Myotonic dystrophy (DM), the most common form of muscular dystrophy in adult humans, results from expansion of a CTG repeat in the 3' untranslated region of the DMPK gene. The mutant DMPK messenger RNA (mRNA) contains an expanded CUG repeat and is retained in the nucleus. We have expressed an untranslated CUG repeat in an unrelated mRNA in transgenic mice. Mice that expressed expanded CUG repeats developed myotonia and myopathy, whereas mice expressing a nonexpanded repeat did not. Thus, transcripts with expanded CUG repeats are sufficient to generate a DM phenotype. This result supports a role for RNA gain of function in disease pathogenesis.

We estimated the remaining lifetime risks of developing Alzheimer's disease (AD) and dementia from all causes, based on data from longitudinal population studies. The risk of developing AD during one's lifetime depends on both disease incidence and life expectancy. Conventional estimates of cumulative incidence overestimate the risk when there is a substantial probability of mortality due to competing causes. A total of 2,611 cognitively intact subjects (1,061 men, 1,550 women; mean age, 66 +/- 7 years) were prospectively evaluated for the development of AD or other dementia. A modified survival analysis was used to estimate both cumulative incidence and the sex-specific remaining lifetime risk estimates for quinquennial age groups above age 65 years. Over a 20-year follow-up period, 198 subjects developed dementia (120 with AD). The remaining lifetime risk of AD or other dementia depended on sex, being higher in women, but varied little with age between 65 and 80 years. In a 65-year-old man, the remaining lifetime risk of AD was 6.3% (95% CI, 3.9 to 8.7) and the remaining lifetime risk of developing any dementing illness was 10.9% (95% CI, 8.0 to 13.8); corresponding risks for a 65-year-old woman were 12% (95% CI, 9.2 to 14.8) and 19% (95% CI, 17.2 to 22.5). The cumulative incidence between age 65 and 100 years was much higher: for AD, 25.5% in men and 28.1% in women; for dementia, 32.8% in men and 45% in women. The actual remaining lifetime risk of AD or dementia varies with age, sex, and life expectancy and is lower than the hypothetical risk estimated by a cumulative incidence in the same population.

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Summary Background: Uninvestigated dyspepsia is common in family practice. The prevalence of clinically significant upper gastrointestinal findings (CSFs) in adult uninvestigated dyspepsia patients, and their predictability based on history, is unknown. Methods: Prompt endoscopy was performed within 10 days of referral, in 1040 adult patients presenting with uninvestigated dyspepsia at 49 Canadian family practitioner centres. Subsequent management strategies during a 6‐month follow‐up period were determined by the individual family practitioners. Results: CSFs were identified in 58% (603/1040) of patients. Erosive oesophagitis was most common (43%; N = 451); peptic ulcer was uncommon (5.3%; N = 55). Alarm symptoms were uncommon (2.8%; N = 29). Most patients had at least three dyspepsia symptoms, more than 80% had at least six, and approximately half had eight or more. Based on the dominant symptom, 463 (45%) patients had ulcer‐like, 393 (38%) had reflux‐like and 184 (18%) had dysmotility‐like dyspepsia. The patients' dominant symptom was not predictive of endoscopic findings. Oesophagitis was more common in those with dominant reflux‐like symptoms and was the most common finding in all subgroups. The prevalence of gastroduodenal findings was similar in all symptom subgroups. Helicobacter pylori (H. pylori) infection (30%; 301/1013) was associated with gastroduodenal findings. Conclusions: Dyspepsia subclassifications, based on dominant symptom, are of limited value in predicting the presence and nature of CSFs. Oesophagitis was by far the most common diagnosis (43% of patients). CSFs were common in uninvestigated dyspepsia patients and their nature suggests patients could be initially treated effectively, without endoscopy, using empirical acid suppressive therapy.

Myotonic dystrophy is caused by an expanded CTG repeat in the 39 untranslated region of the DM protein kinase (DMPK) gene. The expanded repeat triggers the nuclear retention of mutant DMPK transcripts, but the resulting underexpression of DMPK probably does not fully account for the severe phenotype. One proposed disease mechanism is that nuclear accumulation of expanded CUG repeats may interfere with nuclear function. Here we show by thermal melting and nuclease digestion studies that CUG repeats form highly stable hairpins. Furthermore, CUG repeats bind to the dsRNA-binding domain of PKR, the dsRNA-activated protein kinase. The threshold for binding to PKR is ;15 CUG repeats, and the affinity increases with longer repeat lengths. Finally, CUG repeats that are pathologically expanded can activate PKR in vitro. These results raise the possibility that the disease mechanism could be, in part, a gain of function by mutant DMPK transcripts that involves sequestration or activation of dsRNA binding proteins.