Molecular Mechanisms of Inherited Ventricular Arrhythmias

Background: Inherited ventricular arrhythmias such as the long QT syndrome (LQTS), Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia (CPVT), idiopathic ventricular fibrillation (VF), and arrhythmogenic right ventricular cardiomyopathy (ARVC) account for a relevant proportion of sudden cardiac death cases in young patients cohorts. The detailed pathogenetic mechanisms of inherited ventricular arrhythmias are still poorly understood because systematic investigations are difficult to perform due to low patient numbers and the lack of appropriate experimental models. However, recent advances in research and science have identified a genetic background for many of these diseases. Present Knowledge: In LQTS, various mutations in different genes encoding for cardiac potassium and sodium channel proteins have been identified ("channelopathy"), and initial progress in genotype-phenotype correlation is made. Mutations in the cardiac sodium channel gene have also been identified in a subset of patients with Brugada syndrome, whereas a genetic background has not yet been demonstrated in idiopathic VF and right ventricular outflow-tract tachycardia (RVO-VT). Very recently, mutations in the cardiac ryanodine receptor gene have been identified in CPVT and in a subgroup of patients with ARVC. Although several chromosomal loci were suggested, no other responsible genes or mutations have been found in autosomal dominant forms of ARVC. However, in Naxos disease, a recessive form of ARVC with coexpression of palmoplantar keratoderma and woolly hair, a mutation in the plakoglobin gene has recently been discovered, thus underscoring the potential role of genetic alterations in cytoskeletal proteins in ARVC. Future Perspectives: In the next years, significant progress in the genetic diagnosis pathophysiologic understanding of disease mechanisms, genotype-phenotype correlation, and the development of gene- or target-directed treatment strategies can be expected in the field of inherited ventricular arrhythmias. Conclusion: This review summarizes the current knowledge of the molecular mechanisms, including aspects of pathoanatomy, autonomic innervation, genetics, and genotype-phenotype correlations with their potential implications for diagnosis and treatment of inherited ventricular arrhythmias. Hintergrund: Angeborene ventrikuläre Arrhythmien wie QT-Syndrom (LQTS), Brugada-Syndrom, katecholamingerge polymorphe ventrikuläre Tachykardie (CPVT), idiopathisches Kammerflimmern sowie arrhythmogene rechtsventrikuläre Kardiomyopathie (ARVC) sind wesentliche Ursachen plötzlicher Herztodesfälle bei jungen Patienten. Die detaillierten pathogenetischen Mechanismen sind bislang nur in Anfängen aufgeklärt, da bei geringen Patientenzahlen und fehlenden Tiermodellen systematische Untersuchungen erschwert sind. Dennoch konnten jüngste Fortschritte in klinischer und experimenteller Forschung neue Erkenntnisse zum genetischen Hintergrund angeborener ventrikulärer Arrhythmien beitragen. Aktuelle Erkentnisse: Bei LQTS wurden in den letzten Jahren zahlreiche Mutationen in verschiedenen Genen nachgewiesen, die für Proteine kardialer Kalium- und Natriumkanäle kodieren ("Ionenkanalerkrankung"). Auch wurden erste Ergebnisse bei der Genotyp-Phänotyp-Korrelation erzielt. Mutationen im kardialen Natriumkanalgen wurden auch beim Brugada-Syndrom nachgewiesen, während bei Patienten mit idiopathischem Kammerflimmern und rechtsventrikulärer Ausflusstrakttachykardie bislang keine genetischen Veränderungen gefunden werden. Kürzlich konnten Mutationen im Gen des kardialen Ryanodinrezeptors bei Patienten mit CPVT und einer Untergruppe der ARVC nachgewiesen werden. Dagegen konnte bei anderen Formen autosomal-dominant vererbter ARVC trotz Lokalisation mehrerer chromosomaler Loci bislang kein Gendefekt identifiziert werden. Bei der rezessiv vererbten Naxos-Erkrankung, einer Sonderform der ARVC mit Koexpression von palmoplantarer Keratose, wurde unlängst eine Mutation im Plakoglobingen nachgewiesen, wodurch die potentielle Rolle genetischer Veränderungen in zytoskelettären Proteinen bei ARVC unterstrichen wird. Perspektiven: Auch in den kommenden Jahren sind entscheidende Fortschritte in der genetischen Diagnostik, dem Verständnis pathogenetischer Mechanismen, der Genotyp-Phänotyp-Korrelation und der Entwicklung von gentyporientierten Therapiestrategien bei angeborenen ventrikulären Arrythmien zu erwarten. Schlussfolgerung: Diese Übersicht fasst den aktuellen Wissensstand der molekularen Mechanismen zusammen und diskutiert dabei Aspekte von Pathoanatomie, autonomer Innervation, Genetik, und Genotyp-Phänotyp-Korrelation mit ihren potentiellen Implikationen für die Diagnostik und Therapie angeborener ventrikulärer Arrhythmien.     

Endovascular treatment of unruptured intracranial aneurysms

BACKGROUND AND PURPOSE: Intracranial aneurysms are common, with an overall frequency ranging from 0.8% to 10%. Because prognosis after subarachnoid hemorrhage is still very poor, treatment of unruptured aneurysms, either neurosurgically or endovascularly, has been advocated. However, risk of rupture and subsequent subarachnoid hemorrhage needs to be considered against the risks of elective treatment. We analyzed the technical feasibility, safety, and efficacy of endovascular treatment of a consecutive series of unruptured cerebral aneurysms. METHODS: From July 1997 through December 2000, a total of 76 patients with 82 unruptured cerebral aneurysms were treated at our institution. Endovascular treatment was administered to 39 consecutive patients with a total of 42 unruptured cerebral aneurysms. Thirty-six aneurysms were treated with an endovascular technique; in six patients, the parent artery was occluded to eliminate aneurysmal perfusion. Aneurysms were located either in the anterior (n = 31) or posterior (n = 11) circulation. Eight patients had experienced previous subarachnoid hemorrhage from other aneurysms and were treated electively after complete rehabilitation. Ten patients had neurologic symptoms; in 21 patients, the aneurysm was an incidental finding. Eighteen aneurysms were small (0-5 mm), 11 were medium (6-10 mm), nine were large (11-25 mm), and four were giant (> 25 mm). Occlusion rate was categorized as complete (100%), subtotal (95-99%), and incomplete (< 95%) obliteration. RESULTS: Endovascular treatment was technically feasible for 38 of 42 aneurysms. Complete (100%) or nearly complete (95-99%) occlusion was achieved in 34 of 38 aneurysms. In four aneurysms of the internal carotid artery, only incomplete (< 95%) occlusion was achieved. All patients except one with mild neurologic deficits according to the Glasgow Outcome Scale and one with mild memory dysfunction but no focal neurologic deficit achieved good recovery, resulting in a morbidity rate of 4.8% and a mortality rate of 0%. CONCLUSION: Endovascular embolization of unruptured cerebral aneurysms is an effective therapeutic alternative to neurosurgical clipping and is associated with low morbidity and mortality rates. For the management of unruptured aneurysms, endovascular treatment should be considered.     

HERG potassium channels are constitutively expressed in primary human acute myeloid leukemias and regulate cell proliferation of normal and leukemic hemopoietic progenitors.

An important target in the understanding of the pathogenesis of acute myeloid leukemias (AML) relies on deciphering the molecular features of normal and leukemic hemopoietic progenitors. In particular, the analysis of the mechanisms involved in the regulation of cell proliferation is decisive for the establishment of new targeted therapies. To gain further insight into this topic we report herein a novel approach by analyzing the role of HERG K(+) channels in the regulation of hemopoietic cell proliferation. These channels, encoded by the human ether-a-gò-gò-related gene (herg), belong to a family of K(+) channels, whose role in oncogenesis has been recently demonstrated. We report here that herg is switched off in normal peripheral blood mononuclear cells (PBMNC) as well as in circulating CD34(+) cells, however, it is rapidly turned on in the latter upon induction of the mitotic cycle. Moreover, hergappears to be constitutively activated in leukemic cell lines as well as in the majority of circulating blasts from primary AML. Evidence is also provided that HERG channel activity regulates cell proliferation in stimulated CD34(+) as well as in blast cells from AML patients. These results open new perspectives on the pathogenetic role of HERG K(+) channels in leukemias.     

HERG potassium channels are more frequently expressed in human endometrial cancer as compared to non-cancerous endometrium

HERG K(+)channels, besides contributing to regulate cardiac and neuronal excitability, are preferentially expressed in tumour cell lines of different histogenesis, where their role in the development and maintenance of the neoplastic phenotype is under study. We show here that both herg gene and HERG protein are expressed with high frequency in primary human endometrial cancers, as compared to normal and hyperplastic endometrium. RT-PCR and immunohistochemistry, using specific anti-HERG antibodies developed in our laboratory, were applied to tissue specimens obtained from 18 endometrial cancers and 11 non-cancerous endometrial tissues. herg RNA and HERG protein are expressed in 67% and 82%, respectively, of cancerous, while in only 18% of non-cancerous tissues. In particular, no expression was found in endometrial hyperplasia. Moreover, electrophysiological experiments confirmed the presence of functioning HERG channels on the plasma membrane of tumour cells. On the whole, these data are the first demonstration of the presence of HERG channels in primary human neoplasias, and could candidate HERG as a potential tool capable of marking cancerous versus hyperplastic endometrial growth.     

Phrenic neuropathy in chronic renal failure.

BACKGROUND--Peripheral neuropathy and alterations in diaphragmatic muscle function are frequently caused by uraemia. Phrenic nerve function in patients with end stage renal failure, however, has not been examined to date. METHODS--An electrophysiological study of the phrenic nerve was performed to determine its possible involvement in 32 nondiabetic patients with end stage renal disease undergoing chronic haemodialysis. RESULTS--Seventeen patients had electrophysiological signs of peripheral neuropathy in at least one of the investigated nerves and 14 of the 17 showed pathological phrenic nerve latencies. Delayed phrenic nerve latencies correlated clearly with pathological peroneal nerve conduction velocities. CONCLUSIONS--Phrenic neuropathy is a frequent complication of uraemia.     

Vergleichende Untersuchungen über das Verhalten der Nierenfunktion bei Hochverdünnungsperfusionen mit Glucose,Hämaccel® und Rheomacrodex®

Ohne Zusammenfassung (a. G.)     

QUALITY CARE ASSESSMENT AND ASSURANCE

From its beginnings in 1955, the American College of Nurse-Midwives has supported the concept of Quality Care Assessment and Assurance (QCAA) and charged its members with responsibility to involve themselves in such activities within their practice. Six tools are reviewed that represent a sound basis for the development of QCAA programs within nurse-midwifery practice, the ultimate goal being the provision of optimal health care to women and the childbearing family.     

Scintigraphic molecular imaging

Modern medicine is currently focusing its basic and clinical research towards "molecular medicine". This trend, together with the decoding of the human genome and the resulting design and use of transgenic mouse models of human diseases, demands that innovative imaging approaches are developed for man and mice. Non-invasive imaging modalities capable of quantifying molecular processes in vivo (collectively defined as "molecular imaging" techniques) are extremely interesting in this respect. This review focuses on the clinical and experimental scintigraphic molecular-imaging modalities SPECT and PET, and summarizes their actual and future impact in medicine.     

Case report: successful interdisciplinary treatment of cerebrally disseminated invasive pulmonal aspergillosis in a child with acute myeloid leukemia

Invasive pulmonary aspergillosis (IPA) is a life-threatening infection in immunocompromised patients. Mortality rates of cerebrally disseminated IPA approach 100%. We report on a case of a 9-year-old girl with acute myeloid leukemia, who acquired cerebrally disseminated IPA during chemotherapy-induced leukopenia. Longtime survival was achieved by left pneumonectomy and neurosurgical resection of the intracerebral lesion combined with systemic application of itraconazole and liposomal amphotericin B. A review of literature revealed 7 other cases of cerebrally disseminated IPA with survival of more than 12 months.