Refine
Has Fulltext
- yes (2)
Is part of the Bibliography
- yes (2)
Document Type
- Journal article (2)
Language
- English (2)
Keywords
- BDNF stimulation (1)
- COPD diagnosis (1)
- GOLD (1)
- Medizin (1)
- dynamics of ribosomal assembly (1)
- lower limit of normal (1)
- presynaptic ER dynamics (1)
- spinal muscular atrophy (1)
- validation (1)
Institute
Background: The Global initiative for chronic Obstructive Lung Disease (GOLD) defines COPD as a fixed postbronchodilator ratio of forced expiratory volume in 1 second and forced vital capacity (FEV1/FVC) below 0.7. Agedependent cut-off values below the lower fifth percentile (LLN) of this ratio derived from the general population have been proposed as an alternative. We wanted to assess the diagnostic accuracy and prognostic capability of the GOLD and LLN definition when compared to an expert-based diagnosis. Methods: In a prospective cohort study, 405 patients aged ≥ 65 years with a general practitioner’s diagnosis of COPD were recruited and followed up for 4.5 (median; quartiles 3.9; 5.1) years. Prevalence rates of COPD according to GOLD and three LLN definitions and diagnostic performance measurements were calculated. The reference standard was the diagnosis of COPD of an expert panel that used all available diagnostic information, including spirometry and bodyplethysmography. Results: Compared to the expert panel diagnosis, ‘GOLD-COPD’ misclassified 69 (28%) patients, and the three LLNs misclassified 114 (46%), 96 (39%), and 98 (40%) patients, respectively. The GOLD classification led to more false positives, the LLNs to more false negative diagnoses. The main predictors beyond the FEV1/FVC ratio for an expert diagnosis of COPD were the FEV1 % predicted, and the residual volume/total lung capacity ratio (RV/TLC). Adding FEV1 and RV/TLC to GOLD or LLN improved the diagnostic accuracy, resulting in a significant reduction of up to 50% of the number of misdiagnoses. The expert diagnosis of COPD better predicts exacerbations, hospitalizations and mortality than GOLD or LLN. Conclusions: GOLD criteria over-diagnose COPD, while LLN definitions under-diagnose COPD in elderly patients as compared to an expert panel diagnosis. Incorporating FEV1 and RV/TLC into the GOLD-COPD or LLN-based definition brings both definitions closer to expert panel diagnosis of COPD, and to daily clinical practice.
Background: Axonal degeneration and defects in neuromuscular neurotransmission represent a pathological hallmark
in spinal muscular atrophy (SMA) and other forms of motoneuron disease. These pathological changes do not
only base on altered axonal and presynaptic architecture, but also on alterations in dynamic movements of organelles
and subcellular structures that are not necessarily reflected by static histopathological changes. The dynamic interplay
between the axonal endoplasmic reticulum (ER) and ribosomes is essential for stimulus-induced local translation
in motor axons and presynaptic terminals. However, it remains enigmatic whether the ER and ribosome crosstalk is
impaired in the presynaptic compartment of motoneurons with Smn (survival of motor neuron) deficiency that could
contribute to axonopathy and presynaptic dysfunction in SMA.
Methods: Using super-resolution microscopy, proximity ligation assay (PLA) and live imaging of cultured motoneurons
from a mouse model of SMA, we investigated the dynamics of the axonal ER and ribosome distribution and
activation.
Results: We observed that the dynamic remodeling of ER was impaired in axon terminals of Smn-deficient motoneurons.
In addition, in axon terminals of Smn-deficient motoneurons, ribosomes failed to respond to the brain-derived
neurotrophic factor stimulation, and did not undergo rapid association with the axonal ER in response to extracellular
stimuli.
Conclusions: These findings implicate impaired dynamic interplay between the ribosomes and ER in axon terminals
of motoneurons as a contributor to the pathophysiology of SMA and possibly also other motoneuron diseases.