Use of Paclitaxel-Coated Balloon Catheter Dilation to Reduce In-Stent Restenosis in Transjugular Intrahepatic Portosystemic Shunt (TIPS).

PURPOSE: Paclitaxel-coated balloons (PCB) inhibit neointimal proliferation in arteries. The purpose of this retrospective analysis was to investigate the effect of PCB in in-stent restenosis after transjugular intrahepatic portosystemic shunt (TIPS) in patients with cirrhotic liver disease. MATERIALS AND METHODS: Six patients (mean age: 65 ±â€Š10 years) with recurrent in-stent restenoses in TIPS (5 bare stents, 1 covered stent) underwent a single percutaneous transluminal angioplasty (PTA) with PCB (3 µg paclitaxel/mm(2)). Post-interventional outcome and patency were compared with those of prior plain optimal balloon angioplasty (POBA) in the same patients. During a two-year follow-up period, all patients underwent angiographic examinations at 6-month intervals. In-stent minimal lumen diameter (MLD) and late lumen loss (LLL) were assessed. Paclitaxel residues on balloon and sheath surfaces as well as venous plasma concentrations (0 - 24 hours) were analyzed. RESULTS: PCB decreased the need for clinically driven repeat PTA (POBA: 53 % of angiographic examinations; paclitaxel PTA: 19 %; P = 0.014). LLL/diameter stenosis was higher after POBA (2.4 ±â€Š1.5 mm/28 ±â€Š18 %) than after PCB (0.5 ±â€Š0.8 mm/7 ±â€Š11 %, P = 0.029). Residual paclitaxel on balloons was 28 ±â€Š9 % of dose and 0.2 ±â€Š0.1 % on sheath surfaces. Paclitaxel plasma concentrations were below detectable levels throughout the first 24 hours after the interventions in all patients. The procedure was well tolerated and no clinical side effects attributable to paclitaxel were observed. CONCLUSION: In patients with recurrent in-stent stenoses, a single PTA with PCB resulted in a prolonged secondary patency due to pseudointimahyperplasia without a systemic effect of paclitaxel. KEY POINTS: •Intimahyperplasia is a common reason for long-time TIPS dysfunction. •First-in-man local paclitaxel application in TIPS patients with recurrent in-stent stenoses. •PTA with PCB resulted in a prolonged secondary patency compared to POBA. •No systemic effects of Paclitaxel were detected.

Review of clinical data with Paccocath- coated balloon catheters.

The use of drug-coated balloons (DCB) for preventing restenosis in both coronary and peripheral arteries has received increasing attention. The first successful clinical outcomes in inhibiting restenosis have been reported for paclitaxel-coated balloons. Paclitaxel is a lipophilic substance characterized by rapid intracellular uptake and irreversible binding to microtubules. In this way, paclitaxel alters the cell structure, ultimately reducing proliferation, migration, and signaling. These properties make paclitaxel a very potent antiproliferative drug. Paclitaxel admixed to a small amount of the hydrophilic X-ray contrast medium iopromide (Ultravist™) emerged as a very effective coating matrix from numerous in vitro and in vivo experiments and has been denoted as Paccocath™. The randomized controlled ISR I/II-, Thunder- and FEMPAC studies have been conducted using Paccocath™ balloons. Late lumen loss as the primary endpoint at 6 months proved to be statistically significantly reduced in the coated balloon groups in coronary and peripheral arteries. The slightly modified coating on the SeQuent™ Please balloons (B.Braun, Melsungen, Germany) has been clinically studied in the PEPCAD (Paclitaxel-Eluting PTCA-Catheter in Coronary Artery Disease) clinical trial program. Cotavance™ balloons (MEDRAD Inc, Minneapolis, USA) are also coated with the Paccocath™ formulation. In this review we first outline the development of Paccocath™ balloons to then provide an overview of the clinical results obtained with the modified coating. Furthermore we examine possible mechanism of action by which single administration of an antiproliferative drug dose using paclitaxel-coated balloons inhibits restenosis.

Contemporary issues in cardiac pacing.

This article addresses current pacing practices and issues. Pacing, sensing, sensing amplifiers, and pacing leads are discussed. Cardiac resynchronization is reviewed. Issues of ventricular pacing avoidance, pacemaker lead infections, ionizing radiation effects on pacing and pacing issues after deterioration and expiration of the patient are considered.

Paclitaxel-coated balloons - Survey of preclinical data.

Restenosis following interventions in the coronary or peripheral arteries develops over weeks to months. In coronary arteries the restenosis rate has been markedly reduced since the advent of drug-eluting stents. Non-stent-based methods for local drug delivery enable restenosis inhibition without the need for stent implantation, does not permanently change the structure of the vessel, are repeatable, and seems to be applicable where drug-eluting stents provide insufficient protection. Preclinical data indicate that short exposure of the vessel wall to a lipophilic inhibitor of cell proliferation is sufficient for preventing restenosis. Initial evidence to this effect emerged from an investigation of paclitaxel embedded in a matrix that enhances the solubility and release of the agent from the balloon coating as well as its transfer to the vessel wall. Further corroborating data from preclinical and clinical studies demonstrating a reduction in late lumen loss and lower restenosis rates led to the market introduction of a variety of paclitaxel-coated angioplasty balloons. The effectiveness of restenosis inhibition is not determined by the active agent alone. Other factors that are crucial for the effectiveness and safety of drug-coated angioplasty balloons are the formulation containing the agent and the coating technique. In this review we first outline the development of paclitaxel-coated balloons to then provide an overview of the preclinical results obtained with different paclitaxel-coated balloons and finally compare these with the outcome in patients. The article concludes with a short outlook on initial results with a zotarolimus-coated angioplasty balloon.

Advances on drug-coated balloons.

During the last decades considerable advances have been made in intravascular interventions for the treatment of coronary and peripheral arterial disease. However, long-term outcome remains an area of concern in many applications. Restenosis is still a challenge in endovascular medicine and has thus been referred to as the Achilles' heel of percutaneous intervention. Therefore, novel strategies have been developed to overcome this problem. These include drug-eluting stents, though still associated with stent thrombosis and in-stent restenosis, and the more recently introduced non-stent based local drug delivery systems, especially the paclitaxel-eluting balloon. Results of several preclinical and clinical studies indicate that short-term exposure of injured arteries to paclitaxel eluted from regular PTA and PTCA balloons may be sufficient to reduce late lumen loss and restenosis rates during a critical period of time after angioplasty of diseased coronary and peripheral arteries. Although the number of published trials and patients treated is still limited, available data seem to prove that restenosis inhibition by immediate drug release is feasible. This article reviews the rationale for the use of paclitaxel-coated balloons, data from preclinical and clinical studies, and the perspective of drug-coated balloons in peripheral arterial disease.

[The occurrence of hemodynamic effective elements in the intestinal blood vessel system]. / Uber das Vorkommen hämodynamisch wirksamer Elemente im intestinalen Blutgefässsystem.

Arterioles, precapillary sphincters, capillary endothelium, and pericytes probably regulate the blood flow in the intestinal microvascular bed similar to other regions of the body because of their equipment with contractile filaments. Only throttle veins with their arrangement of pools and their characteristics probably exert influence on the hemodynamic qualities of the blood flow in the intestinal mucosa.

[The alimentary canal of the Siberian chipmunk (Eutamias sibiricus, Laxm. 1769): macroscopic and light microscopic examination]. / Der Rumpfdarm des Burunduk (Eutamias sibiricus, Laxm. 1769): makroskopische und lichtmikroskopische Untersuchungen

The canalis alimentarius of the Burunduk (Eutamias sibiricus), a rodent belonging to the family Sciuridae, were examined macroscopically (12 animals) and light microscopically (three animals). The esophagus is lined with a stratified non-keratinized squamous epithelium. The one-chambered stomach is of a simple type covered with a glandular mucous membrane. When empty and moderately filled, the stomach looks like a curved sack and lies intrathoracally. The filled stomach extends to the left and ventrally into the regio abdominis media. The greater omentum covers incompletely ventrally and in a part laterally the intestinal mass. The intestinal canal averages about 780 mm in length, that is 6.5 as long as the whole body. The relative length of the small intestine compared with the large intestine is 36-64%. The U-shaped Duodenum is composed of a Pars cranialis, descendens and ascendens and possesses a Plica duodenocolica as well as a Plica duodenocolica accessoria. The Jejunum averages about 420 mm length and is mainly located in the right and ventral part of the regio abdominis media. As in other rodents, the cecum is well developed. The length of the ascending colon averages about the body length and forms an Ansa proximalis and two parallel loops, Ansa media and Ansa distalis coli, both lying in the right Cavum abdominis. Peculiar for the colon are Noduli lymphatici solitarii surrounding cavities lined by a surface epithelium. According to the anatomical structure of the gut and based on physiological diet facts the Burunduk is not a mere herbivore but has to be classified as an omnivore depending upon uptake of animal food protein.

[Structure of infrapatellar synovial ligament in dogs]. / Struktur des Ligamentum synoviale infrapatellare beim Hund.

The knee joint of the dog is frequently the subject of surgery if the cruciate ligaments or the menisci are injured. In the knee joint of the dog we find a ligament, which is spread out between the anterior part of the fossa intercondylaris ossis femoris and the corpus adiposus infrapatellaris. This ligamentum synoviale infrapatellare has not previously been described and represents a homologous structure to the plica synovialis infrapatellaris of human knee joint. Just like the latter and just like the cruciate ligaments it is a rudiment of a septum articulare genu, which is spread out between an articulatio femorotibialis and an articulatio femorofibularis in the early phylogenesis of tetrapods. The ligamentum synoviale infrapatellare of the dog consists of a stratum synoviale and a stratum spinosum, which includes blood vessels, nerves, many collagenous fibres and some elastic fibres. We do not find evidence for sensory nerve endings or corpuscular receptors. Therefore a servering of the ligament during knee joint surgery does not affect the proprioceptive potential of the knee joint.

Electron-microscopic detection of cytoskeletal actin in the epithelial cells of bovine abomasum.

The fine structural distribution of cytoskeletal actin was investigated in the oxyntic gland region and in the pyloric gland region of bovine abomasal mucosa using immunoelectron methods. In all exocrine cell types of the gastric epithelium, actin filaments exhibit a polarized pattern of distribution. In the members of the mucus- and protein-synthesizing cell line, the actin filaments form a prominent barrier to the exocytosis of secretory granules underneath the apical membrane. Therefore, actin is supposed to be involved in the control of exocytosis. The basolateral subplasmalemmal cortex of the exocrine cells, however, shows weaker labeling for actin filaments. In this position actin might be responsible for the movement of epithelial cells along the length of the gastric gland during physiological cell renewal and for the maintenance of the integrity of the epithelial unit and of cell polarization. In parietal cells of bovine abomasum, actin filaments are, in addition, associated with the intracellular canaliculus, but not with the tubulovesicular compartment. We assume that actin filaments reorganize the canalicular membrane after membrane translocations in the course of acid secretion. For the first time, actin filaments were documented in the rare brush cell type of bovine abomasum, where they do not form a terminal web beneath the apical membrane and therefore point out the nonexocrine function of the brush cell type. In all polarized cells of the bovine abomasum, actin filaments underlay the two apical members of the junctional complex, the tight junction and the adherens junction, where they might be involved in the regulation of cell adhesion, cell motility and cell shape determination.

[Intraepithelial nerve endings in the lingual marginal papillae of newborn piglets]. / Intraepitheliale Nervenendigungen in den Zungenrandpapillen neugeborener Ferkel.

The structure and occurrence of nerve fibres and nerve terminals in the lingual marginal papillae of newborn piglets are investigated by means of the osmium-zinc-iodate method and by transmission-electron microscopy. Subepithelial nerve fibres primarily accompany the blood vessels. They cross the epithelium with an almost vertical course to terminate in the stratum superficiale or the stratum corneum. Due to rows of varicosities, the axons look like a 'string of pearls'. As a result of the superficial localization and the typical ultrastructure, they seem to have a sensory function. Therefore, the papillae marginales are considered to function as mechanoreceptors.

[Age-dependent changes in the sub-epithelial blood supply to the bovine rumen]. / Altersabhängige Veränderungen an den subepithelialen Blutgefässen des Pansens vom Rind.

Qualitative age-related changes in the structure and the position of subepithelial blood vessels in the bovine atrium ruminis were investigated on the electron microscopical level in 39 fetal, peri- and postnatal individuals as well as in adult animals of different ages. Standardized morphometrical methods were applied and the data were statistically evaluated. The distance between epithelium and capillary endothelium, the endothelial fenestration and the thickness of the endothelial wall as well as the endothelial-epithelial exchange sectors facing each other were distinctly a function of age. Crucial changes of these parameters were either finished until the sixth postnatal month and were pronounced during the period of feeding adaptation from milk to roughage or were not markedly influenced during this period. The degree of endothelial vesiculation showed individual variations but was not a function of age or feeding regime.

Cytoarchitecture of the bovine pyloric epithelium during early ontogenesis.

The cytoarchitecture of the pyloric gland region in the early ontogeny of the bovine abomasal mucosa was investigated using light and transmission electron microscopic methods. Two cell types are involved in forming the lamina epithelialis in the youngest fetus with a 24 mm crown-rump-length (CRL): the indifferent cell and the endocrine cell. With a CRL of 71 mm, two other cell types occur, the granule-containing cell and the brush cell. The indifferent cell represents the first stem cell, which develops into the secretory granule-containing cell type. This seems to be the secondary stem cell lining the top of the epithelium as well as the base of the primitive epithelial tubes, and it differentiates into the surface mucous cell and the pylorocyte. Endocrine cells appear as open and closed types and represent the most differentiated cells already present in the youngest specimen in this investigation. The most rare cell type, the brush cell, appears in the bovine abomasal ontogeny much earlier than in other mammalian species.

[Morphology of the marginal lingual papillae in newborn piglets]. / Zur Morphologie der Zungenrandpapillen neugeborener Ferkel.

The morphology of the marginal lingual papillae in eight newborn pigs aged 1-5 days was examined at the light-microscopical level, as well as, for the first time, using electron transmission and scanning methods. The papillae marginales are arranged tuft-like or rosetted with chief and accessory papillae, the individual papillae varying considerably in shape. Leaf-, tongue- or fingerlike and conical shapes predominate. The stratified squamous epithelium is either keratinized, resembling the epidermal differentiation pathway, or non-keratinized, according to the mucosal pathway. The characteristic morphology of keratinocyte differentiation is shown with special reference to the establishment of the permeability barrier. The connective tissue papillae are intensively surface-enlarged by means of multiple fingerlike protrusions.

[Architecture and fine structure of the terminal blood vessels in the marginal papillae of the tongue in newborn piglets]. / Architektur und Feinstruktur der terminalen Blutgefässe der Zungenrandpapillen neugeborener Ferkel

The vascular architecture of the marginal papillae of the tongue was examined in one to five day old piglets by means of light and transmission electron microscopy and scanning microscopy of vascular corrosion casts. The marginal papillae of the tongue exhibit a "rope ladder-like" principle of blood supply. Every papilla contains one ascending arteriole, which branches into single capillary loops each supplying a protrusion of the multiply branched base of the capillary body. The transition of the arteriole takes place on the tip of the papilla. Subsequently the capillary loops converge onto this venule. Precapillary sphincters are observed at the origin of the capillary loops. This type of vessel arrangement offers the opportunity to use the capillary system at maximum efficiency, thus allowing an erection of the papillae marginales during the process of suckling.

[The spermathecal epithelium of the queen bee (Apis mellifera): morphology, age-dependent changes and cell contacts]. / Das Spermathekalepithel der Bienenkönigin (Apis mellifera): Morphologie, altersabhängige Veränderungen und Zellkontakte.

The spermatheca of the honey bee queen is covered by a single-layered, uniform, polarised epithelium. The apical cell surface is greatly enlarged by protrusions and plasma membrane infoldings, the basal cell surface by numerous interdigitating, long, small processes. Cytoplasmic organelles are chiefly represented by mitochondria. Numerous microtubuli extend throughout the cytoplasm. Golgi and endoplasmic profiles are rare. The cells are subject to senile degeneration: with increasing age, a variety of cytoplasmic inclusions appear, among which are myelinated membranes, dense bodies and dense filamentous aggregates. The spermathecal epithelium does not seem to be involved in exocrine secretion related to nutrition of the long-term stored spermatozoa. The ultra-structure points, however, to ion transport functions and to an engagement in the maintenance of an adequate physicochemical environment ensuring the viability of the spermatozoa. Cellular junctions are represented by luminal zonulae adherentes, focal cell-cell adhering junctions and hemiadhering junctions along the basal plasmalemma. Desmosomal contacts and cytoskeletal intermediate filaments are missing. Along the lateral plasmalemma, gap junctions and septate junctions are found.

Differentiation of oxyntic cells during early ontogenesis in the bovine.

The origin and the differentiation of oxyntic cells in fetal bovine abomasum were investigated using transmission electron and light microscopic methods. In the oxyntic gland region oxyntic cell precursors and immature oxyntic cells appear as early as at the end of the first trimester of gestation--much earlier than described in any other mammalian animal species. Immature oxyntic cells are characterized by long apical microvilli, by their triangular-shaped light cytoplasm rich in large and numerous mitochondria, by the existence of vesicular profiles and by the incipient invagination of the apical plasma membrane forming a primitive intracellular canaliculus expanding into central areas of the cell. The oxyntic cell represents the first exocrine cell type developing from secretory granule-containing cells in the base of the primitive gastric glands.

[The vascular system of the intestines of Gallus domesticus]. / Das Blutgefässsystem des Darmes von Gallus domesticus.

The vascular system of the chicken intestine was investigated by corrosion cast, light and electron microscopic methods. In the intestinal villi the "Fontainentyp" is present with a single arteriole rising to the apex and draining into subepithelial capillaries. Occasionally ramifications of the arteriole occur in the upper third of the villi. Another variation is splitting of the arteriole into a capillary net at the base of the villi in the caeca between the regions with and without villi. At the tip, at the margins and at the base of the villi the capillaries fuse into venules, which proceed to the inside and empty into veins. At the base above the propria they form a superficial net with connecting veins arising to an inferior venous plexus below the region of crypts. The submucosal collecting veins descend from short vascular truncs, which originate from the inferior plexus and cross the muscularis mucosae. Elements of a vasoregulatory system like arterio-venous marginal loops, submucosal arterio-venous anastomoses, sphincter-arteries, precapillary sphincters and sphincter-veins well known in the literature are not found in the intestine of the domestic chicken. Therefore arterioles, capillaries and muscle bundles concentric around the veins in the villi seem to take over this function.

Actin filaments in the ruminal epithelium of cattle.

Phalloidin and immunogold labeling were used to localize actin filaments in the ruminal pilar epithelium of adult cattle on the light and electron microscopic level. Incubation with rhodaminyl-phalloidin permitted an overview of general actin distribution pattern. Distinct subcellular localization of actin was revealed with the biotin-streptavidin bridge technique in a postembedding procedure. Superior fixation of membranes and filaments was achieved with tannic acid-glutaraldehyde. Surface-etching prior to immunoincubation ensured restoration of actin immunoreactivity. Patterns of distribution in non-keratinized and keratinized epithelial cells as well as in pericytes and endothelial cells point to cell-specific cytoskeletal and motile functions of actin filaments.

Ca2+-ATPase in mucous and oxyntico-peptic cells of the fowl proventriculus.

Calcium adenosine triphosphatase (Ca(2+)-ATPase) was localized by means of histo-and ultracytochemistry in the secretory cells of the proventriculus of the domestic fowl. The mucous cells exhibited plasmalemmal-associated enzyme activity on the external aspect of the basolateral cell membrane. Intracellularly, the luminal aspect of Golgi-membranes and of secretory vesicle membranes reacted positively for Ca(2+)-ATPase activity, as did the apical cytosol and the matrix of lysosomes. Oxyntico-peptic cells were characterized by apical and apico-lateral plasmalemmal activity and by an organelle-associated distributional pattern similar to that in the mucous cells. In addition, Ca(2+)-ATPase was associated either with the matrix of mitochondria or with tubuli of the rough-surfaced endoplasmic reticulum. The results are discussed with respect to messenger and effector functions of calcium in the process of proventricular mucus secretion. In addition, Ca(2+)-ATPase distributional patterns in the oxyntico-peptic cell are related to the unique structure and function of these cells.

[Differentiation of the ruminal epithelium of cattle during intrauterine development]. / Differenzierung des Pansenepithels des Rindes während der intrauterinen Entwicklung.

The prenatal development of the bovine ruminal epithelium was studied with light- and electronmicroscopical techniques. During the period of the nonstratified epithelium a pseudostratified epithelium is found in the dorso-cranial part, whereas the other areas possess a one-layered epithelium, which is, like the pseudostratified epithelium, transformed to a multilayered epithelium from the 7th week onwards. From the 9th week the period of the stratified epithelium starts with the formation of the stratum profundum and stratum superficiale. First signs of keratinization are seen in the superficial cells from 2.3 months onwards. With 4 months fetal cornified cells can be identified, with 5.5 months a single-layered stratum basale is seen on the differentiating papillar connective tissue, and the superficial cells are transformed to balloon-cells. In suprapapillar areas, a stratum spinosum is formed at the prenatal age of 7.5 months. During epitheliogenesis a horizontal and vertical differentiation of the cells can be observed. The first one includes the differentiation of undifferentiated, embryonal cells to the basal cells of the stratum profundum, the latter the development of the basal cells to spinous cells and then to fetal cornified and balloon-cells. The ultrastructural changes during the process of keratinization were especially considered.