Ann Manzardo - Academia.edu (original) (raw)
Papers by Ann Manzardo
Drug and alcohol dependence, Jan 8, 2015
Severe alcoholism can be associated with significant nutritional and vitamin deficiency, especial... more Severe alcoholism can be associated with significant nutritional and vitamin deficiency, especially vitamin B1 (thiamine) which is associated with neurological deficits impacting mood and cognition. Alcohol consumption was reduced among female but not male alcoholics after supplementation with the high potency thiamine analog benfotiamine (BF). We examined the relationship between lifetime alcoholism severity, psychiatric symptoms and response to BF among the alcohol dependent men from this cohort. Eighty-five adult men (mean age=48±8 years) meeting DSM-IV-TR criteria for a current alcohol use disorder who were abstinent <30days participated in a randomized, double-blind, placebo-controlled trial of 600mg BF vs placebo (PL) for 6 months. Psychometric testing included a derived Lifetime Alcoholism Severity Score (AS), Symptom Checklist 90R (SCL-90R), and the Barratt Impulsivity Scale (BIS) at baseline and at 6 months. Baseline SCL-90-R scale scores for men with high alcoholism sev...
American journal of medical genetics. Part A, Jan 5, 2015
Prader-Willi syndrome (PWS) is an obesity-related genetic condition, most commonly due to a pater... more Prader-Willi syndrome (PWS) is an obesity-related genetic condition, most commonly due to a paternal deletion of the chromosome 15q11-q13 region. PWS is characterized by growth hormone deficiency, infantile hypotonia and feeding problems, hypogenitalism/hypogonadism, increased pain threshold and thermal instability, decreased gastric motility, and hyperphagia in childhood leading to severe obesity. Neuro-endocrine peptides are known to influence gastric function and pain sensation which led us to measure a specific peptide that may be involved [i.e., neurotensin (NT)] in PWS and compared with unrelated control siblings. Overnight fasting plasma NT levels were obtained from 23 children with confirmed PWS (age: 8.2 ± 2.0 years; range: 5-11 years) and 18 unaffected, unrelated siblings (age: 8.2 ± 2.3 years; range: 5-11 years) and measured using Multiplex sandwich immunoassays with the Luminex magnetic-bead based platform. Plasma NT levels were natural log-transformed and analyzed by AN...
International journal of molecular sciences, 2015
Recently, autism-related research has focused on the identification of various genes and disturbe... more Recently, autism-related research has focused on the identification of various genes and disturbed pathways causing the genetically heterogeneous group of autism spectrum disorders (ASD). The list of autism-related genes has significantly increased due to better awareness with advances in genetic technology and expanding searchable genomic databases. We compiled a master list of known and clinically relevant autism spectrum disorder genes identified with supporting evidence from peer-reviewed medical literature sources by searching key words related to autism and genetics and from authoritative autism-related public access websites, such as the Simons Foundation Autism Research Institute autism genomic database dedicated to gene discovery and characterization. Our list consists of 792 genes arranged in alphabetical order in tabular form with gene symbols placed on high-resolution human chromosome ideograms, thereby enabling clinical and laboratory geneticists and genetic counsellors...
American journal of medical genetics. Part A, 2015
Prader-Willi syndrome (PWS) is caused by loss of paternally expressed genes from the 15q11-q13 re... more Prader-Willi syndrome (PWS) is caused by loss of paternally expressed genes from the 15q11-q13 region and reportedly rearranged as a cause of autism. Additionally, increased inflammatory markers and features of autism are reported in PWS. Cytokines encoded by genes involved with inflammation, cell proliferation, migration, and adhesion play a role in neurodevelopment and could be disturbed in PWS as abnormal plasma cytokine levels are reported in autism. We analyzed 41 plasma cytokines in a cohort of well-characterized children with PWS between 5 and 11 years of age and unaffected unrelated siblings using multiplex sandwich immunoassays with the Luminex magnetic-bead based platform. Data were analyzed using ANOVA testing for effects of diagnosis, gender, body mass index (BMI) and age on the 24 cytokines meeting laboratory criteria for inclusion. No significant effects were observed for age, gender or BMI. The log-transformed levels of the 24 analyzable cytokines were examined simult...
International Journal of …, 2011
The pathogenesis of autistic disorder (AD) is not clearly understood but genetic factors and the ... more The pathogenesis of autistic disorder (AD) is not clearly understood but genetic factors and the immune system have been implicated. Disturbed immunoglobulin levels and autoantibodies to neuronal elements have been reported in AD including cytokines encoded by genes involved with cell proliferation, migration and adhesion but there is a paucity of data comparing cytokine levels in children with AD and unrelated siblings without AD. We analyzed 39 plasma cytokines in 99 well-characterized children with AD between 5 and 10 years of age and 40 age and gender matched healthy unrelated siblings without AD under the same clinical assessments, specimen processing and laboratory conditions. Multiplex sandwich immunoassays were used with the Luminex fluorescent-bead based platform. Log-transformed values of the 29 cytokines meeting laboratory criteria for inclusion were analyzed by analysis of covariance with a general linear model adjusting for diagnosis, gender, diagnosis by gender interaction effects, age and days of specimen handling. The Tukey-Kramer post hoc test was used to control for multiple comparisons. Eight of 29 cytokine levels analyzed were significantly lower in children with AD compared with unrelated siblings without the diagnosis of AD. Three of the cytokines are known to be involved with hematopoiesis and five with attraction of T-cells, natural killer cells and monocytes. Plasma cytokine levels representing chemokines involved in the T-helper cell immune system and hematopoiesis were lower in the children with AD compared with unrelated siblings without AD necessitating further studies to confirm immunological disturbances influencing hematopiesis and antibody production in the children with AD. Linking genes that encode immune related proteins and cytokines are important to study for their impact on critical periods of brain development and function.
International journal of molecular sciences, 2015
Advances made in genetic testing and tools applied to pharmacogenetics are increasingly being use... more Advances made in genetic testing and tools applied to pharmacogenetics are increasingly being used to inform clinicians in fields such as oncology, hematology, diabetes (endocrinology), cardiology and expanding into psychiatry by examining the influences of genetics on drug efficacy and metabolism. We present a clinical case example of an adolescent male with anxiety, attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder who did not tolerate numerous medications and dosages over several years in attempts to manage his symptoms. Pharmacogenetics testing was performed and DNA results on this individual elucidated the potential pitfalls in medication use because of specific pharmacodynamic and pharmacokinetic differences specifically involving polymorphisms of genes in the cytochrome p450 enzyme system. Future studies and reports are needed to further illustrate and determine the type of individualized medicine approach required to treat individuals based on thei...
Advances in Genomics and Genetics, 2015
Journal of pediatric genetics, 2013
We report a 32-month-old female of Peruvian ethnicity identified with a rare 20q13.2-q13.33 delet... more We report a 32-month-old female of Peruvian ethnicity identified with a rare 20q13.2-q13.33 deletion using microarray analysis. She presented with intellectual disability, absent speech, hypotonia, pre- and post-natal growth retardation and an abnormal face with a unilateral cleft lip. Clinical features and genetic findings with the loss of 30 genes, including GNAS, MC3R, CDH4 and TFAP2C, are described in relationship to the very few cases of 20q13 deletion reported in the literature. Deletion of this region may play an important role in neurodevelopment and function and in causing specific craniofacial features.
Alcoholism, clinical and experimental research, 2014
Alcohol abuse is associated with cellular and biochemical disturbances that impact upon protein a... more Alcohol abuse is associated with cellular and biochemical disturbances that impact upon protein and nucleic acid synthesis, brain development, function, and behavioral responses. To further characterize the genetic influences in alcoholism and the effects of alcohol consumption on gene expression, we used a highly sensitive exon microarray to examine mRNA expression in human frontal cortex of alcoholics and control males. Messenger RNA was isolated from the dorsolateral prefrontal cortex (dlPFC; Brodmann area 9) of 7 adult alcoholic (6 males, 1 female, mean age 49 years) and 7 matched controls. Affymetrix Human Exon 1.0 ST array was performed according to standard procedures and the results analyzed at the gene level. Microarray findings were validated using quantitative reverse transcription polymerase chain reaction, and the ontology of disturbed genes characterized using Ingenuity Pathway Analysis (IPA). Decreased mRNA expression was observed for genes involved in cellular adhesi...
Advances in genomics and genetics, 2014
The androgen receptor (AR) gene, located on the X chromosome, contains a common polymorphism invo... more The androgen receptor (AR) gene, located on the X chromosome, contains a common polymorphism involving cytosine-adenine-guanine (CAG) repeats, which impacts disease and could contribute to the unequal sex ratio in alcoholism. CAG repeats in the AR gene are known to correlate with impulsivity in males. We report the first preliminary study examining the association between the number of CAG repeats and measures of impulsivity in females with chronic alcoholism. A total of 35 women and 85 men with chronic alcoholism were previously recruited for a nutritional clinical trial, and 26 well-characterized females (19 African-American and seven Caucasian) with alcoholism agreed to participate for genetic testing. Genomic deoxyribonucleic acid (DNA) was isolated from peripheral blood and CAG repeats determined by analyzing polymerase chain reaction (PCR)-amplified products, using the polymorphic AR gene assay. CAG repeat length was correlated with raw scores from the Barratt Impulsivity Scal...
Genetics research international, 2014
We report our experience with high resolution microarray analysis in infants and young children w... more We report our experience with high resolution microarray analysis in infants and young children with developmental disability and/or aberrant behavior enrolled at the Centro Ann Sullivan del Peru in Lima, Peru, a low income country. Buccal cells were collected with cotton swabs from 233 participants for later DNA isolation and identification of copy number variation (deletions/duplications) and regions of homozygosity (ROH) for estimating consanguinity status in 15 infants and young children (12 males, 3 females; mean age ± SD = 28.1 m ± 7.9 m; age range 14 m-41 m) randomly selected for microarray analysis. An adequate DNA yield was found in about one-half of the enrolled participants. Ten participants showed deletions or duplications containing candidate genes reported to impact behavior or cognitive development. Five children had ROHs which could have harbored recessive gene alleles contributing to their clinical presentation. The coefficient of inbreeding was calculated and thre...
International journal of molecular sciences, 2015
Classical autism or autistic disorder belongs to a group of genetically heterogeneous conditions ... more Classical autism or autistic disorder belongs to a group of genetically heterogeneous conditions known as Autism Spectrum Disorders (ASD). Heritability is estimated as high as 90% for ASD with a recently reported compilation of 629 clinically relevant candidate and known genes. We chose to undertake a descriptive next generation whole exome sequencing case study of 30 well-characterized Caucasian females with autism (average age, 7.7 ± 2.6 years; age range, 5 to 16 years) from multiplex families. Genomic DNA was used for whole exome sequencing via paired-end next generation sequencing approach and X chromosome inactivation status. The list of putative disease causing genes was developed from primary selection criteria using machine learning-derived classification score and other predictive parameters (GERP2, PolyPhen2, and SIFT). We narrowed the variant list to 10 to 20 genes and screened for biological significance including neural development, function and known neurological disor...
Pharmacology Biochemistry and Behavior, 2001
Rats will self-administer dopamine D(1) and D(2) agonists, alone or in combination. Response rate... more Rats will self-administer dopamine D(1) and D(2) agonists, alone or in combination. Response rates and patterns for the D(1):D(2) combinations are nearly identical to those induced by cocaine. Here we examine whether rats prefer cocaine over D(1) or D(2) agonists presented alone or in D(1):D(2) combinations. During daily 3-h tests in a two-lever box, cocaine was available at either the right or left lever and the active side was alternated daily. After response rates had stabilized (+/-10% for 2 days), different groups were offered cocaine (800 microg/kg/injection) at one lever and either another dose (267, 1600, or 2400 microg/kg/injection) of cocaine or a dopamine agonist at the other lever. Animals consistently chose the higher of the presented cocaine doses over the low cocaine dose (267 microg). In choices between cocaine and dopamine agonists, the preferred cocaine dose (800 microg) was chosen over doses of the D(1) (SKF 82958) or D(2) ((+)-PHNO) agonist. However, no preference was shown between 800 microg cocaine and D(1):D(2) agonist mixtures, and the high-dose agonist mixture was preferred to the low cocaine dose. These results suggest that neither D(1) nor D(2) agonists alone fully duplicate the reinforcing actions of cocaine, but agonist combinations may approximate cocaine&amp;#39;s reinforcement strength.
Drug and Alcohol Dependence, 2013
Alcohol dependence is associated with severe nutritional and vitamin deficiency. Vitamin B1 (thia... more Alcohol dependence is associated with severe nutritional and vitamin deficiency. Vitamin B1 (thiamine) deficiency erodes neurological pathways that may influence the ability to drink in moderation. The present study examines tolerability of supplementation using the high-potency thiamine analog, benfotiamine (BF), and BF&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s effects on alcohol consumption in severely affected, self-identified, alcohol dependent subjects. A randomized, double-blind, placebo-controlled trial was conducted on 120 non-treatment seeking, actively drinking, alcohol dependent men and women volunteers (mean age=47 years) from the Kansas City area who met DSM-IV-TR criteria for current alcohol dependence. Subjects were randomized to receive 600 mg benfotiamine or placebo (PL) once daily by mouth for 24 weeks with 6 follow-up assessments scheduled at 4 week intervals. Side effects and daily alcohol consumption were recorded. Seventy (58%) subjects completed 24 weeks of study (N=21 women; N=49 men) with overall completion rates of 55% (N=33) for PL and 63% (N=37) for BF groups. No significant adverse events were noted and alcohol consumption decreased significantly for both treatment groups. Alcohol consumption decreased from baseline levels for 9 of 10 BF treated women after 1 month of treatment compared with 2 of 11 on PL. Reductions in total alcohol consumption over 6 months were significantly greater for BF treated women (BF: N=10, -611 ± 380 standard drinks; PL: N=11, -159 ± 562 standard drinks, p-value=0.02). BF supplementation of actively drinking alcohol dependent men and women was well-tolerated and may discourage alcohol consumption among women. The results do support expanded studies of BF treatment in alcoholism.
Clinical Chemistry and Laboratory Medicine, 2000
Brain Research, 2002
Smoking is considered the leading cause of preventable death in the United States, but studies in... more Smoking is considered the leading cause of preventable death in the United States, but studies in animals suggest that nicotine is only weakly reinforcing. The maintenance of a dangerous habit by a weakly reinforcing agent has been the topic of some dispute. Using a two-lever "choice" self-administration procedure developed in our laboratory, we evaluated drug preferences as an index of relative reward strength for nicotine versus cocaine in nicotine-trained rats. Rats were initially exposed to each drug separately in single-lever self-administration sessions and then allowed to choose between them in a two-lever choice test session offering both drugs. When offered choices between different nicotine doses [8, 25, and 75 microg/kg/injection (inj), free base], rats responded approximately equally for any dose, regardless of which doses were compared. Rats clearly preferred 267 or 800 microg/kg/inj cocaine hydrochloride to any of the nicotine doses. These results indicate that cocaine has greater reward strength than nicotine and supports previous findings that self-administering rats seek to maximize reward magnitude regardless of the self-administered drug or training history. It is possible that dependence elevates nicotine's reward magnitude or nicotine addiction may rely more importantly upon negative rather than pure positive reinforcement.
American Journal of Therapeutics, 1997
We evaluated the utility of a 7-day drug holiday in the restoration of chronic dosing all-trans-r... more We evaluated the utility of a 7-day drug holiday in the restoration of chronic dosing all-trans-retinoic acid (tRA) blood levels in 11 non-small cell lung carcinoma patients. Baseline kinetic studies (day 1) were compared to postchronic dosing (day 7) and drug holiday kinetics (day 14). High levels of baseline pharmacokinetic variability and variability in response to prolonged tRA therapy were evident. Median area under the curve (AUC) decreased from a baseline level of 1.2 to 0.69 microg/ml/h (p = 0.03). t (1/2) showed no significant alterations. A near-significant increase in T (lag) (p = 0.08) was noted, which suggests modulation of absorbance parameters. Trends in AUC were strongly correlated with C (max) as was T (max) with T (lag). After a 7-day drug holiday the median AUC significantly increased from the day 7 value to 1.8 microg/ml/h p = 0.01). Since post-drug holiday values for parameters were not statistically different from baseline pharmacokinetic values, this suggests a complete restoration of tRA bioavailability.
Alcoholism: Clinical & Experimental Research, 2005
Acta Psychiatrica Scandinavica, 2007
Drug and alcohol dependence, Jan 8, 2015
Severe alcoholism can be associated with significant nutritional and vitamin deficiency, especial... more Severe alcoholism can be associated with significant nutritional and vitamin deficiency, especially vitamin B1 (thiamine) which is associated with neurological deficits impacting mood and cognition. Alcohol consumption was reduced among female but not male alcoholics after supplementation with the high potency thiamine analog benfotiamine (BF). We examined the relationship between lifetime alcoholism severity, psychiatric symptoms and response to BF among the alcohol dependent men from this cohort. Eighty-five adult men (mean age=48±8 years) meeting DSM-IV-TR criteria for a current alcohol use disorder who were abstinent <30days participated in a randomized, double-blind, placebo-controlled trial of 600mg BF vs placebo (PL) for 6 months. Psychometric testing included a derived Lifetime Alcoholism Severity Score (AS), Symptom Checklist 90R (SCL-90R), and the Barratt Impulsivity Scale (BIS) at baseline and at 6 months. Baseline SCL-90-R scale scores for men with high alcoholism sev...
American journal of medical genetics. Part A, Jan 5, 2015
Prader-Willi syndrome (PWS) is an obesity-related genetic condition, most commonly due to a pater... more Prader-Willi syndrome (PWS) is an obesity-related genetic condition, most commonly due to a paternal deletion of the chromosome 15q11-q13 region. PWS is characterized by growth hormone deficiency, infantile hypotonia and feeding problems, hypogenitalism/hypogonadism, increased pain threshold and thermal instability, decreased gastric motility, and hyperphagia in childhood leading to severe obesity. Neuro-endocrine peptides are known to influence gastric function and pain sensation which led us to measure a specific peptide that may be involved [i.e., neurotensin (NT)] in PWS and compared with unrelated control siblings. Overnight fasting plasma NT levels were obtained from 23 children with confirmed PWS (age: 8.2 ± 2.0 years; range: 5-11 years) and 18 unaffected, unrelated siblings (age: 8.2 ± 2.3 years; range: 5-11 years) and measured using Multiplex sandwich immunoassays with the Luminex magnetic-bead based platform. Plasma NT levels were natural log-transformed and analyzed by AN...
International journal of molecular sciences, 2015
Recently, autism-related research has focused on the identification of various genes and disturbe... more Recently, autism-related research has focused on the identification of various genes and disturbed pathways causing the genetically heterogeneous group of autism spectrum disorders (ASD). The list of autism-related genes has significantly increased due to better awareness with advances in genetic technology and expanding searchable genomic databases. We compiled a master list of known and clinically relevant autism spectrum disorder genes identified with supporting evidence from peer-reviewed medical literature sources by searching key words related to autism and genetics and from authoritative autism-related public access websites, such as the Simons Foundation Autism Research Institute autism genomic database dedicated to gene discovery and characterization. Our list consists of 792 genes arranged in alphabetical order in tabular form with gene symbols placed on high-resolution human chromosome ideograms, thereby enabling clinical and laboratory geneticists and genetic counsellors...
American journal of medical genetics. Part A, 2015
Prader-Willi syndrome (PWS) is caused by loss of paternally expressed genes from the 15q11-q13 re... more Prader-Willi syndrome (PWS) is caused by loss of paternally expressed genes from the 15q11-q13 region and reportedly rearranged as a cause of autism. Additionally, increased inflammatory markers and features of autism are reported in PWS. Cytokines encoded by genes involved with inflammation, cell proliferation, migration, and adhesion play a role in neurodevelopment and could be disturbed in PWS as abnormal plasma cytokine levels are reported in autism. We analyzed 41 plasma cytokines in a cohort of well-characterized children with PWS between 5 and 11 years of age and unaffected unrelated siblings using multiplex sandwich immunoassays with the Luminex magnetic-bead based platform. Data were analyzed using ANOVA testing for effects of diagnosis, gender, body mass index (BMI) and age on the 24 cytokines meeting laboratory criteria for inclusion. No significant effects were observed for age, gender or BMI. The log-transformed levels of the 24 analyzable cytokines were examined simult...
International Journal of …, 2011
The pathogenesis of autistic disorder (AD) is not clearly understood but genetic factors and the ... more The pathogenesis of autistic disorder (AD) is not clearly understood but genetic factors and the immune system have been implicated. Disturbed immunoglobulin levels and autoantibodies to neuronal elements have been reported in AD including cytokines encoded by genes involved with cell proliferation, migration and adhesion but there is a paucity of data comparing cytokine levels in children with AD and unrelated siblings without AD. We analyzed 39 plasma cytokines in 99 well-characterized children with AD between 5 and 10 years of age and 40 age and gender matched healthy unrelated siblings without AD under the same clinical assessments, specimen processing and laboratory conditions. Multiplex sandwich immunoassays were used with the Luminex fluorescent-bead based platform. Log-transformed values of the 29 cytokines meeting laboratory criteria for inclusion were analyzed by analysis of covariance with a general linear model adjusting for diagnosis, gender, diagnosis by gender interaction effects, age and days of specimen handling. The Tukey-Kramer post hoc test was used to control for multiple comparisons. Eight of 29 cytokine levels analyzed were significantly lower in children with AD compared with unrelated siblings without the diagnosis of AD. Three of the cytokines are known to be involved with hematopoiesis and five with attraction of T-cells, natural killer cells and monocytes. Plasma cytokine levels representing chemokines involved in the T-helper cell immune system and hematopoiesis were lower in the children with AD compared with unrelated siblings without AD necessitating further studies to confirm immunological disturbances influencing hematopiesis and antibody production in the children with AD. Linking genes that encode immune related proteins and cytokines are important to study for their impact on critical periods of brain development and function.
International journal of molecular sciences, 2015
Advances made in genetic testing and tools applied to pharmacogenetics are increasingly being use... more Advances made in genetic testing and tools applied to pharmacogenetics are increasingly being used to inform clinicians in fields such as oncology, hematology, diabetes (endocrinology), cardiology and expanding into psychiatry by examining the influences of genetics on drug efficacy and metabolism. We present a clinical case example of an adolescent male with anxiety, attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder who did not tolerate numerous medications and dosages over several years in attempts to manage his symptoms. Pharmacogenetics testing was performed and DNA results on this individual elucidated the potential pitfalls in medication use because of specific pharmacodynamic and pharmacokinetic differences specifically involving polymorphisms of genes in the cytochrome p450 enzyme system. Future studies and reports are needed to further illustrate and determine the type of individualized medicine approach required to treat individuals based on thei...
Advances in Genomics and Genetics, 2015
Journal of pediatric genetics, 2013
We report a 32-month-old female of Peruvian ethnicity identified with a rare 20q13.2-q13.33 delet... more We report a 32-month-old female of Peruvian ethnicity identified with a rare 20q13.2-q13.33 deletion using microarray analysis. She presented with intellectual disability, absent speech, hypotonia, pre- and post-natal growth retardation and an abnormal face with a unilateral cleft lip. Clinical features and genetic findings with the loss of 30 genes, including GNAS, MC3R, CDH4 and TFAP2C, are described in relationship to the very few cases of 20q13 deletion reported in the literature. Deletion of this region may play an important role in neurodevelopment and function and in causing specific craniofacial features.
Alcoholism, clinical and experimental research, 2014
Alcohol abuse is associated with cellular and biochemical disturbances that impact upon protein a... more Alcohol abuse is associated with cellular and biochemical disturbances that impact upon protein and nucleic acid synthesis, brain development, function, and behavioral responses. To further characterize the genetic influences in alcoholism and the effects of alcohol consumption on gene expression, we used a highly sensitive exon microarray to examine mRNA expression in human frontal cortex of alcoholics and control males. Messenger RNA was isolated from the dorsolateral prefrontal cortex (dlPFC; Brodmann area 9) of 7 adult alcoholic (6 males, 1 female, mean age 49 years) and 7 matched controls. Affymetrix Human Exon 1.0 ST array was performed according to standard procedures and the results analyzed at the gene level. Microarray findings were validated using quantitative reverse transcription polymerase chain reaction, and the ontology of disturbed genes characterized using Ingenuity Pathway Analysis (IPA). Decreased mRNA expression was observed for genes involved in cellular adhesi...
Advances in genomics and genetics, 2014
The androgen receptor (AR) gene, located on the X chromosome, contains a common polymorphism invo... more The androgen receptor (AR) gene, located on the X chromosome, contains a common polymorphism involving cytosine-adenine-guanine (CAG) repeats, which impacts disease and could contribute to the unequal sex ratio in alcoholism. CAG repeats in the AR gene are known to correlate with impulsivity in males. We report the first preliminary study examining the association between the number of CAG repeats and measures of impulsivity in females with chronic alcoholism. A total of 35 women and 85 men with chronic alcoholism were previously recruited for a nutritional clinical trial, and 26 well-characterized females (19 African-American and seven Caucasian) with alcoholism agreed to participate for genetic testing. Genomic deoxyribonucleic acid (DNA) was isolated from peripheral blood and CAG repeats determined by analyzing polymerase chain reaction (PCR)-amplified products, using the polymorphic AR gene assay. CAG repeat length was correlated with raw scores from the Barratt Impulsivity Scal...
Genetics research international, 2014
We report our experience with high resolution microarray analysis in infants and young children w... more We report our experience with high resolution microarray analysis in infants and young children with developmental disability and/or aberrant behavior enrolled at the Centro Ann Sullivan del Peru in Lima, Peru, a low income country. Buccal cells were collected with cotton swabs from 233 participants for later DNA isolation and identification of copy number variation (deletions/duplications) and regions of homozygosity (ROH) for estimating consanguinity status in 15 infants and young children (12 males, 3 females; mean age ± SD = 28.1 m ± 7.9 m; age range 14 m-41 m) randomly selected for microarray analysis. An adequate DNA yield was found in about one-half of the enrolled participants. Ten participants showed deletions or duplications containing candidate genes reported to impact behavior or cognitive development. Five children had ROHs which could have harbored recessive gene alleles contributing to their clinical presentation. The coefficient of inbreeding was calculated and thre...
International journal of molecular sciences, 2015
Classical autism or autistic disorder belongs to a group of genetically heterogeneous conditions ... more Classical autism or autistic disorder belongs to a group of genetically heterogeneous conditions known as Autism Spectrum Disorders (ASD). Heritability is estimated as high as 90% for ASD with a recently reported compilation of 629 clinically relevant candidate and known genes. We chose to undertake a descriptive next generation whole exome sequencing case study of 30 well-characterized Caucasian females with autism (average age, 7.7 ± 2.6 years; age range, 5 to 16 years) from multiplex families. Genomic DNA was used for whole exome sequencing via paired-end next generation sequencing approach and X chromosome inactivation status. The list of putative disease causing genes was developed from primary selection criteria using machine learning-derived classification score and other predictive parameters (GERP2, PolyPhen2, and SIFT). We narrowed the variant list to 10 to 20 genes and screened for biological significance including neural development, function and known neurological disor...
Pharmacology Biochemistry and Behavior, 2001
Rats will self-administer dopamine D(1) and D(2) agonists, alone or in combination. Response rate... more Rats will self-administer dopamine D(1) and D(2) agonists, alone or in combination. Response rates and patterns for the D(1):D(2) combinations are nearly identical to those induced by cocaine. Here we examine whether rats prefer cocaine over D(1) or D(2) agonists presented alone or in D(1):D(2) combinations. During daily 3-h tests in a two-lever box, cocaine was available at either the right or left lever and the active side was alternated daily. After response rates had stabilized (+/-10% for 2 days), different groups were offered cocaine (800 microg/kg/injection) at one lever and either another dose (267, 1600, or 2400 microg/kg/injection) of cocaine or a dopamine agonist at the other lever. Animals consistently chose the higher of the presented cocaine doses over the low cocaine dose (267 microg). In choices between cocaine and dopamine agonists, the preferred cocaine dose (800 microg) was chosen over doses of the D(1) (SKF 82958) or D(2) ((+)-PHNO) agonist. However, no preference was shown between 800 microg cocaine and D(1):D(2) agonist mixtures, and the high-dose agonist mixture was preferred to the low cocaine dose. These results suggest that neither D(1) nor D(2) agonists alone fully duplicate the reinforcing actions of cocaine, but agonist combinations may approximate cocaine&amp;#39;s reinforcement strength.
Drug and Alcohol Dependence, 2013
Alcohol dependence is associated with severe nutritional and vitamin deficiency. Vitamin B1 (thia... more Alcohol dependence is associated with severe nutritional and vitamin deficiency. Vitamin B1 (thiamine) deficiency erodes neurological pathways that may influence the ability to drink in moderation. The present study examines tolerability of supplementation using the high-potency thiamine analog, benfotiamine (BF), and BF&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s effects on alcohol consumption in severely affected, self-identified, alcohol dependent subjects. A randomized, double-blind, placebo-controlled trial was conducted on 120 non-treatment seeking, actively drinking, alcohol dependent men and women volunteers (mean age=47 years) from the Kansas City area who met DSM-IV-TR criteria for current alcohol dependence. Subjects were randomized to receive 600 mg benfotiamine or placebo (PL) once daily by mouth for 24 weeks with 6 follow-up assessments scheduled at 4 week intervals. Side effects and daily alcohol consumption were recorded. Seventy (58%) subjects completed 24 weeks of study (N=21 women; N=49 men) with overall completion rates of 55% (N=33) for PL and 63% (N=37) for BF groups. No significant adverse events were noted and alcohol consumption decreased significantly for both treatment groups. Alcohol consumption decreased from baseline levels for 9 of 10 BF treated women after 1 month of treatment compared with 2 of 11 on PL. Reductions in total alcohol consumption over 6 months were significantly greater for BF treated women (BF: N=10, -611 ± 380 standard drinks; PL: N=11, -159 ± 562 standard drinks, p-value=0.02). BF supplementation of actively drinking alcohol dependent men and women was well-tolerated and may discourage alcohol consumption among women. The results do support expanded studies of BF treatment in alcoholism.
Clinical Chemistry and Laboratory Medicine, 2000
Brain Research, 2002
Smoking is considered the leading cause of preventable death in the United States, but studies in... more Smoking is considered the leading cause of preventable death in the United States, but studies in animals suggest that nicotine is only weakly reinforcing. The maintenance of a dangerous habit by a weakly reinforcing agent has been the topic of some dispute. Using a two-lever "choice" self-administration procedure developed in our laboratory, we evaluated drug preferences as an index of relative reward strength for nicotine versus cocaine in nicotine-trained rats. Rats were initially exposed to each drug separately in single-lever self-administration sessions and then allowed to choose between them in a two-lever choice test session offering both drugs. When offered choices between different nicotine doses [8, 25, and 75 microg/kg/injection (inj), free base], rats responded approximately equally for any dose, regardless of which doses were compared. Rats clearly preferred 267 or 800 microg/kg/inj cocaine hydrochloride to any of the nicotine doses. These results indicate that cocaine has greater reward strength than nicotine and supports previous findings that self-administering rats seek to maximize reward magnitude regardless of the self-administered drug or training history. It is possible that dependence elevates nicotine's reward magnitude or nicotine addiction may rely more importantly upon negative rather than pure positive reinforcement.
American Journal of Therapeutics, 1997
We evaluated the utility of a 7-day drug holiday in the restoration of chronic dosing all-trans-r... more We evaluated the utility of a 7-day drug holiday in the restoration of chronic dosing all-trans-retinoic acid (tRA) blood levels in 11 non-small cell lung carcinoma patients. Baseline kinetic studies (day 1) were compared to postchronic dosing (day 7) and drug holiday kinetics (day 14). High levels of baseline pharmacokinetic variability and variability in response to prolonged tRA therapy were evident. Median area under the curve (AUC) decreased from a baseline level of 1.2 to 0.69 microg/ml/h (p = 0.03). t (1/2) showed no significant alterations. A near-significant increase in T (lag) (p = 0.08) was noted, which suggests modulation of absorbance parameters. Trends in AUC were strongly correlated with C (max) as was T (max) with T (lag). After a 7-day drug holiday the median AUC significantly increased from the day 7 value to 1.8 microg/ml/h p = 0.01). Since post-drug holiday values for parameters were not statistically different from baseline pharmacokinetic values, this suggests a complete restoration of tRA bioavailability.
Alcoholism: Clinical & Experimental Research, 2005
Acta Psychiatrica Scandinavica, 2007