Morphologic and electroretinographic phenotype of SR-BI knockout mice after a long-term atherogenic diet.

PURPOSE: To evaluate functional and ultrastructural changes in the retina of scavenger receptor B1 (SR-BI) knockout (KO) mice consuming a high fat cholate (HFC) diet. METHODS: Three-month-old male KO and wild-type (WT) mice were fed an HFC diet for 30 weeks. After diet supplementation, plasma cholesterol levels and electroretinograms were analyzed. Neutral lipids were detected with oil red O, and immunohistochemistry was performed on cryostat ocular tissue sections. The retina, Bruch's membrane (BM), retinal pigment epithelium (RPE), and choriocapillaris (CC) were analyzed by transmission electron microscopy. RESULTS: Using the WT for reference, ultrastructural changes were recorded in HFC-fed SR-BI KO mice, including lipid inclusions, a patchy disorganization of the photoreceptor outer segment (POS) and the outer nuclear layer (ONL), and BM thickening with sparse sub-RPE deposits. Within the CC, there was abnormal disorganization of collagen fibers localized in ectopic sites with sparse and large vacuolization associated with infiltration of macrophages in the subretinal space, reflecting local inflammation. These lesions were associated with electroretinographic abnormalities, particularly increasing implicit time in a- and b-wave scotopic responses. Abnormal vascular endothelial growth factor (VEGF) staining was detected in the outer nuclear layer. CONCLUSIONS: HFC-fed SR-BI KO mice thus presented sub-RPE lipid-rich deposits and functional and morphologic alterations similar to some features observed in dry AMD. The findings lend further support to the hypothesis that atherosclerosis causes retinal and subretinal damage that increases susceptibility to some forms of AMD.

The building blocks of international ecological footprint inequality: a regression-based decomposition

This paper performs an empirical Decomposition of International Inequality in Ecological Footprint in order to quantify to what extent explanatory variables such as a country’s affluence, economic structure, demographic characteristics, climate and technology contributed to international differences in terms of natural resource consumption during the period 1993-2007. We use a Regression-Based Inequality Decomposition approach. As a result, the methodology extends qualitatively the results obtained in standard environmental impact regressions as it comprehends further social dimensions of the Sustainable Development concept, i.e. equity within generations. The results obtained point to prioritizing policies that take into account both future and present generations.

The Building Blocks of International Ecological Footprint inequality: A Regression-Base Decomposition

This paper performs an empirical Decomposition of International Inequality in Ecological Footprint in order to quantify to what extent explanatory variables such as a country’s affluence, economic structure, demographic characteristics, climate and technology contributed to international differences in terms of natural resource consumption during the period 1993-2007. We use a Regression- Based Inequality Decomposition approach. As a result, the methodology extends qualitatively the results obtained in standard environmental impact regressions as it comprehends further social dimensions of the Sustainable Development concept, i.e. equity within generations. The results obtained point to prioritizing policies that take into account both future and present generations. Keywords: Ecological Footprint Inequality, Regression-Based Inequality Decomposition, Intragenerational equity, Sustainable development.

Temporal SNR characteristics in segmented 3D-EPI at 7T.

Three-dimensional segmented echo planar imaging (3D-EPI) is a promising approach for high-resolution functional magnetic resonance imaging, as it provides an increased signal-to-noise ratio (SNR) at similar temporal resolution to traditional multislice 2D-EPI readouts. Recently, the 3D-EPI technique has become more frequently used and it is important to better understand its implications for fMRI. In this study, the temporal SNR characteristics of 3D-EPI with varying numbers of segments are studied. It is shown that, in humans, the temporal variance increases with the number of segments used to form the EPI acquisition and that for segmented acquisitions, the maximum available temporal SNR is reduced compared to single shot acquisitions. This reduction with increased segmentation is not found in phantom data and thus likely due to physiological processes. When operating in the thermal noise dominated regime, fMRI experiments with a motor task revealed that the 3D variant outperforms the 2D-EPI in terms of temporal SNR and sensitivity to detect activated brain regions. Thus, the theoretical SNR advantage of a segmented 3D-EPI sequence for fMRI only exists in a low SNR situation. However, other advantages of 3D-EPI, such as the application of parallel imaging techniques in two dimensions and the low specific absorption rate requirements, may encourage the use of the 3D-EPI sequence for fMRI in situations with higher SNR.

Intravaginal and subcutaneous immunization induced vaccine specific CD8 T cells and tumor regression in the bladder.

PURPOSE: Vaccines targeting tumor associated antigens are in development for bladder cancer. Most of these cancers are nonmuscle invasive at diagnosis and confined in the mucosa and submucosa. However, to our knowledge how vaccination may induce the regression of tumors at such mucosal sites has not been examined previously. We compared different immunization routes for the ability to induce vaccine specific antitumor CD8 T cells in the bladder and bladder tumor regression in mice. MATERIALS AND METHODS: In the absence of a murine bladder tumor model expressing a tumor antigen relevant for human use we established an orthotopic model expressing the HPV-16 tumor antigen E7 as a model. We used an adjuvant E7 polypeptide to induce CD8 T cell mediated tumor regression. RESULTS: Subcutaneous and intravaginal but not intranasal vaccination induced a high number of TetE7(+)CD8(+) T cells in the bladder as well as bladder tumor regression. The entry of vaccine specific T cells in the bladder was not the only key since persistent regression of established bladder tumors by intravaginal or subcutaneous immunization was associated with tumor infiltration of total CD4 and CD8 T cells. This resulted in an increase in TetE7(+)CD8(+) T cells and a decrease in T regulatory cells, leading to an increased number of effector interferon-γ secreting vaccine specific CD8 T cells in the regressing bladder tumor. CONCLUSIONS: These data show that immunization routes should be tailored to each mucosal tumor site. Subcutaneous or intravaginal vaccination may be of additional value to treat patients with bladder cancer.

A bi-dimensional genome scan for prolificacy traits in pigs shows the existence of multiple epistatic QTL

Background: Prolificacy is the most important trait influencing the reproductive efficiency of pig production systems. The low heritability and sex-limited expression of prolificacy have hindered to some extent the improvement of this trait through artificial selection. Moreover, the relative contributions of additive, dominant and epistatic QTL to the genetic variance of pig prolificacy remain to be defined. In this work, we have undertaken this issue by performing one-dimensional and bi-dimensional genome scans for number of piglets born alive (NBA) and total number of piglets born (TNB) in a three generation Iberian by Meishan F2 intercross. Results: The one-dimensional genome scan for NBA and TNB revealed the existence of two genome-wide highly significant QTL located on SSC13 (P < 0.001) and SSC17 (P < 0.01) with effects on both traits. This relative paucity of significant results contrasted very strongly with the wide array of highly significant epistatic QTL that emerged in the bi-dimensional genome-wide scan analysis. As much as 18 epistatic QTL were found for NBA (four at P < 0.01 and five at P < 0.05) and TNB (three at P < 0.01 and six at P < 0.05), respectively. These epistatic QTL were distributed in multiple genomic regions, which covered 13 of the 18 pig autosomes, and they had small individual effects that ranged between 3 to 4% of the phenotypic variance. Different patterns of interactions (a × a, a × d, d × a and d × d) were found amongst the epistatic QTL pairs identified in the current work.Conclusions: The complex inheritance of prolificacy traits in pigs has been evidenced by identifying multiple additive (SSC13 and SSC17), dominant and epistatic QTL in an Iberian × Meishan F2 intercross. Our results demonstrate that a significant fraction of the phenotypic variance of swine prolificacy traits can be attributed to first-order gene-by-gene interactions emphasizing that the phenotypic effects of alleles might be strongly modulated by the genetic background where they segregate.

Acute seizures in acute ischemic stroke: does thrombolysis have a role to play?

Seizures appear at stroke presentation, during the acute phase or as a late complication of stroke. Thrombolysis has not been investigated as a risk factor despite its potential neurotoxic effect. We try to identify risk factors for seizures during the acute phase of ischemic stroke in a cohort including thrombolysed patients. We undertook a case-control study at a single stroke center using data from Acute Stroke Registry and Analyse of Lausanne (ASTRAL). Patients with seizure occurring during the first 7 days following stroke were retrospectively identified. Bi-variable and multivariable statistical analyses were applied to compare cases and randomly selected controls. We identified 28 patients experiencing from seizures in 2,327 acute ischemic strokes (1.2 %). All seizures occurred during the first 72 h. Cortical involvement, thrombolysis with rt-PA, arterial recanalization, and higher initial NIHSS were statistically associated with seizures in univariated analysis. Backward linear regression identified cortical involvement (OR 7.53, 95 % CI 1.6-35.2, p < 0.01) and thrombolysis (OR 4.6, 95 % CI 1.6-13.4, p = 0.01) as being independently associated with seizure occurrence. Overall, 3-month outcome measured by the modified Rankin scale (mRS) was comparable in both groups. In the subgroup of thrombolysed patients, outcome was significantly worse at 3 months in the seizure group with 9/12 (75 %) patients with mRS ≥3, compared to 6/18 (33.3 %) in the seizure-free group (p = 0.03). Acute seizures in acute ischemic stroke were relatively infrequent. Cortical involvement and thrombolysis with rt-PA are the principal risk factors. Seizures have a potential negative influence on clinical outcome in thrombolysed patients.

Intravaginal TLR agonists increase local vaccine-specific CD8 T cells and human papillomavirus-associated genital-tumor regression in mice.

Human papillomaviruses (HPV)-related cervical cancer is the second leading cause of cancer death in women worldwide. Despite active development, HPV E6/E7 oncogene-specific therapeutic vaccines have had limited clinical efficacy to date. Here, we report that intravaginal (IVAG) instillation of CpG-ODN (TLR9 agonist) or poly-(I:C) (TLR3 agonist) after subcutaneous E7 vaccination increased ∼fivefold the number of vaccine-specific interferon-γ-secreting CD8 T cells in the genital mucosa (GM) of mice, without affecting the E7-specific systemic response. The IVAG treatment locally increased both E7-specific and total CD8 T cells, but not CD4 T cells. This previously unreported selective recruitment of CD8 T cells from the periphery by IVAG CpG-ODN or poly-(I:C) was mediated by TLR9 and TLR3/melanoma differentiation-associated gene 5 signaling pathways, respectively. For CpG, this recruitment was associated with a higher proportion of GM-localized CD8 T cells expressing both CCR5 and CXCR3 chemokine receptors and E-selectin ligands. Most interestingly, IVAG CpG-ODN following vaccination led to complete regression of large genital HPV tumors in 75% of mice, instead of 20% with vaccination alone. These findings suggest that mucosal application of immunostimulatory molecules might substantially increase the effectiveness of parenterally administered vaccines.Mucosal Immunology advance online publication 12 September 2012; doi:10.1038/mi.2012.83.

Language Regression Associated With Autistic Regression and Electroencephalographic (EEG) Abnormalities: A Prospective Study.

We report a boy, referred at 25 months following a dramatic isolated language regression antedating autistic-like symptomatology. His sleep electroencephalogram (EEG) showed persistent focal epileptiform activity over the left parietal and vertex areas never associated with clinical seizures. He was started on adrenocorticotropic hormone (ACTH) with a significant improvement in language, behavior, and in EEG discharges in rapid eye movement (REM) sleep. Later course was characterized by fluctuations/regressions in language and behavior abilities, in phase with recrudescence of EEG abnormalities prompting additional ACTH courses that led to remarkable decrease in EEG abnormalities, improvement in language, and to a lesser degree, in autistic behavior. The timely documentation of regression episodes suggesting an "atypical" autistic regression, striking therapy-induced improvement, fluctuation of symptomatology over time could be ascribed to recurrent and persisting EEG abnormalities.

U.S. Universities’ Net Returns from Patenting and Licensing: A Quantile Regression Analysis, September 2006

In line with the rights and incentives provided by the Bayh-Dole Act of 1980, U.S. universities have increased their involvement in patenting and licensing activities through their own technology transfer offices. Only a few U.S. universities are obtaining large returns, however, whereas others are continuing with these activities despite negligible or negative returns. We assess the U.S. universities’ potential to generate returns from licensing activities by modeling and estimating quantiles of the distribution of net licensing returns conditional on some of their structural characteristics. We find limited prospects for public universities without a medical school everywhere in their distribution. Other groups of universities (private, and public with a medical school) can expect significant but still fairly modest returns only beyond the 0.9th quantile. These findings call into question the appropriateness of the revenue-generating motive for the aggressive rate of patenting and licensing by U.S. universities.

Long-term outcome after cognitive and behavioral regression in non-lesional epilepsy with CSWS

Purpose: To present the long-term outcome (LTO) of 10 adolescents and young adults with documented cognitive and behavioral regression as children due to non-lesional focal, mainly frontal epilepsy with continuous spike-waves during slow wave sleep (CSWS). Method: Past medical and EEG data of all patients were reviewed and neuropsychological tests exploring main cognitive functions were administered. Result: After a mean duration of follow-up of 15.6 years (range 8-23 years), none of the 10 patients had recovered fully, but four regained borderline to normal intelligence and were almost independent. Patients with prolonged global intellectual regression had the worst outcome, whereas those with more specific and short-lived deficits recovered best. The marked behavioral disorders that were so disturbing during the active period (AP) resolved in all but one patient. Executive functions were neither severely nor homogenously affected. Three patients with a frontal syndrome during the AP disclosed only mild residual executive and social cognition deficits. The main cognitive gains occurred shortly after the AP, but qualitative improvements continued to occur. LTO correlated best with duration of CSWS. Conclusion: Our findings emphasize that cognitive recovery after cessation of CSWS depends on the severity and duration of the initial regression. None of our patients had major executive and social cognition deficits with preserved intelligence as reported in adults with destructive lesions of the frontal lobes during childhood. Early recognition of epilepsy with CSWS and rapid introduction of effective therapy are crucial for a best possible outcome.

Fusion of data sets in multivariate linear regression with errors-in-variables

We consider the application of normal theory methods to the estimation and testing of a general type of multivariate regressionmodels with errors--in--variables, in the case where various data setsare merged into a single analysis and the observable variables deviatepossibly from normality. The various samples to be merged can differ on the set of observable variables available. We show that there is a convenient way to parameterize the model so that, despite the possiblenon--normality of the data, normal--theory methods yield correct inferencesfor the parameters of interest and for the goodness--of--fit test. Thetheory described encompasses both the functional and structural modelcases, and can be implemented using standard software for structuralequations models, such as LISREL, EQS, LISCOMP, among others. An illustration with Monte Carlo data is presented.