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1.  A 3-year Randomized Therapeutic Trial of Nitisinone in Alkaptonuria 
Molecular genetics and metabolism  2011;103(4):307-314.
Alkaptonuria is a rare, autosomal recessive disorder of tyrosine degradation due to deficiency of the third enzyme in the catabolic pathway. As a result, homogentisic acid (HGA) accumulates and is excreted in gram quantities in the urine, which turns dark upon alkalization. The first symptoms, occurring in early adulthood, involve a painful, progressively debilitating arthritis of the spine and large joints. Cardiac valvular disease and renal and prostate stones occur later. Previously suggested therapies have failed to show benefit, and management remains symptomatic. Nitisinone, a potent inhibitor of the second enzyme in the tyrosine catabolic pathway, is considered a potential therapy; proof-of-principle studies showed 95% reduction in urinary HGA. Based on those findings, a prospective, randomized clinical trial was initiated in 2005 to evaluate 40 patients over a 36-month period. The primary outcome parameter was hip total range of motion with measures of musculoskeletal function serving as secondary parameters. Biochemically, this study consistently demonstrated 95% reduction of HGA in urine and plasma over the course of 3 years. Clinically, primary and secondary parameters did not prove benefit from the medication. Side effects were infrequent. This trial illustrates the remarkable tolerability of nitisinone, its biochemical efficacy, and the need to investigate its use in younger individuals prior to development of debilitating arthritis.
PMCID: PMC3148330  PMID: 21620748
Alkaptonuria; Ochronosis; Nitisinone; Homogentisic acid
2.  Bone mineral density in children and young adults with neurofibromatosis type 1 
Endocrine-related cancer  2012;19(6):817-825.
Concern for impaired bone health in children with neurofibromatosis type 1 (NF-1) has led to increased interest in bone densitometry in this population. Our study assessed bone mineral apparent density (BMAD) and whole-body bone mineral content (BMC)/height in pediatric patients with NF-1 with a high plexiform neurofibroma burden. Sixty-nine patients with NF-1 (age range 5.2–24.8; mean 13.7±4.8 years) were studied. Hologic dual-energy X-ray absorptiometry scans (Hologic, Inc., Bedford, MA, USA) were performed on all patients. BMD was normalized to derive a reference volume by correcting for height through the use of the BMAD, as well as the BMC. BMAD of the lumbar spine (LS 2–4), femoral neck (FN), and total body BMC/height were measured and Z-scores were calculated. Impaired bone mineral density was defined as a Z-score ≤−2. Forty-seven percent of patients exhibited impaired bone mineral density at any bone site, with 36% at the LS, 18% at the FN, and 20% total BMC/height. BMAD Z-scores of the LS (−1.60±1.26) were more impaired compared with both the FN (−0.54±1.58; P=0.0003) and the whole-body BMC/height Z-scores (−1.16±0.90; P=0.036). Plexiform neurofibroma burden was negatively correlated with LS BMAD (rs=−0.36, P=0.01). In pediatric and young adult patients with NF-1, LS BMAD was more severely affected than the FN BMAD or whole-body BMC/height.
PMCID: PMC4132947  PMID: 23089139
3.  Increased uptake of [123I]-meta-iodobenzylguanidine and [18F]-dopamine in mouse pheochromocytoma cells and tumors after treatment with the histone deacetylase inhibitors romidepsin and trichostatin A 
Endocrine-related cancer  2011;18(1):143-157.
[131I]-meta-iodobenzylguanidine ([131I]-MIBG) is the most commonly employed treatment for metastatic pheochromocytoma and paraganglioma; however, its success is limited. Its efficacy depends on the [131I]-MIBG concentration reached within the tumor through its uptake via the norepinephrine transporter and retention in neurosecretory granules. Purpose is to enhance [123I]-MIBG uptake in cells and liver pheochromocytoma tumors.
Experimental Design
We report the in vitro effects of two histone deacetylase (HDAC) inhibitors, romidepsin and trichostatin A, on increased uptake of [3H]-norepinephrine and [123I]-MIBG in mouse pheochromocytoma (MPC) cells, and the effect of romidepsin on [18F]-fluorodopamine and [123I]-MIBG uptake in a mouse model of metastatic pheochromocytoma. The effects of both inhibitors on norepinephrine transporter activity were assessed in MPC cells by [123I]-MIBG uptake studies with and without the transporter blocking agent desipramine and the vesicular blocking agent reserpine.
Both HDAC inhibitors increased [3H]-norepinephrine, [123I]-MIBG, and [18F]-fluorodopamine uptake through the norepinephrine transporter in MPC cells. In vivo, inhibitor treatment resulted in increased uptake of [18F]-fluorodopamine and in pheochromocytoma liver metastases as measured by maximal standardized uptake values on PET imaging (p < 0.001). Analysis of biodistribution after inhibitor treatment confirmed the PET results in that uptake of [123I]-MIBG was significantly increased in liver metastases (p < 0.05). Therefore, HDAC inhibitor treatment increased radioisotope uptake in MPC cells in vitro and in liver metastases in vivo, through increased norepinephrine transporter activity.
These results suggest that HDAC inhibitors could enhance the therapeutic efficacy of [131I]-MIBG treatment in patients with malignant pheochromocytoma.
PMCID: PMC4110720  PMID: 21098082
histone deacetylase; meta-iodobenzylguanidine; pheochromocytoma; romidepsin; trichostatin A
4.  History of Weight Control Attempts Among Adolescent Girls with Loss of Control Eating 
Loss of control (LOC) eating and a weight control attempt (WCA) history during adolescence are important behavioral risk factors for eating disorders and obesity. The current study investigated the significance of the presence of a WCA history among adolescent girls with LOC eating.
Participants were 114 obesity prevention-seeking 12–17-year-old (M=14.5, SD=1.7 years) girls who were between the 75th and 97th body mass index (BMI) percentile (BMI-z: M=1.5, SD=0.3) and reported LOC eating episodes during the previous month (M=4.0, SD=4.9 episodes; Median=2.0). Measures included the Eating Disorder Examination to assess LOC eating, eating pathology, and WCA history, and self-report questionnaires for symptoms of general psychopathology. Eating behavior was observed during a laboratory meal designed to capture a LOC eating episode.
67.5% reported a WCA history. As compared to girls without a WCA history (no-WCA), those with a WCA history (WCA) had greater disordered eating attitudes and depressive symptoms (ps<.04). There were no significant group differences in BMI-z or LOC eating (ps>.10). During the laboratory meal, WCA consumed less energy from snack-type foods than no-WCA (M=245.0, SD=156.1 vs. M=341.6, SD=192.3 kcal; p=.01).
Reported WCAs are highly prevalent and are associated with greater psychopathology symptoms among adolescent girls with LOC eating. Prospective data are needed to determine whether these overlapping risk behaviors confer differential vulnerability for developing eating disorders and obesity.
PMCID: PMC3795881  PMID: 23815764
Loss of control eating; dieting; weight control behavior; eating disorders; obesity
Transplantation  1997;63(2):186-194.
The effects of acute (AR) and chronic rejection (CR) on intestinal smooth muscle that are responsible for the dysmotility following small bowel transplantation (SBTX) are incompletely understood. Jejunal and ileal specimens from normal control dogs (n=7), and auto-transplanted dogs were examined at 7 days (n=6) and 1 (n=7), 3 (n=6), 6 (n=6), and 12 months (n=6). Allo-transplanted dogs that developed AR (n=8) and CR (n=5) were examined for gross and microscopic morphology (muscle thickness, the number and size of myocytes, and inflammatory infiltrate), and for contractile and intracellular electrical function in vitro. Auto-SBTX did not alter morphology at any period, but contractile function was impaired at 7 days (73.6%) compared with normal intestine. Acute rejection did not influence myocyte number or size, but was associated with a prominent infiltrate of neutrophils and lymphocytes, and severely impaired contractile function (20.6%) compared with auto-SBTX controls. Acute rejection also significantly inhibited the amplitude of slow waves and of inhibitory junction potentials. Chronic rejection caused thickening of muscularis propria by both hyperplasia (175.5%) and hypertrophy (202.6%) accompanied by moderate inflammatory cell infiltrate compared with auto-SBTX controls. We conclude that the marked inflammatory infiltrate into the muscularis propria indicates that the graft muscle is injured by both acute and chronic rejection; impaired function of intestinal smooth muscle following SBTX results from both rejection and the injury associated with transplantation, and chronic rejection following SBTX is associated with both hyperplasia and hypertrophy of the muscularis propria.
PMCID: PMC3154774  PMID: 9020316
6.  Direct Determination of Urinary Creatinine by Reactive-Thermal Desorption-Extractive Electrospray-Ion Mobility-Tandem Mass Spectrometry. 
Analytical Chemistry  2013;86(1):357-361.
A direct, ambient ionization method has been developed for the determination of creatinine in urine that combines derivatization and thermal desorption with extractive electrospray ionization and ion mobility-mass spectrometry. The volatility of creatinine was enhanced by a rapid on-probe aqueous acylation reaction, using a custom-made thermal desorption probe, allowing thermal desorption and ionization of the monoacylated derivative. The monoacyl creatinine [M + H]+ ion (m/z 156) was subjected to mass-to-charge selection and collision induced dissociation to remove the acyl group, generating the protonated creatinine [M + H]+ product ion at m/z 114 before an ion mobility separation was applied to reduce chemical noise. Stable isotope dilution using creatinine-d3 as internal standard was used for quantitative measurements. The direct on-probe derivatization allows high sample throughput with a typical cycle time of 1 min per sample. The method shows good linearity (R2 = 0.986) and repeatability (%RSD 8–10%) in the range of 0.25–2.0 mg/mL. The creatinine concentrations in diluted urine samples from a healthy individual were determined to contain a mean concentration of 1.44 mg/mL creatinine with a precision (%RSD) of 9.9%. The reactive ambient ionization approach demonstrated here has potential for the determination of involatile analytes in urine and other biofluids.
PMCID: PMC3953925  PMID: 24279641
7.  Serum Leptin and Loss of Control Eating in Children and Adolescents 
Both insufficiency and resistance to the actions of the adipocyte-derived hormone leptin promote hunger, increased food intake, and greater body weight. Some studies suggest adults reporting binge eating have increased serum leptin compared to those without binge eating, even after adjusting for the greater adiposity that characterizes binge eaters. Pediatric binge or loss of control (LOC) eating are prospective risk factors for excessive weight gain and may predict development of metabolic abnormalities, but whether LOC eating is associated with higher leptin among children is unknown. We therefore examined leptin and LOC eating in a pediatric cohort.
A convenience sample of 506 lean and obese youth (7–18y) was recruited from Washington, DC and its suburbs. Serum leptin was collected after an overnight fast. Adiposity was measured by dual-energy x-ray absorptiometry or air displacement plethysmography. LOC eating was assessed by interview methodology.
Leptin was strongly associated with fat mass (r=.79, p<.001). However, even after adjusting for adiposity and other relevant covariates, youth with LOC eating had higher serum leptin compared to those without LOC episodes (15.42±1.05 vs. 12.36±1.04 ng/mL, p<.001). Neither reported amount of food consumed during a recent LOC episode nor number of LOC episodes in the previous month accounted for differences in leptin (ps>.05). The relationship between LOC eating and leptin appeared to be significant for females only (p=0.002).
Reports of LOC eating were associated with higher fasting leptin in youth, beyond the contributions of body weight. Prospective studies are required to elucidate if LOC eating promotes greater leptin or if greater leptin resistance may promote LOC eating.
PMCID: PMC3900593  PMID: 23835660
Binge Eating; Leptin; Loss of Control Eating; Hormone Resistance; Adiposity
8.  Direct Detection of a Sulfonate Ester Genotoxic Impurity by Atmospheric-Pressure Thermal Desorption–Extractive Electrospray–Mass Spectrometry 
Analytical Chemistry  2013;85(13):6224-6227.
A direct, ambient ionization method has been developed using atmospheric pressure thermal desorption–extractive electrospray–mass spectrometry (AP/TD-EESI-MS) for the detection of the genotoxic impurity (GTI) methyl p-toluenesulfonate (MTS) in a surrogate pharmaceutical matrix. A custom-made thermal desorption probe was used to the desorb and vaporize MTS from the solid state, by rapid heating to 200 °C then cooling to ambient temperature, with a cycle time of 6 min. The detection of MTS using EESI with a sodium acetate doped solvent to generate the [MTS+Na]+ adduct ion provided a significant sensitivity enhancement relative to the [M+H]+ ion generated using a 0.1% formic acid solvent modifier. The MTS detection limit is over an order of magnitude below the long-term daily threshold of toxicological concern (TTC) of 1.5 μg/g and the potential for quantitative analysis has been determined using starch as a surrogate active pharmaceutical ingredient (API).
PMCID: PMC3949410  PMID: 23750985
9.  Daily Parathyroid Hormone 1-34 Replacement Therapy for Hypoparathyroidism Induces Marked Changes in Bone Turnover and Structure 
Journal of Bone and Mineral Research  2012;27(8):1811-1820.
Parathyroid hormone (PTH) has variable actions on bone. Chronically increased PTH is catabolic leading to osteoporosis, yet intermittent administration is anabolic and increases bone mass. PTH deficiency is associated with decreased bone remodeling and increased bone mass. However, the effects of PTH replacement therapy on bone in hypoparathyroidism are not well known. We discontinued calcitriol therapy and treated five hypoparathyroid subjects (2 adults and 3 adolescents) with synthetic human PTH 1-34 (hPTH 1-34), injected 2-3 times daily for 18 months, with doses individualized to maintain serum calcium at 1.9-2.25 mmol/L. Biochemical markers and bone density (BMD) were assessed every 6 months; iliac-crest biopsies were performed before and after 1 year of treatment. hPTH 1-34 therapy significantly increased bone markers to supranormal levels. Histomorphometry revealed that treatment dramatically increased cancellous bone volume and trabecular number and decreased trabecular separation. Changes in trabecular width were variable, suggesting that the increase in trabecular number was due to the observed intratrabecular tunneling. Cortical width remained unchanged, however, hPTH 1-34 treatment increased cortical porosity. Cancellous bone remodeling was also stimulated, inducing significant changes in osteoid, mineralizing surface, and bone formation rate. Similar changes were seen in endocortical and intracortical remodeling. BMD Z-scores were unchanged at the spine and femoral neck. Total hip Z-scores increased, however, total body BMD Z-scores decreased during the first 6 months of treatment and then stabilized, remaining significantly decreased compared to baseline. Radial Z-scores also decreased with treatment; this was most pronounced in the growing adolescent. Daily hPTH 1-34 therapy for hypoparathyroidism stimulated bone turnover, increased bone volume, and altered bone structure in the iliac crest. These findings suggest that treatment with hPTH 1-34 in hypoparathyroid adults and adolescents has varying effects in the different skeletal compartments, leading to an increase in trabecular bone and an apparent trabecularization of cortical bone.
PMCID: PMC3399961  PMID: 22492501
10.  SLC26A4 Genotypes and Phenotypes Associated with Enlargement of the Vestibular Aqueduct 
Enlargement of the vestibular aqueduct (EVA) is the most common inner ear anomaly detected in ears of children with sensorineural hearing loss. Pendred syndrome (PS) is an autosomal recessive disorder characterized by bilateral sensorineural hearing loss with EVA and an iodine organification defect that can lead to thyroid goiter. Pendred syndrome is caused by mutations of the SLC26A4 gene. SLC26A4 mutations may also be identified in some patients with nonsyndromic EVA (NSEVA). The presence of two mutant alleles of SLC26A4 is correlated with bilateral EVA and Pendred syndrome, whereas unilateral EVA and NSEVA are correlated with one (M1) or zero (M0) mutant alleles of SLC26A4. Thyroid gland enlargement (goiter) appears to be primarily dependent on the presence of two mutant alleles of SLC26A4 in pediatric patients, but not in older patients. In M1 families, EVA may be associated with a second, undetected SLC26A4 mutation or epigenetic modifications. In M0 families, there is probably etiologic heterogeneity that includes causes other than, or in addition to, monogenic inheritance.
PMCID: PMC3709178  PMID: 22116369
SLC26A4; Pendred syndrome; Hearing; Deafness; Inner ear; Genotype-phenotype correlation
11.  Correction: Do Premenopausal Women with Major Depression Have Low Bone Mineral Density? A 36-Month Prospective Study 
PLoS ONE  2012;7(10):10.1371/annotation/193f2b29-b8b0-41e8-808a-290df5577a53.
PMCID: PMC3935646
12.  Do Premenopausal Women with Major Depression Have Low Bone Mineral Density? A 36-Month Prospective Study 
PLoS ONE  2012;7(7):e40894.
An inverse relationship between major depressive disorder (MDD) and bone mineral density (BMD) has been suggested, but prospective evaluation in premenopausal women is lacking.
Participants of this prospective study were 21 to 45 year-old premenopausal women with MDD (n = 92) and healthy controls (n = 44). We measured BMD at the anteroposterior lumbar spine, femoral neck, total hip, mid-distal radius, trochanter, and Ward's triangle, as well as serum intact parathyroid hormone (iPTH), ionized calcium, plasma adrenocorticotropic hormone (ACTH), serum cortisol, and 24-hour urinary-free cortisol levels at 0, 6, 12, 24, and 36 months. 25-hydroxyvitamin D was measured at baseline.
At baseline, BMD tended to be lower in women with MDD compared to controls and BMD remained stable over time in both groups. At baseline, 6, 12, and 24 months intact PTH levels were significantly higher in women with MDD vs. controls. At baseline, ionized calcium and 25-hydroxyvitamin D levels were significantly lower in women with MDD compared to controls. At baseline and 12 months, bone-specific alkaline phosphatase, a marker of bone formation, was significantly higher in women with MDD vs. controls. Plasma ACTH was also higher in women with MDD at baseline and 6 months. Serum osteocalcin, urinary N-telopeptide, serum cortisol, and urinary free cortisol levels were not different between the two groups throughout the study.
Women with MDD tended to have lower BMD than controls over time. Larger and longer studies are necessary to extend these observations with the possibility of prophylactic therapy for osteoporosis.
Trial Registration NCT 00006180
PMCID: PMC3407177  PMID: 22848407
The Journal of Clinical Psychiatry  2010;71(8):1079-1087.
Major depressive disorder (MDD) is associated with immune system dysfunction and disruption of multiple circadian systems. Adiponectin is an adipocytokine with anti-inflammatory and anti-atherogenic effects. Circulating concentrations are inversely related to adiposity and risks of metabolic syndrome and diabetes mellitus. Our goals were to: A) establish whether premenopausal women with MDD exhibit decreased plasma adiponectin concentrations and/or disruption of circadian adiponectin rhythmicity; B) assess whether there is a relationship between adiponectin and MDD; C) explore the temporal relationships among adiponectin, leptin, ACTH and cortisol secretion.
Case-control study of community-dwelling premenopausal women with MDD and age- and BMI-matched-control subjects (N=23/group). Main outcome measures were circulating concentrations of adiponectin, leptin, ACTH, and cortisol measured hourly for 24h.
Women with MDD had approximately 30% lower mean 24h concentrations of adiponectin than did control subjects. Adiponectin was inversely related to depression severity and total duration of disease, suggesting a causal link. In contrast, nocturnal leptin concentrations were higher in the MDD versus control groups. Leptin was inversely related to cortisol and adiponectin both in subjects with depression and in control subjects. In cross-correlation analyses, the relationship between ACTH and cortisol was stronger in women with MDD than in control subjects, consistent with HPA-axis activation in MDD.
Reduced daily adiponectin production may increase the risk of diabetes mellitus, and elevated leptin may contribute to osteoporosis, in premenopausal women with MDD.
PMCID: PMC3277206  PMID: 20492842
women’s health; psychosomatic medicine; antidepressants; stress system; circadian rhythmicity; inflammation; adipocytokines: ACTH; cortisol: insulin resistance, cardiovascular risk; osteoporosis; osteopenia
14.  A Better Index of Body Adiposity 
Obesity (Silver Spring, Md.)  2011;19(5):1083-1089.
Obesity is a growing problem in the United States and throughout the world. It is a risk factor for many chronic diseases. The BMI has been used to assess body fat for almost 200 years. BMI is known to be of limited accuracy, and is different for males and females with similar %body adiposity. Here, we define an alternative parameter, the body adiposity index (BAI = ((hip circumference)/((height)1.5) − 18)). The BAI can be used to reflect %body fat for adult men and women of differing ethnicities without numerical correction. We used a population study, the “BetaGene” study, to develop the new index of body adiposity. %Body fat, as measured by the dual-energy X-ray absorptiometry (DXA), was used as a “gold standard” for validation. Hip circumference (R = 0.602) and height (R = −0.524) are strongly correlated with %body fat and therefore chosen as principal anthropometric measures on which we base BAI. The BAI measure was validated in the “Triglyceride and Cardiovascular Risk in African-Americans (TARA)” study of African Americans. Correlation between DXA-derived %adiposity and the BAI was R = 0.85 for TARA with a concordance of C_b = 0.95. BAI can be measured without weighing, which may render it useful in settings where measuring accurate body weight is problematic. In summary, we have defined a new parameter, the BAI, which can be calculated from hip circumference and height only. It can be used in the clinical setting even in remote locations with very limited access to reliable scales. The BAI estimates %adiposity directly.
PMCID: PMC3275633  PMID: 21372804
15.  Effects of Metformin on Body Weight and Body Composition in Obese Insulin-Resistant Children 
Diabetes  2011;60(2):477-485.
Metformin can decrease adiposity and ameliorate obesity-related comorbid conditions, including abnormalities in glucose homeostasis in adolescents, but there are few data evaluating the efficacy of metformin among younger children. Our objective was to determine whether metformin treatment causes weight loss and improves obesity-related comorbidities in obese children, who are insulin-resistant.
This study was a randomized double-blind placebo-controlled trial consisting of 100 severely obese (mean BMI 34.6 ± 6.6 kg/m2) insulin-resistant children aged 6–12 years, randomized to 1,000 mg metformin (n = 53) or placebo (n = 47) twice daily for 6 months, followed by open-label metformin treatment for 6 months. All children and their parents participated in a monthly dietitian-administered weight-reduction program.
Eighty-five percent completed the 6-month randomized phase. Children prescribed metformin had significantly greater decreases in BMI (difference −1.09 kg/m2, CI −1.87 to −0.31, P = 0.006), body weight (difference −3.38 kg, CI −5.2 to −1.57, P < 0.001), BMI Z score (difference between metformin and placebo groups −0.07, CI −0.12 to −0.01, P = 0.02), and fat mass (difference −1.40 kg, CI −2.74 to −0.06, P = 0.04). Fasting plasma glucose (P = 0.007) and homeostasis model assessment (HOMA) insulin resistance index (P = 0.006) also improved more in metformin-treated children than in placebo-treated children. Gastrointestinal symptoms were significantly more prevalent in metformin-treated children, which limited maximal tolerated dosage in 17%. During the 6-month open-label phase, children treated previously with placebo decreased their BMI Z score; those treated continuously with metformin did not significantly change BMI Z score further.
Metformin had modest but favorable effects on body weight, body composition, and glucose homeostasis in obese insulin-resistant children participating in a low-intensity weight-reduction program.
PMCID: PMC3028347  PMID: 21228310
16.  Clinical Subtypes of Depression Are Associated with Specific Metabolic Parameters and Circadian Endocrine Profiles in Women: The Power Study 
PLoS ONE  2012;7(1):e28912.
Major depressive disorder (MDD) has been associated with adverse medical consequences, including cardiovascular disease and osteoporosis. Patients with MDD may be classified as having melancholic, atypical, or undifferentiated features. The goal of the present study was to assess whether these clinical subtypes of depression have different endocrine and metabolic features and consequently, varying medical outcomes.
Premenopausal women, ages 21 to 45 years, with MDD (N = 89) and healthy controls (N = 44) were recruited for a prospective study of bone turnover. Women with MDD were classified as having melancholic (N = 51), atypical (N = 16), or undifferentiated (N = 22) features. Outcome measures included: metabolic parameters, body composition, bone mineral density (BMD), and 24 hourly sampling of plasma adrenocorticotropin (ACTH), cortisol, and leptin.
Compared with control subjects, women with undifferentiated and atypical features of MDD exhibited greater BMI, waist/hip ratio, and whole body and abdominal fat mass. Women with undifferentiated MDD characteristics also had higher lipid and fasting glucose levels in addition to a greater prevalence of low BMD at the femoral neck compared to controls. Elevated ACTH levels were demonstrated in women with atypical features of depression, whereas higher mean 24-hour leptin levels were observed in the melancholic subgroup.
Pre-menopausal women with various features of MDD exhibit metabolic, endocrine, and BMD features that may be associated with different health consequences.
Trial Registration NCT00006180
PMCID: PMC3250402  PMID: 22235252
17.  Fecal Incontinence: Prevalence, Severity, and Quality of Life Data from an Outpatient Gastroenterology Practice 
Background. The prevalence of fecal incontinence varies tremendously as a result of inadequate data collection methods. Few office-based studies have assessed the prevalence of fecal incontinence and none have looked at modifiable risk factors or effect on quality of life. Design, Settings, Patients, and Main Outcome Measures. Five hundred patients who visited our inner city, university-based gastroenterology practice, were asked about symptoms of fecal incontinence. We also retrospectively reviewed 500 charts to identify the frequency of patient-physician reporting of fecal incontinence. Results. Of the 500 patients that were directly questioned, 58 (12%, 43 women, 15 men) admitted to fecal incontinence compared to 12 (2.4%) in the retrospective arm. Patients with fecal incontinence and loose/watery stool reported the lowest quality of life scores. While the average severity score was similar between men and women, women had a significantly lower average quality of life score (3.04 versus 2.51; P < 0.03). Conclusions. The identification of fecal incontinence increases when patients are directly questioned. Identifying and treating patients with loose stool is a potential strategy to improve quality of life in this patient population. In men and women with similar severity of fecal incontinence, women have a significantly lower quality of life.
PMCID: PMC3180067  PMID: 21960998
18.  Expression of Benign and Malignant Thyroid Tissue in Ovarian Teratomas and the Importance of Multimodal Management as Illustrated by a BRAF-Positive Follicular Variant of Papillary Thyroid Cancer 
Thyroid  2010;20(9):981-987.
The most common type of ovarian germ cell tumor is the teratoma. Thyroid tissue, both benign and malignant, may be a component of an ovarian teratoma. Here we review this topic and illustrate major features by presenting multimodal management of a patient with BRAF-positive disseminated follicular thyroid cancer arising in an ovarian teratoma.
Malignant thyroid tissue is often difficult to distinguish from benign thyroid tissue arising in ovarian teratomas. Preoperatively, an elevated thyroglobulin (Tg) level, laboratory or clinical evidence of hyperthyroidism, or ultrasonography appearance of “struma pearl” should prompt referral to oncologist for surgical management of a possibly malignant ovarian teratoma. Postoperatively, tumor tissue should be referred to pathologists experienced with differentiating benign from malignant struma ovarii. Once diagnosed, treatment of this rare condition should be handled by a team of specialists with combined treatment modalities. We cared for woman with disseminated thyroid cancer arising in an ovarian teratoma whose history illustrates the complexity of managing ovarian teratomas with malignant thyroid tissue. At age 33 she had an intraoperative rupture of an ovarian cyst, thought to be struma ovarii. During her next pregnancy, pelvic masses were noted; biopsies revealed well-differentiated papillary thyroid carcinoma, follicular variant. She was euthyroid, but had elevated serum Tg levels. Surgical staging demonstrated widely metastatic intraabdominal dissemination. A thyroidectomy revealed no malignancy. A post-131I treatment scan revealed diffuse uptake throughout the abdomen. She then developed abdominal pain and, on computed tomography, was found to have multiple intraabdominal foci of disease. Serum Tg was 264 ng/mL while on L-thyroxine for hypothyroidism and to obtain thyrotropin suppression. A 18 fluorodeoxyglucose positron emission tomography scan showed no pathological uptake. The tumor was found to be BRAF mutation positive (K601E). She underwent extensive secondary debulking and a second course of 131I with lithium pretreatment. Posttreatment scan revealed diffuse abdominal uptake. Six months posttherapy, the patient is asymptomatic with a serum Tg of 18.1 ng/mL.
Aggressive multimodal management appears to be the most promising approach for malignant thyroid tissue arising in ovarian teratomas.
PMCID: PMC2964358  PMID: 20718682
19.  Effects of Cushing Disease on Bone Mineral Density in a Pediatric Population 
The Journal of pediatrics  2010;156(6):1001-1005.
To evaluate bone mineral density (BMD) in children with Cushing disease before and after transphenoidal surgery (TSS).
Study design
Hologic dual-energy x-ray absorptiometry (DXA) scans of 35 children with Cushing disease were analyzed retrospectively. Sixteen of the 35 patients had follow up DXA scans 13–18 months after TSS. BMD and bone mineral apparent density (BMAD) for lumbar spine (LS) L1–L4 and femoral neck (FN) were calculated.
Preoperatively, 38% and 23% of patients had osteopenia of the LS and FN, respectively. Both BMD and BMAD Z-scores of the LS were worse than those for the FN (−1.60 ± 1.37 vs. −1.04 ± 1.19, p=0.003), and (−1.90 ± 1.49 vs. −0.06 ± 1.90, p<.001); postoperative improvement in BMD and BMAD were more pronounced in LS as compared with the FN (0.84 ± 0.88 vs. 0.15 ± 0.62, p<.001) and (0.73 ± 1.13 vs −0.26 ± 1.21, p=0.015). Pubertal stage, cortisol levels, and length of disease had no effects on BMD.
In children with Cushing disease, vertebral BMD was more severely affected than femoral BMD and was independent of degree or duration of hypercortisolism. BMD for the LS improved significantly after TSS; osteopenia in this group may be reversible.
PMCID: PMC2875346  PMID: 20223476
Glucocorticoid; steroid excess; osteopenia
20.  Amelioration of Intestinal Dysmotility and Stasis by Octreotide Early After Small-Bowel Autotransplantation in Dogs 
American journal of surgery  1995;169(3):294-299.
Intestinal dysmotility and stasis after intestinal transplantation are considered to promote bacterial overgrowth and translocation. Two prokinetic agents, KW5139 (13-leu-motilin) and the somatostatin analogue octreotide acetate, were studied to determine whether they can ameliorate intestinal dysmotility during the early postoperative period.
Motility was recorded by multiple extraluminal strain-gauge transducers in 6 dogs on postoperative days 1, 3, 7, and 14. A barium meal study was performed with a separate group of 8 dogs on postoperative days 3 and 7.
The agent KW5139 induced brief, weak contractions in the graft and had little effect on the dilated bowel; however, octreotide induced motor activity that propelled accumulated intestinal contents into the colon and reduced dilation of the transplanted bowel.
Octreotide, but not KW5139, ameliorates intestinal dysmotility associated with bowel autotransplantation during the early postoperative period. Short-term administration of octreotide may be useful for the treatment of dysmotility following intestinal transplantation.
PMCID: PMC2965452  PMID: 7879829
21.  Evaluation of the Thyroid in Patients With Hearing Loss and Enlarged Vestibular Aqueducts 
To evaluate thyroid structure and function in patients with enlargement of the vestibular aqueduct (EVA) and sensorineural hearing loss.
Prospective cohort survey.
National Institutes of Health Clinical Center, a federal biomedical research facility.
The study population comprised 80 individuals, aged 1.5 to 59 years, ascertained on the basis of EVA and sensorineural hearing loss.
Main Outcome Measures
Associations among the number of mutant alleles of SLC26A4; volume and texture of the thyroid; percentage of iodine 123 (123I) discharged at 120 minutes after administration of perchlorate in the perchlorate discharge test; and peripheral venous blood levels of thyrotropin, thyroxine, free thyroxine, triiodothyronine, thyroglobulin, antithyroid peroxidase and antithyroglobulin antibodies, and thyroid-binding globulin.
Thyroid volume is primarily genotype dependent in pediatric patients but age dependent in older patients. Individuals with 2 mutant SLC26A4 alleles discharged a significantly (P ≤ .001) greater percentage of 123I compared with those with no mutant alleles or 1 mutant allele. Thyroid function, as measured by serologic testing, is not associated with the number of mutant alleles.
Ultrasonography with measurement of gland volume is recommended for initial assessment and follow-up surveillance of the thyroid in patients with EVA. Perchlorate discharge testing is recommended for the diagnostic evaluation of patients with EVA along with goiter, nondiagnostic SLC26A4 genotypes (zero or 1 mutant allele), or both.
PMCID: PMC2941509  PMID: 19620588
22.  Phenotype and Course of Hutchinson–Gilford Progeria Syndrome 
The New England journal of medicine  2008;358(6):592-604.
Hutchinson–Gilford progeria syndrome is a rare, sporadic, autosomal dominant syndrome that involves premature aging, generally leading to death at approximately 13 years of age due to myocardial infarction or stroke. The genetic basis of most cases of this syndrome is a change from glycine GGC to glycine GGT in codon 608 of the lamin A (LMNA) gene, which activates a cryptic splice donor site to produce abnormal lamin A; this disrupts the nuclear membrane and alters transcription.
We enrolled 15 children between 1 and 17 years of age, representing nearly half of the world's known patients with Hutchinson–Gilford progeria syndrome, in a comprehensive clinical protocol between February 2005 and May 2006.
Clinical investigations confirmed sclerotic skin, joint contractures, bone abnormalities, alopecia, and growth impairment in all 15 patients; cardiovascular and central nervous system sequelae were also documented. Previously unrecognized findings included prolonged prothrombin times, elevated platelet counts and serum phosphorus levels, measured reductions in joint range of motion, low-frequency conductive hearing loss, and functional oral deficits. Growth impairment was not related to inadequate nutrition, insulin unresponsiveness, or growth hormone deficiency. Growth hormone treatment in a few patients increased height growth by 10% and weight growth by 50%. Cardiovascular studies revealed diminishing vascular function with age, including elevated blood pressure, reduced vascular compliance, decreased ankle–brachial indexes, and adventitial thickening.
Establishing the detailed phenotype of Hutchinson–Gilford progeria syndrome is important because advances in understanding this syndrome may offer insight into normal aging. Abnormal lamin A (progerin) appears to accumulate with aging in normal cells.
PMCID: PMC2940940  PMID: 18256394
23.  Disordered-Eating Attitudes in Relation to Bone Mineral Density and Markers of Bone Turnover in Overweight Adolescents 
To examine the relationships between cognitive eating restraint and both bone mineral density (BMD) and markers of bone turnover in overweight adolescents.
137 overweight (BMI 39.1±6.8 kg/m2) African American and Caucasian adolescent (age=14.4 ± 1.4y) girls (66.4%) and boys were administered the Eating Disorder Examination (EDE) interview and Eating Inventory (EI) questionnaire and underwent dual energy x-ray absorptiometry (DXA) to measure total lumbar spine BMD. Markers of bone formation (serum bone specific alkaline phosphatase and osteocalcin), bone resorption (24-hour urine N-telopeptides), and stress (urine free cortisol) were measured.
After accounting for the contribution of demographics, height, weight, serum 25-hydroxyvitamin D, and depressive symptoms, adolescents’ weight concern, as assessed by interview, was a significant contributor to a model of urine free cortisol (β =.30, p <.05). Shape concern, as also assessed by interview, was significantly associated with lumbar spine bone mineral density (β =.−.15, p < 05). Dietary restraint was not a significant predictor in any of these models.
These findings suggest that among severely overweight adolescents, dissatisfaction with shape and weight may be salient stressors. Future research is required to illuminate the relationship between bone health and disordered-eating attitudes in overweight adolescents.
PMCID: PMC2722035  PMID: 19541247
adolescents; bone turnover; bone mineral density; disordered-eating attitudes; overweight; cortisol
24.  Hypo-functional SLC26A4 variants associated with nonsyndromic hearing loss and enlargement of the vestibular aqueduct: genotype-phenotype correlation or coincidental polymorphisms? 
Human mutation  2009;30(4):599-608.
Hearing loss with enlargement of the vestibular aqueduct (EVA) can be associated with mutations of the SLC26A4 gene encoding pendrin, a transmembrane Cl−/I−/HCO3− exchanger. Pendrin’s critical transport substrates are thought to be I− in the thyroid gland and HCO3− in the inner ear. We previously reported that bi-allelic SLC26A4 mutations are associated with Pendred syndromic EVA whereas one or zero mutant alleles are associated with nonsyndromic EVA. One study proposed a correlation of nonsyndromic EVA with SLC26A4 alleles encoding pendrin with residual transport activity. Here we describe the phenotypes and SLC26A4 genotypes of 47 EVA patients ascertained since our first report of 39 patients. We sought to determine the pathogenic potential of each variant in our full cohort of 86 patients. We evaluated the trafficking of 11 missense pendrin products expressed in COS-7 cells. Products that targeted to the plasma membrane were expressed in Xenopus oocytes for measurement of anion exchange activity. p.F335L, p.C565Y, p.L597S, p.M775T, and p.R776C had Cl−/I− and Cl−/HCO3− exchange rate constants that ranged from 13 to 93% of wild type values. p.F335L, p.L597S, p.M775T and p.R776C are typically found as mono-allelic variants in nonsyndromic EVA. The high normal control carrier rate for p.L597S indicates it is a coincidentally detected nonpathogenic variant in this context. We observed moderate differential effects of hypo-functional variants upon exchange of HCO3− versus I− but their magnitude does not support a causal association with nonsyndromic EVA. However, these alleles could be pathogenic in trans configuration with a mutant allele in Pendred syndrome.
PMCID: PMC2663020  PMID: 19204907
enlargement of the vestibular aqueduct; EVA; deafness; DFNB4; hearing; genotype-phenotype correlation; PDS; pendrin; SLC26A4
25.  Hypocalcemia in a Patient With Osteosarcoma and 22q11.2 Deletion Syndrome 
Hypocalcemia is a rare complication of osteosarcoma, having been described in only 4 reports. We present the case of a 16-year-old male with metastatic osteosarcoma of the right humerus who was found to have severe asymptomatic hypocalcemia. Cytogenetic analysis of peripheral blood revealed a microdeletion in band 22q11.2. Following amputation of the tumor-bearing extremity, the patient’s calcium levels increased, but did not normalize. These findings suggested that the etiology of his hypocalcemia was osteoblastic utilization of calcium by the tumor, exacerbated by 22q11.2 deletion syndrome.
PMCID: PMC2748653  PMID: 18799940
hypocalcemia; osteosarcoma; 22q11.2 deletion syndrome

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