Hybrid solid-state SPECT/CT left atrial innervation imaging for identification of left atrial ganglionated plexi: Technique and validation in patients with atrial fibrillation.

BACKGROUND: Ablating left atrial (LA) ganglionated plexi (GP), identified invasively by high-frequency stimulation (HFS) during pulmonary vein isolation (PVI), may reduce atrial fibrillation (AF) recurrence. 123I-metaiodobenzylguanidine (123I-mIBG) solid-state SPECT LA innervation imaging (LAII) has the spatial resolution to detect LAGP non-invasively but this has never been demonstrated in clinical practice. METHODS: 20 prospective patients with paroxysmal AF scheduled for PVI underwent 123I-mIBG LAII. High-resolution tomograms, reconstructed where possible using cardiorespiratory gating, were co-registered with pre-PVI cardiac CT. Location and reader confidence (1 [low] to 3 [high]) in discrete 123I-mIBG LA uptake areas (DUAs) were recorded and correlated with HFS. RESULTS: A total of 73 DUAs were identified, of which 59 (81%) were HFS positive (HFS +). HFS + likelihood increased with reader confidence (92% [score 3]). 64% of HFS-negative DUAs occurred over the lateral and inferior LA. Cardiorespiratory gating reduced the number of DUAs per patient (4 vs 7, P = .001) but improved: HFS + predictive value (76% vs 49%); reader confidence (2 vs 1, P = .02); and inter-observer, intra-observer, and inter-study agreement (κ = 0.84 vs 0.68; 0.82 vs 0.74; 0.64 vs 0.53 respectively). CONCLUSIONS: 123I-mIBG SPECT/CT LAII accurately and reproducibly identifies GPs verified by HFS, particularly when reconstructed with cardiorespiratory gating.

Influence of two functional polymorphisms in NOS1 on baseline cortisol and working memory in healthy subjects.

INTRODUCTION: The neuronal isoform of the nitric oxide synthase (NOS-I) encoded by NOS1 is the main source of nitric oxide (NO) in the brain. Reduced NO signaling in the prefrontal cortex has been linked to schizophrenia and cognitive processes while reduced striatal NOS1 expression has been associated with impulsive behavior. METHODS: To evaluate the effect of two functional polymorphisms in alternative first exons of NOS1, ex1f-VNTR and ex1c-SNP rs41279104, on the HPA stress axis and neurocognitive abilities, 280 healthy subjects were genotyped, had their salivary cortisol levels measured and were assessed in verbal memory, verbal fluency, working memory and verbal IQ by using the California Verbal Learning Test (CVLT), the Regensburger test of verbal fluency (RWT), a n-back task and subscales of the Wechsler Adult Intelligence Scale III (WAIS-III). RESULTS: Schizophrenia risk (A)-allele carriers of NOS1 ex1c-SNP rs41279104 displayed significantly lower baseline cortisol levels (p = 0.004). NOS1 ex1f-VNTR genotype carriers showed differences in working memory performance (p = 0.05) in a gene-dose effect manner, with homozygous carriers of the short impulsivity-risk allele committing most commission errors. Finally, A-allele carriers of the NOS1 ex1c-SNP rs41279104 tended to react faster during the working memory task (p = 0.065). CONCLUSION: For the first time, we demonstrated an influence of the NOS1 ex1c-SNP rs41279104 on salivary cortisol levels and additionally implicate the A-allele in an enhanced reaction time during a working memory task. Regarding the NOS1 ex1f-VNTR our study supports the previously reported influence on impulsivity, lending further support to the hypothesis that this genetic variant underlies impulsive behavior.

Rosuvastatin vs. protease inhibitor switching for hypercholesterolaemia: a randomized trial.

OBJECTIVES: The aim of the study was to compare the efficacy and safety of rosuvastatin initiation with those of switching of ritonavir-boosted protease inhibitors (PI/rs) in HIV-1-infected adults with hypercholesterolaemia and increased cardiovascular risk scores. METHODS: In this open-label, multicentre study, HIV-1-infected adults on PI/r-based therapy with viral load < 50 HIV-1 RNA copies/mL, fasting total cholesterol ≥ 5.5 mmol/L (both for ≥ 6 months) and elevated cardiovascular risk (Framingham score ≥ 8% or diabetes or family history), and not on lipid-lowering therapy, were randomized to open-label rosuvastatin 10 mg/day or to PI/r switching, both with standardized diet/exercise advice. The primary endpoint was change in total cholesterol at week 12 (intention to treat). RESULTS: There were 43 participants (23 on rosuvastatin). Baseline characteristics were: mean [± standard deviation (SD)] age 55 (8.5) years, 42 (98%) male, 41 (95%) white race, and mean (± SD) total cholesterol 6.2 (1.2) mmol/L. At enrolment, PI/rs were lopinavir/ritonavir (n = 22; 51%), atazanavir/ritonavir (n = 12; 28%) and darunavir/ritonavir (n = 9; 21%). The commonest PI/r substitutes were raltegravir (n = 9; 45%) and rilpivirine (n = 4; 20%). All participants were adherent through to week 12. Rosuvastatin yielded greater declines than PI/r switching in total (- 21.4% vs. - 8.7%, respectively; P = 0.003) and low-density lipoprotein (- 29.9% vs. - 1.0%, respectively; P < 0.001) cholesterol, but smaller declines in very low-density lipoprotein cholesterol and triglycerides (P < 0.01). Cholesterol lowering was greater in participants on atazanavir/ritonavir or once-daily darunavir/ritonavir (vs. lopinavir/ritonavir). More study drug-related adverse events (mostly grade 1 nausea/diarrhoea; 10 vs. one, respectively; P = 0.001) occurred with PI/r switching than with rosuvastatin. CONCLUSIONS: In adults receiving a PI/r, rosuvastatin 10 mg/day for 12 weeks yielded larger decreases in total and low-density lipoprotein cholesterol than PI/r switching, and was better tolerated.

Optical coherence tomography does not support optic nerve involvement in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: In recent years a possible non-motor involvement of the nervous system in amyotrophic lateral sclerosis (ALS) has come into the focus of research and has been investigated by numerous techniques. Optical coherence tomography (OCT) - with its potential to reveal neuroaxonal retinal damage - may be an appropriate tool to investigate whether the anterior visual pathway is involved. Our aim was to determine whether OCT-based measures of retinal nerve fiber layer, ganglion cell layer, inner nuclear layer and outer nuclear layer thickness are abnormal in ALS, or correlated with disease severity. METHODS: Seventy-six ALS patients (144 eyes) and 54 healthy controls (108 eyes; HCs) were examined with OCT, including automated intraretinal macular segmentation. ALS disease severity was determined with the Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised. RESULTS: There was no significant difference between ALS patients and HCs in any of the examined OCT measures. Moreover, OCT parameters showed no correlation with clinical measures of disease severity. CONCLUSIONS: These findings indicate that involvement of the anterior visual pathway is not one of the non-motor manifestations of ALS.

Distinct eosinophil cytokine expression patterns in skin diseases - the possible existence of functionally different eosinophil subpopulations.

BACKGROUND: The function of eosinophils has been attributed to host defense, immunomodulation, and fibrosis. Although eosinophils are found among infiltrating cells in a broad spectrum of skin diseases, their pathogenic role remains uncertain. This study aimed to analyze the cytokine expression by eosinophils in different skin diseases. METHODS: Skin specimens from different skin diseases [allergic/reactive, infectious, autoimmune, and tumors/lymphomas (LY)] were stained by antibodies directed to eosinophil cationic protein, cytokines [tumor necrosis factor (TNF)-α, interleukin (IL)-5, IL-6, IL-10, IL-11, IL-13, IL-17, IL-25, IL-33, interferon-γ, transforming growth factor (TGF)-ß, and thymic stromal lymphopoietin], eotaxins (CCL11, CCL24, and CCL26), metalloproteinase (MMP)-9 as well as extracellular matrix proteins (tenascin-C and procollagen-3) and then analyzed by laser scanning microscopy. RESULTS: The number of eosinophils varied considerably in and between disease groups and did not correlate with the numbers of accompanying inflammatory cells. The expression of IL-5, IL-6, IL-11, TGF-ß, CCL24, and MMP-9 by eosinophils significantly differed between disease groups. Eosinophils in tumors/LY predominantly expressed IL-6, TGF-ß, and CCL24, but not IL-11. On the other hand, in autoimmune diseases, eosinophils largely contributed to MMP-9 production. IL-5-generating eosinophils were particularly obvious in allergic and infectious diseases. CONCLUSION: In skin diseases, eosinophil expresses a broad spectrum of cytokines. The different cytokine expression patterns suggest distinct functional roles of eosinophils in these diseases that might be related to host defense, immunomodulation, fibrosis, and/or tumor development.

Estimating viral titres in solutions with low viral loads.

An important consideration in the manufacture of products derived from animal or human sources is the virus reduction capacity of the manufacturing process as estimated using validated bench-scale models of relevant manufacturing steps. In these studies, manufacturing process intermediates are spiked with virus and processed using the bench-scale model and the resulting viral titres of input and output samples are typically determined using cell-based infectivity assays. In these assays, the Spearman-Kärber (SK) method is commonly used to estimate titres when there is one or more positive observation (i.e., the presence of any viral cytopathic effect). The SK method is most accurate when the proportion of positive observations ranges from <0.1 to >0.9 across dilutions but can be biased otherwise. Maximum likelihood (ML) based on a single-hit Poisson model is an alternative widely used estimation method. We compared SK with ML and found the methods to have similar properties except for situations in which the concentration of virus is low but measurable. In this case, the SK method produces upwardly biased estimates of titres. Based on our results, we recommend the use of either ML or SK at most virus concentrations; however, at low virus concentrations ML is preferred.

Does the frequency of HIV and STI testing among men who have sex with men in primary care adhere with Australian guidelines?

OBJECTIVES: Australian guidelines recommend annual testing for HIV and sexually transmitted infections (STIs) for all men who have sex with men (MSM) and 3-6 monthly testing for those at higher risk as defined by behavioural criteria. We assessed HIV/STI re-testing rates among MSM attending primary care clinics. METHODS: We conducted a retrospective follow-up of HIV negative MSM tested for HIV or STIs (chlamydia or syphilis) at four primary care clinics in the 9-month period: April to December 2006. Re-testing rates for these infections were calculated over 18 months. Logistic regression was undertaken to identify predictors of guideline adherence. RESULTS: Of the MSM requiring annual HIV testing according to the guidelines, the re-testing rates at 1 y were 35% (762/2163). Among the higher risk MSM, 6-monthly HIV re-testing rates were 15% (283/1862). Within the subgroup who reported 11 or more male sexual partners within the past 6 months, HIV re-testing rates within 6 months were 19%. Independent predictors of HIV re-testing within 6 months in higher-risk MSM were reporting 11 or more male sexual partners in the last 6 months (AOR 3.1, 95% CI 1.8 to 4.8); being born overseas (AOR 2.0, 95% CI 1.2 to 3.4); and previous HIV testing more than 12 months earlier (AOR 3.3, 95% CI 1.9 to 5.5). CONCLUSION: There is poor adherence to national guidelines that recommend regular re-testing of MSM for STIs, particularly among those at higher risk who require more frequent testing. Clinical strategies are urgently needed to encourage more frequent HIV/STI testing among MSM, especially in the higher risk subgroup.

A critical review of frameworks used for evaluating reliability and relevance of (eco)toxicity data: Perspectives for an integrated eco-human decision-making framework.

Considerable efforts have been invested so far to evaluate and rank the quality and relevance of (eco)toxicity data for their use in regulatory risk assessment to assess chemical hazards. Many frameworks have been developed to improve robustness and transparency in the evaluation of reliability and relevance of individual tests, but these frameworks typically focus on either environmental risk assessment (ERA) or human health risk assessment (HHRA), and there is little cross talk between them. There is a need to develop a common approach that would support a more consistent, transparent and robust evaluation and weighting of the evidence across ERA and HHRA. This paper explores the applicability of existing Data Quality Assessment (DQA) frameworks for integrating environmental toxicity hazard data into human health assessments and vice versa. We performed a comparative analysis of the strengths and weaknesses of eleven frameworks for evaluating reliability and/or relevance of toxicity and ecotoxicity hazard data. We found that a frequent shortcoming is the lack of a clear separation between reliability and relevance criteria. A further gaps and needs analysis revealed that none of the reviewed frameworks satisfy the needs of a common eco-human DQA system. Based on our analysis, some key characteristics, perspectives and recommendations are identified and discussed for building a common DQA system as part of a future integrated eco-human decision-making framework. This work lays the basis for developing a common DQA system to support the further development and promotion of Integrated Risk Assessment.

Perspectives for integrating human and environmental exposure assessments.

Integrated Risk Assessment (IRA) has been defined by the EU FP7 HEROIC Coordination action as "the mutual exploitation of Environmental Risk Assessment for Human Health Risk Assessment and vice versa in order to coherently and more efficiently characterize an overall risk to humans and the environment for better informing the risk analysis process" (Wilks et al., 2015). Since exposure assessment and hazard characterization are the pillars of risk assessment, integrating Environmental Exposure assessment (EEA) and Human Exposure assessment (HEA) is a major component of an IRA framework. EEA and HEA typically pursue different targets, protection goals and timeframe. However, human and wildlife species also share the same environment and they similarly inhale air and ingest water and food through often similar overlapping pathways of exposure. Fate models used in EEA and HEA to predict the chemicals distribution among physical and biological media are essentially based on common properties of chemicals, and internal concentration estimations are largely based on inter-species (i.e. biota-to-human) extrapolations. Also, both EEA and HEA are challenged by increasing scientific complexity and resources constraints. Altogether, these points create the need for a better exploitation of all currently existing data, experimental approaches and modeling tools and it is assumed that a more integrated approach of both EEA and HEA may be part of the solution. Based on the outcome of an Expert Workshop on Extrapolations in Integrated Exposure Assessment organized by the HEROIC project in January 2014, this paper identifies perspectives and recommendations to better harmonize and extrapolate exposure assessment data, models and methods between Human Health and Environmental Risk Assessments to support the further development and promotion of the concept of IRA. Ultimately, these recommendations may feed into guidance showing when and how to apply IRA in the regulatory decision-making process for chemicals.

Efficacy of the repellent N,N-diethyl-3-methyl-benzamide (DEET) against tabanid flies on horses evaluated in a field test in Switzerland.

Female tabanid flies (Diptera: Tabanidae) can be a serious nuisance for horses because of their painful bites during blood feeding. They also play a primary role in mechanical transmission of a lentivirus causing Equine Infectious Anemia (EIA), a virus that has spread within Europe in recent years. According to the European law for products intended for use as a repellent on horses (recreational and sport horses), a field test is mandatory to demonstrate sufficient repellency of such a substance against the specific target fly species, but currently no agreed protocols are available for testing of potential repellents. The aim of the present study was to establish a protocol for a field test to investigate the efficacy of N,N-diethyl-3-methyl-benzamide (DEET, Brum®, Huebeli-Stud Horse Care AG) in a 15-17% oil-water emulsion against tabanid flies on horses up to four hours. Between July and August 2015, four horses on three farms each were tested on two consecutive days in a cross-over design. The four horses on Farm A were used in the pre-test as well as in the main test. Two and a half hours after repellent application the horses were lunged until sweating. Tabanid fly infestations were both photographed and directly counted during five minutes 3 and 4h after repellent application on the right side of the horses in the area from the head to the flank, belly and first third of the foreleg. Without repellent application, up to 29 tabanid flies were counted on a horse, whereas the maximum for the repellent treated horses was four. In 50% of the horses treated with DEET there were no Tabanids observed (efficacy 100%), and in all horses the tabanid fly counts were lower than in the control horses with one exemption at 4h. The efficacy of the DEET repellent was at least 80% and 71% respectively, three or four hours after application (with a confidence level of 89%). A fly trap (Horse Pal) revealed the presence of the tabanid species Tabanus brominus and Haematopota pluvialis, but also non-specified arthropods. The design of the present study simulated practical conditions, allowed to quantify the number of tabanids flies and to demonstrate repellency of DEET in horses.

White paper on the promotion of an integrated risk assessment concept in European regulatory frameworks for chemicals.

The vision of a sustainable and safe use of chemicals to protect human health, preserve the environment and maintain the ecosystem requires innovative and more holistic approaches to risk assessment (RA) in order to better inform decision making. Integrated risk assessment (IRA) has been proposed as a solution to current scientific, societal and policy needs. It is defined as the mutual exploitation of environmental risk assessment (ERA) for human health risk assessment (HHRA) and vice versa in order to coherently and more efficiently characterize an overall risk to humans and the environment for better informing the risk analysis process. Extrapolating between species which are relevant for HHRA and ERA requires a detailed understanding of pathways of toxicity/modes of action (MoA) for the various toxicological endpoints. Significant scientific advances, changes in chemical legislation, and increasing environmental consciousness have created a favourable scientific and regulatory environment to develop and promote the concept and vision of IRA. An initial proof of concept is needed to foster the incorporation of IRA approaches into different chemical sectorial regulations and demonstrate their reliability for regulatory purposes. More familiarity and confidence with IRA will ultimately contribute to an overall reduction in in vivo toxicity testing requirements. However, significant progress will only be made if long-term support for MoA-related research is secured. In the short term, further exchange and harmonization of RA terminology, models and methodologies across chemical categories and regulatory agencies will support these efforts. Since societal values, public perceptions and cultural factors are of increasing importance for the acceptance of risk analysis and successful implementation of risk mitigation measures, the integration of socio-economic analysis and socio-behavioural considerations into the risk analysis process may help to produce a more effective risk evaluation and consideration of the risks and benefits associated with the use of chemicals.

Simple convergent-nozzle aerosol injector for single-particle diffractive imaging with X-ray free-electron lasers.

A major challenge in high-resolution x-ray free-electron laser-based coherent diffractive imaging is the development of aerosol injectors that can efficiently deliver particles to the peak intensity of the focused X-ray beam. Here, we consider the use of a simple convergent-orifice nozzle for producing tightly focused beams of particles. Through optical imaging we show that 0.5 µm particles can be focused to a full-width at half maximum diameter of 4.2 µm, and we demonstrate the use of such a nozzle for injecting viruses into a micro-focused soft-X-ray FEL beam.

Effects of cigarette smoking upon frequencies of EEG alpha rhythm and finger tapping.

Under the influence of nicotine, an increase in EEG alpha frequency as well as finger tapping speed has been reported from separate experiments, and it has also been shown that tapping and alpha frequencies may correlate in defined experimental settings. The present study aimed at the analysis of smoking effects using parallel recordings of both EEG and finger tapping. Twelve healthy subjects were tested in two sessions (smoking deprivation versus smoking). After smoking, both dominant alpha frequency (P less than 0.05) and tapping performance (P less than 0.001) were higher than during deprivation. In most subjects, the increase of both parameters developed in parallel, and during phases of very stable tapping the ratio of alpha and tapping frequencies was close to 2:1. Both frequencies correlated during the deprived (r = 0.6108, P = 0.035) as well as the smoking (r = 0.7009, P = 0.011) conditions. Results confirm earlier findings regarding the effect of smoking upon EEG and tapping, and the parallel changes of both parameters may be attributed to the pharmacological properties of nicotine. Besides possible peripheral and spinal effects of nicotine, the increase of tapping performance parallels the increased frequency of central nervous pacemakers.

Smoking deprivation in "early" and "late" smokers and memory functions.

Reports on smoking and nicotine effects upon memory are contradictory: improvement, no change, and impairment have been observed. These inconsistencies may be due at least in part to different types of learning tasks and to experimental designs: in most studies, acute nicotine effects were analysed after previous smoking deprivation. This study compared learning, retention, and retrieval between nonsmoking after previous deprivation and "usual" smoking without previous deprivation. Twenty female smokers (S) participated in two sessions, between 8.00 and 11.00 a.m. The Austin maze and a Word Recognition Task (WRT) were applied. During the WRT, ERP were recorded from Fz and Cz scalp locations. Heart rate, CO, and subjective ratings (dizziness and smoking need) but neither WRT nor maze performance discriminated between deprivation and smoking. However, significant differences were obtained between those Ss who usually start smoking within 1 h after getting up (ES) and those who start later (LS). In maze learning and WRT, LS performed better when deprived than smoking, and ES performed better when smoking than deprived, i.e. when the time of the tests met their usual smoking habits. Results are discussed in terms of a modulation of smoking effects on memory functions by the Ss' internal state.

Early effects of ionizing radiation on the microvascular networks in normal tissue.

Microvascular networks, which control the delivery of oxygen and nutrients and the removal of metabolic waste, are the most sensitive part of the vascular system to ionizing radiation. Structural and functional changes in microvascular networks were studied in locally irradiated (single 10-Gy dose) hamster cremaster muscles observed 3, 7 and 30 days post-irradiation. Networks were selected in reference to a well-defined location in the tissue to reduce heterogeneity due to spatial variations. Intravital microscopy was used to measure structural and functional parameters in vivo. A factorial design was used to examine the effects of radiation status, time postirradiation, and network vessel type on the structure and function of microvascular networks. While the diameter of microvessels in control animals increased significantly with age, vessel diameter in irradiated vessels decreased significantly with age. Red blood cell velocity in irradiated networks at 3 and 30 days postirradiation was significantly lower than in control networks. There was a significant decrease in capillary surface area and a significant increase in vessel hematocrit in irradiated animals. Blood flow in irradiated vessels was significantly lower than in control vessels. Changes in functional parameters were evident at 3 days postirradiation while changes in structural parameters occurred later. All vessel types were not damaged equally by radiation at every time examined.

Pseudoaccommodation and progressive addition lenses.

The limitations of traditional multifocal lenses to replace normal ocular accommodation are well known. The recent development of progressive addition lenses circumvent many of those problems, furnishing smoothly varying power in desired amounts for various distances and allowing freedom from distracting lines. Optical characteristics, screening considerations, prescribing and fitting requirements, and the advantages and limitations of progressive addition lenses are discussed.

A randomized trial of nelfinavir, ritonavir, or delavirdine in combination with saquinavir-SGC and stavudine in treatment-experienced HIV-1-infected patients.

PURPOSE: To evaluate the 24-week impact of saquinavir-enhancing antiretroviral therapy on viral replication in patients previously treated with nucleoside analogues with or without prior saquinavir hard-gel capsules (HGC). METHOD: Patients were randomized in three groups to receive the following: Group 1-nelfinavir (750 mg tid), saquinavir soft-gel capsule (SGC) (800 mg tid), and stavudine (40 mg bid); Group II-ritonavir (400 mg bid), saquinavir-SGC (400 mg bid), and stavudine (40 mg bid); or Group III-delavirdine (400 mg tid), saquinavir-SGC (800 mg tid), and stavudine (40 mg bid). Viral loads, CD4 count, and safety were assessed over a 24-week period with an additional 6-month follow-up. RESULTS: 73 patients received randomized therapy; 14 of whom were SQV naïve, with a median baseline viral load of 3.6 log(10) and a CD4 count of 370 cells/mm(3). By 6 months, the median decreases in plasma viral loads were 0.26, 0.71, and 0.29 log(10) copies/mL for groups I, II, and III, respectively. The median increases in CD4 counts, for groups I, II, and III, were 52, 40, and 69 cells/mm(3) at 6 months, respectively. Changes in viral load and CD4 counts at 6 months and 1 year were not significantly different between the treatment groups. More patients discontinued therapy in the ritonavir arm (35%) for drug intolerance or toxicity compared to either the nelfinavir or delavirdine arms (15% and 5%, respectively). In a multivariate analysis, baseline viral load, younger age, and baseline saquinavir resistance were significantly associated with detectable viral load at 24 weeks. CONCLUSION: The use of antiretroviral agents that pharmacokinetically boost saquinavir levels has a modest benefit in saquinavir-experienced patients.

Increased locomotor activity of rats by self-stimulation in a running wheel.

A method was developed in which the intracranial self-stimulation of rats was dependent on their locomotor activity. During each rotation of a running wheel (= 0.75 m), six stimulus trains were administered via electrodes in the medial forebrain bundle. Under these conditions, animals increased their locomotor activity 112-fold, compared to a control condition without self-stimulation. This method may be a valuable procedure in various research fields where extreme increases in motor activity of laboratory animals are advantageous.