Overnight sleep duration and obesity in 2-5 year-old American Indian children.

BACKGROUND: Sleep has emerged as a potentially modifiable risk factor for obesity in children. OBJECTIVES: The purpose of this investigation was to evaluate the association between overnight sleep duration and obesity among American Indian (AI) children ages 2-5 years. METHODS: Data were examined from the baseline assessment of children enrolling in the Healthy Children, Strong Families study, which is a randomized lifestyle intervention trial in five diverse rural and urban AI communities nationally among children ages 2-5 years. Multivariable models were built to assess the relationship between sleep duration and BMI z-score while controlling for potential sociodemographic and behavioural covariates. RESULTS: Three hundred and ninety-eight children had sufficient data to be included in analysis. In multivariable models controlling for potential covariates, overnight sleep duration was significantly and inversely associated with BMI z-score (B = -0.158, t = -1.774, P = 0.006). Similarly, when controlling for covariates, children who slept 12 or more hours had significantly lower BMI z-scores compared with those who slept 8 to 10 h (P = 0.018) or less than 8 h (P = 0.035); the difference between 12+ hours and 10 to 12-h groups did not reach statistical significance (P = 0.073) but supported a linear relationship between overnight sleep duration and BMI. Weekday-to-weekend variability in overnight sleep duration was not associated with BMI z-score (B = 0.010, t = 0.206, P = 0.837). CONCLUSIONS: Overnight sleep duration is independently and inversely related to BMI z-score among AI children ages 2-5 years, even when controlling for important sociodemographic and obesogenic lifestyle factors. This represents the first report, to our knowledge, of sleep duration as a risk factor for obesity among AI children.

Multipoint genome-wide linkage scan for nonword repetition in a multigenerational family further supports chromosome 13q as a locus for verbal trait disorders.

Verbal trait disorders encompass a wide range of conditions and are marked by deficits in five domains that impair a person's ability to communicate: speech, language, reading, spelling, and writing. Nonword repetition is a robust endophenotype for verbal trait disorders that is sensitive to cognitive processes critical to verbal development, including auditory processing, phonological working memory, and motor planning and programming. In the present study, we present a six-generation extended pedigree with a history of verbal trait disorders. Using genome-wide multipoint variance component linkage analysis of nonword repetition, we identified a region spanning chromosome 13q14-q21 with LOD = 4.45 between 52 and 55 cM, spanning approximately 5.5 Mb on chromosome 13. This region overlaps with SLI3, a locus implicated in reading disability in families with a history of specific language impairment. Our study of a large multigenerational family with verbal trait disorders further implicates the SLI3 region in verbal trait disorders. Future studies will further refine the specific causal genetic factors in this locus on chromosome 13q that contribute to language traits.

Familial and individual predictors of obesity and insulin resistance in urban Hispanic children.

BACKGROUND: High intake of sugar-sweetened beverages (SSB) has been suggested to contribute to the pediatric obesity epidemic, however, how the home food environment influence children's intake of SSB among Hispanic families is still poorly understood. OBJECTIVES: To evaluate the relationships between the home food environment and Hispanic children's diet in relation to weight status and insulin resistance (IR). METHODS: A food frequency questionnaire was administered to 187 Hispanic children (ages 10 to 14 years) and anthropometrics were measured. IR was estimated from fasting insulin and glucose levels using the homeostasis model assessment of insulin resistance (HOMAIR ). Parents reported on family demographics and the home food environment. A structural equation modelling approach was applied to examine the hypothesized relationships among variables. RESULTS: The prevalence of childhood overweight and obesity was 52.8% and it was positively associated with HOMAIR (ß = 0.687, P < .0001). Children's SSB consumption was positively associated with children's body mass index z-score (ß = 0.151, P < 0.05) and subsequently to HOMAIR . Children's SSB consumption was predicted by home availability (ß = 0.191) and parental intake of SSB (ß = 0.419) (P < 0.05). The model fit indices [χ(2) = 45.821 (d.f. = 30, P > 0.01 and < 0.05), χ(2) /d.f. = 1.53, root mean square error of approximation = 0.053 (90% confidence interval = 0.016, 0.082), comparative fit index = 0.904] suggested a satisfactory goodness-of-fit. CONCLUSIONS: The home food environment and parental diet seem to play an important role in the children's access to and intake of SSB, which in turn predicted children's weight status.

The DEK oncogene promotes cellular proliferation through paracrine Wnt signaling in Ron receptor-positive breast cancers.

Disease progression and recurrence are major barriers to survival for breast cancer patients. Understanding the etiology of recurrent or metastatic breast cancer and underlying mechanisms is critical for the development of new treatments and improved survival. Here, we report that two commonly overexpressed breast cancer oncogenes, Ron (Recepteur d'Origine Nantaise) and DEK, cooperate to promote advanced disease through multipronged effects on ß-catenin signaling. The Ron receptor is commonly activated in breast cancers, and Ron overexpression in human disease stimulates ß-catenin nuclear translocation and is an independent predictor of metastatic dissemination. Dek is a chromatin-associated oncogene whose expression has been linked to cancer through multiple mechanisms, including ß-catenin activity. We demonstrate here that Dek is a downstream target of Ron receptor activation in murine and human models. The absence of Dek in the MMTV-Ron mouse model led to a significant delay in tumor development, characterized by decreased cell proliferation, diminished metastasis and fewer cells expressing mammary cancer stem cell markers. Dek complementation of cell lines established from this model was sufficient to promote cellular growth and invasion. Mechanistically, Dek expression stimulated the production and secretion of Wnt ligands to sustain an autocrine/paracrine canonical ß-catenin signaling loop. Finally, we show that Dek overexpression promotes tumorigenic phenotypes in immortalized human mammary epithelial MCF10A cells and, in the context of Ron receptor activation, correlates with disease recurrence and metastasis in patients. Overall, our studies demonstrate that DEK overexpression, due in part to Ron receptor activation, drives breast cancer progression through the induction of Wnt/ß-catenin signaling.

DEK promotes HPV-positive and -negative head and neck cancer cell proliferation.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide, and patient outcomes using current treatments remain poor. Tumor development is etiologically associated with tobacco or alcohol use and/or human papillomavirus (HPV) infection. HPV-positive HNSCCs, which frequently harbor wild-type p53, carry a more favorable prognosis and are a biologically distinct subgroup when compared with their HPV-negative counterparts. HPV E7 induces expression of the human DEK gene, both in vitro and in vivo. In keratinocytes, DEK overexpression is sufficient for causing oncogenic phenotypes in the absence of E7. Conversely, DEK loss results in cell death in HPV-positive cervical cancer cells at least in part through p53 activation, and Dek knockout mice are relatively resistant to the development of chemically induced skin papillomas. Despite the established oncogenic role of DEK in HPV-associated cervical cancer cell lines and keratinocytes, a functional role of DEK has not yet been explored in HNSCC. Using an established transgenic mouse model of HPV16 E7-induced HNSCC, we demonstrate that Dek is required for optimal proliferation of E7-transgenic epidermal cells and for the growth of HNSCC tumors. Importantly, these studies also demonstrate that DEK protein is universally upregulated in both HPV-positive and -negative human HNSCC tumors relative to adjacent normal tissue. Furthermore, DEK knockdown inhibited the proliferation of HPV-positive and -negative HNSCC cells, establishing a functional role for DEK in human disease. Mechanistic studies reveal that attenuated HNSCC cell growth in response to DEK loss was associated with reduced expression of the oncogenic p53 family member, ΔNp63. Exogenous ΔNp63 expression rescued the proliferative defect in the absence of DEK, thereby establishing a functional DEK-ΔNp63 oncogenic pathway that promotes HNSCC. Taken together, our data demonstrate that DEK stimulates HNSCC cellular growth and identify ΔNp63 as a novel DEK effector.

Impact of exercise and dietary fatty acid composition from a high-fat diet on markers of hunger and satiety.

To compare the effects of both dietary fatty acid composition and exercise vs. sedentary conditions on circulating levels of hunger and satiety hormones. Eight healthy males were randomized in a 2 × 2 crossover design. The four treatments were 3 days of HF diets (50% of energy) containing high saturated fat (22% of energy) with exercise (SE) or sedentary (SS) conditions, and high monounsaturated fat (30% of energy) with exercise (UE) or sedentary (US) conditions. Cycling exercise was completed at 45% of VO(2)max for 2h daily. On the third HF day, 20 blood samples were drawn over a 24h period for each hormone (leptin, insulin, ghrelin, and peptide YY (PYY)). A visual analog scale (VAS) was completed hourly between 0800 and 2200. Average 24h leptin and insulin levels were lower while 24h PYY was higher during exercise vs. sedentary conditions. FA composition did not differentially affect 24h hormone values. VAS scores for hunger and fullness did not differ between any treatment but did correlate with ghrelin, leptin, and insulin. High saturated or unsaturated fat diets did not differ with respect to markers of hunger or satiety. Exercise decreased 24h leptin and insulin while increasing PYY regardless of FA composition.

Influence of dietary fatty acid composition and exercise on changes in fat oxidation from a high-fat diet.

Acute high-fat (HF) diets can lead to short-term positive fat balances until the body increases fat oxidation to match intake. The purpose of this study was to examine the effects of a HF diet, rich in either mono-unsaturated or saturated fatty acids (FAs) and exercise, on the rate at which the body adapts to a HF diet.(13)C-labeled oleate and (2)H-labeled palmitate were also given to determine the contribution of exogenous vs. global fat oxidation. Eight healthy men (age of 18-45 yr; body mass index of 22 ± 3 kg/m(2)) were randomized in a 2 × 2 crossover design. The four treatments were a high saturated fat diet with exercise (SE) or sedentary (SS) conditions and a high monounsaturated fat diet with exercise (UE) or sedentary (US) conditions. Subjects stayed for 5 days in a metabolic chamber. All meals were provided. On day 1, 30% of energy intake was from fat, whereas days 2-5 had 50% of energy as fat. Subjects exercised on a stationary cycle at 45% of maximal oxygen uptake for 2 h each day. Respiratory gases and urinary nitrogen were collected to calculate fat oxidation. Change from day 1 to day 5 showed both exercise treatments increased fat oxidation (SE: 76 ± 30 g, P = 0.001; UE: 118 ± 31 g, P < 0.001), whereas neither sedentary condition changed fat oxidation (SS: -10 ± 33 g, P = not significant; US: 41 ± 14 g, P = 0.07). No differences for dietary FA composition were found. Exercise led to a faster adaptation to a HF diet by increasing fat oxidation and achieving fat balance by day 5. Dietary FA composition did not differentially affect 24-h fat oxidation.

Acute effect of pimobendan and furosemide on the circulating renin-angiotensin-aldosterone system in healthy dogs.

BACKGROUND: The renin-angiotensin-aldosterone system (RAAS) is activated in states of decreased cardiac output and by certain cardiovascular therapeutic agents, such as loop diuretics and vasodilators. HYPOTHESIS: Short-term treatment with the inodilator, pimobendan, will not activate the circulating RAAS because its vasodilatory action will be offset by its positive inotropic property, thereby ameliorating RAAS stimulation at the juxtaglomerular apparatus. Furthermore, pimobendan will suppress RAAS activation produced by furosemide. ANIMALS: Nine healthy laboratory dogs were used in this study. METHODS: Experimental, cross-over study. Dogs were administered pimobendan (0.5 mg/kg q12h) for 4 days followed by furosemide (2 mg/kg q12h) and then, after a wash-out period, a combination of the drugs. Aldosterone : creatinine (A : Cr) was measured at the end of each treatment cycle. RESULTS: There was no significant increase in the average urinary A : Cr with the administration of pimobendan (control urinary A : Cr = 0.46, standard deviation (SD) 0.33; pimobendan A : Cr = 0.48, SD 0.28). There was a significant increase in the average urinary A : Cr after administration of furosemide (urinary A : Cr = 1.3, SD 0.70) and with the combination of furosemide and pimobendan (urinary A : Cr = 2.9, SD 1.6). CONCLUSIONS AND CLINICAL RELEVANCE: Short-term administration of high-dose pimobendan, does not activate the RAAS in healthy dogs. Pimobendan did not prevent RAAS activation associated with furosemide therapy. These results in healthy dogs suggest that furosemide therapy, with or without pimobendan, should be accompanied by RAAS suppressive therapy.

Crosslink formation in porcine valves stabilized by dye-mediated photooxidation.

Bovine pericardial and porcine valve materials stabilized by dye-mediated photooxidation have shown potential for bioprosthetic valve use. Previously, in vitro and in vivo stability of these materials was demonstrated through enzymatic, chemical, extraction, rat subcutaneous, and functional challenges. Here, we examine the stability of photooxidized porcine aortic valves through amino acid, crosslink, and hydrothermal isometric tension analysis. Photooxidation reduced intact histidine residues from 17.0 to 0 residues per 1000, indicating the photooxidative alteration of this amino acid. Diphenyl borinic acid-derivitized hydrolyzates of proteins were separated by high-performance liquid chromatography, which identified several amino acid crosslinks that appeared with photooxidation that were absent in untreated controls. Thermal relaxation analysis indicated a significantly higher (p < 0.0002) thermal stability for photooxidized porcine cusps than that of untreated controls, with mean relaxation times for untreated cusps of 14,000 +/- 4650 versus 22,900 +/- 2480 s for photooxidized cusps. In summary, porcine aortic valve tissue treated by dye-mediated photooxidation contains new chemical species and exhibits properties consistent with intermolecular crosslink formation, which explain the increased biostability of this material and its potential for use in bioprosthetic devices.

Calcification resistance, biostability, and low immunogenic potential of porcine heart valves modified by dye-mediated photooxidation.

The calcification potential, biostability, and immunogenic response of materials intended for long-term in vivo use, such as in heart-valve bioprostheses, are essential components of device performance. Here we explore these properties in photooxidized porcine heart valves. To study immunological sensitization, we injected tissue extracts intradermally into guinea pigs. Test and control animals received a challenge patch of the appropriate extract and were scored for dermal reactions. Neither cottonseed oil nor sodium chloride extracts of photooxidized heart-valve tissues caused any dermal inflammatory response. After implantation in the rat subcutaneous model for 90 days, the calcium content of 48-h-treated photooxidized cusp tissue [0.04 +/- 0.00 mg/g wet weight (gww)] was comparable to that of unimplanted control tissues (usually <1 mg/gww) and much lower than that of glutaraldehyde-treated controls (71 +/- 15 mg/gww). The porcine aortic wall calcium content (49 +/- 31 mg/gww) was comparable to that of glutaraldehyde-treated controls (59 +/- 8 mg/gww). Histologically, a time-dependent decrease in inflammation and vascularization with increasing photooxidation time was noted in the rat model along with an increase in the stability and organization of collagen bundles. In summary, porcine valve tissues treated by dye-mediated photooxidation were resistant to calcification, were biostable, and demonstrated a low immunogenic response, indicating potential for use in heart-valve bioprostheses.

Use of infrared thermographic calorimetry to determine energy expenditure in preterm infants.

BACKGROUND: Measurement of infant energy expenditure in the clinical setting is difficult and is rarely done. Both indirect and direct calorimetry require long measurement periods and frequent calibration. OBJECTIVE: The objective of this study was to validate in infants a newly developed method of determining energy expenditure, infrared thermographic calorimetry (ITC), against an established method, respiratory indirect calorimetry (IC). ITC measures mean infant body surface temperature. ITC was used in conjunction with heat loss theory to calculate radiant, convective, evaporative, and conductive heat losses and thereby determine total energy expenditure. DESIGN: Ten healthy preterm infants were studied by obtaining concurrent ITC and IC measurements over a 3.5-5.5-h study period. Continuous IC measurements were compared with ITC measurements taken every 10 min during study periods. IC values were summed over 10-min intervals covering the 5 min before and 5 min after each ITC measurement, to allow comparisons between the 2 methods. RESULTS: Comparison of paired ITC and IC mean measurements for all 10 infants over the entire study period showed no significant difference between the 2 methods. However, individual paired IC and ITC values were significantly different for 7 of 10 infants. The overall mean difference between the 2 methods was 1.3%. CONCLUSIONS: ITC is an accurate, noninvasive method for measurement of heat loss and energy expenditure in healthy preterm infants, and therefore it may be a useful clinical and research tool.

Antioxidant vitamins and the prevention of coronary heart disease.

Clinical use of antioxidant vitamin supplementation may help to prevent coronary heart disease (CHD). Epidemiologic studies find lower CHD morbidity and mortality in persons who consume larger quantities of antioxidants in foods or supplements. Clinical trials indicate that supplementation with certain nutrients is beneficial in reducing the incidence of CHD events. Recent studies show that supplementation with antioxidant vitamins E and C have benefits in CHD prevention; however, supplementation with beta-carotene may have deleterious effects and is not recommended. Current evidence suggests that patients with CHD would probably benefit from taking vitamin E in a dosage of 400 IU per day and vitamin C in a dosage of 500 to 1,000 mg per day. Clinicians may also want to consider vitamin supplementation for CHD prevention in high-risk patients. Folate lowers elevated homocysteine levels, but evidence for routine supplemental use does not yet exist. Other nutritional supplements are currently under investigation.

Human influenza: viral mutations and altered tropisms.

Influenza is a virus that is capable of causing a pandemic of the human race. Influenza has the ability to infect humans by mutating and altering its pathogenic characteristics. Efforts must be made worldwide to educate people about the possibilities of a potential outbreak. Awareness of optimal conditions which could lead to viral mutation and human to human transmission of a neogenetic strain of influenza appears to be a key deterrent against future cases.

Why do we need Royal Colleges?

Today's Royal Colleges can be traced to the guilds that arose during the 13th and 14th centuries. They fulfil similar roles: to maintain the highest standards of practice, professional integrity and self-regulation. This paper traces the development of the Royal Colleges, together with the emergence of specialisation within medicine, with particular reference to anaesthesia as a modern specialty. It considers whether these functions are still appropriate for the rapidly changing practice of medicine today. The colleges have unique strengths, but they also have weaknesses and must be prepared to counter threats to their professional function.

Metabolism, uptake, and excretion of a D-glucaric acid salt and its potential use in cancer prevention.

D-Glucaric acid (GA) is a nontoxic, natural compound. One of its derivatives is the potent beta-glucuronidase inhibitor D-glucaro-1,4-lactone (1,4-GL). The goal of this study was to demonstrate the in vivo formation of 1,4-GL from a D-glucarate salt and determine its metabolism, uptake by selected organs, and excretion following oral administration of potassium hydrogen D-[14C]glucarate to male and female Sprague-Dawley rats. 1,4-GL increases detoxification of carcinogens and tumor promoters/progressors by inhibiting beta-glucuronidase and preventing hydrolysis of their glucuronides. 1,4-GL and its precursors, such as potassium hydrogen D-glucarate and calcium D-glucarate, may exert their anticancer action, in part, through alterations in steroidogenesis accompanied by changes in the hormonal environment and the proliferative status of the target organ. Thus, GA derivatives may be useful as new or adjuvant cancer preventive and therapeutic agents. In our study, 1,4-GL was found to be formed from the D-glucarate salt in the stomach of rats. It was apparently absorbed from the gastrointestinal tract, transported with the blood to different internal organs, and excreted in the urine and to a lesser extent in bile. There were no significant differences in the metabolism of PHG between male and female rats. Thus, formation of 1,4-GL from D-glucaric acid derivatives may be prerequisite for their inhibition of chemical carcinogenesis in rodents and prevention of breast, prostate, and colon cancer in humans.

Specific DNA replication mutations affect telomere length in Saccharomyces cerevisiae.

To investigate the relationship between the DNA replication apparatus and the control of telomere length, we examined the effects of several DNA replication mutations on telomere length in Saccharomyces cerevisiae. We report that a mutation in the structural gene for the large subunit of DNA replication factor C (cdc44/rfc1) causes striking increases in telomere length. A similar effect is seen with mutations in only one other DNA replication gene: the structural gene for DNA polymerase alpha (cdc17/pol1) (M.J. Carson and L. Hartwell, Cell 42:249-257, 1985). For both genes, the telomere elongation phenotype is allele specific and appears to correlate with the penetrance of the mutations. Furthermore, fluorescence-activated cell sorter analysis reveals that those alleles that cause elongation also exhibit a slowing of DNA replication. To determine whether elongation is mediated by telomerase or by slippage of the DNA polymerase, we created cdc17-1 mutants carrying deletions of the gene encoding the RNA component of telomerase (TLC1). cdc17-1 strains that would normally undergo telomere elongation failed to do so in the absence of telomerase activity. This result implies that telomere elongation in cdc17-1 mutants is mediated by the action of telomerase. Since DNA replication involves transfer of the nascent strand from polymerase alpha to replication factor C (T. Tsurimoto and B. Stillman, J. Biol. Chem. 266:1950-1960, 1991; T. Tsurimoto and B. Stillman, J. Biol. Chem. 266:1961-1968, 1991; S. Waga and B. Stillman, Nature [London] 369:207-212, 1994), one possibility is that this step affects the regulation of telomere length.