Repetitive speech phenomena in Parkinson's disease

OBJECTIVES: Repetitive speech phenomena are morphologically heterogeneous iterations of speech which have been described in several neurological disorders such as vascular dementia, progressive supranuclear palsy, Wilson's disease, and Parkinson's disease, and which are presently only poorly understood. The present, prospective study investigated repetitive speech phenomena in Parkinson's disease to describe their morphology, assess their prevalence, and to establish their relation with neuropsychological and clinical background data. METHODS: Twenty four patients with advanced Parkinson's disease and 29 subjects with mid-stage, stable idiopathic disease were screened for appearance, forms, and frequency of repetitive speech phenomena, and underwent a neuropsychological screening procedure comprising tests of general mental functioning, divergent thinking and memory. Patients with advanced Parkinson's disease had a significantly higher disease impairment, longer disease duration, and an unstable motor response to levodopa with frequent on-off fluctuations. Both groups were well matched as to their demographical, clinical, and cognitive background. Perceptual speech evaluation was used to count and differentiate forms of repetitive speech phenomena in different speech tasks. To compare the effect of the motor state, the appearance of repetitive speech phenomena was also assessed in a subgroup of patients with advanced Parkinson's disease during the on versus the off state. RESULTS: Speech repetitions emerged mainly in two variants, one hyperfluent, formally resembling palilalia, and one dysfluent, stuttering-like. Both forms were present in each patient producing repetitive speech phenomena. The repetitive speech phenomena appeared in 15 patients (28.3 %), 13 of whom belonged to the advanced disease group, indicating a significant preponderance of repetitive speech phenomena in patients with a long term, fluctuating disease course. Repetitive speech phenomena appeared with almost equal frequency during the on and the off state of patients with advanced Parkinson's disease. Their distribution among different variants of speech was disproportional, with effort demanding speech tasks producing a significantly higher number of repetitive speech phenomena over semiautomatic forms of speech. CONCLUSIONS: In idiopathic Parkinson's disease repetitive speech phenomena seem to emerge predominantly in a subgroup of patients with advanced disease impairment; manifest dementia is not a necessary prerequisite. They seem to represent a deficit of motor speech control; however, linguistic factors may also contribute to their generation. It is suggested that repetitions of speech in Parkinson's disease represent a distinctive speech disorder, which is caused by changes related to the progression of Parkinson's disease.     

Neutrophil Extracellular Trap-Related Extracellular Histones Cause Vascular Necrosis in Severe GN

Severe GN involves local neutrophil extracellular trap (NET) formation. We hypothesized a local cytotoxic effect of NET-related histone release in necrotizing GN. In vitro, histones from calf thymus or histones released by neutrophils undergoing NETosis killed glomerular endothelial cells, podocytes, and parietal epithelial cells in a dose-dependent manner. Histone-neutralizing agents such as antihistone IgG, activated protein C, or heparin prevented this effect. Histone toxicity on glomeruli ex vivo was Toll-like receptor 2/4 dependent, and lack of TLR2/4 attenuated histone-induced renal thrombotic microangiopathy and glomerular necrosis in mice. Anti–glomerular basement membrane GN involved NET formation and vascular necrosis, whereas blocking NET formation by peptidylarginine inhibition or preemptive anti-histone IgG injection significantly reduced all aspects of GN (i.e., vascular necrosis, podocyte loss, albuminuria, cytokine induction, recruitment or activation of glomerular leukocytes, and glomerular crescent formation). To evaluate histones as a therapeutic target, mice with established GN were treated with three different histone-neutralizing agents. Anti-histone IgG, recombinant activated protein C, and heparin were equally effective in abrogating severe GN, whereas combination therapy had no additive effects. Together, these results indicate that NET-related histone release during GN elicits cytotoxic and immunostimulatory effects. Furthermore, neutralizing extracellular histones is still therapeutic when initiated in established GN.     

Akuter Schlaganfall – Aufgabe für Notarzt oder Rettungsassistent?

Notfall + Rettungsmedizin -     

Esrrg functions in early branch generation of the ureteric bud and is essential for normal development of the renal papilla

Congenital anomalies of the kidney and urinary tract (CAKUTs) are common disorders of human development affecting the renal parechyma, renal pelvis, ureter, bladder and urethra; they show evidence of shared genetic aetiology, although the molecular basis of this remains unknown in the majority of cases. Breakpoint mapping of a de novo, apparently balanced, reciprocal translocation associated with bilateral renal agenesis has implicated the gene encoding the nuclear steroid hormone receptor ESRRG as a candidate gene for CAKUT. Here we show that the Esrrg protein is detected throughout early ureteric ducts as cytoplasmic/sub-membranous staining; with nuclear localization seen in developing nephrons. In 14.5-16.5 dpc (days post-conception) mouse embryos, Esrrg localizes to the subset of ductal tissue within the kidney, liver and lung. The renal ductal expression becomes localized to renal papilla by 18.5 dpc. Perturbation of function was performed in embryonic mouse kidney culture using pooled siRNA to induce knock-down and a specific small-molecule agonist to induce aberrant activation of Esrrg. Both resulted in severe abnormality of early branching events of the ureteric duct. Mouse embryos with a targeted inactivation of Esrrg on both alleles (Esrrg(-/-)) showed agenesis of the renal papilla but normal development of the cortex and remaining medulla. Taken together, these results suggest that Esrrg is required for early branching events of the ureteric duct that occur prior to the onset of nephrogenesis. These findings confirm ESRRG as a strong candidate gene for CAKUT.     

Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition

Hypoxia has been proposed as an important microenvironmental factor in the development of tissue fibrosis; however, the underlying mechanisms are not well defined. To examine the role of hypoxia-inducible factor-1 (HIF-1), a key mediator of cellular adaptation to hypoxia, in the development of fibrosis in mice, we inactivated Hif-1alpha in primary renal epithelial cells and in proximal tubules of kidneys subjected to unilateral ureteral obstruction (UUO) using Cre-loxP-mediated gene targeting. We found that Hif-1alpha enhanced epithelial-to-mesenchymal transition (EMT) in vitro and induced epithelial cell migration through upregulation of lysyl oxidase genes. Genetic ablation of epithelial Hif-1alpha inhibited the development of tubulointerstitial fibrosis in UUO kidneys, which was associated with decreased interstitial collagen deposition, decreased inflammatory cell infiltration, and a reduction in the number of fibroblast-specific protein-1-expressing (FSP-1-expressing) interstitial cells. Furthermore, we demonstrate that increased renal HIF-1alpha expression is associated with tubulointerstitial injury in patients with chronic kidney disease. Thus, we provide clinical and genetic evidence that activation of HIF-1 signaling in renal epithelial cells is associated with the development of chronic renal disease and may promote fibrogenesis by increasing expression of extracellular matrix-modifying factors and lysyl oxidase genes and by facilitating EMT.