A non-DM1, non-DM2 multisystem myotonic disorder with frontotemporal dementia: phenotype and suggestive mapping of the DM3 locus to chromosome 15q21-24.

The majority of proximal myotonic myopathy syndromes reported so far have been related to the myotonic dystrophy (DM) type 2 (DM2) mutation, an expanded (CCTG)n repeat in the ZNF9 gene. Here, we describe the phenotype and the histological features in muscle and brain of the first large pedigree with a non-myotonic dystrophy type 1 (DM1) non-DM2 multisystem myotonic disorder associated with severe frontotemporal dementia. Thirty individuals from three generations underwent detailed neurological, neuropsychological, electrophysiological, brain imaging and molecular analyses. Ten of them had proximal muscle weakness at onset, clinical/electrical myotonia and DM-type cataracts. The mean age at onset was 46.7 +/- 12.6 years (range: 32-69). Dementia was observed later in the course of the disease. On muscle biopsies, rare nuclear clumps, rimmed vacuoles and small angulated type 1 and type 2 fibres were seen early in the disease. They were replaced by fibrous adipose tissue at later stages. Immunohistochemical analysis of myosin heavy chain isoforms showed no selective fibre type atrophy-both type 1 and type 2 fibres being affected. Cortical atrophy without white matter lesions was seen on brain MRI. A brain single photon emission computed tomography (SPECT) study revealed marked frontotemporal hypoperfusion. Post-mortem examination of the brains of two patients showing prominent frontotemporal spongiosis, neuronal loss and rare neuronal and glial tau inclusions suggested frontotemporal dementia. Western blot analyses of the tau protein showed a triplet of isoforms (60, 64 and 69 kDa) in neocortical areas, and a doublet (64 and 69 kDa) in subcortical areas that distinguish our myotonic disorder from other's myotonic dystrophies. Molecular analyses failed to detect a repeat expansion in the DMPK and ZNF9 genes excluding both DM1 and DM2, whereas a genome-wide linkage analysis strongly suggested a linkage to chromosome 15q21-24. This previously unreported multisystem myotonic disorder including findings resembling DM1, DM2 and frontotemporal dementia provides further evidence of the clinical and genetic heterogeneity of the myotonic dystrophies. We propose to designate this disease myotonic dystrophy type 3, DM3.

A preliminary report of knowledge translation: lessons from taking screening and brief intervention techniques from the research setting into regional systems of care.

This article describes a limited statewide dissemination of an evidence-based technology, screening, brief intervention, and referral to treatment (SBIRT), and evaluation of the effects on emergency department (ED) systems of care, utilizing the knowledge translation framework of reach, effectiveness, adoption, implementation, and maintenance (RE-AIM), using both quantitative and qualitative data sources. Screening and brief intervention (SBI) can detect high-risk and dependent alcohol and drug use in the medical setting, provide early intervention, facilitate access to specialty treatment when appropriate, and improve quality of care. Several meta-analyses demonstrate its effectiveness in primary care, and the federal government has developed a well-funded campaign to promote physician training and adoption of SBI. In the busy environment of the ED, with its competing priorities, researchers have tested a collaborative approach that relies on peer educators, with substance abuse treatment experience and broad community contact, as physician extenders. The ED-SBIRT model of care reflects clinician staff time constraints and resource limitations and is designed for the high rates of prevalence and increased acuity typical of ED patients. This report tracks services provided during dissemination of the ED-SBIRT extender model to seven EDs across a northeastern state, in urban, suburban, and rural community settings. Twelve health promotion advocates (HPAs) were hired, trained, and integrated into seven ED teams. Over an 18-month start-up period, HPAs screened 15,383 patients; of those, 4,899 were positive for high risk or dependent drinking and/or drug use. Among the positive screens, 4,035 (82%) received a brief intervention, and 57% of all positives were referred to the substance abuse treatment system and other community resources. Standardized, confidential interviews were conducted by two interviewers external to the program with 24 informants, including HPAs and their supervisors, clinicians, nurse managers, and ED directors across five sites. A detailed semistructured format was followed, and results were coded for thematic material. Barriers, challenges, and successes are described in the respondents' own words to convey their experience of this demonstration of SBIRT knowledge translation. Five of seven sites were sustained through the second year of the program, despite cutbacks in state funding. The dissemination process provided a number of important lessons for a large rollout. Successful implementation of the ED-SBIRT HPA model depends on 1) external funding for start-up; 2) local ED staff acting as champions to support the HPA role, resolve territorial issues, and promote a cultural shift in the ED treatment of drug and alcohol misuse from "treat and street" to prevention, based on a knowledge of the science of addiction; 3) sustainability planning from the beginning involving administrators, the billing and information technology departments, medical records coders, community service providers, and government agencies; and 4) creation and maintenance of a robust referral network to facilitate patient acceptance and access to substance abuse services.