Universal Quantum Computing with Measurement-Induced Continuous-Variable Gate Sequence in a Loop-Based Architecture.
We propose a scalable scheme for optical quantum computing using measurement-induced continuous-variable quantum gates in a loop-based architecture. Here, time-bin-encoded quantum information in a single spatial mode is deterministically processed in a nested loop by an electrically programmable gate sequence. This architecture can process any input state and an arbitrary number of modes with almost minimum resources, and offers a universal gate set for both qubits and continuous variables. Furthermore, quantum computing can be performed fault tolerantly by a known scheme for encoding a qubit in an infinite-dimensional Hilbert space of a single light mode.


Manipulative therapy for lower extremity conditions: expansion of literature review.
The purpose of this study was to conduct a systematic review on manipulative therapy for lower extremity conditions and expand on a previously published literature review. The Scientific Commission of the Council on Chiropractic Guidelines and Practice Parameters (CCGPP) was charged with developing literature syntheses, organized by anatomical region, to evaluate and report on the evidence base for chiropractic care. This article is the outcome of this charge. As part of the CCGPP process, preliminary drafts of these articles were posted on the CCGPP Web site www.ccgpp.org (2006-8) to allow for an open process and the broadest possible mechanism for stakeholder input. The Cumulative Index to Nursing and Allied Health Literature; PubMed; Manual, Alternative, and Natural Therapy Index System; Science Direct; and Index to Chiropractic Literature were searched from December 2006 to February 2008. Search terms included chiropractic, osteopathic, orthopedic, or physical therapy and MeSH terms for each region. Inclusion criteria required a diagnosis and manipulative therapy (mobilization and manipulation grades I-V) with or without adjunctive care. Exclusion criteria were pain referred from spinal sites (without diagnosis), referral for surgery, and conditions contraindicated for manipulative therapy. Clinical trials were assessed using a modified Scottish Intercollegiate Guidelines Network ranking system. Of the total 389 citations captured, 39 were determined to be relevant. There is a level of C or limited evidence for manipulative therapy combined with multimodal or exercise therapy for hip osteoarthritis. There is a level of B or fair evidence for manipulative therapy of the knee and/or full kinetic chain, and of the ankle and/or foot, combined with multimodal or exercise therapy for knee osteoarthritis, patellofemoral pain syndrome, and ankle inversion sprain. There is also a level of C or limited evidence for manipulative therapy of the ankle and/or foot combined with multimodal or exercise therapy for plantar fasciitis, metatarsalgia, and hallux limitus/rigidus. There is also a level of I or insufficient evidence for manipulative therapy of the ankle and/or foot combined with multimodal or exercise therapy for hallux abducto valgus. There are a growing number of peer-reviewed studies of manipulative therapy for lower extremity disorders.


Method for optimizing coating properties based on an evolutionary algorithm approach.
In industry as well as many areas of scientific research, data collected often contain a number of responses of interest for a chosen set of exploratory variables. Optimization of such multivariable multiresponse systems is a challenge well suited to genetic algorithms as global optimization tools. One such example is the optimization of coating surfaces with the required absolute and relative sensitivity for detecting analytes using devices such as sensor arrays. High-throughput synthesis and screening methods can be used to accelerate materials discovery and optimization; however, an important practical consideration for successful optimization of materials for arrays and other applications is the ability to generate adequate information from a minimum number of experiments. Here we present a case study to evaluate the efficiency of a novel evolutionary model-based multiresponse approach (EMMA) that enables the optimization of a coating while minimizing the number of experiments. EMMA plans the experiments and simultaneously models the material properties. We illustrate this novel procedure for materials optimization by testing the algorithm on a sol-gel synthetic route for production and optimization of a well studied amino-methyl-silane coating. The response variables of the coating have been optimized based on application criteria for micro- and macro-array surfaces. Spotting performance has been monitored using a fluorescent dye molecule for demonstration purposes and measured using a laser scanner. Optimization is achieved by exploring less than 2% of the possible experiments, resulting in identification of the most influential compositional variables. Use of EMMA to optimize control factors of a product or process is illustrated, and the proposed approach is shown to be a promising tool for simultaneously optimizing and modeling multivariable multiresponse systems.


Cytosolic, autocrine alpha-1 proteinase inhibitor (A1PI) inhibits caspase-1 and blocks IL-1β dependent cytokine release in monocytes.
Activation state-dependent secretion of alpha-1 proteinase inhibitor (A1PI) by monocytes and macrophages was first reported in 1985. Since then, monocytes and tissue macrophages have emerged as key sentinels of infection and tissue damage via activation of self-assembling pattern recognition receptors (inflammasomes), which trigger inflammation and cell death in a caspase-1 dependent process. These studies examine the relationship between A1PI expression in primary monocytes and monocytic cell lines, and inflammatory cytokine expression in response to inflammasome directed stimuli. IL-1 β expression was examined in lung macrophages expressing wild type A1PI (A1PI-M) or disease-associated Z isoform A1PI (A1PI-Z). Inflammatory cytokine release was evaluated in THP-1 monocytic cells or THP-1 cells lacking the inflammasome adaptor ASC, transfected with expression vectors encoding A1PI-M or A1PI-Z. A1PI-M was localized within monocytes by immunoprecipitation in hypotonic cell fractions. Cell-free titration of A1PI-M was performed against recombinant active caspase-1 in vitro. IL-1 β expression was elevated in lung macrophages expressing A1PI-Z. Overexpression of A1PI-M in THP-1 monocytes reduced secretion of IL-1β and TNF-α. In contrast, overexpression of A1PI-Z enhanced IL-1β and TNF- α secretion in an ASC dependent manner. A1PI-Z-enhanced cytokine release was inhibited by a small molecule caspase-1 inhibitor but not by high levels of exogenous wtA1PI. Cytosolic localization of A1PI-M in monocytes was not diminished with microtubule-inhibiting agents. A1PI-M co-localized with caspase-1 in gel-filtered cytoplasmic THP-1 preparations, and was co-immunoprecipitated with caspase 1 from nigericin-stimulated THP-1 cell lysate. Plasma-derived A1PI inhibited recombinant caspase-1 mediated conversion of a peptide substrate in a dose dependent manner. Our results suggest that monocyte/macrophage-expressed A1PI-M antagonizes IL-1β secretion possibly via caspase-1 inhibition, a function which disease-associated A1PI-Z may lack. Therapeutic approaches which limit inflammasome responses in patients with A1PI deficiency, in combination with A1PI augmentation, may provide additional respiratory tissue-sparing benefits.


Zinc supplementation inhibits complement activation in age-related macular degeneration.
Age-related macular degeneration (AMD) is the leading cause of blindness in the Western world. AMD is a multifactorial disorder but complement-mediated inflammation at the level of the retina plays a pivotal role. Oral zinc supplementation can reduce the progression of AMD but the precise mechanism of this protective effect is as yet unclear. We investigated whether zinc supplementation directly affects the degree of complement activation in AMD and whether there is a relation between serum complement catabolism during zinc administration and the complement factor H (CFH) gene or the Age-Related Maculopathy susceptibility 2 (ARMS2) genotype. In this open-label clinical study, 72 randomly selected AMD patients in various stages of AMD received a daily supplement of 50 mg zinc sulphate and 1 mg cupric sulphate for three months. Serum complement catabolism-defined as the C3d/C3 ratio-was measured at baseline, throughout the three months of supplementation and after discontinuation of zinc administration. Additionally, downstream inhibition of complement catabolism was evaluated by measurement of anaphylatoxin C5a. Furthermore, we investigated the effect of zinc on complement activation in vitro. AMD patients with high levels of complement catabolism at baseline exhibited a steeper decline in serum complement activation (p<0.001) during the three month zinc supplementation period compared to patients with low complement levels. There was no significant association of change in complement catabolism and CFH and ARMS2 genotype. In vitro zinc sulphate directly inhibits complement catabolism in hemolytic assays and membrane attack complex (MAC) deposition on RPE cells. This study provides evidence that daily administration of 50 mg zinc sulphate can inhibit complement catabolism in AMD patients with increased complement activation. This could explain part of the mechanism by which zinc slows AMD progression. The Netherlands National Trial Register NTR2605.


Deaf readers' response to syntactic complexity: evidence from self-paced reading.
This study was designed to determine the feasibility of using self-paced reading methods to study deaf readers and to assess how deaf readers respond to two syntactic manipulations. Three groups of participants read the test sentences: deaf readers, hearing monolingual English readers, and hearing bilingual readers whose second language was English. In Experiment 1, the participants read sentences containing subject-relative or object-relative clauses. The test sentences contained semantic information that would influence online processing outcomes (Traxler, Morris, & Seely Journal of Memory and Language 47: 69-90, 2002; Traxler, Williams, Blozis, & Morris Journal of Memory and Language 53: 204-224, 2005). All of the participant groups had greater difficulty processing sentences containing object-relative clauses. This difficulty was reduced when helpful semantic cues were present. In Experiment 2, participants read active-voice and passive-voice sentences. The sentences were processed similarly by all three groups. Comprehension accuracy was higher in hearing readers than in deaf readers. Within deaf readers, native signers read the sentences faster and comprehended them to a higher degree than did nonnative signers. These results indicate that self-paced reading is a useful method for studying sentence interpretation among deaf readers.


BRCA1 regulates human mammary stem/progenitor cell fate.
Although it is well established that women with germ-line mutations in the BRCA1 gene have a greatly increased lifetime incidence of breast and ovarian cancer, the molecular mechanisms responsible for this tissue-specific carcinogenesis remain undefined. The majority of these breast cancers are of the basal-like phenotype characterized by lack of expression of ER, PR, and ERBB2. Because this phenotype has been proposed to resemble that of normal breast stem cells, we examined the role of BRCA1 in human mammary stem cell fate. Using both in vitro systems and a humanized NOD/SCID mouse model, we demonstrate that BRCA1 expression is required for the differentiation of ER-negative stem/progenitor cells to ER-positive luminal cells. Knockdown of BRCA1 in primary breast epithelial cells leads to an increase in cells displaying the stem/progenitor cell marker ALDH1 and a decrease in cells expressing luminal epithelial markers and estrogen receptor. In breast tissues from women with germ-line BRCA1 mutations, but not normal controls, we detect entire lobules that, although histologically normal, are positive for ALDH1 expression but are negative for the expression of ER. Loss of heterozygosity for BRCA1 was documented in these ALDH1-positive lobules but not in adjacent ALDH1-negative lobules. Taken together, these studies demonstrate that BRCA1 plays a critical role in the differentiation of ER-negative stem/progenitor cells to ER-positive luminal cells. Because BRCA1 also plays a role in DNA repair, our work suggests that loss of BRCA1 may result in the accumulation of genetically unstable breast stem cells, providing prime targets for further carcinogenic events.


The dissemination of clinical practice guidelines over an intranet: an evaluation.
This study compares two clinical practice guideline dissemination systems. It was hypothesized that placing guidelines on an intranet would make this information easier to retrieve. Retrieval time, retrieval accuracy, and ease of use were empirically evaluated. Sixteen clinicians from Kaiser Permanente volunteered to complete tasks that measured these variables. Time values were significantly longer for tasks completed with intranet guidelines (Intranet = 6.7 minutes, Paper = 5.7 minutes). Tasks completed with paper guidelines had a significantly higher percentage of perfect scores than those completed with the intranet (Paper = 85%, Intranet = 59%). There was no significant difference in reported ease of use. Simply placing clinical information on an electronic system does not guarantee that the information will be easier to retrieve. Such information needs to be fully integrated into the clinical decision making process. Computerizing guidelines may provide a necessary initial step toward this goal, but it does not represent the final solution.


Random 'spot' urinary metanephrines compared with 24-h-urinary and plasma results in phaeochromocytomas and paragangliomas.
In patients with phaeochromocytomas or paragangliomas (PPGLs), 24-h urine collections for metanephrines (uMNs) are cumbersome. To evaluate the diagnostic utility of ratios to creatinine of 'spot' uMNs. Concentrations of uMNs and plasma metanephrines (pMNs) were measured by HPLC-mass-spectrometry. We retrospectively compared correlations of 24-h-urine output and ratio to creatinine in historical specimens and prospectively assessed 24-h and contemporaneous spot urines and, where possible, pMNs. Using trimmed log-transformed values, we derived reference intervals based on age and sex for spot urines. We used multiples of upper limit of normal (ULNs) to compare areas under curves (AUCs) for receiver-operator characteristic curves of individual, and sum and product of, components. In 3143 24-h-urine specimens on 2416 patients, the correlation coefficients between the ratios and outputs of metanephrine, normetanephrine and 3-methoxytyramine in 24-h urines were 0.983, 0.905 and 0.875, respectively. In 96 patients, the correlations between plasma concentrations, urine output and ratios in spot specimens were similar to those for raw output or ratios in 24-h specimens. Of the 160 patients with PPGLs, the CIs for AUCs for individual metabolites overlapped for all four types of measurement, as did those for the sum of the multiple ULNs although these were slightly higher (AUC for spot urine: 0.838 (0.529-1), plasma: 0.929 (0.874-0.984) and output: 0.858 (0.764-0.952)). Ratios of fractionated metanephrines to creatinine in spot urine samples appear to have a similar diagnostic power to other measurements. The ease of spot urine collection may facilitate diagnosis and follow-up of PPGLs through improved patient compliance.


Immuno-endocrine interactions in early pregnancy.
First we recall briefly the status of inflammatory cytokines in the early implantation period. We then describe the status of leukaemia inhibiting factor (LIF) production in an in-vitro, relatively short-term, human decidual explant culture system. We show that in most infertile women with recurrent implantation failure following successful in-vitro fertilization, LIF production is statistically much lower than normal. Other parameters of LIF production in vitro are summarized briefly, and the effects of RU486 are shown. The TH2 status of normal pregnancy is described, together with the production of TH2 cytokines by decidua and placenta. These cytokines are deficient in the CBAXDBA/2 model of murine spontaneous early pregnancy loss. The defect can be corrected by alloimmunization, and more importantly by the injection of tau interferon. The significance of these data for early pregnancy signalling is discussed.


The neural signature of social norm compliance.
All known human societies establish social order by punishing violators of social norms. However, little is known about how the brain processes the punishment threat associated with norm violations. We use fMRI to study the neural circuitry behind social norm compliance by comparing a treatment in which norm violations can be punished with a control treatment in which punishment is impossible. Individuals' increase in norm compliance when punishment is possible exhibits a strong positive correlation with activations in the lateral orbitofrontal cortex and right dorsolateral prefrontal cortex. Moreover, lateral orbitofrontal cortex activity is strongly correlated with Machiavellian personality characteristics. These findings indicate a neural network involved in social norm compliance that might constitute an important basis for human sociality. Different activations of this network reveal individual differences in the behavioral response to the punishment threat and might thus provide a deeper understanding of the neurobiological sources of pathologies such as antisocial personality disorder.


Scavenging on a pulsed resource: quality matters for corvids but density for mammals.
Human food subsidies can provide predictable food sources in large quantities for wildlife species worldwide. In the boreal forest of Fennoscandia, gut piles from moose (Alces alces) harvest provide a potentially important food source for a range of opportunistically scavenging predators. Increased populations of predators can negatively affect threatened or important game species. As a response to this, restrictions on field dressing of moose are under consideration in parts of Norway. However, there is a lack of research to how this resource is utilized. In this study, we used camera-trap data from 50 gut piles during 1043 monitoring days. We estimated depletion of gut piles separately for parts with high and low energy content, and used these results to scale up gut pile density in the study area. We identified scavenger species and analyzed the influences of gut pile quality and density on scavenging behavior of mammals and corvids (family Corvidae). Main scavengers were corvids and red fox (Vulpes vulpes). Parts with high energy content were rapidly consumed, mainly by corvids that were present at all gut piles shortly after the remains were left at the kill site. Corvid presence declined with days since harvest, reflecting reduction in gut pile quality over time independent of gut pile density. Mammals arrived 7-8 days later at the gut piles than corvids, and their presence depended only on gut pile density with a peak at intermediate densities. The decline at high gut pile densities suggest a saturation effect, which could explain accumulation of gut pile parts with low energy content. This study shows that remains from moose harvest can potentially be an important food resource for scavengers, as it was utilized to a high degree by many species. This study gives novel insight into how energy content and density of resources affect scavenging patterns among functional groups of scavengers.


Transcriptional Regulation of Cysteine and Methionine Metabolism in Lactobacillus paracasei FAM18149.
Lactobacillus paracasei is common in the non-starter lactic acid bacteria (LAB) community of raw milk cheeses. This species can significantly contribute to flavor formation through amino acid metabolism. In this study, the DNA and RNA of L. paracasei FAM18149 were sequenced using next-generation sequencing technologies to reconstruct the metabolism of the sulfur-containing amino acids cysteine and methionine. Twenty-three genes were found to be involved in cysteine biosynthesis, the conversion of cysteine to methionine and vice versa, the S-adenosylmethionine recycling pathway, and the transport of sulfur-containing amino acids. Additionally, six methionine-specific T-boxes and one cysteine-specific T-box were found. Five of these were located upstream of genes encoding transporter functions. RNA-seq analysis and reverse-transcription quantitative polymerase reaction assays showed that expression of genes located downstream of these T-boxes was affected by the absence of either cysteine or methionine. Remarkably, the cysK2-ctl1-cysE2 operon, which is associated with te methionine-to-cysteine conversion and is upregulated in the absence of cysteine, showed high read coverage in the 5'-untranslated region and an antisense-RNA in the 3'-untranslated region. This indicates that this operon is regulated by the combination of cis- and antisense-mediated regulation mechanisms. The results of this study may help in the selection of L. paracasei strains to control sulfuric flavor formation in cheese.


Reproductive preferences and contraceptive use: a comparison of monogamous and polygamous couples in northern Malawi.
There is now widespread agreement on the importance of men's role in reproductive decision-making. Several studies have argued that fertility preferences and their translation into behaviour differ between polygamous and monogamous unions. Studies investigating the dominance of men's preferences over women's preferences, in cases of couple disagreement, found mixed evidence of the effect of polygamy. However, an often cited limitation of these studies has been the inability to link husband's intention with each of his wives in a polygamous union. By adding fertility-intention questions to an on-going Demographic Surveillance Site in Karonga District in northern Malawi the fertility preferences and contraceptive use of husbands and wives were investigated. An analysis of the relationship between the level of agreement and disagreement between husbands' and wives' fertility preferences was then performed to gain insight into the reproductive decision-making process of polygamous couples.


Three-dimensional positioning of B chromosomes in fibroblast nuclei of the red fox and the chinese raccoon dog.
Great progress has been achieved over the last years in studies on chromosome arrangement in mammalian cell nuclei. Growing evidence indicates that the genome's spatial organization is of functional relevance. So far, no attention has been paid to the nuclear organization of B chromosomes (Bs). In this study we have examined nuclear positioning of Bs in 2 species from the Canidae family--the red fox and the Chinese raccoon dog. Using 2D and 3D fluorescence in situ hybridization and 2 gene-specific probes (C-KIT and PDGFRA), we analyzed the location of Bs in fibroblast nuclei. We found that small Bs of the red fox occupied mostly the interior of the nucleus, while medium-sized Bs of the Chinese raccoon dog were observed in the peripheral area of the nucleus as well as in intermediate and interior locations. The more uniform distribution of B chromosomes in the Chinese raccoon dog may be the result of differences in their size, since 3 morphological types of Bs are distinguished in this species. Our results indicate that 3D positioning of B chromosomes in fibroblast nuclei of the 2 canid species is in agreement with the chromosome size-dependent theory.


Mitogen and Stress-Activated Kinases 1 and 2 Mediate Endothelial Dysfunction.
Inflammation promotes endothelial dysfunction, but the underlying mechanisms remain poorly defined in vivo. Using translational vascular function testing in myocardial infarction patients, a situation where inflammation is prevalent, and knock-out (KO) mouse models we demonstrate a role for mitogen-activated-protein-kinases (MAPKs) in endothelial dysfunction. Myocardial infarction significantly lowers mitogen and stress kinase 1/2 (MSK1/2) expression in peripheral blood mononuclear cells and diminished endothelial function. To further understand the role of MSK1/2 in vascular function we developed in vivo animal models to assess vascular responses to vasoactive drugs using laser Doppler imaging. Genetic deficiency of MSK1/2 in mice increased plasma levels of pro-inflammatory cytokines and promoted endothelial dysfunction, through attenuated production of nitric oxide (NO), which were further exacerbated by cholesterol feeding. MSK1/2 are activated by toll-like receptors through MyD88. MyD88 KO mice showed preserved endothelial function and reduced plasma cytokine expression, despite significant hypercholesterolemia. MSK1/2 kinases interact with MAPK-activated proteins 2/3 (MAPKAP2/3), which limit cytokine synthesis. Cholesterol-fed MAPKAP2/3 KO mice showed reduced plasma cytokine expression and preservation of endothelial function. MSK1/2 plays a significant role in the development of endothelial dysfunction and may provide a novel target for intervention to reduce vascular inflammation. Activation of MSK1/2 could reduce pro-inflammatory responses and preserve endothelial vasodilator function before development of significant vascular disease.


Loss of caveolin-1 in bronchiolization in lung fibrosis.
Bronchiolization is a key process in fibrosing lung in which the proliferative status of bronchiolar epithelium changes, leading to abnormal epithelial morphology. Within the context that caveolin-1 acts to suppress epithelial proliferation, we postulated that stimulating epithelial injury would lead to caveolin-1 downregulation and encourage proliferation. The present study evaluates the expression of caveolin-1, especially in bronchiolization, in C57BL/6J mice with bleomycin-induced lung fibrosis and in various types of re-epithelialization in human interstitial pneumonias (IPs). Immunohistochemically, levels of caveolin-1 decreased in the bronchiolar epithelium of mice treated with bleomycin. Levels of caveolin-1 mRNA in the whole lung were decreased at 7 and 14 days. Caveolin-1 mRNA was also decreased in laser-capture microdissection- retrieved bronchiolar epithelial cells at 7 days. Among patients with 12 IPs, including four usual IPs (UIPs) and eight nonspecific IPs (NSIPs), whole lung caveolin-1 was significantly decreased compared with 12 controls at both mRNA and protein levels. By scoring immunointensity, caveolin-1 was significantly reduced in bronchiolization and squamous metaplasia as well as in bronchiolar epithelium in 23 IPs (12 UIPs and 11 NSIPs) compared with bronchiolar epithelium from seven controls. These data suggested that loss of caveolin-1 is associated with abnormal re-epithelialization in lung fibrosis.


Semaphorins in axon regeneration: developmental guidance molecules gone wrong?
Semaphorins are developmental axon guidance cues that continue to be expressed during adulthood and are regulated by neural injury. During the formation of the nervous system, repulsive semaphorins guide axons to their targets by restricting and channelling their growth. They affect the growth cone cytoskeleton through interactions with receptor complexes that are linked to a complicated intracellular signal transduction network. Following injury, regenerating axons stop growing when they reach the border of the glial-fibrotic scar, in part because they encounter a potent molecular barrier that inhibits growth cone extension. A number of secreted semaphorins are expressed in the glial-fibrotic scar and at least one transmembrane semaphorin is upregulated in oligodendrocytes surrounding the lesion site. Semaphorin receptors, and many of the signal transduction components required for semaphorin signalling, are present in injured central nervous system neurons. Here, we review evidence that supports a critical role for semaphorin signalling in axon regeneration, and highlight a number of challenges that lie ahead with respect to advancing our understanding of semaphorin function in the normal and injured adult nervous system.


Hypoxia. HIF-mediated articular chondrocyte function: prospects for cartilage repair.
In a chronically hypoxic tissue such as cartilage, adaptations to hypoxia do not merely include cell survival responses, but also promotion of its specific function. This review will focus on describing such hypoxia-mediated chondrocyte function, in particular in the permanent articular cartilage. The molecular details of how chondrocytes sense and respond to hypoxia and how this promotes matrix synthesis have recently been examined, and specific manipulation of hypoxia-induced pathways is now considered to have potential therapeutic application to maintenance and repair of articular cartilage.


Aminoglutethimide dose and hormone suppression in advanced breast cancer.
The effect of the dose of aminoglutethimide on the suppression of oestrone, oestradiol and dehydroepiandrosterone sulphate (DHAS) levels was studied in 36 women with advanced postmenopausal breast cancer, all of whom received 20 mg hydrocortisone twice daily as replacement glucocorticoid. Aminoglutethimide (AG) 250 mg twice a day was as effective as AG 250 mg 3 times a day or AG 250 mg 4 times a day. Side-effects were less at the lowest dosage and were age-related. On-treatment oestrone levels were higher in non-responders to treatment. Lower doses of AG than are currently used may be as effective therapeutically.


The Role of Vegetated Coastal Wetlands for Marine Megafauna Conservation.
Habitat loss is accelerating a global extinction crisis. Conservation requires understanding links between species and habitats. Emerging research is revealing important associations between vegetated coastal wetlands and marine megafauna, such as cetaceans, sea turtles, and sharks. But these links have not been reviewed and the importance of these globally declining habitats is undervalued. Here, we identify associations for 102 marine megafauna species that utilize these habitats, increasing the number of species with associations based on current International Union for the Conservation of Nature (IUCN) species assessments by 59% to 174, accounting for over 13% of all marine megafauna. We conclude that coastal wetlands require greater protection to support marine megafauna, and present a simple, effective framework to improve the inclusion of habitat associations within species assessments.


Drug resistance in leishmaniasis.
The treatment options of leishmaniasis are limited and far from satisfactory. For more than 60 years, treatment of leishmaniasis has centered around pentavalent antimonials (Sb(v)). Widespread misuse has led to the emergence of Sb(v) resistance in the hyperendemic areas of North Bihar. Other antileishmanials could also face the same fate, especially in the anthroponotic cycle. The HIV/ visceral leishmaniasis (VL) coinfected patients are another potential source for the emergence of drug resistance. At present no molecular markers of resistance are available and the only reliable method for monitoring resistance of isolates is the technically demanding in vitro amastigote-macrophage model. As the armametrium of drugs for leishmaniasis is limited, it is important that effective monitoring of drug use and response should be done to prevent the spread of resistance. Regimens of simultaneous or sequential combinations should be seriously considered to limit the emergence of resistance.


Iron overload causes endolysosomal deficits modulated by NAADP-regulated 2-pore channels and RAB7A.
Various neurodegenerative disorders are associated with increased brain iron content. Iron is known to cause oxidative stress, which concomitantly promotes cell death. Whereas endolysosomes are known to serve as intracellular iron storage organelles, the consequences of increased iron on endolysosomal functioning, and effects on cell viability upon modulation of endolysosomal iron release remain largely unknown. Here, we show that increasing intracellular iron causes endolysosomal alterations associated with impaired autophagic clearance of intracellular protein aggregates, increased cytosolic oxidative stress and increased cell death. These effects are subject to regulation by NAADP, a potent second messenger reported to target endolysosomal TPCNs (2-pore channels). Consistent with endolysosomal iron storage, cytosolic iron levels are modulated by NAADP, and increased cytosolic iron is detected when overexpressing active, but not inactive TPCNs, indicating that these channels can modulate endolysosomal iron release. Cell death triggered by altered intralysosomal iron handling is abrogated in the presence of an NAADP antagonist or when inhibiting RAB7A activity. Taken together, our results suggest that increased endolysosomal iron causes cell death associated with increased cytosolic oxidative stress as well as autophagic impairments, and these effects are subject to modulation by endolysosomal ion channel activity in a RAB7A-dependent manner. These data highlight alternative therapeutic strategies for neurodegenerative disorders associated with increased intracellular iron load.


Cytoskeletal interactions with glutamate receptors at central synapses.
The data presented here are clearly just the beginning of any comprehensive understanding of the set of regulatory and cytoskeletal proteins that interact with membrane receptors in the postsynaptic density. They do, however, indicate that both glutamate channels at central excitatory synapses are involved in complex protein-protein interactions. For example, while NR2A is important for Ca-dependent inactivation of NMDA receptors, studies in several systems suggest that the other major NR2 subunit in hippocampal neurons, NR2B, predominates at critical times during synapse formation. In addition, the COOH terminus of NR2B binds to several novel cytoskeletal proteins. These results provide circumstantial evidence that NR2B may play specific roles in function and localization of receptors at excitatory synapses. The possible role of NR2B in early synaptic function gains additional support from functional data suggesting that NMDA receptors have specific roles during development (Komuro and Rakic, 1993; Rabacchi et al., 1992; Yen et al., 1993). The essential role of NR1 and NR2B in development is graphically demonstrated by the neonatal death of transgenic mice lacking either of these two subunits (Forrest et al., 1994; Kutsuwada et al., 1996) whereas NR2A and NR2C-deficient mice are less severely affected (Sakimura et al., 1995; Ebralidze et al., 1996).


Fracture Incidence in Adult Kidney Transplant Recipients.
It remains uncertain whether kidney transplant recipients are a high-risk group for fracture. We conducted a cohort study using Ontario, Canada health care databases to estimate the 3-, 5- and 10-year cumulative incidence of nonvertebral fracture (proximal humerus, forearm, hip) in adult kidney transplant recipients between 1994 and 2009, stratifying by sex and age (<50 versus ≥50 years) at transplant. We also assessed the 3-year cumulative incidence of all fracture locations (excluding skull, toes, and fingers) and falls, 10-year cumulative incidence of hip fracture alone, and nonvertebral fracture incidence in recipients compared to nontransplant reference groups matched on age, sex, and cohort entry year. We studied 4821 recipients (median age, 50 years). Among the age and sex strata, female recipients aged 50 years or older had the highest 3-year cumulative incidence of nonvertebral fracture (3.1%; 95% confidence interval [95% CI], 2.1-4.4%). Recipients had a higher 3-year cumulative incidence of nonvertebral fracture (1.6%; 95% CI, 1.3-2.0%) compared to the general population with no previous nonvertebral fracture (0.5%; 95% CI, 0.4-0.6%; P < 0.0001) and nondialysis chronic kidney disease (1.1%; 95% CI, 0.9-1.2%; P = 0.03), but a lower fracture incidence than the general population with a previous nonvertebral fracture (2.3%; 95% CI, 1.9-2.8%; P = 0.007). The 10-year cumulative incidence of hip fracture in all recipients was 1.7% (≥3% defined as high risk in clinical guidelines). Kidney transplant recipients may have a lower fracture risk than previously suggested in the literature. Results inform our understanding of fracture incidence after kidney transplantation and how it compares to nontransplant populations.


Untangling the Ecology, Taxonomy, and Evolution of Chaetogaster limnaei (Oligochaeta: Naididae) Species Complex.
Within Oligochaeta, Chaetogaster limnaei is unusual in exhibiting a parasitic relationship with freshwater pulmonate snails. Taxonomic confusion has been caused by differences in what have been considered 2 subspecies of this worm: Chaetogaster limnaei limnaei is an ectosymbiont and is present inside the mantle cavity of the snail, whereas Chaetogaster limnaei vaghini is parasitic and lives in the kidney of the snail. This study explored the distribution of these annelids in central New York and used mitochondrial DNA sequence data from the COI locus to examine the relationship, evolution, and species status of the ectosymbiotic and parasitic forms of C. limnaei. Snails ( Physa gyrina ) were collected from 6 streams and lakes in central New York, with additional specimens collected from a lake in Massachusetts for comparison. One hundred and forty snails were examined, and at least 1 form of Chaetogaster was present in 88 specimens, a prevalence of 62.9%. COI sequence data from New York and Massachusetts did not reveal separate ectosymbiotic and parasitic lineages. Instead, all parasitic forms were part of a mixed clade that included both ectosymbiotic and parasitic forms. This mixed clade was nested within clades of ectosymbiotic forms only, suggesting that a plastic lineage of C. limnaei, able to be both ectosymbionts and parasites, evolved from ectoparasitic ancestors.


Repressed Ca(2+) clearance in parthenolide-treated murine brain bEND.3 endothelial cells.
Parthenolide is a sesquiterpene lactone compound isolated from the leaves and flowerheads of the plant feverfew (Tanacetum parthenium). The anticancer effects of parthenolide have been well studied and this lactone compound is currently under clinical trials. Parthenolide is also a protective agent in cardiac reperfusion injury via its inhibition of nuclear factor-κB (NF-κB). Not much is known if this compound affects signal transduction in non-tumor cells. We investigated whether parthenolide affected Ca(2+) signaling in endothelial cells, key components in regulating the vascular tone. In this work using mouse cortical microvascular bEND.3 endothelial cells, we found that a 15-h treatment with parthenolide resulted in amplified ATP-triggered Ca(2+) signal; the latter had a very slow decay rate suggesting suppression of Ca(2+) clearance. Evidence suggests parthenolide suppressed Ca(2+) clearance by inhibiting the plasmalemmal Ca(2+) pump; such suppression did not result from decreased expression of the plasmalemmal Ca(2+) pump protein. Rather, such suppression was possibly a consequence of endoplasmic reticulum (ER) stress, since salubrinal (an ER stress protector) was able to alleviate parthenolide-induced Ca(2+) clearance suppression. Given the current deployment of parthenolide as an anti-cancer drug in clinical trials and the potential usage of this lactone as a cardioprotectant, it is important to examine in details the perturbing effects of parthenolide on Ca(2+) homeostasis in endothelial cells and neighboring vascular smooth muscle cells, activities of which exert profound effects on hemodynamics.


Predicting high-cost pediatric patients: derivation and validation of a population-based model.
Health care administrators often lack feasible methods to prospectively identify new pediatric patients with high health care needs, precluding the ability to proactively target appropriate population health management programs to these children. To develop and validate a predictive model identifying high-cost pediatric patients using parent-reported health (PRH) measures that can be easily collected in clinical and administrative settings. Retrospective cohort study using 2-year panel data from the 2001 to 2011 rounds of the Medical Expenditure Panel Survey. A total of 24,163 children aged 5-17 with family incomes below 400% of the federal poverty line were included in this study. Predictive performance, including the c-statistic, sensitivity, specificity, and predictive values, of multivariate logistic regression models predicting top-decile health care expenditures over a 1-year period. Seven independent domains of PRH measures were tested for predictive capacity relative to basic sociodemographic information: the Children with Special Health Care Needs (CSHCN) Screener; subjectively rated health status; prior year health care utilization; behavioral problems; asthma diagnosis; access to health care; and parental health status and access to care. The CSHCN screener and prior year utilization domains exhibited the highest incremental predictive gains over the baseline model. A model including sociodemographic characteristics, the CSHCN screener, and prior year utilization had a c-statistic of 0.73 (95% confidence interval, 0.70-0.74), surpassing the commonly used threshold to establish sufficient predictive capacity (c-statistic>0.70). The proposed prediction tool, comprising a simple series of PRH measures, accurately stratifies pediatric populations by their risk of incurring high health care costs.


The fundamental role of storytelling and practical wisdom in facilitating the ethics education of junior doctors.
Practical wisdom is a key concept in the field of virtue ethics, and it has played a significant role in the thinking of those who make use of virtue when theorising medical practice and ethics. In this article, we examine how storytelling and practical wisdom play integral roles in the medical ethics education of junior doctors. Using a qualitative approach, we conducted 46 interviews with a cohort of junior doctors to explore the role doctors feel phronesis has in their medical ethics practice and how they acquire practical wisdom through storytelling as an essential part of their medical ethics education. Through thematic analysis of the interviews, we discuss the key role storytelling about moral exemplars and role models plays in developing medical ethics education, and how telling stories about role models is considered to be one of the most useful ways to learn medical ethics. We finish by developing an argument for why practical wisdom should be an important part of medical ethics training, focusing on the important role that phronesis narratives should have in teaching medical ethics.


Obesity, weight loss and prognosis in type 2 diabetes.
Medical records were reviewed of all 263 Type 2 diabetic patients from the Aberdeen diabetic clinic who were known to have died in 1985 or 1986. Mean age was 65 years (interquartile range 57-75 years) at diagnosis and 72 (66-80) years for men, 75 (72-83) years for women, at death. Life expectancy at age 65 was 35% less than published figures for the general population. Analysis of survival in 233 patients who lived more than 1 year (189 overweight) using stepwise multiple regression indicated as significant (p less than 0.05) adverse independent variables: age at diagnosis, presence of clinical ischaemic heart disease at diagnosis, plasma glucose at diagnosis; and as significant favourable variables: oral hypoglycaemic drug therapy, weight loss in the first year, and an interaction between weight loss and BMI for patients with BMI greater than 25 kg m-2. Changes in fashions over the years are likely to have biased these results towards including oral hypoglycaemic therapy and excluding the expected adverse effect of smoking. Mean weight loss at 1 year was 2.6 kg for those with BMI 25-30 kg m-2, 6.8 kg with BMI greater than 30 kg m-2, following standard dietetic advice. For the average patient each 1 kg weight loss was associated with 3-4 months prolonged survival.


Synthetic Analogs of Curcumin Modulate the Function of Multidrug Resistance-Linked ATP-Binding Cassette Transporter ABCG2.
Multidrug resistance (MDR) caused by the overexpression of ATP-binding cassette (ABC) transporters in cancer cells is a major obstacle in cancer chemotherapy. Previous studies have shown that curcumin, a natural product and a dietary constituent of turmeric, inhibits the function of MDR-related ABC transporters, including ABCB1, ABCC1, and especially ABCG2. However, the limited bioavailability of curcumin prevents its use for modulation of the function of these transporters in the clinical setting. In this study, we investigated the effects of 24 synthetic curcumin analogs with increased bioavailability on the transport function of ABCG2. The screening of the 24 synthetic analogs by means of flow cytometry revealed that four of the curcumin analogs (GO-Y030, GO-Y078, GO-Y168, and GO-Y172) significantly inhibited the efflux of the ABCG2 substrates, mitoxantrone and pheophorbide A, from ABCG2-overexpressing K562/breast cancer resistance protein (BCRP) cells. Biochemical analyses showed that GO-Y030, GO-Y078, and GO-Y172 stimulated the ATPase activity of ABCG2 at nanomolar concentrations and inhibited the photolabeling of ABCG2 with iodoarylazidoprazosin, suggesting that these analogs interact with the substrate-binding sites of ABCG2. In addition, when used in cytotoxicity assays, GO-Y030 and GO-Y078 were found to improve the sensitivity of the anticancer drug, SN-38, in K562/BCRP cells. Taken together, these results suggest that nontoxic synthetic curcumin analogs with increased bioavailability, especially GO-Y030 and GO-Y078, inhibit the function of ABCG2 by directly interacting at the substrate-binding site. These synthetic curcumin analogs could therefore be developed as potent modulators to overcome ABCG2-mediated MDR in cancer cells.


The effects of resistance training on muscle strength, joint pain, and hand function in individuals with hand osteoarthritis: a systematic review and meta-analysis.
Hand osteoarthritis is a common condition characterised by joint pain and muscle weakness. These factors are thought to contribute to ongoing disability. Some evidence exists that resistance training decreases pain, improves muscle strength, and enhances function in people with knee and hip osteoarthritis. However, there is currently a lack of consensus regarding its effectiveness in people with hand osteoarthritis. Therefore, the aim of this systematic review and meta-analysis was to establish whether resistance training in people with hand osteoarthritis increases grip strength, decreases joint pain, and improves hand function. Seven databases were searched from 1975 until July 1, 2016. Randomised controlled trials were included. The Cochrane Risk of Bias Tool was used to assess studies' methodological quality. The Grade of Recommendations Assessment, Development, and Evaluation system was adopted to rate overall quality of evidence. Suitable studies were pooled using a random-effects meta-analysis. Five studies were included with a total of 350 participants. The majority of the training programs did not meet recommended intensity, frequency, or progression criteria for muscle strengthening. There was moderate-quality evidence that resistance training does not improve grip strength (mean difference = 1.35; 95% confidence interval (CI) = -0.84, 3.54; I 2 = 50%; p = 0.23 ). Low-quality evidence showed significant improvements in joint pain (standardised mean difference (SMD) = -0.23; 95% CI = -0.42, -0.04; I 2 = 0%; p = 0.02) which were not clinically relevant. Low-quality evidence demonstrated no improvements in hand function following resistance training (SMD = -0.1; 95% CI = -0.33, 0.13; I 2 = 28%; p = 0.39). There is no evidence that resistance training has a significant effect on grip strength or hand function in people with hand osteoarthritis. Low-quality evidence suggests it has a small, clinically unimportant pain-relieving effect. Future studies should investigate resistance training regimes with adequate intensity, frequency, and progressions to achieve gains in muscle strength.


Cancer-Induced Alterations of NK-Mediated Target Recognition: Current and Investigational Pharmacological Strategies Aiming at Restoring NK-Mediated Anti-Tumor Activity.
Despite evidence of cancer immune-surveillance, which plays a key role in tumor rejection, cancer cells can escape immune recognition through different mechanisms. Thus, evasion to Natural killer (NK) cell-mediated anti-tumor activity is commonly described and is mediated by various mechanisms, mainly cancer cell-induced down-regulation of NK-activating receptors (NCRs, NKG2D, DNAM-1, and CD16) as well as up-regulation of inhibitory receptors (killer-cell immunoglobulin-like receptors, KIRs, NKG2A). Alterations of NK cells lead to an impaired recognition of tumor cells as well as a decreased ability to interact with immune cells. Alternatively, cancer cells downregulate expression of ligands for NK cell-activating receptors and up-regulate expression of the ligands for inhibitory receptors. A better knowledge of the extent and the mechanisms of these defects will allow developing pharmacological strategies to restore NK cell ability to recognize and lyse tumor cells. Combining conventional chemotherapy and immune modulation is a promising approach likely to improve clinical outcome in diverse neoplastic malignancies. Here, we overview experimental approaches as well as strategies already available in the clinics that restore NK cell functionality. Yet successful cancer therapies based on the manipulation of NK cell already have shown efficacy in the context of hematologic malignancies. Additionally, the ability of cytotoxic agents to increase susceptibility of tumors to NK cell lysis has been studied and may require improvement to maximize this effect. More recently, new strategies were developed to specifically restore NK cell phenotype or to stimulate NK cell functions. Overall, pharmacological immune modulation trends to be integrated in therapeutic strategies and should improve anti-tumor effects of conventional cancer therapy.


Ultradian rhythms in Arabidopsis thaliana leaves in microgravity.
Ultradian movements of Arabidopsis thaliana rosette leaves were discovered and studied under microgravity conditions in space. Weightlessness revealed new facets of these movements. The European Modular Cultivation System (EMCS) was used in a long-term white-light, light-darkness (LD; 16 : 8 h) experiment on the International Space Station (ISS). Leaves reacted with slow up or down movement (time constant several hours) after transitions to darkness or light, respectively. Superimposed movements with periods of c. 80-90 min and small-amplitude pulsed movements of 45 min were present in the light. Signal analysis (fast Fourier transform (FFT) analysis) revealed several types and frequencies of movements. Identical phase coupling was observed between the 45-min movements of the leaves of one plant. In darkness, movements of c. 120-min period were recorded. The EMCS allowed 0-g to 1-g transitions to be created. Leaves on plants germinated in microgravity started a negative gravitropic reaction after a delay of c. 30 min. Leaves grown on a 1-g centrifuge reacted to the same transition with an equal delay but had a weaker gravitropic response. The experiments provide unequivocal demonstrations of ultradian, self-sustained rhythmic movements in A. thaliana rosette leaves in the absence of the effect of gravity.


Bone density and structure in healthy postmenopausal women treated with exemestane for the primary prevention of breast cancer: a nested substudy of the MAP.3 randomised controlled trial.
Exemestane can prevent breast cancer in postmenopausal women. Because of potential widespread use, we examined the safety of exemestane on bone health. In this nested safety substudy of the MAP.3 trial (a randomised, placebo-controlled, double-blind trial of exemestane 25 mg a day for the primary prevention of breast cancer), we included postmenopausal women from five centres who were eligible to participate in MAP.3, not osteoporotic, not receiving drugs for bone-related disorders, with baseline lumbar spine, total hip, and femoral neck T-scores above -2·0. The primary endpoint was percent change from baseline to 2 years in total volumetric bone mineral density (BMD) at the distal radius by high-resolution peripheral quantitative CT. The primary analysis was per protocol using a non-inferiority margin. This analysis was done earlier than originally planned because of the impending announcement of MAP.3 results and subsequent unmasking of patients to treatment assignment. This study is registered with ClinicalTrials.gov, number NCT01144468, and has been extended to 5 years of unmasked follow-up. 351 women (176 given exemestane, 175 given placebo; median age 61·3 years [IQR 59·2-64·9]) met our inclusion criteria and completed baseline assessment. At the time of clinical cutoff, 242 women had completed 2-year follow-up (124 given exemestane, 118 given placebo). From baseline to 2 years, the mean percent change in total volumetric BMD at the distal radius was -6·1% (95% CI -7·0 to -5·2) in the exemestane group and -1·8% (-2·4 to -1·2) in the placebo group (difference -4·3%, 95% CI -5·3 to -3·2; p<0·0001). The lower limit of the 95% CI was lower than our non-inferiority margin of negative 4% (one-sided test for non-inferiority p=0·70), meaning the hypothesis that exemestane was inferior could not be rejected. At the distal tibia, the mean percent change in total volumetric BMD from baseline to 2 years was -5·0% (95% CI -5·5 to -4·4) in the exemestane group and -1·3% (-1·7 to -1·0) in the placebo group (difference -3·7%, 95% CI -4·3 to -3·0; p<0·0001). The mean percent change in cortical thickness was -7·9% (SD 7·3) in the exemestane group and -1·1% (5·7) in the placebo group at the distal radius (difference -6·8%, 95% CI -8·5 to -5·0; p<0·0001) and -7·6% (SD 5·9) in the exemestane group and -0·7% (4·9) in the placebo group at the distal tibia (difference -6·9%, -8·4 to -5·5; p<0·0001). Decline in areal BMD, as measured by dual-energy x-ray absorptiometry, in the exemestane group compared with the placebo group occurred at the lumbar spine (-2·4% [95% CI -3·1 to -1·7] exemestane vs -0·5% [-1·1 to 0·2] placebo; difference -1·9%, 95% CI -2·9 to -1·0; p<0·0001), total hip (-1·8% [-2·3 to -1·2] exemestane vs -0·6% [-1·1 to -0·1] placebo; difference -1·2%, -1·9 to -0·4; p=0·004), and femoral neck (-2·4% [-3·2 to -1·7] exemestane vs -0·8% [-1·5 to 0·1] placebo; difference -1·6%, -2·7 to -0·6; p=0·002). 2 years of treatment with exemestane worsens age-related bone loss in postmenopausal women despite calcium and vitamin D supplementation. Women considering exemestane for the primary prevention of breast cancer should weigh their individual risks and benefits. For women taking exemestane, regular bone monitoring plus adequate calcium and vitamin D supplementation are important. To assess the effect of our findings on fracture risk, long-term follow-up is needed. Canadian Breast Cancer Research Alliance (Canadian Institutes of Health Research/Canadian Cancer Society).


Schwannoma of the foot: report of four cases and literature review.
Schwannoma is a soft tissue tumor that rarely presents in the foot. Patients are usually asymptomatic, but in some cases symptoms typically result from the mass effect and direct involvement of the nerve and surrounding tissue. We report on four consecutive cases. The first patient was a 57-years-old female that referred symptoms similar to the Morton's neuroma with a mass arising from the medial plantar nerve. The second patient was treated for a schwannoma in the plantar area. The third case was a female with a schwannoma arising from the sural nerve and the fourth patient had a tumor arising from the medial plantar nerve. All patients underwent surgical excision and histological evaluation. No signs of neurological deficit or recurrence were observed at final follow-up. Purpose of the study was to define clinical features, optimal management and outcome of schwannomas of the foot, through an accurate review of the literature.


Human bites in children. A six-year experience.
Three hundred twenty-two human bites in children, occurring during a six-year period, were reviewed. The majority occurred during warm-weather months between 2 PM and 11 PM. The upper extremities (42%), face and neck (33%), and trunk (22%) were most commonly bitten. At the time of injury, children were most often engaged in fights (61%) or play (26%). Seventy-five percent of wounds were superficial abrasions, 13% were punctures, and 11% were lacerations. None of the 242 abrasions became infected as opposed to 38% of the punctures and 37% of the lacerations. Other factors associated with increased risk of infection were delay in initial physician assessment beyond 18 hours after injury, location of the bite on the upper extremities, and occurrence of injury during sports activities. Prophylactic use of penicillin was probably not effective in reducing infection rates in these children; however, prospective data are needed to properly address this issue.


HIV's evasion of host's NK cell response and novel ways of its countering and boosting anti-HIV immunity.
NK cells were characterized by their ability to spontaneously kill certain tumor and virus-infected cells. They constitute first line of defense against invading pathogens and usually become activated in viral infections particularly in early phases. Activated NK cells play a crucial role in the induction and amplification of virus-specific immunity by providing IFN-gamma and "danger signal". The functional activities of NK cells are regulated by a balance between the engagement of their inhibitory and activating receptors. In recent years, the discovery of several MHC and non-MHC binding NK receptors has provided important insights regarding NK cell biology and its role in viral infections. These receptors are increasingly being viewed as important regulators of immune response. Like many other viruses, HIV also seems to activate NK cells. However, several studies have reported compromised NK cell functions in HIV-infected individuals. The virus employs several strategies to counter the host's NK cell response, e.g., a differential downregulation of MHC class I molecules on the surface of infected cells, a dysregulated production of NK cell function-enhancing cytokines, direct inhibitory effects of certain viral proteins on NK cell functions, and changes in the expression of NK cell receptors, etc. The individuals expressing activating NK cell receptors and their cognate MHC ligands have activated NK cells. The development of AIDS is significantly delayed in these individuals after HIV infection. The discovery of NK receptors and their ligands has opened new avenues of developing AIDS vaccine and boosting innate and adaptive antiviral immunity in HIV-infected individuals.


Language Characteristics of Individuals with Down Syndrome.
On average, language and communication characteristics of individuals with Down syndrome (the most common genetic cause of intellectual disability) follow a consistent profile. Despite considerable individual variability, receptive language is typically stronger than expressive language, with particular challenges in phonology and syntax. We review the literature on language and literacy skills of individuals with Down syndrome, with emphasis on the areas of phonology, vocabulary, syntax, and pragmatics. We begin by describing the hearing, oral-motor, cognitive, social, and prelinguistic and early nonverbal communication characteristics of individuals with Down syndrome. We conclude with a discussion of clinical implications and research directions.


Biomechanical implications of skeletal muscle hypertrophy and atrophy: a musculoskeletal model.
Muscle hypertrophy and atrophy occur frequently as a result of mechanical loading or unloading, with implications for clinical, general, and athletic populations. The effects of muscle hypertrophy and atrophy on force production and joint moments have been previously described. However, there is a paucity of research showing how hypertrophy and atrophy may affect moment arm (MA) lengths. The purpose of this model was to describe the mathematical relationship between the anatomical cross-sectional area (ACSA) of a muscle and its MA length. In the model, the ACSAs of the biceps brachii and brachialis were altered to hypertrophy up to twice their original size and to atrophy to one-half of their original size. The change in MA length was found to be proportional to the arcsine of the square root of the change in ACSA. This change in MA length may be a small but important contributor to strength, especially in sports that require large joint moments at slow joint angular velocities, such as powerlifting. The paradoxical implications of the increase in MA are discussed, as physiological factors influencing muscle contraction velocity appear to favor a smaller MA length for high velocity movements but a larger muscle MA length for low velocity, high force movements.


Guideline of guidelines: Muscle-invasive bladder cancer.
Muscle-invasive bladder cancer accounts for 25% of bladder cancer cases and represents a spectrum of disease, which can result in significant morbidity and mortality for anyone affected. Current management has evolved through years of research and clinical practice. It is based on a risk-benefit approach, which is often tailored to the individual requirements of patients and involves cystectomy, neoadjuvant and adjuvant therapies, and multimodal surveillance paradigms to achieve high survival rates. Multiple guidelines exist to assist the clinicians in this decision-making process, but their adherence is often variable. In this article, we aimed to review the 4 most commonly used guidelines from the European Association of Urology, the National Institute for Health and Care Excellence, the National Comprehensive Cancer Network, and the American Urological Association.


Virulence factor expression patterns in Pseudomonas aeruginosa strains from infants with cystic fibrosis.
Pseudomonas aeruginosa is the leading cause of morbidity and mortality in cystic fibrosis (CF). This study examines the role of organism-specific factors in the pathogenesis of very early P. aeruginosa infection in the CF airway. A total of 168 longitudinally collected P. aeruginosa isolates from children diagnosed with CF following newborn screening were genotyped by pulsed-field gel electrophoresis (PFGE) and phenotyped for 13 virulence factors. Ninety-two strains were identified. Associations between virulence factors and gender, exacerbation, persistence, timing of infection and infection site were assessed using multivariate regression analysis. Persistent strains showed significantly lower pyoverdine, rhamnolipid, haemolysin, total protease, and swimming and twitching motility than strains eradicated by aggressive antibiotic treatments. Initial strains had higher levels of virulence factors, and significantly higher phospholipase C, than subsequent genotypically different strains at initial isolation. Strains from males had significantly lower pyoverdine and swimming motility than females. Colony size was significantly smaller in strains isolated during exacerbation than those isolated during non-exacerbation periods. All virulence factors were higher and swimming motility significantly higher in strains from bronchoalveolar lavage (BAL) and oropharyngeal sites than BAL alone. Using unadjusted regression modelling, age at initial infection and age at isolation of a strain showed U-shaped profiles for most virulence factors. Among subsequent strains, longer time since initial infection meant lower levels of most virulence factors. This study provides new insight into virulence factors underpinning impaired airway clearance seen in CF infants, despite aggressive antibiotic therapy. This information will be important in the development of new strategies to reduce the impact of P. aeruginosa in CF.


Cone beam computed tomography guidance for setup of patients receiving accelerated partial breast irradiation.
To evaluate the role of cone-beam CT (CBCT) guidance for setup error reduction and soft tissue visualization in accelerated partial breast irradiation (APBI). Twenty patients were recruited for the delivery of radiotherapy to the postoperative cavity (3850 cGy in 10 fractions over 5 days) using an APBI technique. Cone-beam CT data sets were acquired after an initial skin-mark setup and before treatment delivery. These were registered online using the ipsilateral lung and external contours. Corrections were executed for translations exceeding 3 mm. The random and systematic errors associated with setup using skin-marks and setup using CBCT guidance were calculated and compared. A total of 315 CBCT data sets were analyzed. The systematic errors for the skin-mark setup were 2.7, 1.7, and 2.4 mm in the right-left, anterior-posterior, and superior-inferior directions, respectively. These were reduced to 0.8, 0.7, and 0.8 mm when CBCT guidance was used. The random errors were reduced from 2.4, 2.2, and 2.9 mm for skin-marks to 1.5, 1.5, and 1.6 mm for CBCT guidance in the right-left, anterior-posterior, and superior-inferior directions, respectively. A skin-mark setup for APBI patients is sufficient for current planning target volume margins for the population of patients studied here. Online CBCT guidance minimizes the occurrence of large random deviations, which may have a greater impact for the accelerated fractionation schedule used in APBI. It is also likely to permit a reduction in planning target volume margins and provide skin-line visualization and dosimetric evaluation of cardiac and lung volumes.


Education policy initiatives to address the nurse shortage in the United States.
Employment opportunities are expected to grow much faster for registered nurses (RNs) than for most other occupations. Yet a major shortage of nurses is projected by 2020. A nurse faculty shortage and financially strapped colleges and universities are limiting the ability of U.S. nursing schools to take advantage of historically high numbers of qualified applicants. Increased public subsidies are needed to provide greater access to nursing education, with a priority on baccalaureate and graduate nursing education, where job growth is expected to be the greatest.


Profiling the best-performing community medicine distributors for mass drug administration: a comprehensive, data-driven analysis of treatment for schistosomiasis, lymphatic filariasis, and soil-transmitted helminths in Uganda.
The most prevalent neglected tropical diseases are treated through blanket drug distribution that is reliant on lay community medicine distributors (CMDs). Yet, treatment rates achieved by CMDs vary widely and it is not known which CMDs treat the most people. In Mayuge District, Uganda, we tracked 6779 individuals (aged 1+ years) in 1238 households across 31 villages. Routine, community-based mass drug administration (MDA) was implemented for schistosomiasis, lymphatic filariasis, and soil-transmitted helminths. For each CMD, the percentage of eligible individuals treated (offered and ingested medicines) with at least one drug of praziquantel, albendazole, or ivermectin was examined. CMD attributes (more than 25) were measured, ranging from altruistic tendencies to socioeconomic characteristics to MDA-specific variables. The predictors of treatment rates achieved by CMDs were selected with least absolute shrinkage and selection operators and then analyzed in ordinary least squares regression with standard errors clustered by village. The influences of participant compliance and the ordering of drugs offered also were examined for the treatment rates achieved by CMDs. Overall, only 44.89% (3043/6779) of eligible individuals were treated with at least one drug. Treatment rates varied amongst CMDs from 0% to 84.25%. Treatment rate increases were associated (p value< 0.05) with CMDs who displayed altruistic biases towards their friends (13.88%), had friends who helped with MDA (8.43%), were male (11.96%), worked as fishermen/fishmongers (14.93%), and used protected drinking water sources (13.43%). Only 0.24% (16/6779) of all eligible individuals were noncompliant by refusing to ingest all offered drugs. Distributing praziquantel first was strongly, positively correlated (p value < 0.0001) with treatment rates for albendazole and ivermectin. These findings profile CMDs who treat the most people during routine MDA. Criteria currently used to select CMDs-community-wide meetings, educational attainment, age, years as a CMD, etc.-were uninformative. Participant noncompliance and the provision of praziquantel before albendazole and ivermectin did not negatively impact treatment rates achieved by CMDs. Engaging CMD friend groups with MDA, selecting CMDs who practise good preventative health behaviours, and including CMDs with high-risk occupations for endemic infections may improve MDA treatment rates. Evidence-based guidelines are needed to improve the monitoring, selection, and replacement of CMDs during MDA.


Role of diet in prostate cancer development and progression.
Increasing evidence supports the important role of nutrition in cancer prevention, including prevention of prostate cancer. In this review, we summarize data for some of the most consistently observed dietary associations for prostate cancer incidence, briefly consider possible postdiagnostic effects of nutrition on prostate cancer progression/survival, discuss new but limited data on diet-gene interactions, and comment on current areas of controversy for future research focus. Potential protective dietary elements include tomatoes/lycopene, other carotenoids, cruciferous vegetables, vitamin E, selenium, fish/marine omega-3 fatty acids, soy, isoflavones and polyphenols; whereas milk, dairy, calcium, zinc at high doses, saturated fat, grilled meats, and heterocyclic amines may increase risk. It is important to note that randomized clinical trial data exist only for vitamin E, calcium, beta-carotene, and selenium (all of which suggest inverse or no association). Several genes, such as MnSOD, XRCC1, and GST, may modify the association of specific nutrients and foods with prostate cancer risk; and further research is warranted to confirm these initial observed relationships. Until further clinical trial data are available on specific supplements and prostate cancer prevention, it would be prudent to emphasize a diet consisting of a wide variety of plant-based foods and fish; this is similar to what is recommended (and what is more well established) for the primary prevention of heart disease.


Biological significance of genome-wide DNA methylation profiles in keloids.
To obtain biological insight into keloid pathogenesis and treatment using pathway analysis of genome-wide differentially methylated gene profiles between keloid and normal skin. Prospective cohort. Genome-wide profiling was previously done, with institutional review board approval, on six fresh keloid and six fresh normal skin tissue samples, using the Infinium HumanMethylation450 BeadChip kit. Statistically significant differentially methylated cytosine-phosphodiester bond-guanines (CpGs, n = 197) between keloid and normal tissue mapped to 152 genes. These genes were uploaded into Ingenuity Pathway Analysis (IPA) software to identify biological functions or regulatory networks interacting. The pathways (or "network") with an enrichment probability value ≤ .01 were subjected to a heuristic filter of keywords associated with keloid pathogenesis. Of the 197 CpGs, 191 were found in the IPA database and mapped to 152 unique genes. The top 10 hypermethylated genes were ACTR3C, LRRC61, PAQR4, C1orf109, SLCO2B1, CMKLR1, AHDC1, FYCO1, CCDC34, and CACNB2. The top 10 hypomethylated genes were GALNT3, SCML4, PPP1R13L, ANKRD11, WIPF1, MX2, IFFO1, DENND1C, CFH, and GHDC. IPA identified nine pathways with enrichment probability values ≤ .01, of which five (histidine degradation V1, phospholipase C signaling, colorectal cancer metastasis signaling, P2Y purinergic receptor signaling, and Gαi signaling) were associated with keloid keywords and contained "keloid genes" (P < .05). Genes differentially methylated between keloid and normal skin reside in known bionetwork pathways involved in critical biological functioning and signaling events in the cell. This information could be used to refine screening processes for biological significance to better understand keloid pathogenesis and to develop molecular-targeted therapy. NA Laryngoscope, 127:70-78, 2017.


The impact of sleep loss on sustained and transient attention: an EEG study.
Sleep is one of our most important physiological functions that maintains physical and mental health. Two studies examined whether discrete areas of attention are equally affected by sleep loss. This was achieved using a repeated-measures within-subjects design, with two contrasting conditions: normal sleep and partial sleep restriction of 5-h. Study 1 compared performance on a sustained attention task (Psychomotor Vigilance task; PVT) with performance on a transient attention task (Attentional Blink; AB). PVT performance, but not performance on the AB task, was impaired after sleep restriction. Study 2 sought to determine the neural underpinnings of the phenomenon, using electroencephalogram (EEG) frequency analysis, which measured activity during the brief eyes-closed resting state before the tasks. AB performance was unaffected by sleep restriction, despite clearly observable changes in brain activity. EEG results showed a significant reduction in resting state alpha oscillations that was most prominent centrally in the right hemisphere. Changes in individual alpha and delta power were also found to be related to changes in subjective sleepiness and PVT performance. Results likely reflect different levels of impairment in specific forms of attention following sleep loss.


Clinical differentiation of patent foramen ovale and secundum atrial septal defect: a survey of pediatric cardiologists in Dallas, Texas, USA.
Public health birth defect surveillance registries rely on health care provider diagnosis and definition of congenital anomalies. Major anomalies are likely to have consistent diagnoses across providers; however, definition of some more common, often minor, defects can be problematic. Of particular frustration are the transient neonatal heart findings: patent ductus arteriosus, patent foramen ovale, and pulmonary artery branch stenosis. Under certain circumstances these findings may be considered true anomalies-patent foramen ovale (PFO) as a clinical finding overlaps significantly with atrial septal defect (ASD) of secundum type, the latter being considered a true congenital malformation. Some criteria must be established to separate these conditions in case ascertainment. It is therefore helpful to understand the clinical definitions of patent foramen ovale and secundum atrial septal defect. Pediatric cardiologists in the greater Dallas, Texas metropolitan area were surveyed by telephone, fax, and/or email and asked what criteria they use to distinguish a PFO from a secundum ASD. This was an open-ended question. No baseline parameters were suggested or introduced by the interviewer. Pediatric cardiology fellowship training was identified for each physician to examine the hypothesis that graduates of a given program would use the same diagnostic criteria. Responses were obtained from 22 of 23 pediatric cardiologists. Four measurement criteria were identified: size of the opening, presence or absence of a flap of septal tissue, appearance of the defect on echocardiogram and presence/absence/amount of blood shunting across through the opening. Though there was overlap, diagnostic criteria differentiating PFO and secundum ASD varied among pediatric cardiologists. Two fellowship programs were well represented by the respondent population. Eight respondents were trained at Fellowship 1 and 5 at Fellowship 2. Place of fellowship training was not a strong indicator of which diagnostic criteria were used, even when graduates were in practice together. Physicians in private practice were more likely to report objective measurements as bases for their diagnostic decision. The pronounced variability in clinical definitions will be a problem for birth defect surveillance and research based upon the resultant database. When different physicians use different diagnostic criteria for borderline defects, it is impossible to know whether a defect ascertained and coded with a standard protocol is the same across the population. Since it is unlikely that consistent diagnostic criteria can be put in place, the surveillance program is burdened with compensating for the variability.


Near-infrared characterization on the secondary structure of regenerated Bombyx mori silk fibroin.
Several advantages of the near-infrared (NIR) technique in the characterization of the secondary structure of regenerated Bombyx mori silk fibroin are demonstrated. Silk fibroin films with thicknesses ranging from 50 to 300 microm are suitable for the NIR measurement. The bands due to hydrogen-bonded water are independent in the NIR spectra and facilitate our investigation of the amide region. Analysis of the combination modes of amide groups in the NIR spectra could lead to a profile of conformation ratio of silk fibroin, which was supported by nuclear magnetic resonance (NMR) observations.


Effect of Preoperative Risk Group Stratification on Oncologic Outcomes of Patients with Adverse Pathologic Findings at Radical Prostatectomy.
Current National Comprehensive Cancer Network guidelines recommend postoperative radiation therapy based only on adverse pathologic findings (APFs), irrespective of preoperative risk group. We assessed whether a model incorporating both the preoperative risk group and APFs could predict long-term oncologic outcomes better than a model based on APFs alone. We retrospectively reviewed 4,404 men who underwent radical prostatectomy (RP) at our institution between 1992 and 2014. After excluding patients receiving neoadjuvant therapy or with incomplete pathological or follow-up data, 3,092 men were included in the final analysis. APFs were defined as extraprostatic extension (EPE), seminal vesicle invasion (SVI), or a positive surgical margin (PSM). The adequacy of model fit to the data was compared using the likelihood-ratio test between the models with and without risk groups, and model discrimination was compared with the concordance index (c-index) for predicting biochemical recurrence (BCR) and prostate cancer-specific mortality (PCSM). We performed multivariate Cox proportional hazard model and competing risk regression analyses to identify predictors of BCR and PCSM in the total patient group and each of the risk groups. Adding risk groups to the model containing only APFs significantly improved the fit to the data (likelihood-ratio test, p <0.001) and the c-index increased from 0.693 to 0.732 for BCR and from 0.707 to 0.747 for PCSM. A RP Gleason score (GS) ≥8 and a PSM were independently associated with BCR in the total patient group and also each risk group. However, only a GS ≥8 and SVI were associated with PCSM in the total patient group (GS ≥8: hazard ratio [HR] 5.39 and SVI: HR 3.36) and the high-risk group (GS ≥8: HR 6.31 and SVI: HR 4.05). The postoperative estimation of oncologic outcomes in men with APFs at RP was improved by considering preoperative risk group stratification. Although a PSM was an independent predictor for BCR, only a RP GS ≥8 and SVI were associated with PCSM in the total patient and high-risk groups.


Dynamics of HSPC repopulation in nonhuman primates revealed by a decade-long clonal-tracking study.
In mice, clonal tracking of hematopoietic stem cells (HSCs) has revealed variations in repopulation characteristics. However, it is unclear whether similar properties apply in primates. Here, we examined this issue through tracking of thousands of hematopoietic stem and progenitor cells (HSPCs) in rhesus macaques for up to 12 years. Approximately half of the clones analyzed contributed to long-term repopulation (over 3-10 years), arising in sequential groups and likely representing self-renewing HSCs. The remainder contributed primarily for the first year. The long-lived clones could be further subdivided into functional groups contributing primarily to myeloid, lymphoid, or both myeloid and lymphoid lineages. Over time, the 4%-10% of clones with robust dual lineage contribution predominated in repopulation. HSPCs expressing a CCR5 shRNA transgene behaved similarly to controls. Our study therefore documents HSPC behavior in a clinically relevant model over a long time frame and provides a substantial system-level data set that is a reference point for future work.


The genetic associations and epistatic effects of the CCR5 promoter and CCR2-V64I polymorphisms on susceptibility to HIV-1 infection in a Northern Han Chinese population.
The outcome of human immunodeficiency virus (HIV)-1 infection and course to AIDS are variable among individuals. Both chemokine receptor 5 (CCR5) and CCR2 gene polymorphisms play essential roles in the susceptibility of HIV-1 infection. To investigate the main and epistatic effects of the CCR5 promoter and CCR2-V64I polymorphisms on HIV-1 infection in the Northern Han Chinese, subjects of 91 HIV-1-infected patients and 91 health controls were recruited. Single-nucleotide polymorphisms (SNPs) in the CCR5 promoter region and CCR2-V64I variants were genotyped. In the single-locus analysis, CCR5 58755-G and CCR5 59653-T alleles were significantly associated with HIV-1 infection (odds ratio [OR]=0.529, 95% confidence interval [CI]: 0.295-0.948; OR=1.710, 95% CI: 1.039-2.814). After adjustment with age and gender, subjects with the CCR5 59653-CT genotype showed the increased risk of HIV-1 infection compared with those with the wild-type CC genotype (adjusted OR=2.502; 95% CI: 1.332-4.698). No positive association was observed in other SNPs. Haplotype-based association analysis revealed that the haplotype TATGC was associated with the susceptibility to HIV-1 infection (p=0.003). Besides, we found the significant epistatic effects between the CCR5 58755-A/G and CCR5 59029-A/G polymorphisms associated with the lower risk of HIV-1 infection. In addition, we also identified the best three-factor interaction model, including the CCR5 58755-A/G, 59029-A/G, and CCR2-V64I polymorphisms, indicating that there were also strong gene-gene interactions between the CCR5 promoter and CCR2 polymorphisms on the susceptibility of HIV-1 infection. These findings contribute to understanding the genetic mechanism for the susceptibility of HIV-1 infection in Northern Han Chinese.


Most atolls will be uninhabitable by the mid-21st century because of sea-level rise exacerbating wave-driven flooding.
Sea levels are rising, with the highest rates in the tropics, where thousands of low-lying coral atoll islands are located. Most studies on the resilience of these islands to sea-level rise have projected that they will experience minimal inundation impacts until at least the end of the 21st century. However, these have not taken into account the additional hazard of wave-driven overwash or its impact on freshwater availability. We project the impact of sea-level rise and wave-driven flooding on atoll infrastructure and freshwater availability under a variety of climate change scenarios. We show that, on the basis of current greenhouse gas emission rates, the nonlinear interactions between sea-level rise and wave dynamics over reefs will lead to the annual wave-driven overwash of most atoll islands by the mid-21st century. This annual flooding will result in the islands becoming uninhabitable because of frequent damage to infrastructure and the inability of their freshwater aquifers to recover between overwash events. This study provides critical information for understanding the timing and magnitude of climate change impacts on atoll islands that will result in significant, unavoidable geopolitical issues if it becomes necessary to abandon and relocate low-lying island states.


Surface-enhanced spatially-offset Raman spectroscopy (SESORS) for detection of neurochemicals through the skull at physiologically relevant concentrations.
Detection techniques for neurotransmitters that are rapid, label-free, and non-invasive are needed to move towards earlier diagnosis of neurological disease. Surface-enhanced Raman spectroscopy (SERS) allows for sensitive and selective detection of target analytes. The combination of SERS with spatially offset Raman spectroscopy (SORS) in a technique termed surface enhanced spatially offset Raman spectroscopy (SESORS) permits a sensitive and selective detection of neurotransmitters through the skull. Here, we present the SESORS detection of individual neurotransmitters and mixtures of neurotransmitters at physiologically relevant concentrations, while also establishing limits of detection.


Unravelling the correlation between metal induced aggregation and cellular uptake/subcellular localization of Znsalen: an overlooked rule for design of luminescent metal probes.
Unravelling the unique effects of metal coordination on biological behaviours is of importance to design metal based therapeutic and diagnostic agents. In this work, we chose luminescent Znsalen (ZnL1 ) as a case study to demonstrate that metal induced aggregation arising from the intermolecular Zn···O interaction influences its cellular uptake and subcellular localization. Comparative studies with the free bases (L1 and L2 ) show that ZnL1 undergoes cellular uptake through caveolae-mediated endocytosis and internalizes in endosomal/lysosomal compartments, in contrast to the localization of L1 and L2 in the mitochondria. Further studies of photophysical properties, TEM imaging and DLS analysis suggest that ZnL1 tends to form large sized fibrous structures in aqueous media. To investigate the relationship between ZnL1 aggregation and the biological behaviour, we used pyridine to tune the "aggregation-to-deaggregation" transition and found that, in the presence of pyridine, ZnL1 could localize in the mitochondria and internalize into cells through the passive diffusion pathway. Such distinctive biological behaviours resulting from the different Znsalen species clearly point out the importance of metal induced aggregation or metal speciation analysis in designing metal complexes as biological probes.


Microvascular perfusion and resistance in extracorporeal cardiopulmonary bypass under hypothermia with high-dose narcotic anesthesia--animal model.
Microvascular perfusion of the liver, kidney (cortex and medulla), pancreas and spleen was measured by laser-Doppler flowmetry under hypothermia in extracorporeal cardiopulmonary bypass, to determine the effectiveness of high-dose fentanyl in improving the microcirculation of these visceral organs. Twenty-four mongrel dogs in two groups were monitored by arterial catheter, Swan-Ganz catheter and laser-Doppler flowmeter. Cardiopulmonary bypass was carried out to induce hypothermia to 20 degrees C through the cannulation of inferior vena cava and aorta. Microvascular perfusion was measured by either needle or suturable probes of laser-Doppler flowmeter in liver, kidney (cortex and medulla), pancreas and spleen. With high-dose of fentanyl (100 micrograms/kg), decrease of microvascular perfusion in liver, pancreas and kidney (cortex and medulla) was less than the control group, especially at 20 degrees C. Notably, the trend of these changes had its unique pattern in each organ due to their own specific anatomical and physiological characteristics, while spleen did not show significant difference in both groups. In summary, high-dose of fentanyl improved the hepatic, renal and pancreatic microvascular perfusion, in agreement with our previous observation, might protect the function of these visceral organs from the damage of microvascular ischemia under hypothermia in the extracorporeal cardiopulmonary bypass.


Vaccine development in Staphylococcus aureus: taking the biofilm phenotype into consideration.
Vaccine development against pathogenic bacteria is an imperative initiative as bacteria are gaining resistance to current antimicrobial therapies and few novel antibiotics are being developed. Candidate antigens for vaccine development can be identified by a multitude of high-throughput technologies that were accelerated by access to complete genomes. While considerable success has been achieved in vaccine development against bacterial pathogens, many species with multiple virulence factors and modes of infection have provided reasonable challenges in identifying protective antigens. In particular, vaccine candidates should be evaluated in the context of the complex disease properties, whether planktonic (e.g. sepsis and pneumonia) and/or biofilm associated (e.g. indwelling medical device infections). Because of the phenotypic differences between these modes of growth, those vaccine candidates chosen only for their efficacy in one disease state may fail against other infections. This review will summarize the history and types of bacterial vaccines and adjuvants as well as present an overview of modern antigen discovery and complications brought about by polymicrobial infections. Finally, we will also use one of the better studied microbial species that uses differential, multifactorial protein profiles to mediate an array of diseases, Staphylococcus aureus, to outline some of the more recently identified problematic issues in vaccine development in this biofilm-forming species.


The artificial sweetener acesulfame potassium affects the gut microbiome and body weight gain in CD-1 mice.
Artificial sweeteners have been widely used in the modern diet, and their observed effects on human health have been inconsistent, with both beneficial and adverse outcomes reported. Obesity and type 2 diabetes have dramatically increased in the U.S. and other countries over the last two decades. Numerous studies have indicated an important role of the gut microbiome in body weight control and glucose metabolism and regulation. Interestingly, the artificial sweetener saccharin could alter gut microbiota and induce glucose intolerance, raising questions about the contribution of artificial sweeteners to the global epidemic of obesity and diabetes. Acesulfame-potassium (Ace-K), a FDA-approved artificial sweetener, is commonly used, but its toxicity data reported to date are considered inadequate. In particular, the functional impact of Ace-K on the gut microbiome is largely unknown. In this study, we explored the effects of Ace-K on the gut microbiome and the changes in fecal metabolic profiles using 16S rRNA sequencing and gas chromatography-mass spectrometry (GC-MS) metabolomics. We found that Ace-K consumption perturbed the gut microbiome of CD-1 mice after a 4-week treatment. The observed body weight gain, shifts in the gut bacterial community composition, enrichment of functional bacterial genes related to energy metabolism, and fecal metabolomic changes were highly gender-specific, with differential effects observed for males and females. In particular, ace-K increased body weight gain of male but not female mice. Collectively, our results may provide a novel understanding of the interaction between artificial sweeteners and the gut microbiome, as well as the potential role of this interaction in the development of obesity and the associated chronic inflammation.


Intercellular communication mediated by VIP in the cerebral cortex.
A growing number of biologically active peptides is being identified within the central nervous system (CNS). According to currently accepted criteria, several of these peptides, including VIP, can be viewed as neurotransmitters. Recent immunohistochemical and pharmacological investigations have been directed at the characterization of the position of VIP neurons in the circuitry of the cerebral cortex. From these studies some views on the possible function of VIP neurons in this CNS region are beginning to emerge. In the cerebral cortex, VIP neurons constitute a rather homogeneous population of intracortical, bipolar and radially oriented cells, which arborize locally, within cortical columns of 60-100 micron diameter. The cellular actions of VIP in the cerebral cortex include the stimulation of cAMP formation and of glycogen breakdown. A certain degree of cellular resolution of these two actions of VIP has been achieved by using purified preparations. Thus VIP stimulates cAMP formation in cerebral microvessels and in cultured astrocytes; in this latter cell type VIP also promotes glycogenolysis. Furthermore, VIP interacts synergistically with norepinephrine to stimulate cAMP formation and to inhibit the firing rate of spontaneously active identified cortical neurons. VIP neurons appear therefore to be strategically positioned to regulate the coupling between energy metabolism, blood flow and neuronal activity with great spatial selectivity and at a fine level of cortical resolution.


Epidemiology, ventilation management and outcome in patients receiving intensive care after non-thoracic surgery - Insights from the LAS VEGAS study.
Information about epidemiology, ventilation management and outcome in postoperative intensive care unit (ICU) patients remains scarce. The objective was to test whether postoperative ventilation differs from that in the operation room. This was a substudy of the worldwide observational LAS VEGAS study, including patients undergoing non-thoracic surgeries. Of 146 study sites participating in the LAS VEGAS study, 117 (80%) sites reported on the postoperative ICU course, including ventilation and complications. The coprimary outcomes were two key elements of ventilator management, i.e., tidal volume (VT) and positive end-expiratory pressure (PEEP). Secondary outcomes included the proportion of patients receiving low VT ventilation (LTVV, defined as ventilation with a median VT < 8.0 ml/kg PBW), and the proportion of patients developing postoperative pulmonary complications (PPC), including ARDS, pneumothorax, pneumonia and need for escalation of ventilatory support, ICU and hospital length of stay, and mortality at day 28. Of 653 patients who were admitted to the ICU after surgery, 274 (42%) patients received invasive postoperative ventilation. Median postoperative VT was 8.4 [7.3-9.8] ml/kg predicted body weight (PBW), PEEP was 5 [5-5] cm H2O, statistically significant but not meaningfully different from median intraoperative VT (8.1 [7.3-8.9] ml/kg PBW; P < 0.001) and PEEP (4 [2-5] cm H2O; P < 0.001). The proportion of patients receiving LTVV after surgery was 41%. The PPC rate was 10%. Length of stay in ICU and hospital was independent of development of a PPC, but hospital mortality was higher in patients who developed a PPC (24 versus 4%; P < 0.001). In this observational study of patients undergoing non-thoracic surgeries, postoperative ventilation was not meaningfully different from that in the operating room. Like in the operating room, there is room for improved use of LTVV. Development of PPC is associated with mortality.


Barriers and enablers to the use of seasonal climate forecasts amongst organisations in Europe.
Seasonal climate forecasts (SCF) provide information about future climate variability that has the potential to benefit organisations and their decision-making. However, the production and availability of SCF does not guarantee its use in decision-making per se as a range of factors and conditions influence its use in different decision-making contexts. The aim of this paper is to identify the barriers and enablers to the use of SCF across organisations in Europe. To achieve that, we conducted 75 in-depth interviews with organisations working across eight sectors (including energy, transport, water and agriculture) and 16 countries. The majority of the organisations interviewed do not currently use SCF. This was due to the low reliability and skill of SCF in Europe but also with other non-technical aspects such as the lack of relevance and awareness of SCF in the organisations. Conversely, the main enabler to the use of SCF was the interactions with the providers of SCF. In addition, the level of organisational resources, capacity and expertise were also significant enablers to the use of SCF in organisations. This paper provides the first empirical assessment of the use of SCF in Europe. Such insights provide not only an overview of the existing barriers and enablers to the use of SCF in Europe and how these can be overcome and negotiated to enhance the usability of SCF, but can also help inform the broader and emerging context of climate services development in Europe.


Diabetes, leukoencephalopathy and rage.
Longstanding diabetes mellitus damages kidney, retina, peripheral nerve and blood vessels, but brain is not usually considered a primary target. We describe direct involvement of the brain, particularly white matter, in long-term (9 months) experimental diabetes of mice, not previously modeled, correlating magnetic resonance (MR) imaging with quantitative histological assessment. Leukoencephalopathy and cerebral atrophy, resembling that encountered in diabetic humans, developed in diabetic mice and was accompanied by time-related development of cognitive changes in behavioural testing. Increased RAGE (receptor for advanced glycation end products) expression, a mediator of widespread diabetic complications, increased dramatically at sites of white matter damage in regions of myelination. RAGE expression was also elevated within neurons, astrocytes and microglia in grey matter and within oligodendrocytes in white matter. RAGE null diabetic mice had significantly less neurodegenerative changes when compared to wild-type diabetic mice. Our findings identify a robust and novel model of cerebral, particularly white matter, involvement with diabetes associated with abnormal RAGE signaling.