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1.  Behavioral and Social Phenotypes in Boys With 47,XYY Syndrome or 47,XXY Klinefelter Syndrome 
Pediatrics  2012;129(4):769-778.
To contrast the behavioral and social phenotypes including a screen for autistic behaviors in boys with 47,XYY syndrome (XYY) or 47,XXY Klinefelter syndrome (KS) and controls and investigate the effect of prenatal diagnosis on the phenotype.
Patients included 26 boys with 47,XYY, 82 boys with KS, and 50 control boys (ages 4–15 years). Participants and parents completed a physical examination, behavioral questionnaires, and intellectual assessments.
Most boys with XYY or KS had Child Behavior Checklist parental ratings within the normal range. On the Child Behavior Checklist, mean problem behaviors t scores were higher in the XYY versus KS groups for the Problem Behavior, Externalizing, Withdrawn, Thought Problems, and Attention Problems subscales. On the Conners’ Parent Rating Scale–Revised, the XYY versus KS group had increased frequency of hyperactive/impulsive symptoms (P < .006). In addition, 50% and 12% of the XYY and KS groups, respectively, had scores >15 for autism screening from the Social Communication Questionnaire. For the boys with KS, prenatal diagnosis was associated with fewer problem behaviors.
A subset of the XYY and KS groups had behavioral difficulties that were more severe in the XYY group. These findings could guide clinical practice and inform patients and parents. Boys diagnosed with XYY or KS should receive a comprehensive psychoeducational evaluation and be screened for learning disabilities, attention-deficit/hyperactivity disorder, and autism spectrum disorders.
PMCID: PMC3356148  PMID: 22412026
XXY; XYY; Klinefelter syndrome; autism; ADHD
2.  Testosterone replacement therapy among elderly males: the Testim Registry in the US (TRiUS) 
Testosterone levels naturally decline with age in men, often resulting in testosterone deficiency (hypogonadism). However, few studies have examined hypogonadal characteristics and treatment in older (≥65 years) men.
To compare data at baseline and after 12 months of testosterone replacement therapy (TRT) in hypogonadal men ≥65 vs <65 years old. Data for participants 65–74 vs ≥75 years old were also compared.
Data were from TRiUS (Testim Registry in the United States), which enrolled 849 hypogonadal men treated with Testim® 1% (50–100 mg testosterone gel/day) for the first time. Anthropometric, laboratory, and clinical measures were taken at baseline and 12 months, including primary outcomes of total testosterone (TT), free testosterone (FT), and prostate-specific antigen (PSA) levels. Comparisons of parameters were made using Fisher’s exact test or analysis of variance. Nonparametric Spearman’s ρ and first-order partial correlation coefficients adjusted for the effect of age were used to examine bivariate correlations among parameters.
Of the registry participants at baseline with available age information, 16% (133/845) were ≥65 years old. They were similar to men <65 years old in the duration of hypogonad-ism prior to enrollment (∼1 year), TT and FT levels at baseline, TT and FT levels at 12-month follow-up, and in reported compliance with treatment. Older patients were more likely to receive lower doses of TRT. PSA levels did not statistically differ between groups after 12 months of TRT (2.18 ± 2.18 ng/mL for ≥65 vs 1.14 ± 0.84 ng/mL for <65 years old, P = 0.1). Baseline values for the >75-year-old subcohort were not significantly different from subcohorts aged 65–74 years and <65 years.
Hypogonadal men ≥65 years old showed significant benefit from TRT over 12 months, similar to that found for hypogonadal men <65 years old. TRT was well tolerated in older patients, successfully increased testosterone level regardless of age, and did not significantly increase PSA levels in older men.
PMCID: PMC3430096  PMID: 22956867
male hypogonadism; elderly; testosterone replacement therapy; testosterone gel; TRiUS registry; Testim
3.  Effect of 12 months of testosterone replacement therapy on metabolic syndrome components in hypogonadal men: data from the Testim Registry in the US (TRiUS) 
Recent evidence suggests that there may be a bidirectional, physiological link between hypogonadism and metabolic syndrome (MetS), and testosterone replacement therapy (TRT) has been shown to improve some symptoms of MetS in small patient populations. We examined the effect of 12 months of TRT on MetS components in a large cohort of hypogonadal men.
Data were obtained from TRiUS (Testim® Registry in the United States), a 12-month, multicenter, prospective observational registry (N = 849) of hypogonadal men prescribed Testim 1% testosterone gel (5-10 g/day). Data analyzed included age, total testosterone (TT), free testosterone (FT), sex hormone-binding globulin (SHBG), and MetS components: waist circumference, blood pressure, fasting blood glucose, plasma triglycerides, and HDL cholesterol.
Of evaluable patients (581/849) at baseline, 37% were MetS+ (n = 213) and 63% were MetS- (n = 368). MetS+ patients had significantly lower TT (p < 0.0001) and SHBG (p = 0.01) levels. Patients with the lowest quartile TT levels (<206 ng/dL [<7.1 nmol/L]) had a significantly increased risk of MetS+ classification vs those with highest quartile TT levels (≥331 ng/dL [≥11.5 nmol/L]) (odds ratio 2.66; 95% CI, 1.60 to 4.43). After 12 months of TRT, TT levels significantly increased in all patients (p < 0.005). Despite having similar TT levels after TRT, only MetS+ patients demonstrated significant decreases in waist circumference, fasting blood glucose levels, and blood pressure; lowest TT quartile patients demonstrated significant decreases in waist circumference and fasting blood glucose. Neither HDL cholesterol nor triglyceride levels changed significantly in either patient population.
Hypogonadal MetS+ patients were more likely than their MetS- counterparts to have lower baseline TT levels and present with more comorbid conditions. MetS+ patients and those in the lowest TT quartile showed improvement in some metabolic syndrome components after 12 months of TRT. While it is currently unclear if further cardiometabolic benefit can be seen with longer TRT use in this population, testing for low testosterone may be warranted in MetS+ men with hypogonadal symptoms.
PMCID: PMC3217857  PMID: 22044661
Testosterone; metabolic syndrome; obesity; testosterone gel; testosterone replacement; TRiUS registry; Testim; hypogonadism; testosterone deficiency; fasting glucose
Cancer  2010;116(7):1709-1717.
Patients with oral premalignant lesions (OPL) present with oral squamous cell carcinomas (OSCC) at a much higher rate than the general population. There are currently no useful markers that indicate specifically which OPLs are most likely to progress. Three SIBLING family proteins, bone sialoprotein (BSP), osteopontin (OPN), and dentin sialophosphoprotein (DSPP), have been shown to be up-regulated in many cancers, including OSCC. The status of SIBLING expression in OPLs and their correlation to transition to oral cancer are unknown.
Sixty archival surgical biopsies of dysplastic OPLs were evaluated by immunohistochemistry for expression of BSP, DSPP and OPN and correlated with local transformation to OSCC at sites adjacent to surgically removed dysplastic OPL
The OPL patient population was representative of previous studies with 20% progressing to OSCC, and no correlation between degree of dysplasia and progression. 87% were positive for at least one SIBLING protein. OPN expression had no correlation with progression. The BSP+/DSPP− expression pattern however correlated with decreased transformation to OSCC (Point Prevalence=0%, 95%CI=0–20.6%) while the BSP−/DSPP+ pattern was associated with more frequent progression (Point Prevalence=77.8%, 95%CI=47.8–95.4%). Incrementally higher expression scores (0 to 3+) of BSP and DSPP were also associated with increased predictive values (OR=25.53, 95%CI=2.14–304.7 and 10.13, 95%CI=2.0–50.0, respectively, for each increment).
BSP and DSPP are excellent candidate markers for successful OPL surgical intervention and may be predictors of OPL-OSCC progression.
PMCID: PMC2847022  PMID: 20186700
SIBLINGs; Oral-cance; Oral Premalignant Lesions; Dysplasia; Biomarkers; BSP; DSPP; OPN; Transition
5.  An extra X or Y chromosome: contrasting the cognitive and motor phenotypes in childhood in boys with 47,XYY syndrome or 47,XXY Klinefelter syndrome 
The goal of this study was to contrast the cognitive phenotypes in boys with 47,XYY (XYY) karyotype and boys with 47,XXY karyotype (Klinefelter syndrome, KS), who share an extra copy of the X-Y pseudoautosomal region but differ in their dosage of strictly sex-linked genes.
Neuropsychological evaluation of general cognitive ability, language, memory, attention, visual-spatial abilities, visual-motor skills, and motor function.
Study cohort: 21 boys with 47,XYY and 93 boys with 47,XXY (KS), ages 4-17 years, and 36 age-matched control boys. Both the XYY and KS groups performed less well, on average, than the controls on tests of general cognitive ability, achievement, language, verbal memory, some aspects of attention and executive function, and motor function. The boys with XYY on average had more severe and pervasive language impairment, at both simple and complex levels, and the boys with KS on average had greater motor impairment in gross motor function and coordination, especially in running speed and agility.
The results from these large XYY and KS cohorts have important neurocognitive and educational implications. From the neurocognitive standpoint, the presenting findings afford an opportunity to gain insights into brain development in boys with XYY and those with KS. From the educational standpoint, it is critical that boys with XYY or KS receive appropriate educational interventions that target their specific learning challenges. These findings also provide important information for counseling clinicians and families about these disorders.
PMCID: PMC2876236  PMID: 20014371
XYY; XXY; Klinefelter syndrome; sex chromosome
6.  Validity of the Reduced-Sample-Insulin-Modified-Frequently Sampled Intravenous Glucose Tolerance Test Using the Nonlinear Regression Approach 
The Disposition Index, the product of the insulin sensitivity index (SI) and the acute insulin response to glucose, is linked in African-Americans to chromosome 11q. This link was determined with SI calculated with the nonlinear regression approach to the minimal model and data from the Reduced-Sampled-Insulin-Modified-Frequently-Sampled-Intravenous-Glucose-Tolerance-Test (Reduced-Sample-IM-FSIGT). However, the application of the nonlinear regression approach to calculate SI using data from the Reduced-Sample-IM-FSIGT has been challenged as being not only inaccurate but also having a high failure rate in insulin-resistant subjects. Our goal was to determine the accuracy and failure rate of the Reduced-Sample-IM-FSIGT using the nonlinear regression approach to the minimal model. With SI from the Full-Sample-IM-FISGT considered the standard and using the nonlinear regression approach to the minimal model, we compared the agreement between SI from the Full and Reduced-Sample-IM-FSIGT protocols. One hundred African-Americans, (BMI 31.3±7.6 kg/m2 (mean±SD), range 19.0-56.9 kg/m2) had FSIGTs. Glucose (0.3g/kg) was given at baseline. Insulin was infused from 20 to 25 minutes (total insulin dose 0.02U/kg). For the Full-Sample-IM-FSIGT, SI was calculated based on the glucose and insulin samples taken at -1, 1, 2, 3, 4, 5, 6, 7, 8,10, 12, 14, 16, 19, 22, 23, 24, 25, 27, 30, 40, 50, 60, 70, 80, 90, 100, 120, 150, 180. For the Reduced-Sample-FSIGT, SI was calculated based on the timepoints which appear in bold. Agreement was determined by Spearman correlation, concordance and the Bland-Altman method. In addition, for both protocols, the population was divided into tertiles of SI. Insulin resistance was defined by the lowest tertile of SI from the Full-Sample-IM-FSIGT. The distribution of subjects across tertiles was compared by rank order and kappa statistic. We found that the rate of failure of resolution of SI by the Reduced-Sample-IM-FSIGT was 3%(3/100). For the remaining 97 subjects, SI for the Full and Reduced-Sample-IM-FSIGT were: 3.76±2.41 L.mU-1.min-1, range 0.58-14.50 and 4.29±2.89 L.mU-1.min-1, range 0.52-14.42, relative error 21±18%, Spearman r=0.97, concordance 0.94, (both P<0.001). After log transformation the Bland Altman limits of agreement were: -0.29 and 0.53. The exact agreement for distribution of the population in the insulin-resistant tertile versus the insulin-sensitive tertiles was 92%, kappa 0.82±0.06. Using the nonlinear regression approach and data from the Reduced-Sample-IM-FSIGT in subjects with a wide range of insulin sensitivity, failure to resolve SI occurred in only 3% of subjects. The agreement and maintenance of rank order of SI between protocols supports the use of the nonlinear regression approach to the minimal model and the Reduced-Sample-IM-FSIGT in clinical studies.
PMCID: PMC2652479  PMID: 19154955
7.  Plasma Lipid Concentrations in Non-Diabetic, African American Adults 
Despite higher rates of cardiovascular disease, African Americans have a more favorable lipid profile. The purpose of the study was to examine the association between plasma lipid concentrations and insulin resistance in African Americans and to determine if insulin resistance is present at a lower triglyceride (TG) threshold than is used for metabolic syndrome criteria.
Data were examined on 185 non-diabetic African American men (N=61) and women (N=124), mean 39.8 years. Measurements included blood pressure, anthropometrics, oral glucose tolerance test, and insulin sensitivity (M), by insulin clamp. The relationship between lipids and insulin sensitivity was analyzed by correlation analysis and by comparing triglyceride levels among tertiles of M.
Despite relatively low mean TG (87.8 ± 55.2 mg/dL), there were statistically significant correlations of M with TG (r = -.23, P<0.002), high density lipoprotein cholesterol (HDL-C; r =.19, P < 0.01)), and TG/HDL-C ratio (r = -.23, P<0.002). The correlations were strongest in men. Subjects with TG in an intermediate range (110-149 mg/dL) had insulin resistance equivalent to the high TG group (≥ 150 mg/dL).
In African Americans, triglyceride levels below the current metabolic syndrome threshold criterion are associated with insulin resistance.
PMCID: PMC1950893  PMID: 17570258
Insulin; Metabolic Syndrome; Insulin Resistance; Triglycerides; High Density Lipoprotein
8.  A Turner syndrome neurocognitive phenotype maps to Xp22.3 
Turner syndrome (TS) is associated with a neurocognitive phenotype that includes selective nonverbal deficits, e.g., impaired visual-spatial abilities. We previously reported evidence that this phenotype results from haploinsufficiency of one or more genes on distal Xp. This inference was based on genotype/phenotype comparisons of individual girls and women with partial Xp deletions, with the neurocognitive phenotype considered a dichotomous trait. We sought to confirm our findings in a large cohort (n = 47) of adult women with partial deletions of Xp or Xq, enriched for subjects with distal Xp deletions.
Subjects were recruited from North American genetics and endocrinology clinics. Phenotype assessment included measures of stature, ovarian function, and detailed neurocognitive testing. The neurocognitive phenotype was measured as a quantitative trait, the Turner Syndrome Cognitive Summary (TSCS) score, derived from discriminant function analysis. Genetic analysis included karyotyping, X inactivation studies, fluorescent in situ hybridization, microsatellite marker genotyping, and array comparative genomic hybridization.
We report statistical evidence that deletion of Xp22.3, an interval containing 31 annotated genes, is sufficient to cause the neurocognitive phenotype described by the TSCS score. Two other cardinal TS features, ovarian failure and short stature, as well as X chromosome inactivation pattern and subject's age, were unrelated to the TSCS score.
Detailed mapping suggests that haploinsufficiency of one or more genes in Xp22.3, the distal 8.3 megabases (Mb) of the X chromosome, is responsible for a TS neurocognitive phenotype. This interval includes the 2.6 Mb Xp-Yp pseudoautosomal region (PAR1). Haploinsufficiency of the short stature gene SHOX in PAR1 probably does not cause this TS neurocognitive phenotype. Two genes proximal to PAR1 within the 8.3 Mb critical region, STS and NLGN4X, are attractive candidates for this neurocognitive phenotype.
PMCID: PMC1891305  PMID: 17517138
9.  Efficacy of collagenase in patients who did and did not have previous hand surgery for Dupuytren's contracture 
Collagenase Clostridium histolyticum (CCH) is a non-surgical, efficacious therapy for Dupuytren's contracture (DC). This study evaluated the efficacy and safety of CCH in patients with previous DC surgery. Data from 12 CCH clinical trials were pooled. At screening, patients provided details about the type/date of previous DC surgery. Reviewers coded descriptions to the Operated Hand, finger, and joint. Of 1082 patients, 422 (39%) had previous DC surgery. For these patients with previous surgery, the CCH treatment was coded on the Operated (n = 206) or Non-operated Hand (n = 196). End-points included changes in fixed-flexion contracture (FFC) and range of motion (ROM). Adverse events (AEs) were monitored. After treatment with CCH, FFC at metacarpophalangeal joints was reduced by 75% in previously Operated Hands and by 80% for Non-operated Hands (p = 0.6). Improvements in ROM were 32° and 32°, respectively (p = 0.9). For proximal inter-phalangeal joints, the reductions in FFC for the Operated and Non-operated Hands were 52% and 50%, respectively (p = 0.6); improvements in ROM were 24° and 26°, respectively (p = 0.3). Some AE rates were significantly higher in the Operated vs Non-operated Hand groups, but were not clinically relevant. There were no between-group significant differences in AE duration (p > 0.08). Previous surgery for DC does not affect efficacy or safety of CCH, suggesting CCH is an option in patients with recurring DC. Some AE rates were significantly higher, but not clinically relevant.
PMCID: PMC3469218  PMID: 22670890
Dupuytren's disease; surgery; recurrence; collagenase; contracture; range of motion

Results 1-9 (9)