Reversible skeletal abnormalities in gamma-glutamyl transpeptidase-deficient mice.
Gamma-glutamyl transpeptidase (GGT) is a widely distributed ectopeptidase responsible for the degradation of glutathione in the gamma-glutamyl cycle. This cycle is implicated in the metabolism of cysteine, and absence of GGT causes a severe intracellular decrease in this amino acid. GGT-deficient (GGT-/-) mice have multiple metabolic abnormalities and are dwarf. We show here that this latter phenotype is due to a decreased of the growth plate cartilage total height resulting from a proliferative defect of chondrocytes. In addition, analysis of vertebrae and tibiae of GGT-/- mice revealed a severe osteopenia. Histomorphometric studies showed that this low bone mass phenotype results from an increased osteoclast number and activity as well as from a marked decrease in osteoblast activity. Interestingly, neither osteoblasts, osteoclasts, nor chondrocytes express GGT, suggesting that the observed defects are secondary to other abnormalities. N-acetylcysteine supplementation has been shown to reverse the metabolic abnormalities of the GGT-/- mice and in particular to restore the level of IGF-1 and sex steroids in these mice. Consistent with these previous observations, N-acetylcysteine treatment of GGT-/- mice ameliorates their skeletal abnormalities by normalizing chondrocytes proliferation and osteoblastic function. In contrast, resorbtion parameters are only partially normalized in GGT-/- N-acetylcysteine-treated mice, suggesting that GGT regulates osteoclast biology at least partly independently of these hormones. These results establish the importance of cysteine metabolism for the regulation of bone remodeling and longitudinal growth.


Integrating motion information across sensory modalities: the role of top-down factors.
Recent studies have highlighted the influence of multisensory integration mechanisms in the processing of motion information. One central issue in this research area concerns the extent to which the behavioral correlates of these effects can be attributed to late post-perceptual (i.e., response-related or decisional) processes rather than to perceptual mechanisms of multisensory binding. We investigated the influence of various top-down factors on the phenomenon of crossmodal dynamic capture, whereby the direction of motion in one sensory modality (audition) is strongly influenced by motion presented in another sensory modality (vision). In Experiment 1, we introduced extensive feedback in order to manipulate the motivation level of participants and the extent of their practice with the task. In Experiment 2, we reduced the variability of the irrelevant (visual) distractor stimulus by making its direction predictable beforehand. In Experiment 3, we investigated the effects of changing the stimulus-response mapping (task). None of these manipulations exerted any noticeable influence on the overall pattern of crossmodal dynamic capture that was observed. We therefore conclude that the integration of multisensory motion cues is robust to a number of top-down influences, thereby revealing that the crossmodal dynamic capture effect reflects the relatively automatic integration of multisensory motion information.


The Immediate Aesthetic and Functional Restoration of Maxillary Incisors Compromised by Periodontitis Using Short Implants with Single Crown Restorations: A Minimally Invasive Approach and Five-Year Follow-Up.
The functional and aesthetic restoration of teeth compromised due to aggressive periodontitis presents numerous challenges for the clinician. Horizontal bone loss and soft tissue destruction resulting from periodontitis can impede implant placement and the regeneration of an aesthetically pleasing gingival smile line, often requiring bone augmentation and mucogingival surgery, respectively. Conservative approaches to the treatment of aggressive periodontitis (i.e., treatments that use minimally invasive tools and techniques) have been purported to yield positive outcomes. Here, we report on the treatment and five-year follow-up of patient suffering from aggressive periodontitis using a minimally invasive surgical technique and implant system. By using the methods described herein, we were able to achieve the immediate aesthetic and functional restoration of the maxillary incisors in a case that would otherwise require bone augmentation and extensive mucogingival surgery. This technique represents a conservative and efficacious alternative to the aesthetic and functional replacement of teeth compromised due to aggressive periodontitis.


Ethambutol Partitioning in Tuberculous Pulmonary Lesions Explains Its Clinical Efficacy.
Clinical trials and practice have shown that ethambutol is an important component of the first-line tuberculosis (TB) regime. This contrasts the drug's rather modest potency and lack of activity against nongrowing persister mycobacteria. The standard plasma-based pharmacokinetic-pharmacodynamic profile of ethambutol suggests that the drug may be of limited clinical value. Here, we hypothesized that this apparent contradiction may be explained by favorable penetration of the drug into TB lesions. First, we utilized novel in vitro lesion pharmacokinetic assays and predicted good penetration of the drug into lesions. We then employed mass spectrometry imaging and laser capture microdissection coupled to liquid chromatography and tandem mass spectrometry (LCM and LC/MS-MS, respectively) to show that ethambutol, indeed, accumulates in diseased tissues and penetrates the major human-like lesion types represented in the rabbit model of TB disease with a lesion-to-plasma exposure ratio ranging from 9 to 12. In addition, ethambutol exhibits slow but sustained passive diffusion into caseum to reach concentrations markedly higher than those measured in plasma at steady state. The results explain why ethambutol has retained its place in the first-line regimen, validate our in vitro lesion penetration assays, and demonstrate the critical importance of effective lesion penetration for anti-TB drugs. Our findings suggest that in vitro and in vivo lesion penetration evaluation should be included in TB drug discovery programs. Finally, this is the first time that LCM with LC-MS/MS has been used to quantify a small molecule at high spatial resolution in infected tissues, a method that can easily be extended to other infectious diseases.


Causing harm and allowing harm: a study of beliefs in obsessional problems.
This study investigates two factors hypothesised as relevant to obsessional problems because of the way in which they influence decisions whether or not to act to prevent harm. These are (i) the way in which intrusive thoughts increase the internal awareness of harm, and confront the person with the possibility of taking action to prevent such harm and (ii) the extent to which there is some obvious external factor which increases awareness of the possibility of preventing harm. Obsessional patients, anxious and non-clinical controls completed a scale which systematically measured these factors across a wide range of situations. Results across all situations evaluated confirmed previous findings that both obsessionals and nonobsessionals were more likely to report acting to prevent harm when awareness of it is prompted by an intrusion than when it is not. It was also found that participants in all groups acted more 'obsessionally' when a scenario is described in ways which suggest that harm may be by 'commission' than when it is described in terms of an 'omission'. When scenarios about which each individual is most disturbed were analysed, anxious and non-clinical controls continued to differentially rate omission and commission situations; as predicted, this differential was not present for obsessional patients. It is concluded that obsessionals are more sensitive to omission than are nonobsessionals when considering scenarios about which they are concerned, and that this sensitivity is one factor influencing the decision whether to act to prevent harm.


Mitochondrial and nuclear genes-based phylogeography of Arvicanthis niloticus (Murinae) and sub-Saharan open habitats pleistocene history.
A phylogeographic study was conducted on the Nile grass rat, Arvicanthis niloticus, a rodent species that is tightly associated with open grasslands from the Sudano-Sahelian regions. Using one mitochondrial (cytochrome b) and one nuclear (intron 7 of Beta Fibrinogen) gene, robust patterns were retrieved that clearly show that (i) the species originated in East Africa concomitantly with expanding grasslands some 2 Ma, and (ii) four parapatric and genetically well-defined lineages differentiated essentially from East to West following Pleistocene bioclimatic cycles. This strongly points towards allopatric genetic divergence within savannah refuges during humid episodes, then dispersal during arid ones; secondary contact zones would have then stabilized around geographic barriers, namely, Niger River and Lake Chad basins. Our results pertinently add to those obtained for several other African rodent as well as non-rodent species that inhabit forests, humid zones, savannahs and deserts, all studies that now allow one to depict a more comprehensive picture of the Pleistocene history of the continent south of the Sahara. In particular, although their precise location remains to be determined, at least three Pleistocene refuges are identified within the West and Central African savannah biome.


A narrative analysis positioning HIV relative to personal (sexual) relationship challenges in an agony aunt column in the Western Cape, South Africa - Aunty Mona's "love advice".
HIV prevalence and incidence in South Africa remain high, making HIV a part of everyday life. Community narratives on HIV treatment and prevention are important and influence official and unofficial health messaging and community perceptions and understandings of HIV. We explore how contributors and the columnist of an agony aunt column position HIV relative to choices made about love, partnership, and sex over three years. We analysed all columns of an agony aunt series (Antie Mona) published between December 2012 and November 2015. The column is published in a South African, Afrikaans-language newspaper "Son", prioritising sensationalist news items. Trends were identified through narrative analysis. Data were managed in ATLAS.ti and inductive, iterative coding conducted. It was found that letters to the agony aunt rarely refer to HIV directly (less than 7%). Euphemisms such as diseases of the flesh and the great flu were more commonly used instead of HIV or AIDS. Letters addressed HIV in three ways: direct references to experiences living with HIV; direct questions about HIV prevention; and scenarios where HIV could (from a public health perspective) have been the main concern, but everyday issues took precedence. The majority of letters fell into this latter category where the writers focused on the immediate concerns of good sexual relations, problems related to love and romantic relationships, good moral behaviour of others, and issues of oppressive life conditions rather than on HIV directly. The findings illustrate that informal, public contributions to health information, such as agony aunts, are important narratives that inform popular perspectives on HIV and health. A better appreciation of this context would allow health implementers to ensure that these role players receive updated health messaging to avoid the risk of HIV-related stigma where HIV is used as a moral rod to punish perceived moral transgressions.


Biomechanical Role of Bone Anisotropy Estimated on Clinical CT Scans by Image Registration.
Image-based modeling is a popular approach to perform patient-specific biomechanical simulations. Accurate modeling is critical for orthopedic application to evaluate implant design and surgical planning. It has been shown that bone strength can be estimated from the bone mineral density (BMD) and trabecular bone architecture. However, these findings cannot be directly and fully transferred to patient-specific modeling since only BMD can be derived from clinical CT. Therefore, the objective of this study was to propose a method to predict the trabecular bone structure using a µCT atlas and an image registration technique. The approach has been evaluated on femurs and patellae under physiological loading. The displacement and ultimate force for femurs loaded in stance position were predicted with an error of 2.5% and 3.7%, respectively, while predictions obtained with an isotropic material resulted in errors of 7.3% and 6.9%. Similar results were obtained for the patella, where the strain predicted using the registration approach resulted in an improved mean squared error compared to the isotropic model. We conclude that the registration of anisotropic information from of a single template bone enables more accurate patient-specific simulations from clinical image datasets than isotropic model.


Synthesis, structural characterization, VHPO mimicking peroxidative bromination and DNA nuclease activity of oxovanadium(V) complexes.
The two novel oxovanadium(V) complexes [VO(PyDC)(BHA)] (1) [PyDC = pyridine-2,6-dicarboxylate, BHA = benzohydroxamate] and [VO(PyDC)(BPHA)] (2) [BPHA = benzophenyl hydroxamate] were synthesized by successive addition of a methanolic solution of H2PyDC and the corresponding hydroxamic acid ligand to the aqueous solution of ammonium metavanadate (NH4VO3). The hydroxamic acid ligands were characterized by elemental analysis, IR, UV-vis and NMR studies whereas the complexes were characterized by IR, UV-vis, CHN, molar conductance, magnetic moment, mass and NMR spectroscopic methods. The structures of the complexes were determined by single crystal X-ray crystallography. The structures of both complexes reveal that vanadium(V) has distorted octahedral geometry. The bromoperoxidase activities of these complexes have been demonstrated through the activation of C-H bonds of phenol, o-cresol and p-cresol. The catalytic products have been characterized by GC-MS analysis which shows that good conversions have been achieved. So far as the catalytic efficiency of the complexes are concerned complex 2 is found to be superior to complex 1. Both the complexes were tested for DNA nuclease activity with pUC19 plasmid DNA. The results show that both of them exhibited nuclease activity against pUC19 circular plasmid DNA. The complexes produced both nicked coils and linear forms. In this case also it is observed that complex 2 shows better nuclease activity than complex 1.


Final report of the Cosmetic Ingredient Review Expert Panel safety assessment of polymethyl methacrylate (PMMA), methyl methacrylate crosspolymer, and methyl methacrylate/glycol dimethacrylate crosspolymer.
Polymethyl methacrylate (PMMA) and related cosmetic ingredients methyl methacrylate crosspolymer and methyl methacrylate/glycol dimethacrylate crosspolymer are polymers that function as film formers and viscosity-increasing agents in cosmetics. The Food and Drug Administration (FDA) determination of safety of PMMA use in several medical devices, which included human and animal safety data, was used as the basis of safety of PMMA and related polymers in cosmetics by the Cosmetic Ingredient Review (CIR) Expert Panel. The PMMA used in cosmetics is substantially the same as in medical devices. The Panel concluded that these ingredients are safe as cosmetic ingredients in the practices of use and concentrations as described in this safety assessment.


Differential changes in dopamine D2- and D1-receptor mRNA levels induced by hypoxia in the arterial chemoreflex pathway organs in one-day-old and adult rabbits.
This study determined: (1) whether dopamine (DA) D2-receptor (R) and D1-R mRNA levels in the carotid body (CB), petrosal ganglion (PG) and superior cervical ganglion (SCG) are modulated by hypoxia; (2) the role of hypoxia intensity and exposure duration, and (3) whether the pattern of modulation differs between newborn (1-day-old) and adult rabbits. Rabbits were exposed to five FiO2 conditions: 21% (control); 15%/6 h; 15%/24 h; 8%/6 h and 8%/24 h. D2- and D1-R mRNA expression levels were calculated for each hypoxia condition relative to control using RT-PCR analysis. In the CB of 1-day-old rabbits, D2- and D1-R transcript levels increased and decreased after exposure to 15 and 8% O2, respectively. In the adult CB, D2- and D1-R transcript levels decreased independently of hypoxia intensities. Only changes in D1-R mRNA levels were dependent on exposure time. In the PG, both hypoxia intensities decreased the D2-R transcript levels in 1-day-old and adult rabbits; but for the D1-R mRNA levels, hypoxia decreased its level in 1-day-old rabbits and increased it in adults regardless of exposure duration. In the SCG, hypoxia had no determinant effect on the D2-R mRNA levels either in newborn or adult rabbits while it induced a decrease of D1-R transcript levels in 1-day-old rabbits and an increase in adult rabbits. It is concluded that hypoxia affects DA D2- or D1-R mRNA levels in the chemoreflex pathway in an age-dependent and site-specific manner.


Research review: reading comprehension in developmental disorders of language and communication.
Deficits in reading airment (SLI), Down syndrome (DS) and autism spectrum disorders (ASD). In this review (based on a search of the ISI Web of Knowledge database to 2011), the Simple View of Reading is used as a framework for considering reading comprehension in these groups. There is substantial evidence for reading comprehension impairments in SLI and growing evidence that weaknesses in this domain are common in DS and ASD. Further, in these groups reading comprehension is typically more impaired than word recognition. However, there is also evidence that some children and adolescents with DS, ASD and a history of SLI develop reading comprehension and word recognition skills at or above the age appropriate level. This review of the literature indicates that factors including word recognition, oral language, nonverbal ability and working memory may explain reading comprehension difficulties in SLI, DS and ASD. In addition, it highlights methodological issues, implications of poor reading comprehension and fruitful areas for future research.


Association of transient ischemic attack/stroke symptoms assessed by standardized questionnaire and algorithm with cerebrovascular risk factors and carotid artery wall thickness. The ARIC Study, 1987-1989.
The baseline examination (1987-1989) for the Atherosclerosis Risk in Communities (ARIC) Study was conducted in 15,792 free-living residents aged 45-64 years in four geographically dispersed US communities. A questionnaire on symptoms of transient ischemic attack (TIA) and stroke was evaluated by computer algorithm for 12,205 of these participants. Data were also collected on lipoprotein levels, hemostasis, hematology, anthropometry, blood pressure, medical history, lifestyle, socioeconomic status, and medication use. Noninvasive high resolution B-mode ultrasonographic imaging was used to determine carotid arterial intimal-medial wall thickness (IMT). The cross-sectional relation between the prevalence of TIA/stroke symptoms and putative risk factors was assessed by logistic regression, controlling for age and community. Odds ratios for TIA/stroke symptoms were significantly elevated (p < or = 0.01) for diabetes mellitus, current smoking, hypertension, lower levels of education, income, and work activity, and higher levels of lipoprotein(a), IMT, hemostasis factor VIII, and von Willebrand factor. However, the relations with education and carotid IMT were not present for black Americans. In whites, the relations of TIA/stroke symptoms to IMT were nonlinear. Only at extreme levels of IMT were symptoms substantially more frequent: For example, men with an IMT greater than 1.17 mm or women with an IMT greater than 0.85 mm had approximately twice the odds of having positive TIA/stroke symptoms as those with lower IMTs. The authors plan in future analyses to address the issue prospectively, as well as to examine the relation with magnetic resonance imaging-defined outcomes and clinically defined incident stroke.


Predicting adenocarcinoma recurrence using computational texture models of nodule components in lung CT.
To investigate the importance of presurgical computed tomography (CT) intensity and texture information from ground-glass opacities (GGO) and solid nodule components for the prediction of adenocarcinoma recurrence. For this study, 101 patients with surgically resected stage I adenocarcinoma were selected. During the follow-up period, 17 patients had disease recurrence with six associated cancer-related deaths. GGO and solid tumor components were delineated on presurgical CT scans by a radiologist. Computational texture models of GGO and solid regions were built using linear combinations of steerable Riesz wavelets learned with linear support vector machines (SVMs). Unlike other traditional texture attributes, the proposed texture models are designed to encode local image scales and directions that are specific to GGO and solid tissue. The responses of the locally steered models were used as texture attributes and compared to the responses of unaligned Riesz wavelets. The texture attributes were combined with CT intensities to predict tumor recurrence and patient hazard according to disease-free survival (DFS) time. Two families of predictive models were compared: LASSO and SVMs, and their survival counterparts: Cox-LASSO and survival SVMs. The best-performing predictive model of patient hazard was associated with a concordance index (C-index) of 0.81 ± 0.02 and was based on the combination of the steered models and CT intensities with survival SVMs. The same feature group and the LASSO model yielded the highest area under the receiver operating characteristic curve (AUC) of 0.8 ± 0.01 for predicting tumor recurrence, although no statistically significant difference was found when compared to using intensity features solely. For all models, the performance was found to be significantly higher when image attributes were based on the solid components solely versus using the entire tumors (p < 3.08 × 10(-5)). This study constitutes a novel perspective on how to interpret imaging information from CT examinations by suggesting that most of the information related to adenocarcinoma aggressiveness is related to the intensity and morphological properties of solid components of the tumor. The prediction of adenocarcinoma relapse was found to have low specificity but very high sensitivity. Our results could be useful in clinical practice to identify patients for which no recurrence is expected with a very high confidence using a presurgical CT scan only. It also provided an accurate estimation of the risk of recurrence after a given duration t from surgical resection (i.e., C-index = 0.81 ± 0.02).


Ad Hoc Modeling of Root Zone Soil Water with Landsat Imagery and Terrain and Soils Data.
Agricultural producers require knowledge of soil water at plant rooting depths,while many remote sensing studies have focused on surface soil water or mechanisticmodels that are not easily parameterized. We developed site-specific empirical models topredict spring soil water content for two Montana ranches. Calibration data sample sizeswere based on the estimated variability of soil water and the desired level of precision forthe soil water estimates. Models used Landsat imagery, a digital elevation model, and asoil survey as predictor variables. Our objectives were to see whether soil water could bepredicted accurately with easily obtainable calibration data and predictor variables and toconsider the relative influence of the three sources of predictor variables. Independentvalidation showed that multiple regression models predicted soil water with average error(RMSD) within 0.04 mass water content. This was similar to the accuracy expected basedon a statistical power test based on our sample size (n = 41 and n = 50). Improvedprediction precision could be achieved with additional calibration samples, and rangemanagers can readily balance the desired level of precision with the amount of effort tocollect calibration data. Spring soil water prediction effectively utilized a combination ofland surface imagery, terrain data, and subsurface soil characterization data. Rancherscould use accurate spring soil water content predictions to set stocking rates. Suchmanagement can help ensure that water, soil, and vegetation resources are usedconservatively in irrigated and non-irrigated rangeland systems.


Chromosomal scale assembly of parasitic wasp genome reveals symbiotic virus colonization.
Endogenous viruses form an important proportion of eukaryote genomes and a source of novel functions. How large DNA viruses integrated into a genome evolve when they confer a benefit to their host, however, remains unknown. Bracoviruses are essential for the parasitism success of parasitoid wasps, into whose genomes they integrated ~103 million years ago. Here we show, from the assembly of a parasitoid wasp genome at a chromosomal scale, that bracovirus genes colonized all ten chromosomes of Cotesia congregata. Most form clusters of genes involved in particle production or parasitism success. Genomic comparison with another wasp, Microplitis demolitor, revealed that these clusters were already established ~53 mya and thus belong to remarkably stable genomic structures, the architectures of which are evolutionary constrained. Transcriptomic analyses highlight temporal synchronization of viral gene expression without resulting in immune gene induction, suggesting that no conflicts remain between ancient symbiotic partners when benefits to them converge.


Genetic influences on cost-efficient organization of human cortical functional networks.
The human cerebral cortex is a complex network of functionally specialized regions interconnected by axonal fibers, but the organizational principles underlying cortical connectivity remain unknown. Here, we report evidence that one such principle for functional cortical networks involves finding a balance between maximizing communication efficiency and minimizing connection cost, referred to as optimization of network cost-efficiency. We measured spontaneous fluctuations of the blood oxygenation level-dependent signal using functional magnetic resonance imaging in healthy monozygotic (16 pairs) and dizygotic (13 pairs) twins and characterized cost-efficient properties of brain network functional connectivity between 1041 distinct cortical regions. At the global network level, 60% of the interindividual variance in cost-efficiency of cortical functional networks was attributable to additive genetic effects. Regionally, significant genetic effects were observed throughout the cortex in a largely bilateral pattern, including bilateral posterior cingulate and medial prefrontal cortices, dorsolateral prefrontal and superior parietal cortices, and lateral temporal and inferomedial occipital regions. Genetic effects were stronger for cost-efficiency than for other metrics considered, and were more clearly significant in functional networks operating in the 0.09-0.18 Hz frequency interval than at higher or lower frequencies. These findings are consistent with the hypothesis that brain networks evolved to satisfy competitive selection criteria of maximizing efficiency and minimizing cost, and that optimization of network cost-efficiency represents an important principle for the brain's functional organization.


Clay-based nanocomposite coating for flexible optoelectronics applying commercial polymers.
Transparency, flexibility, and especially ultralow oxygen (OTR) and water vapor (WVTR) transmission rates are the key issues to be addressed for packaging of flexible organic photovoltaics and organic light-emitting diodes. Concomitant optimization of all essential features is still a big challenge. Here we present a thin (1.5 μm), highly transparent, and at the same time flexible nanocomposite coating with an exceptionally low OTR and WVTR (1.0 × 10(-2) cm(3) m(-2) day(-1) bar(-1) and <0.05 g m(-2) day(-1) at 50% RH, respectively). A commercially available polyurethane (Desmodur N 3600 and Desmophen 670 BA, Bayer MaterialScience AG) was filled with a delaminated synthetic layered silicate exhibiting huge aspect ratios of about 25,000. Functional films were prepared by simple doctor-blading a suspension of the matrix and the organophilized clay. This preparation procedure is technically benign, is easy to scale up, and may readily be applied for encapsulation of sensitive flexible electronics.


Microspatial population genetic structure of the Mediterranean shrub Fumana thymifolia.
Fumana thymifolia (Cistaceae) is an insect-pollinated, gravity-dispersed evergreen shrub, which is a common component of fire-prone Mediterranean shrubland ecosystems. Despite the availability of basic knowledge on its ecology, little is known of its breeding system and no information is available on its population genetic structure. We explored the within-population genetic structure of this species using amplified fragment length polymorphism (AFLP) molecular markers and related this to predictions based on its breeding system, pollen and seed dispersal. Existing information on the reproductive ecology of F. thymifolia was supplemented by artificial pollination experiments. We determined that self-fertilisation can occur in F. thymifolia but results in reduced fruit set. Significant genetic structuring was detected within the population, a likely consequence of localised seed dispersal in combination with a mixed mating system. In a study site covering approximately 0.5 ha, amova revealed that approximately 9% of genetic variability was distributed among population subsamples. Significant spatial genetic structure was detected, with kinship coefficients being significantly elevated above the null expectation in the first six distance classes (maximum 5 m), and a value of Sp of up to 0.0342, comparable with species having similar ecological characteristics. Weak isolation by distance at the plot scale was detected, suggesting that insect-mediated pollen flow is non-random, despite being more extensive than seed dispersal. Fumana thymifolia provides a promising model for the investigation of both short- and long-term population dynamics in relation to fire frequency within this plant community.


Dietary recommendations for prevention of atherosclerosis.
This review aims at summarizing updated evidence on cardiovascular disease (CVD) risk associated with consumption of specific food items to substantiate dietary strategies for atherosclerosis prevention. A systematic search on PubMed was performed to identify meta-analyses of cohort studies and RCTs with CVD outcomes. The evidence is highly concordant in showing that, for the healthy adult population, low consumption of salt and foods of animal origin, and increased intake of plant-based foods-whole grains, fruits, vegetables, legumes, and nuts-are linked with reduced atherosclerosis risk. The same applies for the replacement of butter and other animal/tropical fats with olive oil and other unsaturated-fat-rich oil. Although the literature reviewed overall endorses scientific society dietary recommendations, some relevant novelties emerge. With regard to meat, new evidence differentiates processed and red meat-both associated with increased CVD risk-from poultry, showing a neutral relationship with CVD for moderate intakes. Moreover, the preferential use of low-fat dairies in the healthy population is not supported by recent data, since both full-fat and low-fat dairies, in moderate amounts and in the context of a balanced diet, are not associated with increased CVD risk; furthermore, small quantities of cheese and regular yogurt consumption are even linked with a protective effect. Among other animal protein sources, moderate fish consumption is also supported by the latest evidence, although there might be sustainability concerns. New data endorse the replacement of most high glycemic index (GI) foods with both whole grain and low GI cereal foods. As for beverages, low consumption not only of alcohol, but also of coffee and tea is associated with a reduced atherosclerosis risk while soft drinks show a direct relationship with CVD risk. This review provides evidence-based support for promoting appropriate food choices for atherosclerosis prevention in the general population.


The Blk pathway functions as a tumor suppressor in chronic myeloid leukemia stem cells.
A therapeutic strategy for treating cancer is to target and eradicate cancer stem cells (CSCs) without harming their normal stem cell counterparts. The success of this approach relies on the identification of molecular pathways that selectively regulate CSC function. Using BCR-ABL-induced chronic myeloid leukemia (CML) as a disease model for CSCs, we show that BCR-ABL downregulates the Blk gene (encoding B-lymphoid kinase) through c-Myc in leukemic stem cells (LSCs) in CML mice and that Blk functions as a tumor suppressor in LSCs but does not affect normal hematopoietic stem cells (HSCs) or hematopoiesis. Blk suppresses LSC function through a pathway involving an upstream regulator, Pax5, and a downstream effector, p27. Inhibition of this Blk pathway accelerates CML development, whereas increased activity of the Blk pathway delays CML development. Blk also suppresses the proliferation of human CML stem cells. Our results show the feasibility of selectively targeting LSCs, an approach that should be applicable to other cancers.


Comparison of inducible nitric oxide synthase gene expression and lung inflammation following intratracheal instillation of silica, coal, carbonyl iron, or titanium dioxide in rats.
The pulmonary toxicity of the respirable dusts silica, coal, carbonyl iron, and titanium dioxide on alveolar macrophage (AM) and neutrophil (PMN) inducible nitric oxide synthase (iNOS) gene expression and nitric oxide (NO) production was investigated. Rats were intratracheally instilled with 5 mg/100 g body weight of silica, coal, carbonyl iron, or titanium dioxide. The dust particles averaged less than 5 microns in diameter. Bronchoalveolar lavage was performed 24 h later. Bronchoalveolar lavage cell (BALC) differentials, iNOS gene expression and NO production by BALC (measured indirectly as NO-dependent chemiluminescence), and lavageable lung protein levels were measured. Analyzed on an equal mass basis, silica, coal, and titanium dioxide dusts increased the production of iNOS-dependent NO by AM. Silica and titanium dioxide both increased the levels of iNOS mRNA while carbonyl iron and coal did not. Each dust caused an increase in PMN, indicating an inflammatory response. Carbonyl iron and titanium dioxide decreased the numbers of AM. Levels of acellular lavageable lung protein were increased by silica, carbonyl iron, and titanium dioxide. When exposure was normalized for an equal number of particles, the pneumotoxic dusts, silica and coal, caused more inflammation and NO production than the nuisance dusts, carbonyl iron and titanium dioxide. Therefore, it appears that particle number is a more appropriate metric of exposure than mass when comparing the relative pathogenicity of dusts of different sizes. Furthermore, since the potency of these dusts (on a particle number basis) to increase iNOS gene expression reflects their inflammatory and pathogenic potential, it is proposed that NO may contribute to the early inflammatory damage observed in the lung following dust exposure.


UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia.
The Philadelphia chromosome positive arm of the UKALLXII/ECOG2993 study for adult acute lymphoblastic leukemia (ALL) enrolled 266 patients between 1993 and 2003 (pre-imatinib cohort). In 2003 imatinib was introduced as a single-agent course following induction (N = 86, late imatinib). In 2005 imatinib was added to the second phase of induction (N = 89, early imatinib). The complete remission (CR) rate was 92% in the imatinib cohort vs 82% in the preimatinib cohort (P = .004). At 4 years, the overall survival (OS) of all patients in the imatinib cohort was 38% vs 22% in the preimatinib cohort (P = .003). The magnitude of the difference between the preimatinib and imatinib cohorts in event-free survival (EFS), OS, and relapse-free survival (RFS) seen in univariate analysis was even greater in the multivariate analysis. In the preimatinib cohort, 31% of those starting treatment achieved hematopoietic stem cell transplant (alloHSCT) compared with 46% in the imatinib cohort. A Cox multivariate analysis taking alloHSCT into account showed a modest additional benefit to imatinib (hazard ratio for EFS = 0.64, 95% confidence interval 0.44-0.93, P = .02), but no significant benefit for OS and RFS. Adding imatinib to standard therapy improves CR rate and long-term OS for adults with ALL. A proportion of the OS benefit derives from the fact that imatinib facilitates alloHSCT. This trial was registered at clinicaltrials.gov as NCT00002514.


Long-Term Specialized Physical Therapy in Cervical Dystonia: Outcomes of a Randomized Controlled Trial.
To evaluate the effectiveness of a specialized physical therapy (SPT) program on disability in cervical dystonia (CD) compared to regular physical therapy (RPT). A single-blinded randomized controlled trial. This study was performed by a physical therapist in a primary health care setting. Measurements were performed at baseline, 6 and 12 months in the botulinum toxin (BoNT) outpatient clinic of the neurology department. Patients with primary CD and stable on BoNT treatment for 1 year (N=96). The primary outcome was disability assessed with the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). Secondary outcomes were pain, anxiety, depression, quality of life (QOL), and health related costs over 12 months. A total of 72 participants (30 men, 42 women) finished the study: 40 received SPT, 32 RPT. No significant between group differences were found after 12 months of treatment (P=.326). Over these 12 months both groups improved significantly (P<.001) on the TWSTRS disability scale compared to baseline (SPT 1.7 points, RPT 1.0 points). Short Form 36 (SF-36) General Health Perceptions (P=.046) and self-perceived improvement (P=.007) showed significantly larger improvements after 12 months in favor of SPT. Total health related costs after 12 months were $1373±556 for SPT compared to $1614±917 for RPT. SPT revealed no significant differences compared to RPT after 12 months of treatment on the TWSTRS disability scale. Both groups showed similar improvements compared to baseline. Positive results in the SPT group were higher patient perceived effects and general health perception. Treatment costs were lower in the SPT group. With lower costs and similar effects, the SPT program seems to be the preferred program to treat CD.


Functional and molecular evidence for expression of the renin angiotensin system and ADAM17-mediated ACE2 shedding in COS7 cells.
The renin angiotensin system (RAS) plays a vital role in the regulation of the cardiovascular and renal functions. COS7 is a robust and easily transfectable cell line derived from the kidney of the African green monkey, Cercopithecus aethiops. The aims of this study were to 1) demonstrate the presence of an endogenous and functional RAS in COS7, and 2) investigate the role of a disintegrin and metalloproteinase-17 (ADAM17) in the ectodomain shedding of angiotensin converting enzyme-2 (ACE2). Reverse transcription coupled to gene-specific polymerase chain reaction demonstrated expression of ACE, ACE2, angiotensin II type 1 receptor (AT1R), and renin at the transcript levels in total RNA cell extracts. Western blot and immunohistochemistry identified ACE (60 kDa), ACE2 (75 kDa), AT1R (43 kDa), renin (41 kDa), and ADAM17 (130 kDa) in COS7. At the functional level, a sensitive and selective mass spectrometric approach detected endogenous renin, ACE, and ACE2 activities. ANG-(1-7) formation (m/z 899) from the natural substrate ANG II (m/z 1,046) was detected in lysates and media. COS7 cells stably expressing shRNA constructs directed against endogenous ADAM17 showed reduced ACE2 shedding into the media. This is the first study demonstrating endogenous expression of the RAS and ADAM17 in the widely used COS7 cell line and its utility to study ectodomain shedding of ACE2 mediated by ADAM17 in vitro. The transfectable nature of this cell line makes it an attractive cell model for studying the molecular, functional, and pharmacological properties of the renal RAS.


3D bioprint me: a socioethical view of bioprinting human organs and tissues.
In this article, we review the extant social science and ethical literature on three-dimensional (3D) bioprinting. 3D bioprinting has the potential to be a 'game-changer', printing human organs on demand, no longer necessitating the need for living or deceased human donation or animal transplantation. Although the technology is not yet at the level required to bioprint an entire organ, 3D bioprinting may have a variety of other mid-term and short-term benefits that also have positive ethical consequences, for example, creating alternatives to animal testing, filling a therapeutic need for minors and avoiding species boundary crossing. Despite a lack of current socioethical engagement with the consequences of the technology, we outline what we see as some preliminary practical, ethical and regulatory issues that need tackling. These relate to managing public expectations and the continuing reliance on technoscientific solutions to diseases that affect high-income countries. Avoiding prescribing a course of action for the way forward in terms of research agendas, we do briefly outline one possible ethical framework 'Responsible Research Innovation' as an oversight model should 3D bioprinting promises are ever realised. 3D bioprinting has a lot to offer in the course of time should it move beyond a conceptual therapy, but is an area that requires ethical oversight and regulation and debate, in the here and now. The purpose of this article is to begin that discussion.


Pilot controlled trial of mindfulness meditation and education for dementia caregivers.
The objectives of this study were to evaluate whether a mindfulness meditation intervention may be effective in caregivers of close relatives with dementia and to help refine the protocol for future larger trials. The design was a pilot randomized trial to evaluate the effectiveness of a mindfulness meditation intervention adapted from the Mindfulness-Based Cognitive Therapy program in relation to two comparison groups: an education class based on Powerful Tools for Caregivers serving as an active control group and a respite-only group serving as a pragmatic control. This study was conducted at the Oregon Health & Science University, Portland, OR. The subjects were community-dwelling caregivers aged 45-85 years of close relatives with dementia. The two active interventions lasted 7 weeks, and consisted of one 90-minute session per week along with at-home implementation of knowledge learned. The respite-only condition provided the same duration of respite care that was needed for the active interventions. Subjects were assessed prior to randomization and again after completing classes at 8 weeks. The primary outcome measure was a self-rated measure of caregiver stress, the Revised Memory and Behavior Problems Checklist (RMBPC). Secondary outcome measures included mood, fatigue, self-efficacy, mindfulness, salivary cortisols, cytokines, and cognitive function. We also evaluated self-rated stress in the subjects' own environment, expectancy of improvement, and credibility of the interventions. There were 31 caregivers randomized and 28 completers. There was a significant effect on RMBPC by group covarying for baseline RMBPC, with both active interventions showing improvement compared with the respite-only group. Most of the secondary outcome measures were not significantly affected by the interventions. There was an intervention effect on the caregiver self-efficacy measure and on cognitive measures. Although mindfulness was not impacted by the intervention, there were significant correlations between mindfulness and self-rated mood and stress scores. Both mindfulness and education interventions decreased the self-rated caregiver stress compared to the respite-only control.


Pimelea trichostachya poisoning (St George disease) in horses.
A dense population of Pimelea trichostachya plants (Family Thymelaeaceae) in pasture poisoned a horse herd in southern inland Queensland in October-November 2005. Plant density was 2 to 45 g wet weight/m(2) (mean 16 g/m(2)) from 5 to 69 plants/m(2) (mean 38 plants/m(2)) representing 3 to 20% (mean 9%) of the volume of pasture on offer. Ten of 35 mares, fillies and geldings were affected. Clinical signs were loss of body weight, profound lethargy, serous nasal discharge, severe watery diarrhoea and subcutaneous oedema of the intermandibular space, chest and ventral midline. Pathological findings were anaemia, leucocytopenia, hypoproteinaemia, dilatation of the right ventricle of the heart, dilated hepatic portal veins and periportal hepatic sinusoids (peliosis hepatis), alimentary mucosal hyperaemia and oedema of mesenteric lymph nodes. Cattle grazing the same pasture were affected by Pimelea poisoning simultaneously. Removal of the horses to Pimelea-free pasture initiated recovery. The one other incident of this syndrome, previously only recognised in cattle in Australia, occurred in horses, in South Australia in 2002, with access to a dense Pimelea simplex population.


Diet quality is independently associated with weight status in children aged 9-10 years.
Although energy imbalance is key to the development of childhood obesity, the association between different dietary components, reflected in diet quality scores, and children's weight status has not been extensively studied. The current study determined if diet quality, characterized according to 3 predefined scores, was associated with weight status in a population-based sample of 9- to 10-y-old British children, independently of factors previously associated with weight status. In a cross-sectional study of 1700 children (56% girls), data from 4-d food diaries were used to calculate 3 diet quality scores modified to be reflective of children's diets: the Diet Quality Index (DQI), Healthy Diet Indicator (HDI), and Mediterranean Diet Score (MDS). Physical activity was measured with 7-d accelerometery, and height, weight, waist, and bio-impedance were objectively measured and used to calculate weight status variables. After multiple adjustments, including physical activity and overall energy density, higher DQI and HDI scores were significantly associated with improved weight status. Comparing extreme quintiles of the scores revealed the DQI and HDI were associated with lower waist circumference (-3.0%, P = 0.005 and -2.5%, P = 0.033, respectively), and lower body fat (-5.1%, P = 0.023 and -4.9%, P = 0.026, respectively). The DQI was also associated with lower weight (-5.9%; P = 0.002) and BMI (-4.2%; P = 0.004). No significant associations were observed with the MDS. These findings suggest that diet quality is independently associated with children's weight status. Future work should consider if diet quality scores could be key components of interventions designed to reduce obesity in children.


Intramuscular versus Vaginal Progesterone Administration in Medicated Frozen Embryo Transfer Cycles: A Randomized Clinical Trial Assessing Sub-Endometrial Contractions.
The study aimed to assess whether sub-endometrial contractility is reduced by the use of intramuscular (IM) progesterone. This is a randomized clinical trial. Patients assigned to a medicated day 5 frozen embryo transfer (FET) were randomly allocated to "vaginal progesterone" or "IM progesterone": patients randomized to the vaginal arm were treated with 200 mg micronized progesterone 3 times daily while patients randomized into the IM progesterone arm were treated with a single daily injection of 50 mg progesterone in oil. The main outcome measure was the number of sub-endometrial contractions (waves) per minute 1 day before a blastocyst embryo transfer. Thirty-four patients were enrolled. The progesterone serum concentration was significantly higher in patients using the IM progesterone (85.2 ± 50.1 vs. 30.3 ± 11.2 nmol/L, respectively) but this did not translate into a lower sub-endometrial contractility (2.4 ± 4.8 vs. 1.4 ± 1.1 contraction/min, respectively). Clinical pregnancy rates were comparable between groups. The number of sub-endometrial waves was significantly lower among pregnant patients (p = 0.02). The use of IM progesterone in medicated FET cycles does not reduce the sub-endometrial activity compared to vaginal progesterone administration. Our data support a poor clinical pregnancy outcome with high wave activity, regardless of the progesterone mode.


Molecular mechanisms of bone metastasis and associated muscle weakness.
Bone is a preferred site for breast cancer metastasis and leads to pathologic bone loss due to increased osteoclast-induced bone resorption. The homing of tumor cells to the bone depends on the support of the bone microenvironment in which the tumor cells prime the premetastatic niche. The colonization and growth of tumor cells then depend on adaptations in the invading tumor cells to take advantage of normal physiologic responses by mimicking bone marrow cells. This concerted effort by tumor cells leads to uncoupled bone remodeling in which the balance of osteoclast-driven bone resorption and osteoblast-driven bone deposition is lost. Breast cancer bone metastases often lead to osteolytic lesions due to hyperactive bone resorption. Release of growth factors from bone matrix during resorption then feeds a "vicious cycle" of bone destruction leading to many skeletal-related events. In addition to activity in bone, some of the factors released during bone resorption are also known to be involved in skeletal muscle regeneration and contraction. In this review, we discuss the mechanisms that lead to osteolytic breast cancer bone metastases and the potential for cancer-induced bone-muscle cross-talk leading to skeletal muscle weakness.


Magnetism and exchange interaction of small rare-earth clusters; Tb as a representative.
Here we follow, both experimentally and theoretically, the development of magnetism in Tb clusters from the atomic limit, adding one atom at a time. The exchange interaction is, surprisingly, observed to drastically increase compared to that of bulk, and to exhibit irregular oscillations as a function of the interatomic distance. From electronic structure theory we find that the theoretical magnetic moments oscillate with cluster size in exact agreement with experimental data. Unlike the bulk, the oscillation is not caused by the RKKY mechanism. Instead, the inter-atomic exchange is shown to be driven by a competition between wave-function overlap of the 5d shell and the on-site exchange interaction, which leads to a competition between ferromagnetic double-exchange and antiferromagnetic super-exchange. This understanding opens up new ways to tune the magnetic properties of rare-earth based magnets with nano-sized building blocks.


Determination of defensin HNP-1 in human saliva of patients with oral mucosal diseases.
Saliva is a biological fluid that is easily obtainable and that can give useful information both in systemic and oral diseases. In this study, a chromatographic method was applied to determine the amount of defensin HNP-1 in human saliva of patients with oral mucosal diseases before and after treatments and compared with controls. Defensin human neutrophil peptide-1 (HNP-1) was identified and confirmed. The concentration of HNP-1 in saliva was determined by comparing the area of eluted HNP-1 with that of HNP-1 standard. Linear calibration range of defensin HNP-1 was 0.10 to 0.90 μg/10 μL with R(2) values of 0.996. The concentrations of HNP-1 in the saliva of patients with oral lichen planus, Behçet's disease, and recurrent apthous stomatitis were 33.6 ± 10.6, 15.5 ± 7.6, and 36.3 ± 9.5 μg mL(-1) (mean ± S.D.), respectively. The salivary defensin-1 concentration was significantly higher in patients with oral mucosal diseases than in healthy volunteers; furthermore, in patients with oral mucosal diseases, the concentration was significantly higher before treatment than after treatment.


Cardiovascular disease-related genes and regulation by diet.
Diets rich in omega-3 polyunsaturated fatty acids (n-3 PUFAs) such as alpha-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid are associated with decreased incidence and severity of cardiovascular disease (CVD). At least some of the beneficial effects of these dietary fatty acids are mediated by metabolites such as prostaglandins, leukotrienes, thromboxanes, and resolvins. The effects of n-3 PUFAs often differ from those of other fatty acids with very similar structures, such as linoleic acid and arachidonic acid (n-6 PUFAs) and their corresponding metabolites. This article reviews the evidence that specific receptors exist for fatty acids or their metabolites that are able to regulate gene expression and coordinately affect metabolic or signaling pathways associated with CVD. Four nuclear receptor subfamilies that respond to dietary and endogenous ligands and have implications for CVD are emphasized in this article: peroxisome proliferator-activated receptors, retinoid X receptors, liver X receptors, and the farnesoid X receptor.


Pregnancy outcomes decline with increasing body mass index: analysis of 239,127 fresh autologous in vitro fertilization cycles from the 2008-2010 Society for Assisted Reproductive Technology registry.
To examine the effect of body mass index (BMI) on IVF outcomes in fresh autologous cycles. Retrospective cohort study. Not applicable. A total of 239,127 fresh IVF cycles from the 2008-2010 Society for Assisted Reproductive Technology registry were stratified into cohorts based on World Health Organization BMI guidelines. Cycles reporting normal BMI (18.5-24.9 kg/m(2)) were used as the reference group (REF). Subanalyses were performed on cycles reporting purely polycystic ovary syndrome (PCOS)-related infertility and those with purely male-factor infertility (34,137 and 89,354 cycles, respectively). None. Implantation rate, clinical pregnancy rate, pregnancy loss rate, and live birth rate. Success rates and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for all pregnancy outcomes were most favorable in cohorts with low and normal BMIs and progressively worsened as BMI increased. Obesity also had a negative impact on IVF outcomes in cycles performed for PCOS and male-factor infertility, although it did not always reach statistical significance. Success rates in fresh autologous cycles, including those done for specifically PCOS or male-factor infertility, are highest in those with low and normal BMIs. Furthermore, there is a progressive and statistically significant worsening of outcomes in groups with higher BMIs. More research is needed to determine the causes and extent of the influence of BMI on IVF success rates in other patient populations.


Barriers to Liposomal Gene Delivery: from Application Site to the Target.
Gene therapy is a therapeutic approach to deliver genetic material into cells to alter their function in entire organism. One promising form of gene delivery system (DDS) is liposomes. The success of liposome-mediated gene delivery is a multifactorial issue and well-designed liposomal systems might lead to optimized gene transfection particularly in vivo. Liposomal gene delivery systems face different barriers from their site of application to their target, which is inside the cells. These barriers include presystemic obstacles (epithelial barriers), systemic barriers in blood circulation and cellular barriers. Epithelial barriers differ depending on the route of administration. Systemic barriers include enzymatic degradation, binding and opsonisation. Both of these barriers can act as limiting hurdles that genetic material and their vector should overcome before reaching the cells. Finally liposomes should overcome cellular barriers that include cell entrance, endosomal escape and nuclear uptake. These barriers and their impact on liposomal gene delivery will be discussed in this review.


Development of an inactivated combined vaccine for protection of cattle against lumpy skin disease and bluetongue viruses.
Lumpy Skin Disease (LSD) and Bluetongue (BT) are the main ruminants viral vector-borne diseases. LSD is endemic in Africa and has recently emerged in Europe and central Asia as a major threat to cattle industry. BT caused great economic damage in Europe during the last decade with a continuous spread to other countries. To control these diseases, vaccination is the only economically viable tool. For LSD, only live-attenuated vaccines (LAVs) are commercially available, whilst for BT both LAVs and inactivated vaccines are available with a limited number of serotypes. In this study, we developed an inactivated, oil adjuvanted bivalent vaccine against both diseases based on LSDV Neethling strain and BTV4. The vaccine was tested for safety and immunogenicity on cattle during a one-year period. Post-vaccination monitoring was carried out by VNT and ELISA. The vaccine was completely safe and elicited high neutralizing antibodies starting from the first week following the second injection up to one year. Furthermore, a significant correlation (R = 0.9040) was observed when comparing VNT and competitive ELISA in BTV4 serological response. Following BTV4 challenge, none of vaccinated and unvaccinated cattle were registered clinical signs, however vaccinated cattle showed full protection from viraemia. In summary, this study highlights the effectiveness of this combined vaccine as a promising solution for both LSD and BT control. It also puts an emphasis on the need for the development of other multivalent inactivated vaccines, which could be greatly beneficial for improving vaccination coverage in endemic countries and prophylaxis of vector-borne diseases.


Characteristics and management of pain in patients with Klippel-Feil syndrome: analysis of a global patient-reported registry.
Klippel-Feil syndrome (KFS) is characterized by congenital fusion of the cervical vertebrae. Due to its rarity, minimal research has been done to assess the quality and management of pain associated with this disorder. Using a large global database, the authors report a detailed analysis of the type, location, and treatment of pain in patients with KFS. Data were obtained from the Coordination of Rare Diseases at Stanford registry and Klippel-Feil Syndrome Freedom registry. The cervical fusions were categorized into Samartzis type I, II, or III. The independent-sample t-test, Wilcoxon rank-sum test, and Friedman test were conducted, with significance set at p < 0.05. Seventy-five patients (60 female, 14 male, and 1 unknown) were identified and classified as having the following types of Samartzis fusion: type I, n = 21 (28%); type II, n = 15 (20%); type III, n = 39 (52%). Seventy participants (93.3%) experienced pain associated with their KFS. The median age of patients at pain onset was 16.0 years (IQR 6.75-24.0 years), and the median age when pain worsened was 28.0 years (IQR 15.25-41.5 years). Muscle, joint, and nerve pain was primarily located in the shoulders/upper back (76%), neck (72%), and back of head (50.7%) and was characterized as tightness (73%), dull/aching (67%), and tingling/pins and needles (49%). Type III fusions were significantly associated with greater nerve pain (p = 0.02), headache/migraine pain (p = 0.02), and joint pain (p = 0.03) compared to other types of fusion. Patients with cervical fusions in the middle region (C2-6) tended to report greater muscle, joint, and nerve pain (p = 0.06). Participants rated the effectiveness of oral over-the-counter medications as 3 of 5 (IQR 1-3), oral prescribed medications as 3 of 5 (IQR 2-4), injections as 2 of 5 (IQR 1-4), and surgery as 3 of 5 (IQR 1-4), with 0 indicating the least pain relief and 5 the most pain relief. Participants who pursued surgical treatment reported significantly more comorbidities (p = 0.02) and neurological symptoms (p = 0.01) than nonsurgically treated participants and were significantly older when pain worsened (p = 0.03), but there was no difference in levels of muscle, joint, or nerve pain (p = 0.32); headache/migraine pain (p = 0.35); total number of cervical fusions (p = 0.77); location of fusions; or age at pain onset (p = 0.16). More than 90% of participants experienced pain. Participants with an increased number of overall cervical fusions or multilevel, contiguous fusions reported greater levels of muscle, joint, and nerve pain. Participants who pursued surgery had more comorbidities and neurological symptoms, such as balance and gait disturbances, but did not report more significant pain than nonsurgically treated participants.


"We almost had the whole block's phone number on the wall": A mixed methods investigation of informal helping in a predominantly rural sample.
Community psychologists have noted the limitations of professional models of mental health treatment, demonstrating that people are more likely to use informal familial or community support during adversity. However, relatively little is known about the forms and functions of informal help seeking and provision. Semistructured interviews (N = 170), in which a sample of predominantly rural-dwelling adolescents and adults described significant life experiences, were coded for instances of receiving help. Codes thematically categorized the type of adversity, role of the helper, and nature of the help received. Most participants (67.64%) reported the presence of at least one informal helper; only 8.82% of participants discussed receiving professional help. Chi-square analyses suggested that the nature of the help received varied by the types of helper and adversity being experienced and that different helpers were more likely to aid with particular adversities. The presence of a nonfamilial, nonprofessional helper was associated with higher posttraumatic growth, generativity, and perceived social support.


Aerobic exercise intensity does not affect the anabolic signaling following resistance exercise in endurance athletes.
This study examined whether intensity of endurance stimulus within a concurrent training paradigm influenced the phosphorylation of signaling proteins associated with the mTOR and AMPK networks. Eight male cyclists completed (1) resistance exercise (RES), 6 × 8 squats at 80% 1-RM; (2) resistance exercise and moderate intensity cycling of 40 min at 65% V̇O2peak, (RES + MIC); (3) resistance exercise and high intensity interval cycling of 40 min with 6 alternating 3 min intervals of 85 and 45% V̇O2peak (RES + HIIC), in a cross-over design. Muscle biopsies were collected at rest and 3 h post-RES. There was a main effect of condition for mTORS2448 (p = 0.043), with a greater response in the RES + MIC relative to RES condition (p = 0.033). There was a main effect of condition for AMPKα2T172 (p = 0.041), with a greater response in RES + MIC, relative to both RES + HIIC (p = 0.026) and RES (p = 0.046). There were no other condition effects for the remaining protein kinases assessed (p > 0.05). These data do not support a molecular interference effect in cyclists under controlled conditions. There was no intensity-dependent regulation of AMPK, nor differential activation of anabolism with the manipulation of endurance exercise intensity.


A transformation-associated 130-kD cell surface glycoprotein is growth controlled in normal human cells.
Two characteristics of cell surface molecules involved in the regulation of cell proliferation are altered expression in relation to growth phase in normal cells and overexpression in transformed cells. Here, we describe a similar pattern of expression for a 130-kD cell surface glycoprotein (gp 130) in human cells. Synthesis and cell surface expression of gp130 were greatly increased in both virally and chemically transformed fibroblasts, fibrosarcomas, a squamous cell carcinoma of the skin, and T cell leukemia lines. Furthermore, gp130 expression was induced in serum-starved fetal fibroblasts by serum stimulation, and in fresh T cells by various activating agents. Expression in response to serum stimulation was associated primarily with the transition from a quiescent state (G0) into the cell cycle (G1).


Towards a thermally regenerative all-copper redox flow battery.
An all-copper redox flow battery based on strong complexation of Cu(+) with acetonitrile is demonstrated, exhibiting reasonable battery performance. More interestingly, the battery can be charged by heat sources of 100 °C, by distilling off the acetonitrile. This destabilizes the Cu(+) complex, leading to recovery of the starting materials.


Delocalized Two-Exciton States in DNA Scaffolded Cyanine Dimers.
The engineering and manipulation of delocalized molecular exciton states is a key component for artificial biomimetic light harvesting complexes as well as alternative circuitry platforms based on exciton propagation. Here we examine the consequences of strong electronic coupling in cyanine homodimers on DNA duplex scaffolds. The most closely spaced dyes, attached to positions directly across the double-helix from one another, exhibit pronounced Davydov splitting due to strong electronic coupling. We demonstrate that the DNA scaffold is sufficiently robust to support observation of the transition from the lowest energy (J-like) one-exciton state to the nonlocal two-exciton state, where each cyanine dye is in the excited state. This transition proceeds via sequential photon absorption and persists for the lifetime of the exciton, establishing this as a controlled method for creating two-exciton states. Our observations suggest that DNA-organized dye networks have potential as platforms for molecular logic gates and entangled photon emission based on delocalized two-exciton states.


(-)-Phenserine tartrate (PhenT) as a treatment for traumatic brain injury.
Traumatic brain injury (TBI) is one of the most common causes of morbidity and mortality of both young adults and the elderly, and is a key contributing factor in about 30% of all injury-associated deaths occurring within the United States of America. Albeit substantial impact has been made to improve our comprehension of the mechanisms that underpin the primary and secondary injury stages initiated by a TBI incident, this knowledge has yet to successfully translate into the development of an effective TBI pharmacological treatment. Developing consent suggests that a TBI can concomitantly trigger multiple TBI-linked cascades that then progress in parallel and, if correct, the multifactorial nature of TBI would make the discovery of a single effective mechanism-targeted drug unlikely. We review recent data indicating that the small molecular weight drug (-)-phenserine tartrate (PhenT), originally developed for Alzheimer's disease (AD), effectively inhibits a broad range of mechanisms pertinent to mild (m) and moderate (mod)TBI, which in combination underpin the ensuing cognitive and motor impairments. In cellular and animal models at clinically translatable doses, PhenT mitigated mTBI- and modTBI-induced programmed neuronal cell death (PNCD), oxidative stress, glutamate excitotoxicity, neuroinflammation, and effectively reversed injury-induced gene pathways leading to chronic neurodegeneration. In addition to proving efficacious in well-characterized animal TBI models, significantly mitigating cognitive and motor impairments, the drug also has demonstrated neuroprotective actions against ischemic stroke and the organophosphorus nerve agent and chemical weapon, soman. In the light of its tolerability in AD clinical trials, PhenT is an agent that can be fast-tracked for evaluation in not only civilian TBI, but also as a potentially protective agent in battlefield conditions where TBI and chemical weapon exposure are increasingly jointly occurring.


Minimally invasive, imaging guided virtual autopsy compared to conventional autopsy in foetal, newborn and infant cases: study protocol for the paediatric virtual autopsy trial.
In light of declining autopsy rates around the world, post-mortem MR imaging is a promising alternative to conventional autopsy in the investigation of infant death. A major drawback of this non-invasive autopsy approach is the fact that histopathological and microbiological examination of the tissue is not possible. The objective of this prospective study is to compare the performance of minimally invasive, virtual autopsy, including CT-guided biopsy, with conventional autopsy procedures in a paediatric population. Foetuses, newborns and infants that are referred for autopsy at three different institutions associated with the University of Zurich will be eligible for recruitment. All bodies will be examined with a commercial CT and a 3 Tesla MRI scanner, masked to the results of conventional autopsy. After cross-sectional imaging, CT-guided tissue sampling will be performed by a multifunctional robotic system (Virtobot) allowing for automated post-mortem biopsies. Virtual autopsy results will be classified with regards to the likely final diagnosis and major pathological findings and compared to the results of conventional autopsy, which remains the diagnostic gold standard. There is an urgent need for the development of alternative post-mortem examination methods, not only as a counselling tool for families and as a quality control measure for clinical diagnosis and treatment but also as an instrument to advance medical knowledge and clinical practice. This interdisciplinary study will determine whether virtual autopsy will narrow the gap in information between non-invasive and traditional autopsy procedures. ClinicalTrials.gov: NCT01888380.


Ganglioside-monosialic acid (GM1) prevents oxaliplatin-induced peripheral neurotoxicity in patients with gastrointestinal tumors.
Oxaliplatin, an effective antineoplastic agent againstgastrointestinal tumors, can cause severe peripheral neurotoxicity, which seriously limits its clinical application. To date, there are no effective treatments for this complication. Ganglioside-monosialic acid (GM1) has been shown to protect neurons against injuries and degeneration. The aim of this study was to evaluate the effects of GM1 on preventing oxaliplatin-induced neurotoxicity in patients with gastrointestinal tumors. In this study, 120 patients with gastrointestinal tumors were enrolled, andthey received the treatment of XELOX (oxaliplatin and capecitabine) and FOLFOX4 (oxaliplatin, leukovolin and 5-fluorouracil). The patients were randomly divided into two groups, the experimental group and control group, with60 patients ineach. On the day chemotherapy was initiated, the experimental group received GM1 intravenously (100 mg once daily) for 3 days, while no neuroprotective agents were applied in the control group. The incidence rates and classification of neurotoxicity in the two groups were evaluated and the differences between the two groups were examined. Furthermore, whether GM1 affected the therapeutic effects of chemotherapy was also examined. The grade of neurotoxicity in the experimental group was significantly lower than in the control group (P<0.05, Mann-Whitney U test). The probability of occurrence of low-grade neurotoxicity (grade 0 and 1) in the experimental group was higher than that in the control group (logistic ordinal regression); whereas the probability of occurrence of high-grade neurotoxicity (grade 2 and 3) in the experimental group was lower than in the control group (logistic ordinal regression). The data suggested that GM1 could reduce the grade of oxaliplatin-induced neurotoxicity and was an effective neuroprotective agent against oxaliplatin-induced high-grade neurotoxicity in patients with gastrointestinal tumors.


Chromoendoscopy detects more adenomas than colonoscopy using intensive inspection without dye spraying.
Conventional colonoscopy misses some neoplastic lesions. We compared the sensitivity of chromoendoscopy and colonoscopy with intensive inspection for detecting adenomatous polyps missed by conventional colonoscopy. Fifty subjects with a history of colorectal cancer or adenomas underwent tandem colonoscopies at one of five centers of the Great Lakes New England Clinical Epidemiology and Validation Center of the Early Detection Research Network. The first exam was a conventional colonoscopy with removal of all visualized polyps. The second exam was randomly assigned as either pan-colonic indigocarmine chromoendoscopy or standard colonoscopy with intensive inspection lasting >20 minutes. Size, histology, and numbers of polyps detected on each exam were recorded. Twenty-seven subjects were randomized to a second exam with chromoendoscopy and 23 underwent intensive inspection. Forty adenomas were identified on the first standard colonoscopies. The second colonoscopies detected 24 additional adenomas: 19 were found using chromoendoscopy and 5 were found using intensive inspection. Chromoendoscopy found additional adenomas in more subjects than did intensive inspection (44% versus 17%) and identified significantly more missed adenomas per subject (0.7 versus 0.2, P < 0.01). Adenomas detected with chromoendoscopy were significantly smaller (mean size 2.66 +/- 0.97 mm) and were more often right-sided. Chromoendoscopy was associated with more normal tissue biopsies and longer procedure times than intensive inspection. After controlling for procedure time, chromoendoscopy detected more adenomas and hyperplastic polyps compared with colonoscopy using intensive inspection alone. Chromoendoscopy detected more polyps missed by standard colonoscopy than did intensive inspection. The clinical significance of these small missed lesions warrants further study.


ACR appropriateness Criteria® Postradical prostatectomy irradiation in prostate cancer.
The purpose of this article is to present an updated set of American College of Radiology consensus guidelines formed from an expert panel on the appropriate use of radiation therapy in postprostatectomy prostate cancer. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. Recent and relevant literature reviewed by the panel led to establishment of criteria for appropriate use of radiation therapy in postprostatectomy prostate cancer. The discussion includes treatment technique, appropriate dose, field design, and the role of prostate-specific antigen (PSA). Ratings and commentary of the panel on multiple treatment parameters were used to reach consensus. Patients with high-risk pathologic features benefit from postprostatectomy radiation therapy.


Cytologic findings in experimental in vivo fallopian tube brush specimens.
The fallopian tube is now recognized as a primary source of precursor neoplastic lesions for pelvic serous adenocarcinomas. Cytologic features of fallopian tube brushings from low-risk patients have not been well described. We describe the cytomorphology of tubal epithelium from prospectively collected experimental in vivo brushings from normal fallopian tubes of 7 low-risk patients. Liquid-based cytology slides and cell blocks were prepared and reviewed on all specimens. Fifteen brush cytology specimens were obtained, ten by laparoscopy, four by hysteroscopy and one following hysterectomy and bilateral salpingo-oophorectomy on an ex vivo specimen. Variable cytologic features were documented for background, cellularity, cellular architecture, cilia, nuclear overlap, mitoses, nuclear pleomorphism, nuclear membrane changes and nucleoli. Negative P53 and Ki-67 stain results were documented in available cell blocks. Histopathologic salpingectomy findings and clinical follow-up were benign. Moderate nuclear pleomorphism and nuclear overlap, prominent single and multiple nucleoli and background granular debris were common challenging cytologic findings in fallopian tube brushings from low-risk patients. With experience, cellular changes can be recognized as benign. Recognition of the range of normal fallopian tube cytology should help to minimize false-positive interpretations of cytology specimens obtained in association with risk-reducing salpingo-oophorectomies.


Psychometric properties of the Fear-Avoidance Beliefs Questionnaire and Tampa Scale of Kinesiophobia in patients with shoulder pain.
To investigate the reliability and validity of 2 commonly used measures of pain related fear in patients with shoulder pain. A preplanned secondary analysis of a prospective single-arm trial involving a repeated-measures design. Outpatient physical therapy clinics. Patients (N=80) with a primary report of shoulder pain. All patients completed the outcome measures at baseline and at follow-up. Patients completed a modified Fear-Avoidance Beliefs Questionnaire (FABQ), the 11-item version of Tampa Scale of Kinesiophobia (TSK-11), and the Shoulder Pain and Disability Index (SPADI) at baseline and at a 48-hour follow-up. Patients were dichotomized as improved or stable at follow-up based on the Global Rating of Change. Factor analysis indicated 3 stable factors for the FABQ and 1 stable factor for the TSK-11. Shoulder specific scoring for the FABQ and TSK-11 were used in subsequent analyses. Test-retest reliability intraclass correlation coefficient (ICC) was substantial for the FABQ and the TSK-11. The FABQ correlated significantly with SPADI pain and disability scores, while the TSK-11 correlated significantly only with SPADI pain scores. The shoulder-specific FABQ-W (work beliefs subscale) was a better than chance predictor of missing days of work during the 48-hour study period. The modified FABQ and TSK-11 may be appropriate for use in patients with shoulder pain. Shoulder-specific scoring of these measures resulted in substantial test-retest reliability, and the FABQ correlated with the SPADI for pain and disability. The FABQ also showed potential for prediction of short-term work loss in this sample. Pain-related fear may be an important variable in patients with shoulder pain and merits future consideration in longitudinal studies.


Characterization of orchardgrass p23, a flowering plant Hsp90 cohort protein.
p23 is a heat shock protein 90 (Hsp90) co-chaperone and stabilizes the Hsp90 heterocomplex in mammals and yeast. In this study, we isolated a complementary DNA (cDNA) encoding p23 from orchardgrass (Dgp23) and characterized its functional roles under conditions of thermal stress. Dgp23 is a 911 bp cDNA with an open reading frame predicted to encode a 180 amino acid protein. Northern analysis showed that expression of Dgp23 transcripts was heat inducible. Dgp23 has a well-conserved p23 domain and interacted with an orchardgrass Hsp90 homolog in vivo, like mammalian and yeast p23 homologs. Recombinant Dgp23 is a small acidic protein with a molecular mass of approximately 27 kDa and pI 4.3. Dgp23 was also shown to function as a chaperone protein by suppression of malate dehydrogenase thermal aggregation. Differential scanning calorimetry thermograms indicated that Dgp23 is a heat-stable protein, capable of increasing the T (m) of lysozyme. Moreover, overexpression of Dgp23 in a yeast p23 homolog deletion strain, Deltasba1, increased cell viability. These results suggest that Dgp23 plays a role in thermal stress-tolerance and functions as a co-chaperone of Hsp90 and as a chaperone.


Cerebrospinal fluid and plasma concentrations of leptin, NPY, and alpha-MSH in obese women and their relationship to negative energy balance.
Leptin and its principal mediators, NPY and alpha-MSH are postulated to play a pivotal role in energy balance. To determine the possibility of the disturbance in neuropeptides in human obesity and their consequent changes in response to negative energy balance, we evaluated plasma and cerebrospinal fluid (CSF) leptin, NPY, and alpha-MSH levels in obese women before and after weight loss in comparison with normal control women. Subjects included 16 obese women [mean body mass index (BMI), 35.6 kg/m(2)] before and after weight loss induced by a 2-wk very low caloric diet (800 kcal/d) and 14 normal weight women (mean BMI, 20.4 kg/m(2)). The CSF to plasma leptin ratio in normal weight subjects was 2.3-fold higher than that in obese subjects. After weight loss in obese subjects, plasma leptin levels decreased by 40% and CSF levels decreased by 51%. There was a positive linear correlation between CSF and plasma leptin levels at baseline in obese subjects (r = 0.74, P < 0.05) and a positive logarithmic correlation in normal weight subjects (r = 0.89, P < 0.05) and in obese subjects after weight loss (r = 0.64, P < 0.05). The BMI was negatively correlated with the CSF to plasma leptin ratio (r = -0.86, P < 0.05) in all subjects. Neither the baseline plasma levels nor the baseline CSF levels of NPY were different between normal weight subjects and obese subjects. After weight loss, the CSF NPY level decreased significantly compared with baseline values in obese subjects. The alpha-MSH levels in plasma and CSF did not differ significantly from controls in obese subjects at baseline or after weight loss. Baseline CSF leptin level correlated with neither the baseline CSF NPY level nor the baseline CSF alpha-MSH level. In conclusion, this study demonstrated that the efficiency of brain leptin delivery is reduced in human obesity and central nervous system leptin uptake involves a combination of a saturable and an unsaturable mechanism. CSF NPY and alpha-MSH did not differ from controls in human obesity, and the CSF NPY level decreased significantly whereas alpha-MSH did not differ after weight loss in obese subjects compared with baseline. There was no significant correlation between CSF leptin and CSF NPY or alpha-MSH. This could be the result of leptin resistance present in human obesity and/or the more complex mechanisms involved in modulating appetite and regulating energy balance in human obesity.


The SNARC and MARC effects measured online: Large-scale assessment methods in flexible cognitive effects.
The Spatial-Numerical Association of Response Codes (SNARC) effect (i.e., faster reactions to small/large numbers on the left-/right-hand side) is usually observed along with the linguistic Markedness of Response Codes (MARC) effect-that is, faster left-/right-hand responses to odd/even numbers. The SNARC effect is one of the most thoroughly investigated phenomena in numerical cognition. However, almost all SNARC and MARC studies to date were conducted with sample sizes smaller than 100. Here we report on a study with 1,156 participants from various linguistic and cultural backgrounds performing a typical parity judgment task. We investigated whether (1) the SNARC and MARC effects can be observed in an online setup, (2) the properties of these effects observed online are similar to those observed in laboratory setups, (3) the effects are reliable, and (4) they are valid. We found robust SNARC and MARC effects. Their magnitude and reliabilities were comparable to values previously reported in in-lab studies. Furthermore, we reproduced commonly observed validity correlations of the SNARC and MARC effects. Namely, SNARC and MARC correlated with mean reaction times and intraindividual variability in reaction times. Additionally, we found interindividual differences in the SNARC and MARC effects (e.g., finger-counting routines for the SNARC and handedness for the MARC). Large-scale testing via web-based data acquisition not only produces SNARC and MARC effects and validity correlations similar to those from small, in-lab studies, but also reveals substantial insights with regard to interindividual differences that usually cannot be revealed in the offline laboratory, due to power considerations.


Mediator of DNA Damage Checkpoint Protein 1 Facilitates V(D)J Recombination in Cells Lacking DNA Repair Factor XLF.
DNA double-strand breaks (DSBs) trigger the Ataxia telangiectasia mutated (ATM)-dependent DNA damage response (DDR), which consists of histone H2AX, MDC1, RNF168, 53BP1, PTIP, RIF1, Rev7, and Shieldin. Early stages of B and T lymphocyte development are dependent on recombination activating gene (RAG)-induced DSBs that form the basis for further V(D)J recombination. Non-homologous end joining (NHEJ) pathway factors recognize, process, and ligate DSBs. Based on numerous loss-of-function studies, DDR factors were thought to be dispensable for the V(D)J recombination. In particular, mice lacking Mediator of DNA Damage Checkpoint Protein 1 (MDC1) possessed nearly wild-type levels of mature B and T lymphocytes in the spleen, thymus, and bone marrow. NHEJ factor XRCC4-like factor (XLF)/Cernunnos is functionally redundant with ATM, histone H2AX, and p53-binding protein 1 (53BP1) during the lymphocyte development in mice. Here, we genetically inactivated MDC1, XLF, or both MDC1 and XLF in murine vAbl pro-B cell lines and, using chromosomally integrated substrates, demonstrated that MDC1 stimulates the V(D)J recombination in cells lacking XLF. Moreover, combined inactivation of MDC1 and XLF in mice resulted in synthetic lethality. Together, these findings suggest that MDC1 and XLF are functionally redundant during the mouse development, in general, and the V(D)J recombination, in particular.


Diphoton production at hadron colliders: a fully differential QCD calculation at next-to-next-to-leading order.
We consider direct diphoton production in hadron collisions, and we compute the next-to-next-to-leading order QCD radiative corrections at the fully differential level. Our calculation uses the q(T) subtraction formalism, and it is implemented in a parton-level Monte Carlo program. The program allows the user to apply arbitrary kinematical cuts on the final-state photons and the associated jet activity and to compute the corresponding distributions in the form of bin histograms. We present selected numerical results related to Higgs boson searches at the LHC and corresponding results at the Tevatron.


Pregnancy and lactation, a challenge for the skeleton.
In this review we discuss skeletal adaptations to the demanding situation of pregnancy and lactation. Calcium demands are increased during pregnancy and lactation, and this is effectuated by a complex series of hormonal changes. The changes in bone structure at the tissue and whole bone level observed during pregnancy and lactation appear to largely recover over time. The magnitude of the changes observed during lactation may relate to the volume and duration of breastfeeding and return to regular menses. Studies examining long-term consequences of pregnancy and lactation suggest that there are small, site-specific benefits to bone density and that bone geometry may also be affected. Pregnancy- and lactation-induced osteoporosis (PLO) is a rare disease for which the pathophysiological mechanism is as yet incompletely known; here, we discuss and speculate on the possible roles of genetics, oxytocin, sympathetic tone and bone marrow fat. Finally, we discuss fracture healing during pregnancy and lactation and the effects of estrogen on this process.


Mapping the elastic properties of granular Au films by contact resonance atomic force microscopy.
Endowed with nanoscale spatial resolution, contact resonance atomic force microscopy (CR-AFM) provides extremely localized elastic property measurements. We advance here the applicability of CR-AFM on surfaces with nanosize features by considering the topography contribution to the CR-AFM signal. On nanosize granular Au films, the elastic modulus at the grain scale has been mapped out by considering a self-consistent deconvolution of the contact geometry effect in the CR-AFM image. Significant variation in the contact area over granular topography arises as the probe is either in single- or multiple-asperity contact with the surface. Consequently, in extracting the elastic modulus from CR-AFM measurements on granular surfaces we considered both the normal and lateral couplings established through multiple-asperity contacts between the tip and the surface. Thus, by appropriately considering the change in the contact mechanics during CR-AFM imaging, variations in the elastic modulus have been revealed in the intergrain regions as well as across individual grains.


Exposure to trichloroethylene II. Metabolites in blood and urine.
Fifteen men were exposed to trichloroethylene (TRI) in three different ways with regard to the concentration of TRI in the air as well as exercise on a bicycle ergometer. The total amount of TRI supplied and taken up by each person was measured. The concentrations of trichloroethanol (TCE) and trichloroacetic acid (TCA) were determined in blood and urine. In spite of large differences in uptake, there were only small differences in the concentration of TCA in blood during the day of exposure. There was a large scatter for the values of TCA in urine within each group. The concentration of TCE in arterial blood increased during exposure. Thereafter the concentrations were almost constant for 2 h and differed among the groups. These results can be interpreted as being due to balanced rates of the formation and elimination of TCE. The levels mentioned were related to the uptake of TRI. The same was found for the rate of excretion of TCE in urine when calculations were made from the morning sample obtained the day after exposure.


Assembly of AKAP82, a protein kinase A anchor protein, into the fibrous sheath of mouse sperm.
The assembly of the mammalian sperm flagellum is a complex developmental event requiring the sequential activation of genes encoding the component parts and the coordinated assembly of these proteins during the differentiation of the haploid spermatid. In this study, the mechanism underlying the assembly of the fibrous sheath surrounding the axoneme was examined. The subject of the study was the major fibrous sheath protein of the mouse sperm flagellum, AKAP82, a member of the A Kinase Anchor Protein (AKAP) family of polypeptides that bind the regulatory (RII) subunit of protein kinase A (PK-A). Immunoelectron microscopy demonstrated that AKAP82 is present throughout the transverse ribs and longitudinal columns of the fibrous sheath. Since AKAP82 is initially synthesized as a precursor (pro-AKAP82) during spermiogenesis, an antiserum was raised against a peptide from the processed region of pro-AKAP82 (M(r) 97,000). In immunoblotting experiments, the antibody detected pro-AKAP82 in condensing spermatids but not in epididymal sperm. In addition, two other immunoreactive proteins of M(r) 109,000 (p109) and M(r) 26,000 (p26, representing the "pro" domain of the precursor) were present in epididymal sperm. Alkaline phosphatase treatment of epididymal sperm proteins demonstrated that p109 was a phosphorylated form of pro-AKAP82 that remained in sperm. By immunofluorescence, pro-AKAP82 was localized to the entire length of the principal piece in testicular sperm, while in epididymal sperm p109 and p26 were present only in the proximal portion of the principal piece. Pro-AKAP82 was solubilized when germ cells were extracted with Triton X-100. However, in sperm, both AKAP82 and p109 were almost totally resistant to these extraction conditions and remained in the particulate fraction even after extraction with Triton and dithiothreitol. Similar to pro-AKAP82, the RII subunit of PK-A was present in the Triton X-100-soluble fraction of developing germ cells. In sperm, much of the RII also became particulate, consistent with the hypothesis that AKAP82 anchors RII in the flagellum. These data indicate that pro-AKAP82 is synthesized in the cell body, transported down the axoneme to its site of assembly in the fibrous sheath, and then proteolytically clipped to form mature AKAP82.


Screening for neuropsychiatric dysfunction. A latent structure analysis of two questionnaires.
Summing up information from interview or questionnaire data into a single number, an index, is not uncommon in social medical research, but the conceptual and mathematical background for this is too often neglected. The so-called "Rasch models" specify circumstances where a single index can be used. The necessary computer programs for doing this are now generally available (10, 11). Two often used questionnaires concerning neurotoxicity due to solvent exposure are tested using a Rasch model. None of the questionnaires were found to be in agreement with the necessary requirements for the model and no single number describes the respondent's degree of neuropsychiatric dysfunction. Much more work is needed before a suitable screening questionnaire is available.


Ambient Air Pollution and the Risk of Atrial Fibrillation and Stroke: A Population-Based Cohort Study.
Although growing evidence links air pollution to stroke incidence, less is known about the effect of air pollution on atrial fibrillation (AF), an important risk factor for stroke. We assessed the associations between air pollution and incidence of AF and stroke. We also sought to characterize the shape of pollutant-disease relationships. The population-based cohort comprised 5,071,956 Ontario residents, age 35–85 y and without the diagnoses of both outcomes on 1 April 2001 and was followed up until 31 March 2015. AF and stroke cases were ascertained using health administrative databases with validated algorithms. Based on annual residential postal codes, we assigned 5-y running average concentrations of fine particulate matter ([Formula: see text]), nitrogen dioxide ([Formula: see text]), and ozone ([Formula: see text]) from satellite-derived data, a land-use regression model, and a fusion-based method, respectively, as well as redox-weighted averages of [Formula: see text] and [Formula: see text] ([Formula: see text]) for each year. Using Cox proportional hazards models, we estimated the hazard ratios (HRs) and 95% confidence intervals (95% CIs) of AF and stroke with each of these pollutants, adjusting for individual- and neighborhood-level variables. We used newly developed nonlinear risk models to characterize the shape of pollutant–disease relationships. Between 2001 and 2015, we identified 313,157 incident cases of AF and 122,545 cases of stroke. Interquartile range increments of [Formula: see text], [Formula: see text], [Formula: see text], and [Formula: see text] were associated with increases in the incidence of AF [HRs (95% CIs): 1.03 (1.01, 1.04), 1.02 (1.01, 1.03), 1.01 (1.00, 1.02), and 1.01 (1.01, 1.02), respectively] and the incidence of stroke [HRs (95% CIs): 1.05 (1.03, 1.07), 1.04 (1.01, 1.06), 1.05 (1.03, 1.06), and 1.05 (1.04, 1.06), respectively]. Associations of similar magnitude were found in various sensitivity analyses. Furthermore, we found a near-linear association for stroke with [Formula: see text], whereas [Formula: see text], [Formula: see text]-, and [Formula: see text] relationships exhibited sublinear shapes. Air pollution was associated with stroke and AF onset, even at very low concentrations. https://doi.org/10.1289/EHP4883.


Distribution of endotoxins in full scale pharmaceutical wastewater treatment plants and its relationship with microbial community structure.
Endotoxins are potential toxics impacting human health through respiration derived in wastewater treatment plants (WWTPs), yet the formation of endotoxins during wastewater treatment processes is still lacking research. In our study, the distribution of endotoxins and bacterial community structure in the wastewater of three full scale pharmaceutical WWTPs were explored using the limulus amebocyte lysate (LAL) test and MiSeq technique. Results showed that higher endotoxin activities in the influent of Plant A and Plant C (560 and 1140 EU/mL), stemming from the fermentation process, were found compared to that of Plant B (135 EU/mL), coming from the process of chemical synthesis. During the anaerobic treatment and the cyclic activated sludge system (CASS) in the three WWTPs, the endotoxin activity increased, while it declined in the aerobic treatment system. In all bioreactors, the relative abundance of Gram-negative bacteria accounted for 50.0-94.6%. Bacteria with high lipopolysaccharide (LPS) in LAL assay were found at the genus level of Bacteroides, Enterococcus, Desulfovibrio, and Megasphaera.