Estimating equations for biomarker based exposure estimation under non-steady-state conditions

Unrealistic steady-state assumptions are often used to estimate toxicant exposure rates from biomarkers. A biomarker may instead be modeled as a weighted sum of historical time-varying exposures. Estimating equations are derived for a zero-inflated gamma distribution for daily exposures with a known exposure frequency. Simulation studies suggest that the estimating equations can provide accurate estimates of exposure magnitude at any reasonable sample size, and reasonable estimates of the exposure variance at larger sample sizes

Geocoding rural addresses in a community contaminated by PFOA: a comparison of methods

BACKGROUND: Location is often an important component of exposure assessment, and positional errors in geocoding may result in exposure misclassification. In rural areas, successful geocoding to a street address is limited by rural route boxes. Communities have assigned physical street addresses to rural route boxes as part of E911 readdressing projects for improved emergency response. Our study compared automated and E911 methods for recovering and geocoding valid street addresses and assessed the impact of positional errors on exposure classification. METHODS: The current study is a secondary analysis of existing data that included 135 addresses self-reported by participants of a rural community study who were exposed via public drinking water to perfluorooctanoate (PFOA) released from a DuPont facility in Parkersburg, West Virginia. We converted pre-E911 to post-E911 addresses using two methods: automated ZP4 address-correction software with the U.S. Postal Service LACS database and E911 data provided by Wood County, West Virginia. Addresses were geocoded using TeleAtlas, an online commercial service, and ArcView with StreetMap Premium North America NAVTEQ 2008 enhanced street dataset. We calculated positional errors using GPS measurements collected at each address and assessed exposure based on geocoded location in relation to public water pipes. RESULTS: The county E911 data converted 89% of the eligible addresses compared to 35% by ZP4 LACS. ArcView/NAVTEQ geocoded more addresses (n = 130) and with smaller median distance between geocodes and GPS coordinates (39 meters) than TeleAtlas (n = 85, 188 meters). Without E911 address conversion, 25% of the geocodes would have been more than 1000 meters from the true location. Positional errors in TeleAtlas geocoding resulted in exposure misclassification of seven addresses whereas ArcView/NAVTEQ methods did not misclassify any addresses. CONCLUSIONS: Although the study was limited by small numbers, our results suggest that the use of county E911 data in rural areas increases the rate of successful geocoding. Furthermore, positional accuracy of rural addresses in the study area appears to vary by geocoding method. In a large epidemiological study investigating the health effects of PFOA-contaminated public drinking water, this could potentially result in exposure misclassification if addresses are incorrectly geocoded to a street segment not serviced by public water

Symmorphosis through dietary regulation: a combinatorial role for proteolysis, autophagy and protein synthesis in normalising muscle metabolism and function of hypertrophic mice after acute starvation

Animals are imbued with adaptive mechanisms spanning from the tissue/organ to the cellular scale which insure that processes of homeostasis are preserved in the landscape of size change. However we and others have postulated that the degree of adaptation is limited and that once outside the normal levels of size fluctuations, cells and tissues function in an aberant manner. In this study we examine the function of muscle in the myostatin null mouse which is an excellent model for hypertrophy beyond levels of normal growth and consequeces of acute starvation to restore mass. We show that muscle growth is sustained through protein synthesis driven by Serum/Glucocorticoid Kinase 1 (SGK1) rather than Akt1. Furthermore our metabonomic profiling of hypertrophic muscle shows that carbon from nutrient sources is being channelled for the production of biomass rather than ATP production. However the muscle displays elevated levels of autophagy and decreased levels of muscle tension. We demonstrate the myostatin null muscle is acutely sensitive to changes in diet and activates both the proteolytic and autophagy programmes and shutting down protein synthesis more extensively than is the case for wild-types. Poignantly we show that acute starvation which is detrimental to wild-type animals is beneficial in terms of metabolism and muscle function in the myostatin null mice by normalising tension production

Progestin Receptor-Mediated Reduction of Anxiety-Like Behavior in Male Rats

BACKGROUND: It is well known progesterone can have anxiolytic-like effects in animals in a number of different behavioral testing paradigms. Although progesterone is known to influence physiology and behavior by binding to classical intracellular progestin receptors, progesterone's anxiety reducing effects have solely been attributed to its rapid non-genomic effects at the GABA A receptor. This modulation occurs following the bioconversion of progesterone to allopregnanolone. Seemingly paradoxical results from some studies suggested that the function of progesterone to reduce anxiety-like behavior may not be entirely clear; therefore, we hypothesized that progesterone might also act upon progestin receptors to regulate anxiety. METHODOLOGY/PRINCIPAL FINDINGS: To test this, we examined the anxiolytic-like effects of progesterone in male rats using the elevated plus maze, a validated test of anxiety, and the light/dark chamber in the presence or absence of a progestin receptor antagonist, RU 486. Here we present evidence suggesting that the anxiolytic-like effects of progesterone in male rats can be mediated, in part, by progestin receptors, as these effects are blocked by prior treatment with a progestin receptor antagonist. CONCLUSION/SIGNIFICANCE: This indicates that progesterone can act upon progestin receptors to regulate anxiety-like behavior in the male rat brain

Deficiency of Antinociception and Excessive Grooming Induced by Acute Immobilization Stress in Per1 Mutant Mice

Acute stressors induce changes in numerous behavioral parameters through activation of the hypothalamic-pituitary-adrenal (HPA) axis. Several important hormones in paraventricular nucleus of the hypothalamus (PVN) play the roles in these stress-induced reactions. Corticotropin-releasing hormone (CRH), arginine-vasopressin (AVP) and corticosterone are considered as molecular markers for stress-induced grooming behavior. Oxytocin in PVN is an essential modulator for stress-induced antinociception. The clock gene, Per1, has been identified as an effecter response to the acute stresses, but its function in neuroendocrine stress systems remains unclear. In the present study we observed the alterations in grooming and nociceptive behaviors induced by acute immobilization stress in Per1 mutant mice and other genotypes (wild types and Per2 mutant). The results displayed that stress elicited a more robust effect on grooming behavior in Per1 mutant mice than in other genotypes. Subsequently, the obvious stress-induced antinociception was observed in the wild-type and Per2 mutant mice, however, in Per1 mutant, this antinociceptive effects were partially-reversed (mechanical sensitivity), or over-reversed to hyperalgesia (thermal sensitivity). The real-time qPCR results showed that in PVN, there were stress-induced up-regulations of Crh, Avp and c-fos in all of genotypes; moreover, the expression change of Crh in Per1 mutant mice was much larger than in others. Another hormonal gene, Oxt, was up-regulated induced by stress in wild-type and Per2 mutant but not in Per1 mutant. In addition, the stress significantly elevated the serum corticosterone levels without genotype-dependent differences, and accordingly the glucocorticoid receptor gene, Nr3c1, expressed with a similar pattern in PVN of all strains. Taken together, the present study indicated that in acute stress treated Per1 mutant mice, there are abnormal hormonal responses in PVN, correlating with the aberrant performance of stress-induced behaviors. Therefore, our findings suggest a novel functional role of Per1 in neuroendocrine stress system, which further participates in analgesic regulation

A Large Specific Deterrent Effect of Arrest for Patronizing a Prostitute

BACKGROUND: Prior research suggests that arrest, compared with no police detection, of some types of offenders does not decrease the chances they will reoffend. METHODOLOGY/PRINCIPAL FINDINGS: We assessed the specific deterrent effect of arrest for patronizing a street prostitute in Colorado Springs by comparing the incidence of arrest for clients of prostitutes first detected through public health surveillance with the incidence of rearrest for clients first detected by police arrest. Although these sets of clients were demographically and behaviorally similar, arrest reduced the likelihood of a subsequent arrest by approximately 70%. In other areas of the United States, arrest did not appear to displace a client's patronizing. CONCLUSIONS/SIGNIFICANCE: Our results suggest that apprehending clients decreases their patronizing behavior substantially

Normal Leptin Expression, Lower Adipogenic Ability, Decreased Leptin Receptor and Hyposensitivity to Leptin in Adolescent Idiopathic Scoliosis

Leptin has been suggested to play a role in the etiology of Adolescent Idiopathic Scoliosis (AIS), however, the leptin levels in AIS girls are still a discrepancy, and no in vitro study of leptin in AIS is reported. We took a series of case-control studies, trying to understand whether Leptin gene polymorphisms are involved in the etiology of the AIS or the change in leptin level is a secondary event, to assess the level of leptin receptor, and to evaluate the differences of response to leptin between AIS cases and controls. We screened all exons of Leptin gene in 45 cases and 45 controls and selected six tag SNPs to cover all the observed variations. Association analysis in 446 AIS patients and 550 healthy controls showed no association between the polymorphisms of Leptin gene and susceptibility/severity to AIS. Moreover, adipogenesis assay of bone mesenchymal stem cells (MSCs) suggested that the adipogenic ability of MSCs from AIS girls was lower than controls. After adjusting the differentiation rate, expressions of leptin and leptin receptor were similar between two groups. Meanwhile, osteogenesis assay of MSC showed the leptin level was similar after adjusting the differentiation rate, but the leptin receptor level was decreased in induced AIS osteoblasts. Immunocytochemistry and western blot analysis showed less leptin receptors expressed in AIS group. Furthermore, factorial designed studies with adipogenesis and osteogenesis revealed that the MSCs from patients have no response to leptin treatment. Our results suggested that Leptin gene variations are not associated with AIS and low serum leptin probably is a secondary outcome which may be related to the low capability of adipogenesis in AIS. The decreased leptin receptor levels may lead to the hyposensitivity to leptin. These findings implied that abnormal peripheral leptin signaling plays an important role in the pathological mechanism of AIS

A Neural Correlate of the Processing of Multi-Second Time Intervals in Primate Prefrontal Cortex

Several areas of the brain are known to participate in temporal processing. Neurons in the prefrontal cortex (PFC) are thought to contribute to perception of time intervals. However, it remains unclear whether the PFC itself can generate time intervals independently of external stimuli. Here we describe a group of PFC neurons in area 9 that became active when monkeys recognized a particular elapsed time within the range of 1–7 seconds. Another group of area 9 neurons became active only when subjects reproduced a specific interval without external cues. Both types of neurons were individually tuned to recognize or reproduce particular intervals. Moreover, the injection of muscimol, a GABA agonist, into this area bilaterally resulted in an increase in the error rate during time interval reproduction. These results suggest that area 9 may process multi-second intervals not only in perceptual recognition, but also in internal generation of time intervals

Enhanced Food Anticipatory Activity Associated with Enhanced Activation of Extrahypothalamic Neural Pathways in Serotonin2C Receptor Null Mutant Mice

The ability to entrain circadian rhythms to food availability is important for survival. Food-entrained circadian rhythms are characterized by increased locomotor activity in anticipation of food availability (food anticipatory activity). However, the molecular components and neural circuitry underlying the regulation of food anticipatory activity remain unclear. Here we show that serotonin2C receptor (5-HT2CR) null mutant mice subjected to a daytime restricted feeding schedule exhibit enhanced food anticipatory activity compared to wild-type littermates, without phenotypic differences in the impact of restricted feeding on food consumption, body weight loss, or blood glucose levels. Moreover, we show that the enhanced food anticipatory activity in 5-HT2CR null mutant mice develops independent of external light cues and persists during two days of total food deprivation, indicating that food anticipatory activity in 5-HT2CR null mutant mice reflects the locomotor output of a food-entrainable oscillator. Whereas restricted feeding induces c-fos expression to a similar extent in hypothalamic nuclei of wild-type and null mutant animals, it produces enhanced expression in the nucleus accumbens and other extrahypothalamic regions of null mutant mice relative to wild-type subjects. These data suggest that 5-HT2CRs gate food anticipatory activity through mechanisms involving extrahypothalamic neural pathways