Deletion of dystrophin In-Frame Exon 5 leads to a severe phenotype: Guidance for Exon skipping strategies

Duchenne and Becker muscular dystrophy severity depends upon the nature and location of the DMD gene lesion and generally correlates with the dystrophin open reading frame. However, there are striking exceptions where an in-frame genomic deletion leads to severe pathology or protein-truncating mutations (nonsense or frame-shifting indels) manifest as mild disease. Exceptions to the dystrophin reading frame rule are usually resolved after molecular diagnosis on muscle RNA. We report a moderate/severe Becker muscular dystrophy patient with an in-frame genomic deletion of DMD exon 5. This mutation has been reported by others as resulting in Duchenne or Intermediate muscular dystrophy, and the loss of this in-frame exon in one patient led to multiple splicing events, including omission of exon 6, that disrupts the open reading frame and is consistent with a severe phenotype. The patient described has a deletion of dystrophin exon 5 that does not compromise recognition of exon 6, and although the deletion does not disrupt the reading frame, his clinical presentation is more severe than would be expected for classical Becker muscular dystrophy. We suggest that the dystrophin isoform lacking the actin-binding sequence encoded by exon 5 is compromised, reflected by the phenotype resulting from induction of this dystrophin isoform in mouse muscle in vivo. Hence, exon skipping to address DMD-causing mutations within DMD exon 5 may not yield an isoform that confers marked clinical benefit. Additional studies will be required to determine whether multi-exon skipping strategies could yield more functional dystrophin isoforms, since some BMD patients with larger in-frame deletions in this region have been reported with mild phenotypes

Optical coherence tomography-based contact indentation for diaphragm mechanics in a mouse model of transforming growth factor alpha induced lung disease

Funding provided by the National Health and Medical Research Council (NHMRC) of Australia (1027218). P.N. and K.W. are supported by NHMRC Fellowships (1045824, 1090888). P.W. was supported by the William and Marlene Schrader Postgraduate Scholarship, The University of Western Australia, and C.A. by an NHMRC Preterm Infants CRE top-up scholarship.This study tested the utility of optical coherence tomography (OCT)-based indentation to assess mechanical properties of respiratory tissues in disease. Using OCT-based indentation, the elastic modulus of mouse diaphragm was measured from changes in diaphragm thickness in response to an applied force provided by an indenter. We used a transgenic mouse model of chronic lung disease induced by the overexpression of transforming growth factor-alpha (TGF-α), established by the presence of pleural and peribronchial fibrosis and impaired lung mechanics determined by the forced oscillation technique and plethysmography. Diaphragm elastic modulus assessed by OCT-based indentation was reduced by TGF-α at both left and right lateral locations (p < 0.05). Diaphragm elastic modulus at left and right lateral locations were correlated within mice (r = 0.67, p < 0.01) suggesting that measurements were representative of tissue beyond the indenter field. Co-localised images of diaphragm after TGF-α overexpression revealed a layered fibrotic appearance. Maximum diaphragm force in conventional organ bath studies was also reduced by TGF-α overexpression (p < 0.01). Results show that OCT-based indentation provided clear delineation of diseased diaphragm, and together with organ bath assessment, provides new evidence suggesting that TGF-α overexpression produces impairment in diaphragm function and, therefore, an increase in the work of breathing in chronic lung disease.Publisher PDFPeer reviewe

Similarities and Differences of the Soleus and Gastrocnemius H-reflexes during Varied Body Postures, Foot Positions, and Muscle Function: Multifactor Designs for Repeated Measures

<p>Abstract</p> <p>Background</p> <p>Although the soleus (Sol), medial gastrocnemius (MG), and lateral gastrocnemius (LG) muscles differ in function, composition, and innervations, it is a common practice is to investigate them as single H-reflex recording. The purpose of this study was to compare H-reflex recordings between these three sections of the triceps surae muscle group of healthy participants while lying and standing during three different ankle positions.</p> <p>Methods</p> <p>The Sol, MG and LG muscles' H-reflexes were recorded from ten participants during prone lying and standing with the ankle in neutral, maximum dorsiflexion, and maximum plantarflexion positions. Four traces were averaged for each combination of conditions. Three-way ANOVAs (posture X ankle position X muscle) with planned comparisons were used for statistical comparisons.</p> <p>Results</p> <p>Although the H-reflex in the three muscle sections differed in latency and amplitude, its dependency on posture and ankle position was similar. The H-reflex amplitudes and maximum H-reflex to M-response (H/M) ratios were significantly 1) lower during standing compared to lying with the ankle in neutral, 2) greater during standing with the ankle in plantarflexion compared to neutral, and 3) less with the ankle in dorsiflexion compared to neutral during lying and standing for all muscles (<it>p </it>≤ .05).</p> <p>Conclusion</p> <p>Varying demands are required for muscles activated during distinctly different postures and ankle movement tasks.</p

The Viscoelastic Properties of Passive Eye Muscle in Primates. I: Static Forces and Step Responses

The viscoelastic properties of passive eye muscles are prime determinants of the deficits observed following eye muscle paralysis, the root cause of several types of strabismus. Our limited knowledge about such properties is hindering the ability of eye plant models to assist in formulating a patient's diagnosis and prognosis. To investigate these properties we conducted an extensive in vivo study of the mechanics of passive eye muscles in deeply anesthetized and paralyzed monkeys. We describe here the static length-tension relationship and the transient forces elicited by small step-like elongations. We found that the static force increases nonlinearly with length, as previously shown. As expected, an elongation step induces a fast rise in force, followed by a prolonged decay. The time course of the decay is however considerably more complex than previously thought, indicating the presence of several relaxation processes, with time constants ranging from 1 ms to at least 40 s. The mechanical properties of passive eye muscles are thus similar to those of many other biological passive tissues. Eye plant models, which for lack of data had to rely on (erroneous) assumptions, will have to be updated to incorporate these properties

La conservazione preventiva del patrimonio librario come possibile alternativa al restauro tradizionale

The present paper focuses on the close relation between library collections and their preservation environment, aiming, in particular, at highlighting the importance of promoting and sustaining the monitoring. The paper proposes some simple and ready-to-use technologies – smart monitoring – to prevent future damages

Integrated pest management Practical, safe and cost-effective advice on the prevention and control of pests in museums

SIGLEAvailable from British Library Document Supply Centre-DSC:99/39495 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

The physiological effects of IGF-1 (class 1:Ea transgene) over-expression on exercise-induced damage and adaptation in dystrophic muscles of mdx mice

Duchenne muscular dystrophy (DMD) is a genetic disorder in which muscle weakness and fragility contribute to ongoing muscle degeneration. Although exercise-induced muscle damage is associated with adaptation that protects normal muscle from further damage, exploiting this process to protect dystrophic muscle has been avoided for fear of inducing excessive muscle degeneration. However, muscle-specific over-expression of the class 1:Ea isoform of insulin-like growth factor-1 (IGF-1) reduces myofibre necrosis in dystrophic mdx mice (a model for DMD) and, therefore, may enhance the adaptation process in response to eccentric exercise. To test this hypothesis, we evaluated the effect of transgenic class 1:Ea IGF-1 over-expression on the susceptibility to muscle damage and subsequent adaptation in 12-week-old dystrophic mdx and non-dystrophic control mice. Experiments were conducted in vivo using a custom-built isokinetic mouse dynamometer to measure the deficit in joint torque (indicating muscle damage) after 20 maximal lengthening (eccentric) contractions. Adaptation to this damaging exercise was evaluated by repeating the protocol 7 days after the initial exercise. The over-expression of IGF-1 significantly increased the normalised joint torque in non-dystrophic mice and appeared to ameliorate the muscle weakness in dystrophic mice. All mice displayed a marked reduction in the susceptibility to muscle damage on day 7; however, this adaptation was unaffected by IGF-1, showing that IGF-1 does not protect the dystrophic muscles of adult mdx mice against damage resulting from maximal lengthening contractions