A randomized, phase II trial of cetuximab with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic head and neck squamous cell cancer.

BACKGROUND: The phosphotidylinositol-3 kinase (PI3K)/serine-threonine kinase/mammalian target of rapamycin signaling pathway is frequently altered in head and neck squamous cell cancer (HNSCC). PX-866 is an oral, irreversible, pan-isoform inhibitor of PI3K. A phase I trial demonstrated tolerability of this combination. This randomized phase II study evaluated PX-866 combined with cetuximab in patients with advanced, refractory HNSCC. METHODS: Patients with recurrent or metastatic HNSCC who had received at least one and no more than two prior systemic treatment regimens were randomized (1 : 1) to cetuximab with or without PX-866 (8 mg p.o. daily; arms A and B, respectively). The primary end point was progression-free survival (PFS). Secondary end points included objective response rate (ORR), overall survival (OS), toxicity, and correlation of key biomarkers with efficacy outcomes. RESULTS: Eighty-three patients were enrolled. There was a similar response rate between arms (10% versus 7%). Of patients for whom tissue was assessable, 57% were human papillomavirus (HPV) positive. Median PFS was 80 days in both arms and there was no difference in OS between the two arms (211 versus 256 days). Overall toxicity was higher in arm A compared with arm B, especially in terms of nausea (53% versus 23%), vomiting (45% versus 15%), fatigue (43% versus 23%), diarrhea (40% versus 21%), and hypokalemia (25% versus 10%). Grade 3 or higher adverse events were infrequent, but more common in the combination arm although without a specific pattern. PIK3CA mutations were observed in 17% of the cases assessed, and PTEN loss was infrequently observed. CONCLUSION: The addition of PX-866 to cetuximab did not improve PFS, RR, or OS in patients with advanced, refractory HNSCC enrolled without molecular preselection. In this contemporary cohort, HPV-positive patients comprised the majority, and neither HPV-positive nor HPV-negative patients derived clinical benefit for the addition of cetuximab plus PX-866.

A multicenter phase 1 study of PX-866 in combination with docetaxel in patients with advanced solid tumours.

BACKGROUND: This phase I, dose-finding study determined the safety, maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), pharmacokinetics, and antitumour activity of PX-866, a phosphatidylinositol 3-kinase inhibitor, combined with docetaxel in patients with incurable solid tumours. METHODS: PX-866 was administered at escalating doses (4-8 mg daily) with docetaxel 75 mg m⁻² intravenously every 21 days. Archived tumour tissue was assessed for potential predictive biomarkers. RESULTS: Forty-three patients were enrolled. Most adverse events (AEs) were grade 1 or 2. The most frequent study drug-related AE was diarrhoea (76.7%), with gastrointestinal disorders occurring in 79.1% (docetaxel-related) and 83.7% (PX-866-related). No dose-limiting toxicities were observed. The RP2D was 8 mg, the same as the single-agent MTD. Co-administration of PX-866 and docetaxel did not affect either drug's PKs. Best responses in 35 evaluable patients were: 2 partial responses (6%), 22 stable disease (63%), and 11 disease progression (31%). Eleven patients remained on study for >180 days, including 8 who maintained disease control on single-agent PX-866. Overall median progression-free survival (PFS) was 73.5 days (range: 1-569). A non-significant association between longer PFS for PIK3CA-MUT/KRAS-WT vs PIK3CA-WT/KRAS-WT was observed. CONCLUSION: Treatment with PX-866 and docetaxel was well tolerated, without evidence of overlapping/cumulative toxicity. Further investigation with this combination is justified.

Obesity affects short-term folate pharmacokinetics in women of childbearing age.

Maternal folate status and body mass index (BMI) are independent risk factors for neural tube defects (NTD). Population-based studies have identified an inverse association between serum folate and BMI, after adjusting for intake. The objective of this intervention study was to compare the relationship between BMI and the short-term pharmacokinetic response to an oral dose of folic acid. Healthy obese (BMI 30.0 kg m(-2); n=16) and normal-weight (BMI 18.5-24.9 kg m(-2); n=16) women of childbearing age (18-35 years) were administered a single oral dose of folic acid (400 µg). Blood samples were collected over a 10-h period to evaluate the serum folate response. Fasting baseline serum folate was lower in the obese group (P=0.005); in contrast, red blood cell folate was higher (P=0.05). Area-under-the-curve for the absorption phase (0-3 h) and peak serum folate concentrations were lower in obese versus normal-weight women (P<0.005). Overall serum folate response (0-10 h) was lower in obese versus normal-weight women (repeated-measures ANOVA, P=0.001). Data suggest body distribution of folate is significantly affected by obesity, and, should pregnancy occur, may reduce the amount of folate available to the developing embryo. These findings provide additional support for a BMI-adjusted folic acid intake recommendation for NTD risk reduction.

Racial differences in cortical bone and their relationship to biochemical variables in Black and White children in the early stages of puberty.

UNLABELLED: Osteoporotic fracture rates differ according to race with Blacks having up to half the rate of Whites. The current study demonstrates that racial divergence in cortical bone properties develops in early childhood despite lower serum 25-hydroxyvitamin D in Blacks. INTRODUCTION: Racial differences in bone structure likely have roots in childhood as bone size develops predominantly during growth. This study aimed to compare cortical bone health within the tibial diaphysis of Black and White children in the early stages of puberty and explore the contributions of biochemical variables in explaining racial variation in cortical bone properties. METHODS: A cross-sectional study was performed comparing peripheral quantitative computed tomography-derived cortical bone measures of the tibial diaphysis and biochemical variables in 314 participants (n = 155 males; n = 164 Blacks) in the early stages of puberty. RESULTS: Blacks had greater cortical volumetric bone mineral density, mass, and size compared to Whites (all p < 0.01), contributing to Blacks having 17.0 % greater tibial strength (polar strength-strain index (SSIP)) (p < 0.001). Turnover markers indicated that Blacks had higher bone formation (osteocalcin (OC) and bone-specific alkaline phosphatase) and lower bone resorption (N-terminal telopeptide) than Whites (all p < 0.01). Blacks also had lower 25-hydroxyvitamin D (25(OH)D) and higher 1,25-dihydroxyvitamin D (1,25(OH)2D) and parathyroid hormone (PTH) (all p < 0.05). There were no correlations between tibial bone properties and 25(OH)D and PTH in Whites (all p ≥ 0.10); however, SSIP was negatively and positively correlated with 25(OH)D and PTH in Blacks, respectively (all p ≤ 0.02). Variation in bone cross-sectional area and SSIP attributable to race was partially explained by tibial length, 25(OH)D/PTH, and OC. CONCLUSIONS: Divergence in tibial cortical bone properties between Blacks and Whites is established by the early stages of puberty with the enhanced cortical bone properties in Black children possibly being explained by higher PTH and OC.

Multidimensional predictors of fatigue among octogenarians and centenarians.

BACKGROUND: Fatigue is a common and frequently observed complaint among older adults. However, knowledge about the nature and correlates of fatigue in old age is very limited. OBJECTIVE: This study examined the relationship of functional indicators, psychological and situational factors and fatigue for 210 octogenarians and centenarians from the Georgia Centenarian Study. METHODS: Three indicators of functional capacity (self-rated health, instrumental activities of daily living, physical activities of daily living), two indicators of psychological well-being (positive and negative affect), two indicators of situational factors (social network and social support), and a multidimensional fatigue scale were used. Blocked multiple regression analyses were computed to examine significant factors related to fatigue. In addition, multi-group analysis in structural equation modeling was used to investigate residential differences (i.e., long-term care facilities vs. private homes) in the relationship between significant factors and fatigue. RESULTS: Blocked multiple regression analyses indicated that two indicators of functional capacity, self-rated health and instrumental activities of daily living, both positive and negative affect, and social support were significant predictors of fatigue among oldest-old adults. The multiple group analysis in structural equation modeling revealed a significant difference among oldest-old adults based on residential status. CONCLUSION: The results suggest that we should not consider fatigue as merely an unpleasant physical symptom, but rather adopt a perspective that different factors such as psychosocial aspects can influence fatigue in advanced later life.

Life events and personality predicting loneliness among centenarians: findings from the Georgia Centenarian Study.

Regarding the purpose of this study, the researchers analyzed the roles that both life events (life-time positive events and life-time negative events) and personality (Neuroticism, Extraversion, Trust, Competence, and Ideas) played in participants of the Georgia Centenarian Study. The researchers analyzed these variables to determine whether they predicted loneliness. Analyses indicated that life-time negative events significantly predicted loneliness. In essence, the higher was the number of life-time negative life events, the higher was the loneliness score. Moreover, Neuroticism, Competence, and Ideas were all significant predictors of loneliness. The higher was the level of Neuroticism and intellectual curiosity, the higher was the level of loneliness, whereas the lower was the level of Competence, the higher was the level of loneliness. In addition, both life-time positive and life-time negative life events were significant predictors of Neuroticism. The higher was the number of life-time positive events, the lower was the level of Neuroticism, and the higher was the number of life-time negative events, the greater was the level of Neuroticism. These results indicated that life-time negative events indirectly affect loneliness via Neuroticism. Last, our results indicated that the Competence facet mediated the relationship between lifetime negative life events and loneliness. Life-time negative life events significantly affected centenarians' perceived competence, and Competence in turn significantly affected the centenarians' loneliness. These results as a whole not only add to our understanding of the link between personality and loneliness, but also provide new insight into how life events predict loneliness.

Family history and adaptation among centenarians and octogenarians.

BACKGROUND: The purpose of this study was to analyze various 'family history' variables (i.e. childhood health, financial situation while growing up, living with grandparents before age 17, and number of children) among participants of the Georgia Centenarian Study. OBJECTIVE: To determine whether family history variables predict critical outcome areas such as cognitive functioning, activities of daily living, mental health, and economic dependence. METHODS: A total of 318 older adults (236 centenarians and 82 octogenarians) were assessed with regard to their mental status, ADL (activities of daily living) functioning, depression, family history, loneliness, and perceived economic status. RESULTS: Analyses indicated that the number of children significantly predicted the ability to engage in activities of daily living and loneliness. In essence, the more children, the higher the activities of the daily living score and the lower the loneliness scores. In addition, childhood health significantly predicted loneliness. The poorer one's health in childhood, the higher the loneliness scores. CONCLUSION: The results of this study confirm the importance of distal family history variables on present-day functioning.

Predicting happiness among centenarians.

BACKGROUND: Happiness is believed to evolve from the comparison of current circumstances relative to past achievement. However, gerontological literature on happiness in extreme old age has been limited. OBJECTIVE: The purpose of this study was to determine how perceptions of health, social provisions, and economics link past satisfaction with life to current feelings of happiness among persons living to 100 years of age and beyond. METHODS: A total of 158 centenarians from the Georgia Centenarian Study were included to conduct the investigation. Items reflecting congruence and happiness from the Life Satisfaction Index were used to evaluate a model of happiness. Pathways between congruence, perceived economic security, subjective health, perceived social provisions, and happiness were analyzed using structural equation modeling. RESULTS: Congruence emerged as a key predictor of happiness. Furthermore, congruence predicted perceived economic security and subjective health, whereas perceived economic security had a strong influence on subjective health status. CONCLUSION: It appears that past satisfaction with life influences how centenarians frame subjective evaluations of health status and economic security. Furthermore, past satisfaction with life is directly associated with present happiness. This presents implications relative to understanding how perception of resources may enhance quality of life among persons who live exceptionally long lives.

Depression among centenarians and the oldest old: contributions of cognition and personality.

BACKGROUND: An estimated 20% of adults over the age of 55 experience clinical mental disorders such as depression and anxiety. For older adults, mental health concerns are often undetected, concomitant with physical challenges, and ultimately go untreated. These realities have significant implications for older adults' day-to-day functioning, particularly among the oldest old. OBJECTIVE: The present study examined the ability of cognition and personality in explaining depression within a sample of octogenarians and centenarians. METHODS: Participants were assessed during the most recent cross-sectional data collection of the Georgia Centenarian Study. The final eligible sample included 76 octogenarians (mean: 84.25 years, SD: 2.82; range: 81-90) and 158 centenarians and near centenarians (mean: 99.82 years, SD: 1.72; range: 98-109). RESULTS: Hierarchical regression analyses were conducted to examine the relation between key variables and depressive symptoms in the two age groups. Blocks entered into the analyses included: demographics (i.e. age group, residential status, sex, and ethnicity) and functioning, memory and problem-solving ability, and personality (i.e. extraversion and neuroticism). Models differed for octogenarians and centenarians. Decreased problem-solving ability was related to greater depressive symptoms among octogenarians. For centenarians, institutional residence and increased neurotic tendencies were related to greater depressive symptoms. CONCLUSION: Study findings demonstrate the need to examine a variety of factors which influence mental health in later life and to consider the unique contexts and differential experiences of octogenarians and centenarians.

Distal and proximal resource influences on economic dependency among the oldest old.

BACKGROUND: As exceptional survivors, centenarians may have characteristics that reduce their dependency on family and community support systems despite the expectation that their extreme age creates a burden on those systems. The Georgia Centenarian Study obtained information about assistance for income, medical care, and caregiving of all types for a sample of centenarians and octogenarians. Previous studies have not established which characteristics may contribute to economic dependency among the oldest old. OBJECTIVE: To identify distal and proximal resource influences on economic dependency, considering past lifestyle, proximal health, economic resources, personality, and coping behavior. METHODS: Analysis sample sizes ranged from 109 to 138 octogenarians and centenarians. Blockwise multiple regressions predicted whether they received income assistance, number of medical care events, number of caregiving types, and total caregiving hours. RESULTS: Past life style, gender, ethnicity, socioeconomic status, functional health, and coping were not related to economic dependency. With the exception of the number of types of care, centenarians were not more dependent than octogenarians. Cognitive ability had the strongest effects for medical care and caregiving services. 'Extraversion', 'ideas', 'neuroticism', and 'competence' personality factors had significant effects for caregiving types and total hours of care received. CONCLUSION: Monitoring and intervention to maintain cognitive ability are critical practices for autonomy and reduced economic dependency among the oldest old. Psychological resources are more important influences on social support than functional health and other proximal economic resources.

Social resources and longevity: findings from the Georgia centenarian study.

BACKGROUND: As the proportion of adults aged 85 and older increases, investigations of resources essential for adapting to the challenges of aging are required. OBJECTIVE: To comprehensively investigate the social resources of cognitively intact centenarians participating in the Georgia Centenarian Study and the association between these resources and residence status. METHODS: Two widely used measures of social resources were investigated among participants living in private homes, personal care facilities, and nursing homes. Logistic regression was used to determine significant predictors of nursing home residence. RESULTS: Differences in levels of social resources were found between centenarians and octogenarians, and among centenarians in different living situations. Analyses revealed differential findings between self- and proxy reports. Controlling for education, activities of daily living, and financial ability to meet needs, only one of the two social resources measures significantly reduced the odds of nursing home residence. CONCLUSION: The findings of this study add to the existing literature on one of the basic adaptive resources (social resources) for centenarians. Whether a more specific assessment of network contact is employed, or a more global assessment is used, differences in these constructs exist between centenarians and octogenarians, among centenarians in differing living conditions, and across types of informants. Researchers examining the different resources that may contribute to extraordinary longevity and positive adaptation may find it essential to differentiate between the oldest old and centenarians, and to account for differences based upon measure, reporter type, and centenarian residence status.

Expression of CCAAT/enhancer binding protein C/EBPalpha, beta and delta in rat adipose stromal-vascular cells in vitro.

Stromal-vascular (S-V) cells from rat inguinal fat depots were isolated and cultured in medium containing fetal bovine serum (FBS) and differentiated in defined medium until lipid accumulation was apparent. C/EBPalpha, beta and delta levels were evaluated for different growth conditions and at different times using Western blots. Immediately after isolation C/EBPalpha, beta and delta could not be detected in S-V cells. After seeding for 24 h in Dulbecco's modified Eagle's medium (DMEM) with FBS, C/EBPalpha, beta and delta could all be detected. Cells at day 1 of culture in insulin, transferrin, triiodothyronine and selenium (ITTS) had increased levels of C/EBPalpha and continued steady high levels to day 6 of culture. Cultures grown in DMEM alone, with no ITTS, showed C/EBPalpha levels similar to ITTS cultures at day 1 and day 3; however, levels diminished after day 3. DMEM cultures also showed lipid accumulation at day 6; however, the number of cells and the amount of lipid cell were reduced from levels observed in ITTS cultures. C/EBPbeta was expressed uniformly throughout the culture period in either DMEM or ITTS cultures while C/EBPdelta expression was higher with DMEM treatment than with ITTS. Treatment of 2 day DMEM cultures with FBS increased levels of C/EBPbeta and delta but significantly reduced levels of C/EBPalpha. Immunocytochemical analysis of S-V cells at day 1 of culture showed a similar percentage of cells stained in DMEM cultures and ITTS cultures. However, by day 6 of culture the percentage of cells staining positively for C/EBPalpha in DMEM had been reduced by one half while in ITTS the percent positive cells remained about the same. Our results indicate that ITTS is not necessary for the induction of C/EBPalpha and accumulation of lipid in S-V cells. However, ITTS is responsible for maintaining C/EBPalpha and enhanced lipid accumulation. Because C/EBPalpha, beta and delta expression occurs very early in cell culture and C/EBPalpha and delta expression continues to increase in DMEM without any apparent inducing agents, our results suggest that these factors may be expressed by the same cells in vivo before being placed in culture. Thus, a large fraction of S-V cells may be further along in the differentiation program than 3T3 cells are when they begin differentiation.

Differentiation-dependent expression of obese (ob) gene by preadipocytes and adipocytes in primary cultures of porcine stromal-vascular cells.

The relationship between obese (ob) gene expression and preadipocyte differentiation was examined in primary cultures of porcine stromal-vascular (S-V) cells by Northern-blot analysis using a pig ob cDNA probe. Isolated adipocytes expressed high levels of ob gene, but S-V cells did not express the ob gene. Cultures were seeded with fetal bovine serum (FBS) plus dexamethasone (Dex) for 3 days followed by ITS (insulin 5 microg/ml, transferrin 5 microg/ml, and selenium 5 ng/ml) treatment for 6 days. Detectable levels of ob mRNA first appeared at day 1 with very low activity of glycerol phosphate dehydrogenase (GPDH). Levels of ob mRNA increased in parallel with preadipocyte number or GPDH activity at the later times in cultures. The depletion of preadipocytes by complement-mediated cytotoxicity at day 3 of culture resulted in markedly decreased ob mRNA expression. Immunocytochemical analysis showed that ob protein was localized in the cytosol of preadipocytes and adipocytes. These data indicated that the ob gene is expressed by preadipocytes and ob gene expression may be correlated with preadipocyte recruitment as well as fat cell size.

The biology of white adipocyte proliferation.

Expanded adipose tissue mass increases the risk for many clinical conditions including diabetes, hypertension, coronary atherosclerotic heart disease, and some forms of cancer. Therefore, it is imperative that we understand the mechanisms by which fat pads expand. The enlargement of fat cells during the development of obesity has been previously hypothesized to be a triggering factor for the proliferation of new fat cells. There is now a preponderance of evidence that adipose tissue is a source of growth factors such as IGF-I, IGF binding proteins, TNF alpha, angiotensin II, and MCSF that are capable of stimulating proliferation. The relative importance of these autocrine/paracrine factors in the normal control of preadipocyte proliferation is unknown. In addition, the proliferative response of preadipocytes to the paracrine milieu is undoubtedly modulated by neural inputs to fat tissue and/or serum factors. Together, these multiple regulatory controls orchestrate overall and region-specific adipose tissue cellularity responses associated with the development of hyperplastic obesity. Both in vivo and in vitro studies are needed to understand the complex, interacting physiological mechanisms by which growth of this important organ is regulated.

Incentives and health policy: primary and secondary care in the British National Health Service.

This paper argues that issues concerning incentives and motivation are crucial to recent reforms to the British National Health Service. It examines how the incentive structure of General Practitioners with respect to the interface between primary and secondary care changed with the introduction of GP fundholding, and how it might change further with the new Primary Care Groups. It concludes that the effectiveness of the internal incentive structure of the new groups will depend on the location of power within the PCGs, and that the external incentives involving the possibility of heavy central monitoring may affect the behaviour and motivation of GPs in potentially harmful ways.

Tumor necrosis factor-alpha binding in porcine primary stromal-vascular cell cultures.

The binding characteristics of tumor necrosis factor-alpha receptors (TNFRs) in primary stromal-vascular cultures from fat tissue of 7-d-old pigs were analyzed. Cells were plated and maintained in 10% fetal bovine serum from day 0 to day 3 and then switched to serum-free medium from day 3 to day 6 to induce lipid filling. On days 3 and 6 of culture, some of the cells were lysed for ligand and immunoblotting and the remainder subjected to competitive and inhibitory-binding assays. Media from day 6 of culture were subjected to ligand and immunoblotting. Competitive binding analysis showed one-site bindings, with IC50s in the nanomolar and Kds in the picomolar ranges, that were not significantly different at both time-points of measurement. However, the Bmax decreased significantly with differentiation. Preincubation with antibody against TNF receptor type 1 (TNFR1) or TNF receptor type 2 reduced the specific binding by 95 and 15%, respectively, suggesting a dominating role of TNFR1 in 125I-labeled TNFalpha (125I-TNFalpha) binding. This was further supported by ligand blotting of cell lysates. Ligand and immunoblotting of cell lysates indicated that TNFalpha utilizes both types of surface receptors and their isoforms which were not modified during differentiation. Ligand blotting of media revealed soluble receptors with high Mr implying the formation of multimers. Immunoblotting suggested the presence of both types of TNFRs, but a greater abundance of soluble TNFR1. Also, it indicated the additional formation of smaller oligomers from both types of soluble receptors suggesting higher affinity of larger multimers for 125I-TNFalpha.

Effect of ractopamine on insulin sensitivity and response of isolated rat adipocytes.

In vitro effects of the phenethanolamine ractopamine on basal and insulin-stimulated lipid metabolism were determined in adipocytes isolated from epididymal fat pads of Sprague-Dawley rats. Ractopamine appeared to be equipotent to the catecholamine isoproterenol in stimulating basal lipolysis and inhibiting basal lipogenesis, producing maximum effects at 10(-6) M. Addition of a half-maximally stimulating dose of ractopamine (5 x 10(-8) M) to the incubation media decreased insulin sensitivity but not insulin responsiveness of the cells, stimulating lipolysis and inhibiting lipogenesis only in the presence of low media insulin concentrations. This effect was totally reversed by 10 microM/propranolol. Maximally effective concentrations of ractopamine (10(-6) M) significantly decreased both the sensitivity and responsiveness of the isolated adipocytes to insulin. Addition of 10 microM propranolol to the incubation media effectively reversed the lipolytic and anti-lipogenic effects of 10(-6) M ractopamine observed at media insulin concentrations greater than 25 microU/ml, whereas it only partially reduced the ractopamine-induced effects observed at lower insulin concentrations. The results demonstrate 1) that ractopamine has concentration-dependent effects on adipose tissue insulin sensitivity and responsiveness and 2) that these effects may be mediated, in part, through beta-adrenergic receptors.

Somatotropin and adipose tissue metabolism: substrate and temporal effects.

The purpose of these studies was to determine the time course for changes in feed intake, blood metabolites, and lipogenic activity in adipose tissue in response to the initiation of porcine somatotropin (pST) treatment and following withdrawal from treatment in barrows. An initial study was conducted to determine the impact of chronic pST treatment (4 wk of daily injection; 0 vs 4 mg/d) on adipose tissue lipid metabolism in barrows (initial weight 67 kg). Feed efficiency was improved 27%, backfat thickness was decreased 43%, and glucose and lactate oxidation and incorporation into lipid in adipose tissue was reduced 70 to 86% in pST-treated pigs. Palmitate esterification was decreased 44%, whereas palmitate oxidation was unaffected. In vitro metabolism of lactate, glucose, and palmitate in liver slices was not affected by pST treatment. The time-course for changes in intake and adipose tissue metabolism in response to 7 d of pST (0 vs 4 mg/d) treatment and 7 d of withdrawal was examined in subsequent studies in barrows (initial weight 75 kg). Feed intake during pST treatment was significantly (P < .05) less than in control pigs within 24 h of the initiation of treatment and remained low through 3 d after withdrawal. Adipose tissue biopsies were obtained on d 0, 1, 2, 4, and 7 of the treatment phase and on d 2, 4, and 7 after withdrawal from 7 d of treatment. Maximal inhibition of lipogenesis by pST treatment in adipose tissue in vitro was observed on d 4 (-68%) and d 7 (-69%). Similarly, fatty acid synthase activity declined during the treatment period, with the greatest change noted on d 7 (-26%). After withdrawal from treatment, lipogenesis gradually increased, returning to control values 7 d after withdrawal. Levels of IGF-I began to increase from d 1 to d 7 of treatment, continually decreased during withdrawal, and were normalized by the end of the withdrawal period. Plasma urea nitrogen concentrations decreased during treatment, increased during the withdrawal phase, and were normalized 4 d after the last pST treatment. Overall results indicate that most of the metabolic changes in response to pST occur within 1 wk of treatment and return to pretreatment values after 7 d of withdrawal from treatment.

Preadipocyte and adipose tissue differentiation in meat animals: influence of species and anatomical location.

Early in porcine adipose tissue development, the stromal-vascular (SV) elements control and dictate the extent of adipogenesis in a depot-dependent manner. The vasculature and collagen matrix differentiate before overt adipocyte differentiation. In the fetal pig, subcutaneous (SQ) layer development is predictive of adipocyte development, as the outer, middle, and inner layers of dorsal SQ adipose tissue develop and maintain layered morphology throughout postnatal growth of SQ adipose tissue. Bovine and ovine fetuses contain brown adipose tissue but SQ white adipose tissue is poorly developed structurally. Fetal adipose tissue differentiation is associated with the precocious expression of several genes encoding secreted factors and key transcription factors like peroxisome proliferator activated receptor (PPAR)γ and CCAAT/-enhancer-binding protein. Identification of adipocyte-associated genes differentially expressed by age, depot, and species in vivo and in vitro has been achieved using single-gene analysis, microarrays, suppressive subtraction hybridization, and next-generation sequencing applications. Gene polymorphisms in PPARγ, cathepsins, and uncoupling protein 3 have been associated with back fat accumulation. Genome scans have mapped several quantitative trait loci (QTL) predictive of adipose tissue-deposition phenotypes in cattle and pigs.

Association of adenovirus 36 infection with adiposity and inflammatory-related markers in children.

CONTEXT: Although animal studies suggest that adenovirus 36 (Ad36) infection is linked to obesity and systemic inflammation, human data are scant and equivocal. OBJECTIVE: Associations of Ad36 infection with total body adiposity and inflammatory-related markers were determined in 291 children aged 9-13 years (50% female, 49% black). DESIGN: Fasting blood samples were measured for presence of Ad36-specific antibodies and TNF-α, IL-6, vascular endothelial growth factor (VEGF), and monocyte chemoattractant protein-1 (MCP-1). Fat mass and fat-free soft tissue mass were measured by dual-energy X-ray absorptiometry. RESULTS: The overall prevalence of Ad36 seropositivity [Ad36(+)] was 42%. There was a higher percentage of Ad36(+) children in the highest tertiles of TNF-α and IL-6 compared with their respective middle and lowest tertiles (both P < .03). There was also a trend toward a higher prevalence of Ad36(+) children in the highest tertile of VEGF compared with tertiles 1 and 2 (P = .05). Multinomial logistic regression, adjusting for age, race, sex, and fat-free soft tissue mass, revealed that compared with children with the lowest TNF-α, IL-6, and VEGF levels (tertile 1), the adjusted odds ratios for Ad36(+) were 2.2 [95% confidence interval (CI) 1.2-4.0], 2.4 (95% CI 1.4-4.0), and 1.8 (95% CI 1.0-3.3), respectively, for those in the highest TNF-α, IL-6, and VEGF levels (tertile 3). No association was observed between Ad36(+) and greater levels of fat mass or MCP-1 (all P > .05). CONCLUSIONS: In children, our data suggest that Ad36(+) may be associated with biomarkers implicated in inflammation but not with greater levels of fat mass.