Pathophysiology of protein aggregation and extended phenotyping in filaminopathy.

Mutations in FLNC cause two distinct types of myopathy. Disease associated with mutations in filamin C rod domain leading to expression of a toxic protein presents with progressive proximal muscle weakness and shows focal destructive lesions of polymorphous aggregates containing desmin, myotilin and other proteins in the affected myofibres; these features correspond to the profile of myofibrillar myopathy. The second variant associated with mutations in the actin-binding domain of filamin C is characterized by weakness of distal muscles and morphologically by non-specific myopathic features. A frameshift mutation in the filamin C rod domain causing haploinsufficiency was also found responsible for distal myopathy with some myofibrillar changes but no protein aggregation typical of myofibrillar myopathies. Controversial data accumulating in the literature require re-evaluation and comparative analysis of phenotypes associated with the position of the FLNC mutation and investigation of the underlying disease mechanisms. This is relevant and necessary for the refinement of diagnostic criteria and developing therapeutic approaches. We identified a p.W2710X mutation in families originating from ethnically diverse populations and re-evaluated a family with a p.V930_T933del mutation. Analysis of the expanded database allows us to refine clinical and myopathological characteristics of myofibrillar myopathy caused by mutations in the rod domain of filamin C. Biophysical and biochemical studies indicate that certain pathogenic mutations in FLNC cause protein misfolding, which triggers aggregation of the mutant filamin C protein and subsequently involves several other proteins. Immunofluorescence analyses using markers for the ubiquitin-proteasome system and autophagy reveal that the affected muscle fibres react to protein aggregate formation with a highly increased expression of chaperones and proteins involved in proteasomal protein degradation and autophagy. However, there is a noticeably diminished efficiency of both the ubiquitin-proteasome system and autophagy that impairs the muscle capacity to prevent the formation or mediate the degradation of aggregates. Transfection studies of cultured muscle cells imitate events observed in the patient's affected muscle and therefore provide a helpful model for testing future therapeutic strategies.

Clinical and morphological phenotype of the filamin myopathy: a study of 31 German patients.

Mutations in the filamin C gene (FLNC) cause a myofibrillar myopathy (MFM), morphologically characterized by focal myofibrillar destruction and abnormal accumulation of several proteins within skeletal muscle fibres. We studied 31 patients from four German families to evaluate the phenotype of filaminopathy. All patients harboured the same p.W2710X mutation in FLNC. Haplotype analysis suggested a founder mutation in these German filaminopathy families. The mean age at onset of clinical symptoms was 44 +/- 6 years (range, 24-57 years). Slowly progressive muscle weakness was mostly pronounced proximally, initially affecting the lower extremities and involving the upper extremities in the course of disease progression, similar to the distribution of weakness seen in limb-girdle muscular dystrophies (LGMD). Patients frequently developed respiratory muscle weakness. About one-third of the patients showed cardiac abnormalities comprising conduction blocks, tachycardia, diastolic dysfunction and left ventricular hypertrophy indicating a cardiac involvement in filaminopathy. Serum creatine kinase levels varied from normal up to 10-fold of the upper limit. Magnetic resonance imaging studies showed a rather homogenous pattern of muscle involvement in the lower extremities differing from that in other types of MFM. Myopathological features included perturbation of myofibrillar alignment, accumulation of granulofilamentous material similar to that seen in primary desminopathies and abnormal intracellular protein deposits typical of MFM. Decreased activities of oxidative enzymes and fibre hypertrophy seem to be early features, whereas dystrophic changes were present in advanced stages of filaminopathy. Rimmed vacuoles were detected in only a few cases. The intracellular aggregates were composed of a variety of proteins including filamin C, desmin, myotilin, Xin, dystrophin and sarcoglycans. Therapy is so far limited to symptomatic treatment. The German filaminopathy cohort, the largest group of patients studied so far, shares phenotypic features with LGMD and presents with characteristic histopathological findings of MFM.

Paediatric radiology and scientific contributions to radiation dose at the meeting of the German Radiological Society--an analysis of an 11-year period.

AIM: Evaluation of the emphasis on themes pertaining to paediatric radiology and radiation dose at the Meeting of the German Radiological Society from 1998 to 2008 in comparison to international data. MATERIALS AND METHODS: Retrospective analysis of 9440 abstracts with documentation of type of contribution, imaging modality, and examined body region. Abstracts primarily dealing with paediatric radiology and those stating radiation dose were documented. Results were compared with a Pubmed query. RESULTS: 448 contributions in paediatric radiology were presented corresponding to 5% of all abstracts with an increase from 5 (1998) to 7% (2008). The proportion of prospective studies of all congress contributions was 10%, whereas in paediatric radiology, the share of prospective studies was 6%. From 1998 to 2008, the share of MRI fell from 48 to 38%, while CT contributions rose from 30 to 34%. Within paediatric radiology, the proportion of CT rose from 23 to 29%, while MRI and ultrasound fell from 63 to 48% and 35 to 19%, respectively. The share of abstracts dealing with radiation dose rose from 7 to 10% while that primarily pertaining to dose reduction grew from 2 to 4%. Of all abstracts concerning CT, 15% touched on radiation dose, whereas 6% primarily dealt with dose reduction. Among all abstracts dealing with paediatric radiology, 20 and 6% mentioned radiation dose and dose reduction, respectively. In the subgroup of paediatric radiology CT abstracts, radiation dose and dose reduction were mentioned in 34 and 16%, respectively. An online query produced 137,791 publications on CT, of whose abstracts 3% mentioned radiation dose and 0.5% mentioned dose reduction. 11% of all CT publications dealt with paediatric populations and 2% of these publications examined questions of radiation dose. CONCLUSIONS: In the last 11 years the Meeting of the German Radiological Society has presented a growing number of contributions pertaining to paediatric radiology. CT has shown the most pronounced growth of all contributions. Paediatric radiology has significantly more often dealt with questions of radiation exposure than those from general radiology. However, contributions with definite reference to radiation dose, both pertaining to all publications and specifically to those dealing with CT, remain a minority, albeit with a higher proportion when compared to international data.

Paediatrician awareness of radiation dose and inherent risks in chest imaging studies--a questionnaire study.

OBJECTIVE: To assess paediatricians' knowledge regarding radiation exposure of chest imaging. MATERIALS AND METHODS: German paediatricians were surveyed using a questionnaire. Participants were asked to estimate effective dose (ED) of radiographs (CR) and computed tomography (CT). Further questions included dose-saving of paediatric CT-protocols, ALARA principle, and awareness of the link between radiation and cancer development. Length and type of occupation and amount of ordered procedures were evaluated. RESULTS: 137 paediatricians participated with 59% and 39% correctly estimating ED of an adult (0.01-0.1mSv) and newborn CR (0.01-0.1mSv), respectively. ED of an adult chest CT (1-10mSv) was underestimated by 28%, whereas ED of cardiac CT (10-100mSv) was underestimated by 54%. 35% of participants correctly estimated ED of a chest CT in an infant (10-100mSv) which was underestimated by 56%. Neither length nor type of occupation showed significant impact on dose estimations. 14% of paediatricians stated that MRI causes radiation, whereas 4% correctly estimated the potential of paediatric CT-protocols. 15% were familiar with the ALARA principle and 26% were aware of a publication concerning radiation and malignancy. CONCLUSION: Paediatricians demonstrated an increased level of awareness compared to previous surveys. However, estimation of ED of CT remained difficult. Increased information transfer and education seem pressing in the light of increasing radiological examinations.

Immobilization impairs tactile perception and shrinks somatosensory cortical maps.

Use is a major factor driving plasticity of cortical processing and cortical maps. As demonstrated of blind Braille readers and musicians, long-lasting and exceptional usage of the fingers results in the development of outstanding sensorimotor skills and in expansions of the cortical finger representations. However, how periods of disuse affect cortical representations and perception in humans remains elusive. Here, we report that a few weeks of hand and arm immobilization by cast wearing significantly reduced hand use and impaired tactile acuity, associated with reduced activation of the respective finger representations in the somatosensory cortex (SI), measured by functional magnetic resonance imaging. Hemodynamic responses in the SI correlated positively with hand-use frequency and negatively with discrimination thresholds, indicating that reduced activation was most prominent in subjects with severe perceptual impairment. We found, strikingly, compensatory effects on the contralateral, healthy hand consisting of improved perceptual performance compared to healthy controls. Two to three weeks after cast removal, perceptual and cortical changes recovered, whereas tactile acuity on the healthy side remained superior to that on the formerly immobilized side. These findings suggest that brief periods of reduced use of a limb have overt consequences and thus constitute a significant driving force of brain organization equivalent to enhanced use.