Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited myocardial disease that predominantly affects the right ventricle and is associated with ventricular arrhythmias that may lead to sudden cardiac death. Mutations within at least seven separate genes have been identified to cause ARVC, however a genetic culprit remains elusive in approximately 50% of cases. Although negative genetic testing may be secondary to pathogenic mutations within undiscovered genes, an alternative explanation may be the presence of large deletions or duplications involving known genes. These large copy number variants may not be detected with standard clinical genetic testing which is presently limited to direct DNA sequencing. We describe two cases of ARVC possessing large deletions involving plakophilin‐2 (PKP2) identified with microarray analysis and/or multiplex ligation‐dependent probe amplification (MLPA) that would have been classified as genotype negative with standard clinical genetic testing. A deletion of the entire coding region of PKP2 excluding exon 1 was identified in patient 1 and his son. In patient 2, MLPA analysis of PKP2 revealed deletion of the entire gene with subsequent microarray analysis demonstrating a de novo 7.9 Mb deletion of chromosome 12p12.1p11.1. These findings support screening for large copy number variants in clinically suspected ARVC cases without clear disease causing mutations following initial sequencing analysis. 相似文献
Paroxysmal kinesigenic dyskinesia is an episodic movement disorder caused by dominant mutations in the proline-rich transmembrane protein PRRT2, with onset in childhood and typically with improvement or resolution by middle age. Mutations in the same gene may also cause benign infantile seizures, which begin in the first year of life and typically remit by the age of 2 years. Many details of PRRT2 function at the synapse, and the effects of mutations on neuronal excitability in the pathophysiology of epilepsy and dyskinesia, have emerged through the work of several groups over the last decade. However, the age dependence of the phenotypes has not been explored in detail in transgenic models. Here, we report our findings in heterozygous and homozygous Prrt2 knockout mice that recapitulate the age dependence of dyskinesia seen in the human disease. We show that Prrt2 deletion reduces the levels of synaptic proteins in a dose-dependent manner that is most pronounced at postnatal day 5 (P5), attenuates at P60, and disappears by P180. In a test for foot slippage while crossing a balance beam, transient loss of coordination was most pronounced at P60 and less prominent at age extremes. Slower traverse time was noted in homozygous knockout mice only, consistent with the ataxia seen in rare individuals with biallelic loss of function mutations in Prrt2. We thus identify three age-dependent phenotypic windows in the mouse model, which recapitulate the pattern seen in humans with PRRT2-related diseases.
[Purpose] This study investigated the intra-rater, inter-rater and test-retest
reliability of the sideways step test (SST), its correlation with other indicators of
stroke-specific impairment, and the cut-off count best discriminating subjects with stroke
from their healthy counterparts. [Subjects and Methods] Forty-three subjects with chronic
stroke and 41 healthy subjects older than 50 years participated in this study. The SST was
administered along with the Fugl-Meyer motor assessment for the lower extremities
(FMA-LE), the five-times sit to stand (5TSTS) test, the Berg Balance Scale (BBS), the
movement velocity (MVL) by the limits of stability (LOS) test, the ten-metre walk (10mW)
test, the timed “Up and Go” (TUG) test and the Activities-specific Balance Confidence
(ABC) scale. [Results] The SST showed good to excellent intra-rater, inter-rater and
test-retest reliability. The SST counts correlated with 5TSTS times, 10mW times, TUG
times, and the FMA-LE and BBS scores. SST counts of 11 for the paretic leg and 14 for the
non-paretic leg were found to distinguish the healthy adults from subjects with stroke.
[Conclusion] The sideways step test is a reliable clinical test, which correlates with the
functional strength, gait speed, and functional balance of people with chronic stroke.Key words: Balance, Stroke, Rehabilitation相似文献
OBJECTIVE: To determine, over time, the rate and serotypes of pneumococci with reduced penicillin susceptibility obtained from children with invasive infection. DESIGN: Active, hospital-based, multicentre surveillance spanning from 1991 to 1998. SETTING: Eleven Canadian tertiary care paediatric facilities located from coast to coast. POPULATION STUDIED: 1847 children with invasive pneumococcal infection whose isolates (from a normally sterile site) were available for serotyping and standardized testing for penicillin susceptibility at the National Centre for Streptococcus. MAIN RESULTS: The prevalence of reduced penicillin susceptibility increased from 2.5% of 197 cases in 1991 to 13.0% of 276 cases in 1998. In the latter year, 8.7% of isolates had intermediate level resistance, and 4.3% had high level resistance. Since they were first detected in 1992, strains with high level resistance have been encountered only sporadically at most centres, but by 1998, all centres but two had encountered examples. Of 40 isolates with high level resistance and 101 isolates with intermediate level resistance, serotypes matched those included in new seven-valent conjugate vaccines for children in 97.5% and 79.2% of cases, respectively. CONCLUSIONS: Pneumococci with reduced susceptibility to penicillin are increasing in frequency across Canada among children with invasive infection. The Immunization Monitoring Program, Active data indicate that new conjugate vaccines could help to curb infections due to pneumococci with reduced susceptibility to penicillin but are unlikely to control completely the problem of antibiotic resistance. 相似文献
Cytosolic aldehyde dehydrogenase (ALDH), an enzyme responsible for oxidizing intracellular aldehydes, has an important role in ethanol, vitamin A, and cyclophosphamide metabolism. High expression of this enzyme in primitive stem cells from multiple tissues, including bone marrow and intestine, appears to be an important mechanism by which these cells are resistant to cyclophosphamide. However, although hematopoietic stem cells (HSC) express high levels of cytosolic ALDH, isolating viable HSC by their ALDH expression has not been possible because ALDH is an intracellular protein. We found that a fluorescent aldehyde, dansyl aminoacetaldehyde (DAAA), could be used in flow cytometry experiments to isolate viable mouse and human cells based on their ALDH content. The level of dansyl fluorescence exhibited by cells after incubation with DAAA paralleled cytosolic ALDH levels determined by Western blotting and the sensitivity of the cells to cyclophosphamide. Moreover, DAAA appeared to be a more sensitive means of assessing cytosolic ALDH levels than Western blotting. Bone marrow progenitors treated with DAAA proliferated normally. Furthermore, marrow cells expressing high levels of dansyl fluorescence after incubation with DAAA were enriched for hematopoietic progenitors. The ability to isolate viable cells that express high levels of cytosolic ALDH could be an important component of methodology for identifying and purifying HSC and for studying cyclophosphamide-resistant tumor cell populations. 相似文献
Corticosteroids have the ability to suppress the production of growth factors and cytokines and are thus implicated in the negative regulation of hematopoiesis. We have shown that the corticosteroids, prednisolone and dexamethasone, were able to effectively protect progenitor cells in four strains of mice against cell-cycle-specific antimetabolic chemotherapy agents. The highest levels of protection against 5-fluorouracil (FU; 200 mg/kg) were achieved when two or three intraperitoneal injections of dexamethasone were administered between - 7 and +3 hours at a dose of 7.5 mg/kg/injection (optimal dose) or by continuous infusion between -4 and +20 hours. This protective effect is manifested as an increase in the number of high proliferative potential colony-forming cells that survive in the bone marrow 3 days after treatment with FU from between 0.5% and 11% to between 10% and 34% of normal. The bone marrow progenitors and blood cell numbers return to normal from 3 to 5 days and 1 to 2 days earlier, respectively. Less dexamethasone than prednisolone is required to give an equivalent protective effect, which is consistent with their anti-inflammatory potency. These findings are further evidence of the negative regulatory role played by corticosteroids, and indicate that the treatment schedules of corticosteroids during cancer therapy need to be reexamined to obtain the maximum benefit from their use. 相似文献
From a large series of patients referred for endoscopic retrograde cholangiopancreatography to one endoscopist, 49 patients had the duodenoscopic appearance of a periampullary tumour. Thirty eight of these lesions were neoplastic, but the remaining 11 patients had inflammatory non-neoplastic lesions (pseudotumours). These could not be distinguished from the neoplasms on endoscopic appearances. The cholangiopancreatograms were similar except that the diameter of the pancreatic duct tended to be higher in the tumour group and gall stones were present significantly more often in the patients with pseudotumour. Endoscopic biopsy correctly diagnosed 28 of 34 ampullary carcinomas. Two of the 11 pseudotumour patients were subjected to surgical excision biopsy because of suspicious histological features of endoscopic biopsy. In the neoplastic group 19 patients underwent Whipple's procedure, seven surgical bypass, seven endoscopic sphincterotomy only and five died without successful biliary drainage. The overall one year survival was 44.7%. By contrast, the patients with pseudotumours were clinically well at a median follow up 24 months (range 12-41 months), after endoscopic sphincterotomy except for one 89 year old patient who died 22 months later from unrelated causes. 相似文献