1,25(OH)2D3 regulates the proangiogenic activity of pericyte through VDR-mediated modulation of VEGF production and signaling of VEGF and PDGF receptors.
We have previously demonstrated that the active form of vitamin D (calcitriol; 1,25(OH)2D3) is a potent inhibitor of retinal neovascularization. However, the underlying molecular and cellular mechanisms involved remained poorly understood. Perivascular supporting cells including pericytes (PC) play important roles during angiogenesis, vascular maturation, and stabilization of blood vessels. How 1,25(OH)2D3 affects retinal PC proliferation and migration, and whether these effects are mediated through vitamin D receptor (VDR), are unknown. Here, we determined the impact of 1,25(OH)2D3 on retinal PC prepared from wild-type (Vdr+/+) and VDR-deficient (Vdr-/-) mice. Retinal PC expressed significantly higher VDR levels compared to retinal endothelial cells (EC). Unlike retinal EC, 1,25(OH)2D3 significantly decreased PC proliferation and migration and resulted in a G0/G1 cell cycle arrest. Although 1,25(OH)2D3 did not inhibit the proliferation of Vdr-/- PC, it did inhibit their migration. PC adhesion to various extracellular matrix (ECM) proteins and ECM production were also affected by incubation of PC with 1,25(OH)2D3. Vdr-/- PC were more adherent compared with Vdr+/+ cells. Mechanistically, incubation of Vdr+/+ PC with 1,25(OH)2D3 resulted in an increased expression of vascular endothelial growth factor (VEGF) and attenuation of signaling through VEGF-R2 and platelet-derived growth factor receptor-beta. Incubation with soluble VEGF-R1 (sFlt-1) partially reversed the effect of VEGF on Vdr+/+ PC. In addition, incubation of Vdr+/+ PC with VEGF or inhibition of VEGF-R2 increased VDR expression. Together, these results suggest an important role for retinal PC as a target for vitamin D and VDR action for attenuation of angiogenesis.


Obstructive sleep apnea and its association with coronary artery calcium volume in asymptomatic male subjects.
The aim of this study was to analyze the association between various parameters related to obstructive sleep apnea (OSA) and coronary artery calcium (CAC) volume. We retrospectively reviewed the medical records of 315 male subjects who underwent standard polysomnography (PSG) and coronary artery computed tomography. In this study, we found that only the apnea index (AI) and minimal oxygen saturation (minimal SaO2) were independently associated with CAC volume after adjustment for confounders; for a 1/h increase in the AI, the CAC volume increased by 1.311 mm3, and for a 1% increase in the minimal SaO2, the CAC volume decreased by 2.187 mm3. We also found that the CAC volume was significantly different between the habitual snorer and the severe OSA group (21.27 ± 40.79 vs 71.33 ± 175.00, p = 0.042). Moreover, the CAC volume was significantly different between the first and fourth quartile groups of the AI (32.42 ± 59.54% vs. 78.74 ± 198.50, p = 0.048), but not among groups according to the hypopnea index quartile. Therefore, we concluded that among various OSA-related PSG parameters, the AI and minimal SaO2 was independently associated with the CAC volume and significantly related to upcoming cardiovascular events in middle-aged men.


A mortality study of employees at a synthetic rubber manufacturing plant.
A mortality follow-up study was conducted of workers employed at a synthetic rubber manufacturing plant in Baton Rouge, Louisiana. Interest in the potential health effects of exposure to methyl chloride, one of the substances used in the manufacturing process, provided the impetus for this study. The study cohort consisted of 852 male process workers who had worked at least 1 month during the period from startup of operations in 1943 through December 31, 1978. Mortality from all causes was lower than expected when compared with the U.S. male population. No excess mortality from any specific cause of death was found in the study population after analysis by level and duration of exposure.


Loss of Nrf1 rather than Nrf2 leads to inflammatory accumulation of lipids and reactive oxygen species in human hepatoma cells, which is alleviated by 2-bromopalmitate.
Since Nrf1 and Nrf2 are essential for regulating the lipid metabolism pathways, their dysregulation has thus been shown to be critically involved in the non-controllable inflammatory transformation into cancer. Herein, we have explored the molecular mechanisms underlying their distinct regulation of lipid metabolism, by comparatively analyzing the changes in those lipid metabolism-related genes in Nrf1α-/- and/or Nrf2-/- cell lines relative to wild-type controls. The results revealed that loss of Nrf1α leads to lipid metabolism disorders. That is, its lipid synthesis pathway was up-regulated by the JNK-Nrf2-AP1 signaling, while its lipid decomposition pathway was down-regulated by the nuclear receptor PPAR-PGC1 signaling, thereby resulting in severe accumulation of lipids as deposited in lipid droplets. By contrast, knockout of Nrf2 gave rise to decreases in lipid synthesis and uptake capacity. These demonstrate that Nrf1 and Nrf2 contribute to significant differences in the cellular lipid metabolism profiles and relevant pathological responses. Further experimental evidence unraveled that lipid deposition in Nrf1α-/- cells resulted from CD36 up-regulation by activating the PI3K-AKT-mTOR pathway, leading to abnormal activation of the inflammatory response. This was also accompanied by a series of adverse consequences, e.g., accumulation of reactive oxygen species (ROS) in Nrf1α-/- cells. Interestingly, treatment of Nrf1α-/- cells with 2-bromopalmitate (2BP) enabled the yield of lipid droplets to be strikingly alleviated, as accompanied by substantial abolishment of CD36 and critical inflammatory cytokines. Such Nrf1α-/- led inflammatory accumulation of lipids, as well as ROS, was significantly ameliorated by 2BP. Overall, this study provides a potential strategy for cancer prevention and treatment by precision targeting of Nrf1, Nrf2 alone or both.


Interventions for normal tension glaucoma.
Normal tension glaucoma is a clinical condition in which the optic nerve is pathologically excavated and the visual field is disturbed. Nevertheless it has been assumed that intraocular pressure plays a role in the progression of visual field defects in this disease, but other, mainly vascular factors, have been discussed as well. The objective of this review is to assess the effects of medical and surgical treatments for normal tension glaucoma. Trials were identified from the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group trials register), MEDLINE, EMBASE and BIOSIS Previews. Bibliographies of identified trials were searched to find additional trials. In addition, investigators and pharmaceutical companies were contacted. Date of last search: January 2001. This review includes randomised controlled trials in which medical or surgical interventions were compared to no treatment, placebo or other treatment in people with normal tension glaucoma. Two reviewers independently assessed the full text copies of the possibly relevant trials. Trial quality was assessed according to the methods set out in Section 6 of the Cochrane Reviewers' Handbook (Clarke 2000). Data were extracted by two reviewers and results were compared for differences. Discrepancies were resolved by discussion. The heterogeneity of interventions, follow-up periods and outcomes did not allow for statistical combinations of the study results. According to the selection criteria on visual field loss, eight studies were included in this review. Only three studies focussed on patient relevant outcomes. In one trial a beneficial effect of lowering intraocular pressure was found, but only if data were corrected for cataract development. In two small studies a beneficial effect on visual field loss of brovincamine, a calcium antagonist was reported. In one study the effect of intraocular pressure lowering on visual field outcome was only significant when data were corrected for cataract development. The results for calcium antagonists are promising, but larger trials have to be performed. Studies that focussed on reduction of intraocular pressure or haemodynamic variables are not necessarily relevant for the outcome in people with normal tension glaucoma.


Are lower levels of low-density lipoprotein cholesterol beneficial? a review of recent data.
In the 1960s, epidemiologic studies established a link between elevated serum cholesterol and increased risk of cardiovascular events. Extensive clinical trial data subsequently highlighted 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (ie, statins) as the most effective pharmacotherapy for lowering low-density lipoprotein (LDL) cholesterol, and showed that statin-mediated LDL cholesterol reductions were associated with significant improvements in cardiovascular outcomes. Such findings are reflected in current cardiovascular disease management guidelines, which focus on LDL cholesterol as the primary therapeutic target. These guidelines recommend target LDL cholesterol levels. However, a number of clinical trials have failed to identify an LDL cholesterol threshold level below which no further cardiovascular risk reduction occurs. Such findings suggest that optimal risk reduction may require greater reductions in LDL cholesterol than are currently being achieved. This review examines recent data highlighting the benefits of more pronounced LDL cholesterol reductions and considers how this could be achieved in clinical practice when many patients are not even reaching current targets.


The cholinesterase-like domain of thyroglobulin functions as an intramolecular chaperone.
Thyroid hormonogenesis requires secretion of thyroglobulin, a protein comprising Cys-rich regions I, II, and III (referred to collectively as region I-II-III) followed by a cholinesterase-like (ChEL) domain. Secretion of mature thyroglobulin requires extensive folding and glycosylation in the ER. Multiple reports have linked mutations in the ChEL domain to congenital hypothyroidism in humans and rodents; these mutations block thyroglobulin from exiting the ER and induce ER stress. We report that, in a cell-based system, mutations in the ChEL domain impaired folding of thyroglobulin region I-II-III. Truncated thyroglobulin devoid of the ChEL domain was incompetent for cellular export; however, a recombinant ChEL protein ("secretory ChEL") was secreted efficiently. Coexpression of secretory ChEL with truncated thyroglobulin increased intracellular folding, promoted oxidative maturation, and facilitated secretion of region I-II-III, indicating that the ChEL domain may function as an intramolecular chaperone. Additionally, we found that the I-II-III peptide was cosecreted and physically associated with secretory ChEL. A functional ChEL domain engineered to be retained intracellularly triggered oxidative maturation of I-II-III but coretained I-II-III, indicating that the ChEL domain may also function as a molecular escort. These insights into the role of the ChEL domain may represent potential therapeutic targets in the treatment of congenital hypothyroidism.


Incidence of increased intracranial pressure after early surgical treatment of syndromic craniosynostosis.
The late development of intracranial hypertension after an aesthetically successful cranial vault expansion has been noted anecdotally in children with syndromic synostosis. If untreated, this process can lead to neurological and visual deterioration; however, the frequency of this problem is uncertain. In an attempt to detect this process before the onset of irreversible impairment, the authors have since 1991 incorporated routine ophthalmological evaluations into the multidisciplinary follow-up protocol for all patients with complex craniosynostosis. These examinations were performed at initial evaluation and at 6-month intervals thereafter. The present report focuses on the results in 22 consecutive infants with syndromic synostosis who underwent initial surgery between 1991 and 1994. All but 4 children underwent initial cranial reconstruction at 6-18 months of age. Four patients had papilledema preoperatively which in each instance resolved postoperatively. During the follow-up period, 8 children manifested evidence of late intracranial hypertension at a median of 16.5 months after initial operation(s): 4 developed asymptomatic papilledema, 1 had progressive proptosis, and 3 had other subtle clinical signs of increased intracranial pressure (ICP). Further evaluation disclosed a Chiari 1 malformation in 2 children; 4 had a 'beaten copper' appearance on skull radiographs, and 4 underwent lumbar puncture, which in each case demonstrated an opening pressure above 20 cm H2O. Only 3 children exhibited symptoms from the ICP elevation. Six children with a head size < or = the 25th percentile underwent a repeat cranial expansion; after the cranial vault expansion, one child who initially had slit-like ventricles developed ventriculomegaly and, because of persistent papilledema, underwent insertion of ventriculoperitoneal (VP) shunt. Two other patients with a head circumference above the 50th percentile and the development of moderate ventriculomegaly underwent VP shunt insertion alone. All children have had complete resolution of papilledema as well as other symptoms and signs of increased ICP without evidence of optic atrophy or neurological sequelae. This study indicates that the incidence of delayed, asymptomatic increases in ICP among children with complex craniosynostosis is higher than previously estimated. The pathophysiologic bases for this process are discussed. Because the detection of this problem at a presymptomatic stage should optimize the likelihood of a good functional outcome, we strongly recommend close ophthalmological and clinical follow-up as a part of the comprehensive care of all young children with complex craniosynostosis, even after a cosmetically successful cranial expansion.


Aspirin: four score and more.
Pain is a tax levied on man for the privilege of life upon this planet. Some are taxed lightly and others are taxed heavily, but all are taxed. To relieve this stress, from time immemorial man has taken analgesics. In modern times, if home medication fails, professional consultation is available. The important question is the choice of an analgesic. The advantage appears to lie with aspirin because it especially evokes relief of pain caused by inflammation.


Reducing stigma and improving access to care for people with mental health conditions in the community: protocol for a multi-site feasibility intervention study (Indigo-Local).
Stigma and discrimination towards people with mental health conditions by their communities are common worldwide. This can result in a range of negative outcomes for affected persons, including poor access to health care. However, evidence is still patchy from low- and middle-income countries (LMICs) on affordable, community-based interventions to reduce mental health-related stigma and to improve access to mental health care. This study aims to conduct a feasibility (proof-of-principle) pilot study that involves developing, implementing and evaluating a community-based, multi-component, public awareness-raising intervention (titled Indigo-Local), designed to reduce stigma and discrimination and to increase referrals of people with mental health conditions for assessment and treatment. It is being piloted in five LMICs - China, Ethiopia, India, Nepal and Tunisia - and includes several key components: a stakeholder group workshop; a stepped training programme (using a 'Training of Trainers' approach) of community health workers (or similar cadres of workers) and service users that includes repeated supervision and booster sessions; awareness-raising activities in the community; and a media campaign. Social contact and service user involvement are instrumental to all components. The intervention is being evaluated through a mixed-methods pre-post study design that involves quantitative assessment of stigma outcomes measuring knowledge, attitudes and (discriminatory) behaviour; quantitative evaluation of mental health service utilization rates (where feasible in sites); qualitative exploration of the potential effectiveness and impact of the Indigo-Local intervention; a process evaluation; implementation evaluation; and an evaluation of implementation costs. The outcome of this study will be contextually adapted, evidence-based interventions to reduce mental health-related stigma in local communities in five LMICs to achieve improved access to healthcare. We will have replicable models of how to involve people with lived experience as an integral part of the intervention and will produce knowledge of how intervention content and implementation strategies vary across settings. The interventions and their delivery will be refined to be acceptable, feasible and ready for larger-scale implementation and evaluation. This study thereby has the potential to make an important contribution to the evidence base on what works to reduce mental health-related stigma and discrimination and improve access to health care.


Measurement techniques for small absorption coefficients: recent advances.
A review is given of several newly developed methods for measuring low absorption losses in optical rnaterials. Transmission, emittance, and calorimetric techniques are described with special emphasis on how thermocouple and photoacoustic calorimetry can be used to determine both bulk and surface absorption simultaneously. The advantages and disadvantages of the various approaches are discussed, and estimates are given of the sensitivities that can be achieved with the different techniques. Finally, a new ac interferometric calorimetric method for measuring low bulk losses is proposed.


Hyperbolic geometry for colour metrics.
It is well established from both colour difference and colour order perpectives that the colour space cannot be Euclidean. In spite of this, most colour spaces still in use today are Euclidean, and the best Euclidean colour metrics are performing comparably to state-of-the-art non-Euclidean metrics. In this paper, it is shown that a transformation from Euclidean to hyperbolic geometry (i.e., constant negative curvature) for the chromatic plane can significantly improve the performance of Euclidean colour metrics to the point where they are statistically significantly better than state-of-the-art non-Euclidean metrics on standard data sets. The resulting hyperbolic geometry nicely models both qualitatively and quantitatively the hue super-importance phenomenon observed in colour order systems.


Utilising implementation science in building research and evaluation capacity in community health.
It is becoming increasingly important for the community health sector to provide evidence of practice and program effectiveness. Unfortunately many community health centres do not have the capacity to provide such evidence and require the implementation of innovative changes within their organisation to develop their capacity to conduct research and evaluation. In this paper we present our project in which we utilised Donald Ely's model to build research and evaluation capacity in a community health centre. We utilised a qualitative research method that incorporated a co-operative inquiry action research design. Qualitative research methods incorporated data from semi-structured interviews, observations and the recording of relevant meetings. The data were analysed by means of thematic analysis. We found that to successfully build research and evaluation capacity entails the application of a model that is capable of not only addressing significant issues in implementation but that can also identify the conditions within an organisation that are important to achieve change. Ely's Conditions for Change model was most appropriate to implement the necessary changes.


Discriminative and participant-rated effects of methylphenidate in children diagnosed with attention deficit hyperactivity disorder (ADHD).
Despite the demonstrated beneficial effects of methylphenidate and d-amphetamine for the treatment of attention-deficit hyperactivity disorder (ADHD), the discriminative and subjective effects of these compounds in children are not well understood. This study was designed to characterize such effects in children diagnosed with ADHD. In a series of 3 experiments, 17 children were examined to determine whether methylphenidate (n = 12) and d-amphetamine (n = 5) could be reliably discriminated at doses typically used in clinical practice. Under some conditions (e.g., when they were instructed to attend to the drug effects or when a wide range of doses was used), children discriminated methylphenidate (5.0-30.0 mg) from placebo. Children tested under a range of doses of d-amphetamine (2.5-20.0 mg) were unable to discriminate this drug from placebo reliably. Neither methylphenidate nor d-amphetamine produced reliable participant-rated effects.


Anti-histone acetyltransferase activity from allspice extracts inhibits androgen receptor-dependent prostate cancer cell growth.
Histone acetylation depends on the activity of two enzyme families, histone acetyltransferase (HAT) and deacetylase (HDAC). In this study, we screened various plant extracts to find potent HAT inhibitors. Hot water extracts of allspice inhibited HAT activity, especially p300 and CBP (40% at 100 microg/ml). The mRNA levels of two androgen receptor (AR) regulated genes, PSA and TSC22, decreased with allspice treatment (100 microg/ml). Importantly, in IP western analysis, AR acetylation was dramatically decreased by allspice treatment.Furthermore, chromatin immunoprecipitation indicated that the acetylation of histone H3 in the PSA and B2M promoter regions was also repressed. Finally, allspice treatment reduced the growth of human prostate cancer cells, LNCaP (50% growth inhibition at 200 microg/ml). Taken together, our data indicate that the potent HAT inhibitory activity of allspice reduced AR and histone acetylation and led to decreased transcription of AR target genes, resulting in inhibition of prostate cancer cell growth.


Work overload, burnout, and psychological ill-health symptoms: a three-wave mediation model of the employee health impairment process.
The study reported here investigated the causal relationships in the health impairment process of employee well-being, and the mediating role of burnout in the relationship between work overload and psychological ill-health symptoms, over time. The research is deemed important due to the need for longitudinal evidence of the health impairment process of employee well-being over three waves of data. A quantitative survey design was followed. Participants constituted a longitudinal sample of 370 participants, at three time points, after attrition. Descriptive statistics and structural equation modeling methods were implemented. Work overload at time one predicted burnout at time two, and burnout at time two predicted psychological ill-health symptoms at time three. Indirect effects were found between work overload time one and psychological ill-health symptoms time three via burnout time two, and also between burnout time one and psychological ill-health symptoms time three, via burnout time two. The results provided supportive evidence for an "indirect-only" mediation effect, for burnout's causal mediation mechanism in the health impairment process between work overload and psychological ill-health symptoms.


Mesenchymal Stromal Cells in Neuroblastoma: Exploring Crosstalk and Therapeutic Implications.
Neuroblastoma (NB) is the second most common solid cancer in childhood, accounting for 15% of cancer-related deaths in children. In high-risk NB patients, the majority suffers from metastasis. Despite intensive multimodal treatment, long-term survival remains <40%. The bone marrow (BM) is among the most common sites of distant metastasis in patients with high-risk NB. In this environment, small populations of tumor cells can persist after treatment (minimal residual disease) and induce relapse. Therapy resistance of these residual tumor cells in BM remains a major obstacle for the cure of NB. A detailed understanding of the microenvironment and its role in tumor progression is of utmost importance for improving the treatment efficiency of NB. In BM, mesenchymal stromal cells (MSCs) constitute an important part of the microenvironment, where they support hematopoiesis and modulate immune responses. Their role in tumor progression is not completely understood, especially for NB. Although MSCs have been found to promote epithelial-mesenchymal transition, tumor growth, and metastasis and to induce chemoresistance, some reports point toward a tumor-suppressive effect of MSCs. In this review, we aim to compile current knowledge about the role of MSCs in NB development and progression. We evaluate arguments that depict tumor-supportive versus -suppressive properties of MSCs in the context of NB and give an overview of factors involved in MSC-NB crosstalk. A focus lies on the BM as a metastatic niche, since that is the predominant site for NB metastasis and relapse. Finally, we will present opportunities and challenges for therapeutic targeting of MSCs in the BM microenvironment.


Facial Assessment and Injection Guide for Botulinum Toxin and Injectable Hyaluronic Acid Fillers: Focus on the Upper Face.
Techniques for the administration of injectable fillers and neuromodulators for facial aesthetic rejuvenation and enhancement continue to evolve. As the number of physicians with limited experience in providing aesthetic treatments expands, the need for guidance and training from more experienced injectors has become apparent. The use of a slow, careful, and methodical injection technique is imperative in all treatment settings and for all facial areas. Constant attention to local anatomy, particularly arteries, veins, and nerve bundles, is critical for minimizing complications. This first article of a three-part series addresses techniques and recommendations for aesthetic treatment of the upper face. Traditionally, the upper face has been considered a basic area for treatment with neuromodulators but an advanced area for treatment with fillers. Injectable fillers may be used for temple volumization, eyebrow shaping, and forehead contouring. Neuromodulators are well suited for diminishing the appearance of dynamic facial lines such as forehead, glabellar, and crow's feet lines, and eyebrow lifting and eye-aperture widening. These techniques may be used independently or together, sequentially or concurrently, to address rejuvenation of individual or multiple facial regions. Overall, this series provides a practical framework of techniques for physicians who desire to perform safe and effective aesthetic treatments using a multimodal approach.


Training brain injury rehabilitation therapists to use generalized teaching and interaction skills.
Persons sustaining a brain injury often exhibit aberrant response patterns and skill deficits that require remediation. To promote recovery, rehabilitation staff must be competent in use of therapeutic teaching and interaction skills. This study focused on teaching 13 direct-care rehabilitation therapists these skills in a multiple baseline design across skill dimensions. Performance-based approaches were used to promote acquisition of therapist skills, and the 'general case' strategy was used to enhance generalization. The general case approach involved use of multiple examples of teaching and interaction situations selected to sample the range of variability in the rehabilitation setting. Therapists were videotaped in simulations of various teaching and interaction situations before and after staff training. These observations were coded for correct use of teaching and interaction skills. Therapists demonstrated mean increases of approximately 30 percentage points in correct skill use after training. The present training format appears to provide an efficient strategy for training staff to promote rehabilitation efforts.


The usefulness of circulating adipokine levels for the assessment of obesity-related health problems.
Because the prevalence of obesity has increased dramatically in recent years, one of the key targets of public health is obesity and its associated pathological conditions. Obesity occurs as a result of white adipose tissue enlargement, caused by adipocyte hyperplasia and/or hypertrophy. Recently, endocrine aspects of adipose tissue have become an active research area and these adipose tissue-derived factors are referred to as adipokines. These adipokines interact with a range of processes in many different organ systems and influence a various systemic phenomena. Therefore, dysregulated production of adipokines has been found to participate in the development of metabolic and vascular diseases related to obesity. The obese state is also known to be associated with increased local and systemic inflammation. Adipokines influence not only systemic insulin resistance and have pathophysiological roles in the metabolic syndrome and cardiovascular disease, but also contribute toward an increase in local and systemic inflammation. Thus, circulating levels of adipokines can be used as high-throughput biomarkers to assess the obesity-related health problems, including low grade inflammation. This review focuses on the usefulness of measuring circulating adipokine levels for the assessment of obesity-related health problems.


Improving the assessment of predator functional responses by considering alternate prey and predator interactions.
To improve understanding of the complex and variable patterns of predator foraging behavior in natural systems, it is critical to determine how density-dependent predation and predator hunting success are mediated by alternate prey or predator interference. Despite considerable theory and debate seeking to place predator-prey interactions in a more realistic context, few empirical studies have quantified the role of alternate prey or intraspecific interactions on predator-prey dynamics. We assessed functional responses of two similarly sized, sympatric carnivores, lynx (Lynx canadensis) and coyotes (Canis latrans), foraging on common primary (snowshoe hares; Lepus americanus) and alternate (red squirrels; Tamiasciurus hudsonicus) prey in a natural system. Lynx exhibited a hyperbolic prey-dependent response to changes in hare density, which is characteristic of predators relying primarily on a single prey species. In contrast, the lynx-squirrel response was found to be linear ratio dependent, or inversely dependent on hare density. The coyote-hare and coyote-squirrel interactions also were linear and influenced by predator density. We explain these novel results by apparent use of spatial and temporal refuges by prey, and the likelihood that predators commonly experience interference and lack of satiation when foraging. Our study provides empirical support from a natural predator-prey system that (1) predation rate may not be limited at high prey densities when prey are small or rarely captured; (2) interference competition may influence the predator functional response; and (3) predator interference has a variable role across different prey types. Ultimately, distinct functional responses of predators to different prey types illustrates the complexity associated with predator-prey interactions in natural systems and highlights the need to investigate predator behavior and predation rate in relation to the broader ecological community.


Genetic modification of retinal degeneration in tubby mice.
Mice that carry the recessive mutation tub develop neurosensory defects including retinal and cochlear degeneration, as well as maturity-onset obesity associated with insulin resistance. The biological function of the gene and the mechanism by which it induces its phenotypes are still unclear. In order to elucidate the pathways through which tub functions, in the current study, QTL modifiers were identified in an F2 intercross between (C57BL/6J- tub/tub and AKR/J-+/+) F1 hybrids (AKR intercross). The thickness of the outer nuclear layer of the retina and the number of photoreceptor nuclei were assessed in F2 mice homozygous for the tub mutation. A genome-wide scan revealed a significant linkage on chromosome 11 (named motr1) and two suggestive linkages on chromosomes 2 and 8. Interestingly, the same chromosome 2 region identified for the hearing modifier of tubby, the moth1 locus, showed a peak lod score of 2.3 for protection from retinal degeneration. This result suggests that the gene responsible for the QTL on chromosome 2 might be involved in a common pathway through which retinal and cochlear degeneration are induced in tubby mice.


A Bayesian Statistical Approach to Continuous Qualification of a Bioassay.
A validated bioassay is used to measure the potency of commercial lots, and as such, must be accurate, precise, and fit for its intended purpose. Regulatory expectations for a bioassay include a characterization of features, such as accuracy, precision, linearity, and range. The journey of a bioassay typically starts in a development lab, where it is initially qualified and used to support the release and stability testing of clinical lots. As a program moves through the different clinical phases, it may be optimized further, used to support process development, or transferred to new laboratories, with each activity generating additional bioassay data. Finally, the bioassay is fully validated as part of the transfer to the commercial quality control testing laboratories. In this work, rather than capturing the data from each study as a separate, independent report, it is proposed that, beginning with the qualification study, the accuracy and precision of the bioassay be continuously characterized, with each subsequent study result building upon the preceding ones. We call this approach continuous qualification Such a proposition is naturally carried out using Bayesian statistical methods in which the historical study data is used to construct prior knowledge that is blended with the current study data. By doing so, the bioassay accuracy and precision may be assessed with high confidence well ahead of commercial manufacturing. Further, by following the total-variance approach, the method also allows for a robust construction of system suitability and control limits for potency.


Impact of population structure on the apparent outcrossing rate of grain sorghum (Sorghum bicolor).
Population structure, the physical arrangement of related and unrelated individuals, can have profound effects on the apparent outcrossing rate ([Formula: see text]) in a plant population. However, detailed experimental investigations of the impact of population structure on [Formula: see text] are few. We compared the apparent outcrossing rates of experimental populations of grain sorghum with seed families spatially arranged in stratified and overdispersed treatments. Using alcohol dehydrogenase allozymes as genetic markers, [Formula: see text] was calculated for each of the treatments at two locations over three years. For all six comparisons, the overdispersed treatment yielded significantly larger apparent outcrossing estimates than the stratified treatment. In one case, the difference was over five-fold. Site-specific and time-specific differences were small compared to treatment differences. Whether natural structuring plays a role in altering the effective outcrossing rates of natural populations has been addressed by only a few descriptive studies; structuring effects appear to have an impact in only about half of such studies. The sample is still too small to make any generalizations.Population structuring can also be of significance in plant breeding programs. Controllable variation in [Formula: see text] values of the magnitude reported herein may be useful in optimizing selection methods for quantitative characters in experimental plant breeding populations. Further work is under way to determine the effects of the variation in apparent outcrossing rates on genetic gains from selection.


Resveratrol: from diet to topical usage.
The stilbene derivative resveratrol (3,5,4'-trihydroxy-stilbene; RESV) has become the subject of interest of many researchers and the pharmaceutical industries due to its well-acclaimed beneficial biological activities. Although earlier research tended to focus on the effects of RESV on cardiovascular disorders, many other studies have described the beneficial effects of RESV in the areas of cancer chemoprevention and inflammation and interest of researchers on this compound is still increasing. It is now well accepted that the effect of RESV is not just due to its so called "antioxidant" activity but mainly (if not only) because of the ability of this compound to trigger cell signaling pathways and gene expression involved in cellular defense systems. Many "in vitro" studies on RESV did not take into account that although its oral absorption is about 75% it undergoes rapid metabolism and the concentration in the blood stream is almost undetectable. For this reason interest in the topical usage of RESV by cosmeceutical skin care brands has exponentially increased in the last decade reporting in general very promising results on its beneficial effect in protecting the skin from outdoor insults, but there is still some controversy on its topical usage mainly surrounding the concentration used. Therefore, more basic research on the topical application of RESV should be performed to better understand the way it prevents cutaneous damage and whether it could be recommended as a preventive skin aging agent for all skin insults.


Solid-State, Hectogram-Scale Preparation of Red Carbon Dots as Phosphor for Energy-Transfer-Induced High-Quality White LEDs with CRI of 97.
In this study, pre-crystallization-controlled, solid-state preparation of red carbon dots (C-dots) from o-phenylenediamine on a hectogram scale with a 94% yield is reported. Highly efficient red phosphor (C-dots@MCC) is obtained by dispersing the C-dots in microcrystalline cellulose, which matched extremely well with the commercial Y3 Al5 O12 :Ce3+ (YAG) phosphor. White light-emitting diodes (WLEDs) fabricated from the two phosphors emitted warm white light with a correlated color temperature of 3845 K, CIE color coordinates of (0.38, 0.37), and an extremely high color rendering index (CRI) of 95, outperforming all the reported YAG-derived WLEDs. Furthermore, the CRI value of the WLED can be further increased to 97 after fine-tuning, which is the highest CRI for WLEDs of any C-dots derived devices reported so far. The superior performance of the WLED is attributed to a delicate energy transfer between YAG and C-dots@MCC. Most importantly, the WLED maintained excellent stabilities under varied currents, working durations, moistures, and temperatures.


Persistent hypoparathyroidism following magnesium repletion in burn-injured children.
Children suffering severe burns develop hypocalcemia, magnesium (Mg) depletion, hypoparathyroidism, and renal resistance to parathyroid hormone (PTH) infusion. We hypothesized that Mg depletion accounted for both the hypoparathyroidism and the renal resistance to PTH, and that Mg repletion would improve both. Due to a lack of PTH for infusion, we studied only the effect of Mg repletion on the relationship between ionized Ca (iCa) and PTH in the serum of 14 sequentially recruited children burned > or =40% total body surface area. All received a urinary Mg retention test a median of 20 days post burn (range 8-137 days). Seven (50%) of the children remained Mg depleted, which was not attributable to burn size or to time from burn to study. Combined enteral and parenteral Mg intakes were not different between the depleted and repleted groups, 12.2+/-4.4 (SD) mg/kg per day and 14.2+/-6.2 mg/kg per day, respectively. Both groups had low intact PTH levels in relation to serum iCa concentration, indicating persistent hypoparathyroidism. We conclude that Mg depletion is not the chief cause of hypoparathyroidism following thermal injury and we postulate that the persistent hypoparathyroidism is consistent with a reduced set-point for Ca suppression of PTH secretion.


Within-individual plasticity explains age-related decrease in stress response in a short-lived bird.
A crucial problem for every organism is how to allocate energy between competing life-history components. The optimal allocation decision is often state-dependent and mediated by hormones. Here, we investigated how age, a major state variable affects individuals' hormonal response to a standardized stressor: a trait that may reflect allocation between self-maintenance and reproduction. We caught free-living house sparrows and measured their hormonal (corticosterone) response to capture stress in consecutive years. Using a long-term ringing dataset, we determined the age of the birds, and we partitioned the variation into within- and among-individual age components to investigate the effects of plasticity versus selection or gene flow, respectively, on the stress response. We found large among-individual variation in the birds' hormone profiles, but overall, birds responded less strongly to capture stress as they grew older. These results suggest that stress responsiveness is a plastic trait that may vary within individuals in an adaptive manner, and natural selection may act on the reaction norms producing optimal phenotypic response in the actual environment and life-history stage.


Association between blood pressure responses to the cold pressor test and dietary sodium intervention in a Chinese population.
Blood pressure (BP) responses to the cold pressor test (CPT) and to dietary sodium intake might be related to the risk of hypertension. We examined the association between BP responses to the CPT and to dietary sodium and potassium interventions. The CPT and dietary intervention were conducted among 1906 study participants in rural China. The dietary intervention included three 7-day periods of low sodium intake (3 g/d of salt [sodium chloride] [51.3 mmol/d of sodium]), high sodium intake (18 g/d of salt [307.8 mmol/d of sodium]), and high sodium intake plus potassium chloride supplementation (60 mmol/d). A total of 9 BP measurements were obtained during the 3-day baseline observation and the last 3 days of each intervention using a random-zero sphygmomanometer. Blood pressure response to the CPT was significantly associated with BP changes during the sodium and potassium interventions (all P < .001). Compared with the lowest quartile of BP response to the CPT (quartile 1), systolic BP changes (95% confidence intervals) for the quartiles 2, 3, and 4 were -2.02 (-2.87 to -1.16) mm Hg, -3.17 (-4.05 to -2.28) mm Hg, and -5.98 (-6.89 to -5.08) mm Hg, respectively, during the low-sodium intervention. Corresponding systolic BP changes during the high-sodium intervention were 0.40 (-0.36 to 1.16) mm Hg, 0.44 (-0.35 to 1.22) mm Hg, and 2.30 (1.50 to 3.10) mm Hg, respectively, and during the high-sodium plus potassium supplementation intervention were -0.26 (-0.99 to 0.46) mm Hg, -0.95 (-1.70 to -0.20) mm Hg, and -1.59 (-2.36 to -0.83) mm Hg, respectively. These results indicate that BP response to the CPT was associated with salt sensitivity and potassium sensitivity. Furthermore, a low-sodium or high-potassium diet might be more effective to lower BP among individuals with high responses to the CPT.


Transforming pain medicine: adapting to science and society.
The field of chronic pain medicine is currently facing enormous challenges. The incidence of chronic pain is increasing worldwide, particularly in the developed world. As a result, chronic pain is imposing a growing burden on Western societies in terms of cost of medical care and lost productivity. This burden is exacerbated by the fact that despite research efforts and a huge expenditure on treatment for chronic pain, clinicians have no highly effective treatments or definitive diagnostic measures for patients. The lack of an objective measure for pain impedes basic research into the biological and psychological mechanisms of chronic pain and clinical research into treatment efficacy. The development of objective measurements of pain and ability to predict treatment responses in the individual patient is critical to improving pain management. Finally, pain medicine must embrace the development of a new evidence-based therapeutic model that recognizes the highly individual nature of responsiveness to pain treatments, integrates bio-psycho-behavioural approaches, and requires proof of clinical effectiveness for the various treatments we offer our patients. In the long-term these approaches will contribute to providing better diagnoses and more effective treatments to lessen the current challenges in pain medicine.


Laser safety in otolaryngology--head and neck surgery: anesthetic and educational considerations for laryngeal surgery.
Two investigations concerning anesthetic and educational considerations for laser safety in microlaryngeal carbon dioxide laser surgery have been performed. The first study demonstrated that attendance at a "hands-on" laser surgery course that stressed safety precautions was associated with a reduced rate of laser-related complications in the selected group of otolaryngologists who participated in the course, when compared to another selected group of otolaryngologists who were members of a senior otolaryngology society, and surveyed solely on the basis of their society membership. The second series of studies compared the incendiary characteristics of three endotracheal tubes in various mixtures of oxygen, diluted with either helium or nitrogen. It was determined that the polyvinyl chloride tube should not be used for laser surgery, even when wrapped with reflective, metallic tape. The safest anesthetic gas mixture was found to be 30% oxygen in helium; the addition of 2% halothane did not have an adverse effect, as had been previously reported. Both the Xomed Laser-Shield and Rusch red rubber endotracheal tubes were found to be safe, when used with the laser in the pulsed mode in an atmosphere of 100% oxygen. When the laser was used in the continuous mode, both tubes ignited in an atmosphere of 30% oxygen in helium. These findings challenged the previously reported levels of safety associated with the use of an unwrapped Xomed tube. Based on the results of this investigation, it has been concluded that both the Rusch red rubber tube and the Xomed Laser-Shield tube should be wrapped with reflective, metallic tape, when used for cases of microlaryngeal surgery with the carbon dioxide laser.


Nucleotide metabolism and its control in lactic acid bacteria.
Most metabolic reactions are connected through either their utilization of nucleotides or their utilization of nucleotides or their regulation by these metabolites. In this review the biosynthetic pathways for pyrimidine and purine metabolism in lactic acid bacteria are described including the interconversion pathways, the formation of deoxyribonucleotides and the salvage pathways for use of exogenous precursors. The data for the enzymatic and the genetic regulation of these pathways are reviewed, as well as the gene organizations in different lactic acid bacteria. Mutant phenotypes and methods for manipulation of nucleotide pools are also discussed. Our aim is to provide an overview of the physiology and genetics of nucleotide metabolism and its regulation that will facilitate the interpretation of data arising from genetics, metabolomics, proteomics, and transcriptomics in lactic acid bacteria.


Physical growth and socioeconomic background of Stockholm schoolchildren born in 1933-63.
Height, weight and body mass index (BMI) at aged 7, 10 and 13 years for samples of Stockholm schoolchildren born in 1933, 1943, 1953 and 1963 were analysed in relation to their socioeconomic background. In height there were significant socioeconomic differences for boys and girls born in 1933 and 1943 at the ages of 7 and 10 years; children from the lowest socioeconomic group were smaller. For the cohort born in 1953 there were, however, no socioeconomic differences in height--either for boys or for girls. For children born in 1963, socioeconomic differences in height appeared again, but mainly for the boys; boys in the lowest socioeconomic group were smaller. Significant weight differences between socioeconomic groups were for the boys found only in cohorts born in 1943 and in 1963 and for the girls born in 1933, 1943 and 1953. Socioeconomic differences in BMI were found for boys born in 1943, when the middle socioeconomic group had the lowest index, and for boys born in 1963 when the highest socioeconomic group had the highest index. For girls socioeconomic differences in BMI were only found for girls born in 1953 when the lowest group had the highest BMI. The main conclusions from the study were: socioeconomic differences in height formerly present in Stockholm schoolchildren born in 1933 and 1943 were levelled out for the children born in 1953, but reappeared again for children born in 1963--mainly for the boys; these socioeconomic height differences for the 1963 cohort were of about the same magnitudes as those for the cohort born in 1943 during the Second World War. The influence of socioeconomic background on the BMI of Stockholm schoolchildren born 1933-63 was not so marked.


Fulminant hepatic failure in murine hepatitis virus strain 3 infection: tissue-specific expression of a novel fgl2 prothrombinase.
Activation of the immune coagulation system has been implicated in the pathogenesis of fulminant liver failure caused by murine hepatitis virus strain 3 (MHV-3). The recent discovery of the fgl2 gene, which encodes for MHV-3-induced prothrombinase (fgl2 prothrombinase), allows for fundamental studies to determine the molecular basis for fulminant liver failure. Transcription of the fgl2 gene and translation of the protein it encodes were examined in the liver and other organs of susceptible mice following MHV-3 infection. No constitutive expression of the fgl2 gene or the fgl2 prothrombinase was detected. Within 12 to 24 h of MHV-3 infection, however, fgl2 gene transcripts were detected in large amounts in the liver, spleen, and lungs, all of which are rich in reticuloendothelial cells, but were only focally present in small amounts in the kidney and brain. There was sequential detection of fgl2 prothrombinase in the liver, where it was localized specifically to the endothelium of intrahepatic veins and hepatic sinusoids; this was allowed by fibrin deposition, which resulted in confluent hepatocellular necrosis. These results provide further evidence for the role of the selective expression of this novel fgl2 prothrombinase in the pathogenesis of MHV-3-induced fulminant liver failure.


Assessing potential health risks from microcystin toxins in blue-green algae dietary supplements.
The presence of blue-green algae (BGA) toxins in surface waters used for drinking water sources and recreation is receiving increasing attention around the world as a public health concern. However, potential risks from exposure to these toxins in contaminated health food products that contain BGA have been largely ignored. BGA products are commonly consumed in the United States, Canada, and Europe for their putative beneficial effects, including increased energy and elevated mood. Many of these products contain Aphanizomenon flos-aquae, a BGA that is harvested from Upper Klamath Lake (UKL) in southern Oregon, where the growth of a toxic BGA, Microcystis aeruginosa, is a regular occurrence. M. aeruginosa produces compounds called microcystins, which are potent hepatotoxins and probable tumor promoters. Because M. aeruginosa coexists with A. flos-aquae, it can be collected inadvertently during the harvesting process, resulting in microcystin contamination of BGA products. In fall 1996, the Oregon Health Division learned that UKL was experiencing an extensive M. aeruginosa bloom, and an advisory was issued recommending against water contact. The advisory prompted calls from consumers of BGA products, who expressed concern about possible contamination of these products with microcystins. In response, the Oregon Health Division and the Oregon Department of Agriculture established a regulatory limit of 1 microg/g for microcystins in BGA-containing products and tested BGA products for the presence of microcystins. Microcystins were detected in 85 of 87 samples tested, with 63 samples (72%) containing concentrations > 1 microg/g. HPLC and ELISA tentatively identified microcystin-LR, the most toxic microcystin variant, as the predominant congener.


The Nexus between Fire and Soil Bacterial Diversity in the African Miombo Woodlands of Niassa Special Reserve, Mozambique.
(1) Background: the Miombo woodlands comprise the most important vegetation from southern Africa and are dominated by tree legumes with an ecology highly driven by fires. Here, we report on the characterization of bacterial communities from the rhizosphere of Brachystegia boehmii in different soil types from areas subjected to different regimes. (2) Methods: bacterial communities were identified through Illumina MiSeq sequencing (16S rRNA). Vigna unguiculata was used as a trap to capture nitrogen-fixing bacteria and culture-dependent methods in selective media were used to isolate plant growth promoting bacteria (PGPB). PGP traits were analysed and molecular taxonomy of the purified isolates was performed. (3) Results: Bacterial communities in the Miombo rhizosphere are highly diverse and driven by soil type and fire regime. Independent of the soil or fire regime, the functional diversity was high, and the different consortia maintained the general functions. A diverse pool of diazotrophs was isolated, and included symbiotic (e.g., Mesorhizobium sp., Neorhizobium galegae, Rhizobium sp., and Ensifer adhaerens), and non-symbiotic (e.g., Agrobacterium sp., Burkholderia sp., Cohnella sp., Microvirga sp., Pseudomonas sp., and Stenotrophomonas sp.) bacteria. Several isolates presented cumulative PGP traits. (4) Conclusions: Although the dynamics of bacterial communities from the Miombo rhizosphere is driven by fire, the maintenance of high levels of diversity and functions remain unchanged, constituting a source of promising bacteria in terms of plant-beneficial activities such as mobilization and acquisition of nutrients, mitigation of abiotic stress, and modulation of plant hormone levels.


The impact of preoperative information on state anxiety, postoperative pain and satisfaction with pain management.
The primary objective of this study was to test whether specific information given prior to surgery can help patients obtain better pain relief after total knee arthroplasty (TKA). Secondary objectives were to study the impact of preoperative information on state and trait anxiety, satisfaction with pain management and satisfaction with nursing care. The study was an intervention study with two groups of equal size (n=30). The intervention group was given specific information while the control group received routine information. Pain assessments were made preoperatively and every 3h for the first three postoperative days, using the visual analogue scale (VAS). The results of this study suggest that information does influence the experience of pain after surgery and related psychological factors. The postoperative pain declined more rapidly for patients in the treatment group, the degree of preoperative state anxiety was lower and they were more satisfied with the postoperative pain management.


Simultaneous radiofrequency (RF) heating and magnetic resonance (MR) thermal mapping using an intravascular MR imaging/RF heating system.
Previous studies have confirmed the possibility of using an intravascular MR imaging guidewire (MRIG) as a heating source to enhance vascular gene transfection/expression. This motivated us to develop a new intravascular system that can perform MR imaging, radiofrequncy (RF) heating, and MR temperature monitoring simultaneously in an MR scanner. To validate this concept, a series of mathematical simulations of RF power loss along a 0.032-inch MRIG and RF energy spatial distribution were performed to determine the optimum RF heating frequency. Then, an RF generator/amplifier and a filter box were built. The possibility for simultaneous RF heating and MR thermal mapping of the system was confirmed in vitro using a phantom, and the obtained thermal mapping profile was compared with the simulated RF power distribution. Subsequently, the feasibility of simultaneous RF heating and temperature monitoring was successfully validated in vivo in the aorta of living rabbits. This MR imaging/RF heating system offers a potential tool for intravascular MR-mediated, RF-enhanced vascular gene therapy.


Benefits of texture analysis of dual energy CT for Computer-Aided pulmonary embolism detection.
Pulmonary embolism is an avoidable cause of death if treated immediately but delays in diagnosis and treatment lead to an increased risk. Computer-assisted image analysis of both unenhanced and contrast-enhanced computed tomography (CT) have proven useful for diagnosis of pulmonary embolism. Dual energy CT provides additional information over the standard single energy scan by generating four-dimensional (4D) data, in our case with 11 energy levels in 3D. In this paper a 4D texture analysis method capable of detecting pulmonary embolism in dual energy CT is presented. The method uses wavelet-based visual words together with an automatic geodesic-based region of interest detection algorithm to characterize the texture properties of each lung lobe. Results show an increase in performance with respect to the single energy CT analysis, as well as an accuracy gain compared to preliminary work on a small dataset.


Metabolic syndrome independently predicts future diabetes in women with a history of gestational diabetes mellitus.
Metabolic syndrome (MetS) is an established predisposing condition for type 2 diabetes mellitus (T2DM). However, it is not thoroughly evaluated whether MetS increases the risk of T2DM in women with a previous history of gestational diabetes mellitus (GDM) who already at high risk of T2DM compared with the general population. We investigated the impact of MetS on the development of postpartum diabetes in women with a history of GDM.This was a multicenter, prospective cohort study of women diagnosed with GDM. The follow-up evaluations, including the oral glucose tolerance test, were completed at 6 weeks postpartum and annually thereafter. MetS was diagnosed at the initial postpartum evaluation according to the revised criteria of the National Cholesterol Education Program-Adult Treatment Panel III. The risk of developing type 2 diabetes (T2DM) in the follow-up period was analyzed based on the presence of MetS, and the adjusted risk was calculated using a Cox proportional hazards model.A total of 412 women without diabetes at the initial postpartum evaluation participated in the annual follow-up for median 3.8 years. MetS was prevalent in 66 (19.2%) women at the initial postpartum evaluation. The incidences of diabetes in women with and without MetS were 825 and 227 per 10,000 person-years, respectively (P < 0.001). The presence of MetS was an independent risk factor for T2DM, with a hazard ratio (HR) of 2.23 (95% confidence interval 1.04-5.08) in multivariate analysis after adjustment for clinical and metabolic parameters. When we considered MetS and impaired fasting glucose (IFG) separately, women with MetS, IFG, or both had an increased risk of T2DM, with HRs of 4.17, 4.36, and 6.98, respectively.The presence of MetS during the early postpartum period is an independent risk factor for the development of T2DM in women with a previous history of GDM.


Modified Early Warning Score and VitalPac Early Warning Score in geriatric patients admitted to emergency department.
The aim of this study was to evaluate the value of the Modified Early Warning Score (MEWS) and the VitalPac Early Warning Score (VIEWS) in predicting hospitalization and in-hospital mortality in geriatric emergency department (ED) patients. This prospective, single-centered observational study was carried out over 1 month at the ED of a university hospital in patients 65 years of age and older presenting to the ED. The vital parameters of the patients measured on admission to ED were recorded. The MEWS and VIEWS were calculated using the recorded physiological parameters of the patients. Hospitalization and in-hospital mortality were used as the primary outcomes. A total of 671 patients included in the study. The median age of the patients was 75 (11) years, and 375 (55.9%) were men. The MEWS is effective for discriminating patient groups that have been discharged from ED, admitted to a ward and admitted to ICU [1 (2) vs. 1 (1) vs. 3 (3), respectively, P<0.001]. The VIEWS is also effective for discriminating patient groups that have been discharged from ED, admitted to a ward, and admitted to ICU [2 (3) vs. 5 (5) vs. 8 (8), respectively, P<0.001]. The AUCs of the MEWS and VIEWS were 0.727 [95% confidence interval (CI) 0.689-0.765] and 0.756 (95% CI 0.720-0.792) in predicting hospitalization, respectively. The AUCs of the MEWS and VIEWS were 0.891 (95% CI 0.844-0.937) and 0.900 (95% CI 0.860-0.941) in predicting in-hospital mortality, respectively. The MEWS and VIEWS are powerful scoring systems that are easy-to-use for predicting the hospitalization and in-hospital mortality of geriatric ED patients.


Histopathology of the endocrine pancreas of a fresh-water fish, Clarias batrachus (L.) IX: Effect of the new antidiabetic drug, glibenclamide (HB 419).
Oral administration of glibenclamide, the new antidiabetic drug, caused hypoglycemia in Clarias batrachus. The effect was maximal at 15 hours, when some fish had practically no sugar in their plasma. The hypoglycemic effect was insignificant in partially-pancreatectomized fish, indicating that the drug potentiated the effect of insulin in such animals. In fasting normal fish, the drug provoked an increase in the liver glycogen contents while in the diabetic animals, a reverse condition occurred. Significant beta-cell degranulation and vacuolisation was noted in the Langerhans' islets, the effect being synchronous with hypoglycemia. In a few cases, the alpha-cells had also undergone degenerative changes. No significant side effects and discerneable toxicity was observed in the treated-fish. It is stipulated that the drug is endowed with the beta cytotropic property.


Oil and water? Lessons from Maryland's effort to protect safety net providers in moving to Medicaid managed care.
Studies have highlighted the tensions that can arise between Medicaid managed care organizations and safety net providers. This article seeks to identify what other states can learn from Maryland's effort to include protections for safety net providers in its Medicaid managed care program--HealthChoice. Under HealthChoice, traditional provider systems can sponsor managed care organizations, historical providers are assured of having a role, patients can self-refer and have open access to certain public health providers, and capitation rates are risk adjusted through the use of adjusted clinical groups and claims data. The article is based on a week-long site visit to Maryland in fall 1998 that was one part of a seven-state study. Maryland's experience suggests that states have much to gain in the way of "good" public policy by considering the impact of their Medicaid managed care programs on the safety net, but states should not underestimate the challenges involved in balancing the need to protect the safety net with the need to contain costs and minimize the administrative burden on providers. No amount of protection can compensate for a poorly designed or implemented program. As the health care environment continues to change, so may the need for and the types of protections change. It also may be most difficult to guarantee adequate protections to those who need it most--among relatively financially insecure providers that have a limited management infrastructure and that depend heavily on Medicaid and the state for funds to care for the uninsured.


Polymorphism rs368234815 of interferon lambda 4 gene and spontaneous clearance of hepatitis C virus in haemodialysis patients: a case-control study.
In non-uremic subjects, IFNL4 rs368234815 predicts HCV clearance. We investigated whether rs368234815 is associated with spontaneous HCV clearance in haemodialysis patients and whether it is a stronger predictor of HCV resolution than the IFNL polymorphisms already associated with HCV clearance in dialysis subjects. We also evaluated an association of rs368234815 with patients` survival and alterations in transcription factor binding sites (TFBS) caused by IFNL polymorphisms. Among 161 haemodialysis patients with positive anti-HCV antibodies, 68 (42.2%) spontaneously resolved HCV infection, whereas 93 remained HCV RNA positive. Patients were tested for near IFNL3 rs12980275, IFNL3 rs4803217, IFNL4 rs12979860, IFNL4 rs368234815, and near IFNL4 rs8099917. IFNL4 rs368234815 polymorphism (TT/TT, ΔG/TT, ΔG/ΔG) was genotyped by restriction fragment length polymorphism analysis; other IFNL polymorphisms - by high resolution melting curve analysis. We used the Kaplan-Meier method with the log-rank test for survival analysis. In silico analysis included the use of ENCODE TFBS ChIP-seq data, HOCOMOCO, JASPAR CORE, and CIS-BP databases, and FIMO software. The probability (OR, 95%CI, P) of spontaneous HCV clearance for rs368234815 TT/TT patients was higher than for the ΔG allele carriers (2.63, 1.38-5.04, 0.003). This probability for other major homozygotes varied between 2.80, 1.45-5.43, 0.002 for rs12980275 and 2.44, 1.27-4.69, 0.007 for rs12979860. In the additive model, rs368234815 TT/TT was the strongest predictor of HCV clearance (6.38, 1.69-24.2, 0.003). Survival analysis suggested an association of the ΔG allele with mortality due to neoplasms (log-rank P = 0.005). The rs368234815 ∆G allele caused TFBS removal for PLAGL1. In haemodialysis patients, the association of rs368234815 with the spontaneous HCV clearance is better than that documented for other IFNL3/IFNL4 polymorphisms only in the additive mode of inheritance. However, identifying the homozygosity in the variant ∆G allele of rs368234815 means a more potent prediction of persistent HCV infection in haemodialysis subjects that we observe in the case of the variant homozygosity of other tested IFNL3/IFNL4 polymorphisms. Removal of PLAGL1 TFBS in subjects harbouring the rs368234815 ∆G allele may contribute to cancer susceptibility. The association of rs368234815 with cancer-related mortality needs further studies in HCV-exposed subjects.


Mechanisms of photochemistry and reactive oxygen production by fullerene suspensions in water.
Buckminsterfullerene (C60) is a known photosensitizer that produces reactive oxygen species (ROS) in the presence of light; however, its properties in aqueous environments are still not well understood or modeled. In this study, production of both singlet oxygen and superoxide by UV photosensitization of colloidal aggregates of C60 in water was measured by two distinct methods: electron paramagnetic resonance (EPR) with a spin trapping compound, and spectrophotometric detection of the reduced form of the tetrazolium compound XTT. Both singlet oxygen and superoxide were generated by fullerol suspensions while neither was detected in the aqu/nC60 suspensions. A mechanistic framework for photosensitization that takes into account differences in C60 aggregate structure in water is proposed to explain these results. While theory developed for single molecules suggests that alterations to the C60 cage should reduce the quantum yield for the triplet state and associated ROS production, the failure to detect ROS production by aqu/nC60 is explained in part by a more dense aggregate structure compared with the hydroxylated C60.


Racial disparities in thoracic aortic surgery: Myth or reality?
We examined the relationship between Black or White race and adverse outcomes in patients who underwent surgery of the ascending aorta, aortic root, or aortic arch at our center. We analyzed 2335 consecutive patients who identified as Black (n = 217, 9.3%) or White (n = 2118, 90.7%) and underwent proximal aortic surgery. Patient zip codes were used to determine community socioeconomic (CSE) characteristics. The composite adverse outcome comprised mortality, persistent neurologic injury, and renal failure necessitating dialysis at discharge. We performed multivariable analysis, Kaplan-Meier analysis, and propensity score matching adjusted for CSE factors. Median follow-up time was 3.7 years. Compared with White patients, Black patients lived in areas characterized by a higher percentage living below poverty level, lower income, and lower education level (P < .0001). Black patients had higher rates of emergency presentation (P < .0001) and lower 5- and 10-year survival rates (P = .0002). Short-term outcomes were similar between groups, except for respiratory failure and length of stay (P < .0001), which were higher in the Black population. After propensity score matching adjusted for CSE factors, Black and White patients (n = 204 each) had similar short-term outcomes and 5- and 10-year survival rates (P = .30). Multivariable analysis stratified by race showed that CSE factors independently predicted adverse outcomes in Black but not White patients. This is among few studies that have analyzed the relationship between race and proximal aortic surgery. Although outcomes were similar between Black and White patients in our cohort after adjusting for CSE factors, unfavorable CSE factors predicted adverse outcomes in Black but not White patients. More patient-specific studies are needed.


A C. elegans E/Daughterless bHLH protein marks neuronal but not striated muscle development.
The E proteins of mammals, and the related Daughterless (DA) protein of Drosophila, are ubiquitously expressed helix-loop-helix (HLH) transcription factors that play a role in many developmental processes. We report here the characterization of a related C. elegans protein, CeE/DA, which has a dynamic and restricted distribution during development. CeE/DA is present embryonically in neuronal precursors, some of which are marked by promoter activity of a newly described Achaete-scute-like gene hlh-3. In contrast, we have been unable to detect CeE/DA in CeMyoD-positive striated muscle cells. In vitro gel mobility shift analysis detects dimerization of CeE/DA with HLH-3 while efficient interaction of CeE/DA with CeMyoD is not seen. These studies suggest multiple roles for CeE/DA in C. elegans development and provide evidence that both common and alternative strategies have evolved for the use of related HLH proteins in controlling cell fates in different species.


NUT carcinoma presenting in the palate - a case report.
NUT carcinomas (NC) are rare and aggressive tumours characterized by chromosomal rearrangements of the gene encoding for nuclear protein of the testis (NUT) located on chromosome 15q14. This article presents a case of a 60-year-old woman diagnosed with NC presenting as a fast growing primary tumour in the right palate. Further evaluation revealed a tumour mass in the lungs and widespread metastases. A review of the literature did not reveal earlier cases presenting in the palate. In order to improve early diagnosis it is suggested to perform immunohistochemical testing for NUT in all poorly differentiated carcinomas without glandular differentiation arising in the chest, and head and neck (Clin Cancer Res, 18, 2012, 5773).


Dynamic optical rectification and delivery of active particles.
We use moving light patterns to control the motion of Escherichia coli bacteria whose motility is photo-activated. Varying the pattern speed controls the magnitude and direction of the bacterial flux, and therefore the accumulation of cells in up- and down-stream reservoirs. We validate our results with two-dimensional simulations and a 1-dimensional analytic model, and use these to explore parameter space. We find that cell accumulation is controlled by a competition between directed flux and undirected, stochastic transport. Our results point to a number of design principles for using moving light patterns and light-activated micro-swimmers in a range of practical applications.


The role of sex hormone-binding globulin (SHBG), testosterone, and other sex steroids, on the development of type 2 diabetes in a cohort of community-dwelling middle-aged to elderly men.
Contrasting findings exist regarding the association between circulating sex hormone-binding globulin (SHBG) and testosterone levels and type 2 diabetes (T2D) in men. We examined prospective associations of SHBG and sex steroids with incident T2D in a cohort of community-dwelling men. Participants were from a cohort study of community-dwelling (n = 2563), middle-aged to elderly men (35-80 years) from Adelaide, Australia (the Men Androgen Inflammation Lifestyle Environment and Stress (MAILES) study). The current study included men who were followed for 5 years and with complete SHBG and sex steroid levels (total testosterone (TT), dihydrotestosterone (DHT) and oestradiol (E2)), but without T2D at baseline (n = 1597). T2D was identified by either self-report, fasting glucose (≥ 7.0 mmol/L), HbA1c (≥ 6.5%/48.0 mmol/mol), and/or prescriptions for diabetes medications. Logistic binomial regression was used to assess associations between SHBG, sex steroids and incident T2D, adjusting for confounders including age, smoking status, physical activity, adiposity, glucose, triglycerides, symptomatic depression, SHBG and sex steroid levels. During an average follow-up of 4.95 years, 14.5% (n = 232) of men developed new T2D. Multi-adjusted models revealed an inverse association between baseline SHBG, TT, and DHT levels, and incident T2D (odds ratio (OR) = 0.77, 95% CI [0.62, 0.95], p = 0.02; OR 0.70 [0.57, 0.85], p < 0.001 and OR 0.78 [0.63, 0.96], p = 0.02), respectively. However, SHBG was no longer associated with incident T2D after additional adjustment for TT (OR 0.92 [0.71, 1.17], p = 0.48; TT in incident T2D: OR 0.73 [0.57, 0.92], p = 0.01) and after separate adjustment for DHT (OR 0.83 [0.64, 1.08], p = 0.16; DHT in incident T2D: OR 0.83 [0.65, 1.05], p = 0.13). There was no observed effect of E2 in all models of incident T2D. In men, low TT, but not SHBG and other sex steroids, best predicts the development of T2D after adjustment for confounders.


Neurocognitive functioning in adolescents with eating disorders: a population-based study.
Neurocognitive deficits have been identified in eating disorders, including anorexia nervosa and bulimia nervosa. However, current data do not allow for firm conclusions regarding the nature or extent of these deficits. The current study aimed to evaluate neurocognitive functioning in a population-based sample of adolescents with and without eating disorders. Participants (N=669) were drawn from the Western Australian Pregnancy Cohort (Raine) Study. Cognitive testing was conducted using the computerised CogState assessment battery. Eating disorder symptoms were assessed using questions adapted from the Child Eating Disorder Examination and Eating Disorder Examination-Questionnaire. Adolescents who met full or partial criteria for a DSM-IV eating disorder (n=58) were compared to adolescents with no significant eating pathology (n=592). The eating disorder sample showed impaired performance on measures of executive functioning, including global processing and set shifting, but performed better than control participants on measures of visual attention and vigilance. This is the first study to evaluate neurocognitive functioning in a population-based sample of adolescents with eating disorders. Support is provided for weak central coherence and set-shifting difficulties early in the course of eating disorders. Research is needed to determine if these deficits precede and predict eating disorder onset.


Rare inherited disorders with renal involvement-approach to the patient.
The list of rare inherited disorders with renal involvement is rapidly growing. Many are single gene diseases affecting children, but cases are not restricted to pediatrics and diagnosis is often difficult and delayed. The expanding use of next-generation sequencing techniques is expected to discover new diseases, to challenge the definition of rarity, to accelerate and shake up our diagnostic paradigms, to promote 'deep phenotyping', and ultimately improve disease ontology. Rare renal diseases are exemplary of a transition from pediatric to adult-type care and pluridisciplinary approach, necessitating cooperation between geneticists, nephropediatricians, adult nephrologists, other physicians, nurses, social workers, and dietitians. They have raised new ethical issues, not only in genetic counseling, but also in public health, regarding equity, and distribution of care. Patient's organizations have grown and have been very active to promote information and research. Efforts are underway to create interoperable patient's registries and ultimately worldwide networks gathering patients, researchers, clinicians, pharmaceutical industry, and health authorities. Progress in genetics and pathophysiological mechanisms will hopefully increase the number of efficient orphan medicinal products. Finally, new frontiers set by rare nephropathies may improve the understanding, treatments, and outcomes of more frequent renal diseases.


Near-resonant holographic interferometry and absorption measurements of seeded atomic species in a flame.
The development of near-resonant holographic interferometry techniques for use on flows seeded with atomic species is described. A theoretical model for the refractivity that is due to the seed species is outlined, and an approximation to this model is also described that is shown to be valid for practical regimes of interest and allows the number density of the species to be determined without knowledge of line-broadening effects. The details of quantitative number density experiments performed on an air-acetylene flame are given, and a comparison with an alternative absorption-based experiment is made.


Manipulating polarization of light with ultrathin epsilon-near-zero metamaterials.
One of the basic functionalities of photonic devices is the ability to manipulate the polarization state of light. Polarization components are usually implemented using the retardation effect in natural birefringent crystals and, thus, have a bulky design. Here, we have demonstrated the polarization manipulation of light by employing a thin subwavelength slab of metamaterial with an extremely anisotropic effective permittivity tensor. Polarization properties of light incident on the metamaterial in the regime of hyperbolic, epsilon-near-zero, and conventional elliptic dispersions were compared. We have shown that both reflection from and transmission through λ/20 thick slab of the metamaterial may provide nearly complete linear-to-circular polarization conversion or 90° linear polarization rotation, not achievable with natural materials. Using ellipsometric measurements, we experimentally studied the polarization conversion properties of the metamaterial slab made of the plasmonic nanorod arrays in different dispersion regimes. We have also suggested all-optical ultrafast control of reflected or transmitted light polarization by employing metal nonlinearities.


[Biological activity of Budvicia aquatica lipopolysaccharides].
The fatty acid composition of lipopolysaccharides (LPS) lipids A of Budvicia aquatica strains (n = 6)--representatives of Enterobacteriaceae new species are studied for the first time. It was established that fatty acids with the length of carbon chains from C12 to C18 are presented. All of B. aquatica strains tested have been found to contain 3-hydroxytetradecanoic acid (23.1-43.8%, depending on the strain), which was predominat and characteristic of representatives of Enterobacteriaceae family. LPS of the tested strains displayed toxicity and pyrogeneity.


Synthesis of dual functional procaine-derived carbon dots for bioimaging and anticancer therapy.
Aim: Procaine-derived carbon dots, termed P-dots, expectedly offer both fluorescent biomarker function and anticancer activity. Materials & methods: P-dots were synthesized by condensing procaine, citric acid and ethylenediamine via hydrothermal synthesis and characterized by transmission electron microscopy, Fourier transform infrared spectroscopy and x-ray photoelectron spectroscopy. The cellular uptake behavior and the bioimaging performance of P-dots were assessed by confocal laser scanning microscopy. Their antitumor activity was evaluated using the CCK-8 assays and in vivo antitumor experiments, and the underlying mechanism was evaluated by flow cytometry and western blotting. Results: P-dots exhibited excellent luminescence properties suitable for bioimaging and considerable anticancer activity associated with caspase-3-related cell apoptosis. Conclusion: The synthesized procaine-derived carbon dots presented a dual function consisting of bioimaging and anticancer activity, which may enable their implementation as safe and effective clinical nanotherapeutics.


Immune functions and recruitment of plasmacytoid dendritic cells in psoriasis.
Psoriasis is one of the most common chronic T cell-mediated diseases in humans. Among the most proximal event in the innate immunity cascade driving psoriatic inflammation is the secretion of type I IFN by activated plasmacytoid dendritic cells (pDC), a special DC subset strategically positioned in pre-psoriatic symptomless skin. There is an IFN-alpha signature in primary psoriatic plaques, and blocking of type I IFN signalling can prevent the expansion of pathogenetic T cells and development of psoriatic phenotype. Recently, we have demonstrated that pDC infiltration in psoriatic skin correlates with the expression of markers typical of early phases of psoriasis, whereas it is almost absent in long-lasting lesions. Importantly, pDC recruitment in psoriatic skin is strictly associated with the chemerin/ChemR23 axis, and is temporally active during psoriatic plaque development. Pro-chemerin is produced primarily by dermal fibroblasts, but also by mast cells and endothelial cells. Once secreted, it can be activated by enzymes produced by neutrophils and mast cells, which infiltrate early psoriasis lesions. These findings propose the chemerin/ChemR23 axis as a potential novel therapeutic target in psoriasis.


Medical and behavioral surveillance of dogs deployed to the World Trade Center and the Pentagon from October 2001 to June 2002.
To evaluate early medical and behavioral effects of deployment to the World Trade Center, Fresh Kills Landfill, or the Pentagon on responding search-and-rescue (SAR) dogs. Prospective double cohort study. The first cohort included SAR dogs responding to the September 11, 2001, terrorist attacks (deployed), and the second cohort included SAR dogs trained in a similar manner but not deployed (controls). Enrollment occurred from October 2001 to June 2002. Dogs were examined by their local veterinarians; thoracic radiographs and blood samples were shipped to the University of Pennsylvania for analysis. Handlers completed medical and training histories and a canine behavioral survey. Deployed dogs were older and had more search experience than control dogs. Serum concentrations of globulin and bilirubin and activity of alkaline phosphatase were significantly higher in deployed dogs, independent of age and training. Despite significant differences in several blood parameters, values for both groups were within reference ranges. No pulmonary abnormalities were detected on radiographs, and no significant differences in behavior or medical history were detected between groups. Within the first year following the September 11 attacks, there was no evidence that responding dogs developed adverse effects related to their work. Mild but significantly higher serum concentrations of globulin and bilirubin and activity of alkaline phosphatase in deployed dogs suggested higher antigen or toxin exposure. These dogs will be monitored for delayed effects for at least 3 years.


Use of sub-micron sized resin particles for removal of endocrine disrupting compounds and pharmaceuticals from water and wastewater.
Endocrine disrupting compounds (EDCs) and pharmaceuticals pose a challenge for water and wastewater treatment because they exist at very low concentrations in the presence of substances at much higher concentrations competing for adsorption sites. Sub-micron sized resin particles (approximately 300nm in diameter) (SMR) were tested to evaluate their potential as a treatment for EDCs including: 17-β estradiol (E2), 17-α ethinylestradiol (EE2), estrone (E1), bisphenol A (BPA), and diethylstilbestrol (DES) as well as 12 pharmaceuticals. SMR were able to remove 98% of spiked E2, 80% of EE2, 87% of BPA, and up to 97% of DES from water. For a 0.5ppm mixture of E2, EE2, E1, BPA and DES, the minimum removal was 24% (E2) and the maximum was 49% (DES). They were also able to remove the pharmaceuticals from deionized water and wastewater. Overall, SMR are a promising advanced treatment for removal of both EDCs and pharmaceuticals.


Modelling the growth rate of Escherichia coli as a function of pH and lactic acid concentration.
The growth rate responses of Escherichia coli M23 (a nonpathogenic strain) to suboptimal pH and lactic acid concentration were determined. Growth rates were measured turbidimetrically at 20 degrees C in the range of pH 2.71 to 8.45. The total concentration of lactic acid was fixed at specific values, and the pH was varied by the addition of a strong acid (hydrochloric) or base (sodium hydroxide) to enable the determination of undissociated and dissociated lactic acid concentrations under each condition. In the absence of lactic acid, E. coli grew at pH 4.0 but not at pH 3.7 and was unable to grow in the presence of > or = 8.32 mM undissociated lactic acid. Growth rate was linearly related to hydrogen ion concentration in the absence of lactic acid. In the range 0 to 100 mM lactic acid, growth rate was also linearly related to undissociated lactic acid concentration. A mathematical model to describe these observations was developed based on a Bĕlehrádek-like model for the effects of water activity and temperature. This model was expanded to describe the effects of pH and lactic acid by the inclusion of novel terms for the inhibition due to the presence of hydrogen ions, undissociated lactic acid, and dissociated lactic acid species. Preliminary data obtained for 200 and 500 mM total lactic acid concentrations show that the response to very high lactic acid concentrations was less well described by the model. However, for 0 to 100 mM lactic acid, the model described well the qualitative and quantitative features of the response.


Gene Tagging Strategies To Assess Protein Expression, Localization, and Function in Drosophila.
Analysis of gene function in complex organisms relies extensively on tools to detect the cellular and subcellular localization of gene products, especially proteins. Typically, immunostaining with antibodies provides these data. However, due to cost, time, and labor limitations, generating specific antibodies against all proteins of a complex organism is not feasible. Furthermore, antibodies do not enable live imaging studies of protein dynamics. Hence, tagging genes with standardized immunoepitopes or fluorescent tags that permit live imaging has become popular. Importantly, tagging genes present in large genomic clones or at their endogenous locus often reports proper expression, subcellular localization, and dynamics of the encoded protein. Moreover, these tagging approaches allow the generation of elegant protein removal strategies, standardization of visualization protocols, and permit protein interaction studies using mass spectrometry. Here, we summarize available genomic resources and techniques to tag genes and discuss relevant applications that are rarely, if at all, possible with antibodies.


Refined and simplified surgical landmarks for the MacCarty keyhole and orbitozygomatic craniotomy.
Precise placement of the MacCarty keyhole, a burr hole simultaneously exposing the anterior cranial fossa floor and orbit, provides accurate, efficient entry for orbitozygomatic and supraorbital craniotomies. To locate the optimal keyhole site, previous studies have used superficial landmarks that, in our experience, are not always visible or consistent on older crania. Therefore, we present a technique for accurate keyhole placement using landmarks that are easily visible across age ranges. From inside the cranium, 1-mm burr holes were placed along the anterior junction of the floor and lateral wall of the anterior cranial fossa in 50 adult skulls (100 sides, with calvaria removed). Additionally, from inside the orbit, 1-mm burr holes were placed into the lateral orbital roof. Exit sites of intracranial and intraorbital burr holes were referenced to the frontozygomatic suture. The center of the site between the exiting intracranial and intraorbital holes was deemed the best location for the keyhole. The keyhole center was 6.8 mm (mean) superior and 4.5 mm (mean) posterior to the frontozygomatic suture, which was easily identified on all specimens. Although this keyhole center was slightly more superior on right sides than left, this was not statistically significant. In a minority of specimens, the keyhole was located near the meningo-orbital foramen (22%) and the lateral extent of the frontal sinus (2%). We defined an alternative method for locating the MacCarty keyhole, based on a reliable external landmark, approximately 7 mm superior and 5 mm posterior to the frontozygomatic suture.


Resistance of pokeweed mitogen-stimulated B cells to inhibition by deoxyadenosine.
Deoxyadenosine (dAdo) levels above 2 microM inhibit plasma cell (PC) differentiation by human blood lymphocytes in pokeweed mitogen (PWM) stimulated cultures containing deoxycoformycin (dCF), a potent inhibitor of adenosine deaminase (ADA). ADA inhibition by dCF alone did not suppress PC differentiation. Thymidine uptake by T cell blasts continuously cultured in conditioned medium was inhibited by dAdo and dCF; two of five EBV-infected B cell lines were also inhibited while three were resistant. Inhibition of PWM-induced PC differentiation of B cells by dCF and dAdo was reversed when conditioned medium (a source of T cell helper factors) was added to the cultures, and dAdo and dCF added to PWM-stimulated cultures 48 hr after their initiation did not inhibit PC differentiation, though thymidine uptake and the total number of cells recovered from the cultures were reduced. Removal of T cells after 48 hr of culture slightly reduced the numbers of PC in PWM-stimulated lymphocyte cultures but no further inhibition was obtained when dCF and dAdo were added to these T-depleted cultures, nor was their thymidine uptake further reduced. These results suggest that the in vitro suppression of B cell differentiation by dAdo in PWM-stimulated cultures is not due to direct toxicity of purine nucleosides to B cells but may be due to interference with T cell help. This is consistent with the view that a relative lack of helper activity by T cells contributes to the antibody deficiency of patients with ADA deficiency.


Systematic Prioritization of Candidate Genes in Disease Loci Identifies TRAFD1 as a Master Regulator of IFNγ Signaling in Celiac Disease.
Celiac disease (CeD) is a complex T cell-mediated enteropathy induced by gluten. Although genome-wide association studies have identified numerous genomic regions associated with CeD, it is difficult to accurately pinpoint which genes in these loci are most likely to cause CeD. We used four different in silico approaches-Mendelian randomization inverse variance weighting, COLOC, LD overlap, and DEPICT-to integrate information gathered from a large transcriptomics dataset. This identified 118 prioritized genes across 50 CeD-associated regions. Co-expression and pathway analysis of these genes indicated an association with adaptive and innate cytokine signaling and T cell activation pathways. Fifty-one of these genes are targets of known drug compounds or likely druggable genes, suggesting that our methods can be used to pinpoint potential therapeutic targets. In addition, we detected 172 gene combinations that were affected by our CeD-prioritized genes in trans. Notably, 41 of these trans-mediated genes appear to be under control of one master regulator, TRAF-type zinc finger domain containing 1 (TRAFD1), and were found to be involved in interferon (IFN)γ signaling and MHC I antigen processing/presentation. Finally, we performed in vitro experiments in a human monocytic cell line that validated the role of TRAFD1 as an immune regulator acting in trans. Our strategy confirmed the role of adaptive immunity in CeD and revealed a genetic link between CeD and IFNγ signaling as well as with MHC I antigen processing, both major players of immune activation and CeD pathogenesis.


A CHO-cell mutant with a defect in cytokinesis.
In a selection procedure designed to enrich for temperature-sensitive mutant cells blocked in mitosis a CHO-cell mutant was isolated which has a defect in cytokinesis as the basis of its temperature-sensitive phenotype. Cultures of the mutant had an abnormally high percentage (ie. 34%) of polyploid cells at the permissive temperature of 34 degress C and showed further increased frequencies of polyploidy as well as many multinucleated cells at 38.5 degrees 39.5 degrees. When the mutant cells were synchronized in metaphase by Colcemid arrest and then placed into fresh medium at nonpermissive temperature, they did not divide although the completion of mitosis appeared cytologically normal. Ultrastructural examination by electron microscopy of such synchronized cells at telophase revealed no specific defects in cellular components other than failure of development of a normal midbody. The sensitivity of the mutant to cytochalasin B and to Colcemid was the same as for wild-type cells. This mutation behaved as recessive in tetraploid cell hybrids constructed by fusing the mutant with a CHO strain which was wild-type with respect to temperature sensitivty.


Prochlorococcus, a marine photosynthetic prokaryote of global significance.
The minute photosynthetic prokaryote Prochlorococcus, which was discovered about 10 years ago, has proven exceptional from several standpoints. Its tiny size (0.5 to 0.7 microm in diameter) makes it the smallest known photosynthetic organism. Its ubiquity within the 40 degrees S to 40 degrees N latitudinal band of oceans and its occurrence at high density from the surface down to depths of 200 m make it presumably the most abundant photosynthetic organism on Earth. Prochlorococcus typically divides once a day in the subsurface layer of oligotrophic areas, where it dominates the photosynthetic biomass. It also possesses a remarkable pigment complement which includes divinyl derivatives of chlorophyll a (Chl a) and Chl b, the so-called Chl a2 and Chl b2, and, in some strains, small amounts of a new type of phycoerythrin. Phylogenetically, Prochlorococcus has also proven fascinating. Recent studies suggest that it evolved from an ancestral cyanobacterium by reducing its cell and genome sizes and by recruiting a protein originally synthesized under conditions of iron depletion to build a reduced antenna system as a replacement for large phycobilisomes. Environmental constraints clearly played a predominant role in Prochlorococcus evolution. Its tiny size is an advantage for its adaptation to nutrient-deprived environments. Furthermore, genetically distinct ecotypes, with different antenna systems and ecophysiological characteristics, are present at depth and in surface waters. This vertical species variation has allowed Prochlorococcus to adapt to the natural light gradient occurring in the upper layer of oceans. The present review critically assesses the basic knowledge acquired about Prochlorococcus both in the ocean and in the laboratory.


Fluvial Deposition and Land Use Change Control Selenium Occurrence in Mollisols of Cold Region Agroecosystems.
Mollisols support the most productive agroecosystems in the world. Despite their critical links to food quality and human health, the varying distributions of selenium (Se) species and factors governing Se mobility in the mollisol vadose zone remain elusive. This research reveals that, in northern mollisol agroecosystems, Se hotspots (≥0.32 mg/kg) prevail along the regional river systems draining the Lesser Khingan Mountains, where piedmont Se-rich oil shales are the most probable source of regional Se. While selenate and selenite dominate Se species in the water-soluble and absorbed pools, mollisol organic matter is the major host for Se. Poorly crystalline and crystalline Fe oxides are subordinate in Se retention, hosting inorganic and organic Se at levels comparable to those in the adsorbed pool. The depth-dependent distributions of mollisol Se species for the non-cropland and cropland sites imply a predominance of reduced forms of Se under the mildly acidic and reducing conditions that, in turn, are variably impacted by agricultural land use. These findings therefore highlight that fluvial deposition and land use change together are the main drivers of the spatial variability and speciation of mollisol Se.