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PubMed1988

Antiemetic efficacy of high-dose dexamethasone: randomized, double-blind, crossover study with a combination of dexamethasone, metoclopramide and diphenhydramine.

A double-blind, randomized, crossover study was conducted to compare the efficacy and safety of high-dose dexamethasone (Protocol D) with a combination of dexamethasone, metoclopramide and diphenhydramine (Protocol DMD) in the management of chemotherapy-induced nausea and vomiting in cancer patients. All entered patients had received no prior chemotherapy. During the study chemotherapy was administered on an inpatient basis. The majority of patients (94%) were treated with cytotoxic drugs of significant emetogenic activity and 40% of the study group received cis-platin-containing combinations. Of the 60 evaluable patients, complete antinausea and antivomiting effects of D were observed in 30 (50%) and 34 (57%), respectively and of DMD in 17 (28%) and 26 patients (43%) respectively. The difference was not statistically significant (P = 0.09 and 0.24, respectively). Lack of significant difference between the two regimens was demonstrated irrespective of the administered cytotoxic drugs. The DMD protocol caused more adverse reactions than D. While 27 patients (45%) experienced no side effects from D, only 14 (24%) remained free of complications due to DMD (P = 0.001). Furthermore, DMD produced more sedation, insomnia, headache, diaphoresis, dizziness and diarrhoea than the D regimen. In addition it gave rise to more adverse effects on appetite and activity. Upon direct questioning, 37 patients (62%) expressed a preference for D, 14 (23%) preferred DMD and 9 (15%) found no difference between the two regimens. We conclude that, while the short DMD protocol has an antiemetic activity equivalent in its effectiveness to D, its associated adverse reactions would minimize its usefulness. Therefore, further investigations should be conducted to find a safer and more potent combination of antiemetics suitable for therapy in an outpatient setting.

Adolescent↗
PubMed2001

Harnessing the potential of dystrophin-related proteins for ameliorating Duchenne's muscular dystrophy.

Duchenne's muscular dystrophy (DMD) is a fatal disease caused by mutations in the DMD gene that lead to quantitative and qualitative disturbances in dystrophin expression. Dystrophin is a member of the spectrin superfamily of proteins. Dystrophin itself is closely related to three proteins that constitute a family of dystrophin-related proteins (DRPs): the chromosome 6-encoded DRP or utrophin, the chromosome-X encoded, DRP2 and the chromosome-18 encoded, dystrobrevin. These proteins share sequence similarity and functional motifs with dystrophin. Current attempts at somatic gene therapy of DMD face numerous technical problems. An alternative strategy for DMD therapy, that circumvents many of these problems, has arisen from the demonstration that the DRP utrophin can functionally substitute for the missing dystrophin and its overexpression can rescue dystrophin-deficient muscle. Currently, a promising avenue of research consists of identifying molecules that would increase the expression of utrophin and the delivery of these molecules to dystrophin-deficient tissues as a means of DMD therapy. In this review, we will focus on DRPs from the perspective of strategies and issues related to upregulating utrophin expression for DMD therapy. Additionally, we will address the techniques used for anatomical, biochemical and physiological evaluation of the potential benefits of this and other forms of DMD therapy in dystrophin-deficient animal models.

Animals↗
PubMed1991

Dystrophin as a diagnostic marker in Duchenne and Becker muscular dystrophy. Correlation of immunofluorescence and western blot.

Dystrophin is the gene product of the Duchenne (DMD) and Becker (BMD) muscular dystrophy gene locus on the short arm of the X chromosome. Complete lack of dystrophin is pathognomonic for DMD and variable changes of the molecule may be observed in the milder allelic form of BMD. In the present study the two methods available for dystrophin assessment, immunofluorescence detections on cryosections (IF) and Western blotting (WB) were systematically compared using polyclonal and monoclonal antibodies to various regions along the dystrophin molecule. A total of 95 patients with DMD or BMD were investigated including two female patients. Dystrophin assessment revealed abnormal abundance and/or distribution in all 95 patients with DMD or BMD. Only trace amounts of dystrophin were detected in 29% of the DMD patients and complete lack of dystrophin was found in 71%. In two females with DMD but with normal karyotype single dystrophin-positive fibres were found among more than 90% negative fibres. Out of 26 patients with BMD 19 (73%) had a dystrophin molecule of abnormal molecular weight. The results of IF were largely compatible with those from WB but differences were also observed, e.g. one barely symptomatic BMD patient with dystrophin of increased molecular weight showed normal IF. Out of four carriers of BMD three showed evidence of reduced dystrophin immunostaining in some muscle fibres. In 20 other patients limb girdle muscualar dystrophy with "Duchenne-like" or "Becker-like" phenotype was suspected because dystrophin showed normal abundance and distribution. Focal discontinuity of muscle cell-surface dystrophin staining was observed in one patient with a congenital, autosomal recessive muscular dystrophy and in one out of five patients with polymyositis/dermatomyositis. The study emphasizes the need for, and value of, dystrophin assessment in every case of suspected BMD or DMD.

Adolescent↗
PubMed2005

Tissue-specific changes in H19 methylation and expression in mice with hyperhomocysteinemia.

Expression of the imprinted genes H19 and insulin-like growth factor 2 (Igf2), which lie in close proximity on mouse chromosome 7, is regulated by methylation of a differentially methylated domain (DMD) located 5' to H19. Biallelic expression of H19 has been observed in renal disease patients with hyperhomocysteinemia, a cardiovascular disease risk factor. The present study determined whether hyperhomocysteinemia produces decreased tissue methylation capacity, hypomethylation of the H19 DMD, and altered expression of H19 and Igf2 in adult mice. Mice heterozygous for disruption of the gene for cystathionine-beta-synthase (Cbs+/-) and C57BL/6 (Cbs+/+) mice were fed a hyperhomocysteinemic or control diet, respectively, from weaning until 9-12 months of age. Higher plasma total homocysteine (p < 0.001) was found in hyperhomocysteinemic mice than in control mice (95 +/- 12 versus 5.0 +/- 0.3 micromol/liter). Hyperhomocysteinemia was accompanied by higher levels of S-adenosylhomocysteine (p < 0.05) and lower S-adenosylmethionine/S-adenosylhomocysteine ratios (p < 0.001) in liver and brain. The effect of hyperhomocysteinemia on H19 DMD methylation was tissue-specific. In liver, hyperhomocysteinemic mice had decreased H19 DMD methylation (p < 0.001). In brain, hyperhomocysteinemia was accompanied by increased H19 DMD methylation (p < 0.001) and a decrease in the ratio of H19/Igf2 transcripts (p < 0.05). In aorta, hyperhomocysteinemia produced an increase in H19 DMD methylation (p < 0.001) and a 2.5-fold increase in expression of H19 transcripts (p < 0.05). Levels of H19 transcripts in aorta correlated positively with plasma total homocysteine concentration (p < 0.05, r = 0.620). We conclude that hyperhomocysteinemia produces tissue-specific changes in H19 DMD methylation and increased vascular expression of H19 in adult mice.

Animals↗
PubMedDate not supplied

Parental stress in mothers of boys with duchenne muscular dystrophy.

OBJECTIVE: To examine parental stress in mothers of boys with Duchenne muscular dystrophy (DMD). METHOD: Stress and its predictors were examined in mothers of boys with DMD (n = 112). Comparisons were made with mothers of healthy children (n = 800), children with cerebral palsy (CP; n = 28), siblings of boys with DMD (n = 46), and longitudinally (n = 16). RESULTS: The presence of problem child behaviors consistently predicted maternal stress. Stress related to child behavior was higher in the DMD versus the normative group. No differences in stress were found in the DMD versus CP groups. Stress related to boys with DMD versus siblings was not significantly different. Over time, maternal stress related to child variables diminished. CONCLUSION: Stress in mothers of boys with DMD is elevated, possibly due to increased problem behaviors, particularly in social interactions, rather than due to the physical demands of the disease alone.

Adolescent↗
PubMed1999

Analysis of five Duchenne muscular dystrophy exons and gender determination using conventional duplex polymerase chain reaction on single cells.

We have developed five conventional duplex polymerase chain reaction (PCR) protocols on single lymphocytes and blastomeres from embryos, in order to analyse five exons commonly deleted in deletion-type Duchenne muscular dystrophy (DMD). The five DMD gene exons (17, 19, 44, 45 and 48) can be analysed in separate duplex PCR reactions together with the sex-determining region Y (SRY) gene which enables simultaneous gender assignment. We present here PCR amplification results from single lymphocytes isolated from a normal male (220 cells), a normal female (24 cells) and a male DMD patient (40 cells) carrying a deletion of exons 46-49 within the DMD gene. The method failed to produce a PCR signal for the SRY gene in 8/220 normal male cells (3.6%) and for a DMD exon in 0-4.5% of normal male cells. One negative control out of 112 was positive. When this method was used to analyse two blastomeres from each of five embryos, concordant results were obtained for each pair of blastomeres. All embryos produced signals for the DMD exon tested with four of the embryos found to be male and one female. This method is therefore suitable for preimplantation genetic diagnosis and will allow the transfer of healthy embryos (both male and female) in families carrying DMD gene deletions involving at least one of the five exons 17, 19, 44, 45 and 48.

DNA-Binding Proteins↗
PubMed1999

Blood loss in Duchenne muscular dystrophy: vascular smooth muscle dysfunction?

Patients with Duchenne muscular dystrophy (DMD) tend to bleed more during surgery than do patients with other conditions. A retrospective analysis of blood loss after spinal surgery for scoliosis was therefore undertaken in 102 patients undergoing surgery in the senior author's unit. These included 48 patients with DMD, 26 patients with spinal muscular atrophy, and a miscellaneous group of 28 other patients most of whom had idiopathic scoliosis. For each patient the age at surgery, estimated blood volume, duration of operation, Cobb angle, and number of vertebrae fused were recorded and compared. Expression of dystrophin in skeletal muscle and the underlying gene mutation were also determined. The estimated blood loss in patients with DMD was significantly higher than that in patients with spinal muscular atrophy undergoing the same or similar procedure (P < 0.005) and was also significantly greater than that of the third group, which consisted mostly of patients with idiopathic scoliosis (P < 0.0005). Blood loss in the patient group with DMD showed a significant relationship with duration of surgery (P < 0.05). As most patients expressed no dystrophin, this did not correlate with the estimated blood loss. There was also no correlation between the estimated blood loss and the type of gene mutation found causing DMD. The authors' previous observations confirm the increased blood loss in patients with DMD who undergo scoliosis surgery. Because children with DMD lack dystrophin in all muscle types, including smooth muscle, the excessive blood loss may be because of a poor vascular smooth muscle vaso-constrictive response due to a lack of dystrophin.

Adolescent↗
PubMed1984

Comparative study of alterations of skeletal muscle in Duchenne muscular dystrophy and polymyositis.

Histological and ultrastructural alterations of skeletal muscles in Duchenne muscular dystrophy (DMD) (32 cases) and polymyositis (PM) (33 cases) were compared qualitatively and quantitatively. Regeneration is more numerous in PM than DMD throughout all stages. Stromal fibrosis and hyaline fiber with delta lesion are characteristic for DMD. In the electron microscope, we observed the usual preservation of basement membrane in degenerating muscle fibers and uncomplicated muscle regeneration in PM. On the other hand, there were partial disruption of the plasma membrane lining the delta lesion and degeneration of basement membrane and probable invasion of collagen fiber into sarcoplasm in some hypercontracted fibers in DMD. Besides, there appeared atypical form of regeneration in DMD, namely myocytes arrested at the stage of mononuclear myoblast or primitive myotube with degeneration of myofibrils and cytoplasmic organelles. At the advanced stage of DMD, there was scarce activity of regeneration. Stromal fibrosis, abnormality of membrane systems, and failure of regeneration were the characteristics of DMD.

Adult↗
PubMed1990

Physiological properties of skinned fibres from normal and dystrophic (Duchenne) human muscle activated by Ca2+ and Sr2+.

1. Contractile activation properties of various types of normal and dystrophic (Duchenne muscular dystrophy, DMD) human muscle fibres were investigated using mechanically skinned fibres activated in Ca2(+)- and Sr2(+)-buffered solutions at room temperature (21-25 degrees C). 2. The majority of the normal human muscle fibres (18/22; 82%) could be classified according to the Ca2(+)- and Sr2(+)-activation characteristics in the same three major groups as other mammalian skeletal muscle fibres studied previously: slow-twitch (8/22; 36%), fast-twitch (3/22; 14%) and fast-twitch intermediate (7/22; 32%), which correspond to the three major histological fibre types I, II B and IIA respectively. 3. Of these three major groups only the slow-twitch (type I; 14/24; 58%) and the fast-twitch intermediate (type IIA; 3/24; 13%) fibres were found in the DMD muscle, indicating that fast-twitch fibres of type IIB were in very low proportion in DMD muscle. 4. The DMD muscle contained a new group of fibres (4/24; 17%) with different Ca2(+)- and Sr2(+)-activation characteristics from the three major histological types. This group of fibres is likely to be of embryonic type. 5. The maximum tension development ability of DMD fibres was less than 20% of that in normal fibres with the exception of some slow-twitch fibres which could produce near normal tension. 6. A significant proportion of normal (4/22; 18%) and DMD (3/24; 13%) fibres were found to have a mixture of Ca2(+)- and Sr2(+)-activation characteristics. This can be explained by co-existence of various myofibrillar protein isoforms in different proportions with regulatory functions in the same individual fibre. 7. The results demonstrate that DMD leads to marked diminution in the ability of most individual skeletal muscle fibres to develop tension, and causes changes in the overall fibre-type distribution in afflicted muscles.

Calcium↗
PubMed1988

Expression of the murine Duchenne muscular dystrophy gene in muscle and brain.

Complementary DNA clones were isolated that represent the 5' terminal 2.5 kilobases of the murine Duchenne muscular dystrophy (Dmd) messenger RNA (mRNA). Mouse Dmd mRNA was detectable in skeletal and cardiac muscle and at a level approximately 90 percent lower in brain. Dmd mRNA is also present, but at much lower than normal levels, in both the muscle and brain of three different strains of dystrophic mdx mice. The identification of Dmd mRNA in brain raises the possibility of a relation between human Duchenne muscular dystrophy (DMD) gene expression and the mental retardation found in some DMD males. These results also provide evidence that the mdx mutations are allelic variants of mouse Dmd gene mutations.

Animals↗
PubMed1984

Clinical use of DNA markers linked to the gene for Duchenne muscular dystrophy.

Seventy families with Duchenne muscular dystrophy (DMD) known to the Institute of Child Health fall into three categories with respect to potential linkage analysis with the X chromosome DNA markers RC8 and L1.28 that bridge the DMD gene. Families in which there is at least one obligatory female heterozygote (n = 13). Here 'prediction' and 'exclusion' of DMD gene transmission may be possible, the accuracy being dependent on the closeness of the linkage of the DNA marker(s) to the DMD gene; an illustrative case is reported. Families in which there is a single affected boy, who also has one or more healthy brothers (n = 26). Given an informative restriction fragment length polymorphism (RFLP), the probability that the boy represents a new mutation can be reassessed; it is also possible to 'exclude' the DMD gene in a sister. Families with a single affected boy with no brother (n = 30). Here 'exclusion' of the DMD gene in a sister may be possible. Only in one family was there no possibility of useful linkage analysis. The linkage analysis required is described, and the need to check DMD families for informative RFLPs is stressed.

Base Sequence↗
PubMed1986

DNA probe analysis for carrier detection and prenatal diagnosis of Duchenne muscular dystrophy: a standard diagnostic procedure.

Thirteen marker loci localised on the short arm of the X chromosome are available for use in genetic studies for Duchenne muscular dystrophy (DMD). This large number of probes detecting about 20 RFLPs encouraged us to set up a standard procedure using a sequence of selected probes and restriction enzymes for the diagnosis of DMD families. The application of DNA probe analysis for carrier detection and prenatal diagnosis, involving 61 pedigrees of both familial and isolated cases, has yielded the following results. Carrier detection using flanking markers was possible in more than 75% of the cases (104 out of 136 females) with a reliability of better than 98%. Prenatal diagnosis was possible in 95% of the cases (65 out of 68 proven carriers or women at risk). Twenty-three prenatal diagnoses were performed on male fetuses; 13 appeared to have a low risk for DMD (less than 1%) and thus the pregnancies continued. Seven have since come to term and the male infants have normal CK levels. The genetic distances of the loci relative to the DMD locus and their order on the short arm of the X chromosome were deduced from our total DMD family material and are not significantly different from those reported earlier. For 754 (DXS84) we found a genetic distance of 5 cM with a lod score of +12.4 and 95% confidence limits between 2 and 12 cM. Similar data were obtained for pERT87 (DXS164), suggesting that in our family material both loci are tightly linked. Multiply informative recombination showed that both 754 and pERT87 map proximal to the DMD mutations in the cases studied. The high frequency of DMD mutations and its relation to the observed instability in this part of the genome will be discussed. Unequal crossing over is proposed as one of the mechanisms contributing to the high mutation frequency.

Chromosome Mapping↗
PubMed1993

Development and validation of laboratory procedures for preimplantation diagnosis of Duchenne muscular dystrophy.

In order to develop and validate methods for the preimplantation diagnosis of Duchenne muscular dystrophy (DMD), we have established and evaluated PCR assays for the analysis of four loci within the DMD gene and for two Y chromosome sequences in single cells. A model system using buccal cells picked from mouthwash samples has been used for an extensive evaluation of the sensitivity and specificity of the assays, and each assay has been tested in samples containing single cells, two cells, and three cells per tube. The four DMD and two Y assays have been combined in duplex and triplex reactions to enable simultaneous diagnosis of DMD and of fetal sex. One of the DMD markers is a highly polymorphic simple tandem repeat locus which produces a basic DNA profile, and provides a control for contamination by foreign DNA. Amplification of DMD or Y sequences was observed in 78 to 92% of single male cells, rising to 96% and 97% in tubes containing two or three male cells respectively. Coamplification of both a DMD and a Y sequence together occurred with a mean success of 74% in single male cells, increasing to 93% with two, and 95% with three cells per tube. With appropriate precautions, we believe that it is now possible to proceed to clinical application of these procedures.

Base Sequence↗
PubMed1988

Mapping of 12 translocation breakpoints in the Xp21 region with respect to the locus for Duchenne muscular dystrophy.

Over 20 females have been reported to carry reciprocal X; autosome translocations with breakpoints in Xp21 and to suffer from Duchenne muscular dystrophy (DMD). We have positioned nine of these breakpoints with respect to the Duchenne gene by mapping probes from the DMD region against a panel of somatic cell hybrids, each containing one of the translocation chromosomes from a different female patient; further information has also been obtained by in situ hybridization, including the breakpoint location in a tenth DMD patient. We have also characterized two translocation breakpoints that lie in the same chromosomal region but which are not associated with the expression of DMD. All the DMD-associated translocation breakpoints examined lie at several sites within the DMD locus and between the two non-DMD breakpoints.

Cell Line↗
PubMed1978

Muscle wasting and carbohydrate homeostasis in Duchenne muscular dystrophy.

Carbohydrate homeostasis was evaluated in nine patients with Duchenne muscular dystrophy (DMD), and in six age-matched normal boys. Mild carbohydrate intolerance was observed in the DMD patients during an oral glucose tolerance test. Only minor differences were observed between the DMD patients and the normal subjects during an oral glucose tolerance test. Only minor differnences were observed between the DMD patients and the normal subjects during a 30-hour period of caloric deprivation. Despite obvious muscle wasting and significant hypoalaninemia, the DMD group was resistant to fasting hypoglycemia. Plasma glutamine concentrations were the same in both groups under all study conditions. Dueterium-labeled glucose and alanine flux studies documented normal glucose inflow and outflow rates and decreased alanine inflow and outflow rates in the DMD group. The 40 percent reduction in alanine turnover, however, was less than expected for a group of patients with an estimated 67 percent reduction in muscle mass. These observations suggest that there may be accelerated protein degradation in the muscles of DMD patients.

Adolescent↗
PubMed1987

Spreading behaviour of cultured fibroblasts from carriers of Duchenne muscular dystrophy.

Cultured skin fibroblasts from patients with Duchenne muscular dystrophy (DMD) are more sensitive than normal cells to prolonged exposure to the ionophore monensin. In a cell spreading assay in which cells were preincubated with monensin and subsequently allowed to adhere to and spread on a glass substratum in serum-free medium for 100 min, the mean transformed cell area of normal and DMD cells was 5.97 +/- 0.11 and 5.29 +/- 0.03, respectively. Cultured fibroblasts from carriers of DMD yielded a value of 5.59 +/- 0.03, which is intermediate between, and significantly different from, the values for both normal and DMD cultures. This result would be predicted on the basis of random X-chromosome inactivation in female carriers of this disorder. However, comparison of DMD carrier cell spreading data with data obtained from pooled and summated measurements taken from separate experiments using either normal or DMD fibroblasts suggest a more complex situation. Examination of the variance of the means of cell area for the true carrier population and the summated normal and DMD population provides evidence suggesting that some form of cellular interaction may occur between the two cell genotypes in culture.

Cell Adhesion↗
PubMed1989

The kinetics of cell-substratum detachment mediated by trypsin: a comparison of normal and Duchenne fibroblasts.

In previous studies of cell-cell and cell-substratum adhesion, we have identified differences in the behaviour between human skin fibroblasts cultured from normal individuals and patients with Duchenne muscular dystrophy (DMD). In these studies, monolayer cultures were dissociated by trypsinization and no detectable difference was noted in the efficiency of cell dissociation between normal and DMD fibroblast cultures. However, a detailed study by Kent has suggested that Duchenne fibroblasts exhibit increased sensitivity to trypsin. We have re-investigated this finding using an assay that directly measures the number of cells remaining attached to a substratum following trypsinization. In a series of experiments using cultures derived from five normal and five DMD individuals, we can detect no significant difference in the trypsin-induced detachment rates between normal and DMD skin fibroblasts. This observation applies to both growth-phase and stationary-phase cell cultures. This inconsistency with previously reported data on the trypsin-sensitivity of DMD cells is considered in terms of the different assays used and the effects of trypsin on cell-cell and cell-substratum adhesion. The relationship between abnormalities in the behaviour of DMD cells and the localization and primary structure of the DMD gene product are also discussed.

Cell Adhesion↗
PubMed2006

Altered alpha1-syntrophin expression in myofibers with Duchenne and Fukuyama muscular dystrophies.

Alpha1-syntrophin, a scaffolding adapter and modular protein, is a cytoplasmic component of the dystrophin glycoprotein complex. This study investigated immunohistochemically the expression of alpha1-syntrophin in Duchenne and Fukuyama muscular dystrophies (DMD and FCMD, respectively). Biopsied muscles of five DMD, five FCMD, five normal controls and five disease controls (three myotonic and two facioscapulohumeral dystrophies) were analyzed. Immunoblot analysis showed that anti-alpha1-syntrophin antibody had a decreased reaction in both DMD and FCMD muscle extracts. Biopsied muscle sections and their serial sections were immunostained with rabbit anti-alpha1-syntrophin and rabbit anti-muscle-specific beta-spectrin antibodies, respectively. Immunoreactive patterns of sarcolemma were classified into (i) a continuously positive immunostaining pattern, (ii) a partially positive immunostaining pattern, (iii) a negative immunostaining pattern and (iv) a faint but entire surface positive immunostaining pattern. The group mean percentages of alpha1-syntrophin and beta-spectrin immunonegative myofibers in the DMD group were 39.3% and 10.8%, respectively, while those in the FCMD group were 45.5% and 10.4%, respectively. These values were statistically significant compared with those of disease control and normal control muscles. Thus we found that dystrophin-deficient DMD muscles contained significant numbers of alpha1-syntrophin-positive fibers and significant numbers of alpha1-syntrophin-negative fibers were present in dystrophin-positive muscles of severe muscular dystrophy such as FCMD. Alpha-dystrobrevin immunoreactivity was tested in DMD muscles and appreciable amounts of alpha-dystrobrevin that binds to syntrophin were found in DMD muscle membranes.

Adolescent↗