Phosphorylation-dependent inhibition by synapsin I of organelle movement in squid axoplasm.
Synapsin I, a neuron-specific, synaptic vesicle-associated phosphoprotein, is thought to play an important role in synaptic vesicle function. Recent microinjection studies have shown that synapsin I inhibits neurotransmitter release at the squid giant synapse and that the inhibitory effect is abolished by phosphorylation of the synapsin I molecule (Llinas et al., 1985). We have considered the possibility that synapsin I might modulate release by regulating the ability of synaptic vesicles to move to, or fuse with, the plasma membrane. Since it is not yet possible to examine these mechanisms in the intact nerve terminal, we have used video-enhanced microscopy to study synaptic vesicle mobility in axoplasm extruded from the squid giant axon. We report here that the dephosphorylated form of synapsin I inhibits organelle movement along microtubules within the interior of extruded axoplasm and that phosphorylation of synapsin I on sites 2 and 3 by calcium/calmodulin-dependent protein kinase II removes this inhibitory effect. Phosphorylation of synapsin I on site 1 by the catalytic subunit of cAMP-dependent protein kinase only partially reduces the inhibitory effect. In contrast to the inhibition of movement along microtubules seen within the interior of the axoplasm, movement along isolated microtubules protruding from the edges of the axoplasm is unaffected by dephospho-synapsin I, despite the fact that the synapsin I concentration is higher there. Thus, synapsin I does not appear to inhibit the fast axonal transport mechanism itself. Rather, these results are consistent with the possibility that dephospho-synapsin I acts by a crosslinking mechanism involving some component(s) of the cytoskeleton, such as F-actin, to create a dense network that restricts organelle movement. The relevance of the present observations to regulation of neurotransmitter release is discussed.


The Ambiguity Imperative: "Success" in a Maternal Health Program in Uganda.
Global health programs are compelled to demonstrate impact on their target populations. We study an example of social franchising - a popular healthcare delivery model in low/middle-income countries - in the Ugandan private maternal health sector. The discrepancies between the program's official profile and its actual operation reveal the franchise responded to its beneficiaries, but in a way incoherent with typical evidence production on social franchises, which privileges simple narratives blurring the details of program enactment. Building on concepts of not-knowing and the production of success, we consider the implications of an imperative to maintain ambiguity in global health programming and academia.


Anti-estrogenic and anti-aromatase activities of citrus peels major compounds in breast cancer.
Estrogen signaling is crucial for breast cancer initiation and progression. Endocrine-based therapies comprising estrogen receptor (ER) modulators and aromatase inhibitors remain the mainstay of treatment. This study aimed at investigating the antitumor potential of the most potent compounds in citrus peels on breast cancer by exploring their anti-estrogenic and anti-aromatase activities. The ethanolic extract of different varieties of citrus peels along with eight isolated flavonoids were screened against estrogen-dependent breast cancer cell lines besides normal cells for evaluating their safety profile. Naringenin, naringin and quercetin demonstrated the lowest IC50s and were therefore selected for further assays. In silico molecular modeling against ER and aromatase was performed for the three compounds. In vivo estrogenic and anti-estrogenic assays confirmed an anti-estrogenic activity for the isolates. Moreover, naringenin, naringin and quercetin demonstrated in vitro inhibitory potential against aromatase enzyme along with anticancer potential in vivo, as evidenced by decreased tumor volumes. Reduction in aromatase levels in solid tumors was also observed in treated groups. Overall, this study suggests an antitumor potential for naringenin, naringin and quercetin isolated from citrus peels in breast cancer via possible modulation of estrogen signaling and aromatase inhibition suggesting their use in pre- and post-menopausal breast cancer patients, respectively.


CAR T-cells: hot news in cancer therapy.
Cancer immunotherapy has become a standard therapeutic option in oncology over the past few decades. From the early anti-tumor vaccine experiments in the late nineteenth and early twentieth centuries, its journey led through the discovery of the allogeneic hematopoietic stem cell transplantation principles in the nineteen-seventies, introduction of monoclonal antibodies in the nineteen-nineties, their enhancing in the form of immunoconjugates and bispecific antibody constructs, up to todays checkpoint inhibitors and chimeric antigen receptor T-cells (CAR T-cells). Not so long ago, a treatment with genetically modified lymphocytes may have seemed quite like science fiction, but nowadays, these "living drugs" are already being administered to patients with hematological malignancies in the Czech Republic. Some may see CAR T-cells as a breakthrough treatment method and bright future of oncology, others perhaps just as an overhyped sensation, in which the cost far exceeds the efficacy. Either way, CAR T-cells will soon become a relatively routine treatment option for patients with resistant lymphoproliferative diseases. Our article aims to introduce this new interesting method to specialists outside the fields of hematology and oncology.


Detection of human immunodeficiency virus antibody among homosexual men from Bombay.
In India, heterosexual transmission of HIV-infection is considered to be the major mode of transmission. However, no report is available on transmission of HIV-infection among homosexually active men. The prevalence of human immunodeficiency virus-1 (HIV-1) and human immunodeficiency virus-2 (HIV-2) infections among homosexual men from Bombay is discussed. To determine the extent of presence of anti-HIV-1, anti-HIV-2 antibodies, or both anti-HIV-1 and anti-HIV-2 antibodies among homosexual men in India. Sixty-three blood samples were collected from two STD clinics of Bombay over a 6-month period from men with a history of homosexual behavior who were asymptomatic for HIV-infection. The mean age of the subjects was 31.6 years. For serological detection anti-HIV-1 antibody ELISA was used as the primary screening test followed by Western blot to confirm the results. For distinction between anti-HIV-1 and anti-HIV-2 antibody, line immunoassay was used. The sexually transmitted diseases (STDs) were diagnosed clinically, although Venereal Disease Research Laboratory (VDRL) tests were carried out as a routine test for screening STDs. For detection of gonorrhea, Gram stains of urethral smear were done routinely. From the 63 blood samples tested, 10 samples were reactive by ELISA for HIV-1 infection, and three samples were borderline reactive. These three samples were found to be reactive for anti-HIV-2 by the line immunoassay. The above 10 samples were also positive by Western blot for anti-HIV-1 antibody. Two blood samples were positive for both anti-HIV-1 and anti-HIV-2 antibodies. Using clinical diagnosis as the criteria, the different types of STD among the 63 subjects were as follows: condylomata (22), herpes (20), gonorrhea (15), candidiasis (3), and syphilis (3). However with VDRL, seven subjects were found to be reactive. Gram stains indicated gonorrhea in all the 15 subjects. This study reports for the first time the homosexual transmission of both HIV-1 and HIV-2 infections in India, although heterosexual transmission still is the major mode of transmission of the infection. The associated incidence of STDs among these men and that a few of these subjects were bisexual make them at high risk for transmission of HIV infection.


Ultrastructure of the Feeding Apparatus of Rhabdodemania minima Chitwood, 1936 (Enoplida: Rhabdodemaniidae).
The feeding apparatus of the marine nematode Rhabdodemania minima Chitwood, 1936 has been examined with light and transmission electron microscopy. The buccal capsule consists of a posterior region with smooth walls bearing three sets of three minute denticles at its posterior end and three large onchia in its mid region; a middle region with grooved walls; and an anterior region with costae and six odontia. The anterior and middle portions of the buccal capsule are enveloped by the cephalic cuticle, whereas the posterior region, which is set off from the middle region by a buccal seam, is partially enveloped by the anterior end of the esophagus. Two subventral esophageal glands open into the lumen of the esophagus. Secretions of each of three paraesophageal glands are conveyed through a duct in each of the three corresponding corners of the buccal wall to an opening between labia. A pair of wing-like thickenings, termed pterons, embraces the duct of each paraesophageal gland in the posterior and middle regions of the buccal capsule. A model of how the buccal capsule operates is proposed and tested. Morphological and functional aspects of the buccal apparatus and cephalic cuticle are compared with those of other taxa of the Enoplida, and their phylogenetic implications are discussed.


Production and interferon-gamma-mediated regulation of complement component C2 and factors B and D by the astroglioma cell line U105-MG.
In this paper, we demonstrate the synthesis of the complement component C2 and factors B and D by the human astroglioma cell line U105-MG. All three components were structurally and antigenically similar to their serum counterparts, as determined by biosynthetic labelling studies or Western blot analysis. Northern blot analysis demonstrated that the mRNAs of all three components had the same apparent sizes as the equivalent mRNAs from hepatocyte and monocyte cell lines. Interestingly, U105-MG cells produce two C2 transcripts with sizes of approximately 2.8 and 2.3 kb. Interferon-gamma (IFN-gamma) enhanced the expression of C2 and factor B mRNA and protein in a dose- and time-dependent fashion, while factor D expression was refractory to IFN-gamma. IFN-gamma appeared to predominantly enhance the expression of the large (2.8 kb) C2 transcript. Kinetic studies demonstrated peak C2 and factor B expression in 48 h in response to IFN-gamma, similar to the acute-phase response of factor B in serum. These data are the first to demonstrate the synthesis of C2 and factor D by astroglioma cells. Combined with previous reports documenting the synthesis of C3 by astrocytes, our data suggest that endogenous synthesis of complement proteins, and particularly of alternative pathway activation components (C3, factors B and D), may play an important role in host defence in the central nervous system.


The pH independence of mammalian retrovirus infection.
The pH dependence of early steps in the infection of human and other cells by mammalian retroviruses and retroviral pseudotype particles of vesicular stomatitis virus (VSV) was investigated for 10 strains of retrovirus, including C-type and D-type oncoviruses and human lentiviruses. When cells were treated with weak bases (NH4Cl and amantadine) to raise the pH of endocytic vesicles, only ecotropic murine leukaemia virus (MLV-E) and VSV showed pH-dependent entry. Pretreatment of retrovirus stocks in media below pH 5.0 did not reduce their titres but inactivated VSV to less than 10(-8) of the initial titre. VSV (MLV-E) pseudotype infection in five out of six mouse and rat cell lines was inhibited by NH4Cl, indicating that infection proceeds via receptor-mediated endocytosis. In contrast, NH4Cl treatment has no effect on the infection of XC cells in which MLV-E induces syncytia. It is postulated that the pH-independent entry and cell fusion of XC cells by MLV-E may result from the activity of a cell surface proteinase that cleaves viral gp70 at neutral pH.


The common ABCA3E292V variant disrupts AT2 cell quality control and increases susceptibility to lung injury and aberrant remodeling.
ATP-binding cassette class A3 (ABCA3) is a lipid transporter that plays a critical role in pulmonary surfactant function. The substitution of valine for glutamic acid at codon 292 (E292V) produces a hypomorphic variant that accounts for a significant portion of ABCA3 mutations associated with lung disorders spanning from neonatal respiratory distress syndrome and childhood interstitial lung disease to diffuse parenchymal lung disease (DPLD) in adults including pulmonary fibrosis. The mechanisms by which this and similar ABCA3 mutations disrupt alveolar type 2 (AT2) cell homeostasis and cause DPLD are largely unclear. The present study, informed by a patient homozygous for the E292V variant, used an in vitro and a preclinical murine model to evaluate the mechanisms by which E292V expression promotes aberrant lung injury and parenchymal remodeling. Cell lines stably expressing enhanced green fluorescent protein (EGFP)-tagged ABCA3 isoforms show a functional deficiency of the ABCA3E292V variant as a lipid transporter. AT2 cells isolated from mice constitutively homozygous for ABCA3E292V demonstrate the presence of small electron-dense lamellar bodies, time-dependent alterations in macroautophagy, and induction of apoptosis. These changes in AT2 cell homeostasis are accompanied by a spontaneous lung phenotype consisting of both age-dependent inflammation and fibrillary collagen deposition in alveolar septa. Older ABCA3E292V mice exhibit increased vulnerability to exogenous lung injury by bleomycin. Collectively, these findings support the hypothesis that the ABCA3E292V variant is a susceptibility factor for lung injury through effects on surfactant deficiency and impaired AT2 cell autophagy.


The Prevalence of Musculoskeletal Pain and Forward Head Posture among Heroin Users during their Withdrawal with Methadone.
Heroin is an extremely addictive narcotic drug derived from morphine. Its continued use requires increased amounts of the drug to achieve the same effect, resulting in tolerance and addiction. This study was done in order to determine the prevalence of musculoskeletal pain and forward head posture among heroin users during their withdrawal. This research was a cross-sectional study that was done on 90 heroin users (83 males, 7 females) aged between 20 to 40 years (32.5 ± 3.81) during their withdrawal in Shiraz, Iran. They were selected by simple randomized sampling. Data were collected by a form regarding age, sex, the duration of heroin use, and musculoskeletal pain. Pain was measured by VAS (visual analog scale) and forward head posture was evaluated by plumb line. Pearson correlation technique and chi-square were used for analyzing the data. The results revealed that the majority of heroin users suffered from musculoskeletal pain during their withdrawal. At the end of withdrawal 53.4% had severe pain, 38.8% had moderate pain, and 7.8% of them had mild pain. Pain in the lower extremities and low back was more common than the upper extremities. The intensity of pain before withdrawal was mild, during withdrawal was moderate, and at the end was sever, but there was no significant correlation between them. The results also showed 43.3% of subjects had normal posture and 56.7% had forward posture. According to the results, the intensity of pain increased during the withdrawal period; therefore, more attention must be paid to this complication in heroin users for better evaluation and a successful withdrawal.


Alternative splicing of a single transcription factor drives selfish reproductive behavior in honeybee workers (Apis mellifera).
In eusocial insects the production of daughters is generally restricted to mated queens, and unmated workers are functionally sterile. The evolution of this worker sterility has been plausibly explained by kin selection theory [Hamilton W (1964) J Theor Biol 7:1-52], and many traits have evolved to prevent conflict over reproduction among the females in an insect colony. In honeybees (Apis mellifera), worker reproduction is regulated by the queen, brood pheromones, and worker policing. However, workers of the Cape honeybee, Apis mellifera capensis, can evade this control and establish themselves as social parasites by activating their ovaries, parthenogenetically producing diploid female offspring (thelytoky) and producing queen-like amounts of queen pheromones. All these traits have been shown to be strongly influenced by a single locus on chromosome 13 [Lattorff HMG, et al. (2007) Biol Lett 3:292-295]. We screened this region for candidate genes and found that alternative splicing of a gene homologous to the gemini transcription factor of Drosophila controls worker sterility. Knocking out the critical exon in a series of RNAi experiments resulted in rapid worker ovary activation-one of the traits characteristic of the social parasites. This genetic switch may be controlled by a short intronic splice enhancer motif of nine nucleotides attached to the alternative splice site. The lack of this motif in parasitic Cape honeybee clones suggests that the removal of nine nucleotides from the altruistic worker genome may be sufficient to turn a honeybee from an altruistic worker into a parasite.


Managing the risk of lithium-induced nephropathy in the long-term treatment of patients with recurrent affective disorders.
Lithium has been the most effective psychopharmacological drug in the long-term treatment of patients with recurrent unipolar and bipolar affective illness. As a result of its widespread and longtime use in patients with recurrent affective disorders, psychiatrists have become increasingly aware of the whole spectrum of lithium's potential side effects. One of the side effects associated with its chronic use is lithium-induced nephropathy. In a recent cross-sectional study published in BMC Medicine, Alberto Bocchetta et al. add further information to this topic, demonstrating that duration of lithium treatment is associated with impaired glomerular function in patients with recurrent or chronic affective disorders. The present paper will discuss the implications of this and other related recent research on our management of patients with recurrent affective disorders. In this context the importance of shared decision making and close monitoring of kidney function is highlighted, including the regular assessment of the glomerular filtration rate, to provide best possible care to our patients maintained on lithium treatment.See related research article here http://www.biomedcentral.com/1741-7015/11/33.


Tissue-specific and inducer-specific differential induction of ISG56 and ISG54 in mice.
The interferon-stimulated genes (ISGs) ISG56 and ISG54 are strongly induced in cultured cells by type I interferons (IFNs), viruses, and double-stranded RNA (dsRNA), which activate their transcription by various signaling pathways. Here we studied the stimulus-dependent induction of both genes in vivo. dsRNA, which is generated during virus infection, induced the expression of both genes in all organs examined. Induction was not seen in STAT1-deficient mice, indicating that dsRNA-induced gene expression requires endogenous IFN. We further examined the regulation of these ISGs in several organs from mice injected with dsRNA or IFN-beta. Both ISG56 and ISG54 were widely expressed and at comparable levels. However, in organs isolated from mice injected with IFN-alpha the expression of ISG54 was reduced and more restricted in distribution compared with the expression level and distribution of ISG56. When we began to study specific cell types, splenic B cells showed ISG54 but not ISG56 expression in response to all agonists. Finally, in livers isolated from mice infected with vesicular stomatitis virus, the expression of ISG56, but not ISG54, was induced; this difference was observed at both protein and mRNA levels. These studies have revealed unexpected complexity in IFN-stimulated gene induction in vivo. For the first time we showed that the two closely related genes are expressed in a tissue-specific and inducer-specific manner. Furthermore, our findings provide the first evidence of a differential pattern of expression of ISG54 and ISG56 genes by IFN-alpha and IFN-beta.


Effect of prior statin therapy on capillary permeability in the lungs after cardiac or vascular surgery.
Cholesterol-lowering statins can ameliorate severe forms of vascular hyperpermeability in experimental studies, and may thereby ameliorate acute lung injury and sepsis. It is unknown whether this also applies to humans. This study aimed to define whether or not prior statin therapy reduces mild post-operative increases in pulmonary capillary protein permeability associated with acute lung injury after cardiac or major vascular surgery. A prospective observational study was performed in an intensive care unit of a university hospital on 64 patients, 37 after elective cardiac and 27 after major vascular surgery, of whom 68 and 44%, respectively, had received prior statin therapy. A mobile probe system was used to measure the pulmonary leak index (PLI), i.e. the transvascular transport rate of gallium-67-radiolabelled transferrin. For all of the patients together, the mean PLI did not differ between the statin and control groups (22.9 versus 24.4 x 10(-3) min(-1)). The prevalence of an elevated PLI was 57% in the statin and 59% in the control group. Subgroup analysis did not reveal significant differences caused by statins in the PLI of these patients. Prior statin therapy neither has an adverse effect on mildly increased pulmonary capillary permeability in patients after cardiac or major vascular surgery nor does it ameliorate this increased capillary permeability.


What is the role of falls?
There is now firm evidence to support interventions in the prevention of falls in older people, and emerging data support prevention of falls as a method of fracture prevention. This chapter discusses the epidemiology of falls, risk factors associated with an increased risk of falling, assessment of the older faller, and evidence-based approaches to the prevention of falls in the older person. Several randomized controlled trials have found that hip protectors, if worn, probably prevent hip fractures, but that poor compliance is a major issue limiting the effectiveness of this form of intervention. More data are needed to support the role of prevention of falls in preventing fractures, as well as comparative cost-effectiveness data with other evidence-based approaches to preventing fractures in an older population.


Why don't patients enroll in hospice? Can we do anything about it?
United States hospice organizations aim to provide quality, patient-centered end-of-life care to patients in the last 6 months of life, yet some of these organizations observe that some hospice-eligible patients who are referred to hospice do not initially enroll. To identify reasons that eligible patients do not enroll in hospice (phase 1). To identify strategies used by hospice providers to address these reasons (phase 2). Semi-structured interviews analyzed using content analysis. In phase 1, we interviewed 30 patients and/or family members of patients who had a hospice admissions visit, but who did not enroll. In phase 2, we interviewed 19 hospice staff and national experts. In phase 1, we asked participants to describe the patient's illness, the hospice referral, and why they had not enrolled. We performed a content analysis to characterize their reasons for not enrolling in hospice. In phase 2, we enrolled hospice admissions staff and hospice experts. We asked them to describe how they would respond to each reason (from phase 1) during an admissions visit with a potential new hospice patient. We identified key phrases, and summarized their recommendations. Reasons that patients hadn't enrolled fell into three broad categories: patient/family perceptions (e.g., "not ready"), hospice specific issues (e.g., variable definitions of hospice-eligible patients), and systems issues (e.g., concerns about continuity of care). Hospice staff/experts had encountered each reason, and offered strategies at the individual and organizational level for responding. In hopes of increasing hospice enrollment among hospice-eligible patients, non-hospice and hospice clinicians may want to adopt some of the strategies used by hospice staff/experts for talking about hospice with patients/families and may want to familiarize themselves with the differences between hospice organizations in their area. Hospices may want to reconsider their admission policies and procedures in light of patients' and families' perceptions and concerns.


Investigation of the effect of intracolonic melatonin gel formulation on acetic acid-induced colitis.
The aims of the present study were to develop a colon-specific gel formulation of melatonin with sodium alginate and to evaluate its in vitro characteristics and intracolonic performance on oxidative stress parameters, such as nitric oxide (NOx), malondialdehyde (MDA) and glutathione (GSH) levels in rats with acetic acid-induced colitis. The melatonin-alginate gel formulations were prepared and their physico-pharmaceutical properties were determined. Formulation M5, which contained 3% of sodium alginate and 20% polyethylene glycol, was used for in vivo studies. The in vivo studies were conducted in rats with acetic acid-induced colitis. NOx, MDA and GSH levels were determined and histological investigations were performed. It was found that formulation M5 was the most suitable formulation for the colon-specific melatonin gel, in terms of pH, viscosity, drug release and mucoadhesion properties. The MDA levels in the tissues of Group 2 (treated with an intracolonic gel formulation without melatonin) were found to be significantly higher than in Group 1 (the untreated group). NOx levels decreased with the intracolonic and systemic melatonin treatment in the colitis-induced rats. Neither intracolonic nor intra-peritoneal (IP) melatonin treatment affected GSH levels. The epitelization of the colon tissues in groups administered with intracolonic melatonin, IP melatonin, and the intracolonic gel formulation without melatonin was much better than that found in the untreated group. It was concluded that melatonin participated in various defense mechanisms against the colonic inflammatory process, and that the dose, route and formulation type were the most important parameters in the effectiveness of melatonin.


First morphological characterization of 'Candidatus Mycoplasma turicensis' using electron microscopy.
At least three haemotropic mycoplasmas have been recognized in cats: Mycoplasma haemofelis (Mhf), 'Candidatus Mycoplasma haemominutum' (CMhm) and 'Candidatus M. turicensis' (CMt). The latter was originally identified in a Swiss pet cat with haemolytic anaemia and shown to be prevalent in domestic cats and wild felids worldwide using molecular methods. So far, there has been no confirmatory morphological evidence of the existence of CMt presumably due to low blood loads during infection while CMhm has only been characterized by light microscopy with discrepant results. This study aimed to provide for the first time electron microscopic characteristics of CMt and CMhm and to compare them to Mhf. Blood samples from cats experimentally infected with CMt, CMhm and Mhf were used to determine copy numbers in blood by real-time PCR and for transmission and scanning electron microscopy. High resolution scanning electron microscopy revealed CMt and CMhm to be discoid-shaped organisms of 0.3 μm in diameter attached to red blood cells (RBCs). In transmission electron microscopy of CMt, an oval organism of about 0.25 μm with several intracellular electron dense structures was identified close to the surface of a RBC. CMhm and CMt exhibited similar morphology to Mhf but had a smaller diameter. This is the first study to provide morphological evidence of CMt thereby confirming its status as a distinct haemoplasma species, and to present electron microscopic features of CMhm.


Overexpression of PCBP2 contributes to poor prognosis and enhanced cell growth in human hepatocellular carcinoma.
Poly(C)‑binding protein 2 (PCBP2) is a member of the PCBP family, and plays an important role in post‑transcriptional and translational regulation of various signaling molecules through direct binding to single‑stranded poly(C) motifs. PCBP2 has been reported to play a critical role in the development of multiple human tumors. However, whether PCBP2 participates in hepatocellular carcinoma (HCC) development remains largely elusive. Herein, we showed that PCBP2 was upregulated in human HCC tissues and cell lines. Overexpression of PCBP2 predicted significantly worsened prognosis in HCC patients, suggesting that PCBP2 may serve as a prognostic marker of HCC. In addition, we found that depletion of PCBP2 inhibited HCC cell proliferation, accompanying the increase in the cyclin‑dependent kinase inhibitor p27 level. Moreover, we found that high expression of PCBP2 may contribute to sorafenib resistance in HCC cells, involving dysregulated expression of Bax and Bcl‑2 proteins. In conclusion, our results suggest that PCBP2 may serve as a prognostic marker and potential therapeutic target of HCC.


In situ and ex situ low-field NMR spectroscopy and MRI endowed by SABRE hyperpolarization.
By using 5.75 and 47.5 mT nuclear magnetic resonance (NMR) spectroscopy, up to 10(5)-fold sensitivity enhancement through signal amplification by reversible exchange (SABRE) was enabled, and subsecond temporal resolution was used to monitor an exchange reaction that resulted in the buildup and decay of hyperpolarized species after parahydrogen bubbling. We demonstrated the high-resolution low-field proton magnetic resonance imaging (MRI) of pyridine in a 47.5 mT magnetic field endowed by SABRE. Molecular imaging (i.e. imaging of dilute hyperpolarized substances rather than the bulk medium) was conducted in two regimes: in situ real-time MRI of the reaction mixture (in which pyridine was hyperpolarized), and ex situ MRI (in which hyperpolarization decays) of the liquid hyperpolarized product. Low-field (milli-Tesla range, e.g. 5.75 and 47.5 mT used in this study) parahydrogen-enhanced NMR and MRI, which are free from the limitations of high-field magnetic resonance (including susceptibility-induced gradients of the static magnetic field at phase interfaces), potentially enables new imaging applications as well as differentiation of hyperpolarized chemical species on demand by exploiting spin manipulations with static and alternating magnetic fields.


Ortner's syndrome: A systematic review of presentation, diagnosis and management.
Ortner's syndrome (OS), also called cardiovocal syndrome, is a rare condition hallmarked by left recurrent laryngeal nerve palsy due to underlying cardiopulmonary disease. The purpose of this review is to systemically analyze the existing literature for cases of OS to outline typical presentation, methods of diagnosis, and management of these patients. Case reports, case series, and cohort studies describing OS between 1955 and 2021 were identified. Individual manuscripts were reviewed for clinical features, presentation, and management. A total of 117 patient cases were gathered from 92 published articles. Common symptoms included hoarseness, dyspnea, cough, and dysphagia. The most common associated comorbidity was aortic aneurysm (41%), followed by pulmonary hypertension (35%), mitral stenosis (17%), and hypertension (12%). Among those who were managed via surgical intervention, 85.4% reported improvement in their hoarseness. While historically OS was associated with mitral stenosis, in recent decades, aortic aneurysms and dilation of the pulmonary artery from pulmonary hypertension have emerged as primary etiologies of OS. Therefore, OS should be considered in any patient presenting with hoarseness and history of cardiopulmonary disease. Surgical intervention in appropriate candidates resolves OS in most cases.


Has the child welfare profession discovered nepotistic biases?
A major trend in foster care in developed countries over the past quarter century has been a shift toward placing children with "kin" rather than with unrelated foster parents. This change in practice is widely backed by legislation and is routinely justified as being in the best interests of the child. It is tempting to interpret this change as indicating that the child welfare profession has belatedly discovered that human social sentiments are nepotistic in their design, such that kin tend to be the most nurturant alloparents. Arguably, however, the change in practice has been driven by demographic, economic, and political forces rather than by discovery of its benefits. More and better research is needed before we can be sure that children have actually benefitted.


Schistosomiasis elimination in Madagascar: challenges and opportunities for implementing the new WHO guidelines.
Madagascar is one of the countries with the highest burden of schistosomiasis worldwide. The release from the WHO of the new 2021-2030 neglected tropical disease (NTD) roadmap alongside with the schistosomiasis guidelines sets the ambitious goal of eliminating schistosomiasis as a public health problem worldwide. In Madagascar, implementation barriers exist. This paper has the objective of identifying strengths, weaknesses, opportunities and threats in order to build on their basis practices and policies that can help the country to align with the international global health agenda and reach the ambitious goal set by the WHO.


Holographic reprocessing: Empirical evidence to reduce posttraumatic cognitions in women veterans with PTSD from sexual trauma and abuse.
Holographic reprocessing (HR) facilitates holistic reappraisal of attributions regarding interpersonal violence and maltreatment. The authors tested the feasibility to train therapists to run a protocol using HR to reduce negative thoughts associated with posttraumatic stress disorder (PTSD) in women veterans who have had sexual trauma or abuse. The study assessed pre- and postscores on the Posttraumatic Cognitions Inventory (PTCI) in a naturalistic clinical setting with 5 therapists. The protocol consisted of screening for PTSD, followed by an average of 9 HR treatment sessions. Twenty-two women were referred to the study; 17 enrolled and completed treatment (0% dropout rate). Significant decreases were found on all scales of the PTCI, with large effect sizes: total negative thoughts, t(16) = 4.42, p < .000, Cohen's d = 1.52, and 47% of the sample had reliable change (decreased negative thoughts; RC < -1.96). These findings suggest that HR is a promising treatment for sexual trauma PTSD. (PsycINFO Database Record (c) 2010 APA, all rights reserved).


Ameliorative effect of the cinnamon oil from Cinnamomum zeylanicum upon early stage diabetic nephropathy.
The current study was designed to evaluate the ameliorative effect of the cinnamon oil upon early stage diabetic nephropathy owing to its antioxidant and antidiabetic effect. Cinnamon oil was extracted by hydro-distillation of the dried inner bark of Cinnamomum zeylanicum Blume. Further characterization of the extracted oil was carried out using IR, (1)H-NMR, and (13)C-NMR techniques. Early stage of diabetic nephropathy was induced by administration of alloxan (150 mg/kg, I. P.). Cinnamon oil was administered at varying doses (5, 10, 20 mg/kg; I. P.) while the level of fasting blood glucose, total cholesterol, high density lipoprotein, urea, thiobarbituric acid reactive substances, reduced glutathione, and catalase were determined. These parameters in cinnamon oil treated groups were compared with those of standard (glipizide; 10 mg/kg) and vehicle treated groups in order to investigate if cinnamon oil confers a significant protection against diabetic nephropathy. Histological studies of the kidney proved the protective effect of cinnamon oil by reducing the glomerular expansion, eradicating hyaline casts, and decreasing the tubular dilatations. Our results indicate that the volatile oil from cinnamon contains more than 98 % cinnamaldehyde and that it confers dose-dependent, significant protection against alloxan-induced renal damage, the maximum decrease in fasting blood glucose having been achieved at the dose of 20 mg/kg.


Developing Computer-Based Learning on Care of Aged and Dying Incarcerated People.
Corrections agencies are exploring ways to securely and cost-effectively increase access to high-quality, evidence-based educational programs for personnel. Technology-based instructional tools hold strong potential for continuing education. The Institute for Healthcare Improvement's Framework for Going to Full Scale was employed to guide a systematic approach. The purpose of this article is to outline and describe the design and development of a media-rich interactive computer-based learning product, Enhancing Care for Aged and Dying in Prison, which addresses geriatric and end-of-life care issues in corrections. Through an iterative process, the research team developed the computer-based educational program that included program and module-specific objectives in alignment with goals and priorities of the end users, detailed evidence-based content that was engaging and visually appealing, and assessments aimed at testing the user's knowledge. The Enhancing Care for Aged and Dying in Prison contains six modules, created under the careful guidance of the research team and the two advisory boards. Contents, including images and testimonials, were selected purposefully and strategically. Module objectives were developed in alignment with the goals and priorities of each module, and assessments tested user knowledge level pre/post module exposure. Completion of the training product advances the research and development necessary to further the goal of full-scale dissemination of the computer-based education. The goal of this program is to enhance care and improve quality of life for aged and dying inmates. Evidence-based training products are critical in preparing not only forensic nurses who work in corrections but also the broader group of correctional personnel in how to better meet the care needs of incarcerated persons.


Bright light therapy in Parkinson's disease: a pilot study.
Several observations suggest a beneficial effect of melatonin antagonism for Parkinson's disease (PD). Although bright light therapy (BLT) suppresses melatonin release and is an established treatment for depression and sleep disturbances, it has not been evaluated in PD. We examined effects of BLT on motor symptoms, depression, and sleep in PD in a randomized placebo-controlled double-blind study in 36 PD patients, using Parkinson's Disease Rating Scale (UPDRS) I-IV, Beck's Depression Inventory, and Epworth Sleepiness Scale. All patients received BLT for 15 days in the morning, 30 min daily. Illuminance was 7.500 lux in the active treatment group and 950 lux in the placebo group. Although group differences were small, BLT led to significant improvement of tremor, UPDRS I, II, and IV, and depression in the active treatment group but not in the placebo group. It was very well tolerated. Follow up studies in more advanced patient populations employing longer treatment durations are warranted.


Light propagation through a monolayer of discrete scatterers: analysis of coherent transmission and reflection coefficients.
An investigation of the coherent transmission and reflection coefficients of a monolayer of spherical scatterers as a function of their size, optical constants, and concentration is carried out. An analysis is performed of the quasi-crystalline approximation of the multiple-wave scattering theory and on the single-scattering approximation (SSA). The results permit determining the limits of applicability of the SSA to the layers with the partial ordering of spherical scatterers in analyzing the phases of the transmitted and the reflected waves. The phase of the transmitted and the reflected waves is investigated in the conditions of the quenching effect. It is shown that in such a case small changes in the refractive index of particles can cause dramatic phase changes. This effect can be used to modulate the light-wave phase, e.g., by electrically controlled composite liquid-crystals films.


Differential expression of copper-associated and oxidative stress related proteins in a new variant of copper toxicosis in Doberman pinschers.
BACKGROUND: The role of copper accumulation in the onset of hepatitis is still unclear. Therefore, we investigated a spontaneous disease model of primary copper-toxicosis in Doberman pinschers so to gain insights into the pathophysiology of copper toxicosis, namely on genes involved in copper metabolism and reactive oxygen species (ROS) defences. RESULTS: We used quantitative real-time PCR to determine differentially expressed genes within a target panel, investigating different groups ranging from copper-associated subclinical hepatitis (CASH) to a clinical chronic hepatitis with high hepatic copper concentrations (Doberman hepatitis, DH). Furthermore, a non-copper associated subclinical hepatitis group (N-CASH) with normal hepatic copper concentrations was added as a control. Most mRNA levels of proteins involved in copper binding, transport, and excretion were around control values in the N-CASH and CASH group. In contrast, many of these (including ATP7A, ATP7B, ceruloplasmin, and metallothionein) were significantly reduced in the DH group. Measurements on defences against oxidative stress showed a decrease in gene-expression of superoxide dismutase 1 and catalase in both groups with high copper. Moreover, the anti-oxidative glutathione molecule was clearly reduced in the DH group. CONCLUSION: In the DH group the expression of gene products involved in copper efflux was significantly reduced, which might explain the high hepatic copper levels in this disease. ROS defences were most likely impaired in the CASH and DH group. Overall, this study describes a new variant of primary copper toxicosis and could provide a molecular basis for equating future treatments in dog and in man.


Sirolimus-induced lymphoedema.
Sirolimus is an inhibitor of the mammalian target of rapamycin (mTOR), used as an immunosuppressant for solid-organ transplant recipients and patients with autoimmune disorders. We report a case of lymphoedema, a rare complication of sirolimus, and discuss the mechanism of drug action, the adverse effects and the challenges of treating a kidney transplant recipient with this complication in a resource-limited environment. Lymphoedema is a rare complication of sirolimus, and the mechanisms are not completely understood; however, early recognition can prevent permanent disfiguration. This case highlights the need for early recognition of adverse drug effects and further research into their pathophysiology and management.


Development of a primate model to evaluate the effects of ketamine and surgical stress on the neonatal brain.
With advances in pediatric and obstetric surgery, pediatric patients are subject to complex procedures under general anesthesia. The effects of anesthetic exposure on the developing brain may be confounded by several factors including pre-existing disorders and surgery-induced stress. Ketamine, a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, is routinely used as a pediatric general anesthetic. However, controversy remains about whether ketamine exposure may be neuroprotective or induce neuronal degeneration in the developing brain. Here, we report the effects of ketamine exposure on the neonatal nonhuman primate brain under surgical stress. Eight neonatal rhesus monkeys (postnatal days 5-7) were randomly assigned to each of two groups: Group A (n = 4) received 2 mg/kg ketamine via intravenous bolus prior to surgery and a 0.5 mg/kg/h ketamine infusion during surgery in the presence of a standardized pediatric anesthetic regimen; Group B (n = 4) received volumes of normal saline equivalent to those of ketamine given to Group A animals prior to and during surgery, also in the presence of a standardized pediatric anesthetic regimen. Under anesthesia, the surgery consisted of a thoracotomy followed by closing the pleural space and tissue in layers using standard surgical techniques. Vital signs were monitored to be within normal ranges throughout anesthesia. Elevated levels of cytokines interleukin (IL)-8, IL-15, monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein (MIP)-1β at 6 and 24 h after surgery were detected in ketamine-exposed animals. Fluoro-Jade C staining revealed significantly higher neuronal degeneration in the frontal cortex of ketamine-exposed animals, compared with control animals. Intravenous ketamine administration prior to and throughout surgery in a clinically relevant neonatal primate model appears to elevate cytokine levels and increase neuronal degeneration. Consistent with previous data on the effects of ketamine on the developing brain, the results from the current randomized controlled study in neonatal monkeys undergoing simulated surgery show that ketamine does not provide neuroprotective or anti-inflammatory effects.


Physical activity and cardiorespiratory fitness are beneficial for white matter in low-fit older adults.
Physical activity (PA) and cardiorespiratory fitness (CRF) are associated with better cognitive function in late life, but the neural correlates for these relationships are unclear. To study these correlates, we examined the association of both PA and CRF with measures of white matter (WM) integrity in 88 healthy low-fit adults (age 60-78). Using accelerometry, we objectively measured sedentary behavior, light PA, and moderate to vigorous PA (MV-PA) over a week. We showed that greater MV-PA was related to lower volume of WM lesions. The association between PA and WM microstructural integrity (measured with diffusion tensor imaging) was region-specific: light PA was related to temporal WM, while sedentary behavior was associated with lower integrity in the parahippocampal WM. Our findings highlight that engaging in PA of various intensity in parallel with avoiding sedentariness are important in maintaining WM health in older age, supporting public health recommendations that emphasize the importance of active lifestyle.


Changes in biogenic amines of silver carp (Hypophthalmichthys molitrix) fillets stored at different temperatures and their relation to total volatile base nitrogen, microbiological and sensory score.
Biogenic amines have received considerable attention owing to their undesirable effects in humans. There are few studies of changes in biogenic amine contents related to freshwater fish. Silver carp is an important freshwater fish species in China. This study aimed to investigate the changes in biogenic amines and their relation to total volatile base nitrogen (TVB-N), microbiological and sensory score of silver carp fillets stored at 0, 3 and 15 °C. The total biogenic amine contents of all silver carp fillets (regardless of storage time and temperature) ranged from 13.05 to 318.10 mg kg(-1). Putrescine and histamine were the main biogenic amines in silver carp fillets during storage. Cadaverine was only detected after 12 days at 3 °C and after 2 days at 15 °C. Spermidine and spermine contents increased during the early storage period and then slightly decreased. Low temperature could control the quality of silver carp fillets by inhibiting the contents of biogenic amines. Putrescine showed significant correlation with TVB-N, total aerobic content, sensory score, tryptamine and phenylethylamine. Putrescine was a good quality marker of silver carp fillets in the cold chain.


Human haematological and epithelial tumor-derived cell lines express distinct patterns of onco-microRNAs.
MicroRNAs post-transcriptionally regulate gene expression thus playing a critical role in a wide range of physiological and pathological processes, including cancer initiation and progression. Moreover, a growing number of evidences highlights that miRNAs themselves are differentially expressed between normal and malignant tissues. In this study, we analysed differences in miRNA expression profile between haematological and epithelial tumor-derived cell lines and explored their role in definying different cancer cells phenotypes. Cancer Focus microRNA PCR Panel was used to analyze eighty-four oncomiRNAs in two human haematological (K562 and HL-60) and in two epithelial (H460 and MCF-7) cancer cell lines. Bioinformatic tools were used to identify miRNA-specific signatures and to discover potentially deregulated pathways. Our analysis led to the identification of i) a large repertoire of miRNAs commonly expressed in the four cell lines, including two equally highly expressed (UPmiRs) and four equally low expressed (DNmiRs); ii) two miRNAs signatures, one associated with the haematological and one with the epithelial cell lines; iii) miRNA signatures specific for the acute or for the chronic myeloid leukemic cells; iv) miRNA signatures specific for the lung or for the breast carcinoma cells. As a whole, these results strengthen the significance of miRNAs profiling in human cancer subtyping, providing the ground for the identification of novel potential biomarkers for specific cancer cell phenotypes.


Barriers to mental health care utilization among internally displaced persons in the republic of Georgia: a rapid appraisal study.
There is a paucity of evidence on access to services for mental health and psychosocial support for conflict-affected populations in low- and middle-income countries. In the Republic of Georgia, rates of utilization of mental health services among internally displaced people with mental disorders are low. We set out to identify the health system barriers leading to this treatment gap. We used rapid appraisal methods (collection and triangulation of multiple data sources) to investigate barriers to accessing mental health care services among adult IDPs in Georgia. Data collection included review of existing policy documents and other published data, as well as semi-structured interviews with 29 key informants including policy makers, NGO staff, health professionals and patients. The following factors emerged as important barriers affecting access to mental health care services among IDPs in Georgia: inadequate insurance coverage of mental disorders and poor identification and referral systems, underfunding, shortage of human resources, poor information systems, patient out-of-pocket payments and stigmatization. While rapid appraisal methods cannot control for potential biases or achieve representativeness, triangulation supports internal validity and reliability of the data collected, allowing data to be used to inform health care interventions. The appropriateness and potential effectiveness of policy interventions such as insurance coverage of a wider range of mental disorders, integration of services for these at the primary health care level, and community-based approaches in this context should be explored.


Water UV-C treatment alone or in combination with peracetic acid: A technology to maintain safety and quality of strawberries.
Disinfection of fruits is one of the most important steps since they are going to be eaten fresh-or minimally-processed. This step affects quality, safety, and shelf-life of the product. Despite being a common sanitizer in the fruit industry, chlorine may react with organic matter leading to the formation of toxic by-products. Alternative sustainable disinfection strategies to chlorine are under study to minimize environmental and human health impact. Water-assisted UV-C light (WUV-C) is proposed here as an alternative sanitizing method for strawberries. In this study, strawberries were washed for 1 or 5 min in a tank with 2 or 4 lamps on, each emitting UV-C light at 17.2 W/cm2, or in a chlorine solution (200 ppm, pH 6.5). Moreover, trials with 4 lamps on, together with a washing solution consisting on peracetic acid at 40 or 80 ppm, were carried out. Overall, quality and nutritional parameters of strawberries after treatments were maintained. Changes in color were not noticeable and fruits did not lose firmness. No major changes were observed in antioxidant activity, organic acid, anthocyanin, vitamin C, and total phenolic content. Yeasts and molds were not affected by the WUV-C treatment, and 5 min were needed to significantly reduce total aerobic mesophylls population. However, reductions of artificially inoculated Listeria innocua and Salmonella Typhimurium after WUV-C treatments were comparable to those obtained with chlorine-wash, which were 3.0 log CFU / g. Moreover, WUV-C light was effective to minimize microorganisms remaining in washing water, avoiding cross-contamination and thus, allowing water recirculation. This effect was improved when combining the action of UV-C light with peracetic acid, showing the suitability of this combined treatment, understood as an alternative to chlorine sanitation, for sanitizing strawberries and keeping the populations of pathogenic bacteria in washing water lower than 0.6 ± 0.1 log CFU / mL.


Chronic Pain and Pain Management in Older Adults: Protocol and Pilot Results.
Chronic pain occurs in 30% of older adults. This prevalence rate is expected to increase, given the growth in the older adult population and the associated growth of chronic conditions contributing to pain. No population-based studies have provided detailed, longitudinal information on the experience of chronic pain in older adults; the pharmacological and nonpharmacological strategies that older adults use to manage their chronic pain; and the effect of chronic pain on patient-reported outcomes. This article aims to describe the protocol for a population-based, longitudinal study focused on understanding the experience of chronic pain in older adults. The objectives are to determine the prevalence and characteristics of chronic pain; identify the pharmacological and nonpharmacological pain treatments used; evaluate for longitudinal differences in biopsychosocial factors; and examine how pain types and pain trajectories affect important patient-reported outcomes. Also included are the results of a pilot study. A population-based sample of approximately 1,888 older adults will be recruited from the National Opinion Research Center at the University of Chicago's AmeriSpeak Panel to complete surveys at three waves: enrollment (Wave 1), 6 months (Wave 2), and 12 months (Wave 3). To determine the feasibility, a pilot test of the enrollment survey was conducted among 123 older adults. In the pilot study, older adults with chronic pain reported a range of pain conditions, with osteoarthritis being the most common. Participants reported an array of pharmacological and nonpharmacological pain strategies. Compared to participants without chronic pain, those with chronic pain reported lower physical and cognitive function and poorer quality of life. Data collection for the primary, longitudinal study is ongoing. This project will be the first longitudinal population-based study to examine the experience and overall effect of chronic pain in older adults. Pilot study results provide evidence of the feasibility of study methods. Ultimately, this work will inform the development of tailored interventions for older patients targeted to decrease pain and improve function and quality of life.


Dual-energy computed tomography pulmonary angiography with ultra-low dose contrast administration: Comparison of image quality with standard computed tomography pulmonary angiography.
This study aims to compare quantitative and qualitative image quality between standard computed tomography pulmonary angiography and dual-energy computed tomography pulmonary angiography protocols. Between September 2017 and August 2018, a total of 91 consecutive patients (34 males, 57 females; mean age: 65.9±15 years; range, 37 to 91 years) who were referred for computed tomography pulmonary angiography were randomly imaged with either a standard or dual-energy protocol. Standard protocol (n=49) was acquired with a 64-slice multidetector computed tomography scanner using 60 mL contrast media (18 g iodine). A third-generation dual-energy computed tomography scanner was utilized to acquire dual-energy computed tomography pulmonary angiography and simultaneous lung perfusion imaging (n=42), which required 40 mL contrast media (12 g iodine). Two radiologists reviewed images separately to determine interobserver variability. Attenuation and noise in three central and two segmental pulmonary arteries were measured; signal-to-noise ratio and contrast-to-noise ratio were calculated. A five-point scale was utilized to evaluate image quality and image noise qualitatively. The standard protocol required a significantly higher amount of iodine. Comparison of two groups employing quantitative measurements (attenuation value in five pulmonary arteries, mean attenuation value, mean background noise, signal-to-noise ratio, and contrast-to-noise ratio) and employing qualitative measurements (five-point scale scores of image quality and image noise) revealed no significant difference between dual-energy and standard groups (p>0.05). Qualitative and quantitative evaluations demonstrated low interobserver variability. Dual-energy computed tomography pulmonary angiography protocol delivers image quality equal to standard protocol, while requiring less amount of iodinated contrast medium and providing simultaneous lung perfusion imaging to contribute the diagnosis of pulmonary embolism.


Beyond the electric-dipole approximation in simulations of x-ray absorption spectroscopy: Lessons from relativistic theory.
We present three schemes to go beyond the electric-dipole approximation in x-ray absorption spectroscopy calculations within a four-component relativistic framework. The first is based on the full semi-classical light-matter interaction operator and the two others on a truncated interaction within the Coulomb gauge (velocity representation) and multipolar gauge (length representation). We generalize the derivation of the multipolar gauge to an arbitrary expansion point and show that the potentials corresponding to different expansion points are related by a gauge transformation, provided that the expansion is not truncated. This suggests that the observed gauge-origin dependence in the multipolar gauge is more than just a finite-basis set effect. The simplicity of the relativistic formalism enables arbitrary-order implementations of the truncated interactions, with and without rotational averaging, allowing us to test their convergence behavior numerically by comparison to the full formulation. We confirm the observation that the oscillator strength of the electric-dipole allowed ligand K-edge transition of TiCl4, when calculated to the second order in the wave vector, becomes negative but also show that inclusion of higher-order contributions allows convergence to the result obtained using the full light-matter interaction. However, at higher energies, the slow convergence of such expansions becomes dramatic and renders such approaches at best impractical. When going beyond the electric-dipole approximation, we therefore recommend the use of the full light-matter interaction.


The meaning of social support for the critically ill patient.
Social support has been shown to be important for the critically ill patient. However, what constitutes adequate support for these patients has not been investigated. Thus, the purpose of this qualitative study was to investigate patients' perceptions of their need for and adequacy of the social support received while they were critically ill. Thirty adult patients who were critical during some point of their stay in the intensive care unit (ICU) stay were interviewed, once stable. Interviews were tape-recorded and began with an open-ended question regarding the ICU experience. This was followed by open-ended focused questions regarding social support, such as 'Who were your greatest sources of social support while you were critically ill?' 'What did they do that was supportive or unsupportive?' Data were analyzed according to Miles and Huberman (1994). The categories that emerged were need for social support based on patient perceptions (not number of visitors), quality of support (based on perceptions of positive and negative behaviors of supporters) and lack of support. This study found that quality of support was more important than the actual number of visitors. Patients with few visitors may have felt supported, while those with numerous visitors felt unsupported. Patients who felt unsupported also were more critical of the staff and the care they received. Nurses need to individually assess patients regarding their need for support, and assist family/friends to meet these needs.


Cyanide Poisoning.
The goal of this simulation is to educate emergency medicine students, residents, attending physicians, and mid-level practitioners to recognize, diagnose, and manage acute cyanide toxicity. Cyanide has an almond scent and is a naturally occurring compound. It is present within many different types of plants and fruits including apricots, apples, peaches, lima beans, and cassava plants but is harmless.1 The trace amounts of cyanide found within organic materials is of little concern because its high reactivity causes it to be metabolized rapidly and create other compounds. However, modern synthetic materials such as plastics, papers, textiles, and machinery can release a much greater concentration of hydrogen cyanide when exposed to high temperatures.1 As the use of contemporary nitrogen-containing synthetic polymers has expanded, the possibility of cyanide toxicity has become increasingly common and severe. Hydrogen cyanide is especially dangerous to humans because the gaseous form reacts quickly upon inhalation.2When cyanide enters the body via inhalation, it blocks the cells from utilizing oxygen by binding to the cytochrome oxidase in the mitochondria.2 The inability of the cell to use oxygen forces cells from aerobic metabolism into anaerobic metabolism. Anaerobic metabolism results in the production of lactic acid, which causes metabolic acidosis.3 The human body cannot sustain itself with the lack of oxygen and anaerobic metabolism for a prolonged period of time. Ultimately, the body will suffer cardiorespiratory arrest.1Symptoms of cyanide toxicity include headache, nausea, shortness of breath, and altered mental status.1 These are similar to those of carbon monoxide and carbon dioxide inhalation. However, symptoms of cyanide toxicity cannot be treated with supplemental oxygen as carbon monoxide and carbon dioxide are. Cyanide toxicity must be treated with an antidote - sodium thiosulfate, sodium nitrite, and hydroxocobalamin.4 Each of the antidotes works by binding with the highly reactive cyanide, neutralizing the compound, and converting it into a water-soluble product that will be cleared through renal excretion.4Fire victims often present to the emergency department critically ill. They will likely have obvious external thermal burns and traumatic injuries; however, it is important for emergency personnel to recognize the respiratory distress and metabolic derangements that are most likely occurring due to toxic gas inhalation. People who are trapped within a burning structure are exposed to carbon monoxide, carbon dioxide, and cyanide from the combustion of contents within the building. These toxic gasses will cause severe tissue hypoxia without significant vital sign changes.5 The respiratory distress and metabolic compromise will be acutely more fatal than the obvious external injuries and burns. The challenge in treating these patients is for the healthcare team to know the differential diagnoses, prioritize airway, breathing and circulation, and to empirically treat the patient as if they have a confirmed exposure.It is estimated that 35% of all fire victims have toxic levels of cyanide upon arrival to the emergency room.2 Acute cyanide toxicity can become fatal within minutes; however, a prompt diagnosis and treatment can be lifesaving. Unfortunately, due to the limited amount of time the human body can sustain anaerobic metabolism and tissue hypoxia, blood test results are not available in time to be clinically applicable.2 Rather, the emergency room personnel must begin treatment immediately upon recognizing that toxic smoke inhalation may have occurred.We understand the importance of knowing how to treat fire victims. Therefore, the goal of this simulation case is to expose the emergency providers to cyanide poisoning and educate emergency providers about the critical steps of how to approach, diagnose, and treat cyanide toxicity. After the completion of this simulation, participants will have learned how to: 1) identify clues of smoke inhalation based on a physical examination; 2) identify smoke inhalation-induced airway compromise and perform definitive management; 3) create a differential diagnosis for victims of fire cyanide poisoning, carbon monoxide, and carbon dioxide; 4) appropriately treat cyanide poisoning; 5) demonstrate the importance of preemptively treating for cyanide poisoning; 6) perform an initial physical examination and identify physical marks suggesting the patient is a fire and smoke inhalation victim; and 7) familiarize themselves with the Cyanokit and treatment with hydroxocobalamin. This is a high-fidelity simulation case in which participants work through a case of a patient who has been exposed to fire. The participants will be able to work hands-on to evaluate, diagnose, and treat cyanide poisoning in an emergency event. Afterwards, there will be a small group discussion and debriefing of the case in order to review patient care skills, interpersonal and communication skills, medical knowledge, and system-based practice. The participants were instructed to complete a survey before and after the simulation case. A quality Likert Scale was used to assess the participants' comfort level of diagnosing, treating, and managing a patient with toxic smoke inhalation. A score of 1 represented a negative experience and 5 represented a very positive experience. The surveys were then reviewed by the research team to determine if the simulation case improved the participants' comfort level. The survey answers were compared collectively, as well as individually, and were analyzed between the pre-simulation and post-simulation results. Our simulation involved 25 participants: 20 participants were emergency medicine resident physicians and 5 were 4th-year medical students. In the pre-simulation survey, participants reported a mean of 2.7 out of 5 when asked to rate their confidence in their ability to treat a smoke inhalation victim. The post-simulation survey showed a significant increase to a mean of 3.5 out of 5. Participants were also asked to evaluate the usefulness of the simulation: 15 participants rated the case as a 5, which represented "very useful," and the other 10 participants rated the case as a 4, which represented "useful." The mean value when asked to assess the simulation case's usefulness and applicability in emergency medicine was 4.6 out of 5. This simulation allows providers to focus on victims of fire. Fire victims are often critically ill and require time sensitive treatment. This simulation gives providers a chance to review their knowledge and prepare them for real life cases. Based on the survey results, the simulation improved awareness and understanding of the symptoms of acute cyanide toxicity and improved the participant's ability to recognize, diagnose, and treat cyanide poisoning. Cyanide toxicity, carbon monoxide toxicity, cyanide antidote, fire victim, intubation, airway intervention, oxygen treatment, history taking, lab testing ordering, symptom identification, interpretation of lab results, emergency medicine simulation.


Effectiveness of quality improvement strategies for coordination of care to reduce use of health care services: a systematic review and meta-analysis.
Frequent users of health care services are a relatively small group of patients who account for a disproportionately large amount of health care utilization. We conducted a meta-analysis of the effectiveness of interventions to improve the coordination of care to reduce health care utilization in this patient group. We searched MEDLINE, Embase and the Cochrane Library from inception until May 2014 for randomized clinical trials (RCTs) assessing quality improvement strategies for the coordination of care of frequent users of the health care system. Articles were screened, and data abstracted and appraised for quality by 2 reviewers, independently. Random effects meta-analyses were conducted. We identified 36 RCTs and 14 companion reports (total 7494 patients). Significantly fewer patients in the intervention group than in the control group were admitted to hospital (relative risk [RR] 0.81, 95% confidence interval [CI] 0.72-0.91). In subgroup analyses, a similar effect was observed among patients with chronic medical conditions other than mental illness, but not among patients with mental illness. In addition, significantly fewer patients 65 years and older in the intervention group than in the control group visited emergency departments (RR 0.69, 95% CI 0.54-0.89). We found that quality improvement strategies for coordination of care reduced hospital admissions among patients with chronic conditions other than mental illness and reduced emergency department visits among older patients. Our results may help clinicians and policy-makers reduce utilization through the use of strategies that target the system (team changes, case management) and the patient (promotion of self-management).


Mammalian forelimb evolution is driven by uneven proximal-to-distal morphological diversity.
Vertebrate limb morphology often reflects the environment due to variation in locomotor requirements. However, proximal and distal limb segments may evolve differently from one another, reflecting an anatomical gradient of functional specialization that has been suggested to be impacted by the timing of development. Here, we explore whether the temporal sequence of bone condensation predicts variation in the capacity of evolution to generate morphological diversity in proximal and distal forelimb segments across more than 600 species of mammals. Distal elements not only exhibit greater shape diversity, but also show stronger within-element integration and, on average, faster evolutionary responses than intermediate and upper limb segments. Results are consistent with the hypothesis that late developing distal bones display greater morphological variation than more proximal limb elements. However, the higher integration observed within the autopod deviates from such developmental predictions, suggesting that functional specialization plays an important role in driving within-element covariation. Proximal and distal limb segments also show different macroevolutionary patterns, albeit not showing a perfect proximo-distal gradient. The high disparity of the mammalian autopod, reported here, is consistent with the higher potential of development to generate variation in more distal limb structures, as well as functional specialization of the distal elements.


Hydrogen phosphate selectively induces MDA MB 231 triple negative breast cancer cell death in vitro.
Phosphate ions are the most abundant anions inside the cells, and they are increasingly gaining attention as key modulators of cellular function and gene expression. However, little is known about the effect of inorganic phosphate ions on cancer cells, particularly breast cancer cells. Here, we investigated the toxicity of different phosphate compounds to triple-negative human breast cancer cells, particularly, MDA-MB-231, and compared it to that of human monocytes, THP-1. We found that, unlike dihydrogen phosphate (H2PO4-), hydrogen phosphate (HPO42-) at 20 mM or lower concentrations induced breast cancer cell death more than immune cell death, mainly via apoptosis. We correlate this effect to the fact that phosphate in the form of HPO42- raises pH levels to alkaline levels which are not optimum for transport of phosphate into cancer cells. The results in this study highlight the importance of further exploring hydrogen phosphate (HPO42-) as a potential therapeutic for the treatment of breast cancer.


Identification and characterization of chondrogenic progenitor cells in the fascia of postnatal skeletal muscle.
Intramuscular injection of bone morphogenetic proteins (BMPs) has been shown to induce ectopic bone formation. A chondrogenic phase is typically observed in this process, which suggests that there may exist a chondrogenic subpopulation of cells residing in skeletal muscle. Two prospective cell populations were isolated from rat skeletal muscle: fascia-derived cells (FDCs), extracted from gluteus maximus muscle fascia (epimysium) and muscle-derived cells (MDCs) isolated from the muscle body. Both populations were investigated for their cell surface marker profiles (flowcytometry analysis), proliferation rates as well as their myogenic and chondrogenic potentials. The majority of FDCs expressed mesenchymal stromal cell markers but not endothelial cell markers. FDCs underwent chondrogenic differentiation after BMP4 treatment in vitro, but not myogenic differentiation. Although MDCs showed chondrogenic potential, they expressed the myogenic cell marker desmin and readily underwent myogenic differentiation in vitro; however, the chondrogenic potential of the MDCs is confounded by the presence of FDC-like cells residing in the muscle perimysium and endomysium. To clarify the role of the muscle-derived myogenic cells in chondrogenesis, mixed pellets with varying ratios of FDCs and L6 myoblasts were formed and studied for chondrogenic potential. Our results indicated that the chondrogenic potential of the mixed pellets decreased with the increased ratio of myogenic cells to FDCs supporting the role of FDCs in chondrogenesis. Taken together, our results suggest that non-myogenic cells residing in the fascia of skeletal muscle have a strong chondrogenic potential and may represent a novel donor cell source for cartilage regeneration and repair.


Heparan sulphate sulphotransferase expression in mice and Caenorhabditis elegans.
Heparan sulphate (HS) acts as a multifunctional cell regulator, with specific sulphated saccharide sequences designed for selective interactions with many proteins. Functionally, these interactions result in regulation of the protein activities, and there is growing evidence that cells can dynamically alter the structure of HS sequences that they display. HS biosynthesis involves the action of a complex set of enzymes with polymerase, epimerase and sulphotransferase (ST) activities. In higher organisms, multiple isoforms of STs decorate the nascent HS chains with specific patterns of sulphation that confer selective biological functions. The study of HSSTs in model organisms provides a valuable opportunity to examine the expression of these enzymes in relation to the structure and activities of the HS produced. Here we describe that, in mice, there are stage-specific combinations of HSST isoenzymes that underlie the synthesis of different HS species at different times in the developing brain. This differential expression of HSSTs results in the synthesis of structurally variant HS species that form functional signalling complexes with specific fibroblast growth factors and their receptors. Regulated synthesis of specific HS species could be a mechanism for the regulation of proliferation and differentiation in the developing brain. We also describe evidence that a Caenorhabditis elegans orthologue of the mammalian 2OST enzyme, called HST-2, is essential for the normal development of this nematode. Together, these studies emphasize the importance of HSSTs in the biosynthesis of functionally variant HS proteoglycans, and demonstrate the importance of these complex regulatory molecules in developmental processes.


Second-order induction in prediction problems.
Agents make predictions based on similar past cases, while also learning the relative importance of various attributes in judging similarity. We ask whether the resulting "empirically optimal similarity function" (EOSF) is unique and how easy it is to find it. We show that with many observations and few relevant variables, uniqueness holds. By contrast, when there are many variables relative to observations, nonuniqueness is the rule, and finding the EOSF is computationally hard. The results are interpreted as providing conditions under which rational agents who have access to the same observations are likely to converge on the same predictions and conditions under which they may entertain different probabilistic beliefs.


Rotavirus strain diversity in Eastern and Southern African countries before and after vaccine introduction.
The African Rotavirus Surveillance Network has been detecting and documenting rotavirus genotypes in the African sub-continent since 1998 in anticipation of the rollout of rotavirus vaccination in routine Expanded Programme on Immunisation. This paper reports distribution of the rotavirus strains circulating in 15 Eastern and Southern African (ESA) countries from 2010-2015 as part of active World Health Organization (WHO) rotavirus surveillance, and investigates possibility of emergence of non-vaccine or unusual strains in six selected countries post-vaccine introduction. Stool samples were collected from children <5 years of age presenting with acute gastroenteritis at sentinel hospitals pre- and post-rotavirus vaccine introduction. Samples were tested for group A rotavirus using an enzyme immunoassay by the national and sentinel laboratories. At the WHO Rotavirus Regional Reference Laboratory in South Africa, molecular characterisation was determined by PAGE (n = 4186), G and P genotyping (n = 6447) and DNA sequencing for both G and P types (n = 400). The six-year surveillance period demonstrated that 23.8% of the strains were G1P[8], followed by G2P[4] (11.8%), G9P[8] (10.4%), G12P[8] (4.9%), G2P[6] (4.2%) and G3P[6] (3.7%) in 15 ESA countries. There was no difference in circulating strains pre- and post-rotavirus vaccine introduction with yearly fluctuation of strains observed over time. Atypical rotavirus G and P combinations (such as G1P[4], G2P[8], G9P[4] and G12P[4]) that might have arisen through inter-genogroup or inter-genotypes reassortment were detected at low frequency (2%). Close genetic relationship of African strains were reflected on the phylogenetic analysis, strains segregated together to form an African cluster in the same lineages/sub-lineage or monophyletic branch. There has been considerable concern about strain replacement post-vaccine introduction, it was not clear at this early stage whether observed cyclical changes of rotavirus strains were due to vaccine pressure or this was just part of natural annual fluctuations in the six ESA countries, long-term surveillance is required.


[Cutaneous retraction. Data from liposuction and other clinical procedures].
The remarkable capacity of the skin to stretch is used in the skin expander technique. In parallel, the skin is also able to retract, which is very useful for the plastic surgeon. This ability to retract may open the road for new techniques. Suction lipectomy, which allows removal of large volumes of fat without skin resection, is a privileged technique for the study of retractability characteristics. This study compares the pre and postoperative conditions in 392 cases of body liposuction and 108 cases of cervicofacial liposuctions, to determine the factors which influence skin retraction. It appears that age and the total amount of fat removed have an incidence on the time needed to obtain the final result. However the treatment site emerges as a determinant factor on the potential of the skin to retract postoperatively. In practice, the skin elasticity appears to be very different in different treatment sites, and considerable variations can even be observed between two neighbouring regions. In the neck and cheeks the skin seems considerably more retractable than in other sites, and we can trace the boundaries of the optimal retractability for the liposuction: "the golden triangle at the neck". The considerable plasticity of the skin overlying the neck contrasts with the poor ability of facial skin to retract. On the body, the skin resumes its previous form in the vast majority of patients (90%). These data, derived from a liposuction study, may be compared with other clinical observations.(ABSTRACT TRUNCATED AT 250 WORDS)


Current status of intratumour microbiome in cancer and engineered exogenous microbiota as a promising therapeutic strategy.
Research on the relationship between microbiome and cancer has made significant progress in the past few decades. It is now known that the gut microbiome has multiple effects on tumour biology. However, the relationship between intratumoral bacteria and cancers remains unclear. Growing evidence suggests that intratumoral bacteria are important components of the microenvironment in several types of cancers. Furthermore, several studies have demonstrated that intratumoral bacteria may directly influence tumorigenesis, progression and responses to treatment. Limited studies have been conducted on intratumoral bacteria, and using intratumoral bacteria to treat tumours remains a challenge. Bacteria have been studied as anticancer therapeutics since the 19th century when William B. Coley successfully treated patients with inoperable sarcomas using Streptococcus pyogenes. With the development of synthetic biological approaches, several bacterial species have been genetically engineered to increase their applicability for cancer treatment. Genetically engineered bacteria for cancer therapy have unique properties compared to other treatment methods. They can specifically accumulate within tumours and inhibit cancer growth. In addition, genetically engineered bacteria may be used as a vector to deliver antitumour agents or combined with radiation and chemotherapy to synergise the effectiveness of cancer treatment. However, various problems in treating tumours with genetically engineered bacteria need to be addressed. In this review, we focus on the role of intratumoral bacteria on tumour initiation, progression and responses to chemotherapy or immunotherapy. Moreover, we summarised the recent progress in the treatment of tumours with genetically engineered bacteria.


Filter width affects the transmittance of patterned all-dielectric Fabry-Perot filters.
Thin-film all-dielectric Fabry-Perot filters can nowadays be patterned onto pixels of commercial imaging sensors used for spectral imaging. For these patterned filters, standard transfer-matrix thin-film calculations fail to predict their angular dependency. This Letter attributes the discrepancy to the finite filter size and is also, to my knowledge, the first study to analyze this for patterned all-dielectric Fabry-Perot filters. An angular spectrum approach that enables prediction without full knowledge of the filter design is introduced. In addition, the contribution of diffraction at normal incidence is characterized by a single dimensionless parameter. Knowing that patterned filter size matters and having a method to efficiently simulate its effect can guide ongoing miniaturization efforts and filter design.


Comparison of the accuracy of cone beam computed tomography and medical computed tomography: implications for clinical diagnostics with guided surgery.
This study compared the accuracy of cone beam computed tomography (CBCT) and medical-grade CT in the context of evaluating the diagnostic value and accuracy of fiducial marker localization for reference marker-based guided surgery systems. Cadaver mandibles with attached radiopaque gutta-percha markers, as well as glass balls and composite cylinders of known dimensions, were measured manually with a highly accurate digital caliper. The objects were then scanned using a medical-grade CT scanner (Philips Brilliance 64) and five different CBCT scanners (Sirona Galileos, Morita 3D Accuitomo 80, Vatech PaX-Reve3D, 3M Imtech Iluma, and Planmeca ProMax 3D). The data were then imported into commercially available software, and measurements were made of the scanned markers and objects. CT and CBCT measurements were compared to each other and to the caliper measurements. The difference between the CBCT measurements and the caliper measurements was larger than the difference between the CT measurements and the caliper measurements. Measurements of the cadaver mandible and the geometric reference markers were highly accurate with CT. The average absolute errors of the human mandible measurements were 0.03 mm for CT and 0.23 mm for CBCT. The measurement errors of the geometric objects based on CT ranged between 0.00 and 0.12 mm, compared to an error range between 0.00 and 2.17 mm with the CBCT scanners. CT provided the most accurate images in this study, closely followed by one CBCT of the five tested. Although there were differences in the distance measurements of the hard tissue of the human mandible between CT and CBCT, these differences may not be of clinical significance for most diagnostic purposes. The fiducial marker localization error caused by some CBCT scanners may be a problem for guided surgery systems.


How Receptive Are Patients With Late Stage Cancer to Rehabilitation Services and What Are the Sources of Their Resistance?
To describe the proportion and characteristics of patients with late stage cancer that are and are not receptive to receiving rehabilitation services, and the rationale for their level of interest. Prospective mixed-methods study. Comprehensive cancer center in a quaternary medical center. Adults with stage IIIC or IV non-small cell or extensive stage small cell lung cancer (N=311). Not applicable. Telephone-acquired responses to the administration of (1) the Activity Measure for Post Acute Care Computer Adaptive Test (AM-PAC-CAT); (2) numerical rating scales for pain, dyspnea, fatigue, general emotional distress, and distress associated with functional limitations; (3) a query regarding receptivity to receipt of rehabilitation services, and (4) a query about rationale for nonreceptivity. Overall, 99 (31.8%) of the study's 311 participants expressed interest in receiving rehabilitation services: 38 at the time of enrollment and an additional 61 during at least 1 subsequent contact. Participants expressing interest were more likely to have a child as primary caregiver (18.18% vs 9.91%, P=.04) and a musculoskeletal comorbidity (42.4% vs 31.6%, P=.05). Function-related distress was highly associated with receptivity, as were lower AM-PAC-CAT scores. Reasons provided for lack of interest in receiving services included a perception of their limited benefit, being too busy, and prioritization below more pressing tasks/concerns. One-third of patients with late stage lung cancer are likely to be interested in receiving rehabilitation services despite high levels of disability and related distress. These findings suggest that patient misperception of the role of rehabilitation services may be a barrier to improved function and quality of life. Efforts to educate patients on the benefits of rehabilitation and to more formally integrate rehabilitation as part of comprehensive care may curb these missed opportunities.


Reductions in prefrontal activation predict off-topic utterances during speech production.
The ability to speak coherently is essential for effective communication but declines with age: older people more frequently produce tangential, off-topic speech. Little is known, however, about the neural systems that support coherence in speech production. Here, fMRI was used to investigate extended speech production in healthy older adults. Computational linguistic analyses were used to quantify the coherence of utterances produced in the scanner, allowing identification of the neural correlates of coherence for the first time. Highly coherent speech production was associated with increased activity in bilateral inferior prefrontal cortex (BA45), an area implicated in selection of task-relevant knowledge from semantic memory, and in bilateral rostrolateral prefrontal cortex (BA10), implicated more generally in planning of complex goal-directed behaviours. These findings demonstrate that neural activity during spontaneous speech production can be predicted from formal analysis of speech content, and that multiple prefrontal systems contribute to coherence in speech.


A stable intermediate wetting state after a water drop contacts the bottom of a microchannel or is placed on a single corner.
It is considered that, after a water drop contacts the base of a roughness groove, water should immediately fill this roughness groove. Subsequently, Cassie-Baxter wetting state is transited to that of Wenzel. Accordingly, one of the criteria used to judge the transition from Cassie-Baxter to Wenzel states is whether a water drop has contact with the base of a roughness groove. In this work, through theoretical and experimental investigations, we show that this transition criterion does not always hold true in the case of microchannels. We first theoretically prove that, when an angle criterion is satisfied, there may exist an intermediate wetting state inside a microchannel after a water drop contacts the bottom of the microchannel. In this wetting state, water does not completely fill the microchannel, and air pockets still exist in its bottom corners. Also, the wetting state is stable in the sense that its energy state is lower than that of the Wenzel model. According to the angle criterion, such intermediate states may exist, for example, in microchannels with vertical sidewalls, when contact angles on the inner surfaces of these microchannels are larger than 135°. In addition to microchannels, the aforementioned intermediate state may also exist on a single corner (which is formed by a horizontal plate and an inclined plate), when the angle criterion is met. After theoretical modeling, we then conduct four types of tests on single corners and microchannels to validate the angle criterion. In these tests, once the angle criterion is met, stable intermediate states are observed on the corresponding samples. In addition, it is found from the two types of tests conducted on microchannels that, once Laplace pressure inside a water drop is gradually reduced, such an intermediate wetting state may be transited back to the original Cassie-Baxter state. On the other hand, the Wenzel state may not have such a reversal transition unless an additional force is applied to overcome energy barrier between Wenzel and Cassie-Baxter states.


Differential and persistent risk of excess mortality from Hurricane Maria in Puerto Rico: a time-series analysis.
Hurricane Maria struck Puerto Rico on Sept 20, 2017, devastating the island. Controversy surrounded the official death toll, fuelled by estimates of excess mortality from academics and investigative journalists. We analysed all-cause excess mortality following the storm. We did a time-series analysis in Puerto Rico from September, 2017, to February, 2018. Mortality data were from the Puerto Rico Vital Statistics System. We developed two counterfactual scenarios to establish the population at risk. In the first scenario, the island's population was assumed to track the most recent census estimates. In the second scenario, we accounted for the large-scale population displacement. Expected mortality was projected for each scenario through over-dispersed log-linear regression from July, 2010, to August, 2017, taking into account changing distributions of age, sex, and municipal socioeconomic development, as well as both long-term and seasonal trends in mortality. Excess mortality was calculated as the difference between observed and expected deaths. Between September, 2017, and February, 2018, we estimated that 1191 excess deaths (95% CI 836-1544) occurred under the census scenario. Under the preferred displacement scenario, we estimated that 2975 excess deaths (95% CI 2658-3290) occurred during the same observation period. The ratio of observed to expected mortality was highest for individuals living in municipalities with the lowest socioeconomic development (1·43, 95% CI 1·39-1·46), and for men aged 65 years or older (1·33, 95% CI 1·30-1·37). Excess risk persisted in these groups throughout the observation period. Analysis of all-cause mortality with vital registration data allows for unbiased estimation of the impact of disasters associated with natural hazards and is useful for public health surveillance. It does not depend on certified cause of death, the basis for the official death toll in Puerto Rico. Although all sectors of Puerto Rican society were affected, recovery varied by municipal socioeconomic development and age groups. This finding calls for equitable disaster preparedness and response to protect vulnerable populations in disasters. Forensic Science Bureau, Department of Public Safety, and Milken Institute School of Public Health of The George Washington University (Washington, DC, USA).


Chromatin immunoprecipitation (ChIP) methodology and readouts.
The identification of direct nuclear hormone receptor gene targets provides clues to their contribution to both development and cancer progression. Until recently, the identification of such direct target genes has relied on a combination of expression analysis and in silico searches for consensus binding motifs in gene promoters. Consensus binding motifs for transcription factors are often defined using in vitro DNA binding strategies. Such in vitro strategies fail to account for the many factors that contribute significantly to target selection by transcription factors in cells beyond the recognition of these short consensus DNA sequences. These factors include DNA methylation, chromatin structure, posttranslational modifications of transcription factors, and the cooperative recruitment of transcription factor complexes. Chromatin immunoprecipitation (ChIP) provides a means of isolating transcription factor complexes in the context of endogenous chromatin, allowing the identification of direct transcription factor targets. ChIP can be combined with site-specific PCR for candidate binding sites or alternatively with cloning, genomic microarrays or more recently direct high throughput sequencing to identify novel genomic targets. The application of ChIP-based approaches has redefined consensus binding motifs for transcription factors and provided important insights into transcription factor biology.


A synthetic, bioactive PDGF mimetic with binding to both alpha-PDGF and beta-PDGF receptors.
A multi-domain peptide, PAB2-1c, was designed and synthesized as a bioactive mimic of PDGF. PBA2-1c bound to both alpha- and beta-PDGF receptors as determined by surface plasmon resonance (SPR). The equilibrium dissociation constant (Kd) of binding to alpha-PDGF receptors by PAB2-1c (1.7 x 10(-8) M) compared favorably rhPDGF-AA (1.34 x 10(-8) M). Binding to -PDGF receptor by PAB2-1c (2.2 x 10(-8) M) was less favorable than, that of recombinant human PDGFBB (1.59 x 10(-9) M). Interestingly, PBA2-1c bound to these two receptors with similar affinity suggesting that, PBA2-1c was not PDGF receptor selective. In a murine myoblast cell line C2C12, PBA2-1c increased the tyrosine phosphorylation on PDGF receptors and the phosphorylation of AKT and ERK1/2 in a concentration-related manner. PBA2-1c also stimulated an increase in cell proliferation, cell migration, and collagen gel contraction. In these cell-based assays, PAB2-1c was effective at 1 microg/ml or lesser. The results support the hypothesis that PBA2-1c is a mimetic of PDGF, although it has a more promiscuous receptor interaction.


Tissue specific expression of the retinoic acid receptor-beta 2: regulation by short open reading frames in the 5'-noncoding region.
The 40-S subunit of eukaryotic ribosomes binds to the capped 5'-end of mRNA and scans for the first AUG in a favorable sequence context to initiate translation. Most eukaryotic mRNAs therefore have a short 5'-untranslated region (5'-UTR) and no AUGs upstream of the translational start site; features that seem to assure efficient translation. However, approximately 5-10% of all eukaryotic mRNAs, particularly those encoding for regulatory proteins, have complex leader sequences that seem to compromise translational initiation. The retinoic-acid-receptor-beta 2 (RAR beta 2) mRNA is such a transcript with a long (461 nucleotides) 5'-UTR that contains five, partially overlapping, upstream open reading frames (uORFs) that precede the major ORF. We have begun to investigate the function of this complex 5'-UTR in transgenic mice, by introducing mutations in the start/stop codons of the uORFs in RAR beta 2-lacZ reporter constructs. When we compared the expression patterns of mutant and wild-type constructs we found that these mutations affected expression of the downstream RAR beta 2-ORF, resulting in an altered regulation of RAR beta 2-lacZ expression in heart and brain. Other tissues were unaffected. RNA analysis of adult tissues demonstrated that the uORFs act at the level of translation; adult brains and hearts of transgenic mice carrying a construct with either the wild-type or a mutant UTR, had the same levels of mRNA, but only the mutant produced protein. Our study outlines an unexpected role for uORFs: control of tissue-specific and developmentally regulated gene expression.