Microfabricated double-tilt apparatus for transmission electron microscope imaging of atomic force microscope probe.

Atomic force microscopy (AFM) uses a scanning stylus to directly measure the surface characteristics of a sample. Since AFM relies on nanoscale interaction between the probe and the sample, the resolution of AFM-based measurement is critically dependent on the geometry of the scanning probe tip. This geometry, therefore, can limit the development of related applications. However, AFM itself cannot be effectively used to characterize AFM probe geometry, leading researchers to rely on indirect estimates based on force measurement results. Previous reports have described sample jigs that enable the observation of AFM probe tips using Transmission Electron Microscopy (TEM). However, such setups are too tall to allow sample tilting within more modern high-resolution TEM systems, which can only tilt samples less than a few millimeters in thickness. This makes it impossible to observe atomic-scale crystallographic lattice fringes by aligning the imaging angle perfectly or to view a flat probe tip profile exactly from the side. We have developed an apparatus that can hold an AFM tip for TEM observation while remaining thin enough for tilting, thereby enabling atomic-scale tip characterization. Using this technique, we demonstrated consistent observation of AFM tip crystal structures using tilting in TEM and found that the radii of curvature of nominally identical probes taken from a single box varied widely from 1.4 nm for the sharpest to 50 nm for the most blunt.

Extraoral Versus Intraoral Approach for Removal of Styloid Process in Treatment of Eagle's Syndrome: A Report of Two Cases.

Eagle's syndrome, a condition associated with the elongation of the styloid process or calcification of the stylohyoid ligament, is clinically characterized by throat and neck pain radiating into the mastoid region. The diagnosis can be made through a thorough history, correct clinical and pathological correlation and radiographic examination. The elongated styloid process can be treated conservatively or surgically. Conservative treatment options include transpharyngeal injections of steroids and lignocaine, nonsteroidal anti-inflammatory drugs, diazepam, and the application of heat. The surgical management of Eagle's syndrome consists of two major approaches: the transoral and the transcervical approaches. In this paper, we present a comparative study of two cases of classic bilateral elongated styloid process syndrome, treated with transcervical styloidectomy and transoral styloidectomy, their surgical time, intraoperative difficulties and complications, and recovery time. In conclusion, the management of Eagle's syndrome requires a comprehensive approach that includes a thorough preoperative evaluation of the length of the styloid process via imaging and digital palpation. The choice of surgical approach, whether extraoral or transpharyngeal, should be based on factors such as the surgeon's experience and the patient's comorbidities, as well as the length and palpability of the styloid process. Our comparative study of two cases treated with transcervical and transoral styloidectomy demonstrated that the extraoral method offers a direct and well-controlled approach for excessive styloid processes, while the transpharyngeal approach is preferred for cases where the process can be easily identified by palpation. Therefore, proper patient selection and preoperative planning are essential to achieving successful outcomes with minimal complications.

Thermoresponsive and Injectable Hydrogel for Tissue Agnostic Regeneration.

Injectable hydrogels can support the body's innate healing capability by providing a temporary matrix for host cell ingrowth and neovascularization. The clinical adoption of current injectable systems remains low due to their cumbersome preparation requirements, device malfunction, product dislodgment during administration, and uncontrolled biological responses at the treatment site. To address these challenges, a fully synthetic and ready-to-use injectable biomaterial is engineered that forms an adhesive hydrogel that remains at the administration site regardless of defect anatomy. The product elicits a negligible local inflammatory response and fully resorbs into nontoxic components with minimal impact on internal organs. Preclinical animal studies confirm that the engineered hydrogel upregulates the regeneration of both soft and hard tissues by providing a temporary matrix to support host cell ingrowth and neovascularization. In a pilot clinical trial, the engineered hydrogel is successfully administered to a socket site post tooth extraction and forms adhesive hydrogel that stabilizes blood clot and supports soft and hard tissue regeneration. Accordingly, this injectable hydrogel exhibits high therapeutic potential and can be adopted to address multiple unmet needs in different clinical settings.

Fabricating Silicon Resonators for Analysing Biological Samples.

The adaptability of microscale devices allows microtechnologies to be used for a wide range of applications. Biology and medicine are among those fields that, in recent decades, have applied microtechnologies to achieve new and improved functionality. However, despite their ability to achieve assay sensitivities that rival or exceed conventional standards, silicon-based microelectromechanical systems remain underutilised for biological and biomedical applications. Although microelectromechanical resonators and actuators do not always exhibit optimal performance in liquid due to electrical double layer formation and high damping, these issues have been solved with some innovative fabrication processes or alternative experimental approaches. This paper focuses on several examples of silicon-based resonating devices with a brief look at their fundamental sensing elements and key fabrication steps, as well as current and potential biological/biomedical applications.

A proposed ABCD scoring system for better triage of patients with COVID-19: Use of clinical features and radiopathological findings.

BACKGROUND AND AIMS: Currently there are limited tools available for triage of patients with COVID -19. We propose a new ABCD scoring system for patients who have been tested positive for COVID-19. METHODS: The ABCD score is for patients who have been tested positive for COVID-19 and admitted in a hospital. This score includes age of the patient, blood tests included leukopenia, lymphocytopenia, CRP level, LDH level,D-Dimer, Chest radiograph and CT Scan, Comorbidities and Dyspnea. RESULTS: The triage score had letters from alphabets which included A, B, C, D. The score was developed using these variables which outputs a value from 0 to 1. We had used the code according to traffic signal system; green(mild), yellow moderate) and red(severe). The suggestions for mild (green)category: symptomatic treatment in ward, in moderate (yellow) category: active treatment, semi critical care and oxygen supplementation, in severe (red) category: critical care and intensive care. CONCLUSIONS: This study is, to our knowledge, is the first scoring tool that has been prepared by Indian health care processional's and used alphabets A, B,C,D as variables for evaluation of admitted patients with COVID-19. This triage tool will be helpful in better management of patients with COVID-19. This score component includes clinical and radiopathological findings.A multi-centre study is required to validate all available scoring systems.

Clinical Outcomes and Characteristics With Dofetilide in Atrial Fibrillation Patients Considered for Implantable Cardioverter-Defibrillator.

BACKGROUND: Dofetilide is one of the only anti-arrhythmic agents approved for atrial fibrillation (AF) in patients with reduced left ventricular ejection fraction (LVEF). However, postapproval data and safety outcomes are limited. In this study, we assessed the incidence and predictors of LVEF improvement, safety, and outcomes in patients with AF with LVEF ≤35% without prior implantable cardioverter defibrillator, cardiac resynchronization therapy, or AF ablation. METHODS: An analysis of 168 consecutive patients from 2007 to 2016 was performed. Incidences of adverse events, drug continuation, implantable cardioverter defibrillator and cardiac resynchronization therapy implantation, LVEF improvement (>35%) and recovery (≥50%), AF recurrence, and AF ablation were determined. Multivariable regression analysis to identify predictors of LVEF improvement/recovery was performed. RESULTS: The mean age was 64±12 years. Dofetilide was discontinued before hospital discharge in 46 (27%) because of QT prolongation (14%), torsades de pointe or polymorphic ventricular tachycardia/fibrillation (6% [sustained 3%, nonsustained 3%]), ineffectiveness (5%), or other causes (3%). At 1 year, 43% remained on dofetilide. Freedom from AF was 42% at 1 year, and 40% underwent future AF ablation. LVEF recovered (≥50%) in 45% and improved to >35% in 73%. Predictors of LVEF improvement included presence of AF during echocardiogram (odds ratio, 4.22 [95% CI, 1.71-10.4], P=0.002), coronary artery disease (odds ratio, 0.35 [95% CI, 0.16-0.79], P=0.01), left atrial diameter (odds ratio, 0.52 per 1 cm increase [95% CI, 0.30-0.90], P=0.01), and LVEF (odds ratio, per 1% increase, 1.09 [95% CI, 1.02-1.16], P=0.006). The C statistic was 0.78. CONCLUSIONS: In patients with LVEF ≤35%, who are potential implantable cardioverter defibrillator candidates, treated with dofetilide as an initial anti-arrhythmic strategy for AF, drug discontinuation rates were high, and many underwent future AF ablation. However, most patients had improvement in LVEF, obviating the need for primary prevention implantable cardioverter defibrillator.

Cutaneous manifestation of IgG4-related disease mimicking dermatitis artefacta.

Dermatitis artefacta is a self-inflicted cutaneous disease presenting as sharply delineated ulcers, usually in accessible sites such as the head and neck. IgG4-related disease (IgG4-RD) is a recently recognised immune-mediated condition causing a fibroinflammatory process, resulting in the formation of tumefactive lesions in various organs, rarely presenting primarily in the skin. We report a case of cutaneous IgG4-RD clinically presenting as dermatitis artefacta.

Clinical Profiles and Survival Outcomes of Patients With Well-Differentiated Neuroendocrine Tumors at a Health Network in New South Wales, Australia: Retrospective Study.

BACKGROUND: Neuroendocrine tumors (NETs) are a heterogeneous group of malignancies with varying and often indolent clinicobiological characteristics according to their primary location. NETs can affect any organ and hence present with nonspecific symptoms that can lead to a delay in diagnosis. The incidence of NETs is increasing in Australia; data regarding characteristics of NETs were collected from the cancer registry of Hunter New England, Australia. OBJECTIVE: This study aimed to explore the clinical profiles and treatment and survival outcomes of patients with well-differentiated NETs in an Australian population. METHODS: We reviewed the data of all adult patients who received the diagnosis of NET between 2008 and 2013. The clinicopathological, treatment, and follow-up data were extracted from the local Cancer Clinical Registry. We also recorded the level of remoteness for each patient by matching the patient's residential postcode to the corresponding Australian Bureau of Statistics 2011 remoteness area category. Univariate analysis was used to find the factors associated with NET-related mortality. Survival analysis was computed. RESULTS: Data from 96 patients were included in the study (men: 37/96, 38.5%, and women: 59/96, 61.5%). The median age at diagnosis was approximately 63 years. A higher proportion of patients lived in remote/rural areas (50/96, 52.1%) compared with those living in city/metropolitan regions (46/96, 47.9%). The most common primary tumor site was the gastroenteropancreatic tract, followed by the lung. The factors significantly associated with NET-related mortality were age, primary tumor site, surgical resection status, tumor grade, and clinical stage of the patient. At 5 years, the overall survival rate was found to be 62%, and the disease-free survival rate was 56.5%. CONCLUSIONS: Older age, advanced unresectable tumors, evidence of metastasis, and higher-grade tumors were associated with poorer outcomes. Lung tumors had a higher risk of NET-related mortality compared with other sites.

Unilateral Access Is Safe and Facilitates Peripheral Bailout During Transfemoral-Approach Transcatheter Aortic Valve Replacement.

OBJECTIVES: The aim of this study was to compare the rate and trend of vascular complications when placing a second arterial sheath in the contralateral femoral artery during transcatheter aortic valve replacement (TAVR) unilaterally versus bilaterally. BACKGROUND: Vascular complications occur in approximately 5% to 8% of TAVR procedures. Many operators place a second arterial sheath in the contralateral femoral artery to perform aortic root angiography. The authors surmised that placing the second sheath ipsilateral and distal to the delivery sheath would be an easier option with similar safety. METHODS: The Cleveland Clinic Aortic Valve Center TAVR database was accessed, and data for patients undergoing transfemoral TAVR (TF-TAVR) from January 2014 to December 2017 were analyzed retrospectively. The primary outcome was the rate of peripheral vascular complications. RESULTS: A total of 1,208 patients who underwent TF-TAVR were included in this study. One thousand seven patients (83.36%) underwent bilateral femoral access, and 201 patients (16.64%) underwent TF-TAVR using a unilateral femoral approach. Over the study duration, use of the unilateral access approach trended upward significantly, reaching 43.7% of total cases in 2017. A gradual decline in access site-related vascular complications was observed, from 13.7% in 2014 to 7.4% in 2017. After propensity-score matching, peripheral vascular complications were similar between bilateral access and unilateral access (10.8% vs. 8.6%) (p = 0.543). CONCLUSIONS: There was a significant decline in vascular complications from 2014 to 2017. Unilateral-access TF-TAVR provided similar safety compared with bilateral-access TF-TAVR and is a more accessible approach for managing access site-related complications and possibly achieving better patient satisfaction.

Outcomes of patients with severe tricuspid regurgitation and congestive heart failure.

OBJECTIVES: A substantial number of patients with severe tricuspid regurgitation (TR) and congestive heart failure (CHF) are medically managed without undergoing corrective surgery. We sought to assess the characteristics and outcomes of CHF patients who underwent tricuspid valve surgery (TVS), compared with those who did not. METHODS: Retrospective observational study involving 2556 consecutive patients with severe TR from the Cleveland Clinic Echocardiographic Database. Cardiac transplant patients or those without CHF were excluded. Survival difference between patients who were medically managed versus those who underwent TVS was compared using Kaplan-Meier survival curves. Multivariate analysis was performed to identify variables associated with poor outcomes. RESULTS: Among a total of 534 patients with severe TR and CHF, only 55 (10.3%) patients underwent TVS. Among the non-surgical patients (n=479), 30% (n=143) had an identifiable indication for TVS. At 38 months, patients who underwent TVS had better survival than those who were medically managed (62% vs 35%; p<0.001). On multivariate analysis, advancing age (HR: 1.23; 95% CI 1.12 to 1.35 per 10-year increase in age), moderate (HR: 1.39; 95% CI 1.01 to 1.90) and severe (HR: 2; 95% CI 1.40 to 2.80) right ventricular dysfunction were associated with higher mortality. TVS was associated with lower mortality (HR: 0.44; 95% CI 0.27 to 0.71). CONCLUSION: Although corrective TVS is associated with better outcomes in patients with severe TR and CHF, a substantial number of them continue to be medically managed. However, since the reasons for patients not being referred to surgery could not be ascertained, further randomised studies are needed to validate our findings before clinicians can consider surgical referral for these patients.

Measuring Terrestrial Area of Habitat (AOH) and Its Utility for the IUCN Red List.

The International Union for Conservation of Nature (IUCN) Red List of Threatened Species includes assessment of extinction risk for 98 512 species, plus documentation of their range, habitat, elevation, and other factors. These range, habitat and elevation data can be matched with terrestrial land cover and elevation datasets to map the species' area of habitat (AOH; also known as extent of suitable habitat; ESH). This differs from the two spatial metrics used for assessing extinction risk in the IUCN Red List criteria: extent of occurrence (EOO) and area of occupancy (AOO). AOH can guide conservation, for example, through targeting areas for field surveys, assessing proportions of species' habitat within protected areas, and monitoring habitat loss and fragmentation. We recommend that IUCN Red List assessments document AOH wherever practical.

Time-Integrated Aortic Regurgitation Index Helps Guide Balloon Postdilation During Transcatheter Aortic Valve Replacement and Predicts Survival.

Background Balloon postdilation ( BPD ) has emerged as an effective strategy to reduce paravalvular regurgitation ( PVR ) during transcatheter aortic valve replacement ( TAVR ). We investigated the utility of a time-integrated aortic regurgitation index ( TIARI ) to guide balloon postdilation ( BPD ) after valve deployment. Methods and Results All consecutive patients who had echocardiography, aortography, and hemodynamic tracings recorded immediately after valve deployment during TAVR were included in the study. Catheter-derived invasive hemodynamic parameters were calculated offline. Among 157 patients who underwent TAVR , 49 (32%) patients required BPD to reduce significant PVR after valve deployment. Two experienced operators decided whether the patients required BPD for significant PVR . Median TIARI measured immediately after valve deployment was significantly lower in patients who required BPD when compared with patients who did not require BPD ( P<0.001). In a multivariable analysis, lower TIARI (odds ratio: 0.81; P=0.003) and higher PVR grade on aortography and echocardiography ( P<0.001 for both) were associated with BPD . Adding TIARI to echocardiography and aortographic PVR assessment resulted in a significant increase in global χ2 ( P<0.001), an integrated discrimination index of 9% ( P=0.002), and combined C-statistics of 0.99 for predicting BPD . Higher TIARI after valve deployment was associated with better survival (hazard ratio: 0.94, P=0.014), while other hemodynamic and imaging parameters did not predict mortality after TAVR . Conclusions Among patients undergoing TAVR , a TIARI measured immediately after valve deployment adds incremental value to guide BPD over aortography and echocardiography. Higher residual TIARI is associated with better survival after TAVR .

Association of Time Between Left Ventricular and Aortic Systolic Pressure Peaks With Severity of Aortic Stenosis and Calcification of Aortic Valve.

Importance: Diagnosis of low-gradient severe aortic stenosis (AS) is challenging. We hypothesized that the time between left ventricular (LV) and aortic systolic pressure peaks (TLV-Ao) is associated with aortic stenosis (AS) severity and may have additive value in diagnosing severe AS, especially in patients with low-gradient AS. Objective: To investigate the diagnostic utility of measuring catheter-based TLV-Ao in patients with severe AS. Design, Setting, and Participants: We studied 123 patients with severe AS at the Cleveland Clinic Foundation, a tertiary referral center, who underwent transcatheter aortic valve replacement (TAVR) via femoral access and had pre-TAVR cardiac computed tomography assessment and hemodynamic measurements recorded during a TAVR procedure. All patients received hemodynamic evaluation, echocardiographic assessment, and quantification of aortic valve calcification (AVC) by multidetector computed tomography. Hemodynamic data were collected via left heart catheterization done just before TAVR, and TLV-Ao was calculated offline. Data were analyzed between October 5, 2015, and July 20, 2016. Main Outcomes and Measures: The association between TLV-Ao and AVC or other conventional imaging parameters was analyzed. Results: Of the included patients, the mean (SD) age was 81 (9) years, and 65 (54%) were men (54%). Among 123 patients, 48 patients (39%) had low-gradient AS (<40 mm Hg) and mean (SD) TLV-Ao was 69 (39) milliseconds. In multivariable logistic regression analyses, higher TLV-Ao (odds ratio [OR], 1.02; 95% CI, 1.01-1.04; P = .002) and higher peak aortic valve (AV) velocity (OR, 1.01; 95% CI, 1.00-1.02; P = .008) were independently associated with severe AVC (AVC >1000 AU). Adding TLV-Ao to the peak AV velocity and AV area showed significant incremental value to be associated with AVC, with a net reclassification improvement of 0.61 (95% CI, 0.23-0.99; P = .002) and integrated discriminatory improvement of 0.09 (95% CI, 0.03-0.16; P = .003). In a subgroup of patients with low-grade AS, higher TLV-Ao was the only parameter associated with severe AVC (OR, 1.02; 95% CI, 1.001-1.04; P = .03). Conclusions and Relevance: Prolonged TLV-Ao was associated with severe AVC. This catheter-based hemodynamic index may be an additional surrogate to differentiate low-gradient true severe AS. Larger, prospective studies investigating the role of TLV-Ao as a marker of clinical outcomes in patients undergoing TAVR are required.

Hemodynamic durability of transcatheter aortic valves using the updated Valve Academic Research Consortium-2 criteria.

OBJECTIVES: We investigated the hemodynamic durability of the transcatheter aortic valves (TAVs) using the updated Valve Academic Research Consortium-2 (VARC-2) criteria. BACKGROUND: The updated VARC-2 consensus criteria combine flow-dependent and flow-independent echocardiographic parameters for hemodynamic assessment of TAVR. Data on the hemodynamic durability of TAV and clinical risk factors associated with valve hemodynamic deterioration (VHD) are lacking. METHODS: All patients (n = 276) who received TAV between 2006 and 2012 and had ≥2 follow-up echocardiograms were studied. RESULTS: During a median follow up period of 3.3 (1.8-4.4) years, 8 patients (3%) developed moderate to severe valve stenosis per the VARC-2 criteria, while 20 had mild stenosis. In a Cox proportional hazards model analysis, moderate to severe stenosis by VARC-2 criteria was associated with younger age (P = 0.03, HR 0.94), absence of dual antiplatelet therapy (DAPT) (P = 0.026, HR 0.18), and lower baseline left ventricular ejection fraction (LVEF) (P = 0.006, HR 0.94). Longitudinal analysis using a mixed effect model showed that presence of stenosis by VARC-2 criteria was associated with an increase in aortic valve mean gradient (P < 0.001, +2.34 mmHg per year). In a subset of 93 patients with analyzable fluoroscopic images, deeper valve implantation was associated with increase in mean gradient (P = 0.004, +0.2 mmHg per year per 1 mm increase in implantation depth). CONCLUSION: Despite good hemodynamic durability of TAV, patients with younger age, lower LVEF and those not on DAPT after undergoing a TAV replacement, are at a higher risk for development of VHD.

Noninvasive Multimodality Imaging for the Diagnosis of Constrictive Pericarditis.

There is a need to review the multimodality imaging techniques, as well as the emerging role of the newer noninvasive imaging modalities in the field of constrictive pericarditis (CP). Therefore, the aim of this review is to summarize the current available techniques that are useful for the diagnosis and differentiation of CP from restrictive cardiomyopathy. Also, we provide illustrative images and videos of typical CP noninvasive imaging findings, as well as a diagnostic and management algorithm. CP is a challenging diagnosis; therefore, cardiologists need adequate knowledge about the application of multimodality noninvasive imaging in a systematic and guideline-oriented fashion whenever CP is suspected.

Current Society of Thoracic Surgeons Model Reclassifies Mortality Risk in Patients Undergoing Transcatheter Aortic Valve Replacement.

BACKGROUND: The Society of Thoracic Surgeons (STS) scores are used to screen patients for transcatheter aortic valve replacement (TAVR). The STS scores were also used to risk stratify patients in major TAVR trials. This study evaluates the reclassification of predicted risk of mortality by the currently available online STS score calculator compared with the 2008 STS risk model in patients undergoing TAVR. METHODS AND RESULTS: All patients who underwent TAVR from 2006 to 2016 were included in the study. The STS scores for all included patients were calculated by applying the 2008 STS risk model and again using the current STS online calculator. Among 1209 patients who underwent TAVR, 30-day mortality was 27 (2.2%). The overall predicted risk of mortality estimated by using the current online STS risk calculator was significantly lower than the 2008 STS risk model (6.3±4.4 vs 7.3±4.9; P<0.001). A total of 235 (19%) patients were reclassified into a lower risk category per the current STS risk model. In a multivariable logistic regression analysis, patients with persistent atrial fibrillation (odds ratio, 1.4; 95% CI, 1.0-1.9; P=0.03), chronic heart failure (odds ratio, 6.0; 95% CI, 3.8-10.1; P<0.001), and New York Heart Association class IV heart failure (odds ratio, 2.4; 95% CI, 1.3-4.4; P=0.007) were more likely to be reclassified into a lower risk category per the current STS risk model. CONCLUSIONS: The current STS calculation method produces significantly lower predicted risk of mortality than the 2008 calculator, more pronounced in patients with certain comorbid conditions. These results should be considered while evaluating data from prior studies of TAVR.

Real-time observation of slipping and rolling events in DLC wear nanoparticles.

Real-time observation of the actual contact area between surface interfaces at the nanoscale enables more precise examination of what happens during friction. We have combined micro electro mechanical system actuators and transmission electron microscopy (TEM) observation, to both apply and measure forces across nanoscale junctions and contacts. This custom-designed experimental system can measure the true surface area of a contact site from a lateral viewpoint, while simultaneously measuring the friction force. We scratched surfaces coated with diamond like carbon, a classical solid lubricant, and observed the formation of wear particles that slipped and rolled between the interface. TEM images showed that the shape of the surface at the nanoscale underwent permanent deformation when acted upon with forces as low as several tens of nano newtons. The results demonstrated the limitations of friction analyses relying on friction force measurements without real-time surface profiling.

Nitric Oxide Contributes to Vasomotor Tone in Hypertensive African Americans Treated With Nebivolol and Metoprolol.

Endothelial dysfunction is more prevalent in African Americans (AAs) compared with whites. The authors hypothesized that nebivolol, a selective ß1 -antagonist that stimulates nitric oxide (NO), will improve endothelial function in AAs with hypertension when compared with metoprolol. In a double-blind, randomized, crossover study, 19 AA hypertensive patients were randomized to a 12-week treatment period with either nebivolol 10 mg or metoprolol succinate 100 mg daily. Forearm blood flow (FBF) was measured using plethysmography at rest and after intra-arterial infusion of acetylcholine and sodium nitroprusside to estimate endothelium-dependent and independent vasodilation, respectively. Physiologic vasodilation was assessed during hand-grip exercise. Measurements were repeated after NO blockade with L-N(G) -monomethylarginine (L-NMMA) and after inhibition of endothelium-derived hyperpolarizing factor (EDHF) with tetraethylammonium chloride (TEA). NO blockade with L-NMMA produced a trend toward greater vasoconstriction during nebivolol compared with metoprolol treatment (21% vs 12% reduction in FBF, P=.06, respectively). This difference was more significant after combined administration of L-NMMA and TEA (P<.001). Similarly, there was a contribution of NO to exercise-induced vasodilation during nebivolol but not during metoprolol treatment. There were significantly greater contributions of NO and EDHF to resting vasodilator tone and of NO to exercise-induced vasodilation with nebivolol compared with metoprolol in AAs with hypertension.

Mechanisms and clinical significance of histone deacetylase inhibitors: epigenetic glioblastoma therapy.

Glioblastoma is the most common and deadliest of malignant primary brain tumors (Grade IV astrocytoma) in adults. Current standard treatments have been improving but patient prognosis still remains unacceptably devastating. Glioblastoma recurrence is linked to epigenetic mechanisms and cellular pathways. Thus, greater knowledge of the cellular, genetic and epigenetic origin of glioblastoma is the key for advancing glioblastoma treatment. One rapidly growing field of treatment, epigenetic modifiers; histone deacetylase inhibitors (HDACis), has now shown much promise for improving patient outcomes through regulation of the acetylation states of histone proteins (a form of epigenetic modulation) and other non-histone protein targets. HDAC inhibitors have been shown, in a pre-clinical setting, to be effective anticancer agents via multiple mechanisms, by up-regulating expression of tumor suppressor genes, inhibiting oncogenes, inhibiting tumor angiogenesis and up-regulating the immune system. There are many HDAC inhibitors that are currently in pre-clinical and clinical stages of investigation for various types of cancers. This review will explain the theory of epigenetic cancer therapy, identify HDAC inhibitors that are being investigated for glioblastoma therapy, explain the mechanisms of therapeutic effects as demonstrated by pre-clinical and clinical studies and describe the current status of development of these drugs as they pertain to glioblastoma therapy.

Effects of storage-aged red blood cell transfusions on endothelial function in hospitalized patients.

BACKGROUND: Clinical and animal studies indicate that transfusions of older stored red blood cells (RBCs) impair clinical outcomes as compared to fresh RBC transfusions. It has been suggested that this effect is due to inhibition of nitric oxide (NO)-mediated vasodilation after transfusion of older RBC units. However, to date this effect has not been identified in human transfusion recipients. STUDY DESIGN AND METHODS: Forty-three hospitalized patients with transfusion orders were randomly assigned to receive either fresh (<14 days) or older stored (>21 days) RBC units. Before transfusion, and at selected time points after the start of transfusion, endothelial function was assessed using noninvasive flow-mediated dilation assays. RESULTS: After transfusion of older RBC units, there was a significant reduction in NO-mediated vasodilation at 24 hours after transfusion (p = 0.045), while fresh RBC transfusions had no effect (p = 0.231). CONCLUSIONS: This study suggests for the first time a significant inhibitory effect of transfused RBC units stored more than 21 days on NO-mediated vasodilation in anemic hospitalized patients. This finding lends further support to the hypothesis that deranged NO signaling mediates adverse clinical effects of older RBC transfusions. Future investigations will be necessary to address possible confounding factors and confirm these results.