stabilization to optimize outcomes. Surgical fixation can be achieved from either the dorsal approach or the volar approach. The location of the fracture, the presence of comminution, the amount of displacement, and associated injuries will determine the best surgical approach for the patient. There has been a tremendous improvement in surgical instrumentation and implants that allows patients the ability to return to function expeditiously and reliably.

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.

A number of natural gas combined cycle (NGCC) power stations recently permitted in the UK have been required to be CO2 capture ready so that carbon capture and storage can be retrofitted once it is commercially viable (or legally required). Several options for future CO2 capture from NGCC units can be envisaged including post-combustion capture technology using flue gas scrubbing with aqueous solvents. When an NGCC plant is designed to be ready for a retrofit with post-combustion capture, one of the most important technical considerations is the steam extraction pressure and flow to provide the energy necessary for solvent regeneration. This is determined by the choice of solvent used, but new solvents are being developed and the exact future requirements, in perhaps 10–20 years time, cannot be predicted. Ways in which designs for the steam cycle of NGCC plants can cope with this challenge are presented. Several alternatives to mitigate the loss of power output of NGCC plants retrofitted with post-combustion capture and to achieve improved plant flexibility are also assessed and compared.

Newly developed fuzzy logic-derived structural parameters were used to characterize trabecular bone architecture in high-resolution magnetic resonance imaging (HR-MRI) of human cadaver calcaneus specimens. These parameters were compared to standard histomorphological structural measures and analyzed concerning performance in discriminating vertebral fracture status and estimating proximal femur fracture load. Sets of 60 sagittal 1.5 T and 3.0 T HR-MRI images of the calcaneus were obtained in 39 cadavers using a fast gradient recalled echo sequence. Structural parameters equivalent to bone histomorphometry and fuzzy logic-derived parameters were calculated using two chosen regions of interest. Calcaneal, spine, and hip bone mineral density (BMD) measurements were also obtained. Fracture status of the thoracic and lumbar spine was assessed on lateral radiographs. Finally, mechanical strength testing of the proximal femur was performed. Diagnostic performance in discriminating vertebral fracture status and estimating femoral fracture load was calculated using regression analyses, two-tailed t-tests of significance, and receiver operating characteristic (ROC) analyses. Significant correlations were obtained at both field strengths between all structural and fuzzy logic parameters (r up to 0.92). Correlations between histomorphological or fuzzy logic parameters and calcaneal BMD were mostly significant (r up to 0.78). ROC analyses demonstrated that standard structural parameters were able to differentiate persons with and without vertebral fractures (area under the curve [A(Z)] up to 0.73). However, none of the parameters obtained in the 1.5-T images and none of the fuzzy logic parameters discriminated persons with and without vertebral fractures. Significant correlations were found between fuzzy or structural parameters and femoral fracture load. Using multiple regression analysis, none of the structural or fuzzy parameters were found to add discriminative value to BMD alone. In summary significant correlations were obtained at both field strengths between all structural and fuzzy logic parameters. However, fuzzy logic-based calcaneal parameters were not well suited for vertebral fracture discrimination. Although significant correlations were found between fuzzy or structural parameters and femoral fracture load, multiple regression analysis showed limited improvement for estimating femoral failure load in addition to femoral BMD alone. Local femoral measurements are still needed to estimate femoral bone strength. Overall, parameters obtained at 3.0 T performed better than those at 1.5 T.

To better characterize parotid masses incidentally identified on imaging.Case series with chart review.Academic medical center.Medical records were reviewed for 771 patients who underwent parotidectomy at the University of Wisconsin from 1994 to 2013. Patients were stratified into 2 groups: those with tumors identified solely on imaging (parotid incidentalomas [PIs]) and those with palpable masses, pain, facial nerve dysfunction, or other reasons their mass was identified (nonincidentals [NIs]). A χ(2) test was employed to compare the prevalence of malignancy in PIs compared with NIs. Trend analysis was performed to determine the prevalence of PIs over the 20-year period.Of the 771 patients, 67 (8.7%) had their mass discovered incidentally on imaging (PIs). There was a significant difference in the rate of malignancy in the NI (32.7%) compared with the PI group (6.0%) (P.01). During the 1994 to 2003 time period, 4.0% of all parotoidectomies performed were for PIs, while during the second decade (2004-2013), this proportion increased to 10.2%. This represents a 155.0% increase in the percentage of parotidectomies carried out for PIs between these 2 periods.In this study, the rate of malignancy in PIs was significantly lower than the rate of malignancy in patients with NIs. The occurrence of PIs has increased over time and now represents greater than 10.0% of all parotidectomies performed at the University of Wisconsin. This information is important to consider when consenting a patient for resection of a PI.

Numerous engineering applications require generation of droplets on demand which are of high uniformity and constant size. The common method to produce droplets is to drive liquid at high pressure through a small orifice/nozzle. The liquid stream disintegrates into small droplets. However this method normally requires large volumes of liquid and is not suitable for applications where single droplets of constant size is required. Such applications require droplet-on-demand generators which commonly employ piezoelectric or pneumatic actuation. It is well known that piezoelectric generators are hard to employ at high pressure and, high temperature applications, and the pneumatic generators often produce satellite (secondary) droplets. This paper describes the development of a novel percussion type droplet-on-demand generator, which overcomes some of the above difficulties and is capable of producing single droplets on demand. The generator consists of a cylindrical liquid filled chamber with a small orifice at the bottom. The top of the chamber is covered with a thin flexible metal disc. A small metal pin is employed to hammer/impact the top metal surface to generate a pressure pulse inside the liquid chamber. The movement and the momentum of the metal pin are controlled using a solenoid device. The pressure pulse generated overcomes the surface tension of the liquid meniscus at the exit of the orifice and ejects a single droplet. The work presented in this paper will demonstrate the capabilities of the droplet generator.

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.

Purpose To evaluate the potential use of the longer tendinous insertion of the superficial head of the brachialis as a local graft source for elbow annular ligament reconstruction. Methods The tendon of the superficial head of the brachialis muscle was harvested as a distally based graft in 24 unmatched, fresh-frozen cadaveric specimens. The tendon insertion on the proximal ulna was preserved, and the graft was passed around the proximal radius to recreate the annular ligament. We measured the total length of the graft, the length of graft required to approximate the posterior insertion of the annular ligament reconstruction, and the length of excess graft. Results The average length of the superficial head of the brachialis muscle tendon available for use in reconstruction was 81 mm. The average length of tendon required to approximate the posterior anatomical insertion of the annular ligament was 69 mm. The average length of excess tendon was 12 mm. The tendon graft of the superficial head permitted potential annular ligament reconstruction in all specimens. Conclusions A distally based tendon graft reconstruction of the annular ligament of the elbow using the tendon of the superficial head of the brachialis muscle would be feasible in most patients, based on this anatomic study. Future studies should consider the biomechanical stability of this ligament reconstruction, choices of optimal posterior graft fixation, and clinical outcomes. Clinical relevance Incompetence of the annular ligament may cause persisting instability of the proximal radius requiring ligament reconstruction. The anatomic feasibility of using the distal tendon of the superficial head of the brachialis muscle as a distally based graft source is evaluated for annular ligament reconstruction.

The fuel economy and emissions performance of a Diesel engine is strongly influenced by the fuel injection process. This paper presents early results of an experimental investigation into diesel spray development carried out in a novel in-house developed optical pressure chamber capable of operating at pressure up to 50 bar and temperatures up to 900 K. The spatial evolution of a diesel spray tends to experience many transitory macroscopic phenomena that directly influence the mixing process. These phenomena are not considered highly reproducible and are extremely short lived, hence recording and understanding these transient effects is difficult. In this study, high-speed backlight-illuminated imaging has been employed in order to capture the transient dynamics of a short signal duration diesel spray injected into incremental back pressures and temperatures reaching a maximum of 10 bar and 473 K respectively. Subsequently, several geometric parameters of the spray were estimated from the high-speed images. It is envisaged that the new optical chamber and the results presented in this work will enable better understanding and awareness of the relative influence of these transitory phenomena on certain diesel spray characteristics. © Copyright 2011 Society of Automotive Engineers of Japan, Inc. and SAE International.

Background The goal of this study was to determine whether sampling error was the major cause for false-negative fine needle aspiration (FNA) results for thyroid nodules. Methods Patients who underwent preoperative FNA between 1994 and 2008 were identified, and the results were compared with surgical pathology findings. Other related variables including nodule number and size were also recorded. Results Excluding the microcarcinomas, the false-negative rate was 4% (19/479). Sampling errors occurred in only 4 (21%) cases in which the malignant nodule was not actually biopsied. Of the other 15 cases, 8 (53%) were solitary nodules, 8 (53%) were ≥4 cm in size, and 5 (33%) had underlying thyroiditis. Because of the missed diagnosis, 9 patients (47%) had lobectomy only as the initial surgery, which then required a completion thyroidectomy. Conclusions Sampling error is a minor cause for false-negative FNAs, suggesting that there are some inherent limitations to cytological evaluation of the thyroid.

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.

Beta-arrestin1 and beta-arrestin2 were initially identified by sequence homology to visual arrestins and by their ability to bind to and inactivate signaling of the beta-2-adrenergic receptor in a process known as desensitization. While the role of beta-arrestins in desensitization has been known for some time, more recent evidence has revealed that beta-arrestins are multifunctional scaffolding proteins that are involved in numerous aspects of G protein-coupled receptor (GPCR) signaling. Interestingly, exciting new data shows that beta-arrestins can mediate signaling in their own right independent of classical second messenger mediated signaling, and that this beta-arrestin-mediated signaling may be cardioprotective. Identifying novel ligands for GPCRs that can block G protein-mediated signaling while simultaneously promoting beta-arrestin-mediated signaling could provide powerful new therapies for 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.