Moderate postnatal hyperoxia accelerates lung growth and attenuates pulmonary hypertension in infant rats after exposure to intra-amniotic endotoxin.

To determine the separate and interactive effects of fetal inflammation and neonatal hyperoxia on the developing lung, we hypothesized that: 1) antenatal endotoxin (ETX) causes sustained abnormalities of infant lung structure; and 2) postnatal hyperoxia augments the adverse effects of antenatal ETX on infant lung growth. Escherichia coli ETX or saline (SA) was injected into amniotic sacs in pregnant Sprague-Dawley rats at 20 days of gestation. Pups were delivered 2 days later and raised in room air (RA) or moderate hyperoxia (O₂, 80% O₂ at Denver's altitude, ∼65% O₂ at sea level) from birth through 14 days of age. Heart and lung tissues were harvested for measurements. Intra-amniotic ETX caused right ventricular hypertrophy (RVH) and decreased lung vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2) protein contents at birth. In ETX-exposed rats (ETX-RA), alveolarization and vessel density were decreased, pulmonary vascular wall thickness percentage was increased, and RVH was persistent throughout the study period compared with controls (SA-RA). After antenatal ETX, moderate hyperoxia increased lung VEGF and VEGFR-2 protein contents in ETX-O₂ rats and improved their alveolar and vascular structure and RVH compared with ETX-RA rats. In contrast, severe hyperoxia (≥95% O₂ at Denver's altitude) further reduced lung vessel density after intra-amniotic ETX exposure. We conclude that intra-amniotic ETX induces fetal pulmonary hypertension and causes persistent abnormalities of lung structure with sustained pulmonary hypertension in infant rats. Moreover, moderate postnatal hyperoxia after antenatal ETX restores lung growth and prevents pulmonary hypertension during infancy.

Another way of thinking about ADHD: the predictive role of early attachment deprivation in adolescents' level of symptoms.

PURPOSE: Attention deficit and hyperactivity disorder (ADHD) is one of the most frequent disorders in childhood and adolescence. Both neurocognitive and environmental factors have been related to ADHD. The current study contributes to the documentation of the predictive relation between early attachment deprivation and ADHD. METHOD: Data were collected from 641 adopted adolescents (53.2 % girls) aged 11-16 years in five countries, using the DSM oriented scale for ADHD of the Child Behavior Checklist (CBCL) (Achenbach and Rescorla, Manual for the ASEBA school-age forms and profiles. University of Vermont, Research Center for Children, Youth and Families, Burlington, 2001). The influence of attachment deprivation on ADHD symptoms was initially tested taking into consideration several key variables that have been reported as influencing ADHD at the adoptee level (age, gender, length of time in the adoptive family, parents' educational level and marital status), and at the level of the country of origin and country of adoption (poverty, quality of health services and values). The analyses were computed using the multilevel modeling technique. RESULTS: The results showed that an increase in the level of ADHD symptoms was predicted by the duration of exposure to early attachment deprivation, estimated from the age of adoption, after controlling for the influence of adoptee and country variables. The effect of the age of adoption was also demonstrated to be specific to the level of ADHD symptoms in comparison to both the externalizing and internalizing behavior scales of the CBCL. CONCLUSION: Deprivation of stable and sensitive care in infancy may have long-lasting consequences for children's development.

A database to aid the identification of chemicals potentially posing a health risk through percutaneous exposure

In the context of recent attempts to redefine the 'skin notation' concept, a position paper summarizing an international workshop on the topic stated that the skin notation should be a hazard indicator related to the degree of toxicity and the potential for transdermal exposure of a chemical. Within the framework of developing a web-based tool integrating this concept, we constructed a database of 7101 agents for which a percutaneous permeation constant can be estimated (using molecular weight and octanol-water partition constant), and for which at least one of the following toxicity indices could be retrieved: Inhalation occupational exposure limit (n=644), Oral lethal dose 50 (LD50, n=6708), cutaneous LD50 (n=1801), Oral no observed adverse effect level (NOAEL, n=1600), and cutaneous NOAEL (n=187). Data sources included the Registry of toxic effects of chemical substances (RTECS, MDL information systems, Inc.), PHYSPROP (Syracuse Research Corp.) and safety cards from the International Programme on Chemical Safety (IPCS). A hazard index, which corresponds to the product of exposure duration and skin surface exposed that would yield an internal dose equal to a toxic reference dose was calculated. This presentation provides a descriptive summary of the database, correlations between toxicity indices, and an example of how the web tool will help industrial hygienist decide on the possibility of a dermal risk using the hazard index.

A comparison of the imaging characteristics of the new Kodak Hyper Speed G film with the current T-MAT G/RA film and the CR 9000 system.

Three standard radiation qualities (RQA 3, RQA 5 and RQA 9) and two screens, Kodak Lanex Regular and Insight Skeletal, were used to compare the imaging performance and dose requirements of the new Kodak Hyper Speed G and the current Kodak T-MAT G/RA medical x-ray films. The noise equivalent quanta (NEQ) and detective quantum efficiencies (DQE) of the four screen-film combinations were measured at three gross optical densities and compared with the characteristics for the Kodak CR 9000 system with GP (general purpose) and HR (high resolution) phosphor plates. The new Hyper Speed G film has double the intrinsic sensitivity of the T-MAT G/RA film and a higher contrast in the high optical density range for comparable exposure latitude. By providing both high sensitivity and high spatial resolution, the new film significantly improves the compromise between dose and image quality. As expected, the new film has a higher noise level and a lower signal-to-noise ratio than the standard film, although in the high frequency range this is compensated for by a better resolution, giving better DQE results--especially at high optical density. Both screen-film systems outperform the phosphor plates in terms of MTF and DQE for standard imaging conditions (Regular screen at RQA 5 and RQA 9 beam qualities). At low energy (RQA 3), the CR system has a comparable low-frequency DQE to screen-film systems when used with a fine screen at low and middle optical densities, and a superior low-frequency DQE at high optical density.

Occupational and patient exposure as well as image quality for full spine examinations with the EOS imaging system.

PURPOSE: EOS (EOS imaging S.A, Paris, France) is an x-ray imaging system that uses slot-scanning technology in order to optimize the trade-off between image quality and dose. The goal of this study was to characterize the EOS system in terms of occupational exposure, organ doses to patients as well as image quality for full spine examinations. METHODS: Occupational exposure was determined by measuring the ambient dose equivalents in the radiological room during a standard full spine examination. The patient dosimetry was performed using anthropomorphic phantoms representing an adolescent and a five-year-old child. The organ doses were measured with thermoluminescent detectors and then used to calculate effective doses. Patient exposure with EOS was then compared to dose levels reported for conventional radiological systems. Image quality was assessed in terms of spatial resolution and different noise contributions to evaluate the detector's performances of the system. The spatial-frequency signal transfer efficiency of the imaging system was quantified by the detective quantum efficiency (DQE). RESULTS: The use of a protective apron when the medical staff or parents have to stand near to the cubicle in the radiological room is recommended. The estimated effective dose to patients undergoing a full spine examination with the EOS system was 290μSv for an adult and 200 μSv for a child. MTF and NPS are nonisotropic, with higher values in the scanning direction; they are in addition energy-dependent, but scanning speed independent. The system was shown to be quantum-limited, with a maximum DQE of 13%. The relevance of the DQE for slot-scanning system has been addressed. CONCLUSIONS: As a summary, the estimated effective dose was 290μSv for an adult; the image quality remains comparable to conventional systems.

Prenatal Exposure to DEHP Affects Spermatogenesis and Sperm DNA Methylation in a Strain-Dependent Manner.

Di-(2-ethylhexyl)phtalate (DEHP) is a plasticizer with endocrine disrupting properties found ubiquitously in the environment and altering reproduction in rodents. Here we investigated the impact of prenatal exposure to DEHP on spermatogenesis and DNA sperm methylation in two distinct, selected, and sequenced mice strains. FVB/N and C57BL/6J mice were orally exposed to 300 mg/kg/day of DEHP from gestation day 9 to 19. Prenatal DEHP exposure significantly decreased spermatogenesis in C57BL/6J (fold-change = 0.6, p-value = 8.7*10-4), but not in FVB/N (fold-change = 1, p-value = 0.9). The number of differentially methylated regions (DMRs) by DEHP-exposure across the entire genome showed increased hyper- and decreased hypo-methylation in C57BL/6J compared to FVB/N. At the promoter level, three important subsets of genes were massively affected. Promoters of vomeronasal and olfactory receptors coding genes globally followed the same trend, more pronounced in the C57BL/6J strain, of being hyper-methylated in DEHP related conditions. In contrast, a large set of micro-RNAs were hypo-methylated, with a trend more pronounced in the FVB/N strain. We additionally analyze both the presence of functional genetic variations within genes that were associated with the detected DMRs and that could be involved in spermatogenesis, and DMRs related with the DEHP exposure that affected both strains in an opposite manner. The major finding in this study indicates that prenatal exposure to DEHP can decrease spermatogenesis in a strain-dependent manner and affects sperm DNA methylation in promoters of large sets of genes putatively involved in both sperm chemotaxis and post-transcriptional regulatory mechanisms.

Childhood sexual and physical abuse: age at exposure modulates impact on functional outcome in early psychosis patients.

BACKGROUND: Evidence suggests a relationship between exposure to trauma during childhood and functional impairments in psychotic patients. However, the impact of age at the time of exposure has been understudied in early psychosis (EP) patients. METHOD: Two hundred and twenty-five patients aged 18-35 years were assessed at baseline and after 2, 6, 18, 24, 30 and 36 months of treatment. Patients exposed to sexual and/or physical abuse (SPA) were classified according to age at the time of first exposure (Early SPA: before age 11 years; Late SPA: between ages 12 and 15 years) and then compared to patients who were not exposed to such trauma (Non-SPA). The functional level in the premorbid phase was measured with the Premorbid Adjustment Scale (PAS) and with the Global Assessment of Functioning (GAF) scale and the Social and Occupational Functioning Assessment Scale (SOFAS) during follow-up. RESULTS: There were 24.8% of patients with a documented history of SPA. Late SPA patients were more likely to be female (p = 0.010). Comparison with non-SPA patients revealed that: (1) both Early and Late SPA groups showed poorer premorbid social functioning during early adolescence, and (2) while patients with Early SPA had poorer functional level at follow-up with lower GAF (p = 0.025) and lower SOFAS (p = 0.048) scores, Late SPA patients did not. CONCLUSION: Our results suggest a link between exposure to SPA and the later impairment of social functioning before the onset of the disease. EP patients exposed to SPA before age 12 may present long-lasting functional impairment, while patients exposed at a later age may improve in this regard and have a better functional outcome.

Lexical Influences on Spoken Spondaic Word Recognition in Hearing-Impaired Patients.

Top-down contextual influences play a major part in speech understanding, especially in hearing-impaired patients with deteriorated auditory input. Those influences are most obvious in difficult listening situations, such as listening to sentences in noise but can also be observed at the word level under more favorable conditions, as in one of the most commonly used tasks in audiology, i.e., repeating isolated words in silence. This study aimed to explore the role of top-down contextual influences and their dependence on lexical factors and patient-specific factors using standard clinical linguistic material. Spondaic word perception was tested in 160 hearing-impaired patients aged 23-88 years with a four-frequency average pure-tone threshold ranging from 21 to 88 dB HL. Sixty spondaic words were randomly presented at a level adjusted to correspond to a speech perception score ranging between 40 and 70% of the performance intensity function obtained using monosyllabic words. Phoneme and whole-word recognition scores were used to calculate two context-influence indices (the j factor and the ratio of word scores to phonemic scores) and were correlated with linguistic factors, such as the phonological neighborhood density and several indices of word occurrence frequencies. Contextual influence was greater for spondaic words than in similar studies using monosyllabic words, with an overall j factor of 2.07 (SD = 0.5). For both indices, context use decreased with increasing hearing loss once the average hearing loss exceeded 55 dB HL. In right-handed patients, significantly greater context influence was observed for words presented in the right ears than for words presented in the left, especially in patients with many years of education. The correlations between raw word scores (and context influence indices) and word occurrence frequencies showed a significant age-dependent effect, with a stronger correlation between perception scores and word occurrence frequencies when the occurrence frequencies were based on the years corresponding to the patients' youth, showing a "historic" word frequency effect. This effect was still observed for patients with few years of formal education, but recent occurrence frequencies based on current word exposure had a stronger influence for those patients, especially for younger ones.

Immunologic work up of subjects who didn't respond appropriately to a rabies post exposure prophylaxis

Background New recommendations for rabies postexposure prophylaxis (rPEP) were published by the Centers for Disease Control and Prevention and the World Health Organization in 2010. In view of these new recommendations, the adequacy of rPEP among patients consulting the travel clinic of the University Hospital of Lausanne has been investigated and 6,8% of patients have been identified as non-responders with the new rPEP regimen. In this study we have selected the non-responders for a complete immunologic work up. Method Clinical and paraclinical immunologic investigations have been done to the non- responders patients. Those investigations have been conducted to look for an increased susceptibility to infections and an immunodeficiency. The investigations included a clinical evaluation, a full blood count, measurement of the immunoglobulin levels, a numeration of the subpopulations of the lymphocytes, a HIV test and an evaluation of the humoral response to tetanus, pneumococcal, and hepatitis B vaccinations. A lymphocyte proliferation assay with rabies antigen was performed to assess the cellular immune response. Results 9 subjects with rabies antibody titers ≤0,5 IU/ml after an rPEP with 4 doses were included in this study (=non-responders). 8/9 of these non-responders had an unremarkable medical history. 9/9 of them had normal paraclinical tests that did not suggest an immunodeficiency. The results of the lymphocyte proliferation assay with rabies antigen showed a significant correlation between the level of the humoral and cellular response. Conclusion These results suggest that a 4 dose intramuscular rPEP elicits in some patients a relatively poor humoral and cellular response, even in the absence of any immunosuppression. A serology on day 21 of the rPEP seems therefore useful to identify the patients who don't respond appropriately. Those non-responders should receive additional doses until they reach an antibody titer above 0.5 IU/ml.

Association between Long-Term Exposure to Traffic-Related Air Pollution and Subclinical Atherosclerosis: The REGICOR Study

Background: Epidemiological evidence of the effects of long-term exposure to air pollu tion on the chronic processes of athero genesis is limited. Objective: We investigated the association of long-term exposure to traffic-related air pollu tion with subclinical atherosclerosis, measured by carotid intima media thickness (IMT) and ankle–brachial index (ABI). Methods: We performed a cross-sectional analysis using data collected during the reexamination (2007–2010) of 2,780 participants in the REGICOR (Registre Gironí del Cor: the Gerona Heart Register) study, a population-based prospective cohort in Girona, Spain. Long-term exposure across residences was calculated as the last 10 years’ time-weighted average of residential nitrogen dioxide (NO2) estimates (based on a local-scale land-use regression model), traffic intensity in the nearest street, and traffic intensity in a 100 m buffer. Associations with IMT and ABI were estimated using linear regression and multinomial logistic regression, respectively, controlling for sex, age, smoking status, education, marital status, and several other potential confounders or intermediates. Results: Exposure contrasts between the 5th and 95th percentiles for NO2 (25 μg/m), traffic intensity in the nearest street (15,000 vehicles/day), and traffic load within 100 m (7,200,000 vehicle-m/day) were associated with differences of 0.56% (95% CI: –1.5, 2.6%), 2.32% (95% CI: 0.48, 4.17%), and 1.91% (95% CI: –0.24, 4.06) percent difference in IMT, respectively. Exposures were positively associated with an ABI of > 1.3, but not an ABI of < 0.9. Stronger associations were observed among those with a high level of education and in men ≥ 60 years of age. Conclusions: Long-term traffic-related exposures were associated with subclinical markers of atherosclerosis. Prospective studies are needed to confirm associations and further examine differences among population subgroups.key words: ankle–brachial index, average daily traffic, cardiovascular disease, exposure assessment, exposure to tailpipe emissions, intima media thickness, land use regression model, Mediterranean diet, nitrogen dioxide

Modeling and Analysis of Noise and Interconnects for On-Chip Communication Link Design

This thesis considers modeling and analysis of noise and interconnects in onchip communication. Besides transistor count and speed, the capabilities of a modern design are often limited by on-chip communication links. These links typically consist of multiple interconnects that run parallel to each other for long distances between functional or memory blocks. Due to the scaling of technology, the interconnects have considerable electrical parasitics that affect their performance, power dissipation and signal integrity. Furthermore, because of electromagnetic coupling, the interconnects in the link need to be considered as an interacting group instead of as isolated signal paths. There is a need for accurate and computationally effective models in the early stages of the chip design process to assess or optimize issues affecting these interconnects. For this purpose, a set of analytical models is developed for on-chip data links in this thesis. First, a model is proposed for modeling crosstalk and intersymbol interference. The model takes into account the effects of inductance, initial states and bit sequences. Intersymbol interference is shown to affect crosstalk voltage and propagation delay depending on bus throughput and the amount of inductance. Next, a model is proposed for the switching current of a coupled bus. The model is combined with an existing model to evaluate power supply noise. The model is then applied to reduce both functional crosstalk and power supply noise caused by a bus as a trade-off with time. The proposed reduction method is shown to be effective in reducing long-range crosstalk noise. The effects of process variation on encoded signaling are then modeled. In encoded signaling, the input signals to a bus are encoded using additional signaling circuitry. The proposed model includes variation in both the signaling circuitry and in the wires to calculate the total delay variation of a bus. The model is applied to study level-encoded dual-rail and 1-of-4 signaling. In addition to regular voltage-mode and encoded voltage-mode signaling, current-mode signaling is a promising technique for global communication. A model for energy dissipation in RLC current-mode signaling is proposed in the thesis. The energy is derived separately for the driver, wire and receiver termination.

Effects of low-level laser therapy on wound healing

OBJECTIVE: To gather and clarify the actual effects of low-level laser therapy on wound healing and its most effective ways of application in human and veterinary medicine.METHODS: We searched original articles published in journals between the years 2000 and 2011, in Spanish, English, French and Portuguese languages, belonging to the following databases: Lilacs, Medline, PubMed and Bireme; Tey should contain the methodological description of the experimental design and parameters used.RESULTS: doses ranging from 3 to 6 J/cm2 appear to be more effective and doses 10 above J/cm2 are associated with deleterious effects. The wavelengths ranging from 632.8 to 1000 nm remain as those that provide more satisfactory results in the wound healing process.CONCLUSION: Low-level laser can be safely applied to accelerate the resolution of cutaneous wounds, although this fact is closely related to the election of parameters such as dose, time of exposure and wavelength.

System-level characterization of Th2 cell development and immune cell responses to ZnO and TiO2 nanoparticles

Asthma and allergy are common diseases and their prevalence is increasing. One of the hypotheses that explains this trend is exposure to inhalable chemicals such as traffi c-related air pollution. Epidemiological research supports this theory, as a correlation between environmental chemicals and allergic respiratory diseases has been found. In addition to ambient airborne particles, one may be exposed to engineered nanosized materials that are actively produced due to their favorable physico-chemical properties compared to their bulk size counterparts. On the cellular level, improper activity of T helper (Th) cells has been connected to allergic reactions. Th cells can differentiate into functionally different effector subsets, which are identifi ed according to their characteristic cytokine profi les resulting in specifi c ability to communicate with other cells. Th2 cells activate humoral immunity and stimulate eradication of extracellular pathogens. However, persistent predominance of Th2 cells is involved in a development of number of allergic diseases. The cytokine environment at the time of antigen recognition is the major factor determining the polarization of a naïve Th cell. Th2 cell differentiation is initiated by IL4, which signals via transcription factor STAT6. Although the importance of this pathway has been evaluated in the mouse studies, the signaling components involved have been largely unknown. The aim of this thesis was to identify molecules, which are under the control of IL4 and STAT6 in Th cells. This was done by using system-level analysis of STAT6 target genes at genome, mRNA and protein level resulting in identifi cation of various genes previously not connected to Th2 cell phenotype acquisition. In the study, STAT6-mediated primary and secondary target genes were dissection from each other and a detailed transcriptional kinetics of Th2 cell polarization of naïve human CD4+ T cells was collected. Integration of these data revealed the hierarchy of molecular events that mediates the differentiation towards Th2 cell phenotype. In addition, the results highlighted the importance of exploiting proteomics tools to complement the studies on STAT6 target genes identifi ed through transcriptional profi ling. In the last subproject, the effects of the exposure with ZnO and TiO2 nanoparticles was analyzed in Jurkat T cell line and in primary human monocyte-derived macrophages and dendritic cells to evaluate their toxicity and potential to cause infl ammation. Identifi cation of ZnO-derived gene expression showed that the same nanoparticles may elicit markedly distinctive responses in different cell types, thus underscoring the need for unbiased profi ling of target genes and pathways affected. The results gave additional proof that the cellular response to nanosized ZnO is due to leached Zn2+ ions. The approach used in ZnO and TiO2 nanoparticle study demonstrated the value of assessing nanoparticle responses through a toxicogenomics approach. The increased knowledge of Th2 cell signaling will hopefully reveal new therapeutic nodes and eventually improve our possibilities to prevent and tackle allergic infl ammatory diseases.

Identification and application of bile metabolites to assess the exposure of fish to pharmaceuticals in the environment

Thousands of tons of pharmaceuticals are consumed yearly worldwide. Due to the continuous and increasing consumption and their incomplete elimination in wastewater treatment plants (WWTP), pharmaceuticals and their metabolites can be detected in receiving waters, although at low concentrations (ng to low μg/L). As bioactive molecules the presence of pharmaceuticals in the aquatic environment must be considered potentially hazardous for the aquatic organisms. In this thesis, the biotransformation and excretion of pharmaceuticals in fish was studied. The main biotransformation pathways of three anti‐inflammatory drugs, diclofenac, naproxen and ibuprofen, in rainbow trout were glucuronidation and taurine conjugation of the parent compounds and their phase I metabolites. The same metabolites were present in fish bile in aquatic exposures as in fish dosed with intraperitoneal injection. Higher bioconcentration factor in bile (BCFbile) was found for ibuprofen when compared to diclofenac and naproxen. Laboratory exposure studies were followed by a study of uptake of pharmaceuticals in a wild fish population living in lake contaminated with WWTP effluents. Of the analyzed 17 pharmaceuticals and six phase I metabolites, only diclofenac, naproxen and ibuprofen was present in bream and roach bile. It was shown, that diclofenac, naproxen and ibuprofen excreted by the liver can be found in rainbow trout and in two native fish species living in the receiving waters. In the bream and roach bile, the concentrations of diclofenac, naproxen and ibuprofen were roughly 1000 times higher than those found in the lake water, while in the laboratory exposures, the bioconcentration of the compounds and their metabolites in rainbow trout bile were at the same level as in wild fish or an order of magnitude higher. Thus, the parent compounds and their metabolites in fish bile can be used as a reliable biomarker to monitor the exposure of fish to environmental pharmaceuticals present in water receiving discharges from WWTPs.

Noise and vibration damping of Fe-Cr-x alloys

The aim of the present work is to study the noise and vibration damping capacity of ferromagnetic Fe-16%Cr base alloys (before and after heat treatment) with different Al and Mo contents. The noise damping was evaluated by the level of sound emission after an impact. The vibration damping was studied using a cantilever device. In addition to these tests, the magnetic structure of the materials was also investigated by Kerr effect. It was verified that the materials can decrease noise level in the frequency range of human earring. The vibration damping is influenced by heat treatment and chemical composition of the alloy. The improvement of vibration damping after heat treatment is ascribed to the decrease of internal stresses in materials and changes in magnetic domain structures.