Browsing by Subject "Age of Onset"
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Item Open Access Application of a rank-based genetic association test to age-at-onset data from the Collaborative Study on the Genetics of Alcoholism study.(BMC Genet, 2005-12-30) Li, YJ; Martin, ER; Zhang, L; Allen, ASAssociation studies of quantitative traits have often relied on methods in which a normal distribution of the trait is assumed. However, quantitative phenotypes from complex human diseases are often censored, highly skewed, or contaminated with outlying values. We recently developed a rank-based association method that takes into account censoring and makes no distributional assumptions about the trait. In this study, we applied our new method to age-at-onset data on ALDX1 and ALDX2. Both traits are highly skewed (skewness > 1.9) and often censored. We performed a whole genome association study of age at onset of the ALDX1 trait using Illumina single-nucleotide polymorphisms. Only slightly more than 5% of markers were significant. However, we identified two regions on chromosomes 14 and 15, which each have at least four significant markers clustering together. These two regions may harbor genes that regulate age at onset of ALDX1 and ALDX2. Future fine mapping of these two regions with densely spaced markers is warranted.Item Open Access Are quit attempts among U.S. female nurses who smoke different from female smokers in the general population? An analysis of the 2006/2007 tobacco use supplement to the current population survey.(BMC Womens Health, 2012-03-19) Sarna, Linda; Bialous, Stella Aguinaga; Nandy, Karabi; Yang, QingBACKGROUND: Smoking is a significant women's health issue. Examining smoking behaviors among occupational groups with a high prevalence of women may reveal the culture of smoking behavior and quit efforts of female smokers. The purpose of this study was to examine how smoking and quitting characteristics (i.e., ever and recent quit attempts) among females in the occupation of nursing are similar or different to those of women in the general population. METHODS: Cross-sectional data from the Tobacco Use Supplement of the Current Population Survey 2006/2007 were used to compare smoking behaviors of nurses (n = 2, 566) to those of non-healthcare professional women (n = 93, 717). Smoking characteristics included years of smoking, number of cigarettes, and time to first cigarette with smoking within the first 30 minutes as an indicator of nicotine dependence. Logistic regression models using replicate weights were used to determine correlates of ever and previous 12 months quit attempts. RESULTS: Nurses had a lower smoking prevalence than other women (12.1% vs 16.6%, p < 0.0001); were more likely to have ever made a quit attempt (77% vs 68%, p = 0.0002); but not in the previous 12 months (42% vs 43%, p = 0.77). Among those who ever made a quit attempt, nurses who smoked within 30 minutes of waking, were more likely to have made a quit attempt compared to other women (OR = 3.1, 95% CI: 1.9, 5.1). When considering quit attempts within the last 12 months, nurses whose first cigarette was after 30 minutes of waking were less likely to have made a quit attempt compared to other females (OR = 0.69, 95% CI: 0.49, 0.98). There were no other significant differences in ever/recent quitting. CONCLUSIONS: Smoking prevalence among female nurses was lower than among women who were not in healthcare occupations, as expected. The lack of difference in recent quit efforts among female nurses as compared to other female smokers has not been previously reported. The link between lower level of nicotine dependence, as reflected by the longer time to first cigarette, and lower quit attempts among nurses needs further exploration.Item Open Access Association of MDMA/ecstasy and other substance use with self-reported sexually transmitted diseases among college-aged adults: a national study.(Public health, 2009-08-04) Wu, L-T; Ringwalt, CL; Patkar, AA; Hubbard, RL; Blazer, DGMDMA/ecstasy use among college students has increased and reportedly leads to risky sexual behaviours. However, little is known about its association with sexually transmitted diseases (STDs). To evaluate this public health concern, this study examined the association between substance use (particularly MDMA) and self-reported STDs (chlamydia, gonorrhoea, herpes and syphilis) among college students and non-students aged 18-22 years (n=20,858).A cross-sectional data analysis of a national survey.Data were drawn from the 2005-2006 National Surveys on Drug Use and Health; a nationally representative survey of non-institutionalized Americans. Self-reported STDs and substance use were assessed by the audio computer-assisted self-interviewing method. The association between MDMA use and STDs was determined while taking into account young adults' use of other substances, healthcare utilization and sociodemographic characteristics.Overall, 2.1% of college students and 2.5% of non-students reported contracting an STD in the past year. MDMA use in the past year was not associated with STDs. Among non-students, onset of MDMA use before 18 years of age increased the odds of past-year STDs. In both groups, alcohol use, marijuana use, female gender and African American race increased the odds of both past-year and lifetime STDs. Additional analyses indicated that, regardless of college-attending status, greater odds of past-year STDs were noted among users of alcohol and drugs, and users of alcohol alone, but not among users of drugs alone.Alcohol use is a robust correlate of STDs. Irrespective of college-attending status, young women and African Americans have a higher rate of STDs than young men and Whites.Item Open Access Concurrent use of methamphetamine, MDMA, LSD, ketamine, GHB, and flunitrazepam among American youths.(Drug and alcohol dependence, 2006-09) Wu, Li-Tzy; Schlenger, William E; Galvin, Deborah MThe magnitude and the characteristics of the use of methamphetamine, MDMA (Ecstasy), LSD (d-lysergic acid diethylamide), ketamine, GHB (gamma-hydroxybutyrate), and flunitrazepam (Rohypnol) were examined in a probability sample of the U.S. civilian population that included multiethnic urban, suburban, and rural youths aged 16-23 (N=19,084).Data were drawn from the National Survey on Drug Use and Health (NSDUH). Logistic regression analyses were conducted to identify the characteristics associated with the use of each of these drugs and of multiple drugs.Approximately 20% of youths aged 16-23 reported having ever used one or more of these drugs. Less than 1% of club drug users used club drugs only, and 82% of them had ever used three or more drug classes. Females were more likely than males to report using multiple club drugs. Recent users of methamphetamine were most likely to be females and adolescents aged 16 or 17. Recent users of MDMA tended to be young adults aged 18-21 and residents of metropolitan areas. Most recent users of LSD were adolescents aged 16-19 and those in low-income families. Ketamine users were primarily employed youths. Staying in school and getting married were associated with decreased odds of club drug use. Club drug use was highly associated with the presence of criminal behaviors and recent alcohol abuse or dependence.Adolescents are more likely than young adults to use multiple drugs. The clustering of multidrug use and alcohol use disorder is a cause of concern.Item Open Access Expanding the phenotype of late-onset Pompe disease: tongue weakness: a new clinical observation.(Muscle & nerve, 2011-12) Dubrovsky, Alberto; Corderi, Jose; Lin, Min; Kishnani, Priya S; Jones, Harrison NIntroduction
Following the clinical observation of lingual weakness in 2 patients with late-onset Pompe disease (LOPD), tongue strength was assessed in 19 consecutive patients to determine the frequency and severity of this neurological sign.Methods
Lingual strength was assessed using manual muscle testing; if weakness was present, severity was established as mild, moderate, or severe.Results
All the patients exhibited lingual weakness, even 2 asymptomatic patients with a positive family history. Weakness was mild in 12 (63%), moderate in 6 (32%), and severe in 1 (5%). Dysarthria and/or dysphagia were observed or reported in 7 of 19 (37%) patients.Conclusions
Lingual weakness may be present as an axial sign of LOPD, even relatively early in the disease course, and may contribute to the differential diagnosis of this now treatable condition. Dysphagia and/or dysarthria may also occur. This finding further expands the phenotype of LOPD.Item Open Access Hippocampus shape analysis and late-life depression.(PLoS One, 2008-03-19) Zhao, Zheen; Taylor, Warren D; Styner, Martin; Steffens, David C; Krishnan, K Ranga R; MacFall, James RMajor depression in the elderly is associated with brain structural changes and vascular lesions. Changes in the subcortical regions of the limbic system have also been noted. Studies examining hippocampus volumetric differences in depression have shown variable results, possibly due to any volume differences being secondary to local shape changes rather than differences in the overall volume. Shape analysis offers the potential to detect such changes. The present study applied spherical harmonic (SPHARM) shape analysis to the left and right hippocampi of 61 elderly subjects with major depression and 43 non-depressed elderly subjects. Statistical models controlling for age, sex, and total cerebral volume showed a significant reduction in depressed compared with control subjects in the left hippocampus (F(1,103) = 5.26; p = 0.0240) but not right hippocampus volume (F(1,103) = 0.41; p = 0.5213). Shape analysis showed significant differences in the mid-body of the left (but not the right) hippocampus between depressed and controls. When the depressed group was dichotomized into those whose depression was remitted at time of imaging and those who were unremitted, the shape comparison showed remitted subjects to be indistinguishable from controls (both sides) while the unremitted subjects differed in the midbody and the lateral side near the head. Hippocampal volume showed no difference between controls and remitted subjects but nonremitted subjects had significantly smaller left hippocampal volumes with no significant group differences in the right hippocampus. These findings may provide support to other reports of neurogenic effects of antidepressants and their relation to successful treatment for depressive symptoms.Item Open Access Injection drug use among stimulant users in a national sample.(The American journal of drug and alcohol abuse, 2004-01) Wu, Li-Tzy; Pilowsky, Daniel J; Wechsberg, Wendee M; Schlenger, William EOBJECTIVE:This study examined the correlates of injection drug use (IDU) in a community sample of psychostimulant users. Factors related to the cessation of illicit drug use and substance abuse service utilization were also determined among a subsample of stimulant users who reported IDU. METHOD:The study sample consisted of 3408 lifetime psychostimulant users from the National Household Survey on Drug Abuse. Logistic regression procedures were used to estimate independent associations of correlates of IDU. RESULTS:Approximately one in seven lifetime stimulant users reported IDU in their lifetime. Stimulant users with a lifetime history of IDU were more likely than those who did not inject to be African-American, not have received a high school diploma, have a history of multiple drug use, and report an onset of stimulant use before age 18. Among recent stimulant users, being aged 26 or older, using stimulants at least weekly, and getting drunk in the past year were associated with increased odds of recent IDU. Only one-half of all injection drug users reported having ever used substance abuse services. Cessation of illicit drug use among injectors with a history of stimulant use is common (44%). CONCLUSIONS:Further studies should clarify the natural history of IDU among stimulant users, including the cessation of drug use without participating in substance abuse treatment services.Item Open Access Neurodevelopmental outcomes of umbilical cord blood transplantation in metachromatic leukodystrophy.(Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2013-04) Martin, Holly R; Poe, Michele D; Provenzale, James M; Kurtzberg, Joanne; Mendizabal, Adam; Escolar, Maria LMetachromatic leukodystrophy (MLD) is an inherited demyelinating disease that causes progressive neurologic deterioration, leading to severe motor disability, developmental regression, seizures, blindness, deafness, and death. The disease presents as a late-infantile, juvenile, or adult form. Hematopoietic stem cell transplantation has been shown to slow disease progression. The purpose of this longitudinal study was to evaluate long-term treatment outcomes after unrelated donor umbilical cord blood (UCB) transplantation in pediatric patients according to disease burden and age at onset (ie, late-infantile versus juvenile). Engraftment, survival, treatment-related toxicity, graft-versus-host disease, neurophysiologic measures, and neurodevelopmental function were assessed. To evaluate whether signal intensity abnormalities on magnetic resonance imaging (ie, modified Loes scores) predict post-transplant cognitive and gross motor development, a general linear mixed model was fit to the data. Twenty-seven patients underwent transplantation after myeloablative chemotherapy; 24 patients engrafted after the initial transplantation. Seven patients died of infection, regimen-related toxicity, or disease progression. Twenty patients (6 with late-infantile onset and 14 with juvenile onset) were followed for a median of 5.1 years (range, 2.4 to 14.7). We found that patients with motor function symptoms at the time of transplant did not improve after transplantation. Brainstem auditory evoked responses, visual evoked potentials, electroencephalogram, and/or peripheral nerve conduction velocities stabilized or improved in juvenile patients but continued to worsen in most patients with the late-infantile presentation. Pretransplant modified Loes scores were highly correlated with developmental outcomes and predictive of cognitive and motor function. Children who were asymptomatic at the time of transplantation benefited most from the procedure. Children with juvenile onset and minimal symptoms showed stabilization or deterioration of motor skills but maintained cognitive skills. Overall, children with juvenile onset had better outcomes than those with late-infantile onset. As in other leukodystrophies, early intervention correlated with optimal outcomes. We conclude that UCB transplantation benefits children with presymptomatic late-infantile MLD or minimally symptomatic juvenile MLD.Item Open Access Neuropeptide Y gene polymorphisms confer risk of early-onset atherosclerosis.(PLoS Genet, 2009-01) Shah, SH; Freedman, NJ; Zhang, L; Crosslin, DR; Stone, DH; Haynes, C; Johnson, J; Nelson, S; Wang, L; Connelly, JJ; Muehlbauer, M; Ginsburg, GS; Crossman, DC; Jones, CJ; Vance, J; Sketch, MH; Granger, CB; Newgard, CB; Gregory, SG; Goldschmidt Clermont, PJ; Kraus, WE; Hauser, ERNeuropeptide Y (NPY) is a strong candidate gene for coronary artery disease (CAD). We have previously identified genetic linkage to familial CAD in the genomic region of NPY. We performed follow-up genetic, biostatistical, and functional analysis of NPY in early-onset CAD. In familial CAD (GENECARD, N = 420 families), we found increased microsatellite linkage to chromosome 7p14 (OSA LOD = 4.2, p = 0.004) in 97 earliest age-of-onset families. Tagged NPY SNPs demonstrated linkage to CAD of a 6-SNP block (LOD = 1.58-2.72), family-based association of this block with CAD (p = 0.02), and stronger linkage to CAD in the earliest age-of-onset families. Association of this 6-SNP block with CAD was validated in: (a) 556 non-familial early-onset CAD cases and 256 controls (OR 1.46-1.65, p = 0.01-0.05), showing stronger association in youngest cases (OR 1.84-2.20, p = 0.0004-0.09); and (b) GENECARD probands versus non-familial controls (OR 1.79-2.06, p = 0.003-0.02). A promoter SNP (rs16147) within this 6-SNP block was associated with higher plasma NPY levels (p = 0.04). To assess a causal role of NPY in atherosclerosis, we applied the NPY1-receptor-antagonist BIBP-3226 adventitially to endothelium-denuded carotid arteries of apolipoprotein E-deficient mice; treatment reduced atherosclerotic neointimal area by 50% (p = 0.03). Thus, NPY variants associate with atherosclerosis in two independent datasets (with strong age-of-onset effects) and show allele-specific expression with NPY levels, while NPY receptor antagonism reduces atherosclerosis in mice. We conclude that NPY contributes to atherosclerosis pathogenesis.Item Open Access Novel long QT syndrome-associated missense mutation, L762F, in CACNA1C-encoded L-type calcium channel imparts a slower inactivation tau and increased sustained and window current.(International journal of cardiology, 2016-10) Landstrom, AP; Boczek, NJ; Ye, D; Miyake, CY; De la Uz, CM; Allen, HD; Ackerman, MJ; Kim, JJBACKGROUND:Mutations in the CACNA1C-encoded L-type calcium channel have been associated with Timothy syndrome (TS) with severe QT prolongation, syndactyly, facial dysmorphisms, developmental delay, and sudden death. Recently, patients hosting CACNA1C mutations with only long QT syndrome (LQTS) have been described. We sought to identify novel variants in CACNA1C associated with either TS or LQTS, and to determine the impact of the mutation on channel function. METHODS/RESULTS:Two probands were identified with mutations in CACNA1C, one with a TS-associated mutation, G406R, and a second with genotype-negative LQTS. Illumina HiSeq 2000 whole exome sequencing on the genotype-negative LQTS proband revealed a novel variant, CACNA1C-L762F, that co-segregated within a multi-generational family. The missense mutation localized to the DII/DIII intracellular interlinker segment of the channel in a highly conserved region in close proximity to the 6th transmembrane segment of domain II (DIIS6). Whole cell patch clamp of heterologously expressed CACNA1C-L762F in TSA201 cells demonstrated slower inactivation tau and increased sustained and window current. Comprehensive review and topological mapping of all described CACNA1C mutations revealed TS-specific hotspots localizing to the cytoplasmic aspect of 6th transmembrane segment of respective domains. Probands hosting TS mutations were associated with elevated QTc, higher prevalence of 2:1 AV block, and a younger age at presentation compared to LQTS. CONCLUSIONS:The CACNA1C-L762F mutation is associated with development of LQTS through slower channel inactivation and increased sustained and window current. TS-associated mutations localize to specific areas of CACNA1C and are associated with a younger age at presentation, higher QTc, and 2:1 AV block than isolated LQTS-associated mutations.Item Open Access Polymorphisms in the SULF1 gene are associated with early age of onset and survival of ovarian cancer.(Journal of experimental & clinical cancer research : CR, 2011-01-07) Han, Chan H; Huang, Yu-Jing; Lu, Karen H; Liu, Zhensheng; Mills, Gordon B; Wei, Qingyi; Wang, Li-ESULF1 (sulfatase 1) selectively removes the 6-O-sulphate group from heparan sulfate, changing the binding sites for extracellular growth factors. SULF1 expression has been reported to be decreased in various cancers, including ovarian cancer. We hypothesized that single nucleotide polymorphisms (SNPs) of SULF1 would impact clinicopathologic characteristics.We genotyped five common (minor allele frequency>0.05) regulatory SNPs with predicted functionalities (rs2623047 G>A, rs13264163 A>G, rs6990375 G>A, rs3802278 G>A, and rs3087714 C>T) in 168 patients with primary epithelial ovarian cancer, using the polymerase chain reaction-restriction fragment length polymorphism method.We found that rs2623047 G>A was significantly associated with an early age of onset of ovarian cancer in the G allele dose-response manner (P = 0.027; Ptrend = 0.007) and that rs2623047 GG/GA genotypes were associated with longer progression-free survival; rs6990375 G>A was also associated with the early age of onset in the A allele dose-response manner (P = 0.013; Ptrend= 0.009). The significant differences in age of disease onset persisted among carriers of haplotypes of rs2623047 and rs6990375 (P = 0.014; Ptrend = 0.004). In luciferase reporter gene assays, rs2623047 G allele showed a slightly higher promoter activity than the A allele in the SKOV3 tumorigenic cell line.These findings suggest that genetic variations in SULF1 may play a role in ovarian cancer onset and prognosis. Further studies with large sample sizes and of the mechanistic relevance of SULF1 SNPs are warranted.Item Open Access Quantitative assessment of lingual strength in late-onset Pompe disease.(Muscle & nerve, 2015-05) Jones, Harrison N; Crisp, Kelly D; Asrani, Priyanka; Sloane, Richard; Kishnani, Priya SIntroduction
Skeletal muscle is common in late-onset Pompe disease (LOPD). Recent data implicate common bulbar muscle involvement (i.e., the tongue).Methods
We used quantitative assessment of lingual strength to retrospectively determine the frequency and severity of lingual weakness in LOPD. We additionally examined associations between lingual strength and the presence or absence of dysarthria, and dysarthria severity.Results
Quantitative assessment revealed lingual weakness to be present in 80% of the sample. In the 24 affected patients, severity was mild in 29%, moderate in 29%, and severe in 42%. Patients with clinical dysarthria had greater lingual weakness than those without. As dysarthria severity increased, lingual strength decreased by an average of 6.82 kPa.Conclusions
These quantitative data provide additional evidence for presence of bulbar muscle disease in patients with LOPD. Further study is necessary to determine functional effects, temporal progression, and effects of treatment.Item Open Access Respiratory muscle training (RMT) in late-onset Pompe disease (LOPD): Effects of training and detraining.(Molecular genetics and metabolism, 2016-02) Jones, Harrison N; Crisp, Kelly D; Robey, Randall R; Case, Laura E; Kravitz, Richard M; Kishnani, Priya SBackground
Determine the effects of a 12-week respiratory muscle training (RMT) program in late-onset Pompe disease (LOPD).Methods
We investigated the effects of 12-weeks of RMT followed by 3-months detraining using a single-subject A-B-A experimental design replicated across 8 adults with LOPD. To assess maximal volitional respiratory strength, our primary outcomes were maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP). Effect sizes for changes in MIP and MEP were determined using Cohen's d statistic. Exploratory outcomes targeted motor function, and peak cough flow (PCF) was measured in the last 5 subjects.Results
From pretest to posttest, all 8 subjects exhibited increases in MIP, and 7 of 8 showed increases in MEP. Effect size data reveal the magnitude of increases in MIP to be large in 4 (d≥1.0) and very large in 4 (d≥2.0), and effect sizes for increases in MEP were large in 1 (d≥1.0) and very large in 6 (d≥2.0). Across participants, pretest to posttest MIP and MEP increased by a mean of 19.6% (sd=9.9) and 16.1% (sd=17.3), respectively. Respiratory strength increases, particularly for the inspiratory muscles, were generally durable to 3-months detraining.Conclusions
These data suggest our 12-week RMT program results in large to very large increases in inspiratory and expiratory muscle strength in adults with LOPD. Additionally, increases in respiratory strength appeared to be relatively durable following 3-months detraining. Although additional research is needed, RMT appears to offer promise as an adjunctive treatment for respiratory weakness in LOPD.Item Open Access Substance abuse, treatment needs and access among female sex workers and non-sex workers in Pretoria, South Africa.(Subst Abuse Treat Prev Policy, 2009-05-27) Wechsberg, Wendee M; Wu, Li-Tzy; Zule, William A; Parry, Charles D; Browne, Felicia A; Luseno, Winnie K; Kline, Tracy; Gentry, AmandaBACKGROUND: This study examined cross-sectional data collected from substance-using female sex workers (FSW) and non-sex workers (non-SW) in Pretoria, South Africa, who entered a randomized controlled trial. METHODS: Women who reported alcohol use and recently engaging in sex work or unprotected sex were recruited for a randomized study. The study sample (N = 506) comprised 335 FSW and 171 female non-SW from Pretoria and surrounding areas. Self-reported data about alcohol and other drug use as well as treatment needs and access were collected from participants before they entered a brief intervention. RESULTS: As compared with female non-SW, FSW were found to have a greater likelihood of having a past year diagnosis of alcohol or other drug abuse or dependence, having a family member with a history of alcohol or other drug abuse, having been physically abused, having used alcohol before age 18, and having a history of marijuana use. In addition, the FSW were more likely to perceive that they had alcohol or other drug problems, and that they had a need for treatment and a desire to go for treatment. Less than 20% of participants in either group had any awareness of alcohol and drug treatment programs, with only 3% of the FSW and 2% of the non-SW reporting that they tried but were unable to enter treatment in the past year. CONCLUSION: FSW need and want substance abuse treatment services but they often have difficulty accessing services. The study findings suggest that barriers within the South African treatment system need to be addressed to facilitate access for substance-using FSW. Ongoing research is needed to inform policy change that fosters widespread educational efforts and sustainable, accessible, woman-sensitive services to ultimately break the cycle for current and future generations of at-risk South African women.Item Open Access Substance use disorders among inhalant users: results from the National Epidemiologic Survey on alcohol and related conditions.(Addictive behaviors, 2008-07) Wu, Li-Tzy; Howard, Matthew Owen; Pilowsky, Daniel JTo assess the prevalence, correlates, and age of onset of DSM-IV substance use disorders (SUDs) among adult inhalant users.Analyses were based on structured psychiatric interviews of a nationally representative sample of 43,093 US adults.The lifetime prevalence of SUDs among adult inhalant users was 96%. Alcohol (87%), marijuana (68%), nicotine (58%), cocaine (35%), hallucinogen (31%), and stimulant (28%) use disorders were more prevalent than inhalant use disorders (19%). An estimated 62% of inhalant users met criteria for a past-year SUD. Less education, residence in non-metropolitan areas, early onset of inhalant use, and a history of substance abuse treatment were associated with increased odds of having an inhalant use disorder. Inhalant users who were under age 30 or who were members of families with low incomes had increased odds of having nicotine dependence and an alcohol or drug use disorder in the past year. Compared with substance users without a history of inhalant use, inhalant users, on average, initiated use of cigarettes, alcohol, and almost all other drugs at younger ages, and had a higher lifetime prevalence of nicotine, alcohol, and any drug use disorder.Lifetime and past-year SUDs are prevalent among adults with a history of inhalant use.Item Open Access The emerging phenotype of late-onset Pompe disease: A systematic literature review.(Molecular genetics and metabolism, 2017-03) Chan, Justin; Desai, Ankit K; Kazi, Zoheb B; Corey, Kaitlyn; Austin, Stephanie; Hobson-Webb, Lisa D; Case, Laura E; Jones, Harrison N; Kishnani, Priya SBackground
Pompe disease is an autosomal recessive disorder caused by deficiency of the lysosomal glycogen-hydrolyzing enzyme acid α-glucosidase (GAA). The adult-onset form, late-onset Pompe disease (LOPD), has been characterized by glycogen accumulation primarily in skeletal, cardiac, and smooth muscles, causing weakness of the proximal limb girdle and respiratory muscles. However, increased scientific study of LOPD continues to enhance understanding of an evolving phenotype.Purpose
To expand our understanding of the evolving phenotype of LOPD since the approval of enzyme replacement therapy (ERT) with alglucosidase alfa (Myozyme™/Lumizyme™) in 2006.Methods
All articles were included in the review that provided data on the charactertistics of LOPD identified via the PubMed database published since the approval of ERT in 2006. All signs and symptoms of the disease that were reported in the literature were identified and included in the review.Results
We provide a comprehensive review of the evolving phenotype of LOPD. Our findings support and extend the knowledge of the multisystemic nature of the disease.Conclusions
With the advent of ERT and the concurrent increase in the scientific study of LOPD, the condition once primarily conceptualized as a limb-girdle muscle disease with prominent respiratory involvement is increasingly recognized to be a condition that results in signs and symptoms across body systems and structures.Item Open Access The high prevalence of substance use disorders among recent MDMA users compared with other drug users: Implications for intervention.(Addictive behaviors, 2009-08) Wu, Li-Tzy; Parrott, Andy C; Ringwalt, Christopher L; Patkar, Ashwin A; Mannelli, Paolo; Blazer, Dan GIn light of the resurgence in MDMA use and its association with polysubstance use, we investigated the 12-month prevalence of substance use disorders (SUDs) among adult MDMA users to determine whether they are at risk of other drug-related problems that would call for targeted interventions.Data were drawn from the 2006 National Survey on Drug Use and Health. Past-year adult drug users were grouped into three mutually exclusive categories: 1) recent MDMA users, who had used the drug within the past year; 2) former MDMA users, who had a history of using this drug but had not done so within the past year; and 3) other drug users, who had never used MDMA. Logistic regression procedures were used to estimate the association between respondents' SUDs and MDMA use while adjusting for their socioeconomic status, mental health, age of first use, and history of polydrug use.Approximately 14% of adults reported drug use in the past year, and 24% of those past-year drug users reported a history of MDMA use. Recent MDMA users exhibited the highest prevalence of disorders related to alcohol (41%), marijuana (30%), cocaine (10%), pain reliever/opioid (8%), and tranquilizer (3%) use. Adjusted logistic regression analyses revealed that, relative to other drug users, those who had recently used MDMA were twice as likely to meet criteria for marijuana and pain reliever/opioid use disorders. They were also about twice as likely as former MDMA users to meet criteria for marijuana, cocaine, and tranquilizer use disorders.Seven out of ten recent MDMA users report experiencing an SUD in the past year. Adults who have recently used MDMA should be screened for possible SUDs to ensure early detection and treatment.Item Open Access Time trends of incidence of age-associated diseases in the US elderly population: Medicare-based analysis.(Age Ageing, 2013-07) Akushevich, Igor; Kravchenko, Julia; Ukraintseva, Svetlana; Arbeev, Konstantin; Yashin, Anatoly IOBJECTIVES: time trends of age-adjusted incidence rates of 19 ageing-related diseases were evaluated for 1992-2005 period with the National Long Term Care Survey and the Surveillance, Epidemiology and End RESULTS Registry data both linked to Medicare data (NLTCS-Medicare and SEER-Medicare, respectively). METHODS: the rates were calculated using individual medical histories (34,077 individuals from NLTCS-Medicare and 199,418 from SEER-Medicare) reconstructed using information on diagnoses coded in Medicare data, dates of medical services/procedures and Medicare enrolment/disenrolment. RESULTS: increases of incidence rates were dramatic for renal disease [the average annual percent change (APC) is 8.56%, 95% CI = 7.62, 9.50%], goiter (APC = 6.67%, 95% CI = 5, 90, 7, 44%), melanoma (APC = 6.15%, 95% CI = 4.31, 8.02%) and Alzheimer's disease (APC = 3.96%, 95% CI = 2.67, 5.26%), and less prominent for diabetes and lung cancer. Decreases of incidence rates were remarkable for angina pectoris (APC = -6.17%, 95% CI = -6.96, -5.38%); chronic obstructive pulmonary disease (APC = -5.14%, 95% CI = -6.78,-3.47%), and ulcer (APC = -5.82%, 95% CI = -6.77,-4.86%) and less dramatic for carcinomas of colon and prostate, stroke, hip fracture and asthma. Incidence rates of female breast carcinoma, myocardial infarction, Parkinson's disease and rheumatoid arthritis were almost stable. For most diseases, an excellent agreement was observed for incidence rates between NLTCS-Medicare and SEER-Medicare. A sensitivity analysis proved the stability of the evaluated time trends. CONCLUSION: time trends of the incidence of diseases common in the US elderly population were evaluated. The results show dramatic increase in incidence rates of melanoma, goiter, chronic renal and Alzheimer's disease in 1992-2005. Besides specifying widely recognised time trends on age-associated diseases, new information was obtained for trends of asthma, ulcer and goiter among the older adults in the USA.Item Open Access Trade-off in the effect of the APOE gene on the ages at onset of cardiocascular disease and cancer across ages, gender, and human generations.(Rejuvenation Res, 2013-02) Kulminski, Alexander M; Culminskaya, Irina; Arbeev, Konstantin G; Ukraintseva, Svetlana V; Arbeeva, Liubov; Yashin, Anatoli IDecades of studies of candidate genes show their complex role in aging-related traits. We focus on apolipoprotein E e2/3/4 polymorphism and ages at onset of cardiovascular diseases (CVD) and cancer in the parental and offspring generations of the Framingham Heart Study participants to gain insights on the role of age and gender across generations in genetic trade-offs. The analyses show that the apolipoprotein E e4 allele carriers live longer lives without cancer than the non-e4 allele carriers in each generation. The role of the e4 allele in onset of CVD is age- and generation-specific, constituting two modes of sexually dimorphic genetic trade-offs. In offspring, the e4 allele confers risk of CVD primarily in women and can protect against cancer primarily in men of the same age. In the parental generation, genetic trade-off is seen in different age groups, with a protective role of the e4 allele against cancer in older men and its detrimental role in CVD in younger women. The puzzling complexity of genetic mechanisms working in different genders, ages, and environments calls for more detail and systemic analyses beyond those adapted in current large-scale genetic association studies.Item Open Access Trade-off in the effects of the apolipoprotein E polymorphism on the ages at onset of CVD and cancer influences human lifespan.(Aging Cell, 2011-06) Kulminski, Alexander M; Culminskaya, Irina; Ukraintseva, Svetlana V; Arbeev, Konstantin G; Arbeeva, Liubov; Wu, Deqing; Akushevich, Igor; Land, Kenneth C; Yashin, Anatoli IProgress in unraveling the genetic origins of healthy aging is tempered, in part, by a lack of replication of effects, which is often considered a signature of false-positive findings. We convincingly demonstrate that the lack of genetic effects on an aging-related trait can be because of trade-offs in the gene action. We focus on the well-studied apolipoprotein E (APOE) e2/3/4 polymorphism and on lifespan and ages at onset of cardiovascular diseases (CVD) and cancer, using data on 3924 participants of the Framingham Heart Study Offspring cohort. Kaplan-Meier estimates show that the e4 allele carriers live shorter lives than the non-e4 allele carriers (log rank = 0.016). The adverse effect was attributed to the poor survival of the e4 homozygotes, whereas the effect of the common e3/4 genotype was insignificant. The e3/4 genotype, however, was antagonistically associated with onsets of those diseases predisposing to an earlier onset of CVD and a later onset of cancer compared to the non-e4 allele genotypes. This trade-off explains the lack of a significant effect of the e3/4 genotype on survival; adjustment for it in the Cox regression model makes the detrimental effect of the e4 allele highly significant (P = 0.002). This trade-off is likely caused by the lipid-metabolism-related (for CVD) and nonrelated (for cancer) mechanisms. An evolutionary rationale suggests that genetic trade-offs should not be an exception in studies of aging-related traits. Deeper insights into biological mechanisms mediating gene action are critical for understanding the genetic regulation of a healthy lifespan and for personalizing medical care.