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A blockade of CD44 can interfere with haematopoietic and leukemic stem cell homing, the latter being considered as a therapeutic option in haematological malignancies. We here aimed to explore the molecular mechanism underlying the therapeutic efficacy of anti-CD44. We noted that in irradiated mice reconstituted with a bone marrow cell transplant, anti-CD44 exerts a stronger effect on haematopoietic reconstitution than on T lymphoma (EL4) growth. Nonetheless, in the non-reconstituted mouse anti-CD44 suffices for a prolonged survival of EL4-bearing mice, where anti-CD44-prohibited homing actively drives EL4 cells into apoptosis. In vitro, a CD44 occupancy results in a 2–4-fold increase in apoptotic EL4 cells. Death receptor expression (CD95, TRAIL, TNFRI) remains unaltered and CD95 cross-linking-mediated apoptosis is not affected. Instead, CD44 ligation promotes mitochondrial depolarization that is accompanied by caspase-9 cleavage and is inhibited in the presence of a caspase-9 inhibitor. Apoptosis becomes initiated by activation of CD44-associated phosphatase 2A (PP2A) and proceeds via ERK1/2 dephosphorylation without ERK1/2 degradation. Accordingly, CD44-induced apoptosis could be mimicked by ERK1/2 inhibition, that also promotes EL4 cell apoptosis through the mitochondrial pathway. Thus, during haematopoietic stem cell reconstitution care should be taken not to interfere by a blockade of CD44 with haematopoiesis, which could be circumvented by selectively targeting leukemic CD44 isoforms. Beyond homing/settlement in the bone marrow niche, anti-CD44 drives leukemic T cells into apoptosis via the mitochondrial death pathway by CD44 associating with PP2A. Uncovering this new pathway of CD44-induced leukemic cell death provides new options of therapeutic interference.

Autosomal recessive spinal muscular atrophy with respiratory distress type 1 (SMARD1), recently referred to as distal spinal muscular atrophy 1 (DSMA1; MIM#604320) and also known as distal hereditary motor neuropathy type 6 (dHMN6 or HMN6), results from mutations in the IGHMBP2 gene on chromosome 11q13.3 encoding the immunoglobulin µ-binding protein 2. In contrast to the infantile spinal muscular atrophy type 1 (SMA1; Werdnig-Hoffmann disease) with weakness predominantly of proximal muscles and bell-shaped thorax deformities due to intercostal muscle atrophy, infants with distal spinal muscular atrophy 1 usually present with distal muscle weakness, foot deformities, and sudden respiratory failure due to diaphragmatic paralysis that often requires urgent intubation. In this article, the authors review the clinical, neuropathological, and genetic aspects of distal spinal muscular atrophy 1 and discuss differential diagnoses.

In this article, we review the clinical, neuropathological and genetic aspects of distal spinal-muscular atrophy 1 (DSMA1; MIM#604320), formerly designated as autosomal recessive spinal muscular atrophy with respiratory distress type 1 (SMARD1) and also known as distal hereditary-motor neuropathy type 6 (dHMN6 or HMN6).

In the context of a larger clinical study in Nouna, Burkina Faso, we evaluated a simplified dual-platform (DP) flow cytometric (FCM) method that allows the determination of major lymphocyte subsets in a single test tube. We compared the phenotyping of lymphocytes with DP FCM and simultaneous measurements with standard single-platform (SP) FCM for samples from 177 individuals. Analysis of the comparative measurements revealed that DP FCM systematically underestimates the proportion of NK cells, overestimates the percentage of CD3 + CD8 + lymphocytes, and yields proportions of B cells and CD4 + T cells comparable with the results from SP FCM. Bland-Altman analysis showed a low bias between both methods and an acceptable precision for percent values of CD4 + T cells (bias ± precision, −1% ± 6%) and CD8 + T cells (−3% ± 6%). The absolute cell numbers of all lymphocyte subpopulations, however, were systematically biased towards lower values being obtained by DP FCM. Reference values for the distribution of T-cell maturation phenotypes in 177 healthy adults were calculated using DP FCM. The mean ± standard deviation (SD) CD4 + -to-CD8 + T-cell ratio was 1.61 ± 0.61, the mean percentage ± SD of CD4 + T cells was 42% ± 7%, and that of CD8 + T cells 29% ± 7%. Among CD4 + lymphocytes, 28% ± 7% were classified as central memory (CD45RA low CCR7 + ), 22% ± 10% as naïve (CD45RA high CCR7 + ), 45% ± 12% as effector memory (CD45RA low CCR7 − ); and 5% ± 3% as terminally differentiated effector memory expressing CD45RA (CD45RA high CCR7 − ). Among CD8 bright lymphocytes, 3% ± 2% had a central memory phenotype, 27% ± 13% were naïve, 37% ± 13% had an effector memory phenotype, and 34% ± 12% were terminally differentiated effector memory cells expressing CD45RA.

We present a boy at the age of 4 months with infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1). Oligohydramnion was registered during pregnancy. Mild hypotonia, weak cry and calcaneovalgus foot deformity were present at birth. He manifested mild delay in psychomotor development and convulsions. On exam he presented with myopathic face, respiratory difficulties, generalized hypotonia, weak cry, opistotonic posture, absent distal tendon reflexes and reduced spontaneous movements. Electromyoneurography showed severe neurogenic lesion more pronounced distally, absent compound evoked potentials on peroneal nerves, decreased nerve conduction on upper extremities and prolonged distal latencies. Muscle biopsy showed neurogenic atrophy, while sural nerve biopsy was normal. Brain MR scans showed delayedmyelination of white matter. Genetic analysis by sequencing the gene encoding immunoglobulin m-binding protein (IGHMBP2 ; chromosome 11q13.2-q13.4) found the previously reported stop codon mutation 388C/T (R130X) in exon 3 and a novel point mutation 1743A/C (R581S) in exon 12 of IGHMBP2. Polymorphism has been excluded. Patient developed respiratory insufficiency at the age of 4 months and was artificially ventilated until he died at the age of 6 months. Delayed CNS maturation might occur in SMARD1 patient associated with mutation R581S in IGHMBP2 gene.

Nat. Genet. 47 803–808 (2015); published online 25 May 2015; corrected after print 8 July 2015 In the version of this article initially published, there was an error with the affiliations for author Roman Chrast. His correct affiliations are: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden; and Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

Motor neuron degeneration is the predominant pathological feature of spinal muscular atrophy (SMA). In patients with severe forms of the disease, additional sensory abnormalities have been reported. However, it is not clear whether the loss of sensory neurons is a common feature in severe forms of the disease, how many neurons are lost and how loss of sensory neurons compares with motor neuron degeneration. We have analysed dorsal root ganglionic sensory neurons in Smn-/-;SMN2 mice, a model of type I SMA. In contrast to lumbar motor neurons, no loss of sensory neurons in the L5 dorsal root ganglia is found at post-natal days 3-5 when these mice are severely paralyzed and die from motor defects. Survival of cultured sensory neurons in the presence of NGF and other neurotrophic factors is not reduced in comparison to wild-type controls. However, isolated sensory neurons have shorter neurites and smaller growth cones, and beta-actin protein and beta-actin mRNA are reduced in sensory neurite terminals. In footpads of Smn-deficient mouse embryos, sensory nerve terminals are smaller, suggesting that Smn deficiency reduces neurite outgrowth during embryogenesis. These data indicate that pathological alterations in severe forms of SMA are not restricted to motor neurons, but the defects in the sensory neurons are milder than those in the motor neurons.

Das HGB verweist 46 im Dritten Buch „Handelsbucher“ — neben der Nennung einiger expliziter Buchfuhrungsvorschriften — auf die gesetzlich nicht naher erlauterten Grundsatze ordnungsmasiger Buchfuhrung. 47 In der Reihenfolge der Verweisungen nach Paragraphen ergibt sich fur den handelsrechtlichen Einzelabschlus 48 das folgende Bild 49: GoB-Verweisungsnorm Regelungsinhalt § 238 Abs. 1 S. 1 Dokumentation der Handelsgeschafte u. der Vermogenslage §239 Abs. 4 S. 1 Furung der Handelsbuher §241 Abs. 1 S. 2, Abs. 2 u. 3 Inventurvereinfachungsverfahren § 243 Abs. 1 Jahresabschlufiaufstellung § 256 S. 1 Bewertungsvereinfachungsvefahren § 257 Abs. 3 S. 1 Aufbewahrung von Unterlagen § 264 Abs. 2 S. 1 Jahresabschlufiaufstellung von KapG § 336 Abs. 2 i.V.m. § 264 Abs. 2 S. 1 Jahresabschlufiaufstellung von Genossenschaften § 340a Abs. 1 i.V.m. § 264 Abs. 2 S. 1 Jahresabschlufiaufstellung von Kreditinstituten und Finanz- dienstleistungsinstituten § 341a Abs. 1 i.V.m. § 264 Abs. 2 S. 1 Jahresabschlufiaufstellung von Versicherungsunternehmen

Respektiert man den hermeneutisch-wertenden GoB-Ermittlungs- und Interpretationsprozes985, so konnen sich nicht kodifizierte erfolgswirksame bGoB durch die folgenden Sachverhalte ergeben: (1) Deduktiv-gepragte Ableitung von unteren bGoB aus dem allgemeinen inneren oberen GoB-System fur bankenspezifische bilanzielle Sachverhalte.986 (2) Induktiv-gepragte Ableitung von oberen und unteren bGoB in Form von bankenspezifischen Gewohnheitsrechten fur bankenspezifische bilanzielle Sachverhalte.987 (3) Deduktiv-gepragte Ableitung von unteren bGoB aus dem bankenspezifischen inneren oberen GoB-System fur branchenubergreifend-gleiche bilanzielle Sachverhalte.988

Insbesondere 392 seit der Aktienrechtsreform 1965 393 wurde der Frage nachgegangen, ob die aktienrechtlichen Rechnungslegungsvorschriften auch fur Nicht-Aktiengesellschaft Gultigkeit erlangen konnen. 394 Die Diskussion ist insofern fur die vorliegende Untersuchung von Bedeutung, als das Aktiengesetz als ein Spezialgesetz fur Aktiengesellschaften geschaffen wurde und deshalb zunachst nur fur diese als unmittelbar gelten- des Recht verbindlich war. Das damit nicht gleichzeitig eine mittelbare Anwendbarkeit fur Nicht-Aktiengesellschaften ausgeschlossen wurde, last sich schon daraus vermuten, das der VI. Senat des BFH durch Beschlus im Jahre 1968 den Grosen Senat zur Entscheidung der Rechtsfrage aufgerufen hat, inwieweit die aktienrechtlichen Rechnungslegungsvorschriften als allgemeingultige GoB fur alle Unternehmen masgeblich seien. 395 Ob eine solche juristische Brucke“ 396, uber die hinweg aktienrechtliche Regelungen auch fur Nicht-Aktiengesellschaften gelten, existiert, wurde in der Literatur unterschiedlich beurteilt: Wahrend ein Teil der Autoren der Meinung war, das die aktienrechtlichen Vorschriften auch von Nicht-Aktiengesellschaften generell zu beachten seien397, sahen andere Autoren zwar auch einige Rechnungslegungsvorschriften der Aktiengesellschaft als gultig fur die Nicht-Aktiengesellschaft an, lehnten jedoch — zumeist aus grundsatzlichen Erwagungen — die generelle Verbindlichkeit dieser Vorschriften in ihrer Gesamtheit fur alle Unternehmensformen ab. 398 Hinsichtlich