Search for the evidence of endocrine disruption in the aquatic environment: Lessons to be learned from joint biological and chemical monitoring in the European Project COMPREHEND

Between January 1999 and December 2001, the European Community project COMPREHEND was performed. The overall aim of COMPREHEND was to assess endocrine disruption in the aquatic environment in Europe, consequent to effluent discharge, with emphasis on estrogenic activity. COMPREHEND demonstrated the widespread occurrence of estrogenic effluents across Europe and presented evidence of impacts on a range of wild fish species. Using a variety of bioassays in combination with chemical analytical methods, estrogenic steroids of human origin from domestic wastewater effluents were identified as the most pervasive problem, although alkylphenols may be important estrogenic components of some industrial effluents. New tools have been developed for the identification of estrogenic effluents, and recommendations are made for the improvement of existing techniques. We have shown that individual fish within natural populations may be feminized to varying degrees, but it has not been possible to show, using traditional fish population parameters, that the survival of fish populations is threatened. However, laboratory-based fish life-cycle studies demonstrate the sensitivity of fish to estrogen (and androgen) exposure and how this might lead to complex (and potentially damaging) genetic changes at the population level. New approaches to this problem, utilizing recent advances made in the field of molecular and population genetics, are recommended. Finally, a study of estrogenic and androgenic activity of waste waters during the treatment process has shown that some of the existing wastewater treatment technologies have the potential to eliminate or minimize the hormonal activity of the final effluent

Memory consolidation in the cerebellar cortex

Several forms of learning, including classical conditioning of the eyeblink, depend upon the cerebellum. In examining mechanisms of eyeblink conditioning in rabbits, reversible inactivations of the control circuitry have begun to dissociate aspects of cerebellar cortical and nuclear function in memory consolidation. It was previously shown that post-training cerebellar cortical, but not nuclear, inactivations with the GABA(A) agonist muscimol prevented consolidation but these findings left open the question as to how final memory storage was partitioned across cortical and nuclear levels. Memory consolidation might be essentially cortical and directly disturbed by actions of the muscimol, or it might be nuclear, and sensitive to the raised excitability of the nuclear neurons following the loss of cortical inhibition. To resolve this question, we simultaneously inactivated cerebellar cortical lobule HVI and the anterior interpositus nucleus of rabbits during the post-training period, so protecting the nuclei from disinhibitory effects of cortical inactivation. Consolidation was impaired by these simultaneous inactivations. Because direct application of muscimol to the nuclei alone has no impact upon consolidation, we can conclude that post-training, consolidation processes and memory storage for eyeblink conditioning have critical cerebellar cortical components. The findings are consistent with a recent model that suggests the distribution of learning-related plasticity across cortical and nuclear levels is task-dependent. There can be transfer to nuclear or brainstem levels for control of high-frequency responses but learning with lower frequency response components, such as in eyeblink conditioning, remains mainly dependent upon cortical memory storage

Attention-dependent modulation of cortical taste circuits revealed by granger causality with signal-dependent noise

We show, for the first time, that in cortical areas, for example the insular, orbitofrontal, and lateral prefrontal cortex, there is signal-dependent noise in the fMRI blood-oxygen level dependent (BOLD) time series, with the variance of the noise increasing approximately linearly with the square of the signal. Classical Granger causal models are based on autoregressive models with time invariant covariance structure, and thus do not take this signal-dependent noise into account. To address this limitation, here we describe a Granger causal model with signal-dependent noise, and a novel, likelihood ratio test for causal inferences. We apply this approach to the data from an fMRI study to investigate the source of the top-down attentional control of taste intensity and taste pleasantness processing. The Granger causality with signal-dependent noise analysis reveals effects not identified by classical Granger causal analysis. In particular, there is a top-down effect from the posterior lateral prefrontal cortex to the insular taste cortex during attention to intensity but not to pleasantness, and there is a top-down effect from the anterior and posterior lateral prefrontal cortex to the orbitofrontal cortex during attention to pleasantness but not to intensity. In addition, there is stronger forward effective connectivity from the insular taste cortex to the orbitofrontal cortex during attention to pleasantness than during attention to intensity. These findings indicate the importance of explicitly modeling signal-dependent noise in functional neuroimaging, and reveal some of the processes involved in a biased activation theory of selective attention

Smart antennas cluster year 2000 report

It has been argued that Horava gravity needs to be extended to include terms that mix spatial and time derivatives in order avoid unacceptable violations of Lorentz invariance in the matter sector. In an earlier paper we have shown that including such mixed derivative terms generically leads to 4th instead of 6th order dispersion relations and this could be (naively) interpreted as a threat to renormalizability. We have also argued that power-counting renormalizability is not actually compromised, but instead the simplest power-counting renormalizable model is not unitary. In this paper we consider the Lifshitz scalar as a toy theory and we generalize our analysis to include higher order operators. We show that models which are power-counting renormalizable and unitary do exist. Our results suggest the existence of a new class of theories that can be thought of as Horava gravity with mixed derivative terms

Variation in plasma calcium analysis in primary care in Sweden - a multilevel analysis

<p>Abstract</p> <p>Background</p> <p>Primary hyperparathyroidism (pHPT) is a common disease that often remains undetected and causes severe disturbance especially in postmenopausal women. Therefore, national recommendations promoting early pHPT detection by plasma calcium (P-Ca) have been issued in Sweden. In this study we aimed to investigate variation of P-Ca analysis between physicians and health care centres (HCCs) in primary care in county of Skaraborg, Sweden.</p> <p>Methods</p> <p>In this cross sectional study of patients' records during 2005 we analysed records from 154 629 patients attending 457 physicians at 24 HCCs. We used multilevel logistic regression analysis (MLRA) and adjusted for patient, physician and HCC characteristics. Differences were expressed as median odds ratio (MOR).</p> <p>Results</p> <p>There was a substantial variation in number of P-Ca analyses between both HCCs (MOR_HCC1.65 [1.44-2.07]) and physicians (MOR_physician1.95 [1.85-2.08]). The odds for a P-Ca analysis were lower for male patients (OR 0.80 [0.77-0.83]) and increased with the number of diagnoses (OR 25.8 [23.5-28.5]). Sex of the physician had no influence on P-Ca test ordering (OR 0.93 [0.78-1.09]). Physicians under education ordered most P-Ca analyses (OR 1.69 [1.35-2.24]) and locum least (OR 0.73 [0.57-0.94]). More of the variance was attributed to the physician level than the HCC level. Different mix of patients did not explain this variance between physicians. Theoretically, if a patient were able to change both GP and HCC, the odds of a P-Ca analysis would in median increase by 2.45. Including characteristics of the patients, physicians and HCCs in the MLRA model did not explain the variance.</p> <p>Conclusions</p> <p>The physician level was more important than the HCC level for the variation in P-Ca analysis, but further exploration of unidentified contextual factors is crucial for future monitoring of practice variation.</p

Differential splicing using whole-transcript microarrays

<p>Abstract</p> <p>Background</p> <p>The latest generation of Affymetrix microarrays are designed to interrogate expression over the entire length of every locus, thus giving the opportunity to study alternative splicing genome-wide. The Exon 1.0 ST (sense target) platform, with versions for Human, Mouse and Rat, is designed primarily to probe every known or predicted exon. The smaller Gene 1.0 ST array is designed as an expression microarray but still interrogates expression with probes along the full length of each well-characterized transcript. We explore the possibility of using the Gene 1.0 ST platform to identify differential splicing events.</p> <p>Results</p> <p>We propose a strategy to score differential splicing by using the auxiliary information from fitting the statistical model, RMA (robust multichip analysis). RMA partitions the probe-level data into probe effects and expression levels, operating robustly so that if a small number of probes behave differently than the rest, they are downweighted in the fitting step. We argue that adjacent poorly fitting probes for a given sample can be evidence of <it>differential </it>splicing and have designed a statistic to search for this behaviour. Using a public tissue panel dataset, we show many examples of tissue-specific alternative splicing. Furthermore, we show that evidence for putative alternative splicing has a strong correspondence between the Gene 1.0 ST and Exon 1.0 ST platforms.</p> <p>Conclusion</p> <p>We propose a new approach, FIRMAGene, to search for differentially spliced genes using the Gene 1.0 ST platform. Such an analysis complements the search for differential expression. We validate the method by illustrating several known examples and we note some of the challenges in interpreting the probe-level data.</p> <p>Software implementing our methods is freely available as an <monospace>R</monospace> package.</p

The "lipid accumulation product" performs better than the body mass index for recognizing cardiovascular risk: a population-based comparison

BACKGROUND: Body mass index (BMI, kg/m(2)) may not be the best marker for estimating the risk of obesity-related disease. Consistent with physiologic observations, an alternative index uses waist circumference (WC) and fasting triglycerides (TG) concentration to describe lipid overaccumulation. METHODS: The WC (estimated population minimum 65 cm for men and 58 cm for women) and TG concentration from the third National Health and Nutrition Examination Survey (N = 9,180, statistically weighted to represent 100.05 million US adults) were used to compute a "lipid accumulation product" [LAP = (WC-65) × TG for men and (WC-58) × TG for women] and to describe the population distribution of LAP. LAP and BMI were compared as categorical variables and as log-transformed continuous variables for their ability to identify adverse levels of 11 cardiovascular risk factors. RESULTS: Nearly half of the represented population was discordant for their quartile assignments to LAP and BMI. When 23.54 million with ordinal LAP quartile > BMI quartile were compared with 25.36 million with ordinal BMI quartile > LAP quartile (regression models adjusted for race-ethnicity and sex) the former had more adverse risk levels than the latter (p < 0.002) for seven lipid variables, uric acid concentration, heart rate, systolic and diastolic blood pressure. Further adjustment for age did not materially alter these comparisons except for blood pressures (p > 0.1). As continuous variables, LAP provided a consistently more adverse beta coefficient (slope) than BMI for nine cardiovascular risk variables (p < 0.01), but not for blood pressures (p > 0.2). CONCLUSION: LAP (describing lipid overaccumulation) performed better than BMI (describing weight overaccumulation) for identifying US adults at cardiovascular risk. Compared to BMI, LAP might better predict the incidence of cardiovascular disease, but this hypothesis needs prospective testing