[Troubleshooting with difficult replacement of voice prostheses and a novel retrograde procedure]. / Tipps und Tricks beim erschwerten Stimmprothesenwechsel und ein neues retrogrades Wechselverfahren.

The implantation of a voice prosthesis has become a standard procedure during a laryngectomy. A voice prostheses enables patients to develop speech shortly after surgery, which strongly improves rehabilitation and quality of life.The lifetime of a voice prosthesis is limited and highly variable due to different causes. A replacement is usually necessary several times a year and can easily been done in an outpatient setting with surface anesthesia. In some cases, replacing the prosthesis becomes difficult. This article will take a closer look at different reasons that can lead to difficulties in prostheses replacement and discuss possible solutions, thereby focusing especially on a retrograde technique. The aim of this article is to help colleagues that already have experience with voice prostheses and want to expand their therapeutic armamentarium.

Long-term clinical outcome after intracoronary application of bone marrow-derived mononuclear cells for acute myocardial infarction: migratory capacity of administered cells determines event-free survival.

BACKGROUND: In the REPAIR-AMI trial, intracoronary infusion of bone marrow-derived cells (BMCs) was associated with a significantly greater recovery of contractile function in patients with acute myocardial infarction (AMI) at 4-month follow-up than placebo infusion. The current analysis investigates clinical outcome and predictors of event-free survival at 5 years. METHODS AND RESULTS: In the multicentre, placebo-controlled, double-blind REPAIR-AMI trial, 204 patients received intracoronary infusion of BMCs (n = 101) or placebo (n = 103) into the infarct vessel 3-7 days following successful percutaneous coronary intervention. Fifteen patients died in the placebo group compared with seven patients in the BMC group (P = 0.08). Nine placebo-treated patients and five BMC-treated patients required rehospitalization for chronic heart failure (P = 0.23). The combined endpoint cardiac/cardiovascular/unknown death or rehospitalisation for heart failure was more frequent in the placebo compared with the BMC group (18 vs. 10 events; P = 0.10). Univariate predictors of adverse outcomes were age, the CADILLAC risk score, aldosterone antagonist and diuretic treatment, changes in left ventricular ejection fraction, left ventricular end-systolic volume, and N-terminal pro-Brain Natriuretic Peptide (all P < 0.01) at 4 months in the entire cohort and in the placebo group. In contrast, in the BMC group, only the basal (P = 0.02) and the stromal cell-derived factor-1-induced (P = 0.05) migratory capacity of the administered BMC were associated with improved clinical outcome. CONCLUSION: In patients of the REPAIR-AMI trial, established clinical parameters are associated with adverse outcome at 5 years exclusively in the placebo group, whereas the migratory capacity of the administered BMC determines event-free survival in the BMC-treated patients. These data disclose a potency-effect relationship between cell therapy and long-term outcome in patients with AMI.

Orthostatic function after renal sympathetic denervation in patients with resistant hypertension.

INTRODUCTION: Catheter-based renal denervation (RDN) reduces local and whole-body sympathetic activity and blood pressure (BP) in patients with resistant hypertension. However, safety concerns exist concerning the development of orthostatic dysfunction after RDN. METHODS AND RESULTS: In 36 patients (65 ± 7.6 years, 75% male) with resistant hypertension (office BP 162 ± 24/91 ± 14 mm Hg) treated with 4.8 ± 1.7 antihypertensive drugs, tilt table testing (TTT) was performed before and three months after RDN. Response to RDN was defined as a reduction in office systolic BP (SBP) ≥ 10 mm Hg three months after RDN. Responders (n=26; 72.2%) and non-responders (n=10; 27.8%) were evaluated separately. After RDN, office SBP and diastolic BP (DBP) were reduced by 29 ± 6.2/14 ± 3.6 mm Hg (p<0.0001; p=0.0002) only in responders. During TTT, SBP and DBP in supine position were only reduced in responders. Resting heart rate (HR) decreased in responders but not in non-responders by 5.9 ± 1.7beats/min (p=0.0016). Mean and minimal SBP were not altered during passive tilting. In the responder group, ∆SBP was reduced in the initial phase of tilting. The adaptive increase of HR was preserved in both groups after RDN, while only in responders mean and minimal HR were reduced after passive tilting. Following drug provocation, mean and minimal SBP during all phases of passive tilting remained unchanged. ∆SBP, ∆HR and total number of (pre-)syncopes were neither influenced by RDN nor differing between responders and non-responders. CONCLUSIONS: In patients with resistant hypertension, RDN reduced office BP, supine BP and HR during TTT without causing orthostatic dysfunction or (pre-)syncopes three months after treatment.

Circulating angiopoietins and cardiovascular mortality in cardiogenic shock.

AIMS: Vascular integrity is disturbed in shock contributing to clinical appearance and serious outcomes. While angiopoietin (Ang)-1 protects from vascular inflammation and leakage, Ang-2 disrupts endothelial barrier function. The imbalance of Ang-1 and Ang-2, their association to haemodynamic deterioration, and their prognostic relevance are not known and, thus, were prospectively evaluated in patients with cardiogenic shock (CS) in this study. METHODS AND RESULTS: Plasma Ang-1 and Ang-2 were determined by the enzyme immunoassay in patients with CS (n = 96), uncomplicated acute myocardial infarction (AMI, n = 20) and age-matched healthy controls (HC, n = 20). Angiopoietin-2 was three-fold elevated in CS compared with HC (P < 0.001), remained elevated in non-survivors, and decreased in survivors (P < 0.001). In contrast, Ang-1 decreased up to 35-fold in CS (P < 0.001). Angiopoietin-1 was correlated and Ang-2 was inversely related to a cardiac power index and mixed venous oxygen saturation, respectively (P < 0.001 for all). To assess the prognostic relevance, two outcome variables were considered: the 28-day mortality and the survival time (follow-up time 1 year). For Ang-2 at admission a cut-off point of 2500 pg/mL had a sensitivity of 61% and a specificity of 80% to determine 28-day mortality in CS (confirmed by receiver operating characteristic analysis, area under the curve = 0.71 ± 0.06, P < 0.001). Angiopoietin-2 levels >2500 pg/mL at admission were observed to be an independent predictor for 1-year mortality in CS confirmed by Cox proportional hazard analysis [hazard ratio (HR) 2.11; 95% confidence interval (CI) 1.03-4.36; P = 0.042]. CONCLUSION: Circulating Angs are closely related to outcome and severity in CS. Angiopoietin-2 emerged as an independent predictor of 28-day and 1-year mortality in CS. Larger studies are required to define the cut-off and predictive values for Ang-2. Angiopoietins may be prognostic biomarkers for survival in CS and might represent a novel therapeutic target.

Cognitive function in patients with decompensated heart failure: the Cognitive Impairment in Heart Failure (CogImpair-HF) study.

AIMS: The objective of this study was to examine cognitive and psychological processes systematically in patients with decompensated chronic heart failure (CHF) and to document changes in cognitive function after compensation. Executive functions, episodic memory, and attention are impaired in patients with stable CHF, influencing health behaviour and disease management. Cognitive function and psychological co-morbidities are associated with hospitalization, disability, and mortality. METHODS AND RESULTS: Cognitive performance, self-perceived quality of life, and depression were compared in 20 patients with decompensated CHF [ejection fraction (EF) 27 ± 8%, N-terminal pro brain natriuretic peptide (NT-proBNP) 10 880 pg/mL, interquartile range (4495-13 683)] before and after compensation, 20 age- and gender-matched stable CHF patients [New York Heart Association (NYHA) III-IV, EF 32 ± 10%, NT-proBNP 1881 pg/mL (323-1502)], and 20 healthy controls (EF 70 ± 5%). Patients with decompensated CHF showed significantly poorer performance in terms of short-term memory, working memory, executive control, and processing speed (P < 0.05) compared with stable CHF patients. Compensation improved the cognitive performance of decompensated CHF patients up to the level of patients with stable CHF. Compared with healthy controls, both patient groups were affected with respect to episodic memory (P < 0.0001) and fluid intelligence (P < 0.01). CONCLUSION: Decompensated heart failure patients are highly impaired in cognitive functioning, which improves but does not normalize after compensation. Neuropsychological diagnostics delivers important details for daily life activities and might identify individuals deserving special care.

Update on myocarditis.

Myocarditis is an inflammatory disease of the heart frequently resulting from viral infections and/or post-viral immune-mediated responses. It is one of the important causes of dilated cardiomyopathy worldwide. The diagnosis is presumed on clinical presentation and noninvasive diagnostic methods such as cardiovascular magnetic resonance imaging. Endomyocardial biopsy remains the gold standard for in vivo diagnosis of myocarditis. The therapeutic and prognostic benefits of endomyocardial biopsy results have recently been demonstrated in several clinical trials. Although remarkable advances in diagnosis, understanding of pathophysiological mechanisms, and treatment of acute myocarditis were gained during the last years, no standard treatment strategies could be defined as yet, apart from standard heart failure therapy and physical rest. In severe cases, mechanical support or heart transplantation may become necessary. There is some evidence that immunosuppressive and immunomodulating therapy are effective for chronic, virus-negative inflammatory cardiomyopathy. Further investigations by controlled, randomized studies are needed to definitively determine their role in the treatment of myocarditis.

Heart-focused anxiety in the general population.

OBJECTIVE: Heart-focused anxiety is a common phenomenon that is related to psychological disorders and cardiac diseases. We investigated heart-focused anxiety in the general population and provided standard values using the Cardiac Anxiety Questionnaire (CAQ). Furthermore, we assessed the reliability of the CAQ and investigated the influence of social variables on heart-focused anxiety. METHODS AND RESULTS: The questionnaire was applied to 2,396 individuals (age range: 18-92; mean age 49 ± 17, 50% male). Three aspects of heart-focused anxiety (fear, attention, and avoidance) were captured by the CAQ. To test the influence of age, gender, and social factors, we performed analyses of variance, correlative statistics, and regression analyses. Heart-focused anxiety showed a linear increase with age (P < 0.001). No gender differences were observed. The degree of anxiety was affected by relationship (P < 0.001), level of education (P < 0.001), employment (P < 0.001), and income (P < 0.001). CONCLUSION: We evaluated heart-focused anxiety in the general population and validated the CAQ. Using percentiles based on a normative sample allows screening for heart-focused anxiety in patients with or without cardiac diseases and the measurement of therapy success after psychotherapeutic or pharmacological intervention.

Cardiorespiratory response to exercise after renal sympathetic denervation in patients with resistant hypertension.

OBJECTIVES: This study sought to investigate the effects of interventional renal sympathetic denervation (RD) on cardiorespiratory response to exercise. BACKGROUND: RD reduces blood pressure at rest in patients with resistant hypertension. METHODS: We enrolled 46 patients with therapy-resistant hypertension as extended investigation of the Symplicity HTN-2 (Renal Denervation With Uncontrolled Hypertension) trial. Thirty-seven patients underwent bilateral RD and 9 patients were assigned to the control group. Cardiopulmonary exercise tests were performed at baseline and 3-month follow-up. RESULTS: In the RD group, compared with baseline examination, blood pressure at rest and at maximum exercise after 3 months was significantly reduced by 31 ± 13/9 ± 13 mm Hg (p < 0.0001) and by 21 ± 20/5 ± 14 mm Hg (p < 0.0001), respectively. Achieved work rate increased by 5 ± 13 W (p = 0.029) whereas peak oxygen uptake remained unchanged. Blood pressure 2 min after exercise was significantly reduced by 29 ± 17/8 ± 15 mm Hg (p < 0.001 for systolic blood pressure; p = 0.002 for diastolic blood pressure). Heart rate at rest decreased after RD (4 ± 11 beats/min; p = 0.028), whereas maximum heart rate and heart rate increase during exercise were not different. Heart rate recovery improved significantly by 4 ± 7 beats/min after renal denervation (p = 0.009). In the control group, there were no significant changes in blood pressure, heart rate, maximum work rate, or ventilatory parameters after 3 months. CONCLUSIONS: RD reduces blood pressure during exercise without compromising chronotropic competence in patients with resistant hypertension. Heart rate at rest decreased and heart rate recovery improved after the procedure. (Renal Denervation With Uncontrolled Hypertension; [Symplicity HTN-2]; NCT00888433).

CD44 as a stem cell marker in head and neck squamous cell carcinoma.

In the recent past, evidence is increasing indicating the existence of a subpopulation of resistant tumor cells in head and neck squamous cell carcinoma (HNSCC) that cannot be eradicated by established antineoplastic treatments. These cancer stem cells (CSCs) have features of somatic stem cells such as selfrenewal, proliferation and differentiation. CD44+ cells in tumors of the head and neck are referred to as CSCs of HNSCC. Expression profiling of CD44 in 29 HNSCC tumors was performed by fluorescence microscopy. ELISA analysis was performed to detect concentration of soluble CD44 in the peripheral blood of 29 HNSCC patients and 11 healthy controls. Expression of CD44 was determined in all HNSCC tissue samples (n=29). In all samples a surface staining pattern was found. The concentration of CD44 in the peripheral blood of HNSCC patients was significantly higher compared to a healthy control group (mHNSCC =13.5 ± 0.5 ng/ ml; mCont = 9.3 ± 0.6 ng/ml; P=0.6 x 10(-12)). The role of CD44 as a marker for CSCs in HNSCC remains to be ascertained. Further experiments might reveal its role as a diagnostic and prognostic factor, and possibly as a therapeutic target.

Sublingual allergen-specific immunotherapy adjuvanted with monophosphoryl lipid A: a phase I/IIa study.

BACKGROUND: Sublingual immunotherapy (SLIT) allergy vaccines have an excellent safety profile, but opinions vary on their efficacy, and treatment regimens are often lengthy. This study assessed the effects of the Toll-like receptor 4 agonist monophosphoryl lipid A (MPL®) on safety/tolerability and clinical and immunological efficacy when combined with grass pollen SLIT formulations in treating patients with seasonal allergic rhinitis. This is the first reported study of adjuvanted SLIT. METHODS: In this double-blind placebo-controlled phase I/IIa study, 80 grass pollen-sensitive subjects were randomized into 4 groups of 20 subjects to receive daily treatment for 8 weeks. Sixteen patients per group received SLIT and 4 received placebo. The formulation given to each group varied with respect to grass pollen extract and MPL content. Grass allergen nasal challenge tests (NCTs) were performed prior to dosing and in weeks 4 and 10. Grass pollen-specific immunoglobulin G (IgG) and IgE antibodies were measured at baseline and prior to dosing in weeks 2, 3, 4, 5 and 10. RESULTS: Local and systemic adverse events were generally comparable for patients who received active treatment and placebo. Patients in the 2 groups given SLIT containing the highest amount of MPL experienced the highest proportion of negative NCTs after 10 weeks (47 and 44%, vs. 20% with placebo). These patients also showed earlier median increases in specific IgG and smaller increases in IgE levels than those receiving other formulations. CONCLUSIONS: These results suggest that SLIT preparations containing MPL are well tolerated and alter the immunological response to grass antigens after 3 weeks of exposure, with an associated suppression of nasal challenge responses.

Spermine and endothelial damage during endotoxemia.

Diazenolate-NO-donors like spermine-NONOate use spermine as a nitric oxide releasing carrier. As one of the naturally occurring polyamines, spermine belongs to the most potent platelet aggregation inhibitors among the polyamines. Recent publications describe a dominating role for platelets and nitric oxide in the setting of endothelial dysfunction during endotoxemia. It is unknown whether spermine as single agent, beside his function as nitric oxide releasing carrier, exerts effects on macromolecular leakage during early endotoxemia. In male Wistar rats, macromolecular efflux was determined in mesenteric postcapillary venules using intravital microscopy at baseline, 60 and 120 min after the start of the experiment. In the first part of the experiments we investigated the effects of spermine and spermine-NONOate during leukocyte-independent states of endotoxemia, using the L- and P-selectin inhibitor fucoidin to suppress leukocyte-endothelial-interaction. In the second part we investigated the effects of spermine on endothelial damage during endotoxemia without co-administration of fucoidin. Combined treatment of animals with spermine and fucoidin was as effective as treatment with spermine-NONOate and fucoidin alone. Spermine and fucoidin as single agents had no effects on macromolecular efflux during endotoxin challenge. Combined treatment of animals with spermine and fucoidin reduce macromolecular efflux to the same degree like treatment with spermine-NONOate and fucoidin. A currently unknown interaction between fucoidin and spermine leads to a significant reduction in macromolecular efflux.

Role of nitric oxide in leukocyte-independent endothelial damage during experimental endotoxemia.

Endothelial damage during early endotoxemia has been shown to be leukocyte independent. Platelet-activating factor and serotonin receptor antagonism has been shown to reduce leukocyte-independent macromolecular leakage significantly. Nevertheless, the exact mechanisms involved in leukocyte-independent endothelial dysfunction are unknown. Therefore, it was the aim of the study to investigate the effects of nitric oxide (NO) on leukocyte-independent endothelial damage during endotoxemia. In male Wistar rats, venular wall shear rate, macromolecular efflux, and leukocyte-endothelial interaction were determined in mesenteric postcapillary venules using intravital microscopy at baseline and at 60 and 120 min after start of the experiment. The animals received fucoidin to prevent leukocyte-endothelial interaction. The experiments were divided into three parts. In part 1, we investigated the effects of the NO-inhibitor L-NAME on leukocyte-independent endothelial damage during endotoxemic and nonendotoxemic conditions. The efficiency of the NO-donor (SIN-1) used, part 2, was investigated by the inhibitory properties of SIN-1 on NO-inhibition-induced macromolecular efflux. Finally, part 3, we analyzed the effects of the NO-donor SIN-1 on endothelial damage during endotoxemia. Both the combined challenge of the animals with L-NAME and endotoxin and the challenge with L-NAME alone resulted in a strong increase in macromolecular efflux, showing significant differences to control groups at an earlier time point than endotoxin challenge alone. Interestingly, combined L-NAME and endotoxin challenge, L-NAME challenge alone, and endotoxin challenge alone showed a similar macromolecular efflux at the end of the experiment. SIN-1 prevented both the increase in macromolecular efflux seen after L-NAME challenge (part 2) and was highly effective in preventing significantly the increase in macromolecular leakage that is seen during leukocyte-independent endotoxemia (part 3). In conclusion, our data indicate that during early states of endotoxemia endogenous NO preserves endothelial integrity in a leukocyte-independent setting. Exogenous NO prevents endothelial damage during early leukocyte-independent endotoxemia. Summarizing these data, endothelial integrity during leukocyte-independent endotoxemia is a NO-mediated event.