Adenom des pigmentierten Ciliarepithels

Zusammenfassung Ein solides Adenom des pigmentierten Ciliarepithels wurde durch 9,0×6,0 mm Blockexcision entfernt (postoperativer Visus 1,0). Der pechschwarze Tumor mit einer samtartigen Oberfläche besteht aus sehr großen mit Melaningranula vollgepackten Zellen. Die Melaningranula weisen eine abnorm und variable Pigmentdichte, innere Struktur und Größe auf. Auffallend sind intracytoplasmatische Vacuolen mit Mucopolysacchariden insbesondere Sialomucinen. Die Literatur über Tumoren des pigmentierten Ciliarepithels wird gesichtet. Kriterien für die Unterscheidung zwischen Adenomen bzw. Adeno-'Carcinomen (8 Fälle, alle ohne Metastasen) und reaktiven Hyperplasien (6 Fälle) werden ausgearbeitet und vorgeschlagen. Die histologischen, histochemischen und elektronenmikroskopischen Befunde des vorgestellten Tumors des pigmentierten Ciliarepithels stimmen auffallend mit denen eines Adenoms des retinalen Pigmentepithels überein.

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Adenoma of the pigmented ciliary epithelium

Summary A solid adenoma of the pigmented ciliary epithelium was removed by 9.0×6.0mm block-excision (postoperative visual acuity 1.0). The black lesion with a velvety surface consists of very large cells packed with melanin granules of abnormal and variable density, structure and size. Striking intracellular vacuoles contain acid mucopolysaccharides, particularly sialomucins.The literature on tumors of the pigmented ciliary epithelium is reviewed. Criteria for the separation of adenomas for adeno-carcinomas (8 cases, all without metastases) from reactive hyperplasia (6 cases) are proposed. The histologic, histochemical and electronmicroscopic findings of our tumor show striking similarities to those of an adenoma of the retinal pigment epithelium.

     

Molecular determinants of angiotensin II type 1 receptor functional selectivity

The angiotensin AT₁ receptor is an important pharmacological target in the treatment of cardiovascular disorders, such as hypertension, diabetic nephropathy, cardiac hypertrophy, arrhythmia and failure. Simultaneously, the AT₁ receptor has emerged to be a prominent model for the emerging concept that receptors may attain multiple active states with differentiated functional outcomes. Two major signalling pathways are employed by the AT₁ receptor, namely 1) the canonical G_q protein-dependent activation of inositol phosphate turnover and intracellular calcium release, and 2) G protein-independent recruitment of β-arrestin-scaffolded signalling complexes that activate protein kinase pathways. Different states of receptor activation with preference for individual downstream pathways (functional selectivity) have been demonstrated in mutational studies of the AT₁ receptor and by pharmacological probing with analogues of angiotensin II. These studies also provide clues about the conformational changes that underlie different functional outcomes. In this review, we evaluate current knowledge of the molecular determinants of AT₁ receptor activation, which may distinguish G protein-dependent and -independent behaviour. While G protein activation is known to be detrimental, G protein-independent signalling by the AT₁ receptor has been associated with phenotypes such as cell survival and renewal, regulation of cardiac contraction and cell migration. It is therefore currently hypothesized that selective blockade of G protein actions and simultaneous activation of G protein-independent signalling will prove to be a feasible strategy for improved cardiovascular therapy. The pharmacological perspectives of functional selectivity by receptors, such as the AT₁ receptor, urge the elucidation of molecular mechanisms that govern disparate signalling events.     

Idiopathische generalisierte Epilepsien und Fotosensitivität

Idiopathic/genetic epilepsies (IGE/GGE) represent a large group among epilepsies of childhood and adolescence. The typical subtypes, childhood and juvenile absence epilepsy, juvenile myoclonic epilepsy, and epilepsy with generalized tonic–clonic seizures on awakening, showed a favourable psychosocial outcome in the majority of cases. They can be treated with valproic acid and ethosuximide as first-line medication, and levetiracetam, lamotrigine, topiramate and perampanel. Each subtype of IGE/GGE is defined by its specific age of onset (childhood or adolescence) and type of generalized seizures, typical findings on the EEG, a normal cerebral MRI and often normal psychomotor development. In the underlying cause of these epilepsies complex genetic defects are believed to play a major role, namely structural genetic variation. For example, copy number variations in loci 15q13.3, 15q11 and 16p13 could be identified as one risk factor. Mutations in calcium channel genes (namely T-type calcium channel, CACNA1H, and P/Q-type calcium channel, CACNAB4 and CACNA1A) seem to take part in the pathomechanism of IGE. Monogenetic defects are seldom found to be the main cause of epilepsy. These monogenetic defects, mainly in the GABA_A-receptor- and GLUT1 genes (SLC2A1), are often associated with other symptoms such as ataxia, movement disorders and mental retardation.Photosensitivity is often seen in IGE, but can also occur without IGE. A genetic cause is also assumed; one of the most important candidate genes is CHD2.     

Voltage-sensor sodium channel mutations cause hypokalemic periodic paralysis type 2 by enhanced inactivation and reduced current

The pathomechanism of familial hypokalemic periodic paralysis (HypoPP) is a mystery, despite knowledge of the underlying dominant point mutations in the dihydropyridine receptor (DHPR) voltage sensor. In five HypoPP families without DHPR gene defects, we identified two mutations, Arg-672-->His and -->Gly, in the voltage sensor of domain 2 of a different protein: the skeletal muscle sodium channel alpha subunit, known to be responsible for hereditary muscle diseases associated with myotonia. Excised skeletal muscle fibers from a patient heterozygous for Arg-672-->Gly displayed depolarization and weakness in low-potassium extracellular solution. Slowing and smaller size of action potentials were suggestive of excitability of the wild-type channel population only. Heterologous expression of the two sodium channel mutations revealed a 10-mV left shift of the steady-state fast inactivation curve enhancing inactivation and a sodium current density that was reduced even at potentials at which inactivation was removed. Decreased current and small action potentials suggested a low channel protein density. The alterations are decisive for the pathogenesis of episodic muscle weakness by reducing the number of excitable sodium channels particularly at sustained membrane depolarization. The results prove that SCN4A, the gene encoding the sodium channel alpha subunit of skeletal muscle is responsible for HypoPP-2 which does not differ clinically from DHPR-HypoPP. HypoPP-2 represents a disease caused by enhanced channel inactivation and current reduction showing no myotonia.