Dietary intake of folate, vitamin B6, vitamin B12 and riboflavin and risk of Parkinson's disease: a case-control study in Japan.
Increased homocysteine levels might accelerate dopaminergic cell death in Parkinson's disease (PD) through neurotoxic effects; thus, increasing intake of B vitamins involved in the regulation of homocysteine metabolism might decrease the risk of PD through decreasing plasma homocysteine. However, epidemiological evidence for the association of dietary B vitamins with PD is sparse, particularly in non-Western populations. We conducted a hospital-based case-control study in Japan to examine associations between dietary intake of folate, vitamin B6, vitamin B12 and riboflavin and the risk of PD. Patients with PD diagnosed using the UK PD Society Brain Bank criteria (n 249) and controls without neurodegenerative diseases (n 368) were recruited. Dietary intake during the preceding month was assessed at the time of study recruitment using a validated, self-administered, semi-quantitative, comprehensive diet history questionnaire. After adjustment for potential dietary and non-dietary confounding factors, intake of folate, vitamin B12 and riboflavin was not associated with the risk of PD (P for trend = 0.87, 0.70 and 0.11, respectively). However, low intake of vitamin B6 was associated with an increased risk of PD, independent of potential dietary and non-dietary confounders. Multivariate OR (95 % CI) for PD in the first, second, third and fourth quartiles of vitamin B6 were 1 (reference), 0.56 (0.33, 0.94), 0.69 (0.38, 1.25) and 0.48 (0.23, 0.99), respectively (P for trend = 0.10). In conclusion, in the present case-control study in Japan, low intake of vitamin B6, but not of folate, vitamin B12 or riboflavin, was independently associated with an increased risk of PD.


Chemoselective quantum control of carbonyl bonds in Grignard reactions using shaped laser pulses.
Grignard reactants like methylmagnesium chloride are not selective with respect to different carbonyl bonds. We present a theoretical study where shaped laser pulses are utilized to prefer specific bonds in a mixture of more than one carbonyl reactant. A mixture of cyclohexanone and cyclopentanone has been chosen as a representative example. The light pulse is supposed to provide the activation energy and to adopt the function of a protecting group. The control aim is to stretch exclusively the C-O bond of one compound to the length required in the Grignard transition state. To guarantee an experimentally realizable bandwidth for the unshaped pulse, we use our recently developed optimal control theory algorithm, which allows the simultaneous optimization of the light field in the time and frequency domain. Highly selective picosecond control pulses could be optimized in the infrared regime suggesting that laser assisted chemoselectivity is possible to a large extent. To obtain control not only on the final product but also on the excitation mechanism, various initial conditions and frequency restrictions were investigated.


Rearing in enriched environment increases parvalbumin-positive small neurons in the amygdala and decreases anxiety-like behavior of male rats.
Early life experiences including physical exercise, sensory stimulation, and social interaction can modulate development of the inhibitory neuronal network and modify various behaviors. In particular, alteration of parvalbumin-expressing neurons, a gamma-aminobutyric acid (GABA)ergic neuronal subpopulation, has been suggested to be associated with psychiatric disorders. Here we investigated whether rearing in enriched environment could modify the expression of parvalbumin-positive neurons in the basolateral amygdala and anxiety-like behavior. Three-week-old male rats were divided into two groups: those reared in an enriched environment (EE rats) and those reared in standard cages (SE rats). After 5 weeks of rearing, the EE rats showed decreased anxiety-like behavior in an open field than the SE rats. Under another anxiogenic situation, in a beam walking test, the EE rats more quickly traversed an elevated narrow beam. Anxiety-like behavior in the open field was significantly and negatively correlated with walking time in the beam-walking test. Immunohistochemical tests revealed that the number of parvalbumin-positive neurons significantly increased in the basolateral amygdala of the EE rats than that of the SE rats, while the number of calbindin-D28k-positive neurons did not change. These parvalbumin-positive neurons had small, rounded soma and co-expressed the glutamate decarboxylase (GAD67). Furthermore, the number of parvalbumin-positive small cells in the basolateral amygdala tended to positively correlate with emergence in the center arena of the open field and negatively correlated with walking time in the beam walking test. Rearing in the enriched environment augmented the number of parvalbumin-containing specific inhibitory neuron in the basolateral amygdala, but not that of calbindin-containing neuronal phenotype. Furthermore, the number of parvalbumin-positive small neurons in the basolateral amygdala was negatively correlated with walking time in the beam walking test and tended to be positively correlated with activity in the center arena in the open field test. The results suggest that rearing in the enriched environment augmented parvalbumin-positive specific neurons in the basolateral amygdala, which induced behavioral plasticity that was reflected by a decrease in anxiety-like behavior in anxiogenic situations.


Caloric restriction may reverse age-related autonomic decline in humans.
Caloric restriction (CR) retards aging in laboratory rodents. No information is available on the effects of long-term CR on physiologic markers of aging and longevity in humans. Heart rate variability (HRV) is a marker for cardiac autonomic functioning. The progressive decline in HRV with aging and the association of higher HRV with better health outcomes are well established. Heart rate variability assessment is a reliable tool by which the effects of CR on autonomic function can be assessed. Time- and frequency-domain analyses compared 24-h HRV in 22 CR individuals aged 35-82 years and 20 age-matched controls eating Western diets (WD). The CR group was significantly leaner than the WD group. Heart rate was significantly lower, and virtually, all HRV values were significantly higher in the CR group than in the WD group (P < 0.002). Heart rate variability in the CR individuals was comparable with published norms for healthy individuals 20 years younger. In addition, when differences in heart rate (HR) and HRV between CR and WD were compared with previously published changes in HRV induced in healthy adults given atenolol, percent differences in each measure were generally similar in direction and magnitude and suggested declines in sympathetic and increases in parasympathetic modulation of HR and increased circadian variability associated with CR. These findings provide evidence that CR has direct systemic effects that counter the expected age-associated changes in autonomic function so that HRV indexes in CR individuals are similar to those of individuals 20 years younger eating WDs.


Barriers to and facilitators for screening women for intimate partner violence in surgical fracture clinics: a qualitative descriptive approach.
Intimate Partner Violence (IPV) is a major health issue that involves any physical, sexual or psychological harm inflicted by a current or former partner. Musculoskeletal injuries represent the second most prevalent clinical manifestation of IPV. Health care professionals, however, rarely screen women for IPV. Using qualitative methods, this study aimed to explore the perceived barriers to IPV screening and potential facilitators for overcoming these barriers among orthopaedic surgeons and surgical trainees. We conducted three focus groups with orthopaedic surgeons, senior surgical trainees, and junior surgical trainees. A semi-structured focus group guide was used to structure the discussions. Transcripts and field notes from the focus groups were analyzed using the qualitative software program N'Vivo (version 10.0; QSR International, Melbourne, Australia). To further inform our focus group findings and discuss policy changes, we conducted interviews with two opinion leaders in the field of orthopaedics. Similar to the focus groups, the interviews were digitally recorded and transcribed, and then analyzed. In the analysis, four categories of barriers were identified: surgeon perception barriers; perceived patient barriers; fracture clinic barriers and orthopaedic health care professional barriers. Some of the facilitators identified included availability of a crisis team; development of a screening form; presence of IPV posters or buttons in the fracture clinic; and the need for established policy or government support for IPV screening. The interviewees identified the need for: the introduction of evidence-based policy aiming to increase awareness about IPV among health care professionals working within the fracture clinic setting, fostering local and national champions for IPV screening, and the need to generate change on a local level. There are a number of perceived barriers to screening women in the fracture clinic for IPV, many of which can be addressed through increased education and training, and additional resources in the fracture clinic. Orthopaedic health care professionals are supportive of implementing an IPV screening program in the orthopaedic fracture clinic.


Effects of room airflow on accurate determination of PUF-PAS sampling rates in the indoor environment.
Accurate and precise interpretation of concentrations from polyurethane passive samplers (PUF-PAS) is important as more studies show elevated concentrations of PCBs and other semivolatile air toxics in indoor air of schools and homes. If sufficiently reliable, these samplers may be used to identify local sources and human health risks. Here we report indoor air sampling rates (Rs) for polychlorinated biphenyl congeners (PCBs) predicted for a frequently used double-dome and a half-dome PUF-PAS design. Both our experimentally calibrated (1.10 ± 0.23 m3 d-1) and modeled (1.08 ± 0.04 m3 d-1) Rs for the double-dome samplers compare well with literature reports for similar rooms. We determined that variability of wind speeds throughout the room significantly (P < 0.001) effected uptake rates. We examined this effect using computational fluid dynamics modeling and 3-D sonic anemometer measurements and found the airflow dynamics to have a significant but small impact on the precision of calculated airborne concentrations. The PUF-PAS concentration measurements were within 27% and 10% of the active sampling concentration measurements for the double-dome and half-dome designs, respectively. While the half-dome samplers produced more consistent concentration measurements, we find both designs to perform well indoors.


Effect of concurrent sexual partnerships on rate of new HIV infections in a high-prevalence, rural South African population: a cohort study.
Concurrent sexual partnerships are widely believed to be one of the main drivers of the HIV epidemic in sub-Saharan Africa. This view is supported by theoretical models predicting that increases in prevalence of concurrent partnerships could substantially increase the rate of spread of the disease. However, the effect of concurrent partnerships on HIV incidence has not been appropriately tested in a sub-Saharan African setting. For this population-based cohort study, we used data from the Africa Centre demographic surveillance site in KwaZulu-Natal, South Africa, to try to find support for the concurrency hypothesis. We used a moving-window approach to construct estimates of the geographical variation in reported concurrent and lifetime partners in sexually active men aged 15-55 years (n=2153) across the study area. We then followed up 7284 HIV-negative women (≥15 years of age) in the population and quantified the effect of the sexual behaviour profiles of men in the surrounding local community on a woman's hazard of HIV acquisition. During 5 years' follow-up, 693 new female HIV infections occurred (incidence 3.60 cases per 100 person-years). We identified substantial intercommunity heterogeneity in the estimated point-prevalence of partnership concurrency (range 4.0-76.3%; mean 31.5%) and mean number of lifetime sexual partners (3.4-12.9; mean 6.3) in sexually active men in this population. After adjustment for individual-level sexual behaviour and demographic, socioeconomic, and environmental factors associated with HIV acquisition, mean lifetime number of partners of men in the immediate local community was predictive of hazard of HIV acquisition in women (adjusted hazard ratio [HR] 1.08, 95% CI 1.03-1.14, p=0.004), whereas a high prevalence of partnership concurrency in the same local community was not associated with any increase in risk of HIV acquisition (adjusted HR 1.02, 95% CI 0.95-1.09, p=0.556). We find no evidence to suggest that concurrent partnerships are an important driver of HIV incidence in this typical high-prevalence rural African population. Our findings suggest that in similar hyperendemic sub-Saharan African settings, there is a need for straightforward, unambiguous messages aimed at the reduction of multiple partnerships, irrespective of whether those partnerships overlap in time. US National Institute of Child Health and Human Development; Wellcome Trust.


Leukotriene B4 release by human lung macrophages via receptor- not voltage-operated Ca2+ channels.
Increased numbers of macrophages and neutrophils in the lung is a key feature of chronic obstructive pulmonary disease (COPD). The major neutrophil chemotactic agent in the airways of COPD patients is leukotriene (LT)B(4) and is released by macrophages. The present study examines the role and mechanism of Ca(2+) in platelet-activating factor (PAF)-stimulated LTB(4) release from human lung macrophages. Macrophages were isolated from lung tissue of subjects undergoing lung resection surgery and monocyte-derived macrophages (MDM) were obtained from nonsmokers, smokers without obstruction and COPD patients. Cells were stimulated with PAF and LTB(4) release and [Ca(2+)](i) was measured. Lung macrophages and MDM released LTB(4) following stimulation with PAF (mean effective concentration: 0.08+/-0.06 microM (n = 5) versus 0.17+/-0.12 microM (n = 17), respectively). Compared with MDM, lung macrophages released approximately eight-fold more LTB(4). Neither smoking nor COPD altered MDM responses. PAF-stimulated LTB(4) release was abrogated by ethylene glycol tetraacetic acid suggesting a role for extracellular Ca(2+). This was substantiated by using store-operated channel blockers econazole, SK&F96365 and Gd(3+). However, econazole and SK&F96365 were more effective in MDM than lung macrophages. Neither LOE908 nor nifedipine could attenuate this response. These data suggest that platelet-activating factor-stimulated leukotriene B(4) release from human lung macrophages is mediated, in part, by Ca(2+) influx through receptor- but not voltage-operated Ca(2+) channels.


The High Cost of HIV-Positive Inpatient Care at an Urban Hospital in Johannesburg, South Africa.
While most HIV care is provided on an outpatient basis, hospitals continue to treat serious HIV-related admissions, which is relatively resource-intensive and expensive. This study reports the primary reasons for HIV-related admission at a regional, urban hospital in Johannesburg, South Africa and estimates the associated lengths of stay and costs. A retrospective cohort study of adult, medical admissions was conducted. Each admission was assigned a reason for admission and an outcome. The length of stay was calculated for all patients (N = 1,041) and for HIV-positive patients (n = 469), actual utilization and associated costs were also estimated. Just under half were known to be HIV-positive admissions. Deaths and transfers were proportionately higher amongst HIV-positive admissions compared to HIV-negative and unknown. The three most common reasons for admission were tuberculosis and other mycobacterial infections (18%, n = 187), cardiovascular disorders (12%, n = 127) and bacterial infections (12%, n = 121). The study sample utilized a total of 7,733 bed days of those, 55% (4,259/7,733) were for HIV-positive patients. The average cost per admission amongst confirmed HIV-positive patients, which was an average of 9.3 days in length, was $1,783 (United States Dollars). Even in the era of large-scale antiretroviral treatment, inpatient facilities in South Africa shoulder a significant HIV burden. The majority of this burden is related to patients not on ART (298/469, 64%), and accounts for more than half of all inpatient resources. Reducing the costs of inpatient care is thus another important benefit of expanding access to ART, promoting earlier ART initiation, and achieving rates of ART retention and adherence.


The different effects of LPS and poly I:C prenatal immune challenges on the behavior, development and inflammatory responses in pregnant mice and their offspring.
In recent years, in vivo animal models of prenatal infection have been developed in an attempt to recreate behavioral and neuropathological features associated to a number of neurological and neuropsychiatric disorders. However, these models are still in their emerging phase and a better understanding of how these types of infections relate to adult-onset of brain-related disorders is needed. Here, we undertook an extensive behavioral characterization of both pregnant females and their pups following late gestational exposure (from gestational days (GD) 15-17) to either lipopolysaccharide (LPS; 120μg/kg i.p.) or polyinosinic:polycytidylic acid (poly I:C; 5mg/kg i.v.). We observed that both LPS and poly I:C treatments produced anxiety-like behaviors in treated pregnant females, although to a lesser extent with LPS. LPS injections, but not poly I:C, led to reduced food intake and consequently decreased weight gain in pregnant dams. In pups, poly I:C treatments triggered a delay in growth and sensorimotor development, as evaluated by righting, geotaxis and grasping reflexes. At the cellular level, both toxins induced an initial inflammatory response while only LPS reduced the expression of brain cell markers in foetuses (GFAP and NeuN), which was no longer observable at postnatal day (PnD) 10. Higher levels of IL-2, IL-5 and IL-6 in plasma and an upregulation of the metabotropic receptor 5 (mGluR5) in foetal brains of 10-day-old offspring prenatally exposed to poly I:C was also observed. Interestingly, the increased mGluR5 expression correlated with impairments of the righting reflex. This study is the first to directly compare reflex development following LPS and poly I:C prenatal immune challenges in mice and sheds light onto the different patterns of behavior and pathology in dams and their offspring.


Embed dynamic content in your poster.
A new technology has emerged that will facilitate the presentation of dynamic or otherwise inaccessible data on posters at scientific meetings. Video, audio, or other digital files hosted on mobile-friendly sites can be linked to through a quick response (QR) code, a two-dimensional barcode that can be scanned by smartphones, which then display the content. This approach is more affordable than acquiring tablet computers for playing dynamic content and can reach many users at large conferences. This resource details how to host videos, generate QR codes, and view the associated files on mobile devices.


Extra-pair mating and evolution of cooperative neighbourhoods.
A striking but unexplained pattern in biology is the promiscuous mating behaviour in socially monogamous species. Although females commonly solicit extra-pair copulations, the adaptive reason has remained elusive. We use evolutionary modelling of breeding ecology to show that females benefit because extra-pair paternity incentivizes males to shift focus from a single brood towards the entire neighbourhood, as they are likely to have offspring there. Male-male cooperation towards public goods and dear enemy effects of reduced territorial aggression evolve from selfish interests, and lead to safer and more productive neighbourhoods. The mechanism provides adaptive explanations for the common empirical observations that females engage in extra-pair copulations, that neighbours dominate as extra-pair sires, and that extra-pair mating correlates with predation mortality and breeding density. The models predict cooperative behaviours at breeding sites where males cooperate more towards public goods than females. Where maternity certainty makes females care for offspring at home, paternity uncertainty and a potential for offspring in several broods make males invest in communal benefits and public goods. The models further predict that benefits of extra-pair mating affect whole nests or neighbourhoods, and that cuckolding males are often cuckolded themselves. Derived from ecological mechanisms, these new perspectives point towards the evolution of sociality in birds, with relevance also for mammals and primates including humans.


The effects of refreshing and elaboration on working memory performance, and their contributions to long-term memory formation.
Refreshing and elaboration are cognitive processes assumed to underlie verbal working-memory maintenance and assumed to support long-term memory formation. Whereas refreshing refers to the attentional focussing on representations, elaboration refers to linking representations in working memory into existing semantic networks. We measured the impact of instructed refreshing and elaboration on working and long-term memory separately, and investigated to what extent both processes are distinct in their contributions to working as well as long-term memory. Compared with a no-processing baseline, immediate memory was improved by repeating the items, but not by refreshing them. There was no credible effect of elaboration on working memory, except when items were repeated at the same time. Long-term memory benefited from elaboration, but not from refreshing the words. The results replicate the long-term memory benefit for elaboration, but do not support its beneficial role for working memory. Further, refreshing preserves immediate memory, but does not improve it beyond the level achieved without any processing.


The effects of the social environment on stress-related cardiovascular activation: current findings, prospects, and implications.
Social relationships have been shown to be health-protective and to improve cardiovascular disease prognosis. One of the mechanisms by which social relationships may alter health status is through altering patterns of neuroendocrine or hemodynamic responding to ongoing activity. For example, research with non-human primates suggests that disrupted social relationships may increase cardiovascular risk through their effects on sympathetic nervous system activation. In humans, a number of recent reports have shown that the presence of an affiliative companion can reduce cardiovascular activity during psychologically challenging tasks, results which are consistent with this proposed mechanism of effect. We review the recent human literature which has examined the effects of the social environment on stress-related cardiovascular activity. Although findings in this literature are generally consistent, recent anomalous results are reviewed which shed light on some of the context-dependent effects of social affiliation. Additional areas for further investigation are examined, including possible mechanisms for explaining these social affiliation effects, individual differences which may moderate these effects, and emerging methodological advances for examining how these effects may generalize to the natural environment.


Targeting Trypanosoma cruzi sterol 14α-demethylase (CYP51).
There are at least two obvious features that must be considered upon targeting specific metabolic pathways/enzymes for drug development: the pathway must be essential and the enzyme must allow the design of pharmacologically useful inhibitors. Here, we describe Trypanosoma cruzi sterol 14α-demethylase as a promising target for anti-Chagasic chemotherapy. The use of anti-fungal azoles, which block sterol biosynthesis and therefore membrane formation in fungi, against the protozoan parasite has turned out to be highly successful: a broad spectrum anti-fungal drug, the triazole compound posaconazole, is now entering phase II clinical trials for treatment of Chagas disease. This review summarizes comparative information on anti-fungal azoles and novel inhibitory scaffolds selective for Trypanosomatidae sterol 14α-demethylase through the lens of recent structure/functional characterization of the target enzyme. We believe our studies open wide opportunities for rational design of novel, pathogen-specific and therefore more potent and efficient anti-trypanosomal drugs.


Nucleic acid reactivity: challenges for next-generation semiempirical quantum models.
Semiempirical quantum models are routinely used to study mechanisms of RNA catalysis and phosphoryl transfer reactions using combined quantum mechanical (QM)/molecular mechanical methods. Herein, we provide a broad assessment of the performance of existing semiempirical quantum models to describe nucleic acid structure and reactivity to quantify their limitations and guide the development of next-generation quantum models with improved accuracy. Neglect of diatomic differential overlap and self-consistent density-functional tight-binding semiempirical models are evaluated against high-level QM benchmark calculations for seven biologically important datasets. The datasets include: proton affinities, polarizabilities, nucleobase dimer interactions, dimethyl phosphate anion, nucleoside sugar and glycosidic torsion conformations, and RNA phosphoryl transfer model reactions. As an additional baseline, comparisons are made with several commonly used density-functional models, including M062X and B3LYP (in some cases with dispersion corrections). The results show that, among the semiempirical models examined, the AM1/d-PhoT model is the most robust at predicting proton affinities. AM1/d-PhoT and DFTB3-3ob/OPhyd reproduce the MP2 potential energy surfaces of 6 associative RNA phosphoryl transfer model reactions reasonably well. Further, a recently developed linear-scaling "modified divide-and-conquer" model exhibits the most accurate results for binding energies of both hydrogen bonded and stacked nucleobase dimers. The semiempirical models considered here are shown to underestimate the isotropic polarizabilities of neutral molecules by approximately 30%. The semiempirical models also fail to adequately describe torsion profiles for the dimethyl phosphate anion, the nucleoside sugar ring puckers, and the rotations about the nucleoside glycosidic bond. The modeling of pentavalent phosphorus, particularly with thio substitutions often used experimentally as mechanistic probes, was problematic for all of the models considered. Analysis of the strengths and weakness of the models suggests that the creation of robust next-generation models should emphasize the improvement of relative conformational energies and barriers, and nonbonded interactions.


Self-harm and suicidal ideation among young people is more often recorded by child protection than health services in an Australian population cohort.
We investigated patterns of service contact for self-harm and suicidal ideation recorded by a range of human service agencies - including health, police and child protection - with specific focus on overlap and sequences of contacts, age of first contact and demographic and intergenerational characteristics associated with different service responses to self-harm. Participants were 91,597 adolescents for whom multi-agency linked data were available in a longitudinal study of a population cohort in New South Wales, Australia. Self-harm and suicide-related incidents from birth to 18 years of age were derived from emergency department, inpatient hospital admission, mental health ambulatory, child protection and police administrative records. Descriptive statistics and binomial logistic regression were used to examine patterns of service contacts. Child protection services recorded the largest proportion of youth with reported self-harm and suicidal ideation, in which the age of first contact for self-harm was younger relative to other incidents of self-harm recorded by other agencies. Nearly 40% of youth with a health service contact for self-harm also had contact with child protection and/or police services for self-harm. Girls were more likely to access health services for self-harm than boys, but not child protection or police services. Suicide prevention is not solely the responsibility of health services; police and child protection services also respond to a significant proportion of self-harm and suicide-related incidents. High rates of overlap among different services responding to self-harm suggest the need for cross-agency strategies to prevent suicide in young people.


The magic and mystery of miR-21.
MicroRNAs (miRNAs) are potent regulators of mRNA stability and thereby protein expression. As such, miRNAs have become of interest as possible therapeutics and/or therapeutic targets. In this context, small complementary miRNA sequences known as antagomirs could be used to inhibit miRNA activity, while miRNA mimics could confer gain-of-function activity. However, a note of caution is sounded by Patrick et al. in this issue of the JCI, as they show that although recent reports have suggested that an miR-21 antagomir might be therapeutically useful in preventing heart failure in mice, genetic deletion of miR-21 does not confer a similar phenotype, suggesting possible confounding factors that are only now beginning to be revealed in the techniques used to study miRNA biology.


Preventing cancer, cardiovascular disease, and diabetes: a common agenda for the American Cancer Society, the American Diabetes Association, and the American Heart Association.
Collectively, cardiovascular disease (including stroke), cancer, and diabetes account for approximately two-thirds of all deaths in the U.S. and about US dollars 700 billion in direct and indirect economic costs each year. Current approaches to health promotion and prevention of cardiovascular disease, cancer, and diabetes do not approach the potential of the existing state of knowledge. A concerted effort to increase application of public health and clinical interventions of known efficacy to reduce prevalence of tobacco use, poor diet, and insufficient physical activity-the major risk factors for these diseases-and to increase utilization of screening tests for their early detection could substantially reduce the human and economic cost of these diseases. In this article, the American Cancer Society, American Diabetes Association, and American Heart Association review strategies for the prevention and early detection of cancer, cardiovascular disease, and diabetes, as the beginning of a new collaboration among the three organizations. The goal of this joint venture is to stimulate substantial improvements in primary prevention and early detection through collaboration between key organizations, greater public awareness about healthy lifestyles, legislative action that results in more funding for and access to primary prevention programs and research, and reconsideration of the concept of the periodic medical checkup as an effective platform for prevention, early detection, and treatment.


Hybrid metal-dielectric ring resonators for homogenizable optical metamaterials with strong magnetic response at short wavelengths down to the ultraviolet range.
We derive an analytical LC model from Maxwell's equations for the magnetic resonance of subwavelength ring resonators. Using the LC model, we revisit the scaling of split-ring resonators. Inspired by the LC model, we propose a hybrid metal-dielectric ring resonator mainly composed of high index dielectric material (e.g., TiO₂) with some gaps filled with metal (e.g., Ag). The saturation frequency of magnetic response for the hybrid metal-dielectric ring resonator is much higher (up to the ultraviolet range) than that for split-ring resonators, and can be controlled by the metal fraction in the ring. The hybrid metal-dielectric ring resonator can also overcome the homogenization problem of all-dielectric magnetic resonators, and therefore can form homogenizable magnetic metamaterials at short wavelengths down to the ultraviolet range.


Effects of temperature, salinity and fish in structuring the macroinvertebrate community in shallow lakes: implications for effects of climate change.
Climate warming may lead to changes in the trophic structure and diversity of shallow lakes as a combined effect of increased temperature and salinity and likely increased strength of trophic interactions. We investigated the potential effects of temperature, salinity and fish on the plant-associated macroinvertebrate community by introducing artificial plants in eight comparable shallow brackish lakes located in two climatic regions of contrasting temperature: cold-temperate and Mediterranean. In both regions, lakes covered a salinity gradient from freshwater to oligohaline waters. We undertook day and night-time sampling of macroinvertebrates associated with the artificial plants and fish and free-swimming macroinvertebrate predators within artificial plants and in pelagic areas. Our results showed marked differences in the trophic structure between cold and warm shallow lakes. Plant-associated macroinvertebrates and free-swimming macroinvertebrate predators were more abundant and the communities richer in species in the cold compared to the warm climate, most probably as a result of differences in fish predation pressure. Submerged plants in warm brackish lakes did not seem to counteract the effect of fish predation on macroinvertebrates to the same extent as in temperate freshwater lakes, since small fish were abundant and tended to aggregate within the macrophytes. The richness and abundance of most plant-associated macroinvertebrate taxa decreased with salinity. Despite the lower densities of plant-associated macroinvertebrates in the Mediterranean lakes, periphyton biomass was lower than in cold temperate systems, a fact that was mainly attributed to grazing and disturbance by fish. Our results suggest that, if the current process of warming entails higher chances of shallow lakes becoming warmer and more saline, climatic change may result in a decrease in macroinvertebrate species richness and abundance in shallow lakes.


Colorectal polyposis and inherited colorectal cancer syndromes.
The majority of colorectal cancer (CRC) cases are sporadic, with hereditary factors contributing to approximately 35% of CRC cases. Less than 5% of CRC is associated with a known genetic syndrome. Although adenomatous polyposis syndromes, hamartomatous polyposis syndromes, and those previously classified as non-polyposis CRC syndromes are quite rare, it is important for clinicians to know the characteristics of each syndrome and to understand the differences in cancer risks between the different conditions. This information is very important when treatment and surveillance plans are formulated for each individual patient.


Responses of Drosophila giant descending neurons to visual and mechanical stimuli.
In Drosophila, the paired giant descending neurons (GDNs), also known as giant fibers, and the paired giant antennal mechanosensory descending neurons (GAMDNs), are supplied by visual and mechanosensory inputs. Both neurons have the largest cell bodies in the brain and both supply slender axons to the neck connective. The GDN axon thereafter widens to become the largest axon in the thoracic ganglia, supplying information to leg extensor and wing depressor muscles. The GAMDN axon remains slender, interacting with other descending neuron axons medially. GDN and GAMDN dendrites are partitioned to receive inputs from antennal mechanosensory afferents and inputs from the optic lobes. Although GDN anatomy has been well studied in Musca domestica, less is known about the Drosophila homolog, including electrophysiological responses to sensory stimuli. Here we provide detailed anatomical comparisons of the GDN and the GAMDN, characterizing their sensory inputs. The GDN showed responses to light-on and light-off stimuli, expanding stimuli that result in luminance decrease, mechanical stimulation of the antennae, and combined mechanical and visual stimulation. We show that ensembles of lobula columnar neurons (type Col A) and mechanosensory antennal afferents are likely responsible for these responses. The reluctance of the GDN to spike in response to stimulation confirms observations of the Musca GDN. That this reluctance may be a unique property of the GDN is suggested by comparisons with the GAMDN, in which action potentials are readily elicited by mechanical and visual stimuli. The results are discussed in the context of descending pathways involved in multimodal integration and escape responses.


Impaired Oral Health in Older Orthopaedic In-Care Patients: The Influence of Medication and Morbidity.
Fall-related injuries are prevalent in older patients and often lead to increased morbidity, medication, and impaired functions. We studied older trauma patients with the aim to describe their oral health in comparison to morbidity and medication. The study included 198 patients, ≥65 years, admitted with an orthopedic trauma. Oral examinations included number of natural teeth, dental implants, missing, decayed and restored teeth, root remnants, and pocket depth. Data on comorbidities and medication were assembled. Statistical analyses were carried out with logistic regression models, adjusted for age, gender, comorbidity, and polypharmacy. Overall, 198 patients participated, 71% women, mean age 81 years (±7.9), 85% resided in their own homes, 86% had hip fractures. Chronic diseases and drug use were present in 98.9%, a mean of 6.67 in Charlson comorbidity index (CCI), 40% heart diseases, 17% diabetes, and 14% dementia. Ninety-one percent were dentate (181), mean number of teeth 19.2 (±6.5), 24% had decayed teeth, 97% filled teeth, 44% <20 teeth, and 26% oral dryness. DFT (decayed, filled teeth) over mean were identified in patients with diabetes (p=0.037), COPD (p=0.048), polypharmacy (p=0.011), diuretics (p=0.007), and inhalation drugs (p=0.032). Use of ≥2 strong anticholinergic drugs were observed in patients with <20 teeth and DFT over mean (p=0.004, 0.003). Adjusted for age, gender, CCI, and polypharmacy. The study showed that impaired oral health was prevalent in older trauma patients and that negative effects on oral health were significantly associated with chronic diseases and drug use. The results emphasize the importance of identifying orthogeriatric patients with oral health problems and to stress the necessity to uphold good oral care during a period when functional decline can be expected.


Mechanism of Na+/H+ antiporting.
Na+/H+ antiporters are central to cellular salt and pH homeostasis. The structure of Escherichia coli NhaA was recently determined, but its mechanisms of transport and pH regulation remain elusive. We performed molecular dynamics simulations of NhaA that, with existing experimental data, enabled us to propose an atomically detailed model of antiporter function. Three conserved aspartates are key to our proposed mechanism: Asp164 (D164) is the Na+-binding site, D163 controls the alternating accessibility of this binding site to the cytoplasm or periplasm, and D133 is crucial for pH regulation. Consistent with experimental stoichiometry, two protons are required to transport a single Na+ ion: D163 protonates to reveal the Na+-binding site to the periplasm, and subsequent protonation of D164 releases Na+. Additional mutagenesis experiments further validated the model.


Evaluation of the state-of-the-art measurement capabilities for selected PBDEs and decaBB in plastic by the international intercomparison CCQM-P114.
An international intercomparison involving eight national metrology institutes (NMIs) was conducted to establish their current measurement capabilities for determining five selected congeners from the brominated flame retardant classes polybrominated diphenyl ethers and polybrominated biphenyls. A candidate reference material consisting of polypropylene fortified with technical mixtures of penta-, octa- and decabromo diphenyl ether and decabromo biphenyl, which was thoroughly assessed for material homogeneity and stability, was used as study material. The analytical procedures applied by the participants differed with regard to sample pre-treatment, extraction, clean-up, employed calibrants and type of calibration procedure as well as regarding analytical methods used for separation, identification and quantification of the flame retardant congeners (gas chromatography coupled to an electron capture detector (GC-ECD), gas chromatography-mass spectrometry in the electron ionisation mode (GC-EI-MS), gas chromatography-mass spectrometry in the electron capture negative ionisation mode (GC-ECNI-MS), and liquid chromatography-inductive coupled plasma-mass spectrometry (LC-ICP-MS)). The laboratory means agreed well with relative standard deviations of the mean of means of 1.9%, 4.8%, 5.5% and 5.4% for brominated diphenyl ether (BDE) 47, 183 and 209 and for the brominated biphenyl (BB) congener 209, respectively. For BDE 206, a relative standard deviation of 28.5% was obtained. For all five congeners, within-laboratory relative standard deviations of six measurements obtained under intermediate precision conditions were between 1% and 10%, and reported expanded measurements uncertainties typically ranged from 4% to 10% (8% to 14% for BDE 206). Furthermore, the results are in good agreement with those obtained in the characterization exercise for determining certified values for the flame retardant congeners in the same material. The results demonstrate the state-of-the-art measurement capabilities of NMIs for quantifying representative BDE congeners and BB 209 in a polymer. The outcome of this intercomparison (pilot study) in conjunction with possible improvements for employing exclusively calibrants with thoroughly assessed purity suggests that a key comparison aiming at underpinning calibration and measurement capability (CMC) claims of NMIs can be conducted.


Concurrent loss of the PTEN and RB1 tumor suppressors attenuates RAF dependence in melanomas harboring (V600E)BRAF.
Identifying the spectrum of genetic alterations that cooperate with critical oncogenes to promote transformation provides a foundation for understanding the diversity of clinical phenotypes observed in human cancers. Here, we performed integrated analyses to identify genomic alterations that co-occur with oncogenic BRAF in melanoma and abrogate cellular dependence upon this oncogene. We identified concurrent mutational inactivation of the PTEN and RB1 tumor suppressors as a mechanism for loss of BRAF/MEK dependence in melanomas harboring (V600E)BRAF mutations. RB1 alterations were mutually exclusive with loss of p16(INK4A), suggesting that whereas p16(INK4A) and RB1 may have overlapping roles in preventing tumor formation, tumors with loss of RB1 exhibit diminished dependence upon BRAF signaling for cell proliferation. These findings provide a genetic basis for the heterogeneity of clinical outcomes in patients treated with targeted inhibitors of the mitogen-activated protein kinase pathway. Our results also suggest a need for comprehensive screening for RB1 and PTEN inactivation in patients treated with RAF and MEK-selective inhibitors to determine whether these alterations are associated with diminished clinical benefit in patients whose cancers harbor mutant BRAF.


The balance of power: innate lymphoid cells in tissue inflammation and repair.
Over the last ten years, immunologists have recognized the central importance of an emerging group of innate lymphoid cells (ILCs) in health and disease. Characterization of these cells has provided a molecular definition of ILCs and their tissue-specific functions. Although the lineage-defining transcription factors, cytokine production, and nomenclature parallel those of T helper cells, ILCs do not require adaptive immune programming. Both environmental and host-derived signals shape the function of these evolutionarily ancient cells, which provide pathogen protection and promote tissue restoration. As such, ILCs function as a double-edged sword, balancing the inflammatory and reparative responses that arise during injury and disease. This Review highlights our recent understanding of tissue-resident ILCs and the signals that regulate their contribution to inflammation and tissue repair in health and disease.


A general synthetic strategy and the anti-proliferation properties on prostate cancer cell lines for natural phenylethanoid glycosides.
A general strategy for the synthesis of phenylethanoid glycosides (PhG) including echinacoside 1, acteoside 2, calceolarioside-A 3 and calceolarioside-B 4 is reported. The strategy features the application of low substrate concentration glycosylation and N-formyl morpholine modulated glycosylation methods for the construction of 1,2-trans β- and α-glycosidic bonds. The reported strategy does not invoke the use of the participatory acyl protecting function, which is incompatible with the ester function present in target PhG compounds. A preliminary study of the anti-proliferation properties of the PhG compounds 1–4 was performed; the acteoside 2 exhibited the best inhibition on the prostatic cancer cell proliferation.


Formalizing biomedical concepts from textual definitions.
Ontologies play a major role in life sciences, enabling a number of applications, from new data integration to knowledge verification. SNOMED CT is a large medical ontology that is formally defined so that it ensures global consistency and support of complex reasoning tasks. Most biomedical ontologies and taxonomies on the other hand define concepts only textually, without the use of logic. Here, we investigate how to automatically generate formal concept definitions from textual ones. We develop a method that uses machine learning in combination with several types of lexical and semantic features and outputs formal definitions that follow the structure of SNOMED CT concept definitions. We evaluate our method on three benchmarks and test both the underlying relation extraction component as well as the overall quality of output concept definitions. In addition, we provide an analysis on the following aspects: (1) How do definitions mined from the Web and literature differ from the ones mined from manually created definitions, e.g., MeSH? (2) How do different feature representations, e.g., the restrictions of relations' domain and range, impact on the generated definition quality?, (3) How do different machine learning algorithms compare to each other for the task of formal definition generation?, and, (4) What is the influence of the learning data size to the task? We discuss all of these settings in detail and show that the suggested approach can achieve success rates of over 90%. In addition, the results show that the choice of corpora, lexical features, learning algorithm and data size do not impact the performance as strongly as semantic types do. Semantic types limit the domain and range of a predicted relation, and as long as relations' domain and range pairs do not overlap, this information is most valuable in formalizing textual definitions. The analysis presented in this manuscript implies that automated methods can provide a valuable contribution to the formalization of biomedical knowledge, thus paving the way for future applications that go beyond retrieval and into complex reasoning. The method is implemented and accessible to the public from: https://github.com/alifahsyamsiyah/learningDL.


A review on brain tumor diagnosis from MRI images: Practical implications, key achievements, and lessons learned.
The successful early diagnosis of brain tumors plays a major role in improving the treatment outcomes and thus improving patient survival. Manually evaluating the numerous magnetic resonance imaging (MRI) images produced routinely in the clinic is a difficult process. Thus, there is a crucial need for computer-aided methods with better accuracy for early tumor diagnosis. Computer-aided brain tumor diagnosis from MRI images consists of tumor detection, segmentation, and classification processes. Over the past few years, many studies have focused on traditional or classical machine learning techniques for brain tumor diagnosis. Recently, interest has developed in using deep learning techniques for diagnosing brain tumors with better accuracy and robustness. This study presents a comprehensive review of traditional machine learning techniques and evolving deep learning techniques for brain tumor diagnosis. This review paper identifies the key achievements reflected in the performance measurement metrics of the applied algorithms in the three diagnosis processes. In addition, this study discusses the key findings and draws attention to the lessons learned as a roadmap for future research.


Optical vortices in twisted elliptical optical fibers with torsional stress.
In the present paper we have derived the analytical expressions for the modes of twisted elliptical fibers with torsional mechanical stress at various relationships of the fiber parameters. It was shown that circularly polarized optical vortices with the topological charges ±1 can propagate in elliptical fibers as generic modes if ellipticity and the twist-induced circular birefringence suppress the spin-orbit interaction. A comparison of the obtained results with the corresponding results for spun elliptical fibers is made.


Farmland biodiversity and agricultural management on 237 farms in 13 European and two African regions.
Farmland is a major land cover type in Europe and Africa and provides habitat for numerous species. The severe decline in farmland biodiversity of the last decades has been attributed to changes in farming practices, and organic and low-input farming are assumed to mitigate detrimental effects of agricultural intensification on biodiversity. Since the farm enterprise is the primary unit of agricultural decision making, management-related effects at the field scale need to be assessed at the farm level. Therefore, in this study, data were collected on habitat characteristics, vascular plant, earthworm, spider, and bee communities and on the corresponding agricultural management in 237 farms in 13 European and two African regions. In 15 environmental and agricultural homogeneous regions, 6-20 farms with the same farm type (e.g., arable crops, grassland, or specific permanent crops) were selected. If available, an equal number of organic and non-organic farms were randomly selected. Alternatively, farms were sampled along a gradient of management intensity. For all selected farms, the entire farmed area was mapped, which resulted in total in the mapping of 11 338 units attributed to 194 standardized habitat types, provided together with additional descriptors. On each farm, one site per available habitat type was randomly selected for species diversity investigations. Species were sampled on 2115 sites and identified to the species level by expert taxonomists. Species lists and abundance estimates are provided for each site and sampling date (one date for plants and earthworms, three dates for spiders and bees). In addition, farmers provided information about their management practices in face-to-face interviews following a standardized questionnaire. Farm management indicators for each farm are available (e.g., nitrogen input, pesticide applications, or energy input). Analyses revealed a positive effect of unproductive areas and a negative effect of intensive management on biodiversity. Communities of the four taxonomic groups strongly differed in their response to habitat characteristics, agricultural management, and regional circumstances. The data has potential for further insights into interactions of farmland biodiversity and agricultural management at site, farm, and regional scale.


Dynamic wave-front generation for the characterization and testing of optical systems.
We describe a simple method for generating known optical aberrations dynamically, using a ferroelectric liquid-crystal spatial light modulator. Aberrations inherent in the optical system are measured and corrected, and as an example Kolmogorov turbulence is simulated for aperture sizes D/r(0) from 0 to 30, varying at frame rates up to 2.5 kHz. A measure of wave-front generation efficiency is introduced and is shown to be better than 86% for Kolmogorov phase screens with D/r(0) in the range from 0 to 30.


Evaluation of Bernese periacetabular osteotomy: prospective studies examining projected load-bearing area, bone density, cartilage thickness and migration.
The typical dysplastic hip joint is characterised by maldirection of the acetabulum and femoral neck, insufficient coverage of the femoral head focally and globally and erosions of the limbus acetabuli (1). An unknown number of persons with hip dysplasia will suffer from pain in hip or groin, decreased hip function and development of osteoarthritis at a young age. The Bernese periacetabular osteotomy is performed to prevent osteoarthritis in patients with hip dysplasia and has been carried out at Aarhus University Hospital, Denmark since 1996 with more than 500 osteotomies performed. Throughout the years, research and quality improvement of the treatment has taken place and this PhD thesis is part of that process. The aims of this PhD thesis were to evaluate outcome aspects after periacetabular osteotomy in terms of I) estimating the projected loadbearing surface before and after periacetabular osteotomy, II) estimating bone density changes in the acetabulum after periacetabular osteotomy, III) developing a technique to precisely and efficiently estimate the thickness of the articular cartilage in the hip joint and IV) examining the stability of the re-orientated acetabulum after periacetabular osteotomy. In study I, we applied a stereologic method based on 3D computed tomography (CT) to estimate the projected loadbearing surface in six normal hip joints and in six dysplastic hips. The dysplastic hips were CT scanned before and after periacetabular osteotomy. We found that the average area of the projected loadbearing surface of the femoral head preoperatively was 7.4 (range 6.5-8.4) cm2 and postoperatively 11 (9.8-14.3) cm2. The area of the projected loadbearing surface was increased significantly with a mean of 49% (34-70%) postoperatively and thus comparable with the load-bearing surface in the normal control group. Double measurements were performed and the error variance of the mean was estimated to be 1.6%. The effect of overprojection, on the projected loadbearing surface was minimal. Consequently, the stereo-logic method proved to be precise and unbiased. The study indicates that this method is applicable in monitoring the loadbearing area in the hip joint of patients undergoing periacetabular osteotomy. In study II, a method based on CT and 3D design-based sampling principles was used to estimate bone density in different regions of the acetabulum. Baseline density was measured within the first seven days following periacetabular osteotomy and compared with density two years postoperatively. Double measurements were performed on three patients, and the error variance was estimated to be 0.05. Six patients with hip dysplasia scheduled for periacetabular osteotomy were consecutively included in the study. Bone density increased significantly in the anteromedial quadrant of the acetabulum as well as in the posteromedial quadrant between the two time-points. In the anterolateral quadrant bone density was unchanged following surgery, and the same was true for the posterolateral quadrant. We suggest that the observed increase in bone density medially represents a remodelling response to an altered load distribution after periacetabular osteotomy. The described method is a precise tool to estimate bone density changes in the acetabulum. Study III. As periacetabular osteotomy is performed on dysplastic hips to prevent osteoarthritic progression, changes in the thickness of the articular cartilage is a central variable to follow over time. 26 dysplastic hips on 22 females and 4 males were magnetic resonance imaged (MRI) preoperatively. The first 13 patients were examined twice, with complete repositioning of the patient and set-up in order to obtain an estimate of the precision of the method used. To show the acetabular and femoral cartilages separately, an ankle traction device was used during MRI. This device pulled the leg distally with a load of 10 kg. The mean thickness of the acetabular cartilage was 1.26 mm, SD 0.04 mm. The mean thickness of the femoral cartilage was 1.18 mm, SD 0.06. The precision calculated as the error variance was estimated for the thickness of the acetabular cartilage to 0.01 and femoral cartilage 0.02. We suggest that the method can be advantageous for assessing the progression of osteoarthritis in dysplastic hips after periacetabular osteotomy. In study IV, 32 dysplastic hips, 27 females and 5 males were included in the study. Radiostereometric examinations (RSA) were done at one week, four weeks, eight weeks and six months. Data are presented as mean + SD. Six months postoperatively, the acetabular fragment had migrated 0.7 mm + 0.8 medially, and 0.7 mm + 0.5 proximally. Mean rotation in adduction was 0.5 degrees + 1.3. In other directions, mean migration was below 0.5 mm/degrees. There was no statistical difference between migration 8 weeks and 24 weeks postoperatively in translation or rotation. Due to the limited migration, we find our postoperative partial weight-bearing regime safe. In conclusion, the studies in the present PhD thesis indicate that the projected loadbearing area of the hip joint increases considerable in patients undergoing periacetabular osteotomy and a method to estimate this area was described. Bone density increases in the medial quadrants two years postoperative and a method is developed to precisely estimate bone density on CT images. Also a method to precisely estimate cartilage thickness was presented and we suggest that the method can be advantageous for assessing the progression of osteoarthritis in dysplastic hips after periacetabular osteotomy. Due to the very limited migration of the acetabular fragment fixated with two screws, we find our fixation sufficient and the postoperative partial weight-bearing regimen safe.


Impact of pretransplant renal function on survival after liver transplantation.
To determine the effect of pretransplant liver function on survival following orthotopic liver transplantation and to quantify the effects of cyclosporine administration on long-term renal function in patients undergoing liver transplant, we performed an analysis of a prospectively maintained database. Data from 569 consecutive patients undergoing liver transplantation alone who were treated with CsA for immunosuppression were used for this study. Actuarial graft and patient survival rates were calculated using Kaplan-Meier statistics. Glomerular filtration rates, serum creatinine, and the use of various immunosuppressives were analyzed for this study. The initial analysis demonstrated that patients presenting for liver transplant with hepatorenal syndrome have a significantly decreased acturial patient survival after liver transplant at 5 years compared with patients without hepatorenal syndrome (60% vs. 68%, P < 0.03). Patients with hepatorenal syndrome recovered their renal function after liver transplant. Patients who had hepatorenal syndrome were sicker and required longer stays in the intensive care unit, longer hospitalizations, and more dialysis treatments after transplantation compared with patients who did not have hepatorenal syndrome. The incidence of end-stage renal disease after liver transplantation in patients who had hepatorenal syndrome was 7%, compared with 2% in patients who did not have hepatorenal syndrome. To more fully examine the effect of pretransplant renal function on posttransplant survival, the non-hepatorenal syndrome patients were divided into quartiles depending upon their pretransplant renal function. The patients with the lowest pretransplant renal function had the same survival as the patients with the highest pretransplant renal function. In addition, there was no increased incidence of acute or chronic rejection in any of the groups. The patients with the lower pretransplant renal function were treated with more azathioprine to maintain renal function and had a negligible decrease in glomerular filtration rate following transplant. Conversely, patients with the highest level of renal function pretransplant had a 40% decline in renal function in the first year, but maintained stable renal function up to 4 years after transplant. We conclude that pretransplant renal function other than hepato-renal syndrome has no effect on patient survival after orthotopic liver transplant. Renal function after liver transplant is stable after an initial decline, despite continued administration of CsA.(ABSTRACT TRUNCATED AT 400 WORDS)


Immunosenescence and the ability to survive bacterial infection in the red flour beetle Tribolium castaneum.
In most animals, ageing is associated with a decline in immune function (immune senescence). However, different components of the immune system seem to age differentially, and many studies do not measure the ultimate fitness consequences of immune function after infection. Previous work shows that immune function may be traded off with other fitness components such as reproduction. It is possible that age alters the nature of these trade-offs, particularly in conjunction with factors such as gender and mating that can also affect investment in immune function. We tested the impact of age, sex and mating on post-infection survivorship in Tribolium castaneum flour beetles, as well as the components of baseline constitutive innate immunity and external (secreted) immune function in uninfected individuals. We also tested whether the reproductive ability of uninfected females is traded off with immune function (baseline innate and external immunity) and post-infection survivorship across age groups. We found that age, sex and mating significantly affected immune components and infection outcome, although the magnitude and nature of the impact varied in each case. We found that older beetles were more susceptible to infection by the pathogen Bacillus thuringiensis even though major components of the constitutive innate immune defence (antibacterial and phenoloxidase activity) remained unchanged or improved with age. Thus, these aspects of innate immunity cannot explain the observed decline in post-infection survival of older beetles. We did not find trade-offs between the reproductive ability of uninfected females and their immune function. In contrast to innate immunity, external immunity showed an overall decline with age but was also affected by sex and mating. Finally, we show that bacterial infection alters external immunity via complex interactions between age, sex and mating status. Our work uncovers novel interactions between age, sex and mating that can determine the evolution and outcome of immunosenescence by affecting the time course of relative investment in different immune and fitness components.


Review: Reactive oxygen and nitrogen species and functional adaptation of the placenta.
The placenta regulates fetal growth and development via transport of nutrients and gases, and synthesis and secretion of steroid and peptide hormones. These functions are determined by vascular development and blood flow and by growth and differentiation of the trophoblast, which contains receptors, transporters and enzymes. The placenta generates reactive oxygen species which may contribute to the oxidative stress seen even in normal pregnancy but this is increased in pregnancies complicated by preeclampsia, IUGR and pregestational diabetes where oxidative and nitrative stress have been clearly documented. Nitrative stress is the covalent modification of proteins and DNA by peroxynitrite formed by the interaction of superoxide and nitric oxide. We have demonstrated nitrative stress by localizing nitrotyrosine residues in these placentas and found increased expression of NADPH oxidase (NOX) enzyme isoforms 1 and 5 as a potential source of superoxide generation. The presence of nitrative stress was associated with diminished vascular reactivity of the fetal placental circulation, a situation that could be reproduced by treatment with peroxynitrite in vitro. We find many nitrated proteins in the placenta, including p38 MAP kinase which has a role in development of the villous vasculature. Nitration of p38 MAPK was increased in the preeclamptic placenta and associated with loss of catalytic activity. We hypothesize that nitration of proteins in the placenta including receptors, transporters, enzymes and structural proteins can alter protein and placental function and this influences fetal growth and development. Increasing nitrative stress but a decrease in oxidative stress, measured as protein carbonylation, is found in the placenta with increasing BMI. Formation of peroxynitrite may then consume superoxide, decreasing nitrative stress. As protein carbonylation is a covalent modification at Lys, Arg, Pro and Thr residues the switch from carbonylation to nitration at tyrosine residues may alter protein function and hence placental function.


On-line concentration of a protein using denaturation by sodium dodecyl sulfate.
A novel method for the on-column sample stacking of proteins is described. The strategy takes advantage of interactions between protein molecules and sodium dodecyl sulfate (SDS) monomers. A long plug of a protein sample (either acidic or basic) is injected into a capillary filled with a background electrolyte (BGE) containing SDS. When a potential is applied, the proteins interact with SDS monomers in the BGE to form protein-SDS complexes that migrate more slowly than the corresponding uncomplexed protein, resulting in protein stacking. Both acidic and basic proteins migrate at an almost identical electrophoretic velocity after stacking, which indicates that the protein-SDS complexes formed in the BGE zone have a similar charge/mass ratio. The mechanism of stacking was investigated using a sample consisting of a basic protein, lysozyme, and a small molecule, methylene blue. The findings clearly show that two interactions with SDS occur, a stepwise binding interaction between protein molecules and SDS monomers and an interaction in which the small molecules enter into micelles formed by SDS molecules. The method was also applied to the detection of a protein labeled with a fluorescent labeling reagent at trace levels. The labeled protein was detected even under labeling conditions where the labeling efficiency was too low to detect by short-plug injection.


Revision knee arthroplasty in rheumatoid arthritis.
Seventy-six revised total knee arthroplasties (TKAs) performed for mechanical, nonseptic failure of the primary arthroplasty in 62 rheumatoid arthritis patients were investigated. The revisions were performed with McIntosh, Marmor, Attenborough, Guepar, and various types of tricompartmental prostheses. Twenty-one of the 76 revisions subsequently failed. Fifteen were mechanical failures and six were deep infections. Thirteen of the 21 failures were treated with another arthroplasty, six with arthrodesis, and two with antibiotics only. After an average of 60 months, 48 of the surviving arthroplasties were examined clinically and roentgenographically. At follow-up examination, eight were clinical failures. One-half of the McIntosh and Marmor arthroplasties and one-third of the Attenborough and Guepar arthroplasties, altogether 17 cases, showed signs of potential roentgenographic failure. The majority of the revised TKAs classified as roentgenographic failures were clinically successful or acceptable. Revision of TKAs in noninfected rheumatoid patients can be performed with acceptable clinical results but with a significantly higher failure rate than after primary procedures.


Coupling vascular and myocardial inflammatory injury into a common phenotype of cardiovascular dysfunction: systemic inflammation and aging - a mini-review.
The rising epidemic of cardiovascular (CV) disease is fuelled by obesity, hypertension and diabetes and, independently and cumulatively, by an aging population. Extensive research identified immunoinflammatory mechanisms as key drivers in the initiation and progression of the disease, from early asymptomatic stages of vascular and myocardial injury leading to the clinically manifest dysfunction and remodeling in advanced stages. Underlying processes include endothelial dysfunction and extracellular matrix restructuration leading to increased vascular stiffness, as well as myocardial remodeling with dilatation and wall thinning. In this, overproduction of tumor necrosis factor-α, amongst others, contributes to generalized CV injury and dysfunction. Moreover, recent insights into the involvement of innate and adaptive immunity in atherosclerosis have shed light on many interesting parallels with chronic systemic inflammatory conditions, such as rheumatoid arthritis, with aggravated inflammation-induced vascular and myocardial injury. Besides, chronologic age has been identified as a potent, independent risk for reduced CV capacity and a plethora of heart diseases, with other modifiable risk factors acting as accelerators. We discuss the available evidence and propose that characterization of inflammatory CV responses might reveal a distinctive CV inflammatory phenotype. A comprehensive noninvasive bio-signature, comprising immunomic biomarkers and integrated noninvasive imaging, may serve as a potential tool in the early diagnosis and prognostication of CV risk.


Environmental and Occupational Exposure to Asbestos as a Result of Consumption and Use in Poland.
Asbestos is harmful to human health; exposure to asbestos causes a wide range of asbestos-related diseases. Malignant mesothelioma (MM) is unique to occupational and environmental asbestos exposure. Environmental asbestos exposure was examined in relation to asbestos use and manufacturing, the quantity of the asbestos-containing products still in use, the concentrations of asbestos fibres in the air and the number of MM cases diagnosed each year per county. The correlation coefficient of the measurements of the asbestos fibre concentrations in the air and the quantity of asbestos-cement products in use is high and amounts to 0.68. Meanwhile, the correlation coefficient of the measurements of asbestos fibre concentrations in air and MM morbidity rate resulting from environmental exposure calculated for particular counties in provinces is low and amounts to 0.37. The highest MM morbidity rate was observed for Małopolskie and Śląskie, a typical industrial area of Poland. There are MM cases which are still attributable to occupational asbestos exposure, although MM cases resulting from environmental exposure to asbestos have an increased MM risk. Poland is among those countries with a low MM incidence rate, which seems to be an underestimation of environmental asbestos exposure. As long as asbestos-cement products are used in the environment, actions should be undertaken to protect public health.


Cardenolide sequestration by the dogbane tiger moth (Cycnia tenera; Arctiidae).
Cycnia tenera adults, reared as larvae onAsclepias humistrata, had 10 times higher cardenolide concentrations, and contained 15 times more total cardenolide, than did moths reared onA. tuberosa. Thin-layer chromatography confirmed that each individual cardenolide visualized in the adult moths reared on the former host plant corresponds to one present in the plant, thus demonstrating that the insects' cardenolides are indeed derived from the larval food. Adult weights were significantly greater when the larvae had been fed upon the higher cardenolide plant species,A. humistrata. Similar results for other milkweed-feeding insects have been interpreted by some authors as evidence against a metabolic cost of handling cardenolides. However, such interpretations confound cardenolide differences among milkweed species with other differences in plant primary and secondary chemistry that affect insect growth and development. While the cooccurrence inC. tenera of other noxious chemicals (e.g., alkaloids) is not precluded, cardenolides sequestered from larval host plants have probably contributed to the evolution of visual and auditory aposematism in this species. As the eggs are laid in large clutches and larvae are gregarious, such aposematism may have evolved via kin selection.


Rudeness and Medical Team Performance.
Rudeness is routinely experienced by medical teams. We sought to explore the impact of rudeness on medical teams' performance and test interventions that might mitigate its negative consequences. Thirty-nine NICU teams participated in a training workshop including simulations of acute care of term and preterm newborns. In each workshop, 2 teams were randomly assigned to either an exposure to rudeness (in which the comments of the patient's mother included rude statements completely unrelated to the teams' performance) or control (neutral comments) condition, and 2 additional teams were assigned to rudeness with either a preventative (cognitive bias modification [CBM]) or therapeutic (narrative) intervention. Simulation sessions were evaluated by 2 independent judges, blind to team exposure, who used structured questionnaires to assess team performance. Rudeness had adverse consequences not only on diagnostic and intervention parameters (mean therapeutic score 3.81 ± 0.36 vs 4.31 ± 0.35 in controls, P < .01), but also on team processes (such as information and workload sharing, helping and communication) central to patient care (mean teamwork score 4.04 ± 0.34 vs 4.43 ± 0.37, P < .05). CBM mitigated most of these adverse effects of rudeness, but the postexposure narrative intervention had no significant effect. Rudeness has robust, deleterious effects on the performance of medical teams. Moreover, exposure to rudeness debilitated the very collaborative mechanisms recognized as essential for patient care and safety. Interventions focusing on teaching medical professionals to implicitly avoid cognitive distraction such as CBM may offer a means to mitigate the adverse consequences of behaviors that, unfortunately, cannot be prevented.


Can knowledge exchange support the implementation of a health-promoting schools approach? Perceived outcomes of knowledge exchange in the COMPASS study.
Despite the potential population-level impact of a health-promoting schools approach, schools face challenges in implementation, indicating a gap between school health research and practice. Knowledge exchange provides an opportunity to reduce this gap; however, there has been limited evaluation of these initiatives. This research explored researchers' and knowledge users' perceptions of outcomes associated with a knowledge exchange initiative within COMPASS, a longitudinal study of Canadian secondary students and schools. Schools received annual tailored summaries of their students' health behaviours and suggestions for action and were linked with knowledge brokers to support them in taking action to improve student health. Qualitative semi-structured interviews were conducted with COMPASS researchers (n = 13), school staff (n = 13), and public health stakeholders (n = 4) to explore their experiences with COMPASS knowledge exchange. Key issues included how knowledge users used school-specific findings, perceived outcomes of knowledge exchange, and suggestions for change. Outcomes for both knowledge users and researchers were identified; interestingly, knowledge users attributed more outcomes to using school-specific findings than knowledge brokering. School and public health participants indicated school-specific findings informed their programming and planning. Importantly, knowledge exchange provided a platform for partnerships between researchers, schools, and public health units. Knowledge brokering allowed researchers to gain feedback from knowledge users to enhance the study and a better understanding of the school environment. Interestingly, COMPASS knowledge exchange outcomes aligned with Samdal and Rowling's eight theory-driven implementation components for health-promoting schools. Hence, knowledge exchange may provide a mechanism to help schools implement a health-promoting schools approach. This research contributes to the limited literature regarding outcomes of knowledge brokering in public health and knowledge exchange in school health research. However, since not all schools engaged in knowledge brokering, and not all schools that engaged discussed these outcomes, further research is needed to determine the amount of engagement required for change and examine the process of COMPASS knowledge brokering to consider how to increase school engagement.


Patterns of care in adults with renal cell carcinoma: findings in a population based sample.
Treatment options in patients with renal cell carcinoma have changed in recent years. However, few studies include detailed information on patient, clinical and health system characteristics in the evaluation of surgical management and the use of systemic therapies in community practice. We evaluated surgical management and the use of systemic treatments in a national population based sample of 1,263 patients with renal cell carcinoma newly diagnosed in 2004. Patients were identified from the Surveillance, Epidemiology and End Results Program as part of the Patterns of Care studies. We used descriptive statistics to assess treatment in the entire sample and logistic regression analysis to evaluate the associations between patient demographic, clinical and health system characteristics, and surgery in the subset of 1,032 patients who were potentially eligible for partial or radical nephrectomy and an open or laparoscopic procedure. Surgical treatment in 64.7% of patients (95% CI 60.0%, 69.1%) was radical nephrectomy and most underwent an open rather than a laparoscopic procedure. Although the proportion of all patients receiving systemic treatments was small, 34.3% (95% CI 23.1, 47.5) of those with stage IV disease received systemic treatment. Few patients participated in clinical trials. On multivariate analysis patients who were female, nonwhite, with larger tumors, without comorbid conditions and treated at hospitals without a residency training program were more likely to undergo radical rather than partial nephrectomy (p <0.05). Patients with larger tumors treated at smaller hospitals were more likely to undergo an open rather than a laparoscopic procedure (p <0.05). In 2004 open radical nephrectomy was the most common surgical management for renal cell carcinoma. Few patients received systemic therapy. Patient demographic, clinical and health system characteristics were associated with surgery. Evaluation of the diffusion of surgical management and newer systemic agents, and trial participation in community practice will be important for future research.


Complexity of force output during static exercise in individuals with Down syndrome.
Force variability is greater in individuals with Down syndrome (DS) compared with persons without DS and is similar to that seen with normal aging. The purpose of this study was to examine the structure (in both time and frequency domains) of force output variability in persons with DS to determine whether deficits in force control are similar between individuals with DS and older adults. An isometric handgrip task at a constant force (30% of maximal voluntary contraction) was completed by individuals with DS (n = 29, age 26 yr), and healthy young (n = 26, age 27 yr) and older (n = 33, age 70 yr) individuals. Mean, standard deviation (SD), and coefficient of variation (CV) were used to analyze the magnitude of force output variability. Spectral analysis and approximate entropy (ApEn) were used to analyze the structure of force output variability. Mean force output for DS was lower than in young controls (P < 0.05) but no different from old controls. Individuals with DS had greater SD and CV than young and old controls (P < 0.05). The DS group had a significantly greater proportion of spectral power within the 0-to 4-Hz bandwidth than the young and older controls (P < 0.05). The DS group had significantly lower ApEn values than the young controls (P < 0.05), but there were no differences in ApEn between the DS group and the old controls (P > 0.05). In conclusion, young persons with DS demonstrate enhanced temporal structure and greater amplitude of low-frequency oscillations in the force output signal than age-matched non-DS peers. Interestingly, young persons with DS and older persons without DS have similar time-dependent structure of force output variability. This would suggest a possible link between premature aging and less complex force output in persons with DS.


Atorvastatin therapy lowers circulating cholesterol but not free radical activity in advance of identifiable clinical benefit in the treatment of mild-to-moderate AD.
Cholesterol-induced production of amyloid beta (Abeta) as a putative neurotoxin in Alzheimer's disease (AD), along with epidemiological evidence, suggests that statin drugs may provide benefit in treatment of the disorder. We tested the effect of once daily atorvastatin calcium (80 mg; two 40 mg tablets) on cognitive and/or behavioral decline in patients with mild-to-moderate AD. The study was designed as a pilot intention-to-treat, proof-of-concept, double-blind, placebo-controlled, randomized (1:1) trial with a 1-year exposure to study medication employing last-observation-carried-forward (LOCF) ANCOVA as the primary statistical method of assessment. Alternate statistical methods were employed to further explore the effect of atorvastatin treatment on progression of deterioration. Of the 98 individuals with mild-to-moderate AD (Mini-Mental State Examination score of 12-28) providing Informed Consent, 71 were eligible for randomization, 67 were randomized and 63 completed the 3-month visit and were statistically evaluable. The primary outcome measures were change in the Alzheimer Disease Assessment Scale-Cognitive (ADAS-cog) performance and the Clinical Global Impression of Change (CGIC). Secondary outcome measures included the MMSE, Geriatric Depression Scale (GDS), the Neuropsychiatric Inventory (NPI) and the ADCS Activities of Daily Living inventory (ADCS-ADL). Tertiary outcome measures included levels of total circulating cholesterol, LDL and VLDL, and circulating activity of the free radical scavenger enzymes superoxide dismutase (SOD) and glutathione peroxidase (GpX). Atorvastatin reduced circulating cholesterol levels and produced a positive signal on each of the clinical outcome measures compared to placebo, but did not elicit a difference in circulating SOD or GpX activities. The observed beneficial clinical effect reached significance for the GDS (p = 0.040) and the ADAS-cog at 6 months (p = 0.003), was all but significant for the ADAS-cog (p = 0.055) at 12 months, and was of marginal significance for the CGIC (p = 0.073) and NPI (p = 0.071) at 12 months when employing the primary statistical approach (ANCOVA with LOCF). Application of repeated measures ANCOVA statistics revealed the difference was significant for the CGIC and marginally significant for the ADAS-cog, but not significant for the other clinical indices. This evaluation indicated significant time-by-treatment interactions (altered progression) for the ADAS-cog and MMSE, but not the CGIC. Application of random intercept regression analysis revealed a significant difference for the CGIC, ADAS-cog and MMSE. Regression analysis also indicated that atorvastatin produced change in the slope of deterioration on the MMSE. Accordingly, atorvastatin therapy may be an effective treatment and may slow the progression of AD among mild-to-moderately affected patients.


Trichloroethylene disrupts cardiac gene expression and calcium homeostasis in rat myocytes.
We have been investigating the molecular mechanisms by which trichloroethylene (TCE) might induce cardiac malformations in the embryonic heart. Previous results indicated that TCE disrupted expression of genes encoding proteins involved in regulation of intracellular Ca2+, [Ca2+](i), in cardiac cells, including ryanodine receptor isoform 2 (Ryr2), and sarcoendoplasmatic reticulum Ca2+ ATPase, Serca2a. These observations are important in light of the notion that altered cardiac contractility can produce morphological defects. The hypothesis tested in this study is that the TCE-induced changes in gene expression of Ca2+-associated proteins resulted in altered Ca2+ flux regulation. We used real-time PCR and digital imaging microscopy to characterize effects of various doses of TCE on gene expression and Ca2+ response to vasopressin (VP) in rat cardiac H9c2 myocytes. We observed a reduction in Serca2a and Ryr2 expression at 12 and 48 h after exposure to TCE. In addition, we found significant differences in Ca2+ response to VP in cells treated with TCE doses as low as 10 parts per billion. Taken all together, our data strongly indicate that exposure to TCE disrupts the ability of myocytes to regulate cellular Ca2+ fluxes. Perturbation of calcium signaling alters cardiac cell physiology and signal transduction and may hint to morphogenetic consequences in the context of heart development. These results point to a novel area of TCE biology and, if confirmed in vivo, may help to explain the apparent cardio-specific toxicity of TCE exposure in the rodent embryo.


Increasing the use of arteriovenous fistula in hemodialysis: economic benefits and economic barriers.
The Fistula First Initiative set a goal of 66% arteriovenous (AV) fistula-based access among US hemodialysis patients. This study modeled the impact of achieving the target AV fistula placement rate on Medicare expenditures and on dialysis patient survival and also reviewed economic disincentives for providers that will inhibit achieving this target. The model projects lifetime costs and survival in the US 2003 incident hemodialysis population. Annual treatment costs were estimated from previous analyses of Medicare expenditures by access modality. Patient survival by mode of access was derived from the Dialysis Morbidity and Mortality Study (DMMS). These parameters were applied to a cohort of patients who meet the 66% AV fistula target and an identical cohort with the current vascular access case mix. Comparison of outcomes yields estimates of differential total expenditures and total patient life-years. If prevalence AV fistula-based access in the 2003 incident hemodialysis cohort were 66% rather than the observed 35%, then the Center for Medicare and Medicaid Services would save $840 million in access-attributed expenditures over the expected lifetime of these patients. However, population survival would increase by 35,000 additional life-years, increasing total lifetime expenditures by a net of $1.4 billion. Relative to the current mix of access modality, the shift to 66% AV fistula would be achieved at a net incremental cost of $40,000 per year of life gained. Economic barriers to reaching this goal include financial disincentives to providing adequate predialysis care, performing AV fistula surgical procedures, and monitoring vascular access flow. Achievement of the 66% AV fistula target is cost-effective. Financial incentives in the form of higher reimbursement to encourage wider use of AV fistula placement also could be cost-effective.


Secular changes in total steps and moderate-to-vigorous physical activity among fourth-grade students in Japan in 2003/2004 and 2016/2017.
No study has investigated secular changes in both total steps and moderate-to-vigorous physical activity (MVPA) among Japanese children. This study examined the secular changes of total steps and MVPA among fourth-grade students in Japan in 2003/2004 and 2016/2017. It was performed at a school in Okayama Prefecture in Japan. A total of 452 participants (226 boys and 226 girls; mean age, 9.6 ± 0.5 years) participated in the study. We measured total steps and MVPA of the participants by using the same methods in 2003/2004 and 2016/2017. An uniaxial accelerometer was used to measure total steps and MVPA. On weekdays and weekends, the total steps and MVPA were lowered by approximately 1,000-3,000 steps/day and 10 min/day, respectively, in boys and by 1,000 steps/day and 5 min/day, respectively, in girls in 2016/2017 in comparison to 2003/2004. In both boys and girls, the percentage of children meeting 60 minutes/day of MVPA decreased in 2016/2017(weekdays: boys 21.8%, girls 6.0%; weekends: boys 3.8%, girls 4.1%) compared with 2003/2004 (weekdays: boys 48.2%, girls 11.6%; weekends: boys 7.8%, girls 7.6%). In conclusion, the results demonstrated that total steps and MVPA of fourth-grade students in Japan were lower in 2016/2017 than in 2003/2004.


Inhibitory effects of estrogen on the growth of a human esophageal carcinoma cell line.
In order to accurately determine sex hormone dependency and hormone responsiveness in human esophageal carcinoma, the effects of sex hormones on the growth of esophageal carcinoma cell lines, KSE-1 and KSE-2 cells, were examined in vitro and in vivo. Cell proliferation of cultured KSE-1 cells was inhibited by treatment of estradiol and enhanced by dihydrotestosterone (DHT), whereas KSE-2 cells were unaffected by these sex hormones. The heterotransplanted tumors of KSE-1 cells in nude mice possessed estrogen receptor (ER) and androgen receptor (AR), while the tumors of the KSE-2 cells had neither ER nor AR. When the tumor growth rates and serum hormone levels were monitored during the continuous administration of either estradiol or DHT, no significant differences were observed in either the serum hormone levels or tumor growth rates between male and female mice. The administration of estradiol significantly inhibited the growth of ER-positive and AR-positive KSE-1 tumors in both males and females in conjunction with an increase in the estradiol levels and a decrease in the DHT levels in the serum. However, the growth of ER-negative and AR-negative KSE-2 tumors was not influenced by either estradiol or DHT administration. These results suggest that the in vivo growth of human esophageal carcinoma cells with sex hormone receptor is influenced by circulating hormone levels and can be manipulated by systemic estradiol administration.


Clinicians' Views of Patient-initiated Follow-up in Head and Neck Cancer: a Qualitative Study to Inform the PETNECK2 Trial.
Current follow-up for head and neck cancer (HNC) is ineffective, expensive and fails to address patients' needs. The PETNECK2 trial will compare a new model of patient-initiated follow-up (PIFU) with routine scheduled follow-up. This article reports UK clinicians' views about HNC follow-up and PIFU, to inform the trial design. Online focus groups with surgeons (ear, nose and throat/maxillofacial), oncologists, clinical nurse specialists and allied health professionals. Clinicians were recruited from professional bodies, mailing lists and personal contacts. Focus groups explored views on current follow-up and acceptability of the proposed PIFU intervention and randomised controlled trial design (presented by the study co-chief investigator), preferences, margins of equipoise, potential organisational barriers and thoughts about the content and format of PIFU. Data were interpreted using inductive thematic analysis. Eight focus groups with 34 clinicians were conducted. Clinicians highlighted already known limitations with HNC follow-up - lack of flexibility to address the wide-ranging needs of HNC patients, expense and lack of evidence - and agreed that follow-up needs to change. They were enthusiastic about the PETNECK2 trial to develop and evaluate PIFU but had concerns that PIFU may not suit disengaged patients and may aggravate patient anxiety/fear of recurrence and delay detection of recurrence. Anticipated issues with implementation included ensuring a reliable route back to clinic and workload burden on nurses and allied health professionals. Clinicians supported the evaluation of PIFU but voiced concerns about barriers to help-seeking. An emphasis on patient engagement, psychosocial issues, symptom reporting and reliable, quick routes back to clinic will be important. Certain patient groups may be less suited to PIFU, which will be evaluated in the trial. Early, meaningful, ongoing engagement with clinical teams and managers around the trial rationale and recruitment process will be important to discourage selective recruitment and address risk-averse behaviour and potential workload burden.


Assessment of left ventricular volumes and ejection fraction using ultra-low-dose thallium-201 SPECT on a CZT camera: a comparison with magnetic resonance imaging.
Cadmium-Zinc-Telluride (CZT) technology allows use of low activities of radiopharmaceuticals. The aim was to verify the values of left ventricular volume parameters, obtained via ultra-low-dose thallium Single Photon Emission Computed Tomography (SPECT) using a CZT camera. Forty-five patients referred for an assessment of myocardial perfusion or viability imaging were examined using CZT-SPECT and 1.5 T magnetic resonance (MRI) scanner. The ultra-low-dose protocol with 0.5 Mbq 201-Tl per kg of body weight was used. The values of end-systolic (ESV) and end-diastolic volumes (EDV), left ventricular ejection fraction (EF) and myocardial mass (MM) were assessed using both techniques. A very good correlation was found between the EF, ESV, and EDV values assessed with CZT-SPECT and cardiac magnetic resonance MRI; the Pearson coefficients were 0.86, 0.95, and 0.91, respectively. A moderate correlation was found for myocardial mass, r = 0.57. Compared to MRI, SPECT systematically overestimated ESV and MM, while it underestimates the EF, with P ≤ .001 in all cases. There was no difference in EDV estimation. Left ventricular volumes and ejection fraction assessed via ultra-low-dose CZT-SPECT showed very good correlation with the values obtained by MRI. A moderate correlation was found for myocardial mass.


Increased levels of transition metals in breast cancer tissue.
High levels of transition metals such as iron, nickel, chromium, copper, and lead are closely related to free radical generation, lipid peroxidation, formation of DNA strand breaks, and tumor growth in cellular systems. In order to determine the correlation to malignant growth in humans, we investigated the accumulation of heavy metals in 20 breast cancer biopsies and compared the findings to the levels found in 8 healthy biopsies. The concentration of transition metals in breast cancer and control biopsies was assessed by a standardized Atomic Absorption Spectrofotometry technique with acidic hydrolysis for sample preparation. Additionally, heavy metal analysis in control biopsies was also performed with an Inductive Coupled Plasma--Mass Spectroscopy technique. For statistical analysis of the results, the Mann-Whitney U Test was applied. A highly significant accumulation of iron (p<0.0001), nickel (p<0.00005), chromium (p<0.00005), zinc (p<0.00001), cadmium (p<0.005), mercury (p<0.005), and lead (p< 0.05) was found in the cancer samples when compared to the control group. Copper and silver showed no significant differences to the control group, whereas tin, gold, and palladium were not detectable in any biopsies. The data suggest that pathological accumulation of transition metals in breast tissue may be closely related to the malignant growth process.


The relationships between environmental bacterial exposure, airway bacterial colonization, and asthma.
Recent application of advanced culture-independent molecular techniques for the identification of microorganisms has contributed to our knowledge on the role of early-life microbial exposure and colonization in health and disease. The purpose of this review is to present the current perspectives regarding the role of microbial exposure and airway bacterial colonization on the development and the activity of asthma. Recent findings continue to support the protective role of early-life diverse microbial exposure against the development of atopic diseases. However, airway bacterial colonization early in life serves as a risk factor for the development of asthma. Culture-independent molecular techniques for the identification of microorganisms have challenged the traditional paradigm that the lower airway is a sterile compartment. Asthmatics, compared with nonasthmatics, appear to have a different lung microbiome composition and some of these differences might contribute to asthma activity, severity, and corticosteroid response. Bacterial presence in the airway appears to influence the inception and may affect the activity of asthma. Complex interactions between different types and routes of bacterial exposures, the airway, and the immune system early in life may determine whether these exposures augment or reduce the risk of asthma development.