[Patients with a wearable cardioverter-defibrillator (WCD) : Prescription, function and rehabilitation support]. / Patienten mit einer tragbaren Defibrillatorweste ("wearable cardioverter-defibrillator", WCD) : Verschreibung, Wirkweise und Nachsorge.

Assessment of a permanent risk of life-threatening ventricular arrhythmia in patients with severely reduced left ventricular ejection fraction (LVEF <35%), e. g. after myocarditis, dilated cardiomyopathy, acute myocardial infarction, in patients with postpartum cardiomyopathy or implantable cardioverter-defibrillator (ICD) and cardiac resynchronization treatment plus defibrillator (CRT-D) infection with temporary explantation of the system is a medical challenge. This is time-consuming and unsafe because life-threatening ventricular arrhythmias may occur during the time of risk assessment. During this phase of risk stratification, a wearable cardioverter-defibrillator (WCD) is indicated. The WCD, which is usually worn by the patient for several months, combines continuous retrievable electrocardiogram (ECG) recordings with a reliable defibrillation capability. The prescription of a WCD guarantees safe rehabilitation procedures for patients following acute inpatient treatment. Rehabilitation measures in patients with a WCD are indicated because of the underlying systolic cardiac insufficiency due to severe myocardial disease. In almost half of the patients, who are potentially threatened by ventricular tachyarrhythmias or sudden cardiac death (SCD), the LVEF and heart failure symptoms improve under controlled medication within a few months. Thus, the risk of SCD is lowered so that in many cases a first line ICD implantation is no longer necessary. The purpose of this article is to provide recommendations for rehabilitation procedures of patients with a WCD. A review of the currently available data on WCD publications was carried out with special emphasis on the current national and international guidelines.

[Aftercare of patients after MitraClip® implantation]. / Die Nachsorge von Patienten nach MitraClip®-Implantation.

Many patients with moderate to severe mitral regurgitation cannot be subjected to surgical therapy due to their multimorbidity. For these patients, MitraClip® implantation is a therapeutic alternative.The aim of this article is to present recommendations for treatment after a MitraClip® procedure. For this purpose, a selective literature review has been carried out based on the current literature, notably on national and international guidelines.After a MitraClip® procedure, rehabilitation is indicated because of the underlying heart failure as well as the treatment of a heart valve. Here, optimization of drug therapy, implementation of standardized heart failure training, the initiation of strength and endurance training and psychosocial support are initiated. Patients will be briefed on endocarditis prophylaxis lasting for at least six months. Furthermore, according to current guidelines, treatment with ACE inhibitors, beta-blockers and aldosterone antagonists are optimized. A special feature is anticoagulation, which is currently empirically accounted for and performed in sinus rhythm typically for four weeks of dual antiplatelet therapy (aspirin and clopidogrel) followed by a monotherapy with aspirin. In atrial fibrillation, lifelong oral anticoagulation is indicated combined with a platelet aggregation inhibitor for four weeks.In particular, echocardiographic control in the rehabilitation clinic and by cardiologists has to be focused on a residual atrial septal defect, the transmitral gradient and a residual mitral regurgitation.

Autophagy supports generation of cells with high CD44 expression via modulation of oxidative stress and Parkin-mediated mitochondrial clearance.

High CD44 expression is associated with enhanced malignant potential in esophageal squamous cell carcinoma (ESCC), among the deadliest of all human carcinomas. Although alterations in autophagy and CD44 expression are associated with poor patient outcomes in various cancer types, the relationship between autophagy and cells with high CD44 expression remains incompletely understood. In transformed oesophageal keratinocytes, CD44Low-CD24High (CD44L) cells give rise to CD44High-CD24-/Low (CD44H) cells via epithelial-mesenchymal transition (EMT) in response to transforming growth factor (TGF)-ß. We couple patient samples and xenotransplantation studies with this tractable in vitro system of CD44L to CD44H cell conversion to investigate the functional role of autophagy in generation of cells with high CD44 expression. We report that high expression of the autophagy marker cleaved LC3 expression correlates with poor clinical outcome in ESCC. In ESCC xenograft tumours, pharmacological autophagy inhibition with chloroquine derivatives depletes cells with high CD44 expression while promoting oxidative stress. Autophagic flux impairment during EMT-mediated CD44L to CD44H cell conversion in vitro induces mitochondrial dysfunction, oxidative stress and cell death. During CD44H cell generation, transformed keratinocytes display evidence of mitophagy, including mitochondrial fragmentation, decreased mitochondrial content and mitochondrial translocation of Parkin, essential in mitophagy. RNA interference-mediated Parkin depletion attenuates CD44H cell generation. These data suggest that autophagy facilitates EMT-mediated CD44H generation via modulation of redox homeostasis and Parkin-dependent mitochondrial clearance. This is the first report to implicate mitophagy in regulation of tumour cells with high CD44 expression, representing a potential novel therapeutic avenue in cancers where EMT and CD44H cells have been implicated, including ESCC.

Disruption of cytochrome c oxidase function induces the Warburg effect and metabolic reprogramming.

Defects in mitochondrial oxidative phosphorylation complexes, altered bioenergetics and metabolic shift are often seen in cancers. Here we show a role for the dysfunction of the electron transport chain component cytochrome c oxidase (CcO) in cancer progression. We show that genetic silencing of the CcO complex by shRNA expression and loss of CcO activity in multiple cell types from the mouse and human sources resulted in metabolic shift to glycolysis, loss of anchorage-dependent growth and acquired invasive phenotypes. Disruption of the CcO complex caused loss of transmembrane potential and induction of Ca2+/Calcineurin-mediated retrograde signaling. Propagation of this signaling includes activation of PI3-kinase, IGF1R and Akt, Ca2(+)-sensitive transcription factors and also TGFß1, MMP16 and periostin, which are involved in oncogenic progression. Whole-genome expression analysis showed the upregulation of genes involved in cell signaling, extracellular matrix interactions, cell morphogenesis, cell motility and migration. The transcription profiles reveal extensive similarity to retrograde signaling initiated by partial mitochondrial DNA depletion, although distinct differences are observed in signaling induced by CcO dysfunction. The possible CcO dysfunction as a biomarker for cancer progression was supported by data showing that esophageal tumors from human patients show reduced CcO subunits IVi1 and Vb in regions that were previously shown to be the hypoxic core of the tumors. Our results show that mitochondrial electron transport chain defect initiates a retrograde signaling. These results suggest that a defect in the CcO complex can potentially induce tumor progression.

Purification and characterization of an acidic trypsin/subtilisin inhibitor from tortoise egg white.

Egg whites of three species of tortoise and turtle have been compared by gel chromatography for inhibitory activity against proteases. The egg white of Geomyda trijuga trijuga Schariggar contains trypsin/subtilisin inhibitor while the egg white of Caretta caretta Linn. contains both trypsin and chymotrypsin inhibitors. No protease inhibitory activity has been detected in the egg white of Trionyx gangeticus Cuvier. An acidic trypsin/subtilisin inhibitor has been purified to homogeneity from the egg white of tortoise (G. trijuga trijuga). It is a single polypeptide chain of 100 amino acid residues, having a molecular weight of 11,700. It contains six disulphide bonds and is devoid of methionine and carbohydrate moiety. Its isoelectric point is at pH 5.95 and is stable at 100 degrees C for 4 hr at neutral pH. The inhibitor inhibits both trypsin and subtilisin by forming enzyme-inhibitor complexes at a molar ratio close to unity. Their dissociation constants are 7.2 x 10(-9) M for bovine trypsin and 5.5 x 10(-7) M for subtilisin. Chemical modification of amino groups with trinitrobenzene sulfonate has reduced its inhibitory activities against both trypsin and subtilisin, but the loss of its trypsin inhibitory activity is faster than that of its subtilisin inhibitory activity. It has independent binding sites for inhibition of trypsin and subtilisin.

LPS induction of gene expression in human monocytes.

Lipopolysaccharide (LPS [endotoxin]) is the principal component of the outer membrane of Gram-negative bacteria. Recent studies have elucidated how LPS is recognized by monocytes and macrophages of the innate immune system. Human monocytes are exquisitely sensitive to LPS and respond by expressing many inflammatory cytokines. LPS binds to LPS-binding protein (LBP) in plasma and is delivered to the cell surface receptor CD14. Next, LPS is transferred to the transmembrane signaling receptor toll-like receptor 4 (TLR4) and its accessory protein MD2. LPS stimulation of human monocytes activates several intracellular signaling pathways that include the IkappaB kinase (IKK)-NF-kappaB pathway and three mitogen-activated protein kinase (MAPK) pathways: extracellular signal-regulated kinases (ERK) 1 and 2, c-Jun N-terminal kinase (JNK) and p38. These signaling pathways in turn activate a variety of transcription factors that include NF-kappaB (p50/p65) and AP-1 (c-Fos/c-Jun), which coordinate the induction of many genes encoding inflammatory mediators.

Mitochondrial SOD2 regulates epithelial-mesenchymal transition and cell populations defined by differential CD44 expression.

Epithelial-mesenchymal transition (EMT) promotes cancer cell invasion, metastasis and treatment failure. EMT may be activated in cancer cells by reactive oxygen species (ROS). EMT may promote conversion of a subset of cancer cells from a CD44(low)-CD24(high) (CD44L) epithelial phenotype to a CD44(high)-CD24(-/low) (CD44H) mesenchymal phenotype, the latter associated with increased malignant properties of cancer cells. ROS are required for cells undergoing EMT, although excessive ROS may induce cell death or senescence; however, little is known as to how cellular antioxidant capabilities may be regulated during EMT. Mitochondrial superoxide dismutase 2 (SOD2) is frequently overexpressed in oral and esophageal cancers. Here, we investigate mechanisms of SOD2 transcriptional regulation in EMT, as well as the functional role of this antioxidant in EMT. Using well-characterized genetically engineered oral and esophageal human epithelial cell lines coupled with RNA interference and flow cytometric approaches, we find that transforming growth factor (TGF)-ß stimulates EMT, resulting in conversion of CD44L to CD44H cells, the latter of which display SOD2 upregulation. SOD2 induction in transformed keratinocytes was concurrent with suppression of TGF-ß-mediated induction of both ROS and senescence. SOD2 gene expression appeared to be transcriptionally regulated by NF-κB and ZEB2, but not ZEB1. Moreover, SOD2-mediated antioxidant activity may restrict conversion of CD44L cells to CD44H cells at the early stages of EMT. These data provide novel mechanistic insights into the dynamic expression of SOD2 during EMT. In addition, we delineate a functional role for SOD2 in EMT via the influence of this antioxidant upon distinct CD44L and CD44H subsets of cancer cells that have been implicated in oral and esophageal tumor biology.

Time course of dimension and function of the autologous pulmonary root in the aortic position.

Although the autologous, fully vital, and compatible pulmonary root theoretically offers the prospect of an ideal aortic valve substitute, this type of replacement is performed in only a few centers. Major concern relates to the fate of root dimension and function in the systemic circulation and is largely unknown. To investigate the fate of the aortic root, we conducted echocardiographic examinations of eight freestanding pulmonary roots used for aortic valve replacement in adults. The studies were performed at discharge from the hospital and up to 21 months (mean 12.5 +/- 6.6 months) after the operation, as well as in 26 matched control subjects. There were no significant differences between the first and second postoperative studies regarding the root diameter (mean 26.6 +/- 2.1 mm and 27.6 +/- 2.6 mm, respectively), which was within control limits, the maximum transvalvular pressure gradient (mean 4.6 +/- 1.2 mm Hg and 6.6 +/- 2.1 mm Hg, respectively), the maximum leaflet separation (mean 22.1 +/- 1.4 mm and 22.1 +/- 1.8 mm, respectively), and the degree of insufficiency. At the first study, grade I aortic regurgitation was found in four patients and grade I-II in one patient. Regurgitation increased slightly in one patient with an abnormal leaflet. In three patients primary grade I regurgitation disappeared. These data suggest that the pulmonary root in the aortic position can withstand systemic circulation without changes in dimension and function for up to 21 months. Furthermore, some evidence is provided to indicate that in certain cases the viable autograft may adapt to systemic pressure, as indicated by the disappearance of primary regurgitation.

Time course of lung function and exercise performance after heart transplantation.

To study the time course of exercise performance and the diffusion capacity after heart transplantation, we submitted two groups of patients to graded symptom-limited supine exercise. Patients in group 1 (n = 11) underwent operation 12.9 +/- 7.0 months before the study; those in group 2 (n = 10) underwent operation 53.9 +/- 14.8 months before the study. Respiratory and cardiovascular parameters were evaluated noninvasively at rest, at individual peak exercise, and 10 minutes later with a commercially available Sensormedics MMC 4400 metabolic measurement chart. Short-term survivors exhibited a lower maximum work capacity compared with that of long-term survivors (63.6 +/- 25.9 versus 100 +/- 50 W, p < 0.05), with a concomitant lower terminal heart rate (123 +/- 19 versus 137 +/- 17 beats/min, p < 0.05) that accounts for the lower cardiac output in this group, but statistical significance was not achieved (13.0 +/- 4.6 versus 17.5 +/- 6.3 L/min, not significant). Interestingly, significant differences were also observed for diffusion capacity before exercise (11.9 +/- 4.8 versus 19.3 +/- 7.3 ml/min/mm Hg, p < 0.05). The improvement of the diffusion capacity may be associated with a time-dependent change in the diffusion characteristics of the alveolocapillary membrane.

Possible involvement of central cholinergic-serotonergic interaction in natural sleep.

Administration of L-5-hydroxytryptophan (L-5-HTP) (200 mg/kg, p.o.) to adult male hamsters (110-120 g) increased non-rapid-eye-movement (NREM) as well as rapid-eye-movement (REM) sleep, with an increase of total sleep time. Methysergide (10 mg/kg, i.p.) facilitated REM sleep and inhibited NREM sleep. Both REM and NREM sleep disappeared with atropine (5 mg/kg, i.p.) both in absence and in presence of L-5-HTP (200 mg/kg, p.o.). Physostigmine (0.1 mg/kg, i.p.) increased REM sleep and decreased NREM sleep without altering the total sleep time. Co-administration of physostigmine (0.1 mg/kg, i.p.) and methysergide (10 mg/kg, i.p.) increased REM but blocked completely NREM sleep. These results suggest that the serotonergic system involved in REM sleep is regulated by the interaction of cholinergic receptor activity and the involvement of the cholinergic system in NREM sleep is regulated by the interaction of serotonergic receptor activity.

The experience of thought-disordered individuals preceding an aggressive incident.

The purpose of this qualitative study was to increase the understanding of the experiences of individuals with thought disorders, which precede incidents of aggression. Twelve individuals, from two hospitals, who had a nursing diagnosis of thought disorder and a history of aggression were interviewed, between one and four times, to collect baseline information and information about particular aggressive incidents. The participants described in their own words their thoughts, feelings and experiences preceding the aggressive incidents. Three themes emerged. First, participants perceived themselves to be strongly affected by the external environment; their responses to aspects of the environment were influential in precipitating the aggressive incident. Second, participants perceived themselves, paradoxically, to be both powerful and powerless; the act of aggression becomes an incident of brief self-empowerment. Third, the aggressive incident occurred in spite of the participants' acknowledgement and previous use of anger-controlling strategies; the participants' perceptions of themselves as powerless in an oppressive environment may have mitigated against the success of these strategies. Nurses need to know what triggers aggressiveness in psychiatric patients, in order to intervene effectively. Mental health professionals must also reexamine the psychiatric hospital environment, to make sure they are not needlessly exacerbating their patients' powerlessness with policies that are unjustifiably controlling.

MUC1-C oncoprotein activates the ZEB1/miR-200c regulatory loop and epithelial-mesenchymal transition.

The epithelial-mesenchymal transition (EMT) is activated in cancer cells by ZEB1, a member of the zinc finger/homeodomain family of transcriptional repressors. The mucin 1 (MUC1) heterodimeric protein is aberrantly overexpressed in human carcinoma cells. The present studies in breast cancer cells demonstrate that the oncogenic MUC1-C subunit induces expression of ZEB1 by a NF-κB (nuclear factor kappa B) p65-dependent mechanism. MUC1-C occupies the ZEB1 promoter with NF-κB p65 and thereby promotes ZEB1 transcription. In turn, ZEB1 associates with MUC1-C and the ZEB1/MUC1-C complex contributes to the transcriptional suppression of miR-200c, an inducer of epithelial differentiation. The co-ordinate upregulation of ZEB1 and suppression of miR-200c has been linked to the induction of EMT. In concert with the effects of MUC1-C on ZEB1 and miR-200c, we show that MUC1-C induces EMT and cellular invasion by a ZEB1-mediated mechanism. These findings indicate that (i) MUC1-C activates ZEB1 and suppresses miR-200c with the induction of EMT and (ii) targeting MUC1-C could be an effective approach for the treatment of breast and possibly other types of cancers that develop EMT properties.

Mitochondrial retrograde signaling induces epithelial-mesenchymal transition and generates breast cancer stem cells.

Metastatic breast tumors undergo epithelial-to-mesenchymal transition (EMT), which renders them resistant to therapies targeted to the primary cancers. The mechanistic link between mtDNA (mitochondrial DNA) reduction, often seen in breast cancer patients, and EMT is unknown. We demonstrate that reducing mtDNA content in human mammary epithelial cells (hMECs) activates Calcineurin (Cn)-dependent mitochondrial retrograde signaling pathway, which induces EMT-like reprogramming to fibroblastic morphology, loss of cell polarity, contact inhibition and acquired migratory and invasive phenotype. Notably, mtDNA reduction generates breast cancer stem cells. In addition to retrograde signaling markers, there is an induction of mesenchymal genes but loss of epithelial markers in these cells. The changes are reversed by either restoring the mtDNA content or knockdown of CnAα mRNA, indicating the causal role of retrograde signaling in EMT. Our results point to a new therapeutic strategy for metastatic breast cancers targeted to the mitochondrial retrograde signaling pathway for abrogating EMT and attenuating cancer stem cells, which evade conventional therapies. We report a novel regulatory mechanism by which low mtDNA content generates EMT and cancer stem cells in hMECs.

Caspase 2-mediated tumor suppression involves survivin gene silencing.

One of the pivotal functions of endogenous tumor suppression is to oppose aberrant cell survival, but the molecular requirements of this process are not completely understood. Here, we show that caspase 2, a death effector with largely unknown functions, represses transcription of the survivin gene, a general regulator of cell division and cytoprotection in tumors. This pathway involves caspase 2 proteolytic cleavage of the nuclear factor kappaB (NFkappaB) activator, RIP1. In turn, loss of RIP1 abolishes transcription of NFkappaB target genes, including survivin, resulting in deregulated mitotic transitions, enhanced apoptosis and suppression of tumorigenicity in vivo. Therefore, caspase 2 functions as an endogenous inhibitor of NFkappaB-dependent cell survival and this mechanism may contribute to tumor suppression in humans.

Physical properties of acetylated and enzyme-modified potato and sweet potato flours.

Textural profile, pasting behavior, gelatinization characteristics, sedimentation volume, and gel consistency of acetylated (Ac) and enzyme (glucoamylase)-modified (EM) potato and sweet potato flours have been investigated to determine their suitability in products such as baked goods, soup, and pudding. Dough hardness of Ac and EM samples was significantly higher than their native samples (P < 0.01). Dough cohesiveness of modified potato did not change, while it decreased in modified sweet potato. With increase in moisture, textural properties of modified samples, in general, showed reduced values. Rapid Visco Analyser showed least pasting viscosities of Ac flours due to restricted swelling of starch granules while EM flours exhibited high viscosities. Acetylated samples showed reduced gelatinization temperature (GT), and enthalpy (DeltaH) compared to native samples, whereas enzyme-treated samples showed no significant changes in GT, indicating their comparable crystallinity values with those of native samples. Modified flour samples had lower sediment volumes and gel consistency, and the gel consistency of EM flour correlated with its cold paste viscosity.

Tissue drug accumulation and ultrastructural changes during amiodarone administration in rats.

Pulmonary and hepatotoxicity are the two major side effects of chronic amiodarone therapy. We studied the accumulation of amiodarone and its principal metabolite, desethylamiodarone, in lung and liver of rats treated ip for 21 to 23 days with either 40 or 80 mg/kg/day amiodarone. The ultrastructural changes in liver, lung, and alveolar macrophages in saline controls and in rats on the two amiodarone dosage regimens were investigated. There was a dose-dependent increase in amiodarone and desethylamiodarone levels in serum and in tissues. The desethylamiodarone/amiodarone ratios in liver and lung, but not in serum, increased significantly with increasing dose. Serum also contained another metabolite, monodeiodinated desethylamiodarone. Increase in vacuolization and presence of whorled lamellar inclusion bodies in alveolar macrophages occurred with an increase in dose and higher lung amiodarone and desethylamiodarone levels. Electron microscopy of the liver of amiodarone-treated rats revealed the presence of large inclusion bodies partially filled with amorphous material in the cytoplasm. The quantitative relationship of the above changes to organ toxicity and to phospholipidosis that accompanies amiodarone administration remains to be established.

Amiodarone toxicity. II. Desethylamiodarone-induced phospholipidosis and ultrastructural changes during repeated administration in rats.

The contribution of desethylamiodarone (DEA), principal metabolite of the antiarrhythmic drug amiodarone, to the major side effects of amiodarone is unclear. The effects of repeated DEA administration to rats on tissue drug accumulation, ultrastructural changes, and phospholipid concentrations were studied. Two groups (n = 8/group) of male Sprague-Dawley rats (250 g body wt) were administered a 5% aqueous solution of DEA (Dose I, 40 mg/kg/day; Dose II, 60 mg/kg/day) intraperitoneally for 21-23 days, while a third group (control, n = 8) received saline. DEA levels were significantly higher with Dose II compared to Dose I in the lung, liver, kidney, spleen, heart, and serum while the tissue to serum ratios were similar with both doses for all tissues except the heart. DEA administration caused a significant elevation in the lipid phosphorus levels of liver, lung, and alveolar macrophages compared to control levels. A strong positive correlation (p less than 0.01) was found between tissue DEA levels and lipid phosphorus for the above tissues. Electron microscopy revealed the presence of lipid inclusion bodies in liver, lung, and alveolar macrophages of DEA-treated rats. A dose-dependent increase in the percentage of vacuolar surface area was found in the lung and alveolar macrophages. The tissue ultrastructural changes after repeated DEA dosing were qualitatively similar to our previous findings with amiodarone. Increased lung and liver phospholipid levels with repeated DEA doses may result from a potent inhibitory action of DEA on tissue phospholipase A as has been observed by others in in vitro studies.

Enzyme chemistry of dithiohemiacetals: synthesis and characterization of S-D-dithiomandeloylglutathione as an alternate substrate for glyoxalase I.

Both the D- and L-forms of S-dithiomandeloylglutathione (1) have been synthesized by a dithioester-interchange reaction between GSH and S-carboxy-methyl(D,L)-dithiomandelate. Kinetic and product analysis studies indicate that yeast glyoxalase I efficiently catalyzes the stereoselective conversion of D-1 to GSH-phenylglyoxal dithiohemiacetal (2), isolated as a disulfide adduct between 2 and a second molecule of GSH. This observation suggests that dithioester substrate analogues should be generally useful as mechanistic probes of enzyme catalyzed reactions involving thiohemiacetal intermediates.