An Arabidopsis gene regulatory network for secondary cell wall synthesis.

The plant cell wall is an important factor for determining cell shape, function and response to the environment. Secondary cell walls, such as those found in xylem, are composed of cellulose, hemicelluloses and lignin and account for the bulk of plant biomass. The coordination between transcriptional regulation of synthesis for each polymer is complex and vital to cell function. A regulatory hierarchy of developmental switches has been proposed, although the full complement of regulators remains unknown. Here we present a protein-DNA network between Arabidopsis thaliana transcription factors and secondary cell wall metabolic genes with gene expression regulated by a series of feed-forward loops. This model allowed us to develop and validate new hypotheses about secondary wall gene regulation under abiotic stress. Distinct stresses are able to perturb targeted genes to potentially promote functional adaptation. These interactions will serve as a foundation for understanding the regulation of a complex, integral plant component.

A longitudinal study of serum insulin and insulin resistance as predictors of weight and body fat gain in African American and Caucasian children.

BACKGROUND: The influence of insulin and insulin resistance (IR) on children's weight and fat gain is unclear. OBJECTIVE: To evaluate insulin and IR as predictors of weight and body fat gain in children at high risk for adult obesity. We hypothesized that baseline IR would be positively associated with follow-up body mass index (BMI) and fat mass. SUBJECTS/METHODS: Two hundred and forty-nine healthy African American and Caucasian children aged 6-12 years at high risk for adult obesity because of early-onset childhood overweight and/or parental overweight were followed for up to 15 years with repeated BMI and fat mass measurements. We examined baseline serum insulin and homeostasis model of assessment-IR (HOMA-IR) as predictors of follow-up BMI Z-score and fat mass by dual-energy X-ray absorptiometry in mixed model longitudinal analyses accounting for baseline body composition, pubertal stage, sociodemographic factors and follow-up interval. RESULTS: At baseline, 39% were obese (BMI⩾95th percentile for age/sex). Data from 1335 annual visits were examined. Children were followed for an average of 7.2±4.3 years, with a maximum follow-up of 15 years. After accounting for covariates, neither baseline insulin nor HOMA-IR was significantly associated with follow-up BMI (Ps>0.26), BMIz score (Ps>0.22), fat mass (Ps>0.78) or fat mass percentage (Ps>0.71). In all models, baseline BMI (P<0.0001), body fat mass (P<0.0001) and percentage of fat (P<0.001) were strong positive predictors for change in BMI and fat mass. In models restricted to children without obesity at baseline, some but not all models had significant interaction terms between body adiposity and insulinemia/HOMA-IR that suggested less gain in mass among those with greater insulin or IR. The opposite was found in some models restricted to children with obesity at baseline. CONCLUSIONS: In middle childhood, BMI and fat mass, but not insulin or IR, are strong predictors of children's gains in BMI and fat mass during adolescence.

Spatiotemporal regulation of cell-cycle genes by SHORTROOT links patterning and growth.

The development of multicellular organisms relies on the coordinated control of cell divisions leading to proper patterning and growth. The molecular mechanisms underlying pattern formation, particularly the regulation of formative cell divisions, remain poorly understood. In Arabidopsis, formative divisions generating the root ground tissue are controlled by SHORTROOT (SHR) and SCARECROW (SCR). Here we show, using cell-type-specific transcriptional effects of SHR and SCR combined with data from chromatin immunoprecipitation-based microarray experiments, that SHR regulates the spatiotemporal activation of specific genes involved in cell division. Coincident with the onset of a specific formative division, SHR and SCR directly activate a D-type cyclin; furthermore, altering the expression of this cyclin resulted in formative division defects. Our results indicate that proper pattern formation is achieved through transcriptional regulation of specific cell-cycle genes in a cell-type- and developmental-stage-specific context. Taken together, we provide evidence for a direct link between developmental regulators, specific components of the cell-cycle machinery and organ patterning.

Effects of metformin on energy intake and satiety in obese children.

AIMS: To investigate the effects of metformin on appetite and energy intake in obese children with hyperinsulinaemia. METHODS: We conducted a 6-month randomized, double-blind, placebo-controlled trial to evaluate the effects of metformin 1000 mg twice daily on body weight and energy balance in 100 obese children with hyperinsulinaemia aged 6-12 years. The children ate ad libitum from standardized food arrays on two separate occasions before and after 6 months of study medication. The first test meal was consumed after an overnight fast. The second was preceded by a pre-meal load. For each test meal, energy intake was recorded, and the children completed scales of hunger, fullness and desire to eat. RESULTS: Data from the meal studies at baseline and after treatment with study medication were available for 84 children (metformin-treated, n = 45; placebo-treated, n = 39). Compared with placebo, metformin treatment elicited significant reductions from baseline in adjusted mean ± standard error of the mean energy intake after the pre-meal load (metformin: -104.7 ± 83.8 kcal vs. placebo: +144.2 ± 96.9 kcal; p = 0.034) independently of changes in body composition. Metformin also significantly decreased ratings of hunger (-1.5 ± 5.6 vs. +18.6 ± 6.3; p = 0.013) and increased ratings of fullness (+10.1 ± 6.2 vs. -12.8 ± 7.0; p = 0.01) after the pre-meal load. CONCLUSIONS: These data suggest that decreased perceived hunger resulting in diminished food intake are among the mechanisms by which metformin treatment reduces body weight in overweight children with hyperinsulinaemia.

Serum leptin and loss of control eating in children and adolescents.

BACKGROUND: 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 that adults reporting binge eating have increased serum leptin compared with 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. METHODS: A convenience sample of 506 lean and obese youth (7-18 years) 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. RESULTS: Leptin was strongly associated with fat mass (r=0.79, P<0.001). However, even after adjusting for adiposity and other relevant covariates, youth with LOC eating had higher serum leptin compared with those without LOC episodes (15.42±1.05 vs 12.36±1.04 ng ml(-1), P<0.001). 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 (P>0.05). The relationship between LOC eating and leptin appeared to be significant for females only (P=0.002). CONCLUSIONS: Reports of LOC eating were associated with higher fasting leptin in youth, beyond the contributions of body weight. Prospective studies are required to elucidate whether LOC eating promotes greater leptin or whether greater leptin resistance may promote LOC eating.

Prediction of maximal oxygen uptake by bioelectrical impedance analysis in overweight adolescents.

AIM: Maximal oxygen uptake (VO(2max)), the gold standard for measurement of cardiorespiratory fitness, is frequently difficult to assess in overweight individuals due to physical limitations. Reactance and resistance measures obtained from bioelectrical impedance analysis (BIA) have been suggested as easily obtainable predictors of cardiorespiratory fitness, but the accuracy with which ht(2)/Z can predict VO(2max) has not previously been examined in overweight adolescents. METHODS: The impedance index was used as a predictor of VO(2max) in 87 overweight girls and 47 overweight boys ages 12 to 17 with mean BMI of 38.6 + or - 7.3 and 42.5 + or - 8.2 in girls and boys respectively. The Bland Altman procedure assessed agreement between predicted and actual VO(2max). RESULTS: Predicted VO(2max) was significantly correlated with measured VO(2max) (r(2)=0.48, P<0.0001). Using the Bland Altman procedure, there was significant magnitude bias (r(2)=0.10; P<0.002). The limits of agreement for predicted relative to actual VO(2max) were -589 to 574 mL O(2)/min. CONCLUSIONS: The impedance index was highly correlated with VO(2max) in overweight adolescents. However, using BIA data to predict maximal oxygen uptake over-predicted VO(2max) at low levels of oxygen consumption and under-predicted VO(2max) at high levels of oxygen consumption. This magnitude bias, along with the large limits of agreement of BIA-derived predicted VO(2max), limit its usefulness in the clinical setting for overweight adolescents.

A pilot study of the effects of niacin administration on free fatty acid and growth hormone concentrations in children with obesity.

CONTEXT: Children with obesity have low spontaneous growth hormone (GH) secretion. High circulating free fatty acid (FFA) concentration is believed to inhibit GH secretion in those with obesity. In adults, lipolytic inhibition with niacin lowers FFA and increases GH, but there are no prior studies in children with obesity. OBJECTIVE: The objective of the study was to determine the dose and frequency of niacin administration required to lower FFA and stimulate GH in children with obesity. DESIGN: Dose-finding study of nondiabetic children ages 6-12 years with body mass index (BMI) ≥ 95th percentile given niacin 250 mg q2h × 3 doses (n = 2), 500 mg q2h × 3 doses (n = 5) or 500 mg q1h × 4 doses (n = 5). PARTICIPANTS: Eight boys and four girls (age 9.7 ± 1.8 years; BMI 26.4 ± 3.1 kg m-2 ; BMIz 2.2 ± .25) were studied. MAIN OUTCOME: Percentage of serum FFA values that were below 0.2 mEq L-1 . GH, insulin and glucose were also measured serially. RESULTS: FFA decreased as the dose and frequency of niacin increased (p = .01). Niacin 500 mg q1h 4 doses suppressed FFA < 0.2 mEq L-1 and significantly increased GH (p = .04). Adverse effects were flushing/warmth (100%), tingling (60%) and GI complaints (20-40%). CONCLUSIONS: Niacin 500 mg q1h significantly lowered serum FFA and increased GH. These pilot data suggest that high FFA is an important suppressor of GH secretion in children with obesity.

Evaluating the contribution of differences in lean mass compartments for resting energy expenditure in African American and Caucasian American children.

BACKGROUND: Resting energy expenditure (REE), adjusted for total lean mass (LM), is lower in African American (AA) than Caucasian American (CA) children. Some adult studies suggest that AA-CA differences in lean mass compartments explain this REE difference. Similar data are limited in children. OBJECTIVE: To evaluate differences in compartment-specific lean mass between AA and CA children and examine the individual contributions of high-metabolic rate-at-rest trunk lean mass (TrLM) and low-metabolic-rate-at-rest appendicular lean mass (AppLM) for AA-CA differences in REE. METHODS: We studied a convenience sample of 594 AA (n = 281) and CA (n = 313) children. REE was measured by using indirect calorimetry; dual-energy X-ray absorptiometry was used to assess body composition. ANCOVAs were performed to examine AA-CA differences in TrLM, AppLM and REE. After accounting for age, sex, height, pubertal development, bone mass and adiposity, REE was evaluated adjusting for total LM (model A) and separately adjusting for TrLM and AppLM (model B). RESULTS: African American children had greater adjusted AppLM (17.8 ± 0.2 [SE] vs. 16.0 ± 0.2 kg, p < 0.001) and lower TrLM (17.2 ± 0.2 vs. 17.7 ± 0.2 kg, p = 0.022) than CA children. REE adjusted for total LM was 77 ± 16 kcal/d lower in AA than CA (p < 0.001). However, after accounting separately for AppLM and TrLM, the discrepancy in REE between the groups declined to 28 ± 19 kcal/d (p = 0.14). In the adjusted model, both TrLM (p < 0.001) and AppLM (p < 0.027) were independently associated with REE. CONCLUSION: In children, AA-CA differences in REE appear mostly attributable to differences in body composition. Lower REE in AA children is likely due to lower TrLM and greater AppLM.

Associations between adiposity and indicators of thyroid status in children and adolescents.

BACKGROUND: In adults, obesity is associated with abnormalities of thyroid function; there are fewer studies in paediatric cohorts. OBJECTIVES: To examine associations of weight and adiposity with indices of thyroid function and thyroid-related metabolic factors in children. DESIGN/METHODS: A sample of 1203 children without obesity (body mass index [BMI] < 95th percentile; N = 631) and with obesity (BMI ≥ 95th percentile; N = 572), age 5-18 years, had height and weight measured (to calculate BMI-Z score for age and sex) and had blood collected in the morning for thyroid-stimulating hormone (TSH), free thyroxine (FT4) and leptin. A subset (N = 829) also underwent measurement of fat mass by dual-energy X-ray absorptiometry. Analyses examined associations of TSH and FT4 with adiposity and obesity-related conditions accounting for sociodemographic factors. RESULTS: Thyroid-stimulating hormone was positively related to BMIz and fat mass (both p-values < 0.001). FT4 was negatively related to BMIz and fat mass (both p-values < 0.001). TSH was positively correlated to leptin (p = 0.001) even after accounting for fat mass. CONCLUSIONS: Paediatric obesity is associated with higher TSH and lower FT4 concentrations and with a greater prevalence of abnormally high TSH. Leptin concentrations may in part explain obesity's effects on thyroid status, perhaps through leptin's effects on TSH secretion.

Automatic labelling and BI-RADS characterisation of mammogram densities.

Intelligent management of medical data is an important field of research in clinical information and decision support systems. Such systems are finding increasing use in the management of patients known to have, or suspected of having, breast cancer. Different types of breast-tissue patterns convey semantic information which is reported by the radiologist when reading mammograms. In this paper, a novel method is presented for the automatic labelling and characterisation of mammographic densities. The presented method is first concerned with the identification of the prominent structures in each mammogram. Subsequently, "dense tissue" is labelled in a mammogram data set, and BI-RADS classification is performed based on a 2D pdf that is contracted from a "ground truth" data set as well as a shape analysis framework. The presented method can be used in large-scale epidemiological studies which involve mammographic measurements of tissue-pattern, especially since breast-tissue density has been linked to an increased risk of breast cancer.

AIDS risk and prevention for the chronic mentally ill.

Some chronic mentally ill populations are at high risk for infection with human immunodeficiency virus. The authors argue that stereotypes of the mentally ill as asexual or neutered have had dangerous consequences, namely the absence of sex education and AIDS prevention as an integral part of treatment. To counter this neglect, the authors developed an AIDS prevention program in a large inner-city mental health center that serves primarily black and Latino patients. Prevention efforts include individual risk assessments and an innovative drop-in group. Central to effective patient education are the distribution of condoms and concrete instruction in their use.

A clinical experience with dantrolene sodium for external urinary sphincter hypertonicity in spinal cord injured patients.

Significant bladder residual urine is secondary to pelvic floor skeletal muscle hypertonicity in some spinal cord injury patients with suprasacral or mixed lesions. Fifteen patients with residual urine volumes greater than 150 cc were treated with dantrolene sodium because of its ability to decrease skeletal muscle contractibility. All of the patients had urethral closure pressures greater than 100 cm. water. Of the 15 patients 8 benefited from dantrolene sodium therapy and were maintained on external condom urinary drainage. Five of these 8 patients required up to 600 mg. dantrolene sodium daily to affect this result. The residual urine volume decreased to less than 100 cc and the post-therapy decrease in urethral pressure averaged 77 cm. water (49 per cent). The patients in the failure group (residual urine greater than 150 cc) had an average decrease in urethral pressure of 21 cm. water (16 per cent). Detrusor hyporeflexia possibly contributed to the failure rate. In summary, dantrolene sodium seems to be beneficial in some patients with external urinary sphincter hypertonicity. However, it will not supplant external sphincterotomy in the more complete male spinal cord injury patient in whom reflex incontinence is of minimal concern. Dantrolene sodium could be an ideal treatment of patients with incomplete neurologic lesions in whom continence might be preserved. The drug will have to be effective at low doses to obviate the major side effect of over-all muscle weakness.

Regulation of hepatic cholesterol and lipoprotein metabolism in ethinyl estradiol-treated rats.

The regulation of hepatic cholesterol and lipoprotein metabolism was studied in the ethinyl estradiol-treated rat in which low density lipoprotein (LDL) receptors are increased many fold. Cholesterol synthesis was reduced at both its diurnal peak and trough by ethinyl estradiol. The diurnal variation in 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase was abolished, whereas that for acyl coenzyme A: cholesterol acyltransferase (ACAT) was retained. LDL receptor number did not vary diurnally. Feeding these animals a cholesterol-rich diet for 48 h suppressed cholesterol synthesis and reductase activities to levels similar to those found in cholesterol-fed control animals, but ACAT activity was unaffected. LDL receptors were reduced about 50%. Intravenously administered cholesterol-rich lipoproteins suppressed HMG-CoA reductase and LDL receptors in 2 h but had a variable effect on ACAT activity. Intragastric administration of mevalonolactone reduced reductase and increased acyltransferase activity but had little effect on LDL receptors when given 2 or 4 h before death. Although animals fed a cholesterol-rich diet before and during ethinyl estradiol treatment became hypocholesterolemic, free and esterified cholesterol concentrations in liver were high as was ACAT activity. HMG-CoA reductase was inhibited to levels found in control animals fed the cholesterol-rich diet. LDL receptors were increased to a level about 50% of that reached in animals receiving a control diet and ethinyl estradiol. These data demonstrate that key enzymes of hepatic cholesterol metabolism and hepatic LDL receptors respond rapidly to cholesterol in the ethinyl estradiol-treated rat. Furthermore, estradiol increases LDL receptor activity several fold in cholesterol-loaded livers.

The Kock pouch: initial experience and complications.

The modified Kock continent internal reservoir procedure has been performed on 15 patients at our medical center since December 1984: 13 underwent simultaneous anterior exenteration for pelvic malignancy, 1 had conversion from an ileal conduit and 1 underwent cystectomy for refractory interstitial cystitis. There was no operative mortality. There were 3 early complications: a urinary leak from the pouch in 2 patients that required re-exploration to close the defect, and an enteric-Kock pouch fistula in 1 that required resection of the small bowel fistula and repair of the pouch defect. All 3 patients are doing well. The late complication in 3 cases was urinary incontinence of the efferent nipple valve with difficulty in catheterization of the stoma. Two patients have undergone revision with a new efferent nipple valve added on to the pouch and creation of a new stoma. One patient is completely dry and continent, 1 has tolerable intermittent leakage and refuses a further operation, and 1 is awaiting revision. Although the initial experience is small, we are encouraged by these results and believe that this procedure is an alternative form of urinary diversion for the properly selected patient.

The diagnosis and management of orbital blowout fractures: update 2001.

A cogent update of orbital blowout history, anatomy, and management are included with a retrospective study of 59 pure orbital blowout fractures which occurred between 1994 and 1998. Our goal is to provide a better understanding of this frequently encountered entity and to help augment the confidence of nonophthalmologists who will often evaluate patients with suspected orbital blowout fractures.

Understanding the interface of HIV, trauma, post-traumatic stress disorder, and substance use and its implications for health outcomes.

Many individuals living with HIV have been exposed to some type of traumatic event during their lives and may be living with symptoms of post-traumatic stress disorder (PTSD). A substantial number of these individuals are also likely to show evidence of a co-morbid substance use disorder (SUD). There is reason to believe that the co-occurrence of HIV and PTSD or co-morbid PTSD and SUD (PTSD/SUD) may predict poorer health outcomes. There are several pathways through which PTSD or PTSD/SUD might adversely impact the health of individuals living with HIV, including participation in negative health behaviours, low levels of adherence to antiretroviral medications, and/or a direct, deleterious effect on immune function. Psychological interventions are needed to treat PTSD and PTSD/SUD in HIV-positive individuals, and reduce the negative impact of these conditions on health outcomes. This article will explore data on the prevalence of trauma exposure, PTSD, and PTSD/SUD among individuals living with HIV, the pathways through which these conditions might affect health, possible interventions for PTSD and PTSD/SUD for individuals living with HIV, and methods for integrating care for individuals with these disorders. Future directions for research related to HIV, PTSD, and PTSD/SUD will also be discussed.