Viral evolution and the emergence of SARS coronavirus.
The recent appearance of severe acute respiratory syndrome coronavirus (SARS-CoV) highlights the continual threat to human health posed by emerging viruses. However, the central processes in the evolution of emerging viruses are unclear, particularly the selection pressures faced by viruses in new host species. We outline some of the key evolutionary genetic aspects of viral emergence. We emphasize that, although the high mutation rates of RNA viruses provide them with great adaptability and explain why they are the main cause of emerging diseases, their limited genome size means that they are also subject to major evolutionary constraints. Understanding the mechanistic basis of these constraints, particularly the roles played by epistasis and pleiotropy, is likely to be central in explaining why some RNA viruses are more able than others to cross species boundaries. Viral genetic factors have also been implicated in the emergence of SARS-CoV, with the suggestion that this virus is a recombinant between mammalian and avian coronaviruses. We show, however, that the phylogenetic patterns cited as evidence for recombination are more probably caused by a variation in substitution rate among lineages and that recombination is unlikely to explain the appearance of SARS in humans.


Current perspectives in analyte extraction strategies for tin and arsenic speciation.
Nowadays, reliable and robust detectors can be considered standard laboratory instrumentation, which, for most of the elements provide quantitation limits in the lower ng/g range. Despite these advances in detector technology, sample preparation is by far the most important error source in modern analytical method development and can be judged as the "Achilles' heel" of any analytical process regarding reliability of the obtained results and time consumption. The aim of the present review is to highlight modern trends for tin and arsenic speciation, as these analytes can be considered as models for challenges in modern method development in this field. First background information, legislative aspects and current needs are elucidated. Then the role of sample treatment within the process of method development in speciation is discussed, followed by a presentation of modern extraction techniques, matching the requirements for arsenic and tin speciation analysis: to provide mild conditions in order to ensure species preservation, to improve species recovery, to enhance sample throughput and to be suitable for hyphenation with chromatographic separation systems. The review includes applications on tin and arsenic speciation, covering the period of 2001-2006.


Response to diet and cholestyramine in a patient with sitosterolemia.
In this report, an 11-year-old boy with diffuse tendinous and tuberous xanthomatosis and a plasma sterol concentration of 555 mg/dL, consisting primarily of cholesterol, is described. Three months after changing from an unrestricted diet to a cholesterol-lowering diet, his plasma sterol concentration decreased to 221 mg/dL. Because of the degree and rapidity of his response to diet, sitosterolemia was suspected. According to results of capillary gas-liquid chromatography of his plasma sterols, there was a sitosterol concentration of 31.3 mg/dL (normal less than 1.0 mg/dL), establishing the diagnosis of sitosterolemia. Addition of cholestyramine therapy (8 g/d) to a low sterol diet further lowered his plasma sterol concentration to 173 mg/dL and led to complete regression of all tuberous xanthomata. Tendinous xanthomata regressed at a slower rate. These findings show that the diagnosis of sitosterolemia should be suspected in severely hypercholesterolemic children (total cholesterol greater than 400 mg/dL) whose plasma cholesterol level is highly responsive to dietary manipulation. The rapid and sustained lowering of plasma cholesterol and regression of xanthomata after treatment with diet and cholestyramine suggest that sitosterolemia is a treatable cause of premature atherosclerosis.


Measuring Quality of Healthcare Outcomes in Type 2 Diabetes from Routine Data: a Seven-nation Survey Conducted by the IMIA Primary Health Care Working Group.
Background: The Institute of Medicine framework defines six dimensions of quality for healthcare systems: (1) safety, (2) effectiveness, (3) patient centeredness, (4) timeliness of care, (5) efficiency, and (6) equity. Large health datasets provide an opportunity to assess quality in these areas. Objective: To perform an international comparison of the measurability of the delivery of these aims, in people with type 2 diabetes mellitus (T2DM) from large datasets. Method: We conducted a survey to assess healthcare outcomes data quality of existing databases and disseminated this through professional networks. We examined the data sources used to collect the data, frequency of data uploads, and data types used for identifying people with T2DM. We compared data completeness across the six areas of healthcare quality, using selected measures pertinent to T2DM management. Results: We received 14 responses from seven countries (Australia, Canada, Italy, the Netherlands, Norway, Portugal, Turkey and the UK). Most databases reported frequent data uploads and would be capable of near real time analysis of healthcare quality.The majority of recorded data related to safety (particularly medication adverse events) and treatment efficacy (glycaemic control and microvascular disease). Data potentially measuring equity was less well recorded. Recording levels were lowest for patient-centred care, timeliness of care, and system efficiency, with the majority of databases containing no data in these areas. Databases using primary care sources had higher data quality across all areas measured. Conclusion: Data quality could be improved particularly in the areas of patient-centred care, timeliness, and efficiency. Primary care derived datasets may be most suited to healthcare quality assessment.


Outcome Priorities for Older Persons With Sarcopenia.
To evaluate patients' preferences for sarcopenia outcomes. Discrete-choice experiment (DCE) SETTING AND PARTICIPANTS: Community-dwelling individuals older than 65 years suffering from sarcopenia recruited in Belgium, France, Germany, Italy, Spain, and Switzerland, who visited the clinic and were cognitively able to understand and fill out the survey. In the DCE survey, participants were repetitively asked to choose which one of the 2 patients suffering from sarcopenia deserves treatment the most. The 2 patients presented different levels of risk for 5 preselected sarcopenia outcomes: quality of life, mobility, domestic activities, fatigue, and falls. The DCE included 12 choice sets. Mixed logit panel model was used to estimate patients' preferences and latent class model was conducted to identify profiles of responses. A total of 216 sarcopenic persons were included for the analysis (68% women; mean age 78 years). All 5 preselected sarcopenia outcomes were shown to be significant. Overall, the most important sarcopenia outcome was mobility (30%), followed by the ability to manage domestic activities (22%), the risk of falls (18%), fatigue (17%), and quality of life (14%). The latent class model identified 2 classes of respondents. In the first class (probability of 56%), participants valued mobility the most (42%), followed by the ability to manage domestic activities (23%) and risk of falls (17%). In the second class, fatigue was the most important outcome (27%) followed by domestic activities (19%) and risk of falls (19%). No statistically significant associations between the latent classes and sociodemographic characteristics were found. This study suggests that all 5 preselected outcomes were important for sarcopenic older individuals. Overall, the most important outcomes were mobility and the ability to manage domestic activities, although variations in preferences were observed between respondents. This could help in incorporating patient preferences when designing appropriate solutions for individuals with sarcopenia.


Effects of Praise Dance on the Quality of Life of Chinese Women.
Religion, spirituality, and health are inseparable in human history. Yet, the effects of religion and spirituality on health are controversial. The objective of this study was to investigate the effects of praise dance on the quality of life (QoL) of women with or without medically diagnosed diseases. This was a pretest-posttest study with one convenience sample that took place at Praise Dance Association Hong Kong (PDA) centers. Two hundred and fifty-six Chinese adult females participated. They were aged ≥45 years and had joined the PDA centers within 4 weeks of the commencement of this study. The intervention lasted for 12 weeks, and the subjects practiced praise dance three times a week in a group with a coach in the first four weeks and subsequently on their own or with the same group at least once a week. Each dancing session lasted for 30 min. The subjects completed the World Health Organization Quality of Life (WHOQOL)-BREF (HK) questionnaire before and after the intervention of the praise dance. The findings showed significant improvement in the psychological well-being of the participants, regardless of their religious background. The improvement in their physical domain was statistically marginal. This is the first empirical study to test the benefit of praise dance on QoL. Promoting praise dance could be beneficial to the psychological well-being of women, regardless of their religious backgrounds. The effect of religion or spirituality on QoL warrants further investigation.


Structural and mutational analysis of human Ad37 and canine adenovirus 2 fiber heads in complex with the D1 domain of coxsackie and adenovirus receptor.
Adenovirus fibers from most serotypes bind the D1 domain of coxsackie and adenovirus receptor (CAR), although the binding residues are not strictly conserved. To understand this further, we determined the crystal structures of canine adenovirus serotype 2 (CAV-2) and the human adenovirus serotype 37 (HAd37) in complex with human CAR D1 at 2.3 and 1.5A resolution, respectively. Structure comparison with the HAd12 fiber head-CAR D1 complex showed that the overall topology of the interaction is conserved but that the interfaces differ in number and identity of interacting residues, shape complementarity, and degree of conformational adaptation. Using surface plasmon resonance, we characterized the binding affinity to CAR D1 of wild type and mutant CAV-2 and HAd37 fiber heads. We found that CAV-2 has the highest affinity but fewest direct interactions, with the reverse being true for HAd37. Moreover, we found that conserved interactions can have a minor contribution, whereas serotype-specific interactions can be essential. These results are discussed in the light of virus evolution and design of adenovirus vectors for gene transfer.


Evaluation of methods to concentrate and purify ocean virus communities through comparative, replicated metagenomics.
Viruses have global impact through mortality, nutrient cycling and horizontal gene transfer, yet their study is limited by complex methodologies with little validation. Here, we use triplicate metagenomes to compare common aquatic viral concentration and purification methods across four combinations as follows: (i) tangential flow filtration (TFF) and DNase + CsCl, (ii) FeCl3 precipitation and DNase, (iii) FeCl3 precipitation and DNase + CsCl and (iv) FeCl3 precipitation and DNase + sucrose. Taxonomic data (30% of reads) suggested that purification methods were statistically indistinguishable at any taxonomic level while concentration methods were significantly different at family and genus levels. Specifically, TFF-concentrated viral metagenomes had significantly fewer abundant viral types (Podoviridae and Phycodnaviridae) and more variability among Myoviridae than FeCl3 -precipitated viral metagenomes. More comprehensive analyses using protein clusters (66% of reads) and k-mers (100% of reads) showed 50-53% of these data were common to all four methods, and revealed trace bacterial DNA contamination in TFF-concentrated metagenomes and one of three replicates concentrated using FeCl3 and purified by DNase alone. Shared k-mer analyses also revealed that polymerases used in amplification impact the resulting metagenomes, with TaKaRa enriching for 'rare' reads relative to PfuTurbo. Together these results provide empirical data for making experimental design decisions in culture-independent viral ecology studies.


Statistical signs of social influence on suicides.
By treating the suicide as a social fact, Durkheim envisaged that suicide rates should be determined by the connections between people and society. Under the same framework, he considered that crime is bound up with the fundamental conditions of all social life. The social effect on the occurrence of homicides has been previously substantiated, and confirmed here, in terms of a superlinear scaling relation: by doubling the population of a Brazilian city results in an average increment of 135% in the number of homicides, rather than the expected isometric increase of 100%, as found, for example, for the mortality due to car crashes. Here we present statistical signs of the social influence on the suicide occurrence in cities. Differently from homicides (superlinear) and fatal events in car crashes (isometric), we find sublinear scaling behavior between the number of suicides and city population, with allometric power-law exponents, β = 0.84 ± 0.02 and 0.87 ± 0.01, for all cities in Brazil and US counties, respectively. Also for suicides in US, but using the Metropolitan Statistical Areas (MSAs), we obtain β = 0.88 ± 0.01.


Haemophore-mediated signalling in Serratia marcescens: a new mode of regulation for an extra cytoplasmic function (ECF) sigma factor involved in haem acquisition.
Bacterial extra cytoplasmic function (ECF) sigma factors control a wide range of cell envelope activities including iron and haem uptake systems. Sigma activity is usually inhibited by membrane-bound antisigma. An extra cytoplasmic signal modulates sigma-antisigma interactions and thereby leads to the transcription of the target operon. Sigma and antisigma genes generally belong to one autoregulated operon. However, ECF sigma and antisigma genes involved in iron acquisition, also called iron starvation ECF, are non-autoregulated exceptions to this rule. We fully reconstituted the has signalling cascade of Serratia marcescens in Escherichia coli. Binding of the haem-loaded haemophore to the outer membrane receptor, HasR, inactivates the antisigma HasS, turning on HasI and thereby allowing has operon transcription. Deletion of the HasR N-terminal extension, present in all characterized outer membrane receptors endowed with signal transduction capacity, abolished the inducing activity but not the transport activity. Induction required the TonB-ExbB-ExbD complex. HasI, like the other iron starvation sigma, is iron repressed but not autoregulated. We found an entirely new regulation for the antisigma hasS gene, the transcription of which is HasI dependent. We suggest that the has system is both activated and repressed by the availability of external haem. When there is enough haem, the HasS antisigma activity is turned off and HasI induces the transcription of hasS. This leads to the storage of inactive HasS molecules which become active when HasR is not occupied by holo-haemophore ligand molecules: as soon as there is a haem shortage transcription is turned off. Positive autoregulation of ECF sigma and antisigma genes is usually considered as a mechanism for amplifying a perceived signal. However, our findings suggest, on the contrary, that antisigma regulation allows fine-tuning to the external signal. The biological significance of ECF sigma and antisigma autoregulation may need to be reconsidered.


Significant correlation between surgical stress of hepatectomy and changes in the serum levels of HGF, IL-6 and soluble Fas in patients with viral hepatitis.
Liver damage after hepatectomy is still a serious concern. The present study was designed to clarify the relations between liver injury/surgical stress and cytokines after hepatectomy, in patients with viral hepatitis. Ten consecutive patients undergoing hepatectomy were studied, all with hepatocellular carcinoma due to viral hepatitis. Blood samples for interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), hepatocyte growth factor (HGF), soluble Fas (sFas), soluble Fas Ligand and soluble tumor necrosis factor receptor (sTNFR) assays were collected before the operation and at the end of the operation. There was a significant and positive correlation between the change in the serum level of HGF and preoperative liver function (ICG-R15). Notably, there were significant correlations between surgical stress and IL-6, HGF and sFas, but not sIL-6R and sTNFR. Furthermore, there was significant correlation between postoperative liver function (total bilirubin, albumin) and HGF, IL-6. There was a close relationship between surgical stress and HGF, IL-6 and sFas after hepatectomy in patients with viral hepatitis. It was useful for the evaluation of surgical stress of hepatectomy to estimate the serum level of HGF, IL-6 and sFas.


Toward a cultural adaptation of pharmacotherapy: Latino views of depression and antidepressant therapy.
Relative to non-Latino Whites, Latinos in the United States with major depressive disorder (MDD) show low engagement in antidepressant therapy, whether engagement is defined as pharmacotherapy access, medication initiation, pill-taking, or treatment retention. One potential reason for this disparity in depression care is the low cultural congruence of pharmacotherapy for this population. To examine Latinos' views of depression and antidepressant therapy, we conducted qualitative interviews with 30 Latino outpatients initiating antidepressants prior to their first treatment visit using the semistructured Treatment Adherence and Retention Questionnaire. These baseline interviews were randomly selected from data collected for a randomized controlled trial testing a novel intervention to enhance engagement by depressed Latino outpatients. Participant narratives were analyzed using open coding and the iterative analytical approach derived from grounded theory. Patient views about depression addressed stigmatizing views held by others in their social circle. Most participants directly refuted these views by providing alternate explanations to depression experiences. Antidepressant therapy narratives also revealed marked stigmatization, but participants tended not to refute these views. Instead, patients expressed concerns about antidepressants and showed marked ambivalence about seeking psychiatric care. Participants, however, did suggest ways in which clinicians and patients might collaborate to address their concerns about antidepressants. Some cultural views, such as concerns about addiction to or dependence on medication, may be negotiable barriers to treatment. Prescribing clinicians should address cultural views and concerns in order to improve Latino engagement in antidepressant therapy.


A femtosecond pulse erbium fiber laser incorporating a saturable absorber based on bulk-structured Bi2Te3 topological insulator.
We experimentally demonstrate the use of a bulk-structured Bi(2)Te(3) topological insulator (TI) as an ultrafast mode-locker to generate femtosecond pulses from an all-fiberized cavity. Using a saturable absorber based on a mechanically exfoliated layer about 15 μm thick deposited onto a side-polished fiber, we show that stable soliton pulses with a temporal width of ~600 fs can readily be produced at 1547 nm from an erbium fiber ring cavity. Unlike previous TI-based mode-locked laser demonstrations, in which high-quality nanosheet-based TIs were used for saturable absorption, we chose to use a bulk-structured Bi(2)Te(3) layer because it is easy to fabricate. We found that the bulk-structured Bi(2)Te(3) layer can readily provide sufficient nonlinear saturable absorption for femtosecond mode-locking even if its modulation depth of ~15.7% is much lower than previously demonstrated nanosheet-structured TI-based saturable absorbers. This experimental demonstration indicates that high-crystalline-quality atomic-layered films of TI, which demand complicated and expensive material processing facilities, are not essential for ultrafast laser mode-locking applications.


Concentrations, deposition, and effects of nitrogenous pollutants in selected California ecosystems.
Atmospheric deposition of nitrogen (N) in California ecosystems is ecologically significant and highly variable, ranging from about 1 to 45 kg/ha/year. The lowest ambient concentrations and deposition values are found in the eastern and northern parts of the Sierra Nevada Mountains and the highest in parts of the San Bernardino and San Gabriel Mountains that are most exposed to the Los Angeles air pollution plume. In the Sierra Nevada Mountains, N is deposited mostly in precipitation, although dry deposition may also provide substantial amounts of N. On the western slopes of the Sierra Nevada, the majority of airborne N is in reduced forms as ammonia (NH3) and particulate ammonium (NH4+) from agricultural activities in the California Central Valley. In southern California, most of the N air pollution is in oxidized forms as nitrogen oxides (NOx), nitric acid (HNO3), and particulate nitrate (NO3-) resulting from fossil fuel combustion and subsequent complex photochemical reactions. In southern California, dry deposition of gases and particles provides most (up to 95%) of the atmospheric N to forests and other ecosystems. In the mixed-conifer forest zone, elevated deposition of N may initially benefit growth of vegetation, but chronic effects may be expressed as deterioration of forest health and sustainability. HNO3 vapor alone has a potential for toxic effects causing damage of foliar surfaces of pines and oaks. In addition, dry deposition of predominantly HNO3 has lead to changes in vegetation composition and contamination of ground- and stream water where terrestrial N loading is high. Long-term, complex interactions between N deposition and other environmental stresses such as elevated ozone (O3), drought, insect infestations, fire suppression, or intensive land management practices may affect water quality and sustainability of California forests and other ecosystems.


Selection of marker-free transgenic plants using the isopentenyl transferase gene.
We have developed a new plant vector system for repeated transformation (called MAT for multi-auto-transformation) in which a chimeric ipt gene, inserted into the transposable element Ac, is used as a selectable marker for transformation. Selectable marker genes conferring antibiotic or herbicide resistance, used to introduce economically valuable genes into crop plants, have three major problems: (i) the selective agents have negative effects on proliferation and differentiation of plant cells; (ii) there is uncertainty regarding the environmental impact of many selectable marker genes; (iii) it is difficult to perform recurrent transformations using the same selectable marker to pyramid desirable genes. The MAT vector system containing the ipt gene and the Ac element is designed to overcome these difficulties. When tobacco leaf segments were transformed and selected, subsequent excision of the modified Ac produced marker-free transgenic tobacco plants without sexual crosses or seed production. In addition, the chimeric ipt gene could be visually used as a selectable marker for transformation of hybrid aspen (Populus sieboldii x Populus grandidentata). The chimeric ipt gene, therefore, is an attractive alternative to the most widely used selectable marker genes. The MAT vector system provides a promising way to shorten breeding time for genetically engineered crops. This method could be particularly valuable for fruit and forest trees, for which long generation times are a more significant barrier to breeding and genetic analysis.


The window period of NEUROGENIN3 during human gestation.
The basic helix-loop-helix transcription factor, NEUROG3, is critical in causing endocrine commitment from a progenitor cell population in the developing pancreas. In human, NEUROG3 has been detected from 8 weeks post-conception (wpc). However, the profile of its production and when it ceases to be detected is unknown. In this study we have defined the profile of NEUROG3 detection in the developing pancreas to give insight into when NEUROG3-dependent endocrine commitment is possible in the human fetus. Immunohistochemistry allowed counting of cells with positively stained nuclei from 7 wpc through to term. mRNA was also isolated from sections of human fetal pancreas and NEUROG3 transcription analyzed by quantitative reverse transcription and polymerase chain reaction. NEUROG3 was detected as expected at 8 wpc. The number of NEUROG3-positive cells increased to peak levels between 10 wpc and 14 wpc. It declined at and after 18 wpc such that it was not detected in human fetal pancreas at 35-41 wpc. Analysis of NEUROG3 transcription corroborated this profile by demonstrating very low levels of transcript at 35-41 wpc, more than 10-fold lower than levels at 12-16 wpc. These data define the appearance, peak and subsequent disappearance of the critical transcription factor, NEUROG3, in human fetal pancreas for the first time. By inference, the window for pancreatic endocrine differentiation via NEUROG3 action opens at 8 wpc and closes between 21 and 35 wpc.


ST-elevation myocardial infarction following heart transplantation as an unusual presentation of coronary allograft vasculopathy: a case report.
The presentation, mechanisms, and incidence of ST elevation myocardial infarction (STEMI) in heart transplant recipients have been characterized only to a limited degree in the current literature. Herein, we present a unique case of STEMI years after heart transplantation with a focus on the salient features of its diagnosis and interventions. We also provide a review of the epidemiology of this phenomenon. A 33-year-old woman who was status post cardiac transplantation for dilated cardiomyopathy presented to the clinic with mild nonspecific fatigue and concern after having noticed relative bradycardia compared with her posttransplantation baseline heart rate. Electrocardiogram (ECG) showed junctional rhythm and inferior ST elevations, likely reflecting nodal ischemia. Troponins were grossly positive and echocardiogram showed marked right ventricular dysfunction. Successful percutaneous coronary intervention (PCI) with aspiration thrombectomy and drug-eluting stent placement was emergently performed. The heart's rhythm soon returned to sinus tachycardia. Right ventricular wall-motion abnormalities resolved. The patient suffered no clinical sequelae of her STEMI. This case illustrated that "classic" symptoms of STEMI may not occur at all in the setting of heart transplantation. To our knowledge, this is the first case of posttransplantation STEMI presenting as asymptomatic bradycardia, and highlights the importance of maintaining high clinical suspicion for ischemia in transplant recipients with subtle changes. In reviewing the epidemiology of this case, we locate and bundle different types of studies that have directly or indirectly looked at STEMI in heart transplantation. For a variety of putative pathophysiological reasons, STEMI is indeed a rare manifestation of the common transplant phenomenon of coronary artery vasculopathy (CAV).


The novel peripherally active cannabinoid type 1 and serotonin type 3 receptor agonist AM9405 inhibits gastrointestinal motility and reduces abdominal pain in mouse models mimicking irritable bowel syndrome.
The endocannabinoid system (ECS) plays a crucial role in numerous physiological processes in the central and peripheral nervous systems. In the gastrointestinal (GI) tract, selective cannabinoid (CB) receptor agonists exert potent inhibitory actions on motility and pain signalling. In the present study, we used mouse models of diarrhea, hypermotility, and abdominal pain to examine whether a novel synthetic CB1 receptor agonist AM9405 [(2-(2,6-dihydroxy-4-(2-methyloctan-2-yl)phenyl)-1,3-dimethyl-1H-benzo[d]imidazol-3-ium bromide); also known as GAT379] exhibits effects of potential therapeutic relevance. AM9405 significantly slowed mouse intestinal motility in physiological conditions. Moreover, AM9405 reversed hypermotility and reduced pain in mouse models mimicking symptoms of functional GI disorders, such as stress-induced diarrhea and writhing test. Interestingly, some of the effects of AM9405 were blocked by a 5-HT3 antagonist suggesting interaction with 5-HT3 receptors. In our study we show that combining CB1 agonism with 5-HT3 agonism may alter physiological functions and experimental pathophysiologies in a manner that make such compounds promising drugs for the future treatment of functional GI disorders.


Acute plant poisoning: analysis of clinical features and circumstances of exposure.
Human contact with potentially toxic plants, which may occur through abuse or by accident or attempted suicide, is frequent and sometimes results in clinically significant toxicity. The aim of the present study was to identify which plants may lead to severe poisoning, and to define the clinical relevance of plant toxicity for humans in Switzerland. We analyzed 42,193 cases of human plant exposure and 255 acute moderate, severe, and lethal poisonings, which were reported to the Swiss Toxicological Information Centre between January 1995 and December 2009. Plant contact was rarely responsible for serious poisonings. Lethal intoxications were extremely rare and were caused by plants with cardiotoxic (Taxus baccata) or mitosis-inhibiting (Colchicum autumnale) properties. Most often, plant contact was accidental and patients remained asymptomatic or developed mild symptoms, which fully resolved within a short time.


American Society of Clinical Oncology guideline on the role of bisphosphonates in breast cancer. American Society of Clinical Oncology Bisphosphonates Expert Panel.
To determine clinical practice guidelines for the use of bisphosphonates in the prevention and treatment of bone metastases in breast cancer and their role relative to other therapies for this condition. An expert multidisciplinary panel reviewed pertinent information from the published literature and meeting abstracts through May 1999. Additional data collected as part of randomized trials and submitted to the United States Food and Drug Administration were also reviewed, and investigators were contacted for more recent information. Values for levels of evidence and grade of recommendation were assigned by expert reviewers and approved by the panel. Expert consensus was used if there were insufficient published data. The panel addressed which patients to treat and when in their course of disease, specific drug delivery issues, duration of therapy, management of bony metastases with other therapies, and the public policy implications. The guideline underwent external review by selected physicians, members of the American Society of Clinical Oncology (ASCO) Health Services Research Committee, and the ASCO Board of Directors. Bisphosphonates have not had an impact on the most reliable cancer end point: overall survival. The benefits have been reductions in skeletal complications, ie, pathologic fractures, surgery for fracture or impending fracture, radiation, spinal cord compression, and hypercalcemia. Intravenous (IV) pamidronate 90 mg delivered over 1 to 2 hours every 3 to 4 weeks is recommended in patients with metastatic breast cancer who have imaging evidence of lytic destruction of bone and who are concurrently receiving systemic therapy with hormonal therapy or chemotherapy. For women with only an abnormal bone scan but without bony destruction by imaging studies or localized pain, there is insufficient evidence to suggest starting bisphosphonates. Starting bisphosphonates in patients without evidence of bony metastasis, even in the presence of other extraskeletal metastases, is not recommended. Studies of bisphosphonates in the adjuvant setting have yielded inconsistent results. Starting bisphosphonates in patients at any stage of their nonosseous disease, outside of clinical trials, despite a high risk for future bone metastasis, is currently not recommended. Oral bisphosphonates are one of several options which can be used for preservation of bone density in premenopausal patients with treatment-induced menopause. The panel suggests that, once initiated, IV bisphosphonates be continued until evidence of substantial decline in a patient's general performance status. The panel stresses that clinical judgment must guide what is a substantial decline. There is no evidence addressing the consequences of stopping bisphosphonates after one or more adverse skeletal events. Symptoms in the spine, pelvis, or femur require careful evaluation for spinal cord compression and pathologic fracture before bisphosphonate use and if symptoms recur, persist, or worsen during therapy. The panel recommends that current standards of care for cancer pain, analgesics and local radiation therapy, not be displaced by bisphosphonates. IV pamidronate is recommended in women with pain caused by osteolytic metastasis to relieve pain when used concurrently with systemic chemotherapy and/or hormonal therapy, since it was associated with a modest pain control benefit in controlled trials. Bisphosphonates provide a meaningful supportive but not life-prolonging benefit to many patients with bone metastases from cancer. Further research is warranted to identify clinical predictors of when to start and stop therapy, to integrate their use with other treatments for bone metastases, to identify their role in the adjuvant setting in preventing bone metastases, and to better determine their cost-benefit consequences.


Unravelling the Prospective Associations Between Mixed Anxiety-Depression and Insomnia During the Course of Cognitive Behavioral Therapy.
Previous studies have suggested that there is a reciprocal relationship between anxiety/depression and insomnia. However, little is known about the prospective relationships between these constructs across the course of cognitive behavioral therapy (CBT). The aim of the study was to examine these relationships in clients who received short-term CBT in a primary care setting. A total of 653 clients (mean [SD] age = 37.8 [12.9], 26.4% men) with mild to moderate levels of anxiety and depression and a treatment duration of at least 7 weeks were included for analyses. The clients completed questionnaires measuring mixed anxiety-depression (MAD - Patient Health Questionnaire Anxiety and Depression Scale) and insomnia (3 items derived from the Karolinska Sleep Questionnaire representing core DSM-V criteria) on a session-to-session basis. The data were analyzed using latent growth curve models and random intercept cross-lagged panel models. The results of the latent growth curve models showed that there was a significant decrease in both MAD (cubic slope; B = .002, p < .001, quadratic slope; B = .036, p < .001, linear slope; B = -.205, p < .001) and insomnia (linear slope; B = -.080, p < .001) across treatment. A strong correlation (r = .838, p < .001) between the linear slopes indicated co-occurring change processes. The cross-lagged panel model showed that insomnia significantly predicted MAD at the subsequent measurements (B = .190, p < .001), but not vice versa (B = .252, p = .343). Changes in MAD and insomnia are co-occurring processes during the course of CBT. Changes in insomnia predicted prospectively changes in MAD, but not vice versa. Targeting insomnia in the context of brief CBT in clients with mild to moderate anxiety and depression may therefore further reduce not only symptoms of insomnia but also symptoms of anxiety and depression.


Estimating nonlinear receptive fields from natural images.
The response of visual cells is a nonlinear function of their stimuli. In addition, an increasing amount of evidence shows that visual cells are optimized to process natural images. Hence, finding good nonlinear models to characterize visual cells using natural stimuli is important. The Volterra model is an appealing nonlinear model for visual cells. However, their large number of parameters and the limited size of physiological recordings have hindered its application. Recently, a substantiated hypothesis stating that the responses of each visual cell could depend on an especially low-dimensional subspace of the image space has been proposed. We use this low-dimensional subspace in the Volterra relevant-space technique to allow the estimation of high-order Volterra models. Most laboratories characterize the response of visual cells as a nonlinear function on the low-dimensional subspace. They estimate this nonlinear function using histograms and by fitting parametric functions to them. Here, we compare the Volterra model with these histogram-based techniques. We use simulated data from cortical simple cells as well as simulated and physiological data from cortical complex cells. Volterra models yield equal or superior predictive power in all conditions studied. Several methods have been proposed to estimate the low-dimensional subspace. In this article, we test projection pursuit regression (PPR), a nonlinear regression algorithm. We compare PPR with two popular models used in vision: spike-triggered average (STA) and spike-triggered covariance (STC). We observe that PPR has advantages over these alternative algorithms. Hence, we conclude that PPR is a viable algorithm to recover the relevant subspace from natural images and that the Volterra model, estimated through the Volterra relevant-space technique, is a compelling alternative to histogram-based techniques.


RebiQoL: A randomized trial of telemedicine patient support program for health-related quality of life and adherence in people with MS treated with Rebif.
RebiQoL was a phase IV multicenter randomized study to assess the impact of a telemedicine patient support program (MSP) on health-related quality of life (HRQoL) in patients with relapsing-remitting MS (RRMS) being administered with Rebif with the RebiSmart device. The primary endpoint was to assess the impact of MSP compared to patients only receiving technical support for RebiSmart on HRQoL at 12 months, using the psychological part of Multiple Sclerosis Impact Scale (MSIS-29), in patients administered with Rebif. A total of 97 patients diagnosed with RRMS were screened for participation in the study of which 3 patients did not fulfill the eligibility criteria and 1 patient withdrew consent. Of the 93 randomized patients, 46 were randomized to MSP and 47 to Technical support only. The demographic characteristics of the patients were well-balanced in the two arms. There were no statistical differences (linear mixed model) in any of the primary (difference of 0.48, 95% CI: -8.30-9.25, p = 0.91) or secondary outcomes (p>0.05). Although the study was slightly underpowered, there was a trend towards better adherence in the MSP group (OR 3.5, 95% CI 0.85-14.40, p = 0.08) although not statistically significant. No unexpected adverse events occurred. This study did not show a statistically significant effect of the particular form of teleintervention used in this study on HRQoL as compared to pure technical support, for MS patients already receiving Rebif with the RebiSmart device. Trial Registration: ClinicalTrials.gov: NCT01791244.


Relationship of cardiometabolic parameters in non-smokers, current smokers, and quitters in diabetes: a systematic review and meta-analysis.
Smoking is associated with increased macrovascular and microvascular complications in people with diabetes. In addition to other concomitant vascular perturbations, it also seems to influence the cardiometabolic parameters, which may partly explain the accelerated rate of vascular complications in smokers with diabetes. While smoking cessation is advocated as a universal component of the management of diabetes, there is some anecdotal evidence that HbA1c could increase following smoking cessation. The aim of this review is to explore the relationship between smoking and its cessation on cardiometabolic parameters in diabetes. Searches were conducted on Medline, EMBASE and CINAHL up to March 2016. After screening 6866 studies (Additional file 1), 14 observational studies with a total of 98,978 participants' with either type 1 or type 2 diabetes were selected for review. Narrative synthesis and meta-analyses were carried out to explore the relationship between smoking and its cessation. Meta-analysis showed that the pooled mean difference of HbA1c between non-smokers and smokers was -0.61% (95% CI -0.88 to -0.33, p < 0.0001). The difference in LDL cholesterol between non-smokers and smokers was -0.11 mmol/l (95% CI -0.21 to -0.01, p = 0.04). The difference in HDL cholesterol between non-smokers and smokers was 0.12 mmol/l (95% CI 0.08-0.15, p < 0.001). However, there was no statistically significant difference in blood pressure between the two groups. The difference in HbA1c between quitters and continued smokers was not statistically significant -0.10% (95% CI -0.42 to 0.21, p = 0.53). However, a narrative synthesis revealed that over a period of 10 years, the HbA1c was comparable between non-smokers and quitters. Non-smokers have a statistically significant lower HbA1c and more favourable lipid profile compared to smokers. Smoking cessation does not lead to an increase in HbA1c in long-term and may reduce vascular complications in diabetes by its favourable impact on lipid profile.


Optics in the kodak research laboratories.
Optics in the Kodak Research Laboratories has largely paralleled the development of this field of science throughout this country and the rest of the world in the last half century. In the earlier part of this period, the emphasis was on geometrical optics and especially problems related to lens design and analysis. Later, frequency-response methods became important and, with them, more emphasis on wave theory and diffraction theory. Some work was done at Kodak on radiative transfer and multiplescatter problems because of their close relation to the optics of photographic emulsions.


Characterization of anaphylaxis after ecallantide treatment of hereditary angioedema attacks.
Ecallantide is a human plasma kallikrein inhibitor indicated for treatment of acute attacks of hereditary angioedema for patients 12 years of age and older. Ecallantide is produced in Pichia pastoris yeast cells by recombinant DNA technology. Use of ecallantide has been associated with a risk of hypersensitivity reactions, including anaphylaxis. The objective of this detailed retrospective data review was to characterize anaphylaxis cases within the ecallantide clinical trials database. Potential cases of hypersensitivity reactions in the ecallantide clinical development program were identified by examining reported adverse events. The National Institute of Allergy and Infectious Disease criteria were used to identify those events that were consistent with anaphylaxis; these cases were then reviewed in detail. Results from investigational antibody testing also were examined. Among patients who received subcutaneous ecallantide (n = 230 patients; 1045 doses of 30 mg ecallantide), 8 patients (3.5%) had reactions that met the National Institute of Allergy and Infectious Disease criteria for anaphylaxis; none occurred on first exposure to the drug. All 8 reactions had symptom onset within 1 hour of exposure and cutaneous manifestations commonly observed in type I hypersensitivity reactions. All the reactions responded to standard management of type I hypersensitivity reactions and resolved without fatal outcomes. IgE antibody testing to ecallantide or P pastoris was not consistently positive in patients who experienced apparent type I hypersensitivity reactions. Anaphylaxis episodes after subcutaneous ecallantide exposure have clinical features suggestive of type I hypersensitivity reactions. However, anti-ecallantide or anti-P pastoris IgE antibody status was not found to be reliably associated with anaphylaxis.


Advanced nursing practice: the case of nurse practitioners in three Australian states.
This paper provides insight into the work of nurse practitioners in three Australian states. Using a case study approach, the aim of the study is to give an account of some of the types of cases/patients who consult with the nurse practitioners in the states visited and to offer insight into one of the policy changes required to support the introduction of the nurse practitioner role. A snowball sampling technique was used to obtain the sample population of both 10 nurse practitioners and other health care personnel. Semi-structured interviews were conducted with the 39 respondents in both samples. The analysis of the 10 nurse practitioner interviews reported here shows that these nurses undertook a wide range of roles. The results of the semi-structured interviews with the nurse practitioners are described using four of the 10 interviews and reporting them as case studies. The results highlighted the need to address legislation issues and to prepare nurses adequately for their clinical setting and address the difficulties of continuing education of rural nurses.


The effect of zirconia thickness on the biaxial flexural strength of zirconiaceramic bilayered discs.
The aim of this study was to assess the effect of zirconia core thickness on the biaxial flexural strength values of zirconia-porcelain bilayered discs. A total of 60 discs with 0.3, 0.4, and 0.5 mm thickness were obtained from a fully sintered zirconia block. A 1.5-mm thick layer of veneer porcelain was fired on the zirconia specimens and biaxial flexural strength tests were performed on the bilayered discs. In each group, the loading surface was the veneer porcelain in half of the specimens (core in tension) and the zirconia core surface in the other half (core in compression). The zirconia core thickness had no effect on the biaxial flexural strength of zirconiaporcelain bilayered discs when the core was in tension (p>0.05). Whereas, when the core was in compression, an increase in the zirconia core thickness resulted in an increase in the biaxial flexural strength (p<0.05).


Free-ranging male koalas use size-related variation in formant frequencies to assess rival males.
Although the use of formant frequencies in nonhuman animal vocal communication systems has received considerable recent interest, only a few studies have examined the importance of these acoustic cues to body size during intra-sexual competition between males. Here we used playback experiments to present free-ranging male koalas with re-synthesised bellow vocalisations in which the formants were shifted to simulate either a large or a small adult male. We found that male looking responses did not differ according to the size variant condition played back. In contrast, male koalas produced longer bellows and spent more time bellowing when they were presented with playbacks simulating larger rivals. In addition, males were significantly slower to respond to this class of playback stimuli than they were to bellows simulating small males. Our results indicate that male koalas invest more effort into their vocal responses when they are presented with bellows that have lower formants indicative of larger rivals, but also show that males are slower to engage in vocal exchanges with larger males that represent more dangerous rivals. By demonstrating that male koalas use formants to assess rivals during the breeding season we have provided evidence that male-male competition constitutes an important selection pressure for broadcasting and attending to size-related formant information in this species. Further empirical studies should investigate the extent to which the use of formants during intra-sexual competition is widespread throughout mammals.


Optimization of immunocytochemical P-glycoprotein assessment in multidrug-resistant plasma cell myeloma using three antibodies.
Seeking to optimize the immunocytochemical assay of P-glycoprotein, a 170-kilodalton (P-170) molecule associated with multidrug resistance, we experimented with a variety of antibodies (JSB-1, C219, and MRK-16), fixation conditions, and titers using both human myeloma cell lines and clinical myeloma specimens. Under optimized conditions, using all three antibodies and the cell lines as standards and controls, the ICC method proved sensitive, specific, reliable, rapid, and within the realm of everyday hospital laboratory expertise. The 3 anti-P-glycoprotein antibodies revealed different reactivities with P-170. Both C219 and JSB1 were optimized by fixation in cold acetone. With MRK-16 optimal results were obtained on unfixed or formalin fixed specimens. Under optimal fixation and titering conditions, low level (DOX 4) detection was possible. Given that the three antibodies differ in reactivity and recognize different P-170 epitopes, it follows that using the antibodies in a small panel is a useful strategy in increasing the likelihood of detecting true P-glycoprotein expression by the immunocytochemical method. In dilution experiments, the immunocytochemical method was as sensitive as RNase protection assay and more sensitive than Western blot detection. Immunocytochemistry coupled to computer-assisted single-cell densitometry, showed a strong correlation (R = 0.98) between cellular P-170 density and in vitro resistance to doxorubicin. Multidrug-resistant specific probes for RNA expression and Western blot assays confirmed the specificity of P-170 expression in both cell lines and clinical samples. Thus, a small panel of antibodies, under optimized immunocytochemical conditions, appears to have potential as a rapid, sensitive, clinically useful assay for multidrug resistance in myeloma.


Pharmacogenomic Study of Clozapine-Induced Agranulocytosis/Granulocytopenia in a Japanese Population.
Clozapine-induced agranulocytosis (CIA)/clozapine-induced granulocytopenia (CIG) (CIAG) is a life-threatening event for schizophrenic subjects treated with clozapine. To examine the genetic factor for CIAG, a genome-wide pharmacogenomic analysis was conducted using 50 subjects with CIAG and 2905 control subjects. We identified a significant association in the human leukocyte antigen (HLA) region (rs1800625, p = 3.46 × 10(-9), odds ratio [OR] = 3.8); therefore, subsequent HLA typing was performed. We detected a significant association of HLA-B*59:01 with CIAG (p = 3.81 × 10(-8), OR = 10.7) and confirmed this association by comparing with an independent clozapine-tolerant control group (n = 380, p = 2.97 × 10(-5), OR = 6.3). As we observed that the OR of CIA (OR: 9.3~15.8) was approximately double that in CIG (OR: 4.4~7.4), we hypothesized that the CIG subjects were a mixed population of those who potentially would develop CIA and those who would not develop CIA (non-CIA). This hypothesis allowed the proportion of the CIG who were non-CIA to be calculated, enabling us to estimate the positive predictive value of the nonrisk allele on non-CIA in CIG subjects. Assuming this model, we estimated that 1) ~50% of CIG subjects would be non-CIA; and 2) ~60% of the CIG subjects without the risk allele would be non-CIA and therefore not expected to develop CIA. Our results suggest that HLA-B*59:01 is a risk factor for CIAG in the Japanese population. Furthermore, if our model is true, the results suggest that rechallenging certain CIG subjects with clozapine may not be always contraindicated.


The association between angiogenic markers and fetal sex: Implications for preeclampsia research.
Current research suggests sexual dimorphism between the male and female fetoplacental units, but with unknown relevance for preeclampsia. We investigated the association between fetal sex and concentrations of the angiogenic markers soluble Fms-like kinase 1 (sFlt-1), placental growth factor (PlGF), and sFlt-1/PlGF ratio in first and second-third trimester in women with/without preeclampsia, and the impact of fetal sex on the prognostic value of angiogenic markers for preeclampsia. Observational study in a prospective, population-based cohort of 2110 singleton pregnancies with 150 preeclampsia cases. Higher sFlt-1 concentrations were observed for women carrying female fetuses in first trimester (all, 1107.65 vs. 992.27pg/ml; preeclampsia cases, 1118.79 vs. 934.49pg/ml, p<0.05) and in second-third trimester (all, 1130.03 vs. 1043.15pg/ml; preeclampsia, 1480.30 vs. 1152.86pg/ml, p<0.05), with similar findings for the sFlt-1/PlGF ratio concentrations in first (29.67 vs. 27.39 p<0.05) and second-third trimester (3.56 vs. 3.22, p<0.05). In first trimester, log transformed concentrations of PlGF, sFlt-1 and sFlt-1/PlGF (all participants) and sFlt-1 (preeclampsia cases) associated with fetal sex in adjusted analyses (p<0.05). In second-third trimester, only log(sFlt-1) associated with fetal sex (all, p=0.028; preeclampsia, p=0.067) In receiver operating curve analysis, prediction of early-onset preeclampsia by sFlt-1/PlGF tended to be superior in pregnancies with female vs. male fetuses (p=0.06). Sexual dimorphism was observed for concentrations of angiogenic markers. Female fetal sex was associated to higher sFlt-1 and sFlt-1/PlGF ratio concentrations in both healthy pregnancies and women developing preeclampsia. Fetal sex should be considered in research and clinical use of angiogenic markers.


Examining the effect of information channel on COVID-19 vaccine acceptance.
Hesitancy towards the COVID-19 vaccine remains high among the US population. Now that the vaccine is available to priority populations, it is critical to convince those that are hesitant to take the vaccine. Public health communication about the vaccine as well as misinformation on the vaccine occurs through a variety of different information channels. Some channels of information are more commonly found to spread misinformation. Given the expansive information environment, we sought to characterize the use of different media channels for COVID-19 vaccine information and determine the relationship between information channel and vaccine acceptance. We used quota sampling of vaccine priority groups [N = 2,650] between December 13 and 23, 2020 and conducted bivariate chi-squared tests and multivariable multinomial logistic regression analyses to determine the relative impact of channels of information on vaccine acceptance. We found traditional channels of information, especially National TV, National newspapers, and local newspapers increased the likelihood of vaccine acceptance. Individuals who received information from traditional media compared to social media or both traditional and social media were most likely to accept the vaccine. The implications of this study suggest social media channels have a role to play in educating the hesitant to accept the vaccine, while traditional media channels should continue to promote data-driven and informed vaccine content to their viewers.


Small-Molecule Polθ Inhibitors Provide Safe and Effective Tumor Radiosensitization in Preclinical Models.
DNA polymerase theta (Polθ, encoded by the POLQ gene) is a DNA repair enzyme critical for microhomology mediated end joining (MMEJ). Polθ has limited expression in normal tissues but is frequently overexpressed in cancer cells and, therefore, represents an ideal target for tumor-specific radiosensitization. In this study we evaluate whether targeting Polθ with novel small-molecule inhibitors is a feasible strategy to improve the efficacy of radiotherapy. We characterized the response to Polθ inhibition in combination with ionizing radiation in different cancer cell models in vitro and in vivo. Here, we show that ART558 and ART899, two novel and specific allosteric inhibitors of the Polθ DNA polymerase domain, potently radiosensitize tumor cells, particularly when combined with fractionated radiation. Importantly, noncancerous cells were not radiosensitized by Polθ inhibition. Mechanistically, we show that the radiosensitization caused by Polθ inhibition is most effective in replicating cells and is due to impaired DNA damage repair. We also show that radiosensitization is still effective under hypoxia, suggesting that these inhibitors may help overcome hypoxia-induced radioresistance. In addition, we describe for the first time ART899 and characterize it as a potent and specific Polθ inhibitor with improved metabolic stability. In vivo, the combination of Polθ inhibition using ART899 with fractionated radiation is well tolerated and results in a significant reduction in tumor growth compared with radiation alone. These results pave the way for future clinical trials of Polθ inhibitors in combination with radiotherapy.


[A case of omental mesothelioma presenting with laminar thickening of omentum-appearances of diffuse malignant peritoneal mesothelioma].
A man in his 60's with no apparent history of asbestos exposure was admitted to our hospital with a chief complaint of abdominal fullness. CA125 levels in serum and ascites were veryhigh. Enhanced abdominal CT confirmed a large amount of ascites, inflexible intestinal canal, short mesentery and laminar thickening of the omentum. SPIO-enhanced MRI-T1WI slightly enhanced the thickened omentum. These T1WI images largely matched portal-phase contrast CT images. Furthermore, the thickened omentum was clearly visualized by lowering the signal for the liver and spleen by SPIO and by suppressing the ascites signal by fluid-attenuated inversion recovery (FLAIR). Gascintigraphy confirmed Ga accumulation in the same areas. Chemotherapy was ineffective, and the patient died of liver metastasis in February 2006. Autopsy confirmed biphasic malignant peritoneal mesothelioma. The involvement of asbestos is clear in the onset of malignant peritoneal mesothelioma. Therefore, it is possible that the patient unintentionally inhaled asbestos. Hence, when levels of CA125 in serum and/or ascites are high, it is important to differentiate malignant peritoneal mesothelioma from primaryserous papillary carcinoma of the peritoneum. Here, we experienced a case of biphasic diffused omental mesothelioma. While studies have documented laminar thickening of the omentum by abdominal incision, this is thought to be first case in Japan in which laminar thickening of the omentum was detected on diagnostic imaging. Laminar thickening of the omentum and short mesentery are thought to be characteristic features of diffused peritoneal mesothelioma when subjective symptoms appear. In addition, Gascintigraphy and FDG-PET are useful auxiliary diagnostic tools. In the future, we hope to differentiate epithelial, sarcomatous and biphasic types based on imaging findings.


Demography of a reintroduced population: moving toward management models for an endangered species, the Whooping Crane.
The reintroduction of threatened and endangered species is now a common method for reestablishing populations. Typically, a fundamental objective of reintroduction is to establish a self-sustaining population. Estimation of demographic parameters in reintroduced populations is critical, as these estimates serve multiple purposes. First, they support evaluation of progress toward the fundamental objective via construction of population viability analyses (PVAs) to predict metrics such as probability of persistence. Second, PVAs can be expanded to support evaluation of management actions, via management modeling. Third, the estimates themselves can support evaluation of the demographic performance of the reintroduced population (e.g., via comparison with wild populations). For each of these purposes, thorough treatment of uncertainties in the estimates is critical. Recently developed statistical methods (namely, hierarchical Bayesian implementations of state-space models) allow for effective integration of different types of uncertainty in estimation. We undertook a demographic estimation effort for a reintroduced population of endangered Whooping Cranes with the purpose of ultimately developing a Bayesian PVA for determining progress toward establishing a self-sustaining population, and for evaluating potential management actions via a Bayesian PVA-based management model. We evaluated individual and temporal variation in demographic parameters based upon a multi-state, mark-recapture model. We found that survival was relatively high across time and varied little by sex. There was some indication that survival varied by release method. Survival was similar to that observed in the wild population. Although overall reproduction in this reintroduced population is poor, birds formed social pairs when relatively young, and once a bird was in a social pair, it had a nearly 50% chance of nesting the following breeding season. Also, once a bird had nested, it had a high probability of nesting again. These results are encouraging, considering that survival and reproduction have been major challenges in past reintroductions of this species. The demographic estimates developed will support construction of a management model designed to facilitate exploration of management actions of interest, and will provide critical guidance in future planning for this reintroduction. An approach similar to what we describe could be usefully applied to many reintroduced populations.


Using law to fight a silent epidemic: the role of health literacy in health care access, quality, & cost.
The dominant rhetoric in the health care policy debate about cost has assumed an inherent tension between access and quality on the one hand, and cost effectiveness on the other; but an emerging discourse has challenged this narrative by presenting a more nuanced relationship between access, quality, and cost. This is reflected in the discourse surrounding health literacy, which is viewed as an important tool for achieving all three goals. Health literacy refers to one's ability to obtain, understand and use health information to make appropriate health decisions. Research shows that improving patients' health literacy can help overcome access barriers and empower patients to be better health care partners, which should lead to better health outcomes. Promoting health literacy can also reduce expenditures for unnecessary or inappropriate treatment. This explains why, as a policy matter, improving health literacy is an objective that has been embraced by almost every sector of the health care system. As a legal matter, however, the role of health literacy in ensuring quality and access is not as prominent. Although the health literacy movement is relatively young, it has roots in longstanding bioethical principles of patient autonomy, beneficence, and justice as well as the corresponding legal principles of informed consent, the right to quality care, and antidiscrimination. Assumptions and concerns about health literacy seem to do important, yet subtle work in these legal doctrines--influencing conclusions about patient understanding in informed consent cases, animating decisions about patient responsibility in malpractice cases, and underlying regulatory guidance concerning the quality of language assistance services that are necessary for meaningful access to care. Nonetheless, health literacy is not explicitly treated as a legally relevant factor in these doctrines. Moreover, there is no coherent legal framework for incorporating health literacy research that challenges traditional assumptions about patient comprehension and decision-making, and that emphasizes the need for providers to improve communication and take affirmative steps to assess patient understanding. The absence of a clear and robust consideration of health literacy in these doctrines undermines core access and quality aims, and it means that such laws are of limited efficacy in promoting health literacy. Returning to the theme that the health literacy problem reflects a complementary view of access, quality and cost, it is likely that the cost implications of this problem (and not concerns about quality and access) will motivate the kind of health literacy reform that may ultimately strengthen existing quality and access standards. One recent example of this can be seen in reforms linked to government, insurer and provider attempts to reduce costly medication errors.


Widespread infection with homologues of human parvoviruses B19, PARV4, and human bocavirus of chimpanzees and gorillas in the wild.
Infections with human parvoviruses B19 and recently discovered human bocaviruses (HBoVs) are widespread, while PARV4 infections are transmitted parenterally and prevalent specifically in injecting drug users and hemophiliacs. To investigate the exposure and circulation of parvoviruses related to B19 virus, PARV4, and HBoV in nonhuman primates, plasma samples collected from 73 Cameroonian wild-caught chimpanzees and gorillas and 91 Old World monkey (OWM) species were screened for antibodies to recombinant B19 virus, PARV4, and HBoV VP2 antigens by enzyme-linked immunosorbent assay (ELISA). Moderate to high frequencies of seroreactivity to PARV4 (63% and 18% in chimpanzees and gorillas, respectively), HBoV (73% and 36%), and B19 virus (8% and 27%) were recorded for apes, while OWMs were uniformly negative (for PARV4 and B19 virus) or infrequently reactive (3% for HBoV). For genetic characterization, plasma samples and 54 fecal samples from chimpanzees and gorillas collected from Cameroonian forest floors were screened by PCR with primers conserved within Erythrovirus, Bocavirus, and PARV4 genera. Two plasma samples (chimpanzee and baboon) were positive for PARV4, while four fecal samples were positive for HBoV-like viruses. The chimpanzee PARV4 variant showed 18% and 15% nucleotide sequence divergence in NS and VP1/2, respectively, from human variants (9% and 7% amino acid, respectively), while the baboon variant was substantially more divergent, mirroring host phylogeny. Ape HBoV variants showed complex sequence relationships with human viruses, comprising separate divergent homologues of HBoV1 and the recombinant HBoV3 species in chimpanzees and a novel recombinant species in gorillas. This study provides the first evidence for widespread circulation of parvoviruses in primates and enables future investigations of their epidemiology, host specificity, and (co)evolutionary histories.


Search for the Higgs Boson Decaying to Two Muons in Proton-Proton Collisions at sqrt[s]=13 TeV.
A search for the Higgs boson decaying to two oppositely charged muons is presented using data recorded by the CMS experiment at the CERN LHC in 2016 at a center-of-mass energy sqrt[s]=13 TeV, corresponding to an integrated luminosity of 35.9 fb^{-1}. Data are found to be compatible with the predicted background. For a Higgs boson with a mass of 125.09 GeV, the 95% confidence level observed (background-only expected) upper limit on the production cross section times the branching fraction to a pair of muons is found to be 3.0 (2.5) times the standard model expectation. In combination with data recorded at center-of-mass energies sqrt[s]=7 and 8 TeV, the background-only expected upper limit improves to 2.2 times the standard model value with a standard model expected significance of 1.0 standard deviation. The corresponding observed upper limit is 2.9 with an observed significance of 0.9 standard deviation. This corresponds to an observed upper limit on the standard model Higgs boson branching fraction to muons of 6.4×10^{-4} and to an observed signal strength of 1.0±1.0(stat)±0.1(syst).


Gene Expression in Placentas From Nondiabetic Women Giving Birth to Large for Gestational Age Infants.
Gestational diabetes, obesity, and excessive weight gain are known independent risk factors for the birth of a large for gestational age (LGA) infant. However, only 1 of the 10 infants born LGA is born by mothers with diabetes or obesity. Thus, the aim of the present study was to compare placental gene expression between healthy, nondiabetic mothers (n = 22) giving birth to LGA infants and body mass index-matched mothers (n = 24) giving birth to appropriate for gestational age infants. In the whole gene expression analysis, only 29 genes were found to be differently expressed in LGA placentas. Top upregulated genes included insulin-like growth factor binding protein 1, aminolevulinate δ synthase 2, and prolactin, whereas top downregulated genes comprised leptin, gametocyte-specific factor 1, and collagen type XVII α 1. Two enriched gene networks were identified, namely, (1) lipid metabolism, small molecule biochemistry, and organismal development and (2) cellular development, cellular growth, proliferation, and tumor morphology.


Testing the hypothesis that a clade has adaptively radiated: iguanid lizard clades as a case study.
The study of adaptive radiations has played a fundamental role in understanding mechanisms of evolution. A recent resurgence in the study of adaptive radiations highlights a gap in our knowledge about determining whether a clade constitutes adaptive diversification. Specifically, no objective criteria exist to judge whether a clade constitutes an adaptive radiation. Most clades, given enough time, will diversify adaptively to some extent; therefore, we argue that the term "adaptive radiation" should be reserved for those clades that are exceptionally diverse in terms of the range of habitats occupied and attendant morphological adaptations. Making such a definition operational, however, requires a comparative analysis of many clades. Only by comparing clades can one distinguish those that are exceptionally diverse (or nondiverse) from those exhibiting a normal degree of adaptive disparity. We propose such a test, focusing on disparity in the ecological morphology of monophyletic groups within the lizard family Iguanidae. We find that two clades, the Polychrotinae and Phrynosomatinae, are exceptionally diverse and that two others, the Crotaphytinae and Oplurinae, are exceptionally nondiverse. Potential explanations for differences in diversity are discussed, as are caveats and future extensions of our approach.


Quantitation of carotid stenosis with continuous-wave (C-W) Doppler ultrasound.
Two methods for determining the degree of stenoses developing on the origin of the internal carotid were tested using non-invasive Doppler ultrasonic imaging (DOPSCAN) of the carotid bifurcations. Spectral analysis of Doppler audio recordings was utilized in determining the maximum frequencies found within the stenosis, as well as the ratio of the frequency downstream to the stenosis, to the frequency within the stenosis. The theoretical relationships between blood flow, velocity, and pressure drop are defined for all grades of stenosis and they predict that carotid flow will not be reduced unless the lumen diameter is less than 1.5 mm. At critical diameter reductions, below 1 mm, the frequencies in human carotids do not exceed 16 KHz because turbulence limits peak velocities. If the maximum systolic frequency exceeds 5 KHZ, when 5 MHZ probes are directed at a 30 degree angle from the body axis, there is always present stenosis up to diameters of less than 3.5 mm by x-ray angiographic measurements. Frequency ratio studies confirm that plaque growth is not symmetrical but they did not improve x-ray angiography correlations because of the limitations of x-ray in measuring cross sectional areas from projection films and limitations of the spot size of x-ray tubes.


Viral mutation and substitution: units and levels.
Viruses evolve within a hierarchy of organisational levels, from cells to host species. We discuss how these nested population structures complicate the meaning and interpretation of two apparently simple evolutionary concepts: mutation rate and substitution rate. We discuss the units in which these fundamental processes should be measured, and explore why, even for the same virus, mutation and substitution can occur at very different tempos at different biological levels. In addition, we explore the ability of whole genome evolutionary analyses to distinguish between natural selection and other population genetic processes. A better understanding of the complexities underlying the molecular evolution of viruses in natural populations is needed before accurate predictions of viral evolution can be made.


Outcome of Lower-Risk Patients With Myelodysplastic Syndromes Without 5q Deletion After Failure of Erythropoiesis-Stimulating Agents.
Purpose Most anemic patients with non-deleted 5q lower-risk myelodysplastic syndromes (MDS) are treated with erythropoiesis-stimulating agents (ESAs), with a response rate of approximately 50%. Second-line treatments, including hypomethylating agents (HMAs), lenalidomide (LEN), and investigational drugs, may be used after ESA failure in some countries, but their effect on disease progression and overall survival (OS) is unknown. Here, we analyzed outcome after ESA failure and the effect of second-line treatments. Patients and Methods We examined an international retrospective cohort of 1,698 patients with non-del(5q) lower-risk MDS treated with ESAs. Results Erythroid response to ESAs was 61.5%, and median response duration was 17 months. Of 1,147 patients experiencing ESA failure, 653 experienced primary failure and 494 experienced relapse after a response. Primary failure of ESAs was associated with a higher risk of acute myeloid leukemia (AML) progression, which did not translate into an OS difference. Of 450 patients (39%) who received second-line treatment, 194 received HMAs, 148 received LEN, and 108 received other treatments (MISC), whereas 697 received RBC transfusions only. Five-year AML cumulative incidence was 20.3%, 20.3%, and 11.3% for those receiving HMAs, LEN, and MISC, respectively ( P = .05). Five-year OS for patients receiving HMA, LEN, and MISC was 36.5%, 41.7%, and 51%, respectively ( P = .21). In a multivariable analysis adjusted for age, sex, revised International Prognostic Scoring System score, and progression at ESA failure, there was no significant OS difference among the three groups. Conclusion In this large, multicenter, retrospective cohort of patients with non-del(5q) lower-risk MDS treated with ESAs, none of the most commonly used second-line treatments (HMA and LEN) significantly improved OS. Early failure of ESAs was associated with a higher risk of AML progression.


Utilization Probability Map for Migrating Bald Eagles in Northeastern North America: A Tool for Siting Wind Energy Facilities and Other Flight Hazards.
Collisions with anthropogenic structures are a significant and well documented source of mortality for avian species worldwide. The bald eagle (Haliaeetus leucocephalus) is known to be vulnerable to collision with wind turbines and federal wind energy guidelines include an eagle risk assessment for new projects. To address the need for risk assessment, in this study, we 1) identified areas of northeastern North America utilized by migrating bald eagles, and 2) compared these with high wind-potential areas to identify potential risk of bald eagle collision with wind turbines. We captured and marked 17 resident and migrant bald eagles in the northern Chesapeake Bay between August 2007 and May 2009. We produced utilization distribution (UD) surfaces for 132 individual migration tracks using a dynamic Brownian bridge movement model and combined these to create a population wide UD surface with a 1 km cell size. We found eagle migration movements were concentrated within two main corridors along the Appalachian Mountains and the Atlantic Coast. Of the 3,123 wind turbines ≥100 m in height in the study area, 38% were located in UD 20, and 31% in UD 40. In the United States portion of the study area, commercially viable wind power classes overlapped with only 2% of the UD category 20 (i.e., the areas of highest use by migrating eagles) and 4% of UD category 40. This is encouraging because it suggests that wind energy development can still occur in the study area at sites that are most viable from a wind power perspective and are unlikely to cause significant mortality of migrating eagles. In siting new turbines, wind energy developers should avoid the high-use migration corridors (UD categories 20 & 40) and focus new wind energy projects on lower-risk areas (UD categories 60-100).


Disruption of muscle membrane and phenotype divergence in two novel mouse models of dysferlin deficiency.
Limb girdle muscular dystrophy type 2B and Miyoshi myopathy are clinically distinct forms of muscular dystrophy that arise from defects in the dysferlin gene. Here, we report two novel lines of dysferlin-deficient mice obtained by (a) gene targeting and (b) identification of an inbred strain, A/J, bearing a retrotransposon insertion in the dysferlin gene. The mutations in these mice were located at the 3' and 5' ends of the dysferlin gene. Both lines of mice lacked dysferlin and developed a progressive muscular dystrophy with histopathological and ultrastructural features that closely resemble the human disease. Vital staining with Evans blue dye revealed loss of sarcolemmal integrity in both lines of mice, similar to that seen in mdx and caveolin-3 deficient mice. However, in contrast to the latter group of animals, the dysferlin-deficient mice have an intact dystrophin glycoprotein complex and normal levels of caveolin-3. Our findings indicate that muscle membrane disruption and myofiber degeneration in dysferlinopathy were directly mediated by the loss of dysferlin via a new pathogenic mechanism in muscular dystrophies. We also show that the mutation in the A/J mice arose between the late 1970s and the early 1980s, and had become fixed in the production breeding stocks. Therefore, all studies involving the A/J mice or mice derived from A/J, including recombinant inbred, recombinant congenic and chromosome substitution strains, should take into account the dysferlin defect in these strains. These new dysferlin-deficient mice should be useful for elucidating the pathogenic pathway in dysferlinopathy and for developing therapeutic strategies.


Region flow: a multi-stage method for colonoscopy tracking.
Co-located optical and virtual colonoscopy images provide important clinical information during routine colonoscopy procedures. Tracking algorithms that rely on image features to align virtual and optical images can fail when they encounter blurry image sequences. This is a common occurrence in colonoscopy images, when the endoscope touches a wall or is immersed in fluid. We propose a region-flow based matching algorithm to determine the large changes between images that bridge such interruptions in the visual field. The region flow field is used as the means to limit the search space for computing corresponding feature points; a sequence of refining steps is performed to identify the most reliable and accurate feature point pairs. The feature point pairs are then used in a deformation based scheme to compute the final camera parameters. We have successfully tested this algorithm on four clinical colonoscopy image sequences containing anywhere from 9-57 consecutive blurry images. Two additional tabletop experiments were performed to quantitatively validate the algorithm: the endoscope was moved along a slightly curved path by 24 mm and along a straight path by 40 mm. Our method reported errors within 1-5% in these experiments.


EARLY LIFE RISKS, ANTISOCIAL TENDENCIES, AND PRETEEN DELINQUENCY.
Early age-of-onset delinquency and substance use confer a major risk for continued criminality, alcohol and drug abuse, and other serious difficulties throughout the life course. Our objective is to examine the developmental roots of preteen delinquency and substance use. Using nationally representative longitudinal data from the UK Millennium Cohort Study (n = 13,221), we examine the influence of early childhood developmental and family risks on latent pathways of antisocial tendencies from ages 3 to 7, and the influence of those pathways on property crime and substance use by age 11. We identified a normative, non-antisocial pathway; a pathway marked by oppositional behavior and fighting; a pathway marked by impulsivity and inattention; and a rare pathway characterized by a wide range of antisocial tendencies. Children with developmental and family risks that emerged by age 3-specifically difficult infant temperament, low cognitive ability, weak parental closeness, and disadvantaged family background-face increased odds of antisocial tendencies. There is minimal overlap between the risk factors for early antisocial tendencies and those for preteen delinquency. Children on an antisocial pathway are more likely to engage in preteen delinquency and substance use by age 11, even after accounting for early life risk factors.


Strengthening responses to the HIV/AIDS pandemic: an internal evaluation of the Caribbean Health Leadership Institute.
Leadership development is a strategy for improving national responses to HIV/AIDS. The University of the West Indies offers the Caribbean Health Leadership Institute (CHLI) to enhance leaders' effectiveness and responses to HIV/AIDS through a cooperative agreement with the Centers for Disease Control and Prevention. CHLI enrolls leaders in annual cohorts numbering 20-40. To examine how CHLI influenced graduates' self-understanding, skills, approaches, vision, commitments, courage, confidence, networks, and contributions to program, organizational, policy, and systems improvements. Web-based surveys and interviews of graduates. CHLI increased graduates' self-understanding and skills and strengthened many graduates' vision, confidence, and commitments to improving systems. It helped graduates improve programs, policies, and systems by: motivating them and giving them ideas for changes to pursue, encouraging them to share their vision, deepening skills in areas such as systems thinking, policy advocacy, and communication, strengthening their inclusion of partners and team members, and influencing how they interacted with others. Training both HIV-focused and general health leaders can help both kinds of leaders foster improvements in HIV services and policies. Learners greatly valued self-assessments, highly interactive sessions, and the opportunity to build a network of professional colleagues. Projects provided opportunities to address substantive issues and immediately apply learning to work. Leadership development evaluations in the United States have also emphasized the complementary benefits of assessment and feedback, skills development, and network development. Global leadership programs should find ways to combine these components in both traditional face-to-face and distance-learning contexts.


Synchronisation of Neural Oscillations and Cross-modal Influences.
At any given moment, we receive multiple signals from our different senses. Prior research has shown that signals in one sensory modality can influence neural activity and behavioural performance associated with another sensory modality. Recent human and nonhuman primate studies suggest that such cross-modal influences in sensory cortices are mediated by the synchronisation of ongoing neural oscillations. In this review, we consider two mechanisms proposed to facilitate cross-modal influences on sensory processing, namely cross-modal phase resetting and neural entrainment. We consider how top-down processes may further influence cross-modal processing in a flexible manner, and we highlight fruitful directions for further research.


Sliding Mode Control of Steerable Needles.
Steerable needles can potentially increase the accuracy of needle-based diagnosis and therapy delivery, provided they can be adequately controlled based on medical image information. We propose a novel sliding mode control law that can be used to deliver the tip of a flexible asymmetric-tipped needle to a desired point, or to track a desired trajectory within tissue. The proposed control strategy requires no a priori knowledge of model parameters, has bounded input speeds, and requires little computational resources. We show that if the standard nonholonomic model for tip-steered needles holds, then the control law will converge to desired targets in a reachable workspace, within a tolerance that can be defined by the control parameters. Experimental results validate the control law for target points and trajectory following in phantom tissue and ex vivo liver. Experiments with targets that move during insertion illustrate robustness to disturbances caused by tissue deformation.


New Genus and Species of Turtle Blood Fluke (Platyhelminthes: Digenea: Schistosomatoidea) Infecting Six-Tubercled Amazon River Turtles, Podocnemis sextuberculata (Pleurodira: Podocnemididae) from the Amazon River Basin (Peru).
Herein we describe a new species of turtle blood fluke (TBF) and propose a new genus to accommodate it, Pitiutrema revelae n. gen., n. sp. This blood fluke infects the heart of six-tubercled Amazon River turtles (Podocnemis sextuberculata [Cornalia, 1849] [Pleurodira: Podocnemididae]) in the headwaters of the Amazon River near Iquitos, Peru. It resembles the other 2 described species of South American freshwater TBFs (Atamatam amazoniensis Bullard and Roberts, 2019, and Paratamatam iquitosiensis Bullard and Roberts, 2019) by having a dorsoventrally flattened and ovoid body, an oral sucker with anteroventral spines, 2 inter-cecal testes arranged in a column, inter-gonadal terminal genitalia, an inter-cecal and post-ovarian Laurer's canal pore, and a Y-shaped excretory bladder. It differs from all other nominal TBFs by having the combination of an aspinose body that lacks mammillae, a tapered (not broadly rounded) posterior body end, a ventral sucker, slightly M-shaped or inverse U-shaped ceca, a deeply-lobed (dendritic) ovary, a transverse uterus, and a dispersed vitellarium. The new genus is further unique among TBF genera by having an anterior to posterior sequence of ventral sucker, anterior testis, ovary, cirrus sac (lateral to posterior half of ovary), and posterior testis. The phylogenetic results and placement of the new taxon (1) were both predicted by our morphological diagnosis and comparisons with related taxa, (2) further indicated monophyly of the nominal South American freshwater TBFs, (3) reaffirmed the marine derived lineage identity of the nominal South American freshwater TBFs, and (4) highlighted that the single cercarial sequence (TBF sp. W-810) from an ampullariid in Brazil does not share a recent common ancestor with any of the nominal South American freshwater TBFs. The new species is the eighth TBF reported from a side-necked turtle (Pleurodira), the first TBF from a member of Podocnemididae, and the third freshwater TBF from South America.


Can radiation damage to protein crystals be reduced using small-molecule compounds?
Recent studies have defined a data-collection protocol and a metric that provide a robust measure of global radiation damage to protein crystals. Using this protocol and metric, 19 small-molecule compounds (introduced either by cocrystallization or soaking) were evaluated for their ability to protect lysozyme crystals from radiation damage. The compounds were selected based upon their ability to interact with radiolytic products (e.g. hydrated electrons, hydrogen, hydroxyl and perhydroxyl radicals) and/or their efficacy in protecting biological molecules from radiation damage in dilute aqueous solutions. At room temperature, 12 compounds had no effect and six had a sensitizing effect on global damage. Only one compound, sodium nitrate, appeared to extend crystal lifetimes, but not in all proteins and only by a factor of two or less. No compound provided protection at T=100 K. Scavengers are ineffective in protecting protein crystals from global damage because a large fraction of primary X-ray-induced excitations are generated in and/or directly attack the protein and because the ratio of scavenger molecules to protein molecules is too small to provide appreciable competitive protection. The same reactivity that makes some scavengers effective radioprotectors in protein solutions may explain their sensitizing effect in the protein-dense environment of a crystal. A more productive focus for future efforts may be to identify and eliminate sensitizing compounds from crystallization solutions.


A case of dilated cardiomyopathy due to nutritional vitamin D deficiency rickets.
Vitamin D deficiency rickets was detected as the cause in a nine-month-old girl with dilated cardiomyopathy and signs of congestive heart failure. The patient responded to calcium and vitamin D supplementation promptly and left ventricular systolic functions normalized at the 3rd month of treatment. Nutritional rickets must be remembered in etiological assessment of dilated cardiomyopathy among infants living in regions in which nutritional rickets is still common.


Intravascular release of intact cellular fibronectin during oxidant-induced injury of the in vitro perfused rabbit lung.
Fibronectin (Fn) is produced by cells in blood vessels at inflammatory sites in vivo. Fn release into the circulation thus may be a marker for vascular injury. In support of this, we found that oxidant-induced vascular injury of isolated perfused rabbit lungs caused elevated circulating Fn levels. Western blot analysis indicated that Fn released from the injured blood vessels was intact, dimeric, and possessed electrophoretic mobility identical with Fn produced by fibroblasts. Unlike Fn isolated from rabbit plasma, Fn derived from lung perfusate or produced by fibroblasts reacted with antibodies raised to a synthetic peptide containing sequences from the extra type III Fn domain that is transcribed in fibroblasts but not hepatocytes. Vascular injury by protease was also associated with intravascular release of Fn, but with cleavage. Oxidant-induced vascular injury causes release of tissue-derived Fn, which can be distinguished from plasma Fn by its size and content of antigenic determinants of the extra type III domain.


Exposure to persistent organic pollutants and sperm sex chromosome ratio in men from the Faroe Islands.
People in the Arctic as well as fishermen on the polluted Swedish east coast are highly exposed to persistent organic pollutants (POPs). These compounds have been shown to affect the sperm Y:X chromosome ratio. In present study, the aim was to investigate whether polychlorinated biphenyl (PCB) congeners and 1,1,-dichloro-2,2,-bis(p-chlorophenyl)ethane (p,p'-DDE) influence sperm sex chromosome ratio in Faroese men, and whether these men differ regarding Y:X ratio compared to Greenland Inuit and Swedish fishermen. The study population (n=449) consisted of young men from the general population (n=276) as well as proven fertile men (n=173). The Y:X ratio was assessed by fluorescent in situ hybridization. Serum concentrations of POPs were measured using gas chromatography. Associations between POP concentrations and Y:X ratio were calculated using linear and non-linear regression models as well as trend analysis and pairwise comparison of exposure data categorized into quartiles. The selected POPs were associated with Y:X ratio in fertile Faroese men, but not in the total population; p,p'-DDE (95% CI for B=-0.005 to -0.001, p=0.005) and ΣPCB (95% CI for B=-0.005 to -0.001, p=0.012). Since p,p'-DDE and ΣPCB correlated significantly (r=0.927, p<0.001), the results involving the exposure variables can be regarded as a single finding. The Y:X ratio for the total Faroese population was 0.500±0.018, which was statistically significantly lower than in both Inuit and Swedish fishermen (0.512 for both). In conclusion, Faroese men presented with lower Y:X ratio than Greenland Inuit and Swedish fishermen. Although no direct health effects are expected due to the lower Faroese Y:X ratio, it could be indicative of adverse effects on the reproductive system.


Hemoglobin diffusion and the dynamics of oxygen capture by red blood cells.
Translational diffusion of macromolecules in cell is generally assumed to be anomalous due high macromolecular crowding of the milieu. Red blood cells are a special case of cells filled quasi exclusively (95% of the dry weight of the cell) with an almost spherical protein: hemoglobin. Hemoglobin diffusion has since a long time been recognized as facilitating the rate of oxygen diffusion through a solution. We address in this paper the question on how hemoglobin diffusion in the red blood cells can help the oxygen capture at the cell level and hence to improve oxygen transport. We report a measurement by neutron spin echo spectroscopy of the diffusion of hemoglobin in solutions with increasing protein concentration. We show that hemoglobin diffusion in solution can be described as Brownian motion up to physiological concentration and that hemoglobin diffusion in the red blood cells and in solutions at similar concentration are the same. Finally, using a simple model and the concentration dependence of the diffusion of the protein reported here, we show that hemoglobin concentration observed in human red blood cells ([Formula: see text]330 g.L -1) corresponds to an optimum for oxygen transport for individuals under strong activity.


The carbon budget of Pinus radiata plantations in south-western Australia under four climate change scenarios.
We conducted a comprehensive modelling study to estimate future stem wood production and net ecosystem production (NEP) of Pinus radiata D. Don plantations in south-western Australia, a region that is predicted to undergo severe rainfall reduction in future decades. The process-based model CenW was applied to four locations where it had previously been tested. Climate change scenarios under four emission scenarios for the period from 2005 to 2066 were considered, in addition to simulations under the current climate. Results showed that stem wood production and NEP were little affected by moderate climate change. However, under the most pessimistic climate change scenario (Special Report on Emission Scenarios A2), stem wood production and NEP decreased strongly. These results could be explained by the trade-off between the positive effect of rising atmospheric CO(2) on plant water use efficiency and the negative effects of decreasing rainfall and increasing temperatures. Because changes in heterotrophic respiration (R(H)) lagged behind changes in plant growth, and because R(H) rates were increased by higher temperatures, NEP was more negatively affected than stem wood production. Stem wood production and NEP also strongly interacted with location, with the site currently having the wettest climate being least affected by climatic change. These results suggest that realistic predictions of forest production and carbon sequestration potential in the context of climate change require (1) the use of modelling tools that describe the important feedbacks between environmental variables, plant physiology and soil organic matter decomposition, (2) consideration of a range of climate change scenarios and (3) simulations that account for a gradual climate change to capture transient effects.


Ranolazine prevents INaL enhancement and blunts myocardial remodelling in a model of pulmonary hypertension.
Pulmonary arterial hypertension (PAH) reflects abnormal pulmonary vascular resistance and causes right ventricular (RV) hypertrophy. Enhancement of the late sodium current (INaL) may result from hypertrophic remodelling. The study tests whether: (i) constitutive INaL enhancement may occur as part of PAH-induced myocardial remodelling; (ii) ranolazine (RAN), a clinically available INaL blocker, may prevent constitutive INaL enhancement and PAH-induced myocardial remodelling. PAH was induced in rats by a single monocrotaline (MCT) injection [60 mg/kg intraperitoneally (i.p.)]; studies were performed 3 weeks later. RAN (30 mg/kg bid i.p.) was administered 48 h after MCT and washed-out 15 h before studies. MCT increased RV systolic pressure and caused RV hypertrophy and loss of left ventricular (LV) mass. In the RV, collagen was increased; myocytes were enlarged with T-tubule disarray and displayed myosin heavy chain isoform switch. INaL was markedly enhanced; diastolic Ca(2+) was increased and Ca(2+) release was facilitated. K(+) currents were down-regulated and APD was prolonged. In the LV, INaL was enhanced to a lesser extent and cell Ca(2+) content was strongly depressed. Electrical remodelling was less prominent than in the RV. RAN completely prevented INaL enhancement and limited most aspects of PAH-induced remodelling, but failed to affect in vivo contractile performance. RAN blunted the MCT-induced increase in RV pressure and medial thickening in pulmonary arterioles. PAH induced remodelling with chamber-specific aspects. RAN prevented constitutive INaL enhancement and blunted myocardial remodelling. Partial mechanical unloading, resulting from an unexpected effect of RAN on pulmonary vasculature, might contribute to this effect.


Cadmium-induced testicular injury.
Cadmium (Cd) is an environmental toxicant and an endocrine disruptor in humans and rodents. Several organs (e.g., kidney, liver) are affected by Cd and recent studies have illustrated that the testis is exceedingly sensitive to Cd toxicity. More important, Cd and other toxicants, such as heavy metals (e.g., lead, mercury) and estrogenic-based compounds (e.g., bisphenols) may account for the recent declining fertility in men among developed countries by reducing sperm count and testis function. In this review, we critically discuss recent data in the field that have demonstrated the Cd-induced toxicity to the testis is probably the result of interactions of a complex network of causes. This is likely to involve the disruption of the blood-testis barrier (BTB) via specific signal transduction pathways and signaling molecules, such as p38 mitogen-activated protein kinase (MAPK). We also summarize current studies on factors that confer and/or regulate the testis sensitivity to Cd, such as Cd transporters and metallothioneins, the impact of Cd on the testis as an endocrine disruptor and oxidative stress inducer, and how it may disrupt the Zn(2+) and/or Ca(2+) mediated cellular events. While much work is needed before a unified mechanistic pathway of Cd-induced testicular toxicity emerges, recent studies have helped to identify some of the likely mechanisms and/or events that take place during Cd-induced testis injury. Furthermore, some of the recent studies have shed lights on potential therapeutic or preventive approaches that can be developed in future studies by blocking or minimizing the destructive effects of Cd to testicular function in men.