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1.  Identification of putative biomarkers for HIV-associated neurocognitive impairment in the CSF of HIV-infected patients under cART therapy determined by mass spectrometry 
Journal of neurovirology  2014;20(5):457-465.
We identified and measured proteins in the cerebral spinal fluid (CSF) involved in HIV-associated neurological disorders. Protein levels were determined by mass spectrometry (MS) in pooled CSF taken from three patient groups (human immunodeficiency virus (HIV)-1-infected patients that developed HIV-associated neurocognitive disorders (HANDs), HIV-1-infected patients without HAND, and healthy controls). Pools were generated from 10 patients each per group. CSF from individual patient groups were digested with trypsin and separately labeled using with isobaric tags for relative and absolute quantitation (iTRAQ). After combining all samples in one, peptides were extensively fractionated by offline two-dimensional separation and identified by tandem MS. One hundred and ninety three proteins were deemed to be interpretable for quantitation based on permutation tests with a 95 % confidence interval with a p value≤0.05. Using a cutoff of 1.5-fold for upregulation and 0.6 for downregulation, 16 proteins were differentially expressed in HIV+HAND (reporter p value ≤0.05) with seven of them previously described as HIV-interacting proteins: endoplasmin, mitochondrial damage mediator-BH3-interacting domanin death agonist, orosomucoid, apolipoprotein E, metalloproteinase inhibitor 2, peroxiredoxin-2, and the nuclear protein, ruvB-like 2. Several previously unidentified proteins with possible neurological implication in HIV patients include forming-binding protein 1, C-reactive protein, leukocyte-associated immunoglobulin receptor 1, renin receptor, mediator of RNA polymerase II transcription subunit 14, multimerin-2, alpha-N-acetylglucosaminidase, caldesmon, and cadherin EGF LAG G-type receptor. Our results suggest that not only a few but possibly a combination of biomarkers that are highly correlated can predict neurocognitive status in HIV-infected patients and might be involved in monocyte or macrophage activation.
PMCID: PMC4493746  PMID: 25056907
Mass spectrometry; i-TRAQ; HIV; Biomarker; Proteomics
3.  Splicing biomarkers of disease severity in myotonic dystrophy 
Annals of neurology  2013;74(6):862-872.
To develop RNA splicing biomarkers of disease severity and therapeutic response in myotonic dystrophy type 1 (DM1) and type 2 (DM2).
In a discovery cohort we used microarrays to perform global analysis of alternative splicing in DM1 and DM2. The newly identified splicing changes were combined with previous data to create a panel of 50 putative splicing defects. In a validation cohort of 50 DM1 subjects we measured the strength of ankle dorsiflexion (ADF) and then obtained a needle biopsy of tibialis anterior (TA) to analyze splice events in muscle RNA. The specificity of DM-associated splicing defects was assessed in disease controls. The CTG expansion size in muscle tissue was determined by Southern blot. The reversibility of splicing defects was assessed in transgenic mice by using antisense oligonucleotides (ASOs) to reduce levels of toxic RNA.
Forty-two splicing defects were confirmed in TA muscle in the validation cohort. Among these, 20 events showed graded changes that correlated with ADF weakness. Five other splice events were strongly affected in DM1 subjects with normal ADF strength. Comparison to disease controls and mouse models indicated that splicing changes were DM-specific, mainly attributable to MBNL1 sequestration, and reversible in mice by targeted knockdown of toxic RNA. Splicing defects and weakness were not correlated with CTG expansion size in muscle tissue.
Alternative splicing changes in skeletal muscle may serve as biomarkers of disease severity and therapeutic response in myotonic dystrophy.
PMCID: PMC4099006  PMID: 23929620
4.  Diagnostic Odyssey of Patients with Myotonic Dystrophy 
Journal of neurology  2013;260(10):2497-2504.
The onset and symptoms of the myotonic dystrophies are diverse, complicating their diagnoses and limiting a comprehensive approach to their clinical care. This report analyzes the diagnostic delay (time from onset of first symptom to diagnosis) in a large sample of myotonic dystrophy (DM) patients enrolled in the US National Registry [679 DM type 1 (DM1) and 135 DM type 2 (DM2) patients]. Age of onset averaged 34.0 ± 14.1 years in DM2 patients compared to 26.1 ± 13.2 years in DM1 (p<0.0001). The most common initial symptom in DM2 patients was leg weakness (32.6%) compared to grip myotonia in DM1 (38.3%). Pain was reported as the first symptom in 11.1% of DM2 and 3.0% of DM1 patients (p<0.0001). Reaching the correct diagnosis in DM2 took 14 years on average (double the time compared to DM1) and a significantly higher percentage of patients underwent extended workup including electromyography, muscle biopsies, and finally genetic testing. DM patients who were index cases experienced similar diagnostic delays to non-index cases of DM. Further evaluation of how to shorten these diagnostic delays and limit their impact on burdens of disease, family planning, and symptom management is needed.
PMCID: PMC4162528  PMID: 23807151
myotonic dystrophy; facioscapulohumeral muscular dystrophy; registry; muscular dystrophy; clinical care guidelines
5.  Evoked myotonia can be “dialed-up” by increasing stimulus train length in Myotonic Dystrophy Type 1 
Muscle & nerve  2010;41(2):191-196.
It is unknown how evoked myotonia varies with stimulus frequency or train length, or how it compares to voluntary myotonia in myotonic dystrophy type 1 (DM1).
First dorsal interosseous (FDI) tetanic contractions evoked by trains of 10–20 ulnar nerve stimuli at 10–50 Hz were recorded in 10 DM1 patients and 10 normals. For comparison, maximum voluntary handgrip contractions were also recorded. An automated computer program placed cursors along the declining (relaxation) phase of the force recordings at 90 and 5% of peak force (PF) and calculated relaxation times (RTs) between these points.
For all stimulus frequencies and train lengths, evoked RTs were much shorter, and evoked PFs were much greater in normals than in DM1. In normals, evoked RT was independent of stimulus frequency and train length, while in DM1, RT was longer for train lengths of 20 stimuli (mean:9 seconds in DM1; 0.20 in normals) than for 10 stimuli (mean:3 seconds in DM1, 0.19 in normals), but it did not change with stimulus frequency. In both groups, PF increased greatly as stimulus frequency rose from 10 to 50 Hz but only slightly as train length rose from 10 to 20 stimuli. Voluntary handgrip RT (mean:1.9 seconds) was less than evoked FDI RT (mean:9 seconds).
In DM1, evoked RT can be “dialed up” by increasing stimulus train length. Evoked myotonia testing utilizing a stimulus paradigm of at least 20 stimuli at 30–50 Hz may be useful in anti-myotonic drug trials, particularly when grip RT is normal or equivocal.
PMCID: PMC4122294  PMID: 19750543
myotonia; myotonic dystrophy; handgrip; relaxation time
6.  A comparison of performance-based measures of function in HIV-associated neurocognitive disorders 
Journal of neurovirology  2011;17(2):159-165.
The objectives of this study are to compare the results of newer performance-based functional assessments in the study of HIV-associated neurocognitive disorders (HAND) and to correlate these functional assessments with specific levels of severity of HAND. One hundred fourteen HIV+ subjects in an existing cohort were evaluated with a medical history, neurological exam, neuropsychological test battery as well as subjective and novel objective measures of functional abilities. Self-reported measures of functional performance included the Karnofsky Performance Scale, a questionnaire for instrumental activities of daily living, and a questionnaire for physical quality of life measures. The newer objective functional performance assessments in cluded the Columbia Medication Management and the San Diego Finances tests. These newer performance-based measures of function were assessed for their ability to predict level of HAND. The two objective measures of functional performance, The Columbia Medication Management Scale and the San Diego Finances Test, were both associated with levels of severity of HAND. The Karnofsky Performance Scale and the questionnaires for role and physical quality of life were subjective measures that were also associated with specific levels of HAND. Newer measures of functional performance can be used to objectively evaluate functional impairment in HAND and validate different levels of HAND.
PMCID: PMC4022137  PMID: 21437751
HIV; HIV-associated neurocognitive disorders; Functional outcome measures
7.  Quantifying Cancer Absolute Risk and Cancer Mortality in the Presence of Competing Events after a Myotonic Dystrophy Diagnosis 
PLoS ONE  2013;8(11):e79851.
Recent studies show that patients with myotonic dystrophy (DM) have an increased risk of specific malignancies, but estimates of absolute cancer risk accounting for competing events are lacking. Using the Swedish Patient Registry, we identified 1,081 patients with an inpatient and/or outpatient diagnosis of DM between 1987 and 2007. Date and cause of death and date of cancer diagnosis were extracted from the Swedish Cause of Death and Cancer Registries. We calculated non-parametric estimates of absolute cancer risk and cancer mortality accounting for the high non-cancer competing mortality associated with DM. Absolute cancer risk after DM diagnosis was 1.6% (95% CI=0.4-4%), 5% (95% CI=3-9%) and 9% (95% CI=6-13%) at ages 40, 50 and 60 years, respectively. Females had a higher absolute risk of all cancers combined than males: 9% (95% CI=4-14), and 13% (95% CI=9-20) vs. 2% (95%CI= 0.7-6) and 4% (95%CI=2-8) by ages 50 and 60 years, respectively) and developed cancer at younger ages (median age =51 years, range=22-74 vs. 57, range=43-84, respectively, p=0.02). Cancer deaths accounted for 10% of all deaths, with an absolute cancer mortality risk of 2% (95%CI=1-4.5%), 4% (95%CI=2-6%), and 6% (95%CI=4-9%) by ages 50, 60, and 70 years, respectively. No gender difference in cancer-specific mortality was observed (p=0.6). In conclusion, cancer significantly contributes to morbidity and mortality in DM patients, even after accounting for high competing DM mortality from non-neoplastic causes. It is important to apply population-appropriate, validated cancer screening strategies in DM patients.
PMCID: PMC3827449  PMID: 24236163
8.  Correlates of Tumor Development in Patients with Myotonic Dystrophy 
Journal of neurology  2012;259(10):2161-2166.
Patients with myotonic dystrophy (DM) have recently been reported to be at increased risk of tumor development, but clinical associations related to this observation are unknown. We calculated the odds ratios (ORs) and 95% confidence intervals (CI) of self-reported tumor development by patients’ demographic and clinical characteristics to evaluate factors associated with tumor development in DM patients, using data from the National Registry of Myotonic Dystrophy and Facioscapulohumeral Dystrophy Patients and Family Members. Of the 911 participants, 47.5% were male and 85.7% had DM type 1 (DM1). Compared with DM1, patients with DM type 2 (DM2) were older at Registry enrollment (median age =55 vs. 44 years, p<0.0001) and at DM diagnosis (median age= 48 vs. 30 years, p<0.0001); and more likely to be females (p=0.001). At enrollment, 95 (10.4%) DM patients reported a history of benign or malignant tumor. Tumors were associated with female gender (OR=1.9, 95% CI=1.2–3.1, p=0.007) and DM1 (OR=2.1, 95% CI=1.1–4.1, p=0.03). In a subgroup analysis of patients with blood-based DNA testing results (397 DM1, 54 DM2), repeat expansion size was not associated with tumor risk in DM1 (p=0.26) or DM2 (p=0.34). In conclusion, female gender and DM1 subtype, but not DNA repeat expansion size, were associated with increased risk of tumors in DM. Follow-up studies are warranted to determine if oncogenes associated with dystrophia myotonica-protein kinase (DMPK) are altered in DM, and to determine if repeat expansion size, as in our study, is not associated with tumor development.
PMCID: PMC3469723  PMID: 22619053
Myotonic dystrophy; comorbidity; neoplasms; risk factors; repeat expansion size
9.  A novel computerized functional assessment for human immunodeficiency virus-associated neurocognitive disorder 
Journal of Neurovirology  2013;19(5):432-441.
Human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) is present in 30–60 % of HIV-positive (HIV+) individuals and can be assessed by neuropsychological testing and level of functional impairment. HAND diagnosis therefore requires accurate assessment of functional impairment. The Computer Assessment of Mild Cognitive Impairment (CAMCI) is a computer-based screening tool that includes performance-based measures of functional impairment. We sought to evaluate the CAMCI as a functional assessment tool in HAND. One hundred fourteen HIV+ patients and 38 HIV-negative (HIV−) patients underwent neuropsychological and CAMCI testing. Cognitive status for HIV+ subjects was classified using the Frascati criteria. HIV+ subjects grouped together and classified by cognitive impairment performed worse than HIV− subjects on several of the CAMCI tasks, including following directions to the supermarket (p = 0.05, p = 0.03), recalling which items to purchase (p = 0.01, p = 0.02), and remembering to stop at a supermarket (p < 0.01, p = 0.01) and the post office (p < 0.01, p = 0.03). After controlling for hepatitis C status and depression symptomatology, the tasks “following directions to the supermarket” and the “recalling which items to purchase” were no longer significant. The “remembering to run two separate errands” tasks retained their significance (p < 0.01 for both tasks). A subset of the CAMCI tasks therefore successfully differentiated HIV+ patients from HIV− individuals. Differences in hepatitis C status and depression symptomatology could account for some of the function assessment differences in the CAMCI. These results suggest the CAMCI could be a useful objective performance-based functional assessment in patients with HIV.
Electronic supplementary material
The online version of this article (doi:10.1007/s13365-013-0195-5) contains supplementary material, which is available to authorized users.
PMCID: PMC3790918  PMID: 24081883
HIV dementia [34]; Assessment of cognitive disorders/dementia [38]; HIV [144]; Neuropsychological assessment [205]
10.  Patient-reported impact of symptoms in myotonic dystrophy type 1 (PRISM-1) 
Neurology  2012;79(4):348-357.
To determine the most critical symptoms in a national myotonic dystrophy type 1 (DM1) population and to identify the modifying factors that have the greatest effect on the severity of these symptoms.
We performed a cross-sectional study of 278 adult patients with DM1 from the national registry of patients with DM1 between April and August 2010. We assessed the prevalence and relative significance of 221 critical DM1 symptoms and 14 disease themes. These symptoms and themes were chosen for evaluation based on prior interviews with patients with DM1. Responses were categorized by age, CTG repeat length, gender, and duration of symptoms.
Participants with DM1 provided symptom rating survey responses to address the relative frequency and importance of each DM1 symptom. The symptomatic themes with the highest prevalence in DM1 were problems with hands or arms (93.5%), fatigue (90.8%), myotonia (90.3%), and impaired sleep or daytime sleepiness (87.9%). Participants identified fatigue and limitations in mobility as the symptomatic themes that have the greatest effect on their lives. We found an association between age and the average prevalence of all themes (p < 0.01) and between CTG repeat length and the average effect of all symptomatic themes on participant lives (p < 0.01).
There are a wide range of symptoms that significantly affect the lives of patients with DM1. These symptoms, some previously underrecognized, have varying levels of importance in the DM1 population and are nonlinearly dependent on patient age and CTG repeat length.
PMCID: PMC3400095  PMID: 22786587
11.  A call for transparent reporting to optimize the predictive value of preclinical research 
Nature  2012;490(7419):187-191.
The US National Institute of Neurological Disorders and Stroke convened major stakeholders in June 2012 to discuss how to improve the methodological reporting of animal studies in grant applications and publications. The main workshop recommendation is that at a minimum studies should report on sample-size estimation, whether and how animals were randomized, whether investigators were blind to the treatment, and the handling of data. We recognize that achieving a meaningful improvement in the quality of reporting will require a concerted effort by investigators, reviewers, funding agencies and journal editors. Requiring better reporting of animal studies will raise awareness of the importance of rigorous study design to accelerate scientific progress.
PMCID: PMC3511845  PMID: 23060188
12.  Muscle weakness in myotonic dystrophy associated with misregulated splicing and altered gating of CaV1.1 calcium channel 
Human Molecular Genetics  2011;21(6):1312-1324.
Myotonic dystrophy type 1 and type 2 (DM1 and DM2) are genetic diseases in which mutant transcripts containing expanded CUG or CCUG repeats cause cellular dysfunction by altering the processing or metabolism of specific mRNAs and miRNAs. The toxic effects of mutant RNA are mediated partly through effects on proteins that regulate alternative splicing. Here we show that alternative splicing of exon 29 (E29) of CaV1.1, a calcium channel that controls skeletal muscle excitation–contraction coupling, is markedly repressed in DM1 and DM2. The extent of E29 skipping correlated with severity of weakness in tibialis anterior muscle of DM1 patients. Two splicing factors previously implicated in DM1, MBNL1 and CUGBP1, participated in the regulation of E29 splicing. In muscle fibers of wild-type mice, the CaV1.1 channel conductance and voltage sensitivity were increased by splice-shifting oligonucleotides that induce E29 skipping. In contrast to human DM1, expression of CUG-expanded RNA caused only a modest increase in E29 skipping in mice. However, forced skipping of E29 in these mice, to levels approaching those observed in human DM1, aggravated the muscle pathology as evidenced by increased central nucleation. Together, these results indicate that DM-associated splicing defects alter CaV1.1 function, with potential for exacerbation of myopathy.
PMCID: PMC3284119  PMID: 22140091
13.  If you build a rare disease registry, will they enroll and will they use it? Methods and data from the National Registry of Myotonic Dystrophy (DM) and Facioscapulohumeral Muscular Dystrophy (FSHD) 
Contemporary Clinical Trials  2011;33(2):302-311.
Registries are becoming increasingly important for rare diseases as experimental therapies develop. This report describes the methodology behind the National Registry of Myotonic Dystrophy (DM) and Facioscapulohumeral Muscular Dystrophy (FSHD) Patients and Family Members to facilitate the development of other rare disease registries. We also highlight data about the pathophysiology and select burdens of DM and FSHD reported at baseline and longitudinally.
The Registry consists of de-identified, patient reported information collected at baseline and annually and information from review of medical records. Investigators can use the Registry to analyze de-identified data and to facilitate recruitment into clinical studies.
To date, the Registry has enrolled 1611 members, facilitated 24 studies, and collected data annually for up to 8 years. Genetic test results were obtained in 56.2% of enrollees. Approximately one-third of members used assistive devices and another one-third reported psychological problems at baseline. Wheelchair use was reported for both short and long distances by 7.0% of DM and 18.1% of FSHD members. Approximately 60% of members reported their employment was affected by their disease.
Strengths of the Registry include large sample sizes, stringent review of clinical and molecular data, annually updated information, and regular interactions between patients and investigators. Registry data provide new insights into the burdens of DM and FSHD, such as, psychological problems and reduced employment. Opportunities abound for investigators to utilize Registry resources to assess the impact of these and other burdens on health care costs, progression of symptoms, and quality of life.
PMCID: PMC3357007  PMID: 22155025
Myotonic dystrophy; Facioscapulohumeral muscular dystrophy; Registry; Disease progression; Burdens of disease
14.  Cancer Risk among Patients with Myotonic Muscular Dystrophy 
Jama  2011;306(22):2480-2486.
Myotonic muscular dystrophy (MMD) is an autosomal dominant multisystem neuromuscular disorder characterized by unstable nucleotide repeat expansions. Case reports have suggested that MMD patients may be at increased risk of malignancy, putative risks which have never been quantified.
To quantitatively evaluate cancer risk in patients with MMD, overall, and by sex and age.
Design, Setting, and Participants
We identified 1,658 patients with an MMD discharge diagnosis in the Swedish Inpatient Hospital or Danish Patient Discharge Registries between 1977 and 2008. We linked these patients to their corresponding cancer registry. Patients were followed from date of first MMD-related inpatient or outpatient contact, to first cancer diagnosis, death, emigration, or completion of cancer registration.
Main Outcome Measures
Risks of all cancers combined, and by anatomic site, stratified by sex and age.
104 patients with an inpatient or outpatient discharge diagnosis of MMD developed cancer during post-discharge follow-up. This corresponds to an observed cancer rate of 73.4/10,000 person-years in MMD versus an expected rate of 36.9/10,000 in the general Swedish and Danish populations combined (SIR =2.0, 95% CI =1.6–2.4). Specifically, we observed significant excess risks of cancers of the endometrium (observed rate=16.1/10,000 person-years: SIR=7.6, 95%CI=4.0–13.2), brain (observed rate=4.9/10,000 person-years: SIR=5.3, 95%CI=2.3–10.4), ovary (observed rate=10.3/10,000 person-years: SIR=5.2, 95% CI=2.3–10.2), and colon (observed rate=7.1/10,000 person-years: SIR=2.9, 95%CI=1.5–5.1). Cancer risks were similar in females and males after excluding genital organ tumors (SIR=1.9, 95% CI=1.4–2.5 vs. 1.8, 95% CI=1.3–2.5, respectively, p-heterogeneity=0.81; observed rates=64.5 and 47.7/10,000 person-years in women and men, respectively), The same pattern of cancer excess was observed first in the Swedish, and then in the Danish cohorts, which were studied sequentially and initially analyzed independently.
MMD patients identified from the Swedish and Danish patient registries were at increased risk of cancer both overall and for selected anatomic sites.
PMCID: PMC3286183  PMID: 22166607
Myotonic dystrophy; genomic instability; cancer risk
15.  Laboratory Abnormalities in Patients with Myotonic Dystrophy Type 2 
Archives of neurology  2011;68(9):1180-1184.
Myotonic dystrophy type-2 (DM2) is a recently discovered adult muscular dystrophy. Similar to DM1, this disease causes progressive debilitating weakness, clinical myotonia, and early cataracts, and is thought to cause widespread physiologic dysfunction of multiple organ systems.
To analyze and compile the laboratory abnormalities of patients with DM2.
Baseline DM2 laboratory data were compiled representing 68 different types of laboratory tests and 1442 total studies.
University Medical Center.
Eighty-three adults with genetically confirmed or clinically probable DM2 were identified. Of these patients, 49 had documented baseline laboratory screening.
Main Outcome Measures
The individual frequencies of abnormal values in the population with DM2 studied.
Of the 1442 studies, results for 359 (24.9%) were outside of their standard reference ranges. Of the 68 types of laboratory tests studied, 43 had values from fifteen or more different patients with DM2. The relative frequency of an abnormally elevated laboratory value was greater than 50% in several tests, including the levels of creatine kinase, total cholesterol, lactate dehydrogenase, and alanine aminotransferase (ALT). In addition, serum levels of immunoglobulin G (IgG) were low in 75% of all DM2 patients tested and absolute lymphocyte counts were low in 54% of all DM2 patients tested.
There is a high frequency of laboratory abnormalities in patients with DM2. These abnormalities provide insight into the widespread pathologic manifestations of DM2 and may form a basis for clinical monitoring and disease screening.
PMCID: PMC3429333  PMID: 21911698
16.  An Open-Label Trial of Recombinant Human Insulin-Like Growth Factor-I/Recombinant Human Insulin-Like Growth Factor Binding Protein-3 (rhIGF-1/rhIGFBP-3) in Myotonic Dystrophy Type 1 
Archives of Neurology  2010;68(1):37-44.
To evaluate the safety and tolerability of recombinant human insulin-like growth factor-1 (rhIGF-1) complexed with IGF binding protein-3 (rhIGF-1/rhIGFBP-3) in patients with myotonic dystrophy type 1 (DM1).
Open-label dose-escalation clinical trial.
University medical center.
Fifteen moderately affected ambulatory participants with genetically-proven DM1.
Participants received escalating dosages of subcutaneous rhIGF-1/rhIGFBP-3 over 24 weeks followed by a 16 week washout period.
Outcome Measures
Serial assessments of safety, muscle mass, muscle function, and metabolic state were performed. The primary outcome variable was the ability of participants to complete 24 weeks on rhIGF-1/rhIGFBP-3 treatment.
All participants tolerated rhIGF-1/rhIGFBP-3. There were no significant changes in muscle strength or functional outcomes measures. Lean body muscle mass measured by dual energy x-ray absorptiometry increased by 1.95 kg (p=0.0007) after treatment. Participants also experienced a mean reduction in triglyceride levels of 47 mg/dL (p=0.002), a mean increase in HDL levels of 5.0 mg/dL (p=0.03), a mean reduction in HbA1c of 0.15% (p=0.03), and a mean increase in testosterone level (in men) of 203 ng/dL (p=0.002) while on rhIGF-1/rhIGFBP-3. Mild reactions at the injection site occurred (n=9 participants), as did mild transient hypoglycemia (n=3), lightheadedness (n=2), and transient papilledema (n=1).
rhIGF-1/rhIGFBP-3 treatment was generally well tolerated in DM1. rhIGF-1/rhIGFBP-3 was associated with increased lean body mass and improvements in metabolism, but not with increased muscle strength or function. Larger randomized controlled trials would be needed to further evaluate the efficacy and safety of this medication in patients with neuromuscular disease.
PMCID: PMC3374954  PMID: 20837825
18.  Hypothesis: neoplasms in myotonic dystrophy 
Cancer causes & control : CCC  2009;20(10):2009-2020.
Tumorigenesis is a multi-step process due to an accumulation of genetic mutations in multiple genes in diverse pathways which ultimately lead to loss of control over cell growth. It is well known that inheritance of rare germline mutations in genes involved in tumorigenesis pathways confer high lifetime risk of neoplasia in affected individuals. Furthermore, a substantial number of multiple malformation syndromes include cancer susceptibility in their phenotype. Studies of the mechanisms underlying these inherited syndromes have added to the understanding of both normal development and the pathophysiology of carcinogenesis. Myotonic dystrophy (DM) represents a group of autosomal dominant, multisystemic diseases that share the clinical features of myotonia, muscle weakness, and early-onset cataracts. Myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2) result from unstable nucleotide repeat expansions in their respective genes. There have been multiple reports of tumors in individuals with DM, most commonly benign calcifying cutaneous tumors known as pilomatricomas. We provide a summary of the tumors reported in DM and a hypothesis for a possible mechanism of tumorigenesis. We hope to stimulate further study into the potential role of DM genes in tumorigenesis, and help define DM pathogenesis, and facilitate developing novel treatment modalities.
PMCID: PMC3110730  PMID: 19642006
Tumorigenesis; Myotonic dystrophy; Repeat expansion disorders; Pilomatricoma; β-Catenin
19.  Comparison of scales to evaluate the progression of HIV-associated neurocognitive disorder 
HIV therapy  2010;4(3):371-379.
First, to compare the characterization of neurocognitive deficits in milder stages of HIV-associated neurocognitive disorder (HAND) derived from existing dementia rating scales of the American Academy of Neurology (AAN) and Memorial Sloan Kettering (MSK) with the 2007 consensus (‘Frascati’) classification. Second, to identify potential sociodemographic and clinical predictors of HAND progression during 1-year follow-up.
104 HIV-infected subjects in an existing cohort system were evaluated with a medical history, exam, neuropsychological test battery and functional assessments. The degree of HAND was rated using the AAN, MSK and Frascati scales. The degree of concordance among these scales was determined. In addition, 45 subjects were reassessed for changes in their neurocognitive status at 1-year follow-up. Associations between age, education, sex, depression ratings, substance abuse, race, hepatitis C serostatus, CD4 count and progression of HAND were examined.
There was excellent concordance (γ > 0.8) among the Frascati, MSK and AAN ratings. Subjects rated as having minor cognitive motor disorder on the AAN scale (n = 45) were evenly split between Frascati rating of asymptomatic neurocognitive impairment (n = 24) and mild neurocognitive disorder (n = 21). At 1-year follow-up of 45 subjects, 31% had worsened, 13% had improved and 56% were stable. Predictors of progression included age older than 50 years (odds ratio: 5.57; p = 0.013) and female gender (odds ratio: 3.13; p = 0.036).
The Frascati HAND rating scale has excellent concordance with previous neurocognitive rating scales and can be used to better characterize milder stages of cognitive impairment. Older individuals and women appeared to be more likely to show neurocognitive progression.
PMCID: PMC2933171  PMID: 20824119
dementia rating scales; Frascati; HIV; HIV-associated neurocognitive disorders; progression
20.  Scaled-down genetic analysis of myotonic dystrophy type 1 and type 2 
Neuromuscular disorders : NMD  2009;19(11):759-762.
Types 1 and 2 myotonic dystrophy are neuromuscular disorders caused by genomic expansions of simple sequence repeats. These mutations are unstable in somatic cells, which leads to an age-dependent increase of expansion length. Studies to determine whether changes in repeat size may influence disease severity are limited by the small amount of DNA that can be recovered from tissue biopsies samples. Here we used locked nucleic acid oligonucleotide probes and rolling circle amplification to determine length of the expanded repeat in sub-microgram quantities of genomic DNA. These methods can facilitate genetic analysis in cells and tissues obtained from individuals with myotonic dystrophy.
PMCID: PMC2767455  PMID: 19713112
Myotonic dystrophy; repeat length; RCA; LNA
21.  Towards an integrative approach to the management of myotonic dystrophy type 1 
Myotonic dystrophy type 1 (DM1) is the most common type of muscular dystrophy in adults. Approximately 60% of individuals report either having difficulty performing or being unable to carry out some activities related to home management, mobility and transportation, work and leisure. Employment, educational level and income are, on average, lower than in the general population. The complexity and variability of disease manifestations in DM1 undoubtedly pose a challenge as regards anticipating all potential problems and developing a plan for health and community management. This article presents a conceptual model for DM1 management as well as a brief discussion of an approach for developing interdisciplinary health and community services.
PMCID: PMC2117723  PMID: 17449544

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