Correcting fixed varus deformity with flexion contracture during total knee arthroplasty: the "inside-out" technique: AAOS exhibit selection.
Traditional methods for correcting a severe varus and flexion deformity of the knee during total knee arthroplasty can often lead to excessive release of the medial collateral ligament, hematoma formation, and reliance on constrained implants. The "inside-out" technique for correction of varus deformities involves performing a posteromedial capsulotomy at the level of the tibial cut and incising the superficial medial collateral ligament in a pie-crust manner in extension followed by serial manipulations with valgus stress. Our hypothesis was that this technique effectively corrects severe knee varus and flexion deformity with a reduced risk of complications. Thirty-one consecutive patients (thirty-four knees) with a severe fixed varus and flexion deformity (varus alignment of ≥ 15° and flexion contracture of ≥ 5°) underwent total knee arthroplasty with use of the inside-out technique between October 2006 and December 2009. Physical examination, radiographs, and multiple outcome instruments were used to evaluate the results. The mean duration of follow-up was 3.1 ± 1.1 years (range, 1.7 to 4.9 years). There were no cases of hematoma formation, excessive release of the medial collateral ligament, or acute or delayed instability. A semi-constrained TC3 implant was used in two cases. The mean preoperative coronal alignment was 21.1° ± 4° of varus, which was corrected to 4.5° ± 1.6° of valgus after surgery. The mean preoperative flexion contracture was 10° ± 3.5°. Postoperatively, two patients (three knees) had a residual flexion contracture, which was ≤5° in all cases. The mean range of knee motion improved from 103.3° ± 14.1° preoperatively to 119.1° ± 8° at the time of final follow-up. The mean Knee Society Score pain subscore improved from 39.5 ± 12.6 to 93.2 ± 10.5, and the function subscore improved from 47.1 ± 17.8 to 78.5 ± 21.9. There was no evidence of implant loosening or osteolysis on radiographs. The technique described was safe, reproducible, and effective in treating combined varus and flexion deformity of the knee during total knee arthroplasty. It reduced the risks of over-release of the medial collateral ligament, hematoma formation, and the need for constrained implants.


Interdependence and cooperation in daily life. Correction to Columbus et al. (2020).
Reports an error in "Interdependence and cooperation in daily life" by Simon Columbus, Catherine Molho, Francesca Righetti and Daniel Balliet (Journal of Personality and Social Psychology, 2021[Mar], Vol 120[3], 626-650). In the article (https://doi.org/10.1037/pspi0000253), due to a mistake in generating Figure 4, two histograms were distorted as the tallest bar in each histogram was completely omitted. The online version of this article has been corrected. (The following abstract of the original article appeared in record 2020-44813-001.) Philosophers and scientists have long debated the nature of human social interactions and the prevalence of mutual dependence, conflict of interests, and power asymmetry in social situations. Yet, there is surprisingly little empirical work documenting the patterns of interdependence that people experience in daily life. We use experience sampling to study how people think about 3 dimensions of interdependence in daily life and how these dimensions relate to cooperation. In Study 1, 139 romantic couples (n = 278) reported on situations experienced with their partner (k = 6,766); in Study 2, individuals (n = 284) reported on situations experienced with any other person (k = 7,248), over the course of 1 week. Across both samples, we found that most social interactions were perceived as containing moderate mutual dependence, equal power, and corresponding interests. When couples reported on the same situation (Study 1), they largely agreed on their experienced interdependence and cooperation, suggesting that their reports reflect an underlying shared reality. In daily interactions across both samples, higher mutual dependence and lower conflict of interests were associated with more cooperation, whereas relative power was not directly related to cooperation. These associations replicated in laboratory experiments (Study 2). In daily life, high mutual dependence and high relative power exacerbated the negative relation between conflict of interests and cooperation. Finally, prevalent patterns of interdependence and the experience of specific interdependent situations affected multiple relationship outcomes. Our findings stress the importance of studying a diverse array of interdependent situations-and especially situations with corresponding interests-to better understand cooperation in daily life. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Novel mechanism for the generation of human xeno-autoantibodies against the nonhuman sialic acid N-glycolylneuraminic acid.
The nonhuman sialic acid N-glycolylneuraminic acid (Neu5Gc) is metabolically incorporated into human tissues from certain mammalian-derived foods, and this occurs in the face of an anti-Neu5Gc "xeno-autoantibody" response. Given evidence that this process contributes to chronic inflammation in some diseases, it is important to understand when and how these antibodies are generated in humans. We show here that human anti-Neu5Gc antibodies appear during infancy and correlate with weaning and exposure to dietary Neu5Gc. However, dietary Neu5Gc alone cannot elicit anti-Neu5Gc antibodies in mice with a humanlike Neu5Gc deficiency. Other postnatally appearing anti-carbohydrate antibodies are likely induced by bacteria expressing these epitopes; however, no microbe is known to synthesize Neu5Gc. Here, we show that trace exogenous Neu5Gc can be incorporated into cell surface lipooligosaccharides (LOS) of nontypeable Haemophilus influenzae (NTHi), a human-specific commensal/pathogen. Indeed, infant anti-Neu5Gc antibodies appear coincident with antibodies against NTHi. Furthermore, NTHi that express Neu5Gc-containing LOS induce anti-Neu5Gc antibodies in Neu5Gc-deficient mice, without added adjuvant. Finally, Neu5Gc from baby food is taken up and expressed by NTHi. As the flora residing in the nasopharynx of infants can be in contact with ingested food, we propose a novel model for how NTHi and dietary Neu5Gc cooperate to generate anti-Neu5Gc antibodies in humans.


Chronic inflammatory injury results in increased coupling of delta opioid receptors to voltage-gated Ca2+ channels.
Opioid receptors regulate a diverse array of physiological functions. Mu opioid receptor agonists are well-known analgesics for treating acute pain. In contrast, animal models suggest that chronic pain is more effectively relieved by delta opioid receptor agonists. A number of studies have shown that chronic pain results in increased function of delta opioid receptors. This is proposed to result from enhanced trafficking of the delta opioid receptor to the cell membrane induced by persistent tissue injury. However, recent studies have questioned this mechanism, which has resulted in some uncertainty as to whether delta opioid receptors are indeed upregulated in chronic pain states. To clarify this question, we have examined the effect of chronic inflammatory pain over time using both an ex vivo measure of delta function: receptor-Ca2+ channel coupling, and an in vivo measure; the relief of chronic pain by a delta opioid receptor agonist. In addition, as beta-arrestin 2 can regulate delta opioid receptor trafficking and signaling, we have further examined whether deleting this scaffolding and signal transduction molecule alters delta opioid receptor function. We used the Complete Freund's Adjuvant model of inflammatory pain, and examined the effectiveness of the delta agonist, SNC80, to both inhibit Ca2+ channels in primary afferent neurons and to attenuate mechanical allodynia. In naïve beta-arrestin 2 wildtype and knockout mice, SNC80 neither significantly inhibited voltage-dependent Ca2+ currents nor produced antinociception. However, following inflammatory pain, both measures showed a significant and long-lasting enhancement of delta opioid receptor function that persisted for up to 14 days post-injury regardless of genotype. Furthermore, although this pain model did not alter Ca2+ current density, the contribution of N-type Ca2+ channels to the total current appeared to be regulated by the presence of beta-arrestin 2. Our results indicate that there is an upregulation of delta opioid receptor function following chronic pain. This gain of function is reflected in the increased efficacy of a delta agonist in both behavioral and electrophysiological measures. Overall, this work confirms that delta opioid receptors can be enhanced following tissue injury associated with chronic pain.


Coil-protected embolization technique for a branch-incorporated aneurysm.
A small branch-incorporated aneurysm is an aneurysm with a small branch incorporated into the sac or the neck. It is one of the most difficult aneurysms to treat with coil embolization. The aim of this study was to evaluate the safety and effectiveness of the coil-protected embolization technique for small-branch incorporated aneurysm. Fourteen aneurysms (2 ruptured and 12 unruptured) in 12 patients (mean age, 56 years, range, 40-73 years; 6 men and 6 women) were treated with the coil-protected embolization technique during the period between February 2007 and October 2011. Clinical and angiographic outcomes were retrospectively evaluated. All aneurysms were successfully treated without any complications during the procedure. Immediate post-treatment angiographies demonstrated complete or near complete occlusion in 12 and incomplete occlusion in 2 patients. Two patients had a delayed small embolic infarction in the relevant posterior circulation territory and middle cerebral artery territory 10 days and 14 days later, respectively, but both recovered completely or almost completely (modified Rankin scale score [mRS score], 0 and 1, respectively). During the clinical follow-up period (mean, 21 months; range: 2-58 months), all patients reported an mRS score of 0 (n = 10) or 1 (n = 2). Vascular imaging follow-up (catheter angiography: n = 3 and MR angiography: n = 8) was available in 11 aneurysms at 6-12 months. All 11 aneurysms showed complete occlusion except for 1 minor neck recurrence that did not require further treatment. In this series of cases, the coil-protected embolization technique seems to be feasible and effective in the treatment of small-branch incorporated aneurysms.


Rapid charge movements and photosensitivity of visual pigments in salamander rods and cones.
1. Photosensitivities of visual pigments were determined by measuring early receptor currents (ERCs) in voltage-clamped photoreceptors from larval salamanders. 2. As expected from previous work of others, the ERC elicited by a brief flash consisted of a rapid inward component followed by a larger and slower outward component. The magnitude of the outward component corresponded to the movement of about 0.18 electronic charge across the membrane per photoisomerization. 3. The time course of the ERC was independent of the flash intensity, the flash wavelength and the magnitude of the response. The outward component of the cone ERC declined about twice as rapidly as the outward component of the rod ERC.. 4. The amplitude of the ERC decreased as successive flashes bleached the cell's pigment. Using the proportional relation between the size of the ERC and the number of pigment molecules photoisomerized, photosensitivities of the native A2 pigments in rods, red-sensitive cones, blue-sensitive cones and UV-sensitive cones were determined. Calculated solution photosensitivities for rhodopsin, red-sensitive and blue-sensitive cone pigments were not significantly different and the average value for all three pigments at their respective absorption maxima was (7.3 +/- 1.6) x 10(-9) micron 2 molecule-1. A value of 44.0 x 10(-9) micron 2 molecule-1 was obtained in a single UV-sensitive cone. 5. Substitution of the native dehydroretinal chromophore in the red-sensitive cone pigment with 11-cis-retinal increased the solution photosensitivity to (9.6 +/- 0.62) x 10(-9) micron 2 molecule-1. 6. We conclude that cone pigments have large molecular absorption cross-sections and high quantum efficiencies of photoisomerization. These properties seem well suited for the receptive molecules of a highly sensitive, miniaturized transducer.


Early phase of plasticity-related gene regulation and SRF dependent transcription in the hippocampus.
Hippocampal organotypic cultures are a highly reliable in vitro model for studying neuroplasticity: in this paper, we analyze the early phase of the transcriptional response induced by a 20 µM gabazine treatment (GabT), a GABA-Ar antagonist, by using Affymetrix oligonucleotide microarray, RT-PCR based time-course and chromatin-immuno-precipitation. The transcriptome profiling revealed that the pool of genes up-regulated by GabT, besides being strongly related to the regulation of growth and synaptic transmission, is also endowed with neuro-protective and pro-survival properties. By using RT-PCR, we quantified a time-course of the transient expression for 33 of the highest up-regulated genes, with an average sampling rate of 10 minutes and covering the time interval [10∶90] minutes. The cluster analysis of the time-course disclosed the existence of three different dynamical patterns, one of which proved, in a statistical analysis based on results from previous works, to be significantly related with SRF-dependent regulation (p-value<0.05). The chromatin immunoprecipitation (chip) assay confirmed the rich presence of working CArG boxes in the genes belonging to the latter dynamical pattern and therefore validated the statistical analysis. Furthermore, an in silico analysis of the promoters revealed the presence of additional conserved CArG boxes upstream of the genes Nr4a1 and Rgs2. The chip assay confirmed a significant SRF signal in the Nr4a1 CArG box but not in the Rgs2 CArG box.


Reconstructing Genomes of Carbon Monoxide Oxidisers in Volcanic Deposits Including Members of the Class Ktedonobacteria.
Microorganisms can potentially colonise volcanic rocks using the chemical energy in reduced gases such as methane, hydrogen (H2) and carbon monoxide (CO). In this study, we analysed soil metagenomes from Chilean volcanic soils, representing three different successional stages with ages of 380, 269 and 63 years, respectively. A total of 19 metagenome-assembled genomes (MAGs) were retrieved from all stages with a higher number observed in the youngest soil (1640: 2 MAGs, 1751: 1 MAG, 1957: 16 MAGs). Genomic similarity indices showed that several MAGs had amino-acid identity (AAI) values >50% to the phyla Actinobacteria, Acidobacteria, Gemmatimonadetes, Proteobacteria and Chloroflexi. Three MAGs from the youngest site (1957) belonged to the class Ktedonobacteria (Chloroflexi). Complete cellular functions of all the MAGs were characterised, including carbon fixation, terpenoid backbone biosynthesis, formate oxidation and CO oxidation. All 19 environmental genomes contained at least one gene encoding a putative carbon monoxide dehydrogenase (CODH). Three MAGs had form I coxL operon (encoding the large subunit CO-dehydrogenase). One of these MAGs (MAG-1957-2.1, Ktedonobacterales) was highly abundant in the youngest soil. MAG-1957-2.1 also contained genes encoding a [NiFe]-hydrogenase and hyp genes encoding accessory enzymes and proteins. Little is known about the Ktedonobacterales through cultivated isolates, but some species can utilise H2 and CO for growth. Our results strongly suggest that the remote volcanic sites in Chile represent a natural habitat for Ktedonobacteria and they may use reduced gases for growth.


Mechanosensitive channel gating transitions resolved by functional changes upon pore modification.
The mechanosensitive channel of large conductance acts as a biological "emergency release valve" that protects bacterial cells from hypoosmotic stress. Although structural and functional studies and molecular dynamic simulations of this channel have led to several models for the structural transitions that occur in the gating process, inconsistencies linger and details are lacking. A previous study, using a method coined as the "in vivo SCAM", identified several residues in the channel pore that were exposed to the aqueous environment in the closed and opening conformations. Briefly, the sulfhydryl reagent MTSET was allowed to react, in the presence or absence of hypoosmotic shock, with cells expressing mechanosensitive channel of large conductance channels that contained cysteine substitutions; channel dysfunction was assessed solely by cell viability. Here we evaluate the MTSET-induced functional modifications to these mechanosensitive channel activities by measuring single channel recordings. The observed changes in residue availability in different states, as well as channel kinetics and sensitivity, have allowed us to elucidate the microenvironment encountered for a number of pore residues, thus testing many aspects of previous models and giving a higher resolution of the pore domain and the structural transitions it undergoes from the closed to open state.


Merkel cell polyomavirus small tumour antigen activates the p38 MAPK pathway to enhance cellular motility.
Merkel cell carcinoma (MCC) is an aggressive skin cancer with high rates of recurrence and metastasis. Merkel cell polyomavirus (MCPyV) is associated with the majority of MCC cases. MCPyV-induced tumourigenesis is largely dependent on the expression of the small tumour antigen (ST). Recent findings implicate MCPyV ST expression in the highly metastatic nature of MCC by promoting cell motility and migration, through differential expression of cellular proteins that lead to microtubule destabilisation, filopodium formation and breakdown of cell-cell junctions. However, the molecular mechanisms which dysregulate these cellular processes are yet to be fully elucidated. Here, we demonstrate that MCPyV ST expression activates p38 MAPK signalling to drive cell migration and motility. Notably, MCPyV ST-mediated p38 MAPK signalling occurs through MKK4, as opposed to the canonical MKK3/6 signalling pathway. In addition, our results indicate that an interaction between MCPyV ST and the cellular phospatase subunit PP4C is essential for its effect on p38 MAPK signalling. These results provide novel opportunities for the treatment of metastatic MCC given the intense interest in p38 MAPK inhibitors as therapeutic agents.


Enhanced chlorhexidine skin penetration with 1,8-cineole.
Chlorhexidine (CHG) penetrates poorly into skin. The purpose of this study was to compare the depth of CHG skin permeation from solutions containing either 2% (w/v) CHG and 70% (v/v) isopropyl alcohol (IPA) or 2% (w/v) CHG, 70% (v/v) IPA and 2% (v/v) 1,8-cineole. An ex-vivo study using Franz diffusion cells was carried out. Full thickness human skin was mounted onto the cells and a CHG solution, with or without 2% (v/v) 1,8-cineole was applied to the skin surface. After twenty-four hours the skin was sectioned horizontally in 100 μm slices to a depth of 2000 μm and the concentration of CHG in each section quantified using high performance liquid chromatography (HPLC). The data were analysed with repeated measures analysis of variance. The concentration of CHG in the skin on average was significantly higher (33.3% [95%, CI 1.5% - 74.9%]) when a CHG solution which contained 1,8-cineole was applied to the skin compared to a CHG solution which did not contain this terpene (P = 0.042). Enhanced delivery of CHG can be achieved in the presence of 1,8-cineole, which is the major component of eucalyptus oil. This may reduce the numbers of microorganisms located in the deeper layers of the skin which potentially could decrease the risk of surgical site infection.


Effects of intravenous administration of allogenic bone marrow- and adipose tissue-derived mesenchymal stem cells on functional recovery and brain repair markers in experimental ischemic stroke.
Stem cell therapy can promote good recovery from stroke. Several studies have demonstrated that mesenchymal stem cells (MSC) are safe and effective. However, more information regarding appropriate cell type is needed from animal model. This study was targeted at analyzing the effects in ischemic stroke of acute intravenous (i.v.) administration of allogenic bone marrow- (BM-MSC) and adipose-derived-stem cells (AD-MSC) on functional evaluation results and brain repair markers. Allogenic MSC (2 × 106 cells) were administered intravenously 30 minutes after permanent middle cerebral artery occlusion (pMCAO) to rats. Infarct volume and cell migration and implantation were analyzed by magnetic resonance imaging (MRI) and immunohistochemistry. Function was evaluated by the Rogers and rotarod tests, and cell proliferation and cell-death were also determined. Brain repair markers were analyzed by confocal microscopy and confirmed by western blot. Compared to infarct group, function had significantly improved at 24 h and continued at 14 d after i.v. administration of either BM-MSC or AD-MSC. No reduction in infarct volume or any migration/implantation of cells into the damaged brain were observed. Nevertheless, cell death was reduced and cellular proliferation significantly increased in both treatment groups with respect to the infarct group. At 14 d after MSC administration vascular endothelial growth factor (VEGF), synaptophysin (SYP), oligodendrocyte (Olig-2) and neurofilament (NF) levels were significantly increased while those of glial fiibrillary acid protein (GFAP) were decreased. i.v. administration of allogenic MSC - whether BM-MSC or AD-MSC, in pMCAO infarct was associated with good functional recovery, and reductions in cell death as well as increases in cellular proliferation, neurogenesis, oligodendrogenesis, synaptogenesis and angiogenesis markers at 14 days post-infarct.


Scrub typhus increases the risk of developing acute coronary syndrome: a nationwide cohort study.
Studies investigating the epidemiological relationship between scrub typhus and the subsequent development of acute coronary syndrome (ACS) are lacking. Therefore, we conducted a nationwide longitudinal cohort study in Taiwan to explore whether patients with scrub typhus are at an increased risk of developing ACS. This study investigated the incidence and risk factors for ACS in 5215 patients newly diagnosed with scrub typhus from the Taiwan National Health Insurance Research Database between 2000 and 2011. The comparison cohort contained 20 860 persons from the general population without scrub typhus. The follow-up period ran from the time of the initial diagnosis for scrub typhus to the date of an ACS event, censoring, or 31 December 2011. We used Cox proportional hazard regression models to analyse the risk of ACS by including the variables of sex, age and comorbidities. The incidence of ACS was higher in patients with scrub typhus than in the comparison cohort (3.10 vs 1.92 per 1000 person-years). The HR of developing ACS increased by 37% in patients with scrub typhus after adjusting for age, sex and comorbidities. Men, increased age, hypertension, diabetes, hyperlipidaemia, chronic obstructive pulmonary disease and coronary artery disease were identified as independent risk factors of developing ACS after controlling for covariates. The prominent effect of scrub typhus on subsequent ACS development appeared within 1 year after infection. This nationwide study determined that patients with scrub typhus exhibited a 37% increase in the risk of subsequently developing ACS compared with that of the general population.


Pentaethylene-terephthalate (PET) bottles: a new device for autoerotic strangulation of the penis causing serious injury.
Strangulation of the penis by application of constricting devices may present a challenge for the treating physician. Depending on the type of constricting material, special equipment is essential for successful removal of the foreign bodies. We report a new form of constricting device, the neck of a Coca Cola bottle made of Pentaethylene-terephthalate (PET). Particular difficulties were encountered upon removal. Technical details of this case are described. Prior literature on the treatment of penile strangulation is discussed.


The Pharmacogenomics of Bipolar Disorder study (PGBD): identification of genes for lithium response in a prospective sample.
Bipolar disorder is a serious and common psychiatric disorder characterized by manic and depressive mood switches and a relapsing and remitting course. The cornerstone of clinical management is stabilization and prophylaxis using mood-stabilizing medications to reduce both manic and depressive symptoms. Lithium remains the gold standard of treatment with the strongest data for both efficacy and suicide prevention. However, many patients do not respond to this medication, and clinically there is a great need for tools to aid the clinician in selecting the correct treatment. Large genome wide association studies (GWAS) investigating retrospectively the effect of lithium response are in the pipeline; however, few large prospective studies on genetic predictors to of lithium response have yet been conducted. The purpose of this project is to identify genes that are associated with lithium response in a large prospective cohort of bipolar patients and to better understand the mechanism of action of lithium and the variation in the genome that influences clinical response. This study is an 11-site prospective non-randomized open trial of lithium designed to ascertain a cohort of 700 subjects with bipolar I disorder who experience protocol-defined relapse prevention as a result of treatment with lithium monotherapy. All patients will be diagnosed using the Diagnostic Interview for Genetic Studies (DIGS) and will then enter a 2-year follow-up period on lithium monotherapy if and when they exhibit a score of 1 (normal, not ill), 2 (minimally ill) or 3 (mildly ill) on the Clinical Global Impressions of Severity Scale for Bipolar Disorder (CGI-S-BP Overall Bipolar Illness) for 4 of the 5 preceding weeks. Lithium will be titrated as clinically appropriate, not to exceed serum levels of 1.2 mEq/L. The sample will be evaluated longitudinally using a wide range of clinical scales, cognitive assessments and laboratory tests. On relapse, patients will be discontinued or crossed-over to treatment with valproic acid (VPA) or treatment as usual (TAU). Relapse is defined as a DSM-IV manic, major depressive or mixed episode or if the treating physician decides a change in medication is clinically necessary. The sample will be genotyped for GWAS. The outcome for lithium response will be analyzed as a time to event, where the event is defined as clinical relapse, using a Cox Proportional Hazards model. Positive single nucleotide polymorphisms (SNPs) from past genetic retrospective studies of lithium response, the Consortium on Lithium Genetics (ConLiGen), will be tested in this prospective study sample; a meta-analysis of these samples will then be performed. Finally, neurons will be derived from pluripotent stem cells from lithium responders and non-responders and tested in vivo for response to lithium by gene expression studies. SNPs in genes identified in these cellular studies will also be tested for association to response. Lithium is an extraordinarily important therapeutic drug in the clinical management of patients suffering from bipolar disorder. However, a significant proportion of patients, 30-40 %, fail to respond, and there is currently no method to identify the good lithium responders before initiation of treatment. Converging evidence suggests that genetic factors play a strong role in the variation of response to lithium, but only a few genes have been tested and the samples have largely been retrospective or quite small. The current study will collect an entirely unique sample of 700 patients with bipolar disorder to be stabilized on lithium monotherapy and followed for up to 2 years. This study will produce useful information to improve the understanding of the mechanism of action of lithium and will add to the development of a method to predict individual response to lithium, thereby accelerating recovery and reducing suffering and cost. ClinicalTrials.gov Identifier: NCT01272531 Registered: January 6, 2011.


Donepezil rescues spatial learning and memory deficits following traumatic brain injury independent of its effects on neurogenesis.
Traumatic brain injury (TBI) is ubiquitous and effective treatments for it remain supportive largely due to uncertainty over how endogenous repair occurs. Recently, we demonstrated that hippocampal injury-induced neurogenesis is one mechanism underlying endogenous repair following TBI. Donepezil is associated with increased hippocampal neurogenesis and has long been known to improve certain aspects of cognition following many types of brain injury through unknown mechanisms. By coupling donepezil therapy with temporally regulated ablation of injury-induced neurogenesis using nestin-HSV transgenic mice, we investigated whether the pro-cognitive effects of donepezil following injury might occur through increasing neurogenesis. We demonstrate that donepezil itself enhances neurogenesis and improves cognitive function following TBI, even when injury-induced neurogenesis was inhibited. This suggests that the therapeutic effects of donepezil in TBI occur separately from its effects on neurogenesis.


CD40 is a functional activation antigen and B7-independent T cell costimulatory molecule on normal human lung fibroblasts.
CD40 is an important signaling and activation Ag found on certain bone marrow-derived cells. Recently, CD40 also has been shown to be expressed by mesenchymal cells, including human fibroblasts. Little is known about the role of CD40 in fibroblasts. The current study investigates the hypothesis that CD40 expressed on lung fibroblasts is an activation structure and mechanism for interaction with hemopoietic cells. Communication between resident tissue fibroblasts and T cells is necessary for normal wound healing, and can be pathologic, resulting in tissue fibrosis. Signaling through CD40 with soluble CD40 ligand stimulated fibroblast activation, as evidenced by mobilization of nuclear factor-kappaB and by induction of the proinflammatory and chemoattractant cytokines IL-6 and IL-8. IFN-gamma-primed lung fibroblasts costimulate T lymphocyte proliferation utilizing CD40, but not the well-studied costimulatory molecules B7-1 and B7-2. Data reported herein support the hypothesis that cognate interactions between tissue fibroblasts and infiltrating T lymphocytes, via the CD40/CD40L pathway, augment inflammation and may promote fibrogenesis by activating both cell types.


Structural basis of inhibition of the human serine hydroxymethyltransferase SHMT2 by antifolate drugs.
Serine hydroxymethyltransferase (SHMT) is the major source of 1-carbon units required for nucleotide synthesis. Humans have cytosolic (SHMT1) and mitochondrial (SHMT2) isoforms, which are upregulated in numerous cancers, making the enzyme an attractive drug target. Here, we show that the antifolates lometrexol and pemetrexed are inhibitors of SHMT2 and solve the first SHMT2-antifolate structures. The antifolates display large differences in their hydrogen bond networks despite their similarity. Lometrexol was found to be the best hSHMT1/2 inhibitor from a panel antifolates. Comparison of apo hSHMT1 with antifolate bound hSHMT2 indicates a highly conserved active site architecture. This structural information offers insights as to how these compounds could be improved to produce more potent and specific inhibitors of this emerging anti-cancer drug target.


Prostate cancer from the horizon of the patient.
The democratization of civil society and the development of modern medicine changed the sacrosanct doctor-patient relationship to a doctor-partner dialogue. Values and respect were lost in the process where common courtesy and empathy in trust were replaced by patient rights. LAUNCH OF EUROPA UOMO: Europa Uomo, the European prostate cancer coalition, represents 22 national, autonomous patient support groups. Its aim includes increasing the awareness of prostate diseases, support individualized treatment as a balance between optimal medical treatment and personalized care delivered by a multiprofessional team. We expect our information/education from dedicated professional societies while in return we share care for properly informed members as well as a fast, unbiased and cheap distribution of information/innovation across the European continent. THE ROLE OF A PATIENT GROUP: Our advocacy role is focused on quality of life, tailored treatment, knowledge of risk factors, support for research and last but not least active partnerships. We believe that we can play a modest but basic role in common actions to overcome inequalities in treatment and care in Europe. Our responsibilities range from defining patient obligations to facilitating translational research and saving scarce health resources. THE HORIZON OF THE PATIENT: Our hope is to plead for a treatment policy on the man first and then on his cancer and to improve treatment outcomes by multiprofessional collaboration and the development of expert Prostate Units. FUTURE EXPECTATIONS: A transparent, open communication line between the multiprofessional team and the patient is mandatory. The existing uncertainties should be discussed with common sense but always leave a factor of hope in survival or quality of life.


Rapid tree carbon stock recovery in managed Amazonian forests.
While around 20% of the Amazonian forest has been cleared for pastures and agriculture, one fourth of the remaining forest is dedicated to wood production. Most of these production forests have been or will be selectively harvested for commercial timber, but recent studies show that even soon after logging, harvested stands retain much of their tree-biomass carbon and biodiversity. Comparing species richness of various animal taxa among logged and unlogged forests across the tropics, Burivalova et al. found that despite some variability among taxa, biodiversity loss was generally explained by logging intensity (the number of trees extracted). Here, we use a network of 79 permanent sample plots (376 ha total) located at 10 sites across the Amazon Basin to assess the main drivers of time-to-recovery of post-logging tree carbon (Table S1). Recovery time is of direct relevance to policies governing management practices (i.e., allowable volumes cut and cutting cycle lengths), and indirectly to forest-based climate change mitigation interventions.


Residual symptoms after natural remission of insomnia: associations with relapse over 4 years.
Chronic insomnia tends to "wax and wane" over lifetime. The presence of residual insomnia symptoms is common, especially among naturally remitted individuals. This study aims to examine the features of these residual symptoms and their potential association with future relapse. A population-based data set on the natural history of insomnia was used for this secondary analysis. Residual insomnia symptoms were investigated in those who had insomnia symptoms/syndrome at baseline and achieved full remission (according to predetermined diagnostic algorithm) within the following 1 year. Cox regressions were used to determine the hazard ratio (HR) of each residual symptom for predicting relapse in the next 4 years. The nature and severity of residual symptoms were examined with an extended version of the Insomnia Severity Index (ISI), which incorporates additional items on sleep quality and specific sleep-related daytime impairments (on daytime fatigue, cognitive functioning, mood, interpersonal relationship, and daily activities). In addition, the presence of depressive symptoms and medical conditions were controlled for in investigating risks of insomnia relapse. A total of 434 participants were included in this study (age ranges from 18 to 94; 65.9% female); 248 of them had relapsed within 4 years. The response rate ranged from 78% to 83%. The most frequently reported residual symptoms with at least moderate severity (ISI items ≥2 on 0-4 ISI item scale) were poor "Quality of sleep" (39.2 %), followed by "difficulty maintaining sleep" (DMS; 27%). The most common residual daytime impairments related to insomnia were fatigue (24.7 %), mood disturbances (23%) and cognitive disturbances (22.6%). After controlling for baseline insomnia and depression severity and concurrent physical diseases, impairments of cognition (HR = 1.46), poor quality of sleep (HR = 1.43), disturbed mood (HR = 1.39), being female (HR = 1.36), DMS (HR = 1.35), and fatigue (HR = 1.24) were significantly associated with insomnia relapse in the next 4 years. Moreover, residual poor sleep quality and daytime insomnia symptoms were independent of DMS in predicting relapse. Subgroup regressions according to sex showed that for male participants, residual cognition impairments (HR = 1.98) was the most significant predictors of future relapse, whereas residual DMS (HR = 1.46) significantly predicted relapse for women only. A wide range of residual symptoms exists in individuals with naturally remitted insomnia. Notably, residual DMS is the most common residual nighttime symptom and the only nighttime symptom associated with insomnia relapse. Additionally, perceived poor sleep quality and cognitive, mood, and somatic impairments attributed to sleep disturbances are also related to future relapse. Attention to these residual symptoms when initiating insomnia treatment is warranted to minimize future relapse.


Precipitating factors and the outcome of hepatic encephalopathy in liver cirrhosis.
To determine precipitants of hepatic encephalopathy (HE) and their impact on hospital stay and mortality. Cross-sectional, analytical study. The Aga Khan University Hospital, from January 2005 to December 2007. Consecutive patients admitted with different grades of HE were evaluated between January 2005 and December 2007. The precipitants of HE were correlated with the different grades of HE, and length of hospital stay and mortality. Chi-square test was used to compare the proportion of precipitating factors versus hospital stay and grade with significance at p<0.05. Of the 404 patients 252 (62%) were males. Hepatitis C virus was the cause of cirrhosis in 283 (70%); Child Turcotte Pugh (CTP) class C was present in 317 (78%) patients. On presentation, 17% patients had grade 1 HE while 44%, 29% and 10% had grades 2, 3 and 4 respectively. The most common precipitant of HE was spontaneous bacterial peritonitis in 83 (20.5%), constipation in 74 (18.3%) and urinary tract infection in 62 (15.3%). One hundred and forty (35%) patients had (3) 2 precipitating factors while no precipitant was noted in 50 (12%) patients. Mean hospital stay was 4+/-3 days. The lesser the number of precipitants, shorter was the length of stay (p<0.01) and lesser was the grade of HE (p=0.025). Complete reversal of HE was noted in 366 patients (91%) while the remaining had grade 1 HE on discharge. Nine (2.2%) patients died during the hospital stay. No mortality was noted in patients without precipitants. Patients presenting with (3) 2 precipitating factors and advanced grade of HE had a prolonged hospital stay. Moreover, patients without precipitants had better outcomes.


Methods for quantitative susceptibility and R2* mapping in whole post-mortem brains at 7T applied to amyotrophic lateral sclerosis.
Susceptibility weighted magnetic resonance imaging (MRI) is sensitive to the local concentration of iron and myelin. Here, we describe a robust image processing pipeline for quantitative susceptibility mapping (QSM) and R2* mapping of fixed post-mortem, whole-brain data. Using this pipeline, we compare the resulting quantitative maps in brains from patients with amyotrophic lateral sclerosis (ALS) and controls, with validation against iron and myelin histology. Twelve post-mortem brains were scanned with a multi-echo gradient echo sequence at 7T, from which susceptibility and R2* maps were generated. Semi-quantitative histological analysis for ferritin (the principal iron storage protein) and myelin proteolipid protein was performed in the primary motor, anterior cingulate and visual cortices. Magnetic susceptibility and R2* values in primary motor cortex were higher in ALS compared to control brains. Magnetic susceptibility and R2* showed positive correlations with both myelin and ferritin estimates from histology. Four out of nine ALS brains exhibited clearly visible hyperintense susceptibility and R2* values in the primary motor cortex. Our results demonstrate the potential for MRI-histology studies in whole, fixed post-mortem brains to investigate the biophysical source of susceptibility weighted MRI signals in neurodegenerative diseases like ALS.


Bifurcated converging pathways for high Ca2+- and TGFbeta-induced inhibition of growth of normal human keratinocytes.
Growth suppression of normal human keratinocytes by high Ca2+ or TGFbeta was shown to be mediated by p21WAF1/CIP1 and Sp1 [Pardali, K., et al. (2000) J. Biol. Chem. 275, 29244-29256; Santini, M. P., Talora, C., Seki, T., Bolgan, L. & Dotto, G. P. (2001) Proc. Nat. Acad. Sci. USA 98, 9575-9580; Al-Daraji, W. I., Grant, K. R., Ryan, K., Saxton, A., & Reynolds, N. J. (2002) J. Invest. Dermatol. 118, 779-788]. We previously demonstrated that S100C/A11 is a key mediator for growth inhibition of normal human epidermal keratinocytes (NHK) triggered by high Ca2+ or TGFbeta [Sakaguchi, M., et al. (2003) J. Cell Biol. 163, 825-835; Sakaguchi, M., et al. (2004) 164, 979-984]. On exposure of NHK cells to either agent, S100C/A11 is transferred to nuclei, where it induces p21WAF1/CIP1 through activation of Sp1/Sp3. In the present study, we found that high Ca2+ activated NFAT1 through calcineurin-dependent dephosphorylation. In growing NHK cells, Krueppel-like factor (KLF)16, a member of the Sp/KLF family, bound to the p21WAF1/CIP1 promoter and, thereby, inhibited the transcription of p21(WAF1/CIP1). Sp1 complexed with NFAT1 in high Ca2+-treated cells or with Smad3 in TGFbeta1-treated cells, but not Sp1 alone, replaced KLF16 from the p21WAF1/CIP1 promoter and transcriptionally activated the p21WAF1/CIP1 gene. Thus, high Ca2+ and TGFbeta1 have a common S100C/A11-mediated pathway in addition to a unique pathway (NFAT1-mediated pathway for high Ca2+ and Smad-mediated pathway for TGFbeta1) for exhibiting a growth inhibitory effect on NHK cells, and both pathways were shown to be indispensable for growth inhibition.


Comparison of gait and pathology outcomes of three meniscal procedures for induction of knee osteoarthritis in sheep.
Meniscectomy (MX) of sheep induces a well-established animal model of human osteoarthritis (OA). This study compared the clinical (lameness) and pathological outcomes of unilateral, complete medial MX vs two less traumatic and more easily performed meniscal destabilisation procedures. Four-year old wethers (n = 6/group) underwent sham operation, cranial pole release (CPR), mid-body transection (MBT) or total MX of the medial meniscus. Joints were assessed for gross pathology (cartilage erosion and osteophytes), histomorphometry, two histopathology scoring methods (modified Mankin-type and Pritzker score), and immunohistology for ADAMTS- and MMP-cleaved neoepitopes, at 12 weeks post-op. Ground reaction forces (GRFs) were determined by force plate in a subset (n = 4/group) at baseline, 2.5, 8, and 12 weeks post-op. Gross pathology scores of operated groups differed significantly from sham animals (P < 0.05) but not from each other, though qualitative differences were noted: CPR sheep developed more cranial and focal lesions, while MBT and MX joints showed more widespread lesions and osteophyte formation. Similarly, histopathology scores were significantly elevated vs sham but did not differ between operated groups at P < 0.05, except for a trend for lower tibial cartilage histopathology in MBT consistent with the immunohistologic pattern of reduced aggrecanase-cleavage neoepitope in that model. CPR sheep developed less femoral subchondral sclerosis, suggesting some residual biomechanical effect from the destabilised but intact meniscus. Few significant differences were noted between operated groups in force plate analyses, though gait abnormalities appeared to be least in CPR sheep, and most persistent (>12 weeks) in MBT animals. The well-validated ovine MX model and the simpler meniscal destabilisation procedures resulted in broadly similar joint pathology and lameness. Meniscal CPR or MBT, as easier and more clinically relevant procedures, may represent preferred models for the induction of OA and evaluation of potential disease-modifying therapies.


Infection Risk in Sterile Operative Procedures.
The main objective of hospital hygiene and infection prevention is to protect patients from preventable nosocomial infections. It was recently stated that the proper goal should be for zero infection rates in sterile surgical procedures. In this article, we attempt to determine whether this demand is supported by the available literature. We systematically searched the Medline and EMBASE databases for studies published in the last 10 years on the efficacy of infection control measures and carried out a meta-analysis according to the PRISMA tool. We used the following search terms: "aseptic surgery," "intervention," "surgical site infection," "nosocomial infection," "intervention," and "prevention." 2277 articles were retrieved, of which 204 were acquired in full text and analyzed. The quantitative analysis included 7 prospective cohort studies on the reduction of nosocomial infection rates after aseptic surgery. The measures used included training sessions, antibiotic prophylaxis, and operative-site disinfection and cleaning techniques. These interventions succeeded in reducing postoperative wound infections (relative risk (RR] 0.99 [0.98; 1.00]). Subgroup analyses on antibiotic prophylaxis (RR 0.99 [0.98; 1.01]) and noncontrolled trials (RR 0.97 [0.92; 1.02]) revealed small, insignificant effects. A multimodal approach with the participation of specialists from various disciplines can further reduce the rate of postoperative infection. A reduction to zero is not realistic and is not supported by available evidence.


HFE genotype in patients with hemochromatosis and other liver diseases.
Hereditary hemochromatosis is a common inherited disorder of iron metabolism. The gene HFE, which contains two missense mutations (C282Y and H63D), was recently identified. To determine how HFE genotyping for the C282Y and H63D mutations contributes to the diagnosis of hemochromatosis and to determine the prevalence of HFE mutations in a group of patients with liver disease. Cross-sectional study. Academic medical center. 66 patients with hereditary hemochromatosis and 132 referred patients with other liver diseases. At initial diagnosis, fasting transferrin saturation, ferritin level, routine chemistry panel, and complete blood count were determined. Percutaneous liver biopsy was done on all patients for histologic analysis and measurement of hepatic iron concentration and hepatic iron index. HFE genotyping for the C282Y and H63D mutations was done on all patients by using genomic DNA samples. Of the 66 patients with hemochromatosis diagnosed on the basis of serum iron studies and liver biopsy findings, 60 (91%) were C282Y homozygotes, 2 (3%) were compound heterozygotes, 1 (1.5%) was a C282Y heterozygote, 2 (3%) were H63D heterozygotes, and 1 (1.5%) was negative for both mutations. Of the 132 patients with liver disease, 6 (5%) were C282Y homozygotes, 8 (6%) were compound heterozygotes, 6 (5%) were C282Y heterozygotes, 5 (4%) were H63D homozygotes, 20 (15%) were H63D heterozygotes, and 87 (66%) were negative for both mutations. All 66 C282Y homozygotes had an elevated hepatic iron concentration, and 65 of the 66 patients (98%) had a transferrin saturation of at least 45%. Ten of the 66 patients (15% [95% CI, 7.5% to 26%]) had a hepatic iron index less than 1.9 mmol/kg per year; hemochromatosis was not suspected in 6 of the 10 patients before genotyping. Cirrhosis or substantial hepatic fibrosis was not seen in any (0% [CI, 0% to 18%]) of the 19 patients younger than 40 years of age who were homozygous for the C282Y mutation. All 66 patients homozygous for the C282Y mutation of HFE had an elevated hepatic iron concentration, but approximately 15% of these patients did not meet a previous diagnostic criterion for hemochromatosis (hepatic iron index > 1.9 mmol/kg per year). Determination of HFE genotype is clinically useful in patients with liver disease and suspected iron overload and may lead to identification of otherwise unsuspected C282Y homozygotes.


Human DNA polymerase alpha uses a combination of positive and negative selectivity to polymerize purine dNTPs with high fidelity.
DNA polymerases accurately replicate DNA by incorporating mostly correct dNTPs opposite any given template base. We have identified the chemical features of purine dNTPs that human pol alpha uses to discriminate between right and wrong dNTPs. Removing N-3 from guanine and adenine, two high-fidelity bases, significantly lowers fidelity. Analogously, adding the equivalent of N-3 to low-fidelity benzimidazole-derived bases (i.e., bases that pol alpha rapidly incorporates opposite all four natural bases) and to generate 1-deazapurines significantly strengthens the ability of pol alpha to identify the resulting 1-deazapurines as wrong. Adding the equivalent of the purine N-1 to benzimidazole or to 1-deazapurines significantly decreases the rate at which pol alpha polymerizes the resulting bases opposite A, C, and G while simultaneously enhancing polymerization opposite T. Conversely, adding the equivalent of adenine's C-6 exocyclic amine (N-6) to 1- and 3-deazapurines also enhances polymerization opposite T but does not significantly decrease polymerization opposite A, C, and G. Importantly, if the newly inserted bases lack N-1 and N-6, pol alpha does not efficiently polymerize the next correct dNTP, whereas if it lacks N-3, one additional nucleotide is added and then chain termination ensues. These data indicate that pol alpha uses two orthogonal screens to maximize its fidelity. During dNTP polymerization, it uses a combination of negative (N-1 and N-3) and positive (N-1 and N-6) selectivity to differentiate between right and wrong dNTPs, while the shape of the base pair is essentially irrelevant. Then, to determine whether to add further dNTPs onto the just added nucleotide, pol alpha appears to monitor the shape of the base pair at the primer 3'-terminus. The biological implications of these results are discussed.


Absolute quantification of multisite phosphorylation by selective reaction monitoring mass spectrometry: determination of inhibitory phosphorylation status of cyclin-dependent kinases.
Multisite phosphorylation is an important mechanism for achieving intricate regulation of protein function. Here we extended the absolute quantification of abundance (AQUA) methodology and validated its applicability to quantitatively study multisite phosphorylation. As a test case, we chose the conserved inhibitory site of the cyclin-dependent kinases (CDKs), Cdk1, Cdk2, and Cdk3, which are important regulators of cell cycle transitions and apoptosis. Inhibitory phosphorylation at Thr(14) and Tyr(15) of the CDKs is modulated by complex regulatory mechanisms involving multiple kinases and phosphatases. Yet the resulting quantitative dynamics among the four possible phosphorylated and non-phosphorylated versions of CDKs (T14p-Y15p, T14p-Y15, T14-Y15p, and T14-Y15) has not been investigated to date. Hence we used the heavy isotope-labeled tryptic peptides spanning the inhibitory site as internal standards and quantified all four versions by LC-selected reaction monitoring. Quantification of the phosphorylation status of the inhibitory site in the cell extracts provided novel quantitative insights. 1) The transition to mitotic phase was dominated by the conversion of "T14p-Y15p" to the "T14-Y15" form, whereas the two monophosphorylated forms were considerably lower in abundance. 2) The amount of all four forms decreased during the progression of apoptosis but with differing kinetics. Analysis of immunoprecipitated Cdk1 and Cdk2 revealed that the inhibitory site phosphorylation state of both kinases at different stages of the cell cycle followed the same trend. Quantitative immunoblotting using antibodies to Cdk1 and Cdk2 and to the T14-Y15p form suggested that quantification by AQUA was reliable and accurate. These results highlight the utility of internal standard peptides to achieve accurate quantification of multisite phosphorylation status.


Comparison of osteoporosis in US adults with type 1 and type 2 diabetes mellitus.
We examined bone mineral density (BMD) and osteoporosis prevalence in those with type 1 compared to type 2 diabetes derived from a nationally representative sample from the civilian community in the United States. Data from the National Health and Nutrition Examination Survey (NHANES) for 2005-2006, 2007-2008, 2009-2010, and 2013-2014 were merged to obtain a large sample of diabetics at least 20 years of age with participation in the interview and medical examination. Osteoporosis status was defined by BMD at the total femur, femoral neck, or total lumbar spine. Self-reported diabetics that were prescribed insulin within the first year of diagnosis, are currently taking insulin, and reported no prescriptions for any diabetic pills were classified as type 1. Remaining self-reported diabetics were deemed as having type 2. A total of 2050 diabetics were included in which 87 (4%) were classified as type 1. Type 1 diabetics were found to have a significantly lower BMD at the total femur and femoral neck, but not at the lumbar spine in the adjusted models. Diabetics with type 1 were 4.7 times more likely to have osteoporosis than those with type 2. There was no significant relationship between diabetes type and BMD or osteoporosis prior to adjustment for confounders. Although our results show an increased likelihood of osteoporosis among those with type 1 diabetes, future studies including a larger sample from a community population are needed. It may benefit diabetics, especially those with type 1, to initiate osteoporosis screening methods including evaluation of fracture risk, bone quality, and BMD measurements at multiple sites earlier than recommended.


Subjective symptoms related to GSM radiation from mobile phone base stations: a cross-sectional study.
We performed a re-analysis of the data from Navarro et al (2003) in which health symptoms related to microwave exposure from mobile phone base stations (BSs) were explored, including data obtained in a retrospective inquiry about fear of exposure from BSs. Cross-sectional study. La Ñora (Murcia), Spain. Participants with known illness in 2003 were subsequently disregarded: 88 participants instead of 101 (in 2003) were analysed. Since weather circumstances can influence exposure, we restricted data to measurements made under similar weather conditions. A statistical method indifferent to the assumption of normality was employed: namely, binary logistic regression for modelling a binary response (eg, suffering fatigue (1) or not (0)), and so exposure was introduced as a predictor variable. This analysis was carried out on a regular basis and bootstrapping (95% percentile method) was used to provide more accurate CIs. The symptoms most related to exposure were lack of appetite (OR=1.58, 95% CI 1.23 to 2.03); lack of concentration (OR=1.54, 95% CI 1.25 to 1.89); irritability (OR=1.51, 95% CI 1.23 to 1.85); and trouble sleeping (OR=1.49, 95% CI 1.20 to 1.84). Changes in -2 log likelihood showed similar results. Concerns about the BSs were strongly related with trouble sleeping (OR =3.12, 95% CI 1.10 to 8.86). The exposure variable remained statistically significant in the multivariate analysis. The bootstrapped values were similar to asymptotic CIs. This study confirms our preliminary results. We observed that the incidence of most of the symptoms was related to exposure levels-independently of the demographic variables and some possible risk factors. Concerns about adverse effects from exposure, despite being strongly related with sleep disturbances, do not influence the direct association between exposure and sleep.


Balancing health care needs in a changing context: nursing highlights from the 2016 European Oncology Nursing Society Congress (EONS10), 17-18 October 2016, Dublin, Ireland.
European cancer nurses have to face many challenges as a result of the rapidly changing economic and political context in which balancing health care needs has become strategic for healthcare delivery. Currently, cancer nurses must overcome many obstacles arising from clinical, organisational, and educational issues. Within this scenario, the European Oncology Nursing Society (EONS) shaped its tenth congress programme to boost discussion and reflections, to share experiences and research, and to see how cancer nurses try to anticipate and embrace changes. The aim of this was to promote innovative solutions and to address the many issues involved with cancer care. EONS10 was held on 17-18 October in Dublin, Ireland. The congress was attended by more than 500 delegates. The programme covered the following themes: caring for families and carers, inequalities and access to cancer care, caring for patients with haematological cancers, palliative care, communication and information exchange, community cancer care (i.e. parallel sessions), roles and responsibility for advanced nursing practice, International Psycho-Oncology Society (IPOS)-Academy workshops (i.e. workshops), cancer survivorship, clinical leadership and new roles, oncology nursing research, symptom experiences and management, palliative care (i.e. proffered papers), poster presentations, and satellite symposia. The aim of this paper is to highlight and discuss the contents of the EONS10 congress.


A recent history of metal accumulation in the sediments of Rijeka harbor, Adriatic Sea, Croatia.
We studied metal pollution in the sediments of Rijeka harbor, including anthropogenic influence during recent decades and at the present time. Sediment profiles were collected at ten sampling points. The concentrations of 63 elements in bulk sediment were obtained using ICP-MS, and the concentrations of selected elements were evaluated by statistical factor analyses. We also calculated metal-enrichment factors and geoaccumulation indices and constructed spatial-distribution maps. Mercury (Hg) was the heaviest pollutant, with concentrations exceeding 4 mg/kg. Silver (Ag) was the second most important pollutant, with constantly increasing values. The average concentrations of the most toxic elements were comparable to those found in sediments of other ports throughout the world, and their toxicity ranged from threshold values [chromium (Cr), arsenic (As)] and midrange-effect values [cadmium (Cd), lead (Pb), copper (Cu), zinc (Zn), nickel (Ni)] to extreme-effect values (Hg). Metal pollution has decreased during recent decades, except for Ag and barium (Ba).


Reduced cell viability and apoptosis induction in human thyroid carcinoma and mesothelioma cells exposed to cidofovir.
Besides its well-recognized antiviral activity, Cidofovir (CDV) has been shown to exert anticancer properties both within in vitro and in vivo models. The aim of this study was to evaluate the effects of CDV on still unexplored cultured cancer cells from human mesothelioma as well as breast, colon, liver, lung, prostate, and thyroid carcinomas. Overall, a dose- and time-dependent inhibition of cell viability was observed after CDV exposure. To clarify the mechanisms underlying CDV action, apoptotic cell death was investigated in two infected cell lines [Ist-Mes1 and Ist-Mes2 mesothelioma cells (SV40+)] and in two uninfected cell lines (NCI-H2425 mesothelioma cells and FTC-133 thyroid cancer cells), which resulted the most sensitive to CDV treatment. Reduced expression of procaspase-3 and increased expression of PARP p85 fragment were observed in both infected and uninfected mesothelioma cells, indicating apoptosis induction by CDV in a virus-independent manner. Similarly, the increase of the pro-apoptotic proteins p53, cytochrome c and caspase-3, the decrease of the survival protein Bcl-x, and the increment of Bax/Bcl-2 ratio revealed the occurrence of apoptosis in CDV-treated FTC-133. The presence of nuclear DNA fragmentation confirmed apoptotic cell death by CDV. Overall, our findings warrant further investigations to explore the therapeutic potential of CDV for human mesothelioma and follicular thyroid carcinoma.


BMPR1a and BMPR1b signaling exert opposing effects on gliosis after spinal cord injury.
Astrogliosis following spinal cord injury (SCI) involves an early hypertrophic response that is beneficial and a subsequent formation of a dense scar. We investigated the role of bone morphogenetic protein (BMP) signaling in gliosis after SCI and find that BMPR1a and BMPR1b signaling exerts opposing effects on hypertrophy. Conditional ablation of BMPR1a from glial fibrillary acidic protein (GFAP)-expressing cells leads to defective astrocytic hypertrophy, increased infiltration by inflammatory cells, and reduced axon density. BMPR1b-null mice conversely develop "hyperactive" reactive astrocytes and consequently have smaller lesion volumes. The effects of ablation of either receptor are reversed in the double knock-out animals. These findings indicate that BMPR1a and BMPR1b exert directly opposing effects on the initial reactive astrocytic hypertrophy. Also, BMPR1b knock-out mice have an attenuated glial scar in the chronic stages following injury, suggesting that it has a greater role in glial scar progression. To elucidate the differing roles of the two receptors in astrocytes, we examined the effects of ablation of either receptor in serum-derived astrocytes in vitro. We find that the two receptors exert opposing effects on the posttranscriptional regulation of astrocytic microRNA-21. Further, overexpression of microRNA-21 in wild-type serum-derived astrocytes causes a dramatic reduction in cell size accompanied by reduction in GFAP levels. Hence, regulation of microRNA-21 by BMP signaling provides a novel mechanism for regulation of astrocytic size. Targeting specific BMPR subunits for therapeutic purposes may thus provide an approach for manipulating gliosis and enhancing functional outcomes after SCI.


Suggested principles of professional ethics for the online provision of mental health services.
The goal of this project was to suggest principles of professional ethics for the online provision of clinical mental health services that could guide both clinicians who provide and patients who receive such services. A joint committee of the International Society for Mental Health Online (ISMHO) and the Psychiatric Society for Informatics (PSI) was formed. Discussion and development of these principles took place online. A set of principles was produced and endorsed by ISMHO on January 9, 2000, and by PSI on May 13, 2000. The principles involve informed consent (about the process, the clinician, the potential risks and benefits, safeguards, and alternatives), standard operating procedure (competence, legal requirements, the structure of the services, evaluation, multiple treatment providers, confidentiality, records, and existing guidelines), and emergencies (procedures and local backup). This project demonstrates that traditional principles of professional ethics can be extended to online services, that comprehensive ethical principles can be developed by groups that cross disciplinary and national boundaries, and that productive collaboration can take place entirely online; and suggest that online clinicians have the potential to regulate themselves.


The chemokine receptor CXCR7 interacts with EGFR to promote breast cancer cell proliferation.
Recent advances have revealed a significant contribution of chemokines and their receptors in tumor growth, survival after chemotherapy, and organ-specific metastasis. The CXC chemokine receptor-7 (CXCR7) is the latest chemokine receptor implicated in cancer. Although over expressed in breast cancer cell lines and tumor tissues, its mechanism of action in breast cancer (BrCa) growth and metastasis is unclear. Studies in other cancers have implicated CXCR7 in cell proliferation, anti-apoptotic activity and cell-cell adhesion. The present study was initiated to examine the pattern of CXCR7 expression and its role in regulation of growth signaling in breast cancer. The contribution of CXCR7 in BrCa cell proliferation was investigated in representative cell lines using real time quantitative PCR (q-PCR), proliferation assays, immunohistochemistry and immunoblotting. Phenotypic changes were examined after CXCR7 specific cDNA and siRNA transfection and expression levels were monitored by q-PCR. Further, the association of CXCR7 with epidermal growth factor receptor (EGFR) and modulation of its activity were investigated by western blotting, immunofluorescence, and in-situ proximity ligation assays in human BrCa cells and tissues. CXCR7 was expressed in both, estrogen receptor (ER) positive and negative BrCa cell lines. CXCR7 was also expressed unevenly in normal breast tissues and to a much higher extent in ER + cancer tissues. Depletion of CXCR7 in MCF7 BrCa cells by RNA interference decreased proliferation and caused cell cycle arrest. Further, proximity ligation assay (PLA) revealed colocalization of CXCR7 with EGFR in cancer tissues and cancer cell lines. CXCR7 depletion reduced levels of phospho-EGFR at Tyrosine1110 after EGF-stimulation and also reduced phosphorylation of ERK1/2, indicating a potentially direct impact on mitogenic signaling in MCF7 cells. Using siRNA to knockdown β-arrestin2 in cells with EGFR over expression we were able to nearly deplete the CXCR7-EGFR colocalization events, suggesting that β-arrestin2 acts as a scaffold to enhance CXCR7 dependent activation of EGFR after EGF stimulation. These results demonstrate coupling of CXCR7 with EGFR to regulate proliferation of BrCa cells and suggest an important ligand-independent role of CXCR7 in BrCa growth. Thus, the CXCR7-EGFR axis is a promising target for breast cancer therapy.


Effects of low power laser irradiation on bone healing in animals: a meta-analysis.
The meta-analysis was performed to identify animal research defining the effects of low power laser irradiation on biomechanical indicators of bone regeneration and the impact of dosage. We searched five electronic databases (MEDLINE, EMBASE, PubMed, CINAHL, and Cochrane Database of Randomised Clinical Trials) for studies in the area of laser and bone healing published from 1966 to October 2008. Included studies had to investigate fracture healing in any animal model, using any type of low power laser irradiation, and use at least one quantitative biomechanical measures of bone strength. There were 880 abstracts related to the laser irradiation and bone issues (healing, surgery and assessment). Five studies met our inclusion criteria and were critically appraised by two raters independently using a structured tool designed for rating the quality of animal research studies. After full text review, two articles were deemed ineligible for meta-analysis because of the type of injury method and biomechanical variables used, leaving three studies for meta-analysis. Maximum bone tolerance force before the point of fracture during the biomechanical test, 4 weeks after bone deficiency was our main biomechanical bone properties for the Meta analysis. Studies indicate that low power laser irradiation can enhance biomechanical properties of bone during fracture healing in animal models. Maximum bone tolerance was statistically improved following low level laser irradiation (average random effect size 0.726, 95% CI 0.08-1.37, p 0.028). While conclusions are limited by the low number of studies, there is concordance across limited evidence that laser improves the strength of bone tissue during the healing process in animal models.


An adenovirus E1A-like transcription factor is regulated during the differentiation of murine embryonal carcinoma stem cells.
The expression of the E2A transcription unit of the adenovirus E1A deletion mutant dl312 in murine embryonal carcinoma (EC) stem cells suggests that they contain an activity that will complement viral E1A. We have prepared from these cells in vitro transcription extracts that use E1A-inducible promoters more efficiently than do extracts from a differentiated cell line. Mixing experiments demonstrate that the EC phenotype is dominant. Gel retardation assays using the E2A promoter detect a binding activity present in F9 and PCC4 EC cells but not in differentiated cells. Our data indicate that EC stem cells contain a transcription factor that is analogous to viral E1A and is likely to be involved in the control of cellular gene expression during differentiation.


Prevalence of Osteosarcopenia and Its Association with Cardiovascular Risk Factors in Iranian Older People: Bushehr Elderly Health (BEH) Program.
Osteosarcopenia is an increasingly recognized geriatric syndrome with a considerable prevalence which increases morbidity and mortality. Although osteosarcopenia is a result of age-related deterioration in muscle and bone, there are many risk factors that provoking osteosarcopenia. These risk factors should be considered by the clinicians to treat osteosarcopenia. We assessed the link between osteosarcopenia and conventional risk factors of cardiovascular diseases. This study was a cross-sectional study that has been conducted within the framework of Bushehr Elderly Health (BEH) program stage II in which participants aged ≥ 60 years were included. Osteopenia/osteoporosis was defined as a t-score ≤ - 1.0 standard deviation below the mean values of a young healthy adult. We defined sarcopenia as reduced skeletal muscle mass plus low muscle strength and/or low physical performance. Osteosarcopenia was considered as the presence of both osteopenia/osteoporosis and sarcopenia. We estimated the age-standardized prevalence of osteosarcopenia for men and women, separately. Using modified Poisson regression analysis, adjusted prevalence ratio (PR) with 95% CI was used to show the measure of associations in the final model. Among 2353 participants, 1205 (51.2%) were women. Age-standardized prevalence of osteosarcopenia was 33.8 (95% CI 31.0-36.5) in men and 33.9 (30.9-36.8) in women. In both sexes, the inverse association was detected with body mass index and having osteosarcopenia (PR 0.84, 95% CI 0.81-0.88 in men and 0.77, 95% CI 0.74-0.80 in women). In both sexes, high-fat mass was positively associated with osteosarcopenia [PR 1.46 (95% CI 1.11-1.92) in men, and 2.25 (95% CI 1.71-2.95) in women]. Physical activity had a significant inverse association in men (PR = 0.64, 95% CI 0.46, 0.88), but not in women. Diabetes was also showed a direct association with osteosarcopenia in men (PR 1.33, 95% CI 1.04-1.69). No associations were detected between the lipid profiles and osteosarcopenia. Results demonstrated a high prevalence of osteosarcopenia in both sexes suggesting a high disease burden in a rapidly aging country. Lifestyle and socioeconomic factors, as well as chronic diseases, were significantly associated with osteosarcopenia.


Retinoic acid signaling organizes endodermal organ specification along the entire antero-posterior axis.
Endoderm organ primordia become specified between gastrulation and gut tube folding in Amniotes. Although the requirement for RA signaling for the development of a few individual endoderm organs has been established a systematic assessment of its activity along the entire antero-posterior axis has not been performed in this germ layer. RA is synthesized from gastrulation to somitogenesis in the mesoderm that is close to the developing gut tube. In the branchial arch region specific levels of RA signaling control organ boundaries. The most anterior endoderm forming the thyroid gland is specified in the absence of RA signaling. Increasing RA in anterior branchial arches results in thyroid primordium repression and the induction of more posterior markers such as branchial arch Hox genes. Conversely reducing RA signaling shifts Hox genes posteriorly in endoderm. These results imply that RA acts as a caudalizing factor in a graded manner in pharyngeal endoderm. Posterior foregut and midgut organ primordia also require RA, but exposing endoderm to additional RA is not sufficient to expand these primordia anteriorly. We show that in chick, in contrast to non-Amniotes, RA signaling is not only necessary during gastrulation, but also throughout gut tube folding during somitogenesis. Our results show that the induction of CdxA, a midgut marker, and pancreas induction require direct RA signaling in endoderm. Moreover, communication between CdxA(+) cells is necessary to maintain CdxA expression, therefore synchronizing the cells of the midgut primordium. We further show that the RA pathway acts synergistically with FGF4 in endoderm patterning rather than mediating FGF4 activity. Our work establishes that retinoic acid (RA) signaling coordinates the position of different endoderm organs along the antero-posterior axis in chick embryos and could serve as a basis for the differentiation of specific endodermal organs from ES cells.


Priority rules govern the organization of traffic on foraging trails under crowding conditions in the leaf-cutting ant Atta colombica.
Foraging in leaf-cutting ants is generally organized along well-defined recruitment trails supporting a bi-directional flow of outbound and nestbound individuals. This study attempts to reveal the priority rules governing the organization of traffic on these trails. Ants were forced to move on a narrow trail, allowing the passage of only two individuals at a time. In this condition, a desynchronization of inbound and outbound traffic was observed, involving the formation of alternating clusters of inbound and outbound ants. Most clusters of inbound ants were headed by laden ants followed by unladen ants. This occurred because inbound unladen ants did not attempt to overtake the laden ants in front of them. As unladen ants move on average faster than laden ants, these ants were thus forced to decrease their speed. By contrast, this decrease was counterbalanced by the fact that, by staying in a cluster instead of moving in isolation, inbound unladen ants limit the number of head-on encounters with outbound ants. Our analysis shows that the delay induced by these head-on encounters would actually be twice as high as the delay induced by the forced decrease in speed incurred by ants staying in a cluster. The cluster organization also promotes information transfer about the level of food availability by increasing the number of contacts between outbound and inbound laden ants, which could possibly stimulate these former to cut and retrieve leaf fragments when reaching the end of the trail.


Improvements in pulmonary and general critical care reduces mortality following ventilator-associated pneumonia.
Ventilator-associated pneumonia (VAP) is the most common hospital-acquired infection in the intensive care unit, with substantial subsequent mortality. The mortality following VAP declined in the 1980s and 1990s. Experts suggest that little progress has been made in the outcomes from VAP since several novel interventions have failed. We nonetheless hypothesized that mortality following VAP has continued to decrease owing to advances in pulmonary critical care. We identified all adult patients with Centers for Disease Control and Prevention-defined, intensive care unit-acquired VAP between January 1, 1997, and December 31, 2008, from a prospectively collected database. A total of 793 cases of VAP occurred in the study period. Cases were divided into four periods (1997-1999, 2000-2002, 2003-2005, or 2006-2008) to compare outcomes over time. Acute Physiology and Chronic Health Evaluation II scores were stable, while mortality was significantly lower in Period 4 when compared with Periods 1 and 2 (p = 0.004 and 0.009, respectively). A logistic regression model predicting death (c statistic = 0.871) revealed age (odds ratio, 1.03; 95% confidence interval, 1.02-1.05), Acute Physiology and Chronic Health Evaluation II score (1.09, 1.05-1.14), white blood cell count (1.03, 1.00-1.06), transplant recipient (3.45, 1.40-8.53), transfusions (3.25, 1.37-7.68), and pulmonary disease (3.01, 1.67-5.45) were independent predictors of death, as was the presence of trauma (0.10, 0.06-0.18), chronic steroid therapy (0.39, 0.17-0.91), and patient length of stay (0.99, 0.98-0.99), with odds ratios less than 1.0. In addition, those patients treated in Period 1 (2.23, 1.16-4.29) or Period 2 (2.13, 1.12-4.06) had twice the risk of death following an episode of VAP when compared with those treated in the most recent period. We have shown that mortality following an episode of VAP continues to decrease over time and attribute this to advancements in pulmonary and general critical care rather than any specific interventions. Prognostic study, level II.


Transcatheter closure of atrial septal defect in adults: time-course of atrial and ventricular remodeling and effects on exercise capacity.
Investigate ventricular and atrial remodeling following atrial septal defect (ASD) closure and examine if pulmonary-to-systemic flow ratio (QP/QS) and right ventricular (RV) volume predict improvement, determined as percentage of predicted oxygen uptake (VO2%). Long-term cardiovascular magnetic resonance (CMR) data on atrial and ventricular remodeling after ASD-closure is limited and treatment effect on exercise capacity is debated. Sixteen patients undergoing transcatheter ASD closure and 16 age and sexmatched controls were studied. CMR was performed before treatment, the day after and 3 and 12 months later. Exercise test with gas analysis was performed before and 12 months after treatment. QP/QS decreased from 2.1 ± 0.5 to 1.4 ± 0.3 at day 1 and 1.1 ± 0.1 at 3 and 12 months. Left ventricular (LV) volumes increased and normalized on day 1 whereas left atrial volumes were unchanged. RV and right atrial volumes decreased the first 3 months. LV and RV volumes had not equalized at 12 months (RV/LV ratio 1.2 ± 0.1, P < 0.01) and RV ejection fraction remained decreased compared to controls. Improvement of VO2% after ASD closure (P < 0.01) was inversely related to QP/QS at rest (r = - 0.56, P < 0.05) but unrelated to RV end-diastolic volume (P = 0.16). Following transcatheter ASD closure, LV adaptation is rapid and RV adaptation is prolonged, with decreased systolic RV function. Patients with smaller shunts had larger improvement in VO2% suggesting patients with defects of borderline hemodynamic significance might benefit from closure. This may be due to impaired LV diastolic function influencing shunt size and exercise capacity following ASD closure.


A unifying mechanism for the rearrangement of vinyl allene oxide geometric isomers to cyclopentenones.
A new mechanism for the rearrangement of vinyl allene oxide geometric isomers to stereodefined cyclopentenones is proposed based on DFT computations. This mechanism comprises two steps, first the ring opening of the oxirane to give a vinylcyclopropanone, and then a [1,3]-C sigmatropic rearrangement. Depending primarily on the allene oxide double bond geometry the stepwise pathway is either competitive (for E allene oxides) or favored (for Z allene oxides) relative to the already described SN2-like concerted pathway. All bond-forming reactions take place through helically chiral transition states, which allows the stereochemical information of the substrates to be transferred to that of the products, in particular in the case of (enantiopure) Z allene oxides. In addition to revealing one more of the fascinating mechanisms with memory of chirality, the results deepen our understanding of the important jasmonate and clavulone biosynthetic pathways that occur in plants and corals.


Somatic and motor components of action simulation.
Seminal studies in monkeys report that the viewing of actions performed by other individuals activates frontal and parietal cortical areas typically involved in action planning and execution. That mirroring actions might rely on both motor and somatosensory components is suggested by reports that action observation and execution increase neural activity in motor and in somatosensory areas. This occurs not only during observation of naturalistic movements but also during the viewing of biomechanically impossible movements that tap the afferent component of action, possibly by eliciting strong somatic feelings in the onlooker. Although somatosensory feedback is inherently linked to action execution, information on the possible causative role of frontal and parietal cortices in simulating motor and sensory action components is lacking. By combining low-frequency repetitive and single-pulse transcranial magnetic stimulation, we found that virtual lesions of ventral premotor cortex (vPMc) and primary somatosensory cortex (S1) suppressed mirror motor facilitation contingent upon observation of possible and impossible movements, respectively. In contrast, virtual lesions of primary motor cortex did not influence mirror motor facilitation. The reported double dissociation suggests that vPMc and S1 play an active, differential role in simulating efferent and afferent components of observed actions.


Imitation of lateralised body movements: doing it the hard way.
Two experiments examined imitation of lateralised body movement sequences presented at six viewing angles (0 degrees , 60 degrees , 120 degrees , 180 degrees , 240 degrees , and 300 degrees rotation relative to the participant's body). Experiment 1 found that, when participants were instructed simply to "do what the model does", at all viewing angles they produced more actions using the same side of the body as the model (anatomical matches), than actions using the opposite side (anatomical non-matches). In Experiment 2 participants were instructed to produce either anatomical matches or anatomical non-matches of observed actions. When the model was viewed from behind (0 degrees ), the anatomically matching group were more accurate than the anatomically non-matching group, but the non-matching group was superior when the model faced the participant (180 degrees and 240 degrees ). No reliable differences were observed between groups at 60 degrees , 120 degrees , and 300 degrees . In combination, the results of Experiments 1 and 2 suggest that, when they are confronting a model, people choose to imitate the hard way; they attempt to match observed actions anatomically, in spite of the fact that anatomical matching is more subject to error than anatomical non-matching.


The impact of video technology on learning: A cooking skills experiment.
This study examines the role of video technology in the development of cooking skills. The study explored the views of 141 female participants on whether video technology can promote confidence in learning new cooking skills to assist in meal preparation. Prior to each focus group participants took part in a cooking experiment to assess the most effective method of learning for low-skilled cooks across four experimental conditions (recipe card only; recipe card plus video demonstration; recipe card plus video demonstration conducted in segmented stages; and recipe card plus video demonstration whereby participants freely accessed video demonstrations as and when needed). Focus group findings revealed that video technology was perceived to assist learning in the cooking process in the following ways: (1) improved comprehension of the cooking process; (2) real-time reassurance in the cooking process; (3) assisting the acquisition of new cooking skills; and (4) enhancing the enjoyment of the cooking process. These findings display the potential for video technology to promote motivation and confidence as well as enhancing cooking skills among low-skilled individuals wishing to cook from scratch using fresh ingredients.


Methods for casting subterranean ant nests.
The study of subterranean ant nests has been impeded by the difficulty of rendering their structures in visible form. Here, several different casting materials are shown to make perfect casts of the underground nests of ants. Each material (dental plaster, paraffin wax, aluminum, zinc) has advantages and limitations, which are discussed. Some of the materials allow the recovery of the ants entombed in the casts, allowing a census of the ants to be connected with features of their nest architecture. The necessary equipment and procedures are described in the hope that more researchers will study this very important aspect of ant natural history.


In vitro and in vivo selective antitumor activity of a novel orally bioavailable proteasome inhibitor MLN9708 against multiple myeloma cells.
The success of bortezomib therapy for treatment of multiple myeloma (MM) led to the development of structurally and pharmacologically distinct novel proteasome inhibitors. In the present study, we evaluated the efficacy of one such novel orally bioactive proteasome inhibitor MLN9708/MLN2238 in MM using well-established in vitro and in vivo models. MM cell lines, primary patient cells, and the human MM xenograft animal model were used to study the antitumor activity of MN2238. Treatment of MM cells with MLN2238 predominantly inhibits chymotrypsin-like activity of the proteasome and induces accumulation of ubiquitinated proteins. MLN2238 inhibits growth and induces apoptosis in MM cells resistant to conventional and bortezomib therapies without affecting the viability of normal cells. In animal tumor model studies, MLN2238 is well tolerated and inhibits tumor growth with significantly reduced tumor recurrence. A head-to-head analysis of MLN2238 versus bortezomib showed a significantly longer survival time in mice treated with MLN2238 than mice receiving bortezomib. Immununostaining of MM tumors from MLN2238-treated mice showed growth inhibition, apoptosis, and a decrease in associated angiogenesis. Mechanistic studies showed that MLN2238-triggered apoptosis is associated with activation of caspase-3, caspase-8, and caspase-9; increase in p53, p21, NOXA, PUMA, and E2F; induction of endoplasmic reticulum (ER) stress response proteins Bip, phospho-eIF2-α, and CHOP; and inhibition of nuclear factor kappa B. Finally, combining MLN2238 with lenalidomide, histone deacetylase inhibitor suberoylanilide hydroxamic acid, or dexamethasone triggers synergistic anti-MM activity. Our preclinical study supports clinical evaluation of MLN9708, alone or in combination, as a potential MM therapy.


The relationship of dietary omega-3 long-chain polyunsaturated fatty acid intake with incident age-related macular degeneration: AREDS report no. 23.
To examine the association of dietary omega-3 long-chain polyunsaturated fatty acid and fish intake with incident neovascular age-related macular degeneration (AMD) and central geographic atrophy (CGA). Multicenter clinic-based prospective cohort study from a clinical trial including Age-Related Eye Disease Study (AREDS) participants with bilateral drusen at enrollment. Main outcome measures were incident neovascular AMD and CGA, ascertained from annual stereoscopic color fundus photographs (median follow-up, 6.3 years). We estimated nutrient and food intake from a validated food frequency questionnaire (FFQ) at baseline, with intake of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), combined EPA and DHA, and fish as primary exposures. After controlling for known covariates, we observed a reduced likelihood of progression from bilateral drusen to CGA among people who reported the highest levels of EPA (odds ratio [OR], 0.44; 95% confidence interval [CI], 0.23-0.87) and EPA+DHA (OR, 0.45; 95% CI, 0.23-0.90) consumption. Levels of DHA were associated with CGA in age-, sex-, and calorie-adjusted models (OR, 0.51; 95% CI, 0.26-1.00); however, this statistical relationship did not persist in multivariable models. Dietary lipid intake is a modifiable factor that may influence the likelihood of developing sight-threatening forms of AMD. Our findings suggest that dietary omega-3 long-chain polyunsaturated fatty acid intake is associated with a decreased risk of progression from bilateral drusen to CGA.


Megabulbus in endoscopy; suspect for superior mesenteric artery syndrome in children.
Rarity of Superior Mesenteric Artery Syndrome (SMAS) and necessity of invasive tests to verify the diagnosis leads to patients receiving symptom-oriented drugs for a long period without any definite diagnosis. Diagnostic tests such as barium series, abdominal CT scan, abdominal angiography or magnetic resonance arteriography are used in patients with suspected SMAS. In pediatric patients, a non-invasive SMAS diagnosis may be considered easily with abdominal ultrasound performed by experienced hands. Megabulbus is used as a radiological term; however, reviewing the literature an endoscopic definition for megabulbus was not found. We decided to mention severely dilated pyloric ring and bulb as megabulbus. Megabulbus might be an indicator for SMAS. This is the first case of SMAS in adult and pediatric age groups presenting with megabulbus.


Induction of ovulation in phase I of the in vitro fertilization and embryo transfer programme at Tygerberg Hospital.
Two different protocols for ovulation induction used in phase I of the in vitro fertilization (IVF) programme at Tygerberg Hospital are presented. Previous experience with gonadotrophins and clomiphene citrate was applied in the development of the protocols. By means of experience gained during ovulation induction it was possible to establish critical values for the parameters of follicle maturity, which are used to determine the optimal time for follicle aspiration. Ultrasonically measured follicle size, critical serum oestradiol levels for each mature follicle and cervical mucus scoring were the parameters used. Fifty-one ova were obtained during 29 of the 34 attempts at follicle aspiration. Only 5 of the ova were immature. At least 1 mature ovum was obtained at 80% of all laparoscopies. Twenty-three embryos were transferred to 15 patients, and 3 pregnancies occurred. As a result of this programme 2 babies were born--the first in South Africa by IVF and embryo transfer.


Growth arrest and DNA damage-inducible protein GADD34 targets protein phosphatase 1 alpha to the endoplasmic reticulum and promotes dephosphorylation of the alpha subunit of eukaryotic translation initiation factor 2.
The growth arrest and DNA damage-inducible protein, GADD34, associates with protein phosphatase 1 (PP1) and promotes in vitro dephosphorylation of the alpha subunit of eukaryotic translation initiation factor 2, (eIF-2 alpha). In this report, we show that the expression of human GADD34 in cultured cells reversed eIF-2 alpha phosphorylation induced by thapsigargin and tunicamycin, agents that promote protein unfolding in the endoplasmic reticulum (ER). GADD34 expression also reversed eIF-2 alpha phosphorylation induced by okadaic acid but not that induced by another phosphatase inhibitor, calyculin A (CA), which is a result consistent with PP1 being a component of the GADD34-assembled eIF-2 alpha phosphatase. Structure-function studies identified a bipartite C-terminal domain in GADD34 that encompassed a canonical PP1-binding motif, KVRF, and a novel RARA sequence, both of which were required for PP1 binding. N-terminal deletions of GADD34 established that while PP1 binding was necessary, it was not sufficient to promote eIF-2 alpha dephosphorylation in cells. Imaging of green fluorescent protein (GFP)-GADD34 proteins showed that the N-terminal 180 residues directed the localization of GADD34 at the ER and that GADD34 targeted the alpha isoform of PP1 to the ER. These data provide new insights into the mode of action of GADD34 in assembling an ER-associated eIF-2 alpha phosphatase that regulates protein translation in mammalian cells.


Sputum eosinophils and exhaled nitric oxide during late asthmatic reaction in patients with western red cedar asthma.
Examination of sputum for eosinophils and measurement of exhaled nitric oxide have been proposed as noninvasive methods of assessing airway inflammation in asthma. The use of these tests in the evaluation of patients with occupational asthma has not been reported. This study investigated the changes in sputum eosinophils and exhaled NO before and at intervals after inhalation challenge with plicatic acid in patients with suspected western red cedar asthma. Of 17 subjects who underwent challenge, nine had a positive bronchoconstrictor reaction (responders) and eight had a negative reaction (nonresponders). At 6 and 24 h after plicatic acid challenge, there was a significant increase in sputum eosinophils among responders, which was inversely related to the fall in forced expiratory volume in one second (FEV1) at 6 h. An increase in sputum eosinophils was also found in three nonresponders. Levels of exhaled NO increased at 24 h after challenge with plicatic acid in both responders and nonresponders, being significant only in nonresponders. No correlation was found between the increase in nitric oxide and the magnitude of the functional changes in the airways. There were significant correlations between the degree of sputum eosinophilia and the level of exhaled NO before and after methacholine and plicatic acid challenge. In conclusion, the late asthmatic reaction induced by plicatic acid in patients with western red cedar asthma is associated with an increase in sputum eosinophils. The usefulness of measuring sputum eosinophils and exhaled nitric oxide in the clinical evaluation of patients with suspected occupational asthma caused by low molecular weight compounds has yet to be determined.


The relationship between wearing incorrectly sized shoes and foot dimensions, foot pain, and diabetes.
Wearing inappropriate shoes can cause biomechanical imbalance, foot problems, and pain and induce falls. To verify the prevalence of wearing incorrectly sized shoes and the relationship between incorrectly sized shoes and foot dimensions, pain, and diabetes among older adults. A cross-sectional study. 399 older adults (227 women and 172 men) age 60 to 90 y. The participants were asked about the presence of diabetes, pain in the lower limbs and back, and pain when wearing shoes. Foot evaluations comprised the variables of width, perimeter, height, length, first metatarsophalangeal angle, the Arch Index, and the Foot Posture Index. The data analysis was performed using a 2-sample t test and chi-square test. The percentage of the participants wearing shoe sizes bigger than their foot length was 48.5% for the women and 69.2% for the men. Only 1 man was wearing a shoe size smaller than his foot length. The older adults wearing the incorrect shoe size presented larger values for foot width, perimeter, and height than those wearing the correct size, but there were no significant differences between the groups with respect to the Arch Index and the Foot Posture Index. Incorrectly sized shoes were associated with ankle pain in women but not with diabetes. Men were more likely to wear incorrectly fitting shoes. The use of correctly sized shoes was associated with back pain in women. The use of incorrectly sized shoes was highly prevalent in the population studied and was associated with larger values for foot width, perimeter, and height and with ankle pain.


Glyoxalase I disruption and external carbonyl stress impair mitochondrial function in human induced pluripotent stem cells and derived neurons.
Carbonyl stress, a specific form of oxidative stress, is reported to be involved in the pathophysiology of schizophrenia; however, little is known regarding the underlying mechanism. Here, we found that disruption of GLO1, the gene encoding a major catabolic enzyme scavenging the carbonyl group, increases vulnerability to external carbonyl stress, leading to abnormal phenotypes in human induced pluripotent stem cells (hiPSCs). The viability of GLO1 knockout (KO)-hiPSCs decreased and activity of caspase-3 was increased upon addition of methylglyoxal (MGO), a reactive carbonyl compound. In the GLO1 KO-hiPSC-derived neurons, MGO administration impaired neurite extension and cell migration. Further, accumulation of methylglyoxal-derived hydroimidazolone (MG-H1; a derivative of MGO)-modified proteins was detected in isolated mitochondria. Mitochondrial dysfunction, including diminished membrane potential and dampened respiratory function, was observed in the GLO1 KO-hiPSCs and derived neurons after addition of MGO and hence might be the mechanism underlying the effects of carbonyl stress. The susceptibility to MGO was partially rescued by the administration of pyridoxamine, a carbonyl scavenger. Our observations can be used for designing an intervention strategy for diseases, particularly those induced by enhanced carbonyl stress or oxidative stress.


Novel Fluorescence Sensor Based on All-Inorganic Perovskite Quantum Dots Coated with Molecularly Imprinted Polymers for Highly Selective and Sensitive Detection of Omethoate.
All-inorganic cesium lead halide perovskites (CsPbX3, X = Cl, Br, and I) have attracted considerable attention with superior electrical and photophysical properties. In this study, luminescent perovskite (CsPbBr3) quantum dots (QDs) as sensing elements combined with molecularly imprinted polymers (MIPs) are used for the detection of omethoate (OMT). The new MIPs@CsPbBr3 QDs were synthesized successfully through the imprinting technology with a sol-gel reaction. The fluorescence (FL) of the MIPs@CsPbBr3 QDs was quenched obviously on loading the MIPs with OMT, the linear range of OMT was from 50 to 400 ng/mL, and the detection limit was 18.8 ng/mL. The imprinting factor was 3.2, which indicated excellent specificity of the MIPs for the inorganic metal halide (IMH) perovskites. The novel composite possesses the outstanding FL capability of CsPbBr3 QDs and the high selectivity of molecular imprinting technology, which can convert the specific interactions between template and the imprinted cavities to apparent changes in the FL intensity. Hence, a selective and simple FL sensor for direct and fast detection of organophosphorus pesticide in vegetable and soil samples was developed here. The present work also illustrates the potential of IMH perovskites for sensor applications in biological and environmental detection.