1,721,059 research outputs found
Myotonic dystrophy type 2 and modifier genes : an update on clinical and pathomolecular aspects
No full textMyotonic dystrophy (DM) is the most common adult muscular dystrophy, characterized by autosomal dominant progressive myopathy, myotonia, and multiorgan involvement. To date, two distinct forms caused by similar mutations in two different genes have been identified: myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2). Aberrant transcription and mRNA processing of multiple genes due to RNA-mediated toxic gain-of function has been suggested to cause the complex phenotype in DM1 and DM2. However, despite clinical and genetic similarities, DM1 and DM2 may be considered as distinct disorders. This review is an update on the latest findings specific to DM2, including explanations for the differences in clinical manifestations and pathophysiology between the two forms of myotonic dystrophies
Effect of glucose stress conditions in BL6T murine melanoma cells
No full textElevated expression of stress proteins can be a characteristic of human cancer and may be involved in the development of resistance to some types of chemotherapeutic agent In this paper, the effect of physiological stress conditions, such as glucose deprivation, was investigated in overexpressing nPKCδ murine melanoma BL6 (BL6T) cells. Glucose stress conditions decreased the proliferative capacity, increasing the percentage of BL6T cells in the G0/G1 phase of the cell cycle. Furthermore, under such conditions, nPKCδ, whose subcellular localization is cell cycle dependent, showed a cytoplasmic and perinuclear localization by immunohistochemistry, this being typical for cells in G0/G1 phase. Moreover, these cells expressed GRP-78, a known stress protein. On the other hand, glucose depletion enhanced intracellular melanin as well as tyrosinase activity and expression. In summary, these data demonstrate that stress conditions can modify the biological characteristics of BL6T cells, and therefore can select a quiescent cellular population
Myotonic dystrophy type 2 and related myotonic disorders
No full textThe myotonic disorders result from dysfunction in either the chloride or sodium channel and these disorders fall in the category of nondystrophic myotonias. The other group is represented by myotonic dystrophies. The myotonic dystrophies are multisystem, autosomal dominantly inherited, highly variable muscle disease more frequent in adults. So far two distinct entities have been described: myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2/PROMM). The latter is similar but distinct from classic, myotonic dystrophy of Steinert. In this review, we will focus on clinical features, genetics, pathophysiology, clinical laboratory tests, and treatment of DM2. Related more frequent myotonic disorders (ie, autosomal-dominant and autosomal-recessive myotonia congenita) will also be described. Sodium channel myotonia and myotonic-like disorders (ie, Schwartz-Jampel syndrome) will not be covered in this review
Influence of physical activity on metabolic control, body composition and cardiovascular system in children and adolescent with T1DM
No full textObjectives: Our study aims to evaluate the effect of physical activity
(PA) on body composition, metabolic control, systolic and diastolic
blood pressure (SBP and DBP) and heart rate (HR) in young patients
with type 1 diabetes mellitus (T1DM).
Methods: We performed a cross-sectional study on 81 patients
(45 male) with T1DM aged 16.0(5.6) years, with disease duration of
86(62) months and free of coeliac disease and/or thyroiditis. Every
patient was asked to report which type of physical activity was used
practicing every week and how long. Depending on the type of sport
practiced and the time spent in their practice, the total hours of physical
activity per week were divided into three categories of exercise:
aerobic, anaerobic and mixed. Body composition was assessed
through body mass index (BMI), body impedance and skinfolds, and
metabolic control was evaluated through mean and SD of HBGM,
HBGI, LBGI and HbA1c. For each patient were also taken into
account the following parameters: systolic and diastolic pressure,
heart rate and insulin need. Data are reported as median (IQR). Simple
and multiple regression analysis and Mann–Whitney test were
used for statistical analysis.
Results: The time spent on PA was inversely correlated with fat mass
% (FM%) (R2 = 0,194; p < 0.0002). FM% was directly correlated with
SDS-DBP (R2 = 0.082; p < 0.01) while BMI was directly correlated with
the SDS-SBP (R2 = 0.066; p = 0.02). Mixed exercise was associated
with significant lower FM% then the aerobic and anaerobic one [17.9
(6.4) vs 27.5 (15); p < 0.001]. We did not find correlations between the
amount and type of PA and any of the others parameters we collected.
Conclusions: Our results seem to highlight a positive effect of exercise,
particularly the mixed one, on body composition and that the
latter improves DBP. Furthermore, it does not seem that PA has a
significative effect on metabolic control
Myotonic dystrophies: An update on clinical aspects, genetic, pathology, and molecular pathomechanisms
No full textAbstractMyotonic dystrophy (DM) is the most common adult muscular dystrophy, characterized by autosomal dominant progressive myopathy, myotonia and multiorgan involvement. To date two distinct forms caused by similar mutations have been identified. Myotonic dystrophy type 1 (DM1, Steinert's disease) is caused by a (CTG)n expansion in DMPK, while myotonic dystrophy type 2 (DM2) is caused by a (CCTG)n expansion in ZNF9/CNBP. When transcribed into CUG/CCUG-containing RNA, mutant transcripts aggregate as nuclear foci that sequester RNA-binding proteins, resulting in spliceopathy of downstream effector genes. However, it is now clear that additional pathogenic mechanism like changes in gene expression, protein translation and micro-RNA metabolism may also contribute to disease pathology. Despite clinical and genetic similarities, DM1 and DM2 are distinct disorders requiring different diagnostic and management strategies. This review is an update on the recent advances in the understanding of the molecular mechanisms behind myotonic dystrophies. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis
Muscle biopsy
No full textMuscle biopsy is required to provide a defini- tive diagnosis in many neuromuscular disorders. It can be performed through an open or needle technique under local anesthesia. The major limitations of the needle biopsy technique are the sample size, which is smaller than that obtained with open biopsy, and the impossibility of direct visualization of the sampling site. However, needle biopsy is a less invasive procedure than open biopsy and is par- ticularly indicated for diagnosis of neuromuscular disease in infancy and childhood. The biopsied muscle should be one affected by the disease but not be too weak or too atrophic. Usually, in case of proximal muscle involvement, the quadriceps and the biceps are biopsied, while under suspicion of mitochondrial disorder, the deltoid is pre- ferred. The samples must be immediately frozen or fixed after excision to prevent loss of enzymatic reactivity, DNA depletion or RNA degradation. A battery of stainings is performed on muscle sections from every frozen muscle biopsy arriving in the pathology laboratory. Histological, histochemical, and histoenzymatic stainings are performed to evaluate fiber atrophy, morphological, and structural changes and metabolic disorders. Moreover, immunohis- tochemistry and Western blotting analysis may be used for expression analysis of muscle proteins to obtain a specific diagnosis. There are myopathies that do not need muscle biopsy since a genetic test performed on a blood sample is enough for definitive diagnosis. Muscle biopsy is a useful technique which can make an enormous contribution in the field of neuromuscular disorders but should be considered and interpreted together with the patient’s family and clinical history
Nuclear MBNL1-containing foci increase in size upon cell-cycle exit in fibroblasts from DM2 patients
No full textMyotonic dystrophies (DM1 and DM2) are multisystemic diseases that belong to non-coding repeat expansion disorders. The presence of the CTG or CCTG expansion respectively, leads to nuclear accumulation of the expanded RNAs that sequester essential proteins (such as MBLN1) and disrupt their normal function in the cells of different tissues. The cytochemical detection of nuclear foci of expanded RNAs or MBNL1 is an accepted diagnostic marker for DM1. It is apparent that in DM patients the most significant pathological features are found in the skeletal muscle, heart and the central nervous system where non-cycling cell populations are mainly found; on the contrary, cells from self-renewing tissues (such as skin fibroblasts or layering epithelial cells) appear much less affected. The mechanisms that underlie the nuclear retention of expanded RNAs and its aggregation into nuclear foci are not currently well understood. A recent study on dynamics of CUG repeat foci in living myoblasts has revealed that these are constantly aggregating and disaggregating structures, and that MBNL1 is directly involved in the stochastic process of foci2. In this investigation, we aimed to elucidate whether in DM tissues the exit of cells from the cell cycle may lead to the increase in size of intranuclear foci due to the progressive sequestration of protein factors (namely MBNL1); to do this, we investigated by immunocytochemical and morphometric techniques the fate of MBNL1-containing foci in proliferating cells during the cell cycle, and in non-cycling cells. Cultured skin fibroblasts from DM2 patients were chosen as a model cell system. We found that nuclear MBNL1-containing foci do not associate with chromosomes at mitosis, and remain in the cytoplasm at cytodieresis, being disassembled in early G1 and re-formed in the nucleus, at each cell cycle. After cells had spontaneously stopped dividing in senescing fibroblast cultures, the nuclear foci were observed to increase in number and size. Interestingly, morphometric measurements of nuclear MBNL1-containing foci in muscle biopsies taken from the same DM2 patients at different ages demonstrated that they become larger with increasing patient’s age
Drug resistant focal epilepsy in a patient with myotonic dystrophy type 2 : casual or causal association?
No full textSarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) pumps play the major role in lowering cytoplasmic calcium concentration in
skeletal muscle by catalyzing the ATP-dependent transport of Ca2+ from the cytosol to the lumen of the sarcoplasmic reticulum (SR). Although SERCA abnormalities have been hypothesized to contribute to the dysregulation of intracellular Ca2+ homeostasis and signaling in muscle of patients with myotonic dystrophy (DM) and hypothyroid myopathy, the characterization of SERCA pumps remains elusive and their impairment is still unclear.We assessed the activity of SR Ca2+-ATPase, expression levels and fiber distribution of SERCA1 and SERCA2, and oligomerization of SERCA1 protein in muscle of patients with DM type 1 and 2, and with hypothyroid myopathy. Our data provide evidence that SR Ca2+ ATPase activity, protein levels and muscle fiber distribution of total SERCA1 and SERCA2, and SERCA1 oligomerization pattern are similar in patients with both DM1 and DM2, hypothyroid myopathy and in control subjects.We prove that SERCA1b, the neonatal isoform of SERCA1, is expressed at protein level in muscle of patients with DM2 and, in lower amount, of patients with DM1. Our present study demonstrates that SERCA function is not altered in muscle of patients with DM and with hypothyroid myopathy
Muscleblind-like protein 1 nuclear sequestration and splicing pattern in myotonic dystrophy type 2
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