Important role of endocannabinoid signaling in the development of functional vision and locomotion in zebrafish.
The developmental role of the endocannabinoid system still remains to be fully understood. Here, we report the presence of a complete endocannabinoid system during zebrafish development and show that the genes that code for enzymes that catalyze the anabolism and catabolism (mgll and dagla) of the endocannabinoid, 2-AG (2-arachidonoylglycerol), as well as 2-AG main receptor in the brain, cannabinoid receptor type 1, are coexpressed in defined regions of axonal growth. By using morpholino-induced transient knockdown of the zebrafish Daglα homolog and its pharmacologic rescue, we suggest that synthesis of 2-AG is implicated in the control of axon formation in the midbrain-hindbrain region and that animals that lack Daglα display abnormal physiological behaviors in tests that measure stereotyped movement and motion perception. Our results suggest that the well-established role for 2-AG in axonal outgrowth has implications for the control of vision and movement in zebrafish and, thus, is likely common to all vertebrates.-Martella, A., Sepe, R. M., Silvestri, C., Zang, J., Fasano, G., Carnevali, O., De Girolamo, P., Neuhauss, S. C. F., Sordino, P., Di Marzo, V. Important role of endocannabinoid signaling in the development of functional vision and locomotion in zebrafish.


Bioaccessibility and Risk of Exposure to Metals and SVOCs in Artificial Turf Field Fill Materials and Fibers.
To reduce maintenance costs, municipalities and schools are starting to replace natural grass fields with a new generation synthetic turf. Unlike Astro-Turf, which was first introduced in the 1960s, synthetic field turf provides more cushioning to athletes. Part of this cushioning comes from materials like crumb rubber infill, which is manufactured from recycled tires and may contain a variety of chemicals. The goal of this study was to evaluate potential exposures from playing on artificial turf fields and associated risks to trace metals, semi-volatile organic compounds (SVOCs), and polycyclic aromatic hydrocarbons (PAHs) by examining typical artificial turf fibers (n = 8), different types of infill (n = 8), and samples from actual fields (n = 7). Three artificial biofluids were prepared, which included: lung, sweat, and digestive fluids. Artificial biofluids were hypothesized to yield a more representative estimation of dose than the levels obtained from total extraction methods. PAHs were routinely below the limit of detection across all three biofluids, precluding completion of a meaningful risk assessment. No SVOCs were identified at quantifiable levels in any extracts based on a match of their mass spectrum to compounds that are regulated in soil. The metals were measurable but at concentrations for which human health risk was estimated to be low. The study demonstrated that for the products and fields we tested, exposure to infill and artificial turf was generally considered de minimus, with the possible exception of lead for some fields and materials.


Cognitive behavioural anger management intervention for people with intellectual disabilities: costs of intervention and impact on health and social care resource use.
Anger and aggression among adults with intellectual disability (ID) are associated with a range of adverse consequences for their well-being and that of their family or staff carers. The aims were to evaluate the effectiveness of an anger management intervention for adults with mild to moderate ID and to evaluate the costs of the intervention and its impact on health and social care resource use. This paper is concerned with the latter aim. A cluster-randomised controlled trial was conducted involving day services for adults with ID in Scotland, England and Wales. Incremental costs of delivering the intervention and its impact on subsequent total health and social care package costs were calculated. Full data comparing costs between baseline and follow-up 10 months later were collected for 67 participants in the intervention arm and 62 participants in the control arm. Cost differences between the groups at follow-up, adjusted for baseline levels, were calculated using non-parametric bootstrapping controlling for clustering. The mean hourly excess cost of intervention over treatment as usual was £12.34. A mean adjusted cost difference of £22.46 per person per week in favour of the intervention group was found but this was not statistically significant. The baseline-adjusted cost difference at follow-up would result in a fairly immediate compensation for the excess costs of intervention, provided the difference is not a statistical artefact. Further research is needed to clarify the extent to which it might represent a real saving in service support costs.


Ruptured uterus in a primigravida: a case report.
Maternal mortality and morbidity have remained very high in the developing countries and one of its commonest causes is ruptured uterus, which in a primigravida is rather unusual. The patient reported was a primigravida with no previous uterine scar who had prenatal care and delivery of a live male infant at a private clinic in Ibadan. The identifiable aetiological factors in this case are pitocin augmentation and manual removal of the placenta. Fortunately, a timely exploratory laparatomy averted another mortality. This is not usually the case in the majority of high-risk patients labouring outside a proper hospital setting consequent upon a declining economy and the rising influence of religion. Methods to reduce this obstetric catastrophy are discussed.


History of Medical Parasitology and Parasitic Infections in Iran.
Parasites and parasitic diseases have been prevalent in Iran according to Iranian ancient scholars and physicians' inscriptions dating back to 865-1496. Some protozoan diseases such as malaria and cutaneous leishmaniasis have been introduced by clinical manifestations and helminthic infections by size and morphology of the worms. Scientific studies of Parasitology started in Iran from 1833, first by foreign physicians and continued from 1909 by Iranian researchers. The pioneer medical parasitologists of Iran were Dr N. Ansari and Dr. Sh. Mofidi who established the Department of Medical Parasitology in the School of Medicine, University of Tehran, 1939. Afterward, a considerable number of researchers and professors of parasitology have been active in training and research works in the fields of medical parasitology throughout the entire nation. At present, some significant parasitic diseases such as bilharsiasis and dracunculiasis are more or less eradicated and malaria is in the elimination phase. The prevalence of most helminthic infections has considerably decreased. Most of the departments of medical Parasitology in Iran are active in training MD, MSPH and PhD students. The Iranian Society of Parasitology established in 1994 is active with many eligible members and its creditable publication, the Iranian Journal of Parasitology, published seasonally since 2006. From 1833, when the scientific studies of Parasitology have started in Iran up to 2013, many researchers have been done on various fields of medical Parasitology and parasitic diseases in Iran and 2517 papers in English and 1890 papers in Persian have been published in national and international scientific journals. In addition, more than 420 books related in the field of medical parasitology field have been published in Persian language.


Long-term care insurance: Does experience matter?
We examine whether long-term care (LTC) experience helps explain the low demand for long-term care insurance (LTCI). We test if expectations about future informal care receipt, expectations about inheritance receipt, and LTCI purchase decisions vary between individuals whose parents or in-laws have used LTC versus those who have not. We find parental use of a nursing home decreases expectations that one's children will provide informal care, consistent with the demonstration effect. Nursing home use by in-laws does not have the same impact, suggesting that individuals are responding to information gained about their own aging trajectory. Nursing home use by either a parent or in-law increases LTCI purchase probability by 0.8 percentage points, with no significant difference in response between parents' and in-laws' use. The estimated increase in purchase probability from experience with LTC is about half the previously estimated increase from tax policy-induced price decreases.


Phosphatidylserine-dependent phagocytosis of apoptotic glioma cells by normal human microglia, astrocytes, and glioma cells.
Apoptotic cells display signals that trigger phagocytic removal by macrophages or neighboring cells. To better understand the signals triggering phagocytosis of apoptotic glioma cells, and to identify the cells that might be involved in the phagocytic process, U-251 MG glioma cells were made apoptotic by etoposide (25 microg/ml) treatment and were incubated with normal human astrocytes (NHA), glioma cells, or microglia. Extent of phagocytosis was assessed by an in vitro phagocytosis assay. After 3 h of incubation with apoptotic cells, phagocytes tested were washed to remove nonengulfed cells, then fixed, stained, and counted to determine phagocytosis index (PI). NHA, glioma cells, and microglia all phagocytosed apoptotic, but not nonapoptotic, glioma cells. Microglia, however, had a PI approximately 4-fold higher than did either NHA or glioma cells. Binding of phosphatidylserine (PS) on apoptotic glioma cell membranes by annexin-V inhibited phagocytosis by 90% in both microglia and NHA. The activity of an enzyme (scramblase) that moves PS from the inner cell membrane to the outer cell membrane was also increased in apoptotic glioma cells. These results suggest that a variety of cells present in and near gliomas in vivo can remove glioma cells in a PS-dependent scramblase-mediated fashion. Manipulation of scramblase and/or PS exposure in glioma cells may therefore be a means of triggering phagocytic removal of glioma cells.


Is the Y chromosome disappearing?--both sides of the argument.
On August 31, 2011 at the 18th International Chromosome Conference in Manchester, Jenny Graves took on Jenn Hughes to debate the demise (or otherwise) of the mammalian Y chromosome. Sex chromosome evolution is an example of convergence; there are numerous examples of XY and ZW systems with varying degrees of differentiation and isolated examples of the Y disappearing in some lineages. It is agreed that the Y was once genetically identical to its partner and that the present-day human sex chromosomes retain only traces of their shared ancestry. The euchromatic portion of the male-specific region of the Y is ~1/6 of the size of the X and has only ~1/12 the number of genes. The big question however is whether this degradation will continue or whether it has reached a point of equilibrium. Jenny Graves argued that the Y chromosome is subject to higher rates of variation and inefficient selection and that Ys (and Ws) degrade inexorably. She argued that there is evidence that the Y in other mammals has undergone lineage-specific degradation and already disappeared in some rodent lineages. She also pointed out that there is practically nothing left of the original human Y and the added part of the human Y is degrading rapidly. Jenn Hughes on the other hand argued that the Y has not disappeared yet and it has been around for hundreds of millions of years. She stated that it has shown that it can outsmart genetic decay in the absence of "normal" recombination and that most of its genes on the human Y exhibit signs of purifying selection. She noted that it has added at least eight different genes, many of which have subsequently expanded in copy number, and that it has not lost any genes since the human and chimpanzee diverged ~6 million years ago. The issue was put to the vote with an exact 50/50 split among the opinion of the audience; an interesting (though perhaps not entirely unexpected) skew however was noted in the sex ratio of those for and against the notion.


Correlation between development of female flower buds and expression of the CS-ACS2 gene in cucumber plants.
Ethylene plays a key role in sex determination of cucumber flowers. Gynoecious cucumber shoots produce more ethylene than monoecious shoots. Because monoecious cucumbers produce both male and female flower buds in the shoot apex and because the relative proportions of male and female flowers vary due to growing conditions, the question arises as to whether the regulation of ethylene biosynthesis in each flower bud determines the sex of the flower. Therefore, the expression of a 1-aminocyclopropane-1-carboxylic acid synthase gene, CS-ACS2, was examined in cucumber flower buds at different stages of development. The results revealed that CS-ACS2 mRNA began to accumulate just beneath the pistil primordia of flower buds at the bisexual stage, but was not detected prior to the formation of the pistil primordia. In buds determined to develop as female flowers, CS-ACS2 mRNA continued to accumulate in the central region of the developing ovary where ovules and placenta form. In gynoecious cucumber plants that produce only female flowers, accumulation of CS-ACS2 mRNA was detected in all flower buds at the bisexual stage and at later developmental stages. In monoecious cucumber, flower buds situated on some nodes accumulated CS-ACS2 mRNA, but others did not. The proportion of male and female flowers in monoecious cucumbers varied depending on the growth conditions, but was correlated with changes in accumulation of CS-ACS2 mRNA in flower buds. These results demonstrate that CS-ACS2-mediated biosynthesis of ethylene in individual flower buds is associated with the differentiation and development of female flowers.


B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma involving bone marrow with an interfollicular pattern.
B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) may involve the bone marrow in nodular, interstitial, diffuse, or mixed patterns. However, B-cell CLL/SLL associated with large reactive germinal centers (the so-called interfollicular pattern) involving the bone marrow is not reported. We describe 2 examples of B-cell CLL/SLL that subtotally replaced the bone marrow with an interfollicular pattern. In both cases, the neoplasms were composed of small round lymphoid cells; proliferation centers also were present. The neoplasms surrounded large reactive germinal centers that were devoid of peripheral mantle zones. The germinal centers were paratrabecular and nonparatrabecular in case 1 and nonparatrabecular in case 2. Flow cytometry immunophenotypic studies done on bone marrow aspiration samples of both cases showed a uniform population of neoplastic cells positive for pan-B-cell antigens and the CD5 and CD23 antigens. Immunohistochemical studies done on bone marrow biopsy sections supported the flow cytometry results and demonstrated that the germinal centers were negative for BCL-2. B-cell CLL/SLL may rarely involve the bone marrow with an interfollicular pattern. Knowledge of this pattern will prevent confusion with follicle center lymphoma and large cell transformation, both of which initially were considered in the differential diagnosis of these cases.


Extracorporeal membrane oxygenation.
Extracorporeal membrane oxygenation (ECMO) is an advanced form of life support technology whereby venous blood is oxygenated outside of the body and returned to the patient. ECMO was initially used as last-resort rescue therapy for patients with severe respiratory failure. Over the last four decades, it has developed into a safe, standard therapy for newborns with progressive cardiorespiratory failure, as a resuscitation therapy after cardiac arrest, and in combination with other treatments such as hypothermia and various blood filtration therapies. ECMO has also become routine for children and adults with all forms of cardiogenic shock and is also routine in early graft failure after transplantation. The one area of ongoing debate is the role of ECMO in adults with hypoxemic respiratory failure. As ECMO equipment becomes safer, earlier use improves patient outcomes. Several modifications of the two basic venovenous and venoarterial ECMO systems are now occurring, as are many minor variations in cannulation strategies and systems of care for patients receiving ECMO. The indications and situations in which ECMO have been tried continue to change, and ECMO for sub-acute and chronic illnesses is now commonplace, as is the use of ECMO in patients with clinical problems previously regarded as contraindications, such as sepsis, malignancy, and immunosuppression.


Gambling exposure in virtual reality and modification of urge to gamble.
The urge to gamble is a psychological, physiological, and emotional state involved in the maintenance of pathological gambling. The ability of repeated exposure to a virtual gambling environment to modify the urge to gamble and perceived self-efficacy (PSE) is investigated. Ten video lottery players move throughout a virtual bar with five video lottery terminals five times. The urge to gamble and PSE do not significantly vary during exposure to the gambling environment. However, the desire to gamble significantly increases when passing from the practice environment to the gambling environment. These findings suggest that virtual reality is viable for use in exposure, but that a sole 20-minute session does not set the extinction process into motion. Future studies should be conducted on virtual exposure over the course of several sessions, with the addition of a cognitive restructuring intervention.


Green Synthesis of Gold and Silver Nanoparticles Using Leaf Extract of Clerodendrum inerme; Characterization, Antimicrobial, and Antioxidant Activities.
Due to their versatile applications, gold (Au) and silver (Ag) nanoparticles (NPs) have been synthesized by many approaches, including green processes using plant extracts for reducing metal ions. In this work, we propose to use plant extract with active biomedical components for NPs synthesis, aiming to obtain NPs inheriting the biomedical functions of the plants. By using leaves extract of Clerodendrum inerme (C. inerme) as both a reducing agent and a capping agent, we have synthesized gold (CI-Au) and silver (CI-Ag) NPs covered with biomedically active functional groups from C. inerme. The synthesized NPs were evaluated for different biological activities such as antibacterial and antimycotic against different pathogenic microbes (B. subtilis, S. aureus, Klebsiella, and E. coli) and (A. niger, T. harzianum, and A. flavus), respectively, using agar well diffusion assays. The antimicrobial propensity of NPs further assessed by reactive oxygen species (ROS) glutathione (GSH) and FTIR analysis. Biofilm inhibition activity was also carried out using colorimetric assays. The antioxidant and cytotoxic potential of CI-Au and CI-Ag NPs was determined using DPPH free radical scavenging and MTT assay, respectively. The CI-Au and CI-Ag NPs were demonstrated to have much better antioxidant in terms of %DPPH scavenging (75.85% ± 0.67% and 78.87% ± 0.19%), respectively. They exhibited excellent antibacterial, antimycotic, biofilm inhibition and cytotoxic performance against pathogenic microbes and MCF-7 cells compared to commercial Au and Ag NPs functionalized with dodecanethiol and PVP, respectively. The biocompatibility test further corroborated that CI-Ag and CI-Au NPs are more biocompatible at the concentration level of 1-50 µM. Hence, this work opens a new environmentally-friendly path for synthesizing nanomaterials inherited with enhanced and/or additional biomedical functionalities inherited from their herbal sources.


Food, Eating, and Happy Aging: The Perceptions of Older Chinese People.
China's government and its people have for a long time focused on food security for its population as one of the most important issues in economic and social development. Many older people in China have lived in times when food security was not stable. Thus, while food has a central position in Chinese culture for all Chinese people, it is of particular pertinence to older people. In this paper we explore the meaning of food and eating in the lives of older Chinese people in China and how it contributes to healthy, thus happy aging. Focus groups and qualitative interviews were used in this study. Participants were recruited from the rural Yongfu Province of Southwest China, and the urban Fangzhuang and Haidan districts in Beijing. Forty-two participants were recruited aged 62-83 years of age. All focus groups and interviews were conducted in Mandarin and audiotaped with the participants' permission. Audio-tapes were transcribed by a Chinese speaking researcher and then were translated into English. Data were analyzed continuously and comparatively, transcripts were coded, and themes and sub-themes were identified. The initial analysis and interpretation were then presented and discussed at a workshop with all the authors. Two major themes emerged-the quantity of food and the quality of food required to have a happy old age. Participants discussed the desire to eat "until you are full" because of their experiences of famine during childhood. However, they also believed that as an older person they should eat less for their health, particularly less high fat foods. The importance of the food quality and food affordability was also discussed. Grain and meat were characterized as "good" foods and important in their diets for a happy old age. The participants, especially those from urban areas, were concerned with food safety. The high cultural importance of food for older Chinese in China was confirmed in this study. Social and economic lifespan experiences continue to impact on the food and eating attitudes and practices of older Chinese. The food related life experiences of older Chinese in China are quite different from younger Chinese and health promotion messaging needs to be informed by these unique perspectives in order to maximize its effectiveness.


BUDDY-system: A web site for constructing a dataset of protein pairs between ligand-bound and unbound states.
Elucidating molecular recognition by proteins, such as in enzyme-substrate and receptor-ligand interactions, is a key to understanding biological phenomena. To delineate these protein interactions, it is important to perform structural bioinformatics studies relevant to molecular recognition. Such studies require a dataset of protein structure pairs between ligand-bound and unbound states. In many studies, the same well-designed and high-quality dataset has been used repeatedly, which has spurred the development of subsequent relevant research. Using previously constructed datasets, researchers are able to fairly compare obtained results with those of other studies; in addition, much effort and time is saved. Therefore, it is important to construct a refined dataset that will appeal to many researchers. However, constructing such datasets is not a trivial task. We have developed the BUDDY-system, a web site designed to support the building of a dataset comprising pairs of protein structures between ligand-bound and unbound states, which are widely used in various areas associated with molecular recognition. In addition to constructing a dataset, the BUDDY-system also allows the user to search for ligand-bound protein structures by its unbound state or by its ligand; and to search for ligands by a particular receptor protein. The BUDDY-system receives input from the user as a single entry or a dataset consisting of a list of ligand-bound state protein structures, unbound state protein structures, or ligands and returns to the user a list of protein structure pairs between the ligand-bound and the corresponding unbound states. This web site is designed for researchers who are involved not only in structural bioinformatics but also in experimental studies. The BUDDY-system is freely available on the web.


Mitigation of antagonistic effects on plant growth due to root co-colonization by dark septate endophytes and ectomycorrhiza.
Dark septate endophytes (DSE) are very common root colonizers of woody plant species. Ascomycetes of the Phialocephala fortinii s.l.-Acephala applanata species complex (PAC) are the main representatives of DSE fungi in forest ecosystems. PAC and mycorrhizal fungi share the same habitat, but interactions among PAC, mycorrhizal fungi and plants are poorly understood. We compared the effects of single and dual inoculation of Norway spruce seedlings with PAC and the ectomycorrhizal (ECM) fungus Hebeloma crustuliniforme on host growth, degree of mycorrhization and density of endophytic PAC biomass. Single colonization by H. crustuliniforme or PAC significantly reduced plant biomass. Dual colonization reduced or neutralized plant growth depression caused by single fungal colonization. The degree of mycorrhization was independent on PAC colonization, and mycorrhization significantly reduced endophytic PAC biomass. Plant biomass of dually colonized plants positively correlated with PAC biomass. These results demonstrate the ability of dual inoculation of PAC and H. crustuliniforme to neutralize plant growth depression caused by single fungal inoculation. Our explanations of enhanced plant growth in dually inoculated plants are the inhibition of PAC during root colonization by the ECM mantle and ECM-mediated access to plant growth-promoting nutrients resulting from the mineralization of the potting medium by PAC.


Identification of an Escherichia coli operon required for formation of the O-antigen capsule.
Escherichia coli produces polysaccharide capsules that, based on their mechanisms of synthesis and assembly, have been classified into four groups. The group 4 capsule (G4C) polysaccharide is frequently identical to that of the cognate lipopolysaccharide O side chain and has, therefore, also been termed the O-antigen capsule. The genes involved in the assembly of the group 1, 2, and 3 capsules have been described, but those required for G4C assembly remained obscure. We found that enteropathogenic E. coli (EPEC) produces G4C, and we identified an operon containing seven genes, ymcD, ymcC, ymcB, ymcA, yccZ, etp, and etk, which are required for formation of the capsule. The encoded proteins appear to constitute a polysaccharide secretion system. The G4C operon is absent from the genomes of enteroaggregative E. coli and uropathogenic E. coli. E. coli K-12 contains the G4C operon but does not express it, because of the presence of IS1 at its promoter region. In contrast, EPEC, enterohemorrhagic E. coli, and Shigella species possess an intact G4C operon.


Current Antivirals and Novel Botanical Molecules Interfering With Herpes Simplex Virus Infection.
Herpes simplex viruses type 1 (HSV-1) and type 2 (HSV-2) are highly prevalent within the human population and are characterized by lifelong infections and sporadic recurrences due to latent neuron infection. Upon reactivations, HSVs may manifest either, symptomatically or asymptomatically and be shed onto others through mucosae body fluids. Although, HSVs can produce severe disease in humans, such as life-threatening encephalitis and blindness, the most common symptoms are skin and mucosal lesions in the oro-facial and the genital areas. Nucleoside analogs with antiviral activity can prevent severe HSV infection, yet they are not very effective for treating skin manifestations produced by these viruses, as they only reduce in a few days at most the duration of lesions. Additionally, HSV variants that are resistant to these antivirals may arise, especially in immunosuppressed individuals. Thus, new antivirals that can reduce the severity and duration of these cutaneous manifestations would certainly be welcome. Here, we review currently available anti-herpetic therapies, novel molecules being assessed in clinical trials and new botanical compounds reported in the last 20 years with antiviral activities against HSVs that might represent future treatments against these viruses.


Fostering the Resilience of People With Dementia: A Narrative Literature Review.
Background: Resilience is a process through which people use resources to adapt to adversity. Interventions aiming to support resilience in people with dementia have been developed. However, the optimal content, structure and impact of these interventions is unclear. This literature review explores the factors through which interventions foster resilience in people with dementia and examines their efficacy. Methods: Eight databases were searched systematically, for literature published from 2000 to 2019. Following the removal of duplicate articles, the titles and abstracts of 6,749 articles were screened. Articles were selected if they: reported empirical studies in English; focused on resilience; involved people with dementia and psychosocial interventions. The full text of 53 articles were examined and three studies, reported in six papers, were included in the final review. Data were systematically extracted, and two authors critiqued the studies using the Critical Appraisal Skills Programme check lists. The studies were examined to determine how resilience was defined and operationalized and their findings were synthesized using the theoretical resilience framework. Results: Five interventions aiming to foster resilience were identified: Dementia Advisors; Peer Support Network Services; Visual Arts Enrichment Activities; Memory Makers; and Early-Stage and Beyond Community Activities. All studies defined resilience as a process and most involved people with mild dementia who had family carers. The interventions impacted resilience by reducing the adversity of stigma and social isolation; increasing personal and social resources, providing stigma-free space and reciprocal support. Interventions empowered people with dementia, increasing their self-esteem and self-worth. Resilience can be fostered both during, and after interventions. However, the efficacy of interventions could not be determined because the research designs utilized did not measure efficacy. Conclusions: Interventions need facilitators to ensure they are strength-based, person-centered and they enable reciprocal social interactions. Future research needs to develop interventions that aim to foster the resilience of people with dementia who lack family carers and/or have more advanced dementia through meaningful activities that are identified by people with dementia as important to their resilience. Robust methodologies, including randomized controlled trials should be used to measure effectiveness and explore the impact of interventions regarding the: interplay between individual and community resources; the importance of reciprocity; and temporal aspects of resilience.


Brief report: isogenic induced pluripotent stem cell lines from an adult with mosaic down syndrome model accelerated neuronal ageing and neurodegeneration.
Trisomy 21 (T21), Down Syndrome (DS) is the most common genetic cause of dementia and intellectual disability. Modeling DS is beginning to yield pharmaceutical therapeutic interventions for amelioration of intellectual disability, which are currently being tested in clinical trials. DS is also a unique genetic system for investigation of pathological and protective mechanisms for accelerated ageing, neurodegeneration, dementia, cancer, and other important common diseases. New drugs could be identified and disease mechanisms better understood by establishment of well-controlled cell model systems. We have developed a first nonintegration-reprogrammed isogenic human induced pluripotent stem cell (iPSC) model of DS by reprogramming the skin fibroblasts from an adult individual with constitutional mosaicism for DS and separately cloning multiple isogenic T21 and euploid (D21) iPSC lines. Our model shows a very low number of reprogramming rearrangements as assessed by a high-resolution whole genome CGH-array hybridization, and it reproduces several cellular pathologies seen in primary human DS cells, as assessed by automated high-content microscopic analysis. Early differentiation shows an imbalance of the lineage-specific stem/progenitor cell compartments: T21 causes slower proliferation of neural and faster expansion of hematopoietic lineage. T21 iPSC-derived neurons show increased production of amyloid peptide-containing material, a decrease in mitochondrial membrane potential, and an increased number and abnormal appearance of mitochondria. Finally, T21-derived neurons show significantly higher number of DNA double-strand breaks than isogenic D21 controls. Our fully isogenic system therefore opens possibilities for modeling mechanisms of developmental, accelerated ageing, and neurodegenerative pathologies caused by T21.


Ovarian cancer cells polarize macrophages toward a tumor-associated phenotype.
Tumor-associated macrophages (TAM) may have tumor-promoting activity, but it is not clear how their phenotype is achieved. In this study, we demonstrate that ovarian cancer cells switch cocultured macrophages to a phenotype similar to that found in ovarian tumors. Tumor cells caused dynamic changes in macrophage cytokine, chemokine, and matrix metalloprotease mRNA, and protein-inducing mediators that are found in human cancer. Macrophage mannose, mannose receptor, and scavenger receptors (SR-As) were also up-regulated by coculture, but not by conditioned medium. To further validate the model, we studied SR-A regulation on TAM in vitro and in vivo. Coculture of murine macrophages from mice deficient in TNF-alpha or its receptors revealed that TNF-alpha was key to SR-A induction via its p75 receptor. SR-A expression was also reduced in TAM from ovarian cancers treated with anti-TNF-alpha Abs or grown in TNF-alpha(-/-) mice. Chemical communication between tumor cells and macrophages may be important in regulating the cancer cytokine microenvironment.


Localization of enkephalin immunoreactivity in diverse tissues and cells of the developing and adult rat.
The distribution of enkephalin, an endogenous opioid, in tissues and cells of the developing and adult rat was determined by immunocytochemistry with antibodies to met- and leu-enkephalin. Met- and leu-enkephalin were found in all developing cells investigated, with staining generally located throughout the cytoplasm; cell nuclei were not immunoreactive. In comparison to developing cells, immunoreactive analogues to met-enkephalin were usually difficult to detect in the adult. Some notable exceptions were reaction products in leukocytes in blood, lung, and cortex of thymus, fibroblasts in the skin, and seminiferous tubules. These results, in concert with earlier reports that opioid receptors are found largely in developing, but not adult, tissues, indicate that endogenous opioids are specifically involved in biological development, particularly cell proliferation and differentiation. Immunoreactivity in adult non-neural cells may be related to their development in some cases, but also could indicate other functions.


Immunocytochemistry of mucosal changes in patients infected with the intestinal nematode Strongyloides stercoralis.
To investigate the immunopathological changes in duodenal tissues induced by strongyloidiasis and to relate these to degrees of clinical severity. Tissues taken from 21 patients showing mild, moderate or severe symptoms of strongyloidiasis, and from non-infected controls, were sectioned and stained immunocytochemically for IgA, secretory component (SC) and HLA-DR. Immunopathology was assessed by changes in numbers, intensity and distribution of stained cells. Parasitised individuals showed villous atrophy and crypt hyperplasia. There was notable infiltration of the lamina propria by IgA positive plasma cells and of the epithelium by intraepithelial lymphocytes. Infection was also associated with increased expression of SC and decreased expression of HLA-DR in epithelial cells. Changes in all parameters correlated with degree of clinical severity. Profound mucosal changes are induced by strongyloidiasis. Some are analogous to those seen in coeliac disease, but others seem quite unusual. It is likely that these changes are functionally related to the immunopathophysiological consequences of infection seen in patients with severe disease.


SEM observations of the neural fold associated with neurulation in the rat.
The topography of the ectoderm was examined by scanning electron microscopy during neurulation in rat embryos at stage 24 (somites 8-11). A zone of altered cell morphology was observed along the crest of neural folds. This zone was located between the presumptive neural tube and the surface ectoderm and exhibited numerous rounded cell blebs, immediately prior to fusion between the folds. It is suggested that the observed surface alterations may reflect a change in the properties of the altered cell which correlate with initial adhesion between the folds.


Rapid mineralization of the phenylurea herbicide diuron by Variovorax sp. strain SRS16 in pure culture and within a two-member consortium.
The phenylurea herbicide diuron [N-(3,4-dichlorophenyl)-N,N-dimethylurea] is widely used in a broad range of herbicide formulations, and consequently, it is frequently detected as a major water contaminant in areas where there is extensive use. We constructed a linuron [N-(3,4-dichlorophenyl)-N-methoxy-N-methylurea]- and diuron-mineralizing two-member consortium by combining the cooperative degradation capacities of the diuron-degrading organism Arthrobacter globiformis strain D47 and the linuron-mineralizing organism Variovorax sp. strain SRS16. Neither of the strains mineralized diuron alone in a mineral medium, but combined, the two strains mineralized 31 to 62% of the added [ring-U-(14)C]diuron to (14)CO(2), depending on the initial diuron concentration and the cultivation conditions. The constructed consortium was used to initiate the degradation and mineralization of diuron in soil without natural attenuation potential. This approach led to the unexpected finding that Variovorax sp. strain SRS16 was able to mineralize diuron in a pure culture when it was supplemented with appropriate growth substrates, making this strain the first known bacterium capable of mineralizing diuron and representatives of both the N,N-dimethyl- and N-methoxy-N-methyl-substituted phenylurea herbicides. The ability of the coculture to mineralize microgram-per-liter levels of diuron was compared to the ability of strain SRS16 alone, which revealed the greater extent of mineralization by the two-member consortium (31 to 33% of the added [ring-U-(14)C]diuron was mineralized to (14)CO(2) when 15.5 to 38.9 mug liter(-1) diuron was used). These results suggest that the consortium consisting of strains SRS16 and D47 could be a promising candidate for remediation of soil and water contaminated with diuron and linuron and their shared metabolite 3,4-dichloroaniline.


Trends in the utilization and outcomes of Medicare patients hospitalized for hip fracture, 2000-2008.
This study examines temporal trends in hip fracture related utilization and outcomes among elderly fee-for-service Medicare beneficiaries. The study uses claims data for a 5% sample of Medicare beneficiaries with an incident hip fracture hospitalization between 2000 and 2008. We present annual mean patient characteristics, health services utilization, and outcomes and use ordinary least squares regressions to examine adjusted trends in utilization and outcomes after controlling for changes in patient characteristics. We observe a statistically significant temporal decline in inpatient acute days and a statistically significant increase in inpatient post-acute days following hip fractures. In models that control for patient characteristics, we observe statistically significant declines in 1-year hip fracture readmission and mortality rates. Rates of nursing home residence 1-year following fracture were unchanged and remain high. Hip fractures remain highly debilitating events and pose significant challenges for the financing of public health insurance programs.


Gaitography on lower-limb amputees: Repeatability and between-methods agreement.
Gaitography is gait parametrization from center-of-pressure trajectories of walking on an instrumented treadmill. Gaitograms may be useful for prosthetic gait analyses, as they can be rapidly and unobtrusively collected over multiple gait cycles without constraining foot placement. However, its reliability must still be established for prosthetic gait. To evaluate (a) within-method test-retest repeatability and (b) between-methods agreement for temporal gait events (foot contact, foot off) and gait characteristics (e.g. step times, single-support duration). Cohort study with repeated measurements. Ten male proficient prosthetic walkers with a unilateral trans-femoral or trans-tibial amputation were equipped with a pressure-insole system and were invited to walk on separate days on an instrumented treadmill. We found better between-methods reproducibility than within-method repeatability in temporal gait characteristics. Step times, stride times, and foot-contact events matched well between the two methods. In contrast, insole-based foot-off events were detected one-to-two samples earlier. Likewise, a similar bias was observed for temporal gait characteristics that incorporated foot-off events. Notwithstanding small systematic biases, the good between-methods agreement indicates that temporal gait characteristics may be determined interchangeably with gaitograms and insoles in persons with a prosthesis. However, the relatively poorer test-retest repeatability hinders longitudinal assessments with either method. Clinical practice could potentially benefit from gaitography as an efficient, unobtrusive, easy to use, automatized, and patient-friendly means to objectively parametrize prosthetic gait, with immediate availability of test results allowing for prompt clinical decision-making. Temporal gait parameters demonstrate good between-methods agreement, but poorer within-method repeatability hinders detecting prosthetic gait changes.


Multifocal intraocular lens providing optimized through-focus performance.
A widespread type of multifocal intraocular lens (MIOL) is based on expanding the depth of focus with specific amounts of spherical aberration. However, knowing the optimal wavefront aberration for multifocality does not directly provide a MIOL geometry. To overcome this issue, we present a new strategy to design MIOLs. The method optimizes directly the IOL surface geometries (aspheres with aspherical coefficients up to tenth order) using a multisurface pseudophakic eye model and a multiconfiguration approach, where the merit function jointly considers the optical quality at different object plane locations. An example of MIOL [22 diopters (D) far distance correction] was designed. For this design, the ocular modulator transfer function (MTF) at 50 cycles per millimeter remained above 0.47 for all object locations. The design provides high optical quality performance for far and intermediate distances and peak optical performance at near distances (MTF>0.57). Additionally, the design shows good performance against pupil changes (3-5 mm pupil diameter range). Finally, when the MIOL was tested on pseudophakic eye models with corneal spherical aberrations within a typical population range, the high multifocal performance was maintained in almost 40% of potential patients (ignoring asymmetric aberrations effects).


Detection of HIV-1 CXCR4 tropism and resistance in treatment experienced subjects receiving CCR5 antagonist-Vicriviroc.
Vicriviroc (VCV), a small-molecule antagonist of the C-C chemokine receptor 5 (CCR5), blocks HIV's entry into CD4+ cells. Small studies have suggested that resistance to CCR5 antagonists is slow to develop. To examine resistance to VCV in isolates from treatment experienced patients who experienced virologic failure in two phase 3 trials. Genotypic and phenotypic susceptibility to VCV, and other antiretroviral drugs were evaluated at baseline and at defined intervals during the study. In a post hoc analysis, viral tropism at baseline was evaluated using the Trofile-ES assay. Only subjects with R5-tropic virus were included in the analysis. Viral envelope sequencing was performed on samples from subjects with emergent VCV resistance defined using a relative MPI cutoff. 71/486 subjects treated with VCV for 48 weeks met the protocol-defined virologic failure criteria. 7/71 (10%) had DM/X4 virus at the time of virologic failure; VCV resistance was identified in 4/486 treated subjects (1%). No control subject had detectable DM/X4 virus or VCV resistance at virologic failure. Clonal analysis of envelope sequences from VCV-resistant virus identified 2-5 amino acid substitutions at or near the crown of the V3 loop; however, no signature V3 mutations were identified. Changes outside the V3 loop were also observed in resistant clones; no consistent variant pattern was observed. In these trials, use of a sensitive tropism assay and potent antiretroviral drug combinations contributed to the infrequent detection of X4-tropic virus and VCV resistance. Substitutions in the V3 loop were associated with VCV resistance, however, no specific pattern of amino acid changes were sufficient to reliably predict VCV susceptibility.


Evidence-based consensus on the insertion of central venous access devices: definition of minimal requirements for training.
There is a lack of standard minimal requirements for the training of insertion techniques and maintenance of central venous access devices (CVADs). An international evidence-based consensus task force was established through the World Congress of Vascular Access (WoCoVA) to provide definitions and recommendations for training and insertion of CVADs. Medical literature published from February 1971 to April 2012 regarding 'central vascular access', 'training', 'competency', 'simulation', and 'ultrasound' was reviewed on Pubmed, BioMed Central, ScienceDirect, and Scopus databases. The GRADE and the GRADE-RAND methods were utilized to develop recommendations. Out of 156 papers initially identified, 83 papers described training for central vascular access placement. Sixteen recommendations are proposed by this task force, each with an evidence level, degree of consensus, and recommendation grade. These recommendations suggest central venous access education include didactic or web-based teaching with insertion procedure, infection prevention, complications, care, and maintenance of devices, along with laboratory models and tools for simulation practice incorporating ultrasound. Clinical competence should be determined by observation during clinical practice using a global rating scale rather than by the number of procedures performed. Ensuring safe insertion and management of central venous devices requires standardized education, simulation practice, and supervised insertions.


miR-31 Modulates Liver Cancer HepG2 Cell Apoptosis and Invasion via ROCK1/F-Actin Pathways.
Liver cancer is one of the most common malignant tumor in the world. miR-31 is downregulated in liver cancer and associated with tumor growth and metastasis. However, the underlying mechanism remains unclear. Cellular apoptosis was detected via MTT, TUNEL assay, LDH release and Annexin V/PI flow-cytometry analysis. Cellular migration and invasion were measured by the Transwell chamber assay. Mitochondrial functions were evaluated via mitochondrial membrane potential JC-1 staining and mPTP opening assessment. The mitophagy activity was examined via Western blots. In the present study, our results confirm that miR-31 promotes apoptosis and inhibits proliferation and metastasis in liver cancer HepG2 cells. In vitro, miR-31 promotes HepG2 cell apoptosis through the mitochondrial pathway as indicated by mitochondrial potential reduction, increased mPTP opening time, cty-c release and imbalance of pro- and anti-apoptotic proteins. Furthermore, miR-31 reduces the energy generation by inhibiting mitochondrial respiratory function. At last, it is demonstrated that miR-31 triggers the mitochondrial damage via ROCK1/F-actin pathway. Inhibiting the ROCK1/F-actin pathway abolishes the effects of miR-31 mimic on mitochondrial injury, apoptosis, proliferation arrest and migration inhibition. Our results reveal that miR-31 can inhibit HepG2 cell survival and metastasis by activating the ROCK1/F-actin pathway.


Preparation and properties of plasma electrolytic oxidation coating on sandblasted pure titanium by a combination treatment.
Plasma electrolytic oxidation (PEO) is one of the most applicable methods to produce bioceramic coating on a dental implant and sandblasting is a primary technique to modify metal surface properties. This study aims to deposit bioceramic Ca- and P-containing coatings on sandblasted commercially pure titanium by PEO technique to improve its bioactive performance. The time-dependent modified surfaces are characterized in terms of their microstructure, phase, chemical composition, mechanical properties and bioactivities. The results show that the combination-treated coating exhibits better properties than the PEO-treated one, especially in bioactivities, as evidenced by the HA formation after immersion in simulated body fluid (SBF) for 5 days and the cell viability after seeding for 1 or 3 days. The enhancement of the modified surface is attributed to a combination of the mechanical sandblasting and the microplasma oxidation.


Predictive models of pregnancy based on data from a preconception cohort study.
Can we derive adequate models to predict the probability of conception among couples actively trying to conceive? Leveraging data collected from female participants in a North American preconception cohort study, we developed models to predict pregnancy with performance of ∼70% in the area under the receiver operating characteristic curve (AUC). Earlier work has focused primarily on identifying individual risk factors for infertility. Several predictive models have been developed in subfertile populations, with relatively low discrimination (AUC: 59-64%). Study participants were female, aged 21-45 years, residents of the USA or Canada, not using fertility treatment, and actively trying to conceive at enrollment (2013-2019). Participants completed a baseline questionnaire at enrollment and follow-up questionnaires every 2 months for up to 12 months or until conception. We used data from 4133 participants with no more than one menstrual cycle of pregnancy attempt at study entry. On the baseline questionnaire, participants reported data on sociodemographic factors, lifestyle and behavioral factors, diet quality, medical history and selected male partner characteristics. A total of 163 predictors were considered in this study. We implemented regularized logistic regression, support vector machines, neural networks and gradient boosted decision trees to derive models predicting the probability of pregnancy: (i) within fewer than 12 menstrual cycles of pregnancy attempt time (Model I), and (ii) within 6 menstrual cycles of pregnancy attempt time (Model II). Cox models were used to predict the probability of pregnancy within each menstrual cycle for up to 12 cycles of follow-up (Model III). We assessed model performance using the AUC and the weighted-F1 score for Models I and II, and the concordance index for Model III. Model I and II AUCs were 70% and 66%, respectively, in parsimonious models, and the concordance index for Model III was 63%. The predictors that were positively associated with pregnancy in all models were: having previously breastfed an infant and using multivitamins or folic acid supplements. The predictors that were inversely associated with pregnancy in all models were: female age, female BMI and history of infertility. Among nulligravid women with no history of infertility, the most important predictors were: female age, female BMI, male BMI, use of a fertility app, attempt time at study entry and perceived stress. Reliance on self-reported predictor data could have introduced misclassification, which would likely be non-differential with respect to the pregnancy outcome given the prospective design. In addition, we cannot be certain that all relevant predictor variables were considered. Finally, though we validated the models using split-sample replication techniques, we did not conduct an external validation study. Given a wide range of predictor data, machine learning algorithms can be leveraged to analyze epidemiologic data and predict the probability of conception with discrimination that exceeds earlier work. The research was partially supported by the U.S. National Science Foundation (under grants DMS-1664644, CNS-1645681 and IIS-1914792) and the National Institutes for Health (under grants R01 GM135930 and UL54 TR004130). In the last 3 years, L.A.W. has received in-kind donations for primary data collection in PRESTO from FertilityFriend.com, Kindara.com, Sandstone Diagnostics and Swiss Precision Diagnostics. L.A.W. also serves as a fibroid consultant to AbbVie, Inc. The other authors declare no competing interests. N/A.


Gentian violet for pyoderma gangrenosum: a retrospective chart review.
Pyoderma gangrenosum is a rare autoinflammatory skin disease. Treatment is multifactorial, addressing inflammation, pain, underlying disease, if present, and the wound. Gentian violet has been used for hundreds of years in a variety of dermatologic conditions for its anti-inflammatory properties. This study aims to evaluate gentian violet in wound healing for pyoderma gangrenosum. We conducted a retrospective chart review of patients with pyoderma gangrenosum treated with gentian violet at the Wake Forest School of Medicine Department of Dermatology in the last 10 years. The primary outcome was clinical improvement. Of the 34 cases that met inclusion criteria, 70% improved with gentian violet, 24% had no documented change, 3% initially improved then worsened, and 3% had unclear results. Gentian violet is a safe and cheap treatment that may improve resolution of pyoderma gangrenosum lesions in addition to systemic therapy.


Inverse relation between Braak stage and cerebrovascular pathology in Alzheimer predominant dementia.
The most common neuropathological substrates of dementia are Alzheimer's disease, cerebrovascular disease, and dementia with Lewy bodies. A preliminary, retrospective postmortem analysis was performed of the relative burden of each pathology in 25 patients with predominantly Alzheimer's disease-type dementia. Log linear modelling was used to assess the relations between ApoE genotype, Alzheimer's disease, and cerebrovascular disease pathology scores. Sixteen of 18 cases (89%) with a Braak neuritic pathology score </=4 had, in addition, significant cerebrovascular disease, or dementia with Lewy bodies, or both. There was a significant inverse relation between cerebrovascular disease and Braak stage (p=0.015). The frequency of the ApoE-epsilon4 allele was 36.4%. No evidence was found for an association between possession of the ApoE-epsilon4 allele and any one pathological variable over another. In this series most brains from patients with dementia for which Alzheimer's disease is the predominant neuropathological substrate also harboured significant cerebrovascular disease or dementia with Lewy bodies. The data suggest that these diseases are perhaps pathogenetically distinct, yet conspire to produce the dementing phenotype.


Immigration and Status Exchange in Australia and the United States.
This paper evaluates the status exchange hypothesis for Australia and the United States, two Anglophone nations with long immigration traditions whose admission regimes place different emphases on skills. Using log-linear methods, we demonstrate that foreign-born spouses trade educational credentials via marriage with natives in both Australian and U.S. marriage markets and, moreover, that nativity is a more salient marriage barrier for men than for women. With some exceptions, immigrant spouses in mixed nativity couples are better educated than native spouses in same nativity couples, but status exchange is more prevalent among the less-educated spouses in both countries. Support for the status exchange hypothesis is somewhat weaker in Australia partly because of lower average levels of education compared with the United States and partly because of less sharply defined educational hierarchy at the postsecondary level.


Regulation of glomerular atrial natriuretic factor receptor subtypes by renal sympathetic nerves.
The modulation of glomerular atrial natriuretic factor (ANF) receptors (ANF-R1 and ANF-R2) was examined in rats after unilateral (Uni-DNx), bilateral (Bil-DNx), and sham renal denervation (Sham-DNx). Glomerular ANF receptor density was higher in both left and right kidneys (1,138 +/- 73 and 952 +/- 100 fmol/mg protein, respectively) of Bil-DNx rats than in Sham-DNx animals (302 +/- 9 and 328 +/- 13 fmol/mg protein, respectively). The denervated (left) kidney from Uni-DNx rats also showed higher ANF receptor density (1,146 +/- 68 fmol/mg protein) than the contralateral untouched kidney (602 +/- 34 fmol/mg protein). Plasma ANF-(99-126) and ANF-(1-98) levels were significantly lower in the Bil-DNx group than in either Uni-DNx or Sham-DNx animals. Affinity cross-linking studies followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography demonstrated that both ANF-R1 and ANF-R2 receptors were upregulated in the same proportion in denervated kidneys. Guanosine 3',5'-cyclic monophosphate production by isolated glomeruli from denervated kidneys of either Bil-DNx or Uni-DNx rats was significantly higher than that of Sham-DNx controls. We conclude that renal sympathetic nerves regulate both glomerular ANF-R1 and ANF-R2-receptor subtypes.


Are gerontological nurses apathetic about apathy in older adults.
Despite its serious health consequences, apathy in older adults is often underrecognized by gerontological nurses and other health care professionals. Within this article, we discuss what apathy is and present a review of the literature and research. Two frameworks emerging from the literature search-one regarding rehabilitation and the other illness-are introduced as ways in which apathy may be conceptualized and addressed. Using these frameworks, implications for gerontological nurses are outlined.


Epidemiologic approaches to the identification of problems in diabetes care.
We conducted two epidemiologic studies in Washington state to identify remediable problems in health care for persons with diabetes. In one study, mortality among persons with diabetes under the age of 45 was found to be 8 times higher than that in nondiabetic individuals of the same age. One-third of the deaths may have been preventable; problems in access to care may have contributed to premature mortality for some of these cases. The second investigation found that in counties with high hospital admission rates for diabetes, medical care may have been suboptimal. In these counties there was greater likelihood of hospitalization for mild metabolic problems, and less vigorous diagnostic and therapeutic management of hospitalized patients with similar case urgency. Population-based epidemiologic studies can identify health care problems and help focus interventions to improve diabetes care.


Inhibition by a peri-fluorine atom of 1,2-dihydrodiol formation as a basis for the lower tumorigenicity of 12-fluoro-5-methylchrysene than of 5-methylchrysene.
12-Fluoro-5-methylchrysene, which has a fluorine atom at a peri position, is less carcinogenic toward mouse skin than is 5-methylchrysene. To determine the basis for this observation, we identified metabolites of 12-fluoro-5-methylchrysene formed by rat liver in vitro, and used these as standards to study the metabolism of [3H]-12-fluoro-5-methylchrysene in mouse liver in vitro and in mouse epidermis in vivo. Metabolites were identified by their ultraviolet, mass, and nuclear magnetic resonance spectra, by comparison to synthetic standards, and by chemical transformations. Dihydrodiols, phenols, and hydroxymethyl derivatives of 12-fluoro-5-methylchrysene were characterized. The extents of formation of 1,2-dihydro-1,2-dihydroxy-12-fluoro-5-methylchrysene and 7,8-dihydro-7,8-dihydroxy-12-fluoro-5-methylchrysene in mouse liver in vitro were strongly influenced by pretreatment with 3-methylcholanthrene, but the ratio of 1,2-dihydrodiol to 7,8-dihydrodiol was lower than in the metabolism of 5-methylchrysene carried out under identical conditions. The major metabolites of [3H]-12-fluoro-5-methylchrysene formed in mouse epidermis, 0.33 to 4 hr after topical application, were 7,8-dihydro-7,8-dihydroxy-12-fluoro-5-methylchrysene and 7-hydroxy-12-fluoro-5-methylchrysene. The ratio of 7,8-dihydro-7,8-dihydroxy-12-fluoro-5-methylchrysene to 1,2-dihydro-1,2-dihydroxy-12-fluoro-5-methylchrysene in mouse epidermis, 2 hr after application of [3H]-12-fluoro-5-methylchrysene, was 68:1, compared to 1:1 for the corresponding dihydrodiols of 5-methylchrysene. These results show that fluorine substitution at the 12-peri position of 5-methylchrysene inhibits formation of the 1,2-dihydrodiol in the adjacent ring. Since the 1,2-dihydrodiol is a major proximate carcinogen of 5-methylchrysene, the results provide an explanation for the relatively low carcinogenicity of 12-fluoro-5-methylchrysene.


Reconstructing the phylogeny of new world monkeys (platyrrhini): evidence from multiple non-coding loci.
Among mammalian phylogenies, those characterized by rapid radiations are particularly problematic. The New World monkeys (NWMs, Platyrrhini) comprise 3 families and 7 subfamilies, which radiated within a relatively short time period. Accordingly, their phylogenetic relationships are still largely disputed. In the present study, 56 nuclear non-coding loci, including 33 introns (INs) and 23 intergenic regions (IGs), from 20 NWM individuals representing 18 species were used to investigate phylogenetic relationships among families and subfamilies. Of the 56 loci, 43 have not been used in previous NWM phylogenetics. We applied concatenation and coalescence tree-inference methods, and a recently proposed question-specific approach to address NWM phylogeny. Our results indicate incongruence between concatenation and coalescence methods for the IN and IG datasets. However, a consensus was reached with a single tree topology from all analyses of combined INs and IGs as well as all analyses of question-specific loci using both concatenation and coalescence methods, albeit with varying degrees of statistical support. In detail, our results indicated the sister-group relationships between the families Atelidae and Pitheciidae, and between the subfamilies Aotinae and Callithrichinae among Cebidae. Our study provides insights into the disputed phylogenetic relationships among NWM families and subfamilies from the perspective of multiple non-coding loci and various tree-inference approaches. However, the present phylogenetic framework needs further evaluation by adding more independent sequence data and a deeper taxonomic sampling. Overall, our work has important implications for phylogenetic studies dealing with rapid radiations.


Cell surface accumulation of overexpressed hamster lysosomal membrane glycoproteins.
We cloned and sequenced cDNAs encoding two lysosomal membrane glycoproteins, lgp-A and lgp-B, from Chinese hamster ovary cells. The deduced amino acid sequences of these proteins are similar to those of the other known members of this conserved family (also known as "LAMP" proteins). We used the cDNAs to generate stable lines of hamster lgp-expressing mouse NIH-3T3 cells, rat NRK cells, and monkey CV-1 cells. We also generated hybridomas that secrete antibodies specific for hamster lgp-A and lgp-B, enabling us to distinguish foreign from endogenous lgps in a wider variety of transfected cell lines. One line of mouse NIH-3T3 cells that expresses hamster lgp-B was studied in detail. Whereas most of the hamster lgp-B appeared to be transported to lysosomes in these cells, butyrate-induced overexpression resulted in the accumulation of a significant proportion of the total on the plasma membrane. In addition, overexpression of this foreign lgp-B also resulted in the appearance of the endogenous mouse lgp-A and lgp-B on the plasma membrane. Characterization of this accumulation suggested that it resulted from competition for one or more limited components in the transport pathway(s) to lysosomes. Endocytosis from the plasma membrane appeared to be one step that was saturable.


Evaluating the role of alcohol consumption in breast and ovarian cancer susceptibility using population-based cohort studies and two-sample Mendelian randomization analyses.
Alcohol consumption is correlated positively with risk for breast cancer in observational studies, but observational studies are subject to reverse causation and confounding. The association with epithelial ovarian cancer (EOC) is unclear. We performed both observational Cox regression and two-sample Mendelian randomization (MR) analyses using data from various European cohort studies (observational) and publicly available cancer consortia (MR). These estimates were compared to World Cancer Research Fund (WCRF) findings. In our observational analyses, the multivariable-adjusted hazard ratios (HR) for a one standard drink/day increase was 1.06 (95% confidence interval [CI]; 1.04, 1.08) for breast cancer and 1.00 (0.92, 1.08) for EOC, both of which were consistent with previous WCRF findings. MR ORs per genetically predicted one standard drink/day increase estimated via 34 SNPs using MR-PRESSO were 1.00 (0.93, 1.08) for breast cancer and 0.95 (0.85, 1.06) for EOC. Stratification by EOC subtype or estrogen receptor status in breast cancers made no meaningful difference to the results. For breast cancer, the CIs for the genetically derived estimates include the point-estimate from observational studies so are not inconsistent with a small increase in risk. Our data provide additional evidence that alcohol intake is unlikely to have anything other than a very small effect on risk of EOC.


The dentist as a member of the palliative care team.
Palliative care is the knowledgeable and compassionate care of the dying patient. Although based on an holistic multidisciplinary philosophy, it does not usually include dentistry in its team approach. Many terminally ill patients have oral problems resulting from anti-cancer therapy and/or poor oral care during lengthy illnesses that require therapeutic intervention. By incorporating dentistry into the palliative care team, the dental needs of the dying patient will be managed more effectively.


Recognition of noisy subsequences using constrained edit distances.
Let X* be any unknown word from a finite dictionary H. Let U be any arbitrary subsequence of X*. We consider the problem of estimating X* by processing Y, which is a noisy version of U. We do this by defining the constrained edit distance between XH and Y subject to any arbitrary edit constraint involving the number and type of edit operations to be performed. An algorithm to compute this constrained edit distance has been presented. Although in general the algorithm has a cubic time complexity, within the framework of our solution the algorithm possesses a quadratic time complexity. Recognition using the constrained edit distance as a criterion demonstrates remarkable accuracy. Experimental results which involve strings of lengths between 40 and 80 and which contain an average of 26.547 errors per string demonstrate that the scheme has about 99.5 percent accuracy.


A comprehensive update of the sequence and structure classification of kinases.
A comprehensive update of the classification of all available kinases was carried out. This survey presents a complete global picture of this large functional class of proteins and confirms the soundness of our initial kinase classification scheme. The new survey found the total number of kinase sequences in the protein database has increased more than three-fold (from 17,310 to 59,402), and the number of determined kinase structures increased two-fold (from 359 to 702) in the past three years. However, the framework of the original two-tier classification scheme (in families and fold groups) remains sufficient to describe all available kinases. Overall, the kinase sequences were classified into 25 families of homologous proteins, wherein 22 families (approximately 98.8% of all sequences) for which three-dimensional structures are known fall into 10 fold groups. These fold groups not only include some of the most widely spread proteins folds, such as the Rossmann-like fold, ferredoxin-like fold, TIM-barrel fold, and antiparallel beta-barrel fold, but also all major classes (all alpha, all beta, alpha+beta, alpha/beta) of protein structures. Fold predictions are made for remaining kinase families without a close homolog with solved structure. We also highlight two novel kinase structural folds, riboflavin kinase and dihydroxyacetone kinase, which have recently been characterized. Two protein families previously annotated as kinases are removed from the classification based on new experimental data. Structural annotations of all kinase families are now revealed, including fold descriptions for all globular kinases, making this the first large functional class of proteins with a comprehensive structural annotation. Potential uses for this classification include deduction of protein function, structural fold, or enzymatic mechanism of poorly studied or newly discovered kinases based on proteins in the same family.


A symptom-related monitoring program following pulmonary embolism for the early detection of CTEPH: a prospective observational registry study.
Chronic thromboembolic pulmonary hypertension (CTEPH) is a long-term complication following an acute pulmonary embolism (PE). It is frequently diagnosed at advanced stages which is concerning as delayed treatment has important implications for favourable clinical outcome. Performing a follow-up examination of patients diagnosed with acute PE regardless of persisting symptoms and using all available technical procedures would be both cost-intensive and possibly ineffective. Focusing diagnostic procedures therefore on only symptomatic patients may be a practical approach for detecting relevant CTEPH.This study aimed to evaluate if a follow-up program for patients with acute PE based on telephone monitoring of symptoms and further examination of only symptomatic patients could detect CTEPH. In addition, we investigated the role of cardiopulmonary exercise testing (CPET) as a diagnostic tool. In a prospective cohort study all consecutive patients with newly diagnosed PE (n=170, 76 males, 94 females within 26 months) were recruited according to the inclusion and exclusion criteria. Patients were contacted via telephone and asked to answer standardized questions relating to symptoms. At the time of the final analysis 130 patients had been contacted. Symptomatic patients underwent a structured evaluation with echocardiography, CPET and complete work-up for CTEPH. 37.7%, 25.5% and 29.3% of the patients reported symptoms after three, six, and twelve months respectively. Subsequent clinical evaluation of these symptomatic patients saw 20.4%, 11.5% and 18.8% of patients at the respective three, six and twelve months time points having an echocardiography suggesting pulmonary hypertension (PH). CTEPH with pathological imaging and a mean pulmonary artery pressure (mPAP) ≥ 25 mm Hg at rest was confirmed in eight subjects. Three subjects with mismatch perfusion defects showed an exercise induced increase of PAP without increasing pulmonary artery occlusion pressure (PAOP). Two subjects with pulmonary hypertension at rest and one with an exercise induced increase of mPAP with normal PAOP showed perfusion defects without echocardiographic signs of PH but a suspicious CPET. A follow-up program based on telephone monitoring of symptoms and further structured evaluation of symptomatic subjects can detect patients with CTEPH. CPET may serve as a complementary diagnostic tool.


Isolation of plant-growth-promoting Bacillus strains from soybean root nodules.
Endophytic bacteria reside within plant tissues and have often been found to promote plant growth. Fourteen strains of putative endophytic bacteria, not including endosymbiotic Bradyrhizobium strains, were isolated from surface-sterilized soybean (Glycine max. (L.) Merr.) root nodules. These isolates were designated as non-Bradyrhizobium endophytic bacteria (NEB). Three isolates (NEB4, NEB5, and NEB17) were found to increase soybean weight when plants were co-inoculated with one of the isolates and Bradyrhizobium japonicum under nitrogen-free conditions, compared with plants inoculated with B. japonicum alone. In the absence of B. japonicum, these isolates neither nodulated soybean, nor did they affect soybean growth. All three isolates were Gram-positive spore-forming rods. While Biolog tests indicated that the three isolates belonged to the genus Bacillus, it was not possible to determine the species. Phylogenetic analysis of 16S rRNA gene hypervariant region sequences demonstrated that both NEB4 and NEB5 are Bacillus subtilis strains, and that NEB17 is a Bacillus thuringiensis strain.


Choroidal effusions after glaucoma surgery.
A diverse range of surgical approaches are now used for glaucoma management. This review compares the reported rates of serous choroidal effusion and suprachoroidal hemorrhage after various glaucoma surgical procedures. As these complications can be visually devastating, we summarize the current literature on prevention strategies and management. Trabeculectomy remains one of the most effective and widely used glaucoma surgeries, but it is also associated with a significant rate of complications, including serous choroidal effusion and suprachoroidal hemorrhage. Alternative surgical techniques for glaucoma management are increasingly utilized due in part to their lower rate of associated complications. Prevention measures for serous choroidal effusion and suprachoroidal hemorrhage include the recognition of patient risk factors and careful selection of glaucoma surgical technique. Management options include observation, medications, office-based procedures, and surgical interventions directed at maximizing patient outcomes. Familiarity with reported rates of postoperative choroidal effusions, patient risk factors, and management strategies will aid in reducing the frequency of these complications and in improving patient care.


Predicting promoter activities of primary human DNA sequences.
We developed a computer program that can predict the intrinsic promoter activities of primary human DNA sequences. We observed promoter activity using a quantitative luciferase assay and generated a prediction model using multiple linear regression. Our program achieved a prediction accuracy correlation coefficient of 0.87 between the predicted and observed promoter activities. We evaluated the prediction accuracy of the program using massive sequencing analysis of transcriptional start sites in vivo. We found that it is still difficult to predict transcript levels in a strictly quantitative manner in vivo; however, it was possible to select active promoters in a given cell from the other silent promoters. Using this program, we analyzed the transcriptional landscape of the entire human genome. We demonstrate that many human genomic regions have potential promoter activity, and the expression of some previously uncharacterized putatively non-protein-coding transcripts can be explained by our prediction model. Furthermore, we found that nucleosomes occasionally formed open chromatin structures with RNA polymerase II recruitment where the program predicted significant promoter activities, although no transcripts were observed.


Associations of knee angles, moments and function among subjects that are healthy and anterior cruciate ligament deficient (ACLD) during straight ahead and crossover cutting activities.
The objective of this study was to compare knee angles and moments of healthy subjects (n=20) and subjects that were anterior cruciate ligament deficient (ACLD) (n=16) during stepping and crossover cutting activities. Subjects that were ACLD were separated into high (n=7) and low (n=9) functioning groups based on knee functional ratings. Knee angles and moments were estimated using three dimensional motion tracking and force plate data. The results suggest that knee angle and moment data were associated with level of functioning of ACLD subjects. Primarily knee frontal and transverse plane moments distinguished the stepping and crossover cut activities. Only some of the findings for the ACLD group were attributed to increasing knee stability.


Dammarane-type triterpene glycosides from Oncoba manii active against methicillin-resistant Staphylococcus aureus.
Drug-resistant bacteria are becoming more prevalent both in the community and in hospitals. In a search for new antibiotic leads, we used a high-throughput natural products chemistry approach to isolate one new (1) and two known (2, 3) dammarane-type triterpenes with mass-limited material from the African plant Oncoba manii. The new compound was determined by spectroscopic methods to be 1beta,2alpha,3beta,20(R)-tetrahydroxydammar-24-ene 3-O-alpha-L-rhamnopyranosyl-(1 --> 2)-beta-D-glucopyranoside. Compounds 1 and 2 inhibited the growth of methicillin-resistant Staphylococcus aureus (MRSA).


Risk Stratification for Cardiotoxicity in Breast Cancer Patients: Predicting Early Decline of LVEF After Treatment.
This study introduces AI-based models in prediction and risk assessment of early cardiac dysfunction in older breast cancer patients, as a side-effect of their cancer treatment. Using only features extracted during the baseline evaluation of each patient the proposed methodology could predict a decline in LVEF values in 4 different follow-up intervals during the first year after treatment initiation (i.e. months 3-12), with a mean accuracy of 66.67% and up to 73.55%. Selected baseline predictive factors were ranked according to their prevalence in the evaluation experiments, replicating the importance of various cardiac disorders at baseline, LVEF value and a higher age, which are all previously reported, while introducing Diabetes as an important risk factor.Clinical Relevance- Healthcare providers can better assess cardiovascular health status and risk of cardiotoxicity in the cancer treatment continuum. This will enable timely intervention and close monitoring on high risk patients while saving resources for low risk patients.


Methodological issues in short-term motor memory research.
Four methodological issues identified and studied by short-term motor memory researchers were examined in this paper: (a) the distributions of three commonly used measures of error (AE, CE, and VE); (b) statistical analysis of these scores as dependent measures in an experiment; (c) within-cell and experiment-wise estimates of the reliability of CE; and (d) the power of the statistical test with CE as the dependent measure. The first two sub-problems were explored theoretically, while the latter two were subjected to empirical examination using four data sets from previously published experiments. The distributions of AE and VE scores were described as non-normal under certain conditions, while the CE score distribution was shown to be normal. Therefore analyses of these three dependent measures may require different statistical procedures. In light of this information, the assumptions affecting estimates of reliability and power in an experimental framework were examined. Based on an analysis of the four data sets, a strategy was proposed in which a relatively small number of subjects could be utilized in an experiment without sacrificing desired experimental controls.


[Pulse wave velocity as an early marker of diastolic heart failure in patients with hypertension].
According to the WHO, hypertension is one of the major causes of death worldwide. It leads to a number of severe complications. Diastolic heart failure, that is heart failure with preserved ejection fraction (HFPEF), is especially common. New, but simple, indices for the early detection of patients who have not yet developed complications or are in their early developmental stages are still searched for. The aim of this study is to examine the correlation between pulse wave velocity (PWV) and markers of diastolic heart failure (DHF) assessed in echocardiography in patients with hypertension and no symptoms of heart failure. The study was comprised of 65 patients with treated hypertension. Patients with symptoms of heart failure, those with diabetes and smokers were excluded. Arterial stiffness was measured with the Mobil-O-Graph NG PWA. Pulse wave velocity (PWV) was estimated. The following markers of diastolic heart failure were assessed in the echocardiographic examination: E/A ratio - the ratio of the early (E) to late (A) ventricular filling velocities, DT - decceleration time, E/E' - the ratio of mitral peak velocity of early filling (E) to early diastolic mitral annular velocity E' in tissue Doppler echocardiography. PWV was statistically significantly higher in the DHF group. In the group of patients with heart failure, the average E/A ratio was significantly lower as compared to the group with no heart failure. Oscillometric measurement of pulse wave velocity is non-invasive, lasts a few minutes and does not require the presence of a specialist. It allows for an early detection of patients at risk of diastolic heart failure even within the conditions of primary health care.


A systematic review concerning early orthodontic treatment of unilateral posterior crossbite.
The aim of this study was to assess the orthodontic treatment effects on unilateral posterior crossbite in the primary and early mixed dentition by systematically reviewing the literature. A literature search was performed by applying the Medline database (Entrez PubMed) and covering the period from January 1966 to October 2002. The inclusion criteria were primary and early mixed dentition with unilateral posterior crossbite, randomized controlled trials (RCT), prospective and retrospective studies with concurrent untreated as well as normal controls, and clinical trials comparing at least two treatment strategies without any untreated or normal group involved. Two reviewers extracted the data independently and also assessed the quality of the studies. The search strategy resulted in 1001 articles, and 12 met the inclusion criteria. Two RCTs of early treatment of crossbite have been performed, and these two studies support grinding as treatment in the primary dentition. There is no scientific evidence available to show which of the treatment modalities, grinding, Quad-helix, expansion plates, or rapid maxillary expansion, is the most effective. Most of the studies have serious problems of lack of power because of small sample size, bias and confounding variables, lack of method error analysis, blinding in measurements, and deficient or lack of statistical methods. To obtain reliable scientific evidence, better-controlled RCTs with sufficient sample sizes are needed to determine which treatment is the most effective for early correction of unilateral posterior crossbite. Future studies should also include assessments of long-term stability as well as analysis of costs and side effects of the interventions.


Hsp90 inhibitor geldanamycin increases hsp70 mRNA stabilisation but fails to activate HSF1 in cells exposed to hydrostatic pressure.
High hydrostatic pressure (HP) increases Hsp70 protein and mRNA levels by increasing the mRNA half-life without activation of HSF1 transcription factor. We investigated whether this change in gene expression requires Hsp90, previously shown to regulate hsp70 genes via HSF1. In HeLa cells, both HP and Hsp90 inhibitor geldanamycin (GA) up-regulated Hsp70 expression through mRNA stabilisation. GA, unlike HP, increased HSF1 activation. However, when exposures were used together a marked Hsp70 response was observed with mRNA stabilisation without coincidence of HSF1 activation. Our data suggests that Hsp90 is involved in hsp70 mRNA stabilisation and the HSF1 activation can be suppressed by high HP.


Quantification of nanoparticle pesticide adsorption: computational approaches based on experimental data.
Quantitative analysis of the interactions between nanomaterials and environmental contamINANts, such as pesticides, in natural water systems and food residuals is crucial for the application of nanomaterials-based tools for the detection of the presence of toxic substances, monitoring pollution levels and environmental remediation. Previously, the Biological Surface Adsorption Index (BSAI) has demonstrated promising capabilities of interaction characterization and prediction based on experimental data from small organic molecules. In this article, the first attempt of the application of such quantitative measures toward environmental endpoints by analyzing the interactions of a selected group of nanomaterials with a variety of pesticides was made. Statistical modeling was conducted on the experimental obtained adsorption data based on polynomial BSAI models, as well as models with the incorporation of artificial neural network methodologies. Finally, clustering analyzes were performed for the categorization of nanomaterials based on surface physicochemical properties using both polynomial indices and physical adsorption modeling parameters. These quantitative computational approaches support the application of BSAI modeling in the area of environmental contamINANt detection and remediation.


Subtype specific estrogen receptor action protects against changes in MMP-2 activation in mouse retinal pigmented epithelial cells.
Eyes with age-related macular degeneration (AMD) demonstrate accumulation of specific deposits and extracellular matrix (ECM) molecules under the retinal pigment epithelium (RPE). AMD is about two times more prevalent in aging postmenopausal women. Therefore we studied whether 17beta-estradiol (E(2)) modulates the expression and activity of the trimolecular complex (MMP-2, TIMP-2 and MMP-14), molecules which are of major importance for ECM turnover in RPE. We used cell lines isolated from estrogen receptor knockout mice (ERKO) to determine which ER (estrogen receptor) subtype was important for ECM regulation in RPE cells. We found that mouse RPE sheets had higher baseline MMP-2 activity in the presence of ERbeta. This correlated with higher MMP-2 activity in RPE cell lines isolated from ERKOalpha mice. Exposure to E(2) increased MMP-2 activity in mouse RPE cell lines. In addition E(2) increased transcriptional activation of the MMP-2 promoter through a functional Sp1 site which required the presence of ERbeta, but not ERalpha. E(2) also maintained levels of pro MMP-2, and MMP-14 and TIMP-2 activity after oxidant injury. Since the direct effects of E(2) on MMP-2 transcriptional activation and the regulation of the trimolecular complex after oxidant-induced injury requires ERbeta, this receptor subtype may have a role as a potential therapeutic target to prevent changes in activation of MMP-2.


Autoantigens signal through chemokine receptors: uveitis antigens induce CXCR3- and CXCR5-expressing lymphocytes and immature dendritic cells to migrate.
We tested the hypothesis that interaction between autoantigens and chemoattractant receptors may be an important step in the development of autoimmunity. The retinal autoantigens S-antigen (S-Ag) and interphotoreceptor retinoid binding protein (IRBP) can induce autoimmune uveitis in rodent models. We evaluated the chemotactic activity of S-Ag and IRBP and found that both induced migration of human and mouse immature dendritic cells (iDCs) and lymphocytes, but not neutrophils, monocytes, or mature DCs. Cross-desensitization studies and single-receptor transfected cells revealed that subfamily of alpha chemokine receptors CXCR5 and CXCR3 mediated the chemotactic effect of IRBP, while only CXCR3 was required for the chemotactic response to S-Ag. Examination of the relationships between chemoattraction and the ability to elicit pathology at the protein or peptide levels in the mouse uveitis model revealed dissociation of the capacity to induce uveitis, lymphocyte proliferation, and chemoattraction. These studies suggest that IRBP and S-Ag can initiate innate and, in sensitive individuals, adaptive immune response by attracting iDCs and T and B cells expressing CXCR3 and CXCR5.


Downregulation of NEDD4L by EGFR signaling promotes the development of lung adenocarcinoma.
Cumulative evidence indicates that the abnormal regulation of the NEDD4 family of E3-ubiquitin ligases participates in the tumorigenesis and development of cancer. However, their role in lung adenocarcinoma (LUAD) remains unclear. This study comprehensively analyzed the NEDD4 family in LUAD data sets from public databases and found only NEDD4L was associated with the overall survival of LUAD patients. Gene set enrichment analysis (GSEA) indicated that NEDD4L might be involved in the regulation of mTORC1 pathway. Both cytological and clinical assays showed that NEDD4L inhibited the activity of the mTOR signaling pathway. In vivo and in vitro experiments showed that NEDD4L could significantly inhibit the proliferation of LUAD cells. In addition, this study also found that the expression of NEDD4L was regulated by EGFR signaling. These findings firstly revealed that NEDD4L mediates an interplay between EGFR and mTOR pathways in LUAD, and suggest that NEDD4L held great potential as a novel biomarker and therapeutic target for LUAD.


Cellular polyploidy in organ homeostasis and regeneration.
Polyploid cells, which contain more than one set of chromosome pairs, are very common in nature. Polyploidy can provide cells with several potential benefits over their diploid counterparts, including an increase in cell size, contributing to organ growth and tissue homeostasis, and improving cellular robustness via increased tolerance to genomic stress and apoptotic signals. Here, we focus on why polyploidy in the cell occurs and which stress responses and molecular signals trigger cells to become polyploid. Moreover, we discuss its crucial roles in cell growth and tissue regeneration in the heart, liver, and other tissues.


Management of acute stroke in the elderly: follow-up of a controlled trial.
Follow-up of a controlled trial of the management of acute stroke in the elderly showed that the improvement in functional outcome at the time of discharge from hospital that had been achieved through establishing a stroke unit had disappeared by one year. Factors that might have contributed to this included overprotection by the families of patients who had been treated in the stroke unit, who were not permitted to carry out activities of daily living in which they were independent, and the early discharge from medical units of patients whose full rehabilitation potential had not been realised. Prolonging the benefits of short-term gains in functional outcome through the intervention of a stroke unit requires that all the links in the chain of stroke rehabilitation are maintained, including the proper orientation of patients' families before discharge from hospital.


MiR-16 regulates crosstalk in NF-κB tolerogenic inflammatory signaling between myeloma cells and bone marrow macrophages.
High levels of circulating miR-16 in the serum of multiple myeloma (MM) patients are independently associated with longer survival. Although the tumor suppressor function of intracellular miR-16 in MM plasma cells (PCs) has been elucidated, its extracellular role in maintaining a nonsupportive cancer microenvironment has not been fully explored. Here, we show that miR-16 is abundantly released by MM cells through extracellular vesicles (EVs) and that differences in its intracellular expression as associated with chromosome 13 deletion (Del13) are correlated to extracellular miR-16 levels. We also demonstrate that EVs isolated from MM patients and from the conditioned media of MM-PCs carrying Del13 more strongly differentiate circulating monocytes to M2-tumor supportive macrophages (TAMs), compared with MM-PCs without this chromosomal aberration. Mechanistically, our data show that miR-16 directly targets the IKKα/β complex of the NF-κB canonical pathway, which is critical not only in supporting MM cell growth, but also in polarizing macrophages toward an M2 phenotype. By using a miR-15a-16-1-KO mouse model, we found that loss of the miR-16 cluster supports polarization to M2 macrophages. Finally, we demonstrate the therapeutic benefit of miR-16 overexpression in potentiating the anti-MM activity by a proteasome inhibitor in the presence of MM-resident bone marrow TAM.


Association Between Serum Tumor Necrosis Factor Receptor 1 and Trajectories of Functional Status: The Northern Manhattan Study.
We hypothesized that tumor necrosis factor receptor 1 (TNFR1) levels are associated with long-term trajectories of functional status independently of vascular risk factors and the occurrence of stroke and myocardial infarction (MI) during follow-up. In the Northern Manhattan Study, stroke-free persons aged ≥40 years in northern Manhattan (New York, New York) had annual assessments with the Barthel index (BI) for a median of 13 years (1993-2015). Assessment of baseline demographic factors, risk factors, and laboratory studies included measurement of TNFR1 (n = 1,863). Generalized estimating equations models were used to estimate standardized associations between TNFR1 and 1) baseline functional status and 2) change in function over time, adjusting for demographic factors, vascular risk factors, social variables, cognition, and depression, as well as stroke and MI occurrence during follow-up. The mean age of participants was 70 (standard deviation (SD), 10) years; 66% were women, and 55% were Hispanic. The mean TNFR1 level was 2.57 mg/L. TNFR1 was associated with baseline BI (-0.93 BI points per SD increment in TNFR1; 95% confidence interval: -1.59, -0.26) and change over time (-0.36 BI points per year per SD increment in TNFR1; 95% confidence interval: -0.69, -0.03). In this large population-based study, higher TNFR1 levels were associated with greater baseline disability and disability over time, even with adjustment for baseline covariates and stroke and MI occurrence during follow-up.


CD36 inhibition prevents lipid accumulation and contractile dysfunction in rat cardiomyocytes.
An increased cardiac fatty acid supply and increased sarcolemmal presence of the long-chain fatty acid transporter CD36 are associated with and contribute to impaired cardiac insulin sensitivity and function. In the present study we aimed at preventing the development of insulin resistance and contractile dysfunction in cardiomyocytes by blocking CD36-mediated palmitate uptake. Insulin resistance and contractile dysfunction were induced in primary cardiomyocytes by 48 h incubation in media containing either 100 nM insulin (high insulin; HI) or 200 μM palmitate (high palmitate; HP). Under both culture conditions, insulin-stimulated glucose uptake and Akt phosphorylation were abrogated or markedly reduced. Furthermore, cardiomyocytes cultured in each medium displayed elevated sarcolemmal CD36 content, increased basal palmitate uptake, lipid accumulation and decreased sarcomere shortening. Immunochemical CD36 inhibition enhanced basal glucose uptake and prevented elevated basal palmitate uptake, triacylglycerol accumulation and contractile dysfunction in cardiomyocytes cultured in either medium. Additionally, CD36 inhibition prevented loss of insulin signalling in cells cultured in HP, but not in HI medium. In conclusion, CD36 inhibition prevents lipid accumulation and lipid-induced contractile dysfunction in cardiomyocytes, but probably independently of effects on insulin signalling. Nonetheless, pharmacological CD36 inhibition may be considered as a treatment strategy to counteract impaired functioning of the lipid-loaded heart.


Cycle Threshold Values Predict COVID-19 Severity and Mortality but Are not Correlated with Laboratory Markers.
Many studies have evaluated the possible utility of cycle threshold (Ct) values as a predictor of Coronavirus disease 2019 (COVID-19) severity and patient outcome. Given the inconsistent results, we aimed to evaluate the association between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Ct values and disease severity, inflammatory markers, and outcomes in Iranian patients with COVID-19. A retrospective study of 528 patients with COVID-19 hospitalized from September 2020 to October 2021 was conducted. Demographic, clinical, and laboratory data of patients were retrieved from electronic medical records. Ct values were analyzed as a continuous variable after subcategorizing into 3 groups: low (Ct values<20), medium (Ct values 20 to 30), and high (Ct values>30). Of the 528 patients (45.1% female) aged 13 to 97 years, 109 patients had low Ct values, 312 patients had medium, and 107 patients had high Ct values. Patients with low Ct values were more likely to present with critical COVID-19, require invasive mechanical ventilation and develop complications such as acute respiratory distress syndrome and pneumonia. Furthermore, patients with low or medium Ct values were more likely to die compared to patients with high Ct values. Multivariate analysis showed that patients with low or medium Ct values were more likely to have severe COVID-19 compared with patients with high Ct values. The multivariate analysis also showed a higher risk of mortality in patients with low Ct values compared to patients with high Ct values, although this was not statistically significant. Our findings revealed that Ct values were an independent predictor of COVID-19 severity. The risk of mortality was higher in patients with low Ct values. However, further investigation is needed to address the correlation between Ct values and inflammatory factors.