Immunohistochemical localization of selected early response genes expressed in trabecular bone of young rats given hPTH 1-34.
Intermittent administration of parathyroid hormone (PTH) increases trabecular bone mass in vivo by stimulating bone formation. To further characterize the cellular and molecular mediators of the anabolic response to PTH, we examined the effect of intermittent synthetic hPTH 1-34 on the expression and localization of selected early response genes, c-fos, c-jun, c-myc, and IL-6 protein, in bone tissue by immunohistochemistry. Young male Sprague-Dawley rats, 70-100 g, were injected s.c. with 8 microg/100 g PTH or vehicle control, once daily for 5 days. Femurs were harvested 1 and 24 hours after the fifth injection, then fixed, decalcified, processed for wax embedding, and sections were immunostained. Early response genes, c-fos, c-jun and IL-6, were strongly expressed in osteoblasts, osteocytes, and megakaryocytes in bones 1 hour after PTH, when compared with vehicle-treated controls or sections from rats, 24 hours after PTH injection. Osteoblasts, osteocytes, and megakaryocytes were also positive for c-myc but the differences in stain intensity between control and treated groups were marginal. Also, scattered islands of hematopoietic cells in the marrow stained intensely for IL-6 by 1 hour after PTH, but the stain intensity decreased to control level 24 hours after the last PTH injection. Scattered islands of hematopoietic cells in the bone marrow stained more strongly for c-fos than either c-jun or c-myc, but neither localization nor stain intensity were regulated by PTH at the time points examined. We conclude that during the immediate early phase of the anabolic response, PTH regulates c-fos, c-jun, and IL-6 expression in osteoblasts, osteocytes, megakaryocytes, and selected bone marrow hematopoietic cells in bone.


An electrocardiographic algorithm for determining the location of pacemaker electrode in patients with right bundle branch block configuration during permanent ventricular pacing.
The expected morphology of right ventricular pacing is a left bundle branch block (LBBB) pattern. However, right bundle branch block (RBBB) can also be seen during permanent right ventricular pacing. The aim of this study was to develop an electrocardiographic algorithm to differentiate this benign condition from septal and free wall perforation with subsequent left ventricular pacing. Three hundred consecutive patients who had permanent ventricular or dual-chamber pacemaker implantation between 1999 and 2000 were screened and 25 patients (8.3%) who exhibited RBBB configuration were included in the study. Echocardiograms and chest radiographs were evaluated in order to identify the pacing lead location in this group. The authors formed a study group with their own 25 patients and 22 cases of RBBB with permanent pacemaker from previous publications (total 47 patients). Frontal axis, QRS morphology in lead V(1), and the precordial transition point, which is defined as the precordial lead where R wave amplitude is equal to S wave amplitude, were examined. Placement of precordial leads V(1) and V(2) 1 interspace lower than the standard location (Klein maneuver) eliminated the RBBB pattern in 12 patients. RBBB pattern with "true right ventricular pacing" was detected in 24 of the 25 patients, and in 11 of the 22 patients reported in the literature (total 35 patients). Right ventricular pacing was correctly identified in 34 of 35 patients with use of criteria including left superior axis deviation, RS or qR morphology in lead V(1), and precordial transition at lead V(3) with a high sensitivity and specificity. A simple surface electrocardiogram can accurately predict the lead location in patients having RBBB morphology with right ventricular pacing.


Internalization of secreted antigen-targeted antibodies by the neonatal Fc receptor for precision imaging of the androgen receptor axis.
Targeting the androgen receptor (AR) pathway prolongs survival in patients with prostate cancer, but resistance rapidly develops. Understanding this resistance is confounded by a lack of noninvasive means to assess AR activity in vivo. We report intracellular accumulation of a secreted antigen-targeted antibody (SATA) that can be used to characterize disease, guide therapy, and monitor response. AR-regulated human kallikrein-related peptidase 2 (free hK2) is a prostate tissue-specific antigen produced in prostate cancer and androgen-stimulated breast cancer cells. Fluorescent and radio conjugates of 11B6, an antibody targeting free hK2, are internalized and noninvasively report AR pathway activity in metastatic and genetically engineered models of cancer development and treatment. Uptake is mediated by a mechanism involving the neonatal Fc receptor. Humanized 11B6, which has undergone toxicological tests in nonhuman primates, has the potential to improve patient management in these cancers. Furthermore, cell-specific SATA uptake may have a broader use for molecularly guided diagnosis and therapy in other cancers.


Sugar or salt ("SOS"): A protocol for a UK multicentre randomised trial of mannitol and hypertonic saline in severe traumatic brain injury and intracranial hypertension.
Hyperosmolar solutions are widely used to treat raised intracranial pressure following severe traumatic brain injury. Although mannitol has historically been the most frequently administered, hypertonic saline solutions are increasingly being used. However, definitive evidence regarding their comparative effectiveness is lacking. The Sugar or Salt Trial is a UK randomised, allocation concealed open label multicentre pragmatic trial designed to determine the clinical and cost-effectiveness of hypertonic saline compared with mannitol in the management of patients with severe traumatic brain injury. Patients requiring intensive care unit admission and intracranial pressure monitoring post-traumatic brain injury will be allocated at random to receive equi-osmolar boluses of either mannitol or hypertonic saline following failure of routine first-line measures to control intracranial pressure. The primary outcome for the study will be the Extended Glasgow Outcome Scale assessed at six months after randomisation. Results will inform current clinical practice in the routine use of hyperosmolar therapy as well as assess the impact of potential side effects. Pre-planned longer term clinical and cost effectiveness analyses will further inform the use of these treatments.


Impact glasses from Belize represent tektites from the Pleistocene Pantasma impact crater in Nicaragua.
Tektites are terrestrial impact-generated glasses that are ejected long distance (up to 11,000 km), share unique characteristics and have a poorly understood formation process. Only four tektite strewn-fields are known, and three of them are sourced from known impact craters. Here we show that the recently discovered Pantasma impact crater (14 km diameter) in Nicaragua is the source of an impact glass strewn-field documented in Belize 530 km away. Their cogenesis is documented by coincidental ages, at 804 ± 9 ka, as well as consistent elemental compositions and isotopic ratios. The Belize impact glass share many characteristics with known tektites but also present several peculiar features. We propose that these glasses represent a previously unrecognized tektite strewn-field. These discoveries shed new light on the tektite formation process, which may be more common than previously claimed, as most known Pleistocene >10 km diameter cratering events have generated tektites.


The anti-cancer effects of (-)-epigallocatechin-3-gallate on the signaling pathways associated with membrane receptors in MCF-7 cells.
(-)-Epigallocatechin-3-gallate (EGCg) has been implicated in cancer chemo-prevention in studies using many different kinds of cancer cells. The present study measured cell viability, osteopontin (OPN) secretion, fatty acid synthase (FAS) expression, and cytosolic Ca(2+) and verified the anti-cancer activities of EGCg in MCF-7 human breast cancer cells. EGCg-induced apoptosis was evidenced by nuclear condensation, increased protein levels of activated caspase-3, down-regulation of gelsolin and tropomyosin-4 (Tm-4), and up-regulation of tropomyosin-1(Tm-1). By disrupting adherens junction formation, EGCg caused accumulation of extra-nuclear β-catenin aggregates in the cytosol and alterations of the protein content and mRNA expression of E-cadherin and β-catenin, but not N-cadherin, in MCF-7 cells. To identify the putative mechanisms underlying the EGCg signaling pathways, EGFP (enhanced green fluorescence protein) was ectopically expressed in MCF-7 cells. This allowed us to monitor the EGCg-induced fluorescence changes associated with the effects of Triton X-100 (to remove plasma membrane) or the addition of laminin, anti-laminin receptor (LR) antibody, epidermal growth factor (EGF), and genistein on the cells. Our results indicated that EGCg acts via the signaling pathways associated with cell membrane to suppress cell proliferation, provoke apoptosis, and disturb cell-cell adhesion in MCF-7 cells. The altered events include the EGFR, LR, FAS, intracellular Ca(2+) , OPN secretion, caspace-3, gelsolin, Tm-4, Tm-1, and adherens junction proteins, E-cadherin and β-catenin.


The visual perception of metal.
The present research was designed to examine how the presence or absence of ambient light influences the appearance of metal. The stimuli depicted three possible objects that were illuminated by three possible patterns of illumination. These were generated by a single point light source, two rectangular area lights, or projecting light onto a translucent white box that contained the object (and the camera) so that the object would be illuminated by ambient light in all directions. The materials were simulated using measured parameters of chrome with four different levels of roughness. Observers rated the metallic appearance and shininess of each depicted object using two sliders. The highest rated appearance of metal and shininess occurred for the surfaces with the lowest roughness in the ambient illumination condition, and these ratings dropped systematically as the roughness was increased. For the objects illuminated by point or area lights, the appearance of metal and shininess were significantly less than in the ambient conditions for the lowest roughness value, and significantly greater than in the ambient condition for intermediate values of roughness. We also included a control condition depicting objects with a shiny plastic reflectance function that had both diffuse and specular components. These objects were rated as highly shiny but they did not appear metallic. A theoretical hypothesis is proposed that the defining characteristic of metal (as opposed to black plastic) is the presence of specular sheen over most of the visible surface area.


Apoferritin as an ubiquitous nanocarrier with excellent shelf life.
Due to many adverse effects of conventional chemotherapy, novel methods of targeting drugs to cancer cells are being investigated. Nanosize carriers are a suitable platform for this specific delivery. Herein, we evaluated the long-term stability of the naturally found protein nanocarrier apoferritin (Apo) with encapsulated doxorubicin (Dox). The encapsulation was performed using Apo's ability to disassemble reversibly into its subunits at low pH (2.7) and reassemble in neutral pH (7.2), physically entrapping drug molecules in its cavity (creating ApoDox). In this study, ApoDox was prepared in water and phosphate-buffered saline and stored for 12 weeks in various conditions (-20°C, 4°C, 20°C, and 37°C in dark, and 4°C and 20°C under ambient light). During storage, a very low amount of prematurely released drug molecules were detected (maximum of 7.5% for ApoDox prepared in PBS and 4.4% for ApoDox prepared in water). Fourier-transform infrared spectra revealed no significant differences in any of the samples after storage. Most of the ApoDox prepared in phosphate-buffered saline and ApoDox prepared in water and stored at -20°C formed very large aggregates (up to 487% of original size). Only ApoDox prepared in water and stored at 4°C showed no significant increase in size or shape. Although this storage caused slower internalization to LNCaP prostate cancer cells, ApoDox (2.5 μM of Dox) still retained its ability to inhibit completely the growth of 1.5×104 LNCaP cells after 72 hours. ApoDox stored at 20°C and 37°C in water was not able to deliver Dox inside the nucleus, and thus did not inhibit the growth of the LNCaP cells. Overall, our study demonstrates that ApoDox has very good stability over the course of 12 weeks when stored properly (at 4°C), and is thus suitable for use as a nanocarrier in the specific delivery of anticancer drugs to patients.


Membrane interactions of peptides representing the polybasic regions of three Rho GTPases are sensitive to the distribution of arginine and lysine residues.
Rho GTPases are a multifunctional family of proteins that are localized at cellular membranes via an isoprenyl group covalently linked to a C-terminal cysteine. Close to this primary site of membrane anchoring there is often found an additional polybasic region (PBR), which plays a secondary role in membrane binding and targeting of the complex. Here, peptides derived from the PBRs of the Rho family proteins Rac1 (K(183)KRKRK), TCL (K(198)KKKKR) and Cdc42 (P(182)KKSRR) were prepared with hexalysine (K(6)) and hexaarginine (R(6)) to study their interactions with multilamellar vesicles of phosphatidylglycerol (DOPG) and headgroup-deuterated dimyristoylphosphatidylcholine (DMPC-d(4)) using (2)H and (31)P NMR. The membranes retained their lamellar architecture after peptide binding, but the (2)H NMR line shapes for DMPC-d(4) indicated that the bound peptides altered the orientation of the choline headgroups, consistent with a change in membrane surface charge. Rac1 and TCL peptides appeared to affect the headgroup orientation similarly to K(6), although the perturbations were weaker and unlike those induced by the Cdc42 peptide and R(6). Magic-angle spinning (31)P NMR spectra of the membranes showed significant and selective broadening of the peak for DMPC after addition of the peptides, with R(6) and the Cdc42 peptide having the greatest effect. The selective broadening may be a consequence of the lipids separating into short-lived domains enriched in peptide-bound DOPG and peptide-free DMPC. These results illustrate that a complex relationship exists between the sequence of PBRs and their behaviour at membrane surfaces, which may have implications for the cellular functions and localization of Rho GTPases.


Outcomes of Contemporary Family Screening in Hypertrophic Cardiomyopathy.
Contemporary hypertrophic cardiomyopathy (HCM) family screening includes clinical evaluation and genetic testing (GT). This screening strategy requires the identification of a pathogenic mutation in the proband. Our aim was to examine the results of this HCM screening strategy. Between 1985 and 2016, 777 relatives of 209 probands were assessed in the context of HCM screening. Genotype-positive (G+) relatives and relatives without genetic testing (GT) underwent repeated clinical evaluations. In genotype-negative (G-) relatives mortality was assessed during follow-up. A pathogenic mutation was identified in 72% of probands. After counseling, GT was performed in 620 (80%) relatives: 264 (43%) were G+ (age 41±18 y) and 356 (57%) were G- (age 48±17 y). At first screening, HCM was diagnosed in 98 (37%) G+ relatives and 28 (17%) relatives without GT (p<0.001). During 9 years follow-up of relatives diagnosed with HCM, 8 (6%) underwent septal reduction therapy, 16 (16%) received primary prevention ICDs, and cardiac mortality was 0.3%/year. During 7 years follow-up of relatives without HCM, 29 (16%) developed HCM. Survival at 5/10 years was 99%/95% in G+ relatives, 97%/94% in G- relatives (p=0.8), and 100%/100% in relatives without GT. HCM was identified in 30% of relatives at first screening, and 16% developed HCM during 7 years of repeated evaluation. GT led to a discharge from clinical follow-up in 46% of the study population. Survival in the relatives was good.


Dissociation of sensorimotor deficits after rostral versus caudal lesions in the primary motor cortex hand representation.
Primary motor cortex (M1) has traditionally been considered a motor structure. Although neurophysiologic studies have demonstrated that M1 is also influenced by somatosensory inputs (cutaneous and proprioceptive), the behavioral significance of these inputs has yet to be fully defined in primates. The present study describes differential sensory-related deficits after small ischemic lesions in either the rostral or caudal subregion of the M1 hand area in a nonhuman primate. Squirrel monkeys retrieved food pellets out of different sized wells drilled into a Plexiglas board. Before the lesion, monkeys retrieved pellets by directing the hand to the well, inserting fingers directly into it, and extracting the pellet. After a lesion to the rostral portion of M1, monkeys frequently failed to direct the hand accurately to the well. Instead, fingers contacted the surface of the board outside the well before entering the well. These aiming errors are consistent with both the large amount of proximal motor outputs and the predominant proprioceptive inputs of rostral M1. Overall, these aiming errors are suggestive of dysfunctional processing of proprioceptive information or the failure to integrate proprioceptive information with motor commands. In contrast, after a lesion to the caudal portion of M1, monkeys frequently examined their palm visually for the presence of the pellet after an attempted retrieval. These errors are consistent with both the large amount of distal motor outputs and the predominant cutaneous inputs of caudal M1. Thus these errors are suggestive of a deficit in processing of cutaneous information or the failure to integrate cutaneous information with motor commands. Rostral and caudal M1 lesions result in different deficits in sensory-dependent motor control that appear to correlate with broad segregation of motor outputs and previously described sensory inputs of M1.


Cav1.4 L-Type Calcium Channels Contribute to Calpain Activation in Degenerating Photoreceptors of rd1 Mice.
Retinitis pigmentosa is an inherited blinding disorder characterized by progressive degeneration and loss of photoreceptors. The exact mechanism of degeneration and cell death of photoreceptors is not known, but is thought to involve disturbed Ca2+-signaling. Ca2+ can enter the photoreceptor cell via outer segment cyclic nucleotide-gated (CNG) channels or synaptic Cav1.4 L-type voltage-gated calcium channels (VGCC). Previously, we have shown that genetic ablation of the Cngb1 gene encoding the B subunit of the rod CNG channel delays the fast progressing degeneration in the rd1 mutant mouse model of retinitis pigmentosa. In this study, we crossbred rd1 mice with the Cacna1f-deficient mouse lacking the Cav1.4 α1 subunit of the L-type VGCC. Longitudinal in vivo examinations of photoreceptor layer thickness by optical coherence tomography revealed a significant, but not sustained delay of retinal degeneration in Cacna1f x rd1 double mutant mice compared to rd1 mice. This was accompanied by a reduction of TUNEL positive cells in the early phase of rod degeneration. Remarkably, Cacna1f x rd1 double mutant mice displayed a strong decrease in the activation of the Ca2+-dependent protease calpain during photoreceptor loss. Our results show that genetic deletion of the synaptic Cav1.4 L-type VGCCs impairs calpain activation and leads to a short-term preservation of photoreceptors in the rd1 mouse.


STAT3 targets suggest mechanisms of aggressive tumorigenesis in diffuse large B-cell lymphoma.
The signal transducer and activator of transcription 3 (STAT3) is a transcription factor that, when dysregulated, becomes a powerful oncogene found in many human cancers, including diffuse large B-cell lymphoma. Diffuse large B-cell lymphoma is the most common form of non-Hodgkin's lymphoma and has two major subtypes: germinal center B-cell-like and activated B-cell-like. Compared with the germinal center B-cell-like form, activated B-cell-like lymphomas respond much more poorly to current therapies and often exhibit overexpression or overactivation of STAT3. To investigate how STAT3 might contribute to this aggressive phenotype, we have integrated genome-wide studies of STAT3 DNA binding using chromatin immunoprecipitation-sequencing with whole-transcriptome profiling using RNA-sequencing. STAT3 binding sites are present near almost a third of all genes that differ in expression between the two subtypes, and examination of the affected genes identified previously undetected and clinically significant pathways downstream of STAT3 that drive oncogenesis. Novel treatments aimed at these pathways may increase the survivability of activated B-cell-like diffuse large B-cell lymphoma.


Evolution of four gene families with patchy phylogenetic distributions: influx of genes into protist genomes.
Lateral gene transfer (LGT) in eukaryotes from non-organellar sources is a controversial subject in need of further study. Here we present gene distribution and phylogenetic analyses of the genes encoding the hybrid-cluster protein, A-type flavoprotein, glucosamine-6-phosphate isomerase, and alcohol dehydrogenase E. These four genes have a limited distribution among sequenced prokaryotic and eukaryotic genomes and were previously implicated in gene transfer events affecting eukaryotes. If our previous contention that these genes were introduced by LGT independently into the diplomonad and Entamoeba lineages were true, we expect that the number of putative transfers and the phylogenetic signal supporting LGT should be stable or increase, rather than decrease, when novel eukaryotic and prokaryotic homologs are added to the analyses. The addition of homologs from phagotrophic protists, including several Entamoeba species, the pelobiont Mastigamoeba balamuthi, and the parabasalid Trichomonas vaginalis, and a large quantity of sequences from genome projects resulted in an apparent increase in the number of putative transfer events affecting all three domains of life. Some of the eukaryotic transfers affect a wide range of protists, such as three divergent lineages of Amoebozoa, represented by Entamoeba, Mastigamoeba, and Dictyostelium, while other transfers only affect a limited diversity, for example only the Entamoeba lineage. These observations are consistent with a model where these genes have been introduced into protist genomes independently from various sources over a long evolutionary time. Phylogenetic analyses of the updated datasets using more sophisticated phylogenetic methods, in combination with the gene distribution analyses, strengthened, rather than weakened, the support for LGT as an important mechanism affecting the evolution of these gene families. Thus, gene transfer seems to be an on-going evolutionary mechanism by which genes are spread between unrelated lineages of all three domains of life, further indicating the importance of LGT from non-organellar sources into eukaryotic genomes.


Geographic coverage of male circumcision in western Kenya.
Voluntary Medical Male Circumcision (VMMC) for human immunodeficiency virus (HIV) prevention has scaled up rapidly among young men in western Kenya since 2008. Whether the program has successfully reached uncircumcised men evenly across the region is largely unknown. Using data from two cluster randomized surveys from the 2008 and 2014 Kenyan Demographic Health Survey (KDHS), we mapped the continuous spatial distribution of circumcised men by age group across former Nyanza Province to identify geographic areas where local circumcision prevalence is lower than the overall, regional prevalence. The prevalence of self-reported circumcision among men 15 to 49 across six counties in former Nyanza Province increased from 45.6% (95% CI = 33.2-58.0%) in 2008 to 71.4% (95% CI = 67.4-75.0%) in 2014, with the greatest increase in men 15 to 24 years of age, from 40.4% (95% CI = 27.7-55.0%) in 2008 to 81.6% (95% CI = 77.2-85.0%) in 2014. Despite the dramatic scale-up of VMMC in western Kenya, circumcision coverage in parts of Kisumu, Siaya, and Homa Bay counties was lower than expected (P < 0.05), with up to 50% of men aged 15 to 24 still uncircumcised by 2014 in some areas. The VMMC program has proven successful in reaching a large population of uncircumcised men in western Kenya, but as of 2014, pockets of low circumcision coverage still existed. Closing regional gaps in VMMC prevalence to reach 80% coverage may require targeting specific areas where VMMC prevalence is lower than expected.


Vision, touch and object manipulation in Senegal parrots Poicephalus senegalus.
Parrots are exceptional among birds for their high levels of exploratory behaviour and manipulatory abilities. It has been argued that foraging method is the prime determinant of a bird's visual field configuration. However, here we argue that the topography of visual fields in parrots is related to their playful dexterity, unique anatomy and particularly the tactile information that is gained through their bill tip organ during object manipulation. We measured the visual fields of Senegal parrots Poicephalus senegalus using the ophthalmoscopic reflex technique and also report some preliminary observations on the bill tip organ in this species. We found that the visual fields of Senegal parrots are unlike those described hitherto in any other bird species, with both a relatively broad frontal binocular field and a near comprehensive field of view around the head. The behavioural implications are discussed and we consider how extractive foraging and object exploration, mediated in part by tactile cues from the bill, has led to the absence of visual coverage of the region below the bill in favour of more comprehensive visual coverage above the head.


Substrate stiffness and VE-cadherin mechano-transduction coordinate to regulate endothelial monolayer integrity.
The vascular endothelium is subject to diverse mechanical cues that regulate vascular endothelial barrier function. In addition to rigidity sensing through integrin adhesions, mechanical perturbations such as changes in fluid shear stress can also activate force transduction signals at intercellular junctions. This study investigated how extracellular matrix rigidity and intercellular force transduction, activated by vascular endothelial cadherin, coordinate to regulate the integrity of endothelial monolayers. Studies used complementary mechanical measurements of endothelial monolayers grown on patterned substrates of variable stiffness. Specifically perturbing VE-cadherin receptors activated intercellular force transduction signals that increased integrin-dependent cell contractility and disrupted cell-cell and cell-matrix adhesions. Further investigations of the impact of substrate rigidity on force transduction signaling demonstrated how cells integrate extracellular mechanics cues and intercellular force transduction signals, to regulate endothelial integrity and global tissue mechanics. VE-cadherin specific signaling increased focal adhesion remodeling and cell contractility, while sustaining the overall mechanical equilibrium at the mesoscale. Conversely, increased substrate rigidity exacerbates the disruptive effects of intercellular force transduction signals, by increasing heterogeneity in monolayer stress distributions. The results provide new insights into how substrate stiffness and intercellular force transduction coordinate to regulate endothelial monolayer integrity.


Reflective acousto-optic modulation with surface acoustic waves.
A reflective optical modulator based on acousto-optic modulation of light by a mirror corrugated with surface acoustic waves is presented. Modulation of optical amplitude, frequency, and phase is demonstrated at visible (633- and 488-nm) and deep UV (244-nm) wavelengths. The reflective modulator has eight channels and achieves a maximum first-order diffraction efficiency of 6.0%.


Assessment of the direct economic losses associated with hydatid disease (Echinococcus granulosus sensu stricto) in beef cattle slaughtered at an Australian abattoir.
Bovine hydatid disease, characterised by fluid-filled hydatid cysts, is regularly found in the offal of beef cattle at slaughter. Organs found to be infected at slaughter are removed to preclude them from entering the human food chain. The organs are either downgraded to pet food or condemned. Previous studies have focussed on total economic losses, but have not calculated the cost of disease per animal, which would be useful information for producers when determining how best to manage hydatid disease. This study estimated the direct losses associated with hydatid disease in beef cattle slaughtered at an Australian beef abattoir both at the population (all cattle slaughtered) and individual animal level. Data on annual prevalence of hydatid disease in beef cattle were obtained from an Australian abattoir for the years 2011-2017. The direct losses resulting from the condemnation and downgrading of offal infected with hydatid cysts at the abattoir were estimated using data stratified by age, sex and feed-type. Official and literature-based sources of organ weight and price were used to estimate direct losses associated with hydatid disease in beef cattle slaughtered at the abattoir. Uncertainty and variability in input parameters were represented using uniform distributions and Monte Carlo sampling was used to model output parameter uncertainty. Out of 1,097,958 beef cattle slaughtered between January 2011 and December 2017, 97,832 (8.9%) were reported infected with hydatid disease. The median estimated direct loss to the abattoir for the duration of the study period was AU$655,560 (95% confidence interval [CI] AU$544,366-787,235). This equated to approximately AU$6.70 (95% CI AU$5.56-8.05) lost per infected animal. The annual median estimated direct losses due to hydatid disease at the abattoir were AU$93,651 (95% CI AU$77,767-112,462). Direct losses varied each year of the study and ranged from AU$38,683 in 2016 to AU$163,006 in 2014. This estimate of the direct losses associated with bovine hydatid disease most likely underestimates the true extent of the overall losses because indirect losses such as reduced carcass weights were not estimated in this study. Nevertheless, these estimates illustrate the negative economic impact of bovine hydatid disease and demonstrate that improved surveillance to enable control of hydatid disease should be considered both in Australia and globally. It would be worthwhile to estimate the losses in other beef abattoirs for the same time period to compare results, and to investigate the cost-benefit of control programs for bovine hydatid disease.


Conserved Dynamic Mechanism of Allosteric Response to L-arg in Divergent Bacterial Arginine Repressors.
Hexameric arginine repressor, ArgR, is the feedback regulator of bacterial L-arginine regulons, and sensor of L-arg that controls transcription of genes for its synthesis and catabolism. Although ArgR function, as well as its secondary, tertiary, and quaternary structures, is essentially the same in E. coli and B. subtilis, the two proteins differ significantly in sequence, including residues implicated in the response to L-arg. Molecular dynamics simulations are used here to evaluate the behavior of intact B. subtilis ArgR with and without L-arg, and are compared with prior MD results for a domain fragment of E. coli ArgR. Relative to its crystal structure, B. subtilis ArgR in absence of L-arg undergoes a large-scale rotational shift of its trimeric subassemblies that is very similar to that observed in the E. coli protein, but the residues driving rotation have distinct secondary and tertiary structural locations, and a key residue that drives rotation in E. coli is missing in B. subtilis. The similarity of trimer rotation despite different driving residues suggests that a rotational shift between trimers is integral to ArgR function. This conclusion is supported by phylogenetic analysis of distant ArgR homologs reported here that indicates at least three major groups characterized by distinct sequence motifs but predicted to undergo a common rotational transition. The dynamic consequences of L-arg binding for transcriptional activation of intact ArgR are evaluated here for the first time in two-microsecond simulations of B. subtilis ArgR. L-arg binding to intact B. subtilis ArgR causes a significant further shift in the angle of rotation between trimers that causes the N-terminal DNA-binding domains lose their interactions with the C-terminal domains, and is likely the first step toward adopting DNA-binding-competent conformations. The results aid interpretation of crystal structures of ArgR and ArgR-DNA complexes.


The HUPO PSI's molecular interaction format--a community standard for the representation of protein interaction data.
A major goal of proteomics is the complete description of the protein interaction network underlying cell physiology. A large number of small scale and, more recently, large-scale experiments have contributed to expanding our understanding of the nature of the interaction network. However, the necessary data integration across experiments is currently hampered by the fragmentation of publicly available protein interaction data, which exists in different formats in databases, on authors' websites or sometimes only in print publications. Here, we propose a community standard data model for the representation and exchange of protein interaction data. This data model has been jointly developed by members of the Proteomics Standards Initiative (PSI), a work group of the Human Proteome Organization (HUPO), and is supported by major protein interaction data providers, in particular the Biomolecular Interaction Network Database (BIND), Cellzome (Heidelberg, Germany), the Database of Interacting Proteins (DIP), Dana Farber Cancer Institute (Boston, MA, USA), the Human Protein Reference Database (HPRD), Hybrigenics (Paris, France), the European Bioinformatics Institute's (EMBL-EBI, Hinxton, UK) IntAct, the Molecular Interactions (MINT, Rome, Italy) database, the Protein-Protein Interaction Database (PPID, Edinburgh, UK) and the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING, EMBL, Heidelberg, Germany).


Comparing trends in mid-life 'deaths of despair' in the USA, Canada and UK, 2001-2019: is the USA an anomaly?
In recent years, 'deaths of despair' due to drugs, alcohol and suicide have contributed to rising mid-life mortality in the USA. We examine whether despair-related deaths and mid-life mortality trends are also changing in peer countries, the UK and Canada. Descriptive analysis of population mortality rates. The USA, UK (and constituent nations England and Wales, Northern Ireland and Scotland) and Canada, 2001-2019. Full population aged 35-64 years. We compared all-cause and 'despair'-related mortality trends at mid-life across countries using publicly available mortality data, stratified by three age groups (35-44, 45-54 and 55-64 years) and by sex. We examined trends in all-cause mortality and mortality by causes categorised as (1) suicides, (2) alcohol-specific deaths and (3) drug-related deaths. We employ several descriptive approaches to visually inspect age, period and cohort trends in these causes of death. The USA and Scotland both saw large relative increases and high absolute levels of drug-related deaths. The rest of the UK and Canada saw relative increases but much lower absolute levels in comparison. Alcohol-specific deaths showed less consistent trends that did not track other 'despair' causes, with older groups in Scotland seeing steep declines over time. Suicide deaths trended slowly upward in most countries. In the UK, Scotland has suffered increases in drug-related mortality comparable with the USA, while Canada and other UK constituent nations did not see dramatic increases. Alcohol-specific and suicide mortalities generally follow different patterns to drug-related deaths across countries and over time, questioning the utility of a cohesive 'deaths of despair' narrative.


Dietary phthalate exposure in pregnant women and the impact of consumer practices.
Phthalates are ubiquitous endocrine-disrupting chemicals that are contaminants in food and contribute to significant dietary exposures. We examined associations between reported consumption of specific foods and beverages and first trimester urinary phthalate metabolite concentrations in 656 pregnant women within a multicenter cohort study, The Infant Development and Environment Study (TIDES), using multivariate regression analysis. We also examined whether reported use of ecofriendly and chemical-free products was associated with lower phthalate biomarker levels in comparison to not following such practices. Consumption of one additional serving of dairy per week was associated with decreases of 1% in the sum of di-2-ethylhexyl phthalate (DEHP) metabolite levels (95% CI: -2.0, -0.2). Further, participants who reported sometimes eating homegrown food had monoisobutyl phthalate (MiBP) levels that were 16.6% lower (95% CI: -29.5, -1.3) in comparison to participants in the rarely/never category. In contrast to rarely/never eating frozen fruits and vegetables, participants who reported sometimes following this practice had monobenzyl phthalate (MBzP) levels that were 21% higher (95% CI: 3.3, 41.7) than rarely/ever respondents. Future study on prenatal dietary phthalate exposure and the role of consumer product choices in reducing such exposure is needed.


Sugar and mineral enriched fraction from olive mill wastewater for promising cosmeceutical application: characterization, in vitro and in vivo studies.
Nowadays, agro-food by-products represent a potential low-cost source of biologically active ingredients which have been paid significant attention as nutraceuticals, medicine, food and cosmetics. In a previous study we evaluated the total sugars, metals and polyphenols of olive mill wastewater (OMWW) from a Cerasuola olive cultivar. In the present work we selectively recovered a sugar and mineral enriched fraction (SMEF) from Cerasuola OMWW by a green adsorption/desorption process. The SMEF was mainly found to be composed of monosaccharides and potassium by HPLC-ELSD and ICP-MS. The in vitro cytotoxicity on human fibroblasts, at different concentrations of the fraction, was investigated by MTT and comet assays. In addition, intracellular reactive oxygen species (ROS) production, apoptosis and cell morphological changes were examined. The physical stability of a formulation containing the SMEF (1% w/w) and its in vivo skin effects were also assessed.Our results highlighted that the SMEF showed a toxic effect at higher concentrations (i.e. cell viability reduction, DNA fragmentation and morphological alterations) well correlated with high ROS levels. Conversely, at low concentrations (0.5% and 1% w/w), no significant changes were observed. For the first time, through stability studies and in vivo tests, we also demonstrated that the SMEF formulation is stable and safe for topical application, since skin hydration improvement without negative effects was observed after 7 days of its use. Therefore, the SMEF has great potential to be used for cosmeceutical applications.


Lower Socioeconomic Position Is Associated with Greater Activity in and Integration within an Allostatic-Interoceptive Brain Network in Response to Affective Stimuli.
Socioeconomic inequities shape physical health and emotional well-being. As such, recent work has examined the neural mechanisms through which socioeconomic position (SEP) may influence health. However, there remain critical gaps in knowledge regarding the relationships between SEP and brain function. These gaps include a lack of research on: (1) the association between SEP and brain functioning in later life, (2) relationships between SEP and functioning of the whole brain beyond specific regions of interest, and (3) how neural responses to positive affective stimuli differ by SEP. The current study addressed these gaps by examining the association between SEP (i.e., education, income) and neural responses to affective stimuli among 122 mid- to late-life adults. During MRI scanning, participants viewed 30 positive, 30 negative, and 30 neutral images; activation and network connectivity analyses explored associations between SEP and neural responses to these affective stimuli. Analyses revealed that those with lower SEP showed greater neural activity to both positive and negative images in regions within the allostatic-interoceptive network, a system of regions implicated in representing and regulating physiological states of the body and the external environment. There were no positive associations between SEP and neural responses to negative or positive images. In addition, graph-theory network analyses showed that individuals with lower SEP demonstrated greater global efficiency within the allostatic-interoceptive network and executive control network, across all task conditions. The findings suggest that lower SEP is associated with enhanced neural sensitivity to affective cues that may be metabolically costly to maintain over time and suggest a mechanism by which SEP might get "under the skull" to influence mental and physical well-being.


Costs of temporary and permanent disability induced by diabetes.
To evaluate the indirect costs of diabetes and show their relationship to the chronic complications of diabetes. The cost of temporary and permanent disability for diabetic patients was studied in a group of La Plata University employees and in a second group at the government institutions of the Buenos Aires Province during 3 consecutive yr (1984-1986). Absences due to temporary disability were similar for the diabetic group without chronic complications and an age- and sex-matched nondiabetic control group. Conversely, diabetic patients with chronic complications had major increases in absences compared with the control subjects. Diabetes mellitus was the third leading cause of permanent disability mainly due to macrovascular and retinal lesions. This disability resulted in an average of 11 yr of work production loss per patient. These results suggest that diabetic individuals without complications incur few additional costs compared with nondiabetic individuals. However, once complications appear, the indirect costs are very high, suggesting that secondary preventions of the diabetic complications might be an optimal approach for reducing the health-care burden of diabetes.


Linking cortical network synchrony and excitability.
Theoretical approaches based on dynamical systems theory can provide useful frameworks to guide experiments and analysis techniques when investigating cortical network activity. The notion of phase transitions between qualitatively different kinds of network dynamics has been such a framework inspiring novel approaches to neurophysiological data analysis over the recent years. One particular intriguing hypothesis has been that cortical networks reside in the vicinity of a phase transition. Although the final verdict on this hypothesis is still out, trying to understand cortex dynamics from this viewpoint has recently led to interesting insights on cortical network function with relevance for clinical practice.


Epidemiologic evidence for clustering of equine motor neuron disease in the United States.
To examine the regional variations in the distribution of equine motor neuron disease (EMND) in the United States and the factors that might explain those variations. Cluster investigation and case-control study. The study population consisted of 97 horses with histopathologically confirmed EMND and 698 controls with diagnosis of other spinal cord disorders at 21 US veterinary teaching hospitals participating in the Veterinary Medical Data Base. The total horse population of the United States was divided into 21 regions, and the regional incidence rates of EMND from January 1985 through January 1995 were estimated. Moran's index of spatial autocorrelation was calculated to test for spatial clustering of the disease. The 21 regions were then joined in broader areas according to the similarity of their EMND rates by means of the cluster analysis statistical technique. Finally, the role of potential confounding factors (age at diagnosis, month of diagnosis, breed, and sex) in the present distribution of EMND was assessed, using logistic regression analysis. Differences in estimated rates across the 21 regions resulted in a strong pattern of spatial clustering of EMND in the United States. The geographic units were grouped into 5 risk regions, with the gradient of EMND incidence rates increasing from the western states (almost 0 cases/1,000,000 horse-years) toward New England (20.78 cases/1,000,000 horse-years). Reported risk factors of EMND (age, breed) and other extraneous factors (sex, month of diagnosis) could not explain the observed geographic variations of disease rates. Nevertheless, there is evidence of some confounding attributable to age and breed. Although the mechanism responsible for the clustering of EMND in northeastern states is still unexplained, it is not an epiphenomenon caused by regional differences in the distribution of the factors investigated.


Response of genioglossus muscle activity to nasal airway occlusion in normal sleeping adults.
To determine the combined effect of increased subatmospheric upper airway pressure and withdrawal of phasic volume feedback from the lung on genioglossus muscle activity, the response of this muscle to intermittent nasal airway occlusion was studied in 12 normal adult males during sleep. Nasal occlusion at end expiration was achieved by inflating balloon-tipped catheters located within the portals of a nose mask. No seal was placed over the mouth. During nose breathing in non-rapid-eye-movement (NREM) sleep, nasal airway occlusion resulted in multiple respiratory efforts before arousal. Mouth breathing was not initiated until arousal. Phasic inspiratory genioglossus activity was present in eight subjects during NREM sleep. In these subjects, comparison of peak genioglossus inspiratory activity on the first three occluded efforts to the value just before occlusion showed an increase of 4.7, 16.1, and 28.0%, respectively. The relative increases in peak genioglossus activity were very similar to respective increases in peak diaphragm activity. Arousal was associated with a large burst in genioglossus activity. During airway occlusion in rapid-eye-movement (REM) sleep, mouth breathing could occur without a change in sleep state. In general, genioglossus responses to airway occlusion in REM sleep were similar in pattern to those in NREM sleep. A relatively small reflex activation of upper airway muscles associated with a sudden increase in subatmospheric pressure in the potentially collapsible segment of the upper airway may help compromise upper airway patency during sleep.


Constraints for nursing in developing a framework for cancer care research.
Oncology nursing has become an important and popular specialist area of care. Evidence indicates that there is a disappointingly low level of funded research. This paper seeks to identify some of the key constraints which have inhibited the development of cancer nursing research. It is proposed that there are two priorities to promoting research. First, there is a need to produce the next generation of research trained cancer nurses. Secondly, the need for a coordinated programme of basic and applied cancer nursing research. This paper discusses the difficulties of obtaining research funding and adequate supervision for higher degrees. In addition, key constraints in clinical nursing and nurse education are identified. In conclusion, it is proposed that there is an urgent need for specific cancer-care research funded studentships and the establishment of a coordinated programme of research.


Designing an Interactive Field Epidemiology Case Study Training for Public Health Practitioners.
Globally, public health practitioners are called upon to respond quickly and capably to mitigate a variety of immediate and incipient threats to the health of their communities, which often requires additional training in new or updated methodologies or epidemiologic phenomena. Competing public health priorities and limited training resources can present challenges in developed and developing countries alike. Training provided to front-line public health workers by ministries of health, donors and/or partner organizations should be delivered in a way that is effective, adaptable to local conditions and culture, and should be an experience perceived as a job benefit. In this review, we share methods for interactive case-study training methodologies, including the use of problem-based scenarios, role-play activities, and other small-group focused efforts that encourage the learner to discuss and synthesize the concepts taught. We have fine-tuned these methods through years of carrying out training of all levels of public health practitioners in dozens of countries worldwide.


Heterometallic Fe2 (II) -U(V) and Ni2 (II) -U(V) Exchange-Coupled Single-Molecule Magnets: Effect of the 3 d Ion on the Magnetic Properties.
Uranium-based compounds have been put forward as ideal candidates for the design of single-molecule magnets (SMMs) with improved properties, but to date, only two examples of exchange-coupled 3d-5f SMM containing uranium have been reported and both are based on the Mn(II) ion. Here we have synthesized the first examples of exchange-coupled uranium SMMs based on Fe(II) and Ni(II) . The SMM behavior of these complexes containing a quasi linear {M-O=U=O-M} core arises from intramolecular Fe-U and Ni-U exchange interactions combined with the high Ising anisotropy of the uranyl(V) moiety. The measured values of the relaxation barrier (53.9±0.9 K in the UFe2 complex and of 27.4±0.5 K in the UNi2 complex) show clearly the dependency on the spin value of the transition metal, providing important new information for the future design of improved uranium-based SMMs.


The role of the extracellular matrix components in cutaneous wound healing.
Wound healing is the physiologic response to tissue trauma proceeding as a complex pathway of biochemical reactions and cellular events, secreted growth factors, and cytokines. Extracellular matrix constituents are essential components of the wound repair phenomenon. Firstly, they create a provisional matrix, providing a structural integrity of matrix during each stage of healing process. Secondly, matrix molecules regulate cellular functions, mediate the cell-cell and cell-matrix interactions, and serve as a reservoir and modulator of cytokines and growth factors' action. Currently known mechanisms, by which extracellular matrix components modulate each stage of the process of soft tissue remodeling after injury, have been discussed.


A Proposed Process for Reliably Updating the Common Rule.
The recent Common Rule revision process took almost a decade and the resulting changes are fairly modest, particularly when compared to the ambitious ideas proposed in the advance notice of proposed rulemaking (ANPRM) and notice of proposed rulemaking (NPRM). Furthermore, the revision process did not even attempt to tackle any of the Common Rule subparts pertaining to vulnerable populations (i.e., pregnant women and fetuses, prisoners, children) where commentators think the rules unduly restrict important research. We believe that this was a missed opportunity to make desirable changes, and that given the usual process the next opportunity to revisit the Common Rule is unacceptably remote. In this article, we argue that the Common Rule should be regularly reassessed, with a mechanism for making substantive (and expeditious) changes. Drawing on lessons learned from the recent revision process, we make recommendations about ways to structure future attempts to maximize the ability to make timely and necessary changes.


Cross-cultural validation of a measure of felt stigma in people with intellectual disabilities.
One trade-off for increased independence of adults with intellectual disabilities in developing countries is that they may find themselves more exposed to the negative perceptions held by the general population regarding the mentally ill and disabled. The aim of this study was to adapt and translate a tool to measure felt stigma in people with intellectual disabilities designed in the United Kingdom (U.K.) to make it culturally viable, and to determine its reliability and validity in the multi-ethnic and multilingual context of South Africa (S.A.) and to compare the item responses and factor structures of the tool between the U.K. and S.A. We translated the tool into local languages and refined it by conducting focus groups and pilot studies with professionals and adults with intellectual disabilities, after which test-retest reliability, factor analysis and internal consistency were calculated. Participants were from three different population groups: Afrikaans (n = 71; 37%), English (n = 67; 35%) and Xhosa (n = 53; 28%), who had mild (n = 106; 56%) or moderate intellectual disabilities (n = 85; 44%). 98 (51%) were re-interviewed. The resulting international version of the perceived stigma measure consisted of 10 questions with good test-retest reliability (κ ranging from 0.41 to 0.59) and a similar factor structure to the UK version, despite including a different set of questions. There is evidence for the validity of felt stigma ratings reported by adults with intellectual disabilities, despite different cultural and health service contexts.


Particulate matters from diesel heavy duty trucks exhaust versus cigarettes emissions: a new educational antismoking instrument.
Indoor smoking in public places and workplaces is forbidden in Italy since 2003, but some health concerns are arising from outdoor secondhand smoke (SHS) exposure for non-smokers. One of the biggest Italian Steel Manufacturer, with several factories in Italy and abroad, the Marcegaglia Group, recently introduced the outdoor smoking ban within the perimeter of all their factories. In order to encourage their smoker employees to quit, the Marcegaglia management decided to set up an educational framework by measuring the PM1, PM2.5 and PM10 emissions from heavy duty trucks and to compare them with the emissions of cigarettes in an indoor controlled environment under the same conditions. The exhaust pipe of two trucks powered by a diesel engine of about 13.000/14.000 cc(3) were connected with a flexible hose to a hole in the window of a container of 36 m(3) volume used as field office. The trucks operated idling for 8 min and then, after adequate office ventilation, a smoker smoked a cigarette. Particulate matter emission was thereafter analyzed. Cigarette pollution was much higher than the heavy duty truck one. Mean of the two tests was: PM1 truck 125.0(47.0), cigarettes 231.7(90.9) p = 0.002; PM2.5 truck 250.8(98.7), cigarettes 591.8(306.1) p = 0.006; PM10 truck 255.8(52.4), cigarettes 624.0(321.6) p = 0.002. Our findings may be important for policies that aim reducing outdoor SHS exposure. They may also help smokers to quit tobacco dependence by giving them an educational perspective that rebuts the common alibi that traffic pollution is more dangerous than cigarettes pollution.


Phase-Shifted PFH@PLGA/Fe3O4 Nanocapsules for MRI/US Imaging and Photothermal Therapy with near-Infrared Irradiation.
Photothermal therapy (PTT) utilizes photothermal conversion reagents to generate heat energy from absorbed light to effectively treat various malignant diseases. This approach has attracted broad and increasing interest in cancer treatment. Near-infrared (NIR)-induced PTT is particularly attractive because of its minimal absorbance by normal tissue and relatively deep tissue penetration. To improve the efficacy of PTT, we have developed nanocapsules encapsulating superparamagnetic iron oxide (Fe3O4) as synergistic agents for NIR-induced PTT. In this study, phase-shift and NIR photoabsorbing poly(lactic-co-glycolic acid) (PLGA) nanocapsules (perfluorohexane (PFH)@PLGA/Fe3O4) were fabricated for MRI/US dual-modal imaging-guided PTT. The multifunctional nanocapsules can be used not only to increase the local tumor temperature by absorbing the NIR energy but also as bimodal contrast agents for both MRI and US imaging. Such nanocapsules can be converted into microbubbles under NIR irradiation, which produces excellent contrast for US imaging and enhanced cancer ablation. We refer to the nanocapsule phase transition process induced by the infrared lamp as NIR radiation droplet vaporization (NIRDV).


A mechanism of resistance to glucocorticoids in multiple myeloma: transient expression of a truncated glucocorticoid receptor mRNA.
Despite their widespread use, little is known of either the mechanism of action of glucocorticoids in the treatment of multiple myeloma or why patients ultimately become resistant to their therapeutic effects. Here, we address these issues by examining the direct effects of the glucocorticoid dexamethasone (DEX) on a hormone-sensitive clone (MM.1S) of a human multiple myeloma line and compare them with those of its hormone-resistant counterpart (MM.1R). MM.1S expresses approximately 50,000 glucocorticoid receptors (GR) per cell, the full-length 7.1-kb GR mRNA at high levels, and is lysed by DEX. DEX-induced cytolysis is effectively blocked by the glucocorticoid antagonist, RU 486, indicating the specificity of this response for the GR. In contrast to MM.1S, MM.1R is not lysed by hormone, has little hormone-binding activity, and expresses the 7.1-kb GR mRNA at low levels. Interestingly, we have found that two distinct phenotypes emerge from MM.1R with increasing periods of growth in culture. The first or "early" form, MM.1Re, expresses high levels of a variant GR mRNA of 5.5 kb that has a deletion in its 3' end. With further growth in the presence or absence of selective media, the expression of this transcript is repressed, resulting in the second or "late" phenotype characteristic of MM.1RL. No discernible differences in the organization of the genomic GR sequence in DEX-sensitive and -resistant cells were detectable by Southern analysis, suggesting that no gross deletions, rearrangements, or allelic variations in the genomic sequence account for the resistant phenotypes of MM.1R.


ARE STEM CELL MARKER EXPRESSION AND CD133 ANALYSIS RELEVANT TO DIFFERENTIATE COLORECTAL CANCER?
A) CD133+ cytoplasmic B) AXL+ combined C) c-MYC+ nuclear. CD133 and AXL have been described as cancer stem cell markers, and c-MYC as a key regulatory cellular mechanism in colorectal cancer (CRC). Evaluate the prognostic role of the biomarkers CD133, AXL and c-MYC and their association with clinicopathologic characteristics in colorectal adenocarcinomas and adenomas. A total of 156 patients with UICC stage I-IV adenocarcinomas (n=122) and adenomas (n=34) were analyzed. Tissue microarrays (TMA) from primary tumors and polyps for CD133, c-MYC and AXL expression were performed and analyzed for their significance with clinicopathologic characteristics. Poorly differentiated adenocarcinomas and disease progression were independent risk factors for poor overall survival. The median overall survival time was 30 months. Positive CD133 expression (35.9% of all cases), particularly of right-sided CRCs (44.8% of the CD133+ cases), was negatively correlated with death in the univariate analysis, which did not reach significance in the multivariate analysis. c-MYC (15.4% of all cases) was predominantly expressed in advanced-stage patients with distant (non-pulmonary/non-hepatic) metastasis. AXL expression was found only occasionally, and predominantly dominated in adenomas, with less penetrance in high-grade dysplasia. CD133 expression was not associated with inferior overall survival in CRC. While AXL showed inconclusive results, c-MYC expression in primary CRCs was associated with distant metastasis.


Prevalence of and Trends in Diabetes Among Adults in the United States, 1988-2012.
Previous studies have shown increasing prevalence of diabetes in the United States. New US data are available to estimate prevalence of and trends in diabetes. To estimate the recent prevalence and update US trends in total diabetes, diagnosed diabetes, and undiagnosed diabetes using National Health and Nutrition Examination Survey (NHANES) data. Cross-sectional surveys conducted between 1988-1994 and 1999-2012 of nationally representative samples of the civilian, noninstitutionalized US population; 2781 adults from 2011-2012 were used to estimate recent prevalence and an additional 23,634 adults from 1988-2010 were used to estimate trends. The prevalence of diabetes was defined using a previous diagnosis of diabetes or, if diabetes was not previously diagnosed, by (1) a hemoglobin A1c level of 6.5% or greater or a fasting plasma glucose (FPG) level of 126 mg/dL or greater (hemoglobin A1c or FPG definition) or (2) additionally including 2-hour plasma glucose (2-hour PG) level of 200 mg/dL or greater (hemoglobin A1c, FPG, or 2-hour PG definition). Prediabetes was defined as a hemoglobin A1c level of 5.7% to 6.4%, an FPG level of 100 mg/dL to 125 mg/dL, or a 2-hour PG level of 140 mg/dL to 199 mg/dL. In the overall 2011-2012 population, the unadjusted prevalence (using the hemoglobin A1c, FPG, or 2-hour PG definitions for diabetes and prediabetes) was 14.3% (95% CI, 12.2%-16.8%) for total diabetes, 9.1% (95% CI, 7.8%-10.6%) for diagnosed diabetes, 5.2% (95% CI, 4.0%-6.9%) for undiagnosed diabetes, and 38.0% (95% CI, 34.7%-41.3%) for prediabetes; among those with diabetes, 36.4% (95% CI, 30.5%-42.7%) were undiagnosed. The unadjusted prevalence of total diabetes (using the hemoglobin A1c or FPG definition) was 12.3% (95% CI, 10.8%-14.1%); among those with diabetes, 25.2% (95% CI, 21.1%-29.8%) were undiagnosed. Compared with non-Hispanic white participants (11.3% [95% CI, 9.0%-14.1%]), the age-standardized prevalence of total diabetes (using the hemoglobin A1c, FPG, or 2-hour PG definition) was higher among non-Hispanic black participants (21.8% [95% CI, 17.7%-26.7%]; P < .001), non-Hispanic Asian participants (20.6% [95% CI, 15.0%-27.6%]; P = .007), and Hispanic participants (22.6% [95% CI, 18.4%-27.5%]; P < .001). The age-standardized percentage of cases that were undiagnosed was higher among non-Hispanic Asian participants (50.9% [95% CI, 38.3%-63.4%]; P = .004) and Hispanic participants (49.0% [95% CI, 40.8%-57.2%]; P = .02) than all other racial/ethnic groups. The age-standardized prevalence of total diabetes (using the hemoglobin A1c or FPG definition) increased from 9.8% (95% CI, 8.9%-10.6%) in 1988-1994 to 10.8% (95% CI, 9.5%-12.0%) in 2001-2002 to 12.4% (95% CI, 10.8%-14.2%) in 2011-2012 (P < .001 for trend) and increased significantly in every age group, in both sexes, in every racial/ethnic group, by all education levels, and in all poverty income ratio tertiles. In 2011-2012, the estimated prevalence of diabetes was 12% to 14% among US adults, depending on the criteria used, with a higher prevalence among participants who were non-Hispanic black, non-Hispanic Asian, and Hispanic. Between 1988-1994 and 2011-2012, the prevalence of diabetes increased in the overall population and in all subgroups evaluated.


Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length.
Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1, PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.


Interleukins and inflammatory markers are useful in predicting the severity of acute pancreatitis.
Acute pancreatitis (AP) is a disease with significant morbidity and mortality. The aim of this study was to evaluate the predictive role of inflammatory markers, particularly interleukins (ILs), in the course of AP and to determine the frequency of etiologic factors of AP. We included patients with AP who were treated at our institution from May 1, 2012 to January 31, 2015. Different laboratory parameters, including ILs, and the severity scoring systems Ranson's criteria and Bedside Index of Severity in Acute Pancreatitis (BISAP) were analyzed. AP was classified into mild and severe, and independent parameters were compared between these groups. The predictive performance of each parameter was evaluated using receiver operating characteristic (ROC) curves and the area under the ROC curve (AUC). A binomial logistic regression was performed to evaluate Ranson's criteria and IL6, IL8, and IL10 (at admission and after 48 hours) in the course of AP. Overall, 96 patients were treated, 59 (61.5%) males and 37 (38.5%) females, average age 62.5 ± 16.8 years (range 22-91 years). The best predictor for the severity of AP was IL6, measured 48 hours after admission (AUC = 0.84). Other useful predictors of the severity of AP were lactate dehydrogenase (p < 0.001), serum glucose (p < 0.006), and difference in the platelet count (p < 0.001) between admission and after 48 hours (p < 0.001), hemoglobin (p < 0.027) and erythrocytes (p < 0.029). The major causes of AP were gallstones and alcohol consumption. According to our results, IL6 and Ranson score are important predictors of the severity of AP.


Physiological Profile and Activity Pattern of Minor Gaelic Football Players.
Cullen, BD, Roantree, M, McCarren, A, Kelly, DT, O'Connor, PL, Hughes, SM, Daly, PG, and Moyna1, NM. Physiological profile and activity pattern of minor Gaelic football players. J Strength Cond Res 31(7): 1811-1820, 2017-The purpose of this study was to evaluate the physiological profile and activity pattern in club- and county-level under-18 (U-18) Gaelic football players relative to playing position. Participants (n = 85) were analyzed during 17 official 15-a-side matches using global positioning system technology (SPI Pro X II; GPSports Systems, Canberra, Australia) and heart rate (HR) telemetry. During the second part of this study, 63 participants underwent an incremental treadmill test to assess their maximal oxygen uptake (V[Combining Dot Above]o2max) and peak HR (HRmax). Players covered a mean distance of 5,774 ± 737 m during a full 60-minute match. The mean %HRmax and %V[Combining Dot Above]O2max observed during the match play were 81.6 ± 4.3% and 70.1 ± 7.75%, respectively. The playing level had no effect on the distance covered, player movement patterns, or %HRmax observed during match play. Midfield players covered significantly greater distance than defenders (p = 0.033). Playing position had no effect on %HRmax or the frequency of sprinting or high-intensity running during match play. The frequency of jogging, cruise running, striding (p = 0.000), and walking (p = 0.003) was greater in the midfield position than in the forward position. Time had a significant effect (F(1,39) = 33.512, p-value = 0.000, and (Equation is included in full-text article.)= 0.462) on distance covered and %HRmax, both of which showed a reduction between playing periods. Gaelic football is predominantly characterized by low-to-moderate intensity activity interspersed with periods of high-intensity running. The information provided may be used as a framework for coaches in the design and prescription of training strategies. Positional specific training may be warranted given the comparatively greater demands observed in the midfield playing position. Replicating the demands of match play in training may reduce the decline in distance covered and %HRmax observed during the second half of match play.


Integration of Palliative Care in the Role of the Oncology Advanced Practice Nurse.
Numerous organizations have cited the increasing demand for palliative care in oncology and the challenge of a limited workforce to deliver specialty palliative care. Advanced practitioners in oncology can provide generalist or primary palliative care to complement the care provided by specialists and enhance the overall provision of care. This article reports on a National Cancer Institute-funded training program to prepare advanced practice nurses to incorporate palliative care within their practice. One-year follow-up of the first three national cohorts (N = 276) included evaluation of goal achievement as these nurses integrated palliative care within their oncology practice. Goal analysis reported here demonstrates the success of the training program in impacting practice as well as the barriers to implementation efforts. The advanced practice registered nurses' implemented goals included extensive training of clinicians across disciplines and numerous systems changes to improve delivery of palliative care. Advanced practice nurses will continue to be a valuable source of extending palliative care into oncology care to support patients and families across the disease trajectory.


Gastruloid optimization.
The young field of gastruloids brings promise to modeling and understanding early embryonic development. However, being a complex model, gastruloids are prone to variability at different levels. In this perspective, we define the different levels of gastruloid variability, and parameters over which it can be measured. We discuss potential sources for variability, and then propose methods to better control and reduce it. We provide an example from definitive endoderm progression in gastruloids, where we harness gastruloid-to-gastruloid variation in early parameters to identify key driving factors for endoderm morphology. We then devise interventions that steer morphological outcome. A better control over the developmental progression of gastruloids will enhance their utility in both basic research and biomedical applications.


The genetic architecture of ecophysiological and circadian traits in Brassica rapa.
Developmental mechanisms that enable perception of and response to the environment may enhance fitness. Ecophysiological traits typically vary depending on local conditions and contribute to resource acquisition and allocation, yet correlations may limit adaptive trait expression. Notably, photosynthesis and stomatal conductance vary diurnally, and the circadian clock, which is an internal estimate of time that anticipates diurnal light/dark cycles, may synchronize physiological behaviors with environmental conditions. Using recombinant inbred lines of Brassica rapa, we examined the quantitative-genetic architecture of ecophysiological and phenological traits and tested their association with the circadian clock. We also investigated how trait expression differed across treatments that simulated seasonal settings encountered by crops and naturalized populations. Many ecophysiological traits were correlated, and some correlations were consistent with expected biophysical constraints; for example, stomata jointly regulate photosynthesis and transpiration by affecting carbon dioxide and water vapor diffusion across leaf surfaces, and these traits were correlated. Interestingly, some genotypes had unusual combinations of ecophysiological traits, such as high photosynthesis in combination with low stomatal conductance or leaf nitrogen, and selection on these genotypes could provide a mechanism for crop improvement. At the genotypic and QTL level, circadian period was correlated with leaf nitrogen, instantaneous measures of photosynthesis, and stomatal conductance as well as with a long-term proxy (carbon isotope discrimination) for gas exchange, suggesting that gas exchange is partly regulated by the clock and thus synchronized with daily light cycles. The association between circadian rhythms and ecophysiological traits is relevant to crop improvement and adaptive evolution.


A NuRD Complex from Xenopus laevis Eggs Is Essential for DNA Replication during Early Embryogenesis.
DNA replication in the embryo of Xenopus laevis changes dramatically at the mid-blastula transition (MBT), with Y RNA-independent random initiation switching to Y RNA-dependent initiation at specific origins. Here, we identify xNuRD, an MTA2-containing assemblage of the nucleosome remodeling and histone deacetylation complex NuRD, as an essential factor in pre-MBT Xenopus embryos that overcomes a functional requirement for Y RNAs during DNA replication. Human NuRD complexes have a different subunit composition than xNuRD and do not support Y RNA-independent initiation of DNA replication. Blocking or immunodepletion of xNuRD inhibits DNA replication initiation in isolated nuclei in vitro and causes inhibition of DNA synthesis, developmental delay, and embryonic lethality in early embryos. xNuRD activity declines after the MBT, coinciding with dissociation of the complex and emergence of Y RNA-dependent initiation. Our data thus reveal an essential role for a NuRD complex as a DNA replication factor during early Xenopus development.


First Report of Erwinia carotovora subsp. carotovora Causing Bacterial Root Rot of Sweetpotato (Ipomoea batatas) in Louisiana.
Bacterial root and stem rot of sweetpotato (Ipomoea batatas (L.) Lam.) was first fully characterized in the U.S. in 1977 (2). It was thought to be caused exclusively by Erwinia chrysanthemi. Although a previous report described sweetpotato as a host for E. carotovora subsp. carotovora, based on artificial inoculations, others have reported that neither E. carotovora subsp. carotovora nor E. carotovora subsp. atroseptica decay sweetpotato storage roots (1). In October 1995, storage roots of sweetpotato cv. Beauregard were received from St. Landry Parish, LA, that displayed typical bacterial root rot. Isolations from these roots yielded bacteria that showed a similarity of 0.945 to E. carotovora subsp. carotovora with the Biolog GN Bacterial Identification System (version 3.50). This isolate (Ecc-LH) also differed from isolates of E. chrysanthemi (Ech) from sweetpotato and other hosts in that it was insensitive to erythromycin, did not produce phosphatase or lecithinase, and did not produce gas from glucose. Ecc-LH differed from known strains of E. carotovora subsp. atroseptica in that it did not produce reducing substances from sucrose or acid from palatinose. When Beauregard storage roots were inoculated by inserting micropipette tips containing 50 μl of 1.0 × 108 CFU/ml, both Ecc-LH and Ech-48 produced typical bacterial root rot symptoms. However, when they were compared by infectivity titrations at 28 to 32°C, Ecc-LH was less virulent than Ech-48. Ecc-LH had an ED50 of approximately 1.0 × 106 CFU/ml and did not cause appreciable disease below inoculum concentrations of 1.0 × 105, whereas Ech-48 had an ED50 of approximately 1.0 × 108 and caused soft rot at the lowest concentration tested, 1.0 × 103. Similar disease incidence was observed in infectivity titrations at 22 to 24°C, but Ech-48 caused less severe soft rot. E. carotovora subsp. carotovora was reisolated from inoculated storage roots and its identity was reconfirmed by Biolog. When terminal vine cuttings of Beauregard were dipped in 1.0 × 108 CFU/ml and planted in a greenhouse, bacterial stem rot symptoms developed on plants inoculated with Ech-48 at about 4 weeks postinoculation, or when new growth began. However, no symptoms developed on plants inoculated with Ecc-LH. This is the first report of natural occurrence of E. carotovora subsp. carotovora causing bacterial root rot of sweetpotato in Louisiana. E. chrysanthemi remains the most important pathogen causing bacterial soft rot in sweetpotato since it is widely associated with sweetpotato, is more virulent on storage roots and also causes a stem rot. E. carotovora subsp. carotovora can cause root rot, but has been isolated in only one location to date, is less virulent on storage roots, and apparently does not cause stem rot on the predominant cultivar in U.S. sweetpotato production, Beauregard. References: (1) C. A. Clark and J. W. Moyer. 1988. Compendium of Sweet Potato Diseases. American Phytopathological Society, St. Paul, MN. (2) N. W. Schaad and D. Brenner. Phytopathology 67:302, 1977.


Sugar-sweetened soda consumption, hyperuricemia, and kidney disease.
The metabolism of high-fructose corn syrup used to sweeten soda drinks may lead to elevations in uric acid levels. Here we determined whether soda drinking is associated with hyperuricemia and, as a potential consequence, reduced kidney function. At baseline, 15,745 patients in the Atherosclerosis Risk in Communities Study completed a dietary questionnaire and had measurements of their serum creatinine and uric acid. After 3 and 9 years of follow-up, multivariate odds ratios from logistic regressions for binary outcome of hyperuricemia and chronic kidney disease (eGFR less than 60 ml/min per 1.73 m(2)) were evaluated. Compared to participants who drank less, consumption of over one soda per day was associated with increased odds of prevalent hyperuricemia and chronic kidney disease. The odds ratio for chronic kidney disease significantly increased to 2.59 among participants who drank more than one soda per day and had a serum uric acid level over 9.0 mg/dl. In longitudinal analyses, however, drinking more than one soda per day was not associated with hyperuricemia or chronic kidney disease. Neither preexistent hyperuricemia nor development of hyperuricemia modified the lack of association between soda drinking and incident chronic kidney disease. Thus our study shows that high consumption of sugar-sweetened soda was associated with prevalent but not incident hyperuricemia and chronic kidney disease.


Plant sterol metabolism. Δ(7)-Sterol-C5-desaturase (STE1/DWARF7), Δ(5,7)-sterol-Δ(7)-reductase (DWARF5) and Δ(24)-sterol-Δ(24)-reductase (DIMINUTO/DWARF1) show multiple subcellular localizations in Arabidopsis thaliana (Heynh) L.
Sterols are crucial lipid components that regulate membrane permeability and fluidity and are the precursors of bioactive steroids. The plant sterols exist as three major forms, free sterols, steryl glycosides and steryl esters. The storage of steryl esters in lipid droplets has been shown to contribute to cellular sterol homeostasis. To further document cellular aspects of sterol biosynthesis in plants, we addressed the question of the subcellular localization of the enzymes implicated in the final steps of the post-squalene biosynthetic pathway. In order to create a clear localization map of steroidogenic enzymes in cells, the coding regions of Δ(7)-sterol-C(5)-desaturase (STE1/DWARF7), Δ(24)-sterol-Δ(24)-reductase (DIMINUTO/DWARF1) and Δ(5,7)-sterol-Δ(7)-reductase (DWARF5) were fused to the yellow fluorescent protein (YFP) and transformed into Arabidopsis thaliana mutant lines deficient in the corresponding enzymes. All fusion proteins were found to localize in the endoplasmic reticulum in functionally complemented plants. The results show that both Δ(5,7)-sterol-Δ(7)-reductase and Δ(24)-sterol-Δ(24)-reductase are in addition localized to the plasma membrane, whereas Δ(7)-sterol-C(5)-desaturase was clearly detected in lipid particles. These findings raise new challenging questions about the spatial and dynamic cellular organization of sterol biosynthesis in plants.


Long-term bFGF neuronal culture: reintroduction into serum medium yields neurons and non-neuronal cells with neuronal characteristics.
The potential use of bFGF immortalized cells as hosts for delivering foreign genes into nervous tissue led us to examine the effect of maintaining, E-18 hippocampal neurons for extended periods in bFGF culture prior to transfer into a standard, serum-containing, medium. We found: (1) many, if not most, precursors seen in bFGF, mature into glia and not into primary neurons after medium exchange; (2) the electrophysiology of the neurons which do mature after medium transfer and replating, is similar to that of neurons in standard cultures; (3) extended culture in bFGF prior to cell harvesting and replating into standard medium generates neurons from the precursors that possess proper neuronal polarization, morphology, and electrophysiology; and (4) extended bFGF also induces the expression, on transfer into standard medium, of an additional cell type with a distinct non-neuronal morphology that stains with the neuronal marker MAP-2. These results illustrate the need for additional characterization of long-term growth factor effects on maintained progenitor cells prior to their use in gene therapy and transplantation.


Development and Validation of Integrated Yoga Module for Obesity in Adolescents.
Obesity is a growing global epidemic and cause of noncommunicable diseases. Yoga is one of the effective ways to reduce stress which is one of the causes of obesity. Nowadays, children in adolescent age are more prone to get obese due to lack of physical activity making them more sedentary. To identify the design and validation of Integrated Approach of Yoga Therapy Module (IAYTM) for obesity in adolescents. Materials and Methods: First phase - IAYTM for obesity was designed based on the literature review of classical texts and recently published research articles. Second phase - Designed IAYTM was validated by 16 subject matter (yoga) experts. Content-validity ratio (CVR) was analyzed using Lawshe's formula. Yoga practices were designed for Integrated Yoga Module for Obesity in Adolescents. Yoga practices with CVR ≥0.5 and which were validated by 16 yoga experts and approved in faculty group discussion were included in final Integrated Yoga Therapy Module. The yoga practices were designed and validated for IAYTM for obesity in adolescents.


Restoration of insulin responsiveness in skeletal muscle of morbidly obese patients after weight loss. Effect on muscle glucose transport and glucose transporter GLUT4.
A major defect contributing to impaired insulin action in human obesity is reduced glucose transport activity in skeletal muscle. This study was designed to determine whether the improvement in whole body glucose disposal associated with weight reduction is related to a change in skeletal muscle glucose transport activity and levels of the glucose transporter protein GLUT4. Seven morbidly obese (body mass index = 45.8 +/- 2.5, mean +/- SE) patients, including four with non-insulin-dependent diabetes mellitus (NIDDM), underwent gastric bypass surgery for treatment of their obesity. In vivo glucose disposal during a euglycemic clamp at an insulin infusion rate of 40 mU/m2 per min was reduced to 27% of nonobese controls (P less than 0.01) and improved to 78% of normal after weight loss of 43.1 +/- 3.1 kg (P less than 0.01). Maximal insulin-stimulated glucose transport activity in incubated muscle fibers was reduced by approximately 50% in obese patients at the time of gastric bypass surgery but increased twofold (P less than 0.01) to 88% of normal in five separate patients after similar weight reduction. Muscle biopsies obtained from vastus lateralis before and after weight loss revealed no significant change in levels of GLUT4 glucose transporter protein. These data demonstrate conclusively that insulin resistance in skeletal muscle of mobidly obese patients with and without NIDDM cannot be causally related to the cellular content of GLUT4 protein. The results further suggest that morbid obesity contributes to whole body insulin resistance through a reversible defect in skeletal muscle glucose transport activity. The mechanism for this improvement may involve enhanced transporter translocation and/or activation.


Comparative approaches to studying strategy: towards an evolutionary account of primate decision making.
How do primates, humans included, deal with novel problems that arise in interactions with other group members? Despite much research regarding how animals and humans solve social problems, few studies have utilized comparable procedures, outcomes, or measures across different species. Thus, it is difficult to piece together the evolution of decision making, including the roots from which human economic decision making emerged. Recently, a comparative body of decision making research has emerged, relying largely on the methodology of experimental economics in order to address these questions in a cross-species fashion. Experimental economics is an ideal method of inquiry for this approach. It is a well-developed method for distilling complex decision making involving multiple conspecifics whose decisions are contingent upon one another into a series of simple decision choices. This allows these decisions to be compared across species and contexts. In particular, our group has used this approach to investigate coordination in New World monkeys, Old World monkeys, and great apes (including humans), using identical methods. We find that in some cases there are remarkable continuities of outcome, as when some pairs in all species solved a coordination game, the Assurance game. On the other hand, we also find that these similarities in outcomes are likely driven by differences in underlying cognitive mechanisms. New World monkeys required exogenous information about their partners' choices in order to solve the task, indicating that they were using a matching strategy. Old World monkeys, on the other hand, solved the task without exogenous cues, leading to investigations into what mechanisms may be underpinning their responses (e.g., reward maximization, strategy formation, etc.). Great apes showed a strong experience effect, with cognitively enriched apes following what appears to be a strategy. Finally, humans were able to solve the task with or without exogenous cues. However, when given the chance to do so, they incorporated an additional mechanism unavailable to the other primates - language - to coordinate outcomes with their partner. We discuss how these results inform not only comparative psychology, but also evolutionary psychology, as they provide an understanding of the evolution of human economic behavior, and the evolution of decision making more broadly.


Development of cellular models for ribosomal protein S19 (RPS19)-deficient diamond-blackfan anemia using inducible expression of siRNA against RPS19.
Diamond-Blackfan anemia (DBA) is a congenital red cell aplasia in which 25% of the patients have a mutation in the ribosomal protein S19 (RPS19) gene. No models exist for RPS19-deficient DBA and the molecular pathogenesis is unknown. To establish an in vitro inducible model for DBA, human erythroid leukemic cell lines, TF-1 and UT-7 cells, were cotransduced with a lentiviral vector expressing the green fluorescent protein (GFP) gene and small interfering RNA (siRNA) against RPS19 controlled by a tet operator regulatory element and another transactivator vector containing the red fluorescent protein (RFP) gene and the cDNA encoding a tetracycline-controllable transcriptional repressor. Following transduction, the RFP-positive and GFP-negative cell population was sorted by flow cytometry. Upon incubation with doxycycline (0.5 mug/ml), more than 98% of cells expressed GFP and the siRNA. Significant suppression of erythroid differentiation, cell growth, and colony formation was observed in cells treated with siRNA against RPS19 but not in cells treated with a control vector. These findings show that RPS19 plays an important role in the regulation of hematopoietic cell proliferation and erythroid differentiation. These novel cell lines represent models for RPS19-deficient DBA and can be used to identify the molecular mechanisms in RPS19-deficient DBA.


Siderotyping of fluorescent pseudomonads: characterization of pyoverdines of Pseudomonas fluorescens and Pseudomonas putida strains from Antarctica.
Five independent fluorescent pseudomonad isolates originating from Antarctica were analysed for their pyoverdine systems. A pyoverdine-related siderotyping, which involved pyoverdine-induced growth stimulation, pyoverdine-mediated iron uptake, pyoverdine analysis by electrophoresis and isoelectric focusing, revealed three different pyoverdine-related siderotypes among the five isolates. One siderotype, including Pseudomonas fluorescens 1W and P. fluorescens 10CW, was identical to that of P. fluorescens ATCC 13525. Two other strains, P. fluorescens 9AW and Pseudomonas putida 9BW, showed identical pyoverdine-related behaviour to each other, whereas the fifth strain, P. fluorescens 51W, had unique features compared to the other strains or to a set of 12 fluorescent Pseudomonas strains used as comparison material. Elucidation of the structure of the pyoverdines produced by the Antarctic strains supported the accuracy of the siderotyping methodology by confirming that pyoverdines from strains 1W and 10CW had the same structures as the P. fluorescens ATCC 13525 pyoverdine, whereas the 9AW and 9BW pyoverdines are probably identical with the pyoverdine of P. fluorescens strain 244. Pyoverdine from strain 51W appeared to be a novel pyoverdine since its structure was different from all previously established pyoverdine structures. Together with the conclusion that the Antarctic Pseudomonas strains have no special features at the level of their pyoverdines and pyoverdine-mediated iron metabolism compared to worldwide strains, the present work demonstrates that siderotyping provides a rapid means of screening for novel pyoverdines.


Validating abbreviated measures of effort-reward imbalance at work in European cohort studies: the IPD-Work consortium.
Effort-reward imbalance (ERI) is an established conceptualisation of work stress. Although a validated effort-reward questionnaire is available for public use, many epidemiological studies adopt shortened scales and proxy measures. To examine the agreement between different abbreviated measures and the original instrument, we compared different versions of the effort-reward scales available in 15 European cohort studies participating in the IPD-Work (Individual-participant-data meta-analysis in working populations) consortium. Five of the 15 studies provide information on the original ('complete') scales measuring 'effort' and 'reward', whereas the 10 remaining studies used 'partial' scales. To compare different versions of the ERI scales, we analyse individual-level data from 31,790 participants from the five studies with complete scales. Pearson's correlation between partial and complete scales was very high in case of 'effort' (where 2 out of 3 items were used) and very high or high in case of 'reward', if at least 4 items (out of 7) were included. Reward scales composed of 3 items revealed good to satisfactory agreement, and in one case, a reward scale consisting of 2 items only demonstrated a modest, but still acceptable degree of agreement. Sensitivity and specificity of a composite measure, the ratio of effort and reward, comparing partial versus complete scales ranged between 59-93 and 85-99 %, respectively. Complete and partial scales were strongly associated with poor self-rated health. Our results support the notion that short proxy measures or partial versions of the original scales can be used to assess effort-reward imbalance.


Corticosteroid injections, eccentric decline squat training and heavy slow resistance training in patellar tendinopathy.
A randomized-controlled single-blind trial was conducted to investigate the clinical, structural and functional effects of peritendinous corticosteroid injections (CORT), eccentric decline squat training (ECC) and heavy slow resistance training (HSR) in patellar tendinopathy. Thirty-nine male patients were randomized to CORT, ECC or HSR for 12 weeks. We assessed function and symptoms (VISA-p questionnaire), tendon pain during activity (VAS), treatment satisfaction, tendon swelling, tendon vascularization, tendon mechanical properties and collagen crosslink properties. Assessments were made at 0 weeks, 12 weeks and at follow-up (half-year). All groups improved in VISA-p and VAS from 0 to 12 weeks (P<0.05). VISA-p and VAS improvements were maintained at follow-up in ECC and HSR but deteriorated in CORT (P<0.05). In CORT and HSR, tendon swelling decreased (-13+/-9% and -12+/-13%, P<0.05) and so did vascularization (-52+/-49% and -45+/-23%, P<0.01) at 12 weeks. Tendon mechanical properties were similar in healthy and injured tendons and were unaffected by treatment. HSR yielded an elevated collagen network turnover. At the half-year follow-up, treatment satisfaction differed between groups, with HSR being most satisfied. Conclusively, CORT has good short-term but poor long-term clinical effects, in patellar tendinopathy. HSR has good short- and long-term clinical effects accompanied by pathology improvement and increased collagen turnover.


Approaches to optimize outcomes in transplant recipients.
Curative therapy with an allogeneic hematopoietic cell transplant (HCT) can now be offered to a wider patient population due to improvements in donor selection, transplant conditioning regimens, and supportive care measures. However, risk of transplant-related morbidity and mortality remains, and thus appropriate transplant candidate workup pre-HCT for risk stratification and a management plan after HCT is crucial for success of the procedure. These include understanding and identifying risk of underlying malignant disease relapse, graft-versus-host disease, and infectious complications a patient may be predisposed toward, irrespective of allogeneic donor type. Progress in these domains with new therapeutic paradigms allows for development of a treatment plan prior to HCT to mitigate these potential risks tailored to the patient's case. Herein, we present case studies to focus on factors that influence decision-making in HCT and the approaches and strategies used to optimize post-HCT outcomes based on the individual HCT recipient's clinical scenario to improve on these high-risk scenarios.


ASSET (Age/Sex Standardised Estimates of Treatment): a research model to improve the governance of prescribing funds in Italy.
The primary objective of this study was to make the first step in the modelling of pharmaceutical demand in Italy, by deriving a weighted capitation model to account for demographic differences among general practices. The experimental model was called ASSET (Age/Sex Standardised Estimates of Treatment). Individual prescription costs and demographic data referred to 3,175,691 Italian subjects and were collected directly from three Regional Health Authorities over the 12-month period between October 2004 and September 2005. The mean annual prescription cost per individual was similar for males (196.13 euro) and females (195.12 euro). After 65 years of age, the mean prescribing costs for males were significantly higher than females. On average, costs for a 75-year-old subject would be 12 times the costs for a 25-34 year-old subject if male, 8 times if female. Subjects over 65 years of age (22% of total population) accounted for 56% of total prescribing costs. The weightings explained approximately 90% of the evolution of total prescribing costs, in spite of the pricing and reimbursement turbulences affecting Italy in the 2000-2005 period. The ASSET weightings were able to explain only about 25% of the variation in prescribing costs among individuals. If mainly idiosyncratic prescribing by general practitioners causes the unexplained variations, the introduction of capitation-based budgets would gradually move practices with high prescribing costs towards the national average. It is also possible, though, that the unexplained individual variation in prescribing costs is the result of differences in the clinical characteristics or socio-economic conditions of practice populations. If this is the case, capitation-based budgets may lead to unfair distribution of resources. The ASSET age/sex weightings should be used as a guide, not as the ultimate determinant, for an equitable allocation of prescribing resources to regional authorities and general practices.