The evolutionary fate of nonfunctional DNA in the bacterial endosymbiont Buchnera aphidicola.
Reduction of the genome size in endosymbiotic bacteria is the main feature linked to the adaptation to a host-associated lifestyle. We have analyzed the fate of the nonfunctional DNA in Buchnera aphidicola, the primary endosymbiont of aphids. At least 164 gene losses took place during the recent evolution of three B. aphidicola strains, symbionts of the aphids Acyrthosiphon pisum (BAp), Schizaphis graminum (BSg), and Baizongia pistacia (BBp). A typical pattern starts with the inactivation of a gene, which produces a pseudogene, and is followed by the progressive loss of its DNA. Our results show that during the period from the separation of the Aphidinae and Pemphiginae lineages (86-164 MYA) to the divergence of BAp and BSg (50-70 MYA) the half-life of a pseudogene was 23.9 Myr. For the remaining periods of evolution, the ranges of values obtained for this parameter are of the same order of magnitude. These results have revealed that a gene inactivated during B. aphidicola evolution requires 40-60 Myr to become almost completely disintegrated. Moreover, we have shown a positive correlation between the decrease in the GC content and the DNA loss for these nonfunctional DNA regions. When gene losses are classified, based on the detection of a pseudogene or otherwise of an absent gene in the modern B. aphidicola genomes, we have observed a drastic reduction of DNA length in the latter versus the former relative to the functional gene. Finally, we have also detected a slight reduction in size of the intergenic regions in the three B. aphidicola strains, when they are compared with the size of the close relative Escherichia coli.


IL-1β suppression of VE-cadherin transcription underlies sepsis-induced inflammatory lung injury.
Unchecked inflammation is a hallmark of inflammatory tissue injury in diseases such as acute respiratory distress syndrome (ARDS). Yet the mechanisms of inflammatory lung injury remain largely unknown. Here we showed that bacterial endotoxin lipopolysaccharide (LPS) and cecal ligation and puncture-induced (CLP-induced) polymicrobial sepsis decreased the expression of transcription factor cAMP response element binding (CREB) in lung endothelial cells. We demonstrated that endothelial CREB was crucial for VE-cadherin transcription and the formation of the normal restrictive endothelial adherens junctions. The inflammatory cytokine IL-1β reduced cAMP generation and CREB-mediated transcription of VE-cadherin. Furthermore, endothelial cell-specific deletion of CREB induced lung vascular injury whereas ectopic expression of CREB in the endothelium prevented the injury. We also observed that rolipram, which inhibits type 4 cyclic nucleotide phosphodiesterase-mediated (PDE4-mediated) hydrolysis of cAMP, prevented endotoxemia-induced lung vascular injury since it preserved CREB-mediated VE-cadherin expression. These data demonstrate the fundamental role of the endothelial cAMP-CREB axis in promoting lung vascular integrity and suppressing inflammatory injury. Therefore, strategies aimed at enhancing endothelial CREB-mediated VE-cadherin transcription are potentially useful in preventing sepsis-induced lung vascular injury in ARDS.


[Consensus document for the detection and management of chronic kidney disease].
Chronic kidney disease (CKD) is an important global health problem, involving to 10% of the Spanish population, promoting high morbidity and mortality for the patient and an elevate consumption of the total health resources for the National Health System. This is a summary of an executive consensus document of ten scientific societies involved in the care of the renal patient, that actualizes the consensus document published in 2007. The central extended document can be consulted in the web page of each society. The aspects included in the document are: Concept, epidemiology and risk factors for CKD. Diagnostic criteria, evaluation and stages of CKD, albuminuria and glomerular filtration rate estimation. Progression factors for renal damage. Patient remission criteria. Follow-up and objectives of each speciality control. Nephrotoxicity prevention. Cardio-vascular damage detection. Diet, life-style and treatment attitudes: hypertension, dyslipidaemia, hyperglycemia, smoking, obesity, hyperuricemia, anemia, mineral and bone disorders. Multidisciplinary management for Primary Care, other specialities and Nephrology. Integrated management of CKD patient in haemodialysis, peritoneal dialysis and renal transplant patients. Management of the uremic patient in palliative care. We hope that this document may be of help for the multidisciplinary management of CKD patients by summarizing the most updated recommendations.


Ethylenediurea (EDU) mitigates the negative effects of ozone in rice: Insights into its mode of action.
Monitoring of ozone damage to crops plays an increasingly important role for the food security of many developing countries. Ethylenediurea (EDU) could be a tool to assess ozone damage to vegetation on field scale, but its physiological mode of action remains unclear. This study investigated mechanisms underlying the ozone-protection effect of EDU in controlled chamber experiments. Ozone sensitive and tolerant rice genotypes were exposed to ozone (108 ppb, 7 hr day-1 ) and control conditions. EDU alleviated ozone effects on plant morphology, foliar symptoms, lipid peroxidation, and photosynthetic parameters in sensitive genotypes. Transcriptome profiling by RNA sequencing revealed that thousands of genes responded to ozone in a sensitive variety, but almost none responded to EDU. Significant interactions between ozone and EDU application occurred mostly in ozone responsive genes, in which up-regulation was mitigated by EDU application. Further experiments documented ozone degrading properties of EDU, as well as EDU deposits on leaf surfaces possibly related to surface protection. EDU application did not mitigate the reaction of plants to other abiotic stresses, including iron toxicity, zinc deficiency, and salinity. This study provided evidence that EDU is a surface protectant that specifically mitigates ozone stress without interfering directly with the plants' stress response systems.


Identification of Phenolic Constituents and Inhibitory Activity of Persimmon Calyx and Shiteito against Tumor Cell Proliferation.
The persistent calyx on the fruit of Diospyros kaki, called "Shitei" in Japanese, is reported to contain phenolic compounds including condensed tannins. In this study, we isolated and characterized a new compound, together with 26 phenolic components, from the 70% acetone extract of Shitei, with structural elucidation based on spectroscopic analyses. In addition, we confirmed the presence of condensed tannins by 13C-NMR spectra, and the weight-average molecular weight was estimated by gel permeation chromatography (GPC) analysis. Next, Shiteito, a Kampo medicine consisting of Shitei, ginger, and clove clinically used to treat chronic hiccoughs occurring in association with anticancer drug treatments, and hot-water extracts of each of its components, were analyzed by HPLC, which determined that the main ingredient in Shiteito was derived from clove. We therefore isolated the ingredients and investigated their anti-tumor cell proliferative activity, together with Shiteito and Shitei extracts. As a result, Shiteito showed weak inhibition of hepatocellular carcinoma (Hep3B) cell proliferation at a high concentration. In contrast, ellagic acid, one of the main constituents of Shiteito, showed significant cytotoxicity against Hep3B cells, and significant inhibition of gastric adenocarcinoma (AGS) cell proliferation in a concentration-dependent manner. The ethyl acetate (EtOAc) fraction of the 70% acetone extract of Shitei significantly inhibited the proliferation of colon adenocarcinoma (Caco-2) and AGS cells at low to middle concentration, while showing strong cytotoxicity against Hep3B. These data indicate that Shiteito and Shitei extracts could enhance cancer drug treatment by preventing the associated chronic hiccups, and have the potential to be adjuvant treatments as well.


Schemes for the identification of tissue types and boundaries at the tool point for surgical needles.
Precise control of automated invasive surgical tools requires real-time identification of tissue types and their deformation. At the focus of this paper is the epidural puncture, for which it is shown that the tissue type and deformation can respectively be determined from laser-based spectroscopy and the change in force required to push the needle through the various tissues. Studies have shown that physiological variations from one patient to another are too great to allow absolute values to be reliably used to indicate the position of the needle tip. However, the pattern of force variation during penetration is shown to be similar between specimens. Interpretation of this information in conjunction with spectroscopic techniques can be used to discriminate between tissues and tissue structure at the needle tip. This paper describes results from an investigation on automatic techniques for interpreting the type and deformation of tissues under tool action.


Solvent Dependent Folding of an Amphiphilic Polyaramid.
A series of synthetic alternating and amphiphilic aromatic amide polymers were synthesized by a step growth polymerization. Alternating meta- and para-linkages were introduced to force the polymer chain into a helical shape in the highly polar solvent water. The polymers were analyzed by 1H NMR spectroscopy and SEC in polar aprotic solvents such as DMSO and DMF. However, the polymers also showed good solubility in water. 1H NMR spectroscopy, small-angle X-ray scattering, and dynamic light scattering provided clear evidence of polymer folding in water but not DMF. We employed parallel tempering metadynamics in the well-tempered ensemble (PTMetaD-WTE) to simulate the free energy surfaces of an analogous model polymer in DMF and water. The simulations gave a molecular model of an unfolded structure in DMF and a helically folded tubular structure in water.


The extended transverse musculocutaneous gracilis flap: vascular anatomy and clinical implications.
The transverse musculocutaneous gracilis (TMG) flap has been used in autologous breast reconstruction, but disadvantages include a small flap volume; therefore, it is only used in small-to-moderate breast reconstructions. We investigated the vascular territory of this flap and the possibility of extending its dimensions. Ten circumferential thigh adipocutaneous flaps attached to the gracilis muscle were harvested from adult cadavers. The following parameters were recorded: diameter and length of pedicles, distance of pedicles from pubis, and number and locations of cutaneous perforators. The major pedicles were injected with contrast and subjected to 3-dimensional computed tomography scanning. Images were viewed using both General Electrics and TeraRecon systems, and the vascular territories were measured. Flaps were then incised to include only tissue that was perfused with contrast, and measured for weight and volume. The major pedicle had a mean length of 6.7 cm, diameter of 2.2 mm, and distance from pubis of 8.6 cm. There was a mean of 4.3 cutaneous perforators associated with this flap. Three-dimensional images from contrast injection of the major pedicle showed a cutaneous vascular territory that extended more posteriorly than anteriorly, and had a vertical component. Tissue perfused with contrast had a mean weight of 573 g and volume of 617 mL. Two clinical cases were included to show applications of the extended TMG flap. The dimensions of a TMG flap can be increased horizontally (superoposterior thigh) as well as vertically. The vertical portion can be harvested either by undermining the skin inferior to the lower transverse skin incision or by raising a trilobed skin paddle to harvest even more tissue from the medial thigh.


Familial hypomagnesemia maps to chromosome 9q, not to the X chromosome: genetic linkage mapping and analysis of a balanced translocation breakpoint.
Familial hypomagnesemia with secondary hypocalcemia (HSH) (MIM 307600) was studied in three inbred Bedouin kindreds from Israel. The three kindreds, one extended and two nuclear families, contained 13 affected individuals, 11 males and two females. Assuming that the individuals affected with hypomagnesemia shared a chromosomal region inherited from a common ancestor, we used a DNA pooling strategy in a genome-wide search for loci which show homozygosity for shared alleles in affected individuals. DNA samples from affected individuals within a single kindred were pooled and used as the template for PCR amplification of short tandem repeat polymorphic markers (STRPs). Pooled DNA from unaffected siblings and parents were used as controls. A shift towards homozygosity was observed in the affected DNA pool compared with the control pools with D9S301 (GATA7D12). Genotyping of individual DNA samples with D9S301 and several flanking markers confirmed linkage to chromosome 9 with maximum LOD scores of 3.4 (theta = 0.05), 3.7 (theta = 0) and 2.3 (theta = 0) for the three families. We have identified a 14 cM interval on chromosome 9 (9q12-9q22.2), flanked by proximal marker D9S1874 and distal marker D9S1807, within which all affected individuals from the three kindreds are homozygous for a shared haplotype. The disease segregates with a common affected haplotype in the three families, suggesting that hypomagnesemia is caused by a common ancestral mutation in these families. Although HSH has been previously reported to be X linked, these linkage data demonstrate that the disorder is an autosomal recessive disease in these kindreds. Mapping of a chromosomal breakpoint in a somatic cell line established from a patient with HSH and a balanced X;9 translocation placed the chromosomal breakpoint in a 500 kb region flanked by D9S1844 and D9S273. Identification of the gene responsible for hypomagnesemia will provide insight into the regulation of this essential cation.


Stem cells as vectors for antitumour therapy.
Recent research suggests that mesenchymal stem cells (MSCs) are able to migrate specifically to tumours and their metastases throughout the body. This has led to considerable excitement about the possibility of modifying these cells to express anticancer molecules and using them as specific targeted anticancer agents. However, there are concerns that systemically delivered MSCs may have non-desirable effects, and there are also many unanswered questions including the mechanism of tumour homing. This review investigates the different MSC-delivered anticancer agents, addresses the questions and concerns, and tries to place this potential therapy in future cancer management.


Efficacy of plasma exchange in anti-MDA5-positive dermatomyositis with interstitial lung disease under combined immunosuppressive treatment.
Rapidly progressive interstitial lung disease (RP-ILD) with poor prognosis often accompanies anti-melanoma differentiation-associated gene 5 (MDA5)-positive DM. Combined immunosuppressive therapy, including glucocorticoids, calcineurin inhibitors and intravenous cyclophosphamide (IVCY) is reportedly effective in DM with RP-ILD, but some patients remain resistant to therapy. We examined the utility of plasma exchange (PE) in such intractable cases and investigated the prognostic factors of the disease. Thirty-eight anti-MDA5-positive DM-ILD patients who received the combined immunosuppressive therapy were retrospectively reviewed. Their serum cytokines were evaluated by multiplex assay before treatment. The patients were divided into two groups: those who achieved remission without exacerbation of respiratory dysfunction (n = 25, group A) and those who progressed to hypoxemia during the treatment (n = 13, group B). PE was carried out in eight group B patients, but none of group A. Five of the eight treated with PE survived, while the five untreated patients died (P =0.04). Higher neutrophil lymphocyte ratio, higher serum ferritin, hypoxemia, high-resolution computed tomography (HRCT) score before treatment and increase of Krebs von Lungen-6 (KL-6) in the first 4 weeks of the treatment were the prognostic factors for disease progression. Serum cytokines such as IL-1, IL-6, IL-8, IL-10, IL-12p70, IL-18 and sCD163 levels were higher in group B than group A. PE should be an effective adjuvant treatment in anti-MDA5-positive DM with RP-ILD. Assessment of basal laboratory tests or monocyte/macrophage-derived cytokines and the increase of KL-6, HRCT score and hypoxemia may help us to predict intractable cases and to make early treatment decisions regarding PE in anti-MDA5-positive DM.


Presumed intraocular Hodgkin's disease.
A 16-year-old girl with nodular sclerosing Hodgkin's disease developed a retinal lesion with decreased visual acuity in one eye during a period of quiescence in her disease. The lesion appeared not to be of infectious or toxic origin and responded well to radiation therapy. The lesion has not recurred, and visual acuity has remained normal despite the systemic recurrence of Hodgkin's disease.


Synthesis of Ge4Se9 nano plates and a reduced graphene oxide composite of Ge4Se9 for electrochemical energy storage application.
In this study, we introduced a facile and single-step synthetic protocol for the scalable synthesis of tetra germanium nonaselenide (Ge4Se9) and it's composite with reduced graphene oxide (RG). The physicochemical properties of the samples were studied systematically, and their electrochemical performances for energy storage in supercapacitors were explored. Herein, the weight percentage of graphene oxide in the composite played a vital role in the enhancement of charge storage. Among other composites, the Ge4Se9/RG1 composite showed an enhanced specific capacitance (220 F g-1) with a higher specific energy (12 W h kg-1) as well as power (4.6 kW kg-1). Moreover, the composite showed excellent cycling stability (with 91% of capacitance retention after 10 000 repeated cycles) and reversibility (∼98% coulombic efficiency). Furthermore, the robustness of the composite was accessed via the post-stability analysis.


Modulation of gut-specific mechanisms by chronic δ(9)-tetrahydrocannabinol administration in male rhesus macaques infected with simian immunodeficiency virus: a systems biology analysis.
Our studies have demonstrated that chronic Δ(9)-tetrahydrocannabinol (THC) administration results in a generalized attenuation of viral load and tissue inflammation in simian immunodeficiency virus (SIV)-infected male rhesus macaques. Gut-associated lymphoid tissue is an important site for HIV replication and inflammation that can impact disease progression. We used a systems approach to examine the duodenal immune environment in 4- to 6-year-old male rhesus monkeys inoculated intravenously with SIVMAC251 after 17 months of chronic THC administration (0.18-0.32 mg/kg, intramuscularly, twice daily). Duodenal tissue samples excised from chronic THC- (N=4) and vehicle (VEH)-treated (N=4) subjects at ∼5 months postinoculation showed lower viral load, increased duodenal integrin beta 7(+)(β7) CD4(+) and CD8(+) central memory T cells, and a significant preferential increase in Th2 cytokine expression. Gene array analysis identified six genes that were differentially expressed in intestinal samples of the THC/SIV animals when compared to those differentially expressed between VEH/SIV and uninfected controls. These genes were identified as having significant participation in (1) apoptosis, (2) cell survival, proliferation, and morphogenesis, and (3) energy and substrate metabolic processes. Additional analysis comparing the duodenal gene expression in THC/SIV vs. VEH/SIV animals identified 93 differentially expressed genes that participate in processes involved in muscle contraction, protein folding, cytoskeleton remodeling, cell adhesion, and cell signaling. Immunohistochemical staining showed attenuated apoptosis in epithelial crypt cells of THC/SIV subjects. Our results indicate that chronic THC administration modulated duodenal T cell populations, favored a pro-Th2 cytokine balance, and decreased intestinal apoptosis. These findings reveal novel mechanisms that may potentially contribute to cannabinoid-mediated disease modulation.


Tonotopic gradients of membrane and synaptic properties for neurons of the chicken nucleus magnocellularis.
Nucleus magnocellularis (NM) is a division of the avian cochlear nucleus that extracts the timing of auditory signals. We compared the membrane excitability and synaptic transmission along the tonotopic axis of NM. Neurons expressed a Kv1.1 potassium channel mRNA and protein predominantly in the high characteristic frequency (CF) region of NM. In contrast, the expression of Kv1.2 mRNA did not change tonotopically. Neurons also showed tonotopic gradients in resting potential, spike threshold, amplitude, and membrane rectification. All neurons were sensitive to 100 nm dendrotoxin, but the effects were most significant in the high CF neurons. The EPSC recorded by minimal stimulation of auditory nerve fibers (ANFs) was 13 times larger in high CF neurons than in low CF neurons. Moreover, EPSCs were generated in an all-or-none manner in the high CF neurons when stimulus intensity was increased, whereas EPSCs were graded in the low CF neurons, indicating multiple axonal inputs. ANF synaptic terminals were visualized by DiI. ANF formed enfolding end-bulbs of Held around the cell body in the high and middle CF region but not in the low CF region. These observations indicate coordinated gradients of neuronal properties both presynaptically and postsynaptically along the tonotopic axis. Such specializations may be suitable for extracting and preserving the timing information of auditory signals over a wide range of acoustic frequencies.


Whole-genome sequencing of two North American Drosophila melanogaster populations reveals genetic differentiation and positive selection.
The prevailing demographic model for Drosophila melanogaster suggests that the colonization of North America occurred very recently from a subset of European flies that rapidly expanded across the continent. This model implies a sudden population growth and range expansion consistent with very low or no population subdivision. As flies adapt to new environments, local adaptation events may be expected. To describe demographic and selective events during North American colonization, we have generated a data set of 35 individual whole-genome sequences from inbred lines of D. melanogaster from a west coast US population (Winters, California, USA) and compared them with a public genome data set from Raleigh (Raleigh, North Carolina, USA). We analysed nuclear and mitochondrial genomes and described levels of variation and divergence within and between these two North American D. melanogaster populations. Both populations exhibit negative values of Tajima's D across the genome, a common signature of demographic expansion. We also detected a low but significant level of genome-wide differentiation between the two populations, as well as multiple allele surfing events, which can be the result of gene drift in local subpopulations on the edge of an expansion wave. In contrast to this genome-wide pattern, we uncovered a 50-kilobase segment in chromosome arm 3L that showed all the hallmarks of a soft selective sweep in both populations. A comparison of allele frequencies within this divergent region among six populations from three continents allowed us to cluster these populations in two differentiated groups, providing evidence for the action of natural selection on a global scale.


The ultimate constant of head and neck oncology—the physician-patient relationship.
Head and neck surgeons have the unique opportunity to engage with humans in life and death situations. We are confronting cancer, cure, failure, self-image, and most of all, a bond with the patient and family. We would like to view our expertise in head and neck surgery and the world of caring for our patients much like a Brigadoon. However, we daily are confronted with ever-changing and evolving approaches to health care that do not involve the physician or the patient. What kind of world is healthcare without a physician-patient interaction? Yes, there is the government-supported electronic medical record, which is here to stay (until our electrical and/or wired network fails). Yes, there is new technology, including robotic surgery and telemedicine and efforts to link these to our cell phones and applications, making care and expertise more available across long distances. And yes, there exist goals to extend care beyond the physician to other health care professions as the buffer between the physician and the patient, sometimes to reduce cost and sometimes to make care more ubiquitous. However, an Internet search will show that most say that the only constant in healthcare is change. I propose that the ultimate constant in healthcare is the physician-patient relationship.


Dopamine-modulated aversive emotion processing fails in alcohol-dependent patients.
Negative mood states after alcohol detoxification may enhance the relapse risk. As recently shown in healthy volunteers, dopamine storage capacity (V d) in the left amygdala was positively correlated with functional activation in the left amygdala and anterior cingulate cortex (ACC) during an emotional task; high functional connectivity between the amygdala and the ACC, a region important for emotion regulation, was associated with low trait anxiety. Based on these findings, we now tested whether detoxified alcohol-dependent patients have a disrupted modulation of the anterior cingulate cortex activation in response to aversive stimuli by amygdala dopamine. Furthermore, we asked whether disrupted functional coupling between amygdala and ACC during aversive processing is related to trait anxiety.We used combined 6-[18F]-fluoro-l-DOPA positron emission tomography (PET), functional magnetic resonance imaging (fMRI) and Spielberger's state-trait anxiety questionnaire (STAI) in 11 male detoxified alcohol-dependent patients compared to 13 matched healthy controls.Unlike healthy controls, patients showed no significant correlation between our PET metric for dopamine storage capacity (FDOPA V d), in left amygdala and activation in left ACC. Moreover, the functional connectivity between amygdala and ACC during processing of aversive emotional stimuli was reduced in patients. Voxel-based morphometry did not reveal any discernible group differences in amygdala volume.These results suggest that dopamine-modulated corticolimbic circuit function is important for responding to emotional information such that apparent functional deficits in this neuromodulatory circuitry may contribute to trait anxiety in alcohol-dependent patients.


Radioprotection With Amifostine Enhances Bone Strength and Regeneration and Bony Union in a Rat Model of Mandibular Distraction Osteogenesis.
Using distraction osteogenesis (DO) to regenerate robust endogenous bone could greatly enhance postoncologic reconstruction of head and neck cancer. However, radiation (XRT) corrosive effects still preclude DO's immense potential. We posit that adjunctive pretreatment with the radioprotectant amifostine (AMF) can optimize wound healing and allow for successful DO with quantifiable enhancements in bony union and strength despite previous surgical bed irradiation. Two groups of murine left hemimandibles were exposed to a human equivalent radiation dosage fractionated over 5 daily doses of 7 Gy. AMF-XRT-DO (n = 30) received AMF before radiation, whereas XRT-DO (n = 22) was untreated. All animals underwent left hemimandibular osteotomy and external fixator placement, followed by distraction to a 5.1-mm gap. Left hemimandibles were harvested and mechanically tested for parameters of strength, yield, and breaking load. Radiation-related complications such as severe alopecia were significantly increased in XRT-DO compared with the AMF-treated group (P = 0.001), whereas infection and death were comparable (P = 0.318). Upon dissection, bony defects were grossly visible in XRT-DO distraction gap compared with AMF-XRT-DO, which exhibited significantly more complete unions (P = 0.004). Those results were significantly increased in the specimens prophylactically treated with AMF (yield: 39.41 N vs 21.78 N, P = 0.023; breaking load: 61.74 N vs 34.77 N, P = 0.044; respectively). Our study revealed that AMF enhances biomechanical strength, regeneration, and bony union after radiation in a murine model of DO. The use of prophylactic AMF in combination with DO offers the promise of an alternative reconstructive option for patients afflicted with head and neck cancer.


Differentiation of marrow stromal cells into photoreceptors in the rat eye.
Retinal degenerations and dystrophies are the major causes of genetically inherited blindness that are characterized by the apoptotic death of the photoreceptor cell layer of the retina. To date, no treatment exists for these diseases and only recently have they been considered as candidates for gene and stem cell therapies. Here we report the ability of adult CD90+ marrow stromal cells (MSCs) to be induced by activin A, taurine, and EGF into cells (20-32%) expressing photoreceptor-specific markers rhodopsin, opsin, and recoverin in vitro. CD90+ cells were either transduced with recombinant adeno-associated virus expressing green fluorescent protein (GFP) or bromodeoxyuridine (BrdU) labeled and then injected into the subretinal space of adult Royal College of Surgeons rats. Fundus photography and angiography showed no adverse effects of CD90+ MSC transplantation. GFP-expressing cells or BrdU-positive cells covered approximately 30% of the entire retinal area. By 2 weeks after injection, CD90+ MSCs integrated into the host retina, forming structures similar to the photoreceptor layer and expressed a photoreceptor-specific marker. No teratoma formation was observed in the recipient retina. The subretinally delivered CD90+ MSCs did not stain for proliferating cell nuclear antigen, indicating that they primarily undergo differentiation rather than proliferation. In addition, we established that transplanted cells can attract synaptic vesicles and hence are potentially capable of signal transduction. This study demonstrates for the first time the partial differentiation of adult CD90+ MSCs into photoreceptors in vitro and in vivo. Our results establish a proof of concept for CD90+ MSC differentiation with autologous transplantation, which may provide a promising therapeutic strategy for the treatment of some forms of genetically inherited retinal degenerations.


Seasonal variation in food availability and relative importance of dietary items in the Gambian epauletted fruit bat (Epomophorus gambianus).
The Gambian epauletted fruit bat (Epomophorus gambianus) is very common across a variety of West African habitats, but very little information is available on its feeding ecology or its contribution to ecosystem function.We investigated seasonal variation in food availability and the relative importance of dietary items used by this species in a forest-savannah transitional ecosystem. Dietary items were identified from 1,470 samples of fecal and ejecta pellets which had been collected under day roosts or from captured bats over a 2-year period (2014-2015).Plant phenology studies illustrated strong seasonal correlations between fruiting and flowering and rainfall patterns: Fruits were available throughout the year but with peaks of abundance during the rainy season, while flowers were mostly abundant during the dry season. Epomophorus gambianus bats utilized fruit and flower resources from 30 plant species. Although the plant species used depended on seasonal availability, there were clear preferences for certain species.Flowers were an important food source for this fruit bat species especially during the dry season, contributing up to 79% of dietary items when fruit abundance was low. Ficus fruits were also important food item for E. gambianus, constituting over 40% of all dietary samples identified. Policy implications. Our results show the importance of flowers in the diet of E. gambianus and highlight this species as an important pollinator and seed disperser, including for economically and ecologically important plant species. These findings contribute to an improved understanding of the ecological importance and potential role of this species in the forest-savannah transition ecosystem for the development of fruit bat conservation management strategies.


Molecular cloning of the mammalian fatty acid synthase gene and identification of the promoter region.
Rat genomic clones encompassing the entire fatty acid synthase gene have been isolated and characterized. The gene is present in a single copy of approx. 20 kb. Genomic DNA sequencing, direct RNA sequencing and S1 nuclease analysis showed that transcription is initiated primarily 1274 nucleotides upstream from the translation start site and that the 87-nucleotide-long 5'-untranslated mRNA sequence is the same in liver, lung and mammary gland. The 5'-flanking region and first intron contain several sequence elements which may be involved in the transcriptional regulation of this gene.


Substrate specificity of mammalian folylpolyglutamate synthetase for 5,10-dideazatetrahydrofolate analogs.
The metabolism of 5,10-dideazatetrahydrofolate (DDATHF [lometrexol]) to polyglutamate derivatives by folylpoly-gamma-glutamate synthetase (FPGS) plays a central role in the activity of this compound as an antineoplastic agent. The availability of a series of DDATHF derivatives differing in structure throughout the molecule has allowed a study of the structural requirements for substrate activity with mouse liver and hog liver FPGS. Kinetics of the polyglutamation reaction in vitro have been related to the potency of these compounds as inhibitors of the growth of human CEM leukemic cells. The structure-activity relationships for enzyme from both sources were nearly identical. FPGS from both species showed a broad acceptance for structural changes in the pyridopyrimidine ring, in the phenyl group, and in the intermediate bridge region, with structural changes in these regions being reflected in changes in Km for FPGS but much more modest alterations in Vmax. The data suggested that the phenyl ring was not contributing to any pi-pi hydrophobic interactions. It appeared to function primarily in maintaining a favorable distance between the pyridopyrimidine ring and the glutamate side chain. The lowest Km values were found for DDATHF analogs in which there were small alterations at the 10 position, e.g., 5-deazatetrahydrofolate, 10-methyl-DDATHF, and 10-formyl-5-deazatetrahydrofolate; the first-order rate constants for these substrates were the highest in this series, an indication of the efficiency of polyglutamation at low substrate concentrations. After correction for the intrinsic inhibitory activity of the parent DDATHF analog as an inhibitor of the target enzyme, the first-order rate constants for FPGS were found to be predictive of the potency of tumor cell growth inhibition for most of the compounds in this structural series.


A lower than expected adult Victorian community attack rate for pandemic (H1N1) 2009.
To determine the community seropositivity of pandemic (H1N1) 2009 influenza in order to estimate immunity and the community attack rate. Selected clusters of participants (n=706) in the 'Victorian Health Monitor' (VHM), from whom blood samples were taken between August and October 2009, were tested opportunistically for antibodies to pandemic (H1N1) 2009 influenza virus. A titre of > or = 1:40 was chosen as the cut-off for recording seropositivity. The proportion (95% CI) of seropositive participants, aged 18 to <65 years of age, were computed for groups of census collection districts (CDs) across metropolitan Melbourne. The observed pandemic (H1N1) 2009 seropositivity rates for all CDs tested in metropolitan Melbourne was 16.0% (95% CI:12.9-19.1%); in northern Melbourne subset was 14.4% (95% CI:12.4-16.3%); and in eastern subset was 16.2% (95% CI:9.7-22.6%). The pre-pandemic (H1N1) 2009 positivity rate was estimated at 6%. Given this study's estimate of 16.0% seropositivity in adults in metropolitan Melbourne, and given the WHO laboratory's estimate of 6% pre-pandemic positivity, the estimated adult community attack rate was 10% for metropolitan Melbourne. This community attack rate is lower than anticipated and suggests that levels of immunity to Pandemic (H1N1) 2009 might be lower than anticipated. Although limited by a low response rate of 34%, this study suggests low adult seropositivity, which may be useful for public health professionals when encouraging the community to get vaccinated.


Epstein-Barr virus and a unilateral neck mass.
Although Epstein-Barr infectious mononucleosis (IM) might be considered in the differential diagnosis of multiple neck masses in a young adult, single large masses are not usually associated with IM. This patient did have a solitary mass. Despite lacking other signs of IM, he did have a positive heterophil-agglutination titer and reactive lymphocytes. Other serologic tests can be of value in confirming the diagnosis, especially if the heterophil titer and reactive lymphocytes are absent. These tests are viral capsid antigen IgM and IgG, early antigen, and nuclear antigen. Surgeons should be aware of their usefulness, especially when trying to confirm a difficult diagnosis.


Crown-ether-mediated crystal structures of the glycosyltransferase PaGT3 from Phytolacca americana.
Uridine diphosphate glycosyltransferases (UGTs) are ubiquitous enzymes that are involved in the glycosylation of small molecules. As glycosylation improves the water solubility and stability of hydrophobic compounds, interest in the use of UGTs for the synthesis of glycosides of poorly soluble compounds is increasing. While sugar-donor recognition in UGTs is conserved with the presence of a plant secondary product glycosyltransferase (PSPG) motif, the basis of the recognition of the sugar acceptor and the regioselectivity of the products is poorly understood owing to low sequence identity around the acceptor-binding region. PaGT3, a glycosyltransferase from the plant Phytolacca americana, can glycosylate a range of acceptors. To illustrate the structure-function relationship of PaGT3, its crystal structure was determined. The sugar-donor and sugar-acceptor binding pockets in PaGT3 were recognized by comparison of its structure with those of other UGTs. The key feature of PaGT3 was the presence of longer loop regions around the hydrophobic acceptor-binding pocket, which resulted in a flexible and wider acceptor binding pocket. In this study, PaGT3 crystals were grown by co-crystallization with 18-crown-6 ether or 15-crown-5 ether. The crown-ether molecule in the asymmetric unit was observed to form a complex with a metal ion, which was coordinated on two sides by the main-chain O atoms of Glu238 from two molecules of the protein. The crown ether-metal complex resembles a molecular glue that sticks two molecules of PaGT3 together to enhance crystal growth. Thus, this result provides an insight into the substrate-recognition strategy in PaGT3 for the study of glycosyltransferases. Additionally, it is shown that crown ether-metal ion complexes can be used as a molecular glue for the crystallization of proteins.


Validation of new ICD-10-based patient safety indicators for identification of in-hospital complications in surgical patients: a study of diagnostic accuracy.
Administrative data systems are used to identify hospital-based patient safety events; few studies evaluate their accuracy. We assessed the accuracy of a new set of patient safety indicators (PSIs; designed to identify in hospital complications). Prospectively defined analysis of registry data (1 April 2010-29 February 2016) in a Canadian hospital network. Assignment of complications was by two methods independently. The National Surgical Quality Improvement Programme (NSQIP) database was the clinical reference standard (primary outcome=any in-hospital NSQIP complication); PSI clusters were assigned using International Classification of Disease (ICD-10) codes in the discharge abstract. Our primary analysis assessed the accuracy of any PSI condition compared with any complication in the NSQIP; secondary analysis evaluated accuracy of complication-specific PSIs. All inpatient surgical cases captured in NSQIP data. We assessed the accuracy of PSIs (with NSQIP as reference standard) using positive and negative predictive values (PPV/NPV), as well as positive and negative likelihood ratios (±LR). We identified 12 898 linked episodes of care. Complications were identified by PSIs and NSQIP in 2415 (18.7%) and 2885 (22.4%) episodes, respectively. The presence of any PSI code had a PPV of 0.55 (95% CI 0.53 to 0.57) and NPV of 0.93 (95% CI 0.92 to 0.93); +LR 6.41 (95% CI 6.01 to 6.84) and -LR 0.40 (95% CI 0.37 to 0.42). Subgroup analyses (by surgery type and urgency) showed similar performance. Complication-specific PSIs had high NPVs (95% CI 0.92 to 0.99), but low to moderate PPVs (0.13-0.61). Validation of the ICD-10 PSI system suggests applicability as a first screening step, integrated with data from other sources, to produce an adverse event detection pathway that informs learning healthcare systems. However, accuracy was insufficient to directly identify or rule out individual-level complications.


Organisational benefits of a strong research culture in a health service: a systematic review.
Objective The aim of the present study was to determine whether there is an association between having research culture in a health service and better organisational performance. Methods Using systematic review methods, databases were searched, inclusion criteria applied and study quality appraised. Data were extracted from selected studies and the results were synthesised descriptively. Results Eight studies were selected for review. Five studies compared health services with high versus low levels of research activity among the workforce. Three studies evaluated the effect of specific interventions focused on the health workforce. All studies reported a positive association between research activity and organisational performance. Improved organisational performance included lower patient mortality rates (two of two studies), higher levels of patient satisfaction (one of one study), reduced staff turnover (two of two studies), improved staff satisfaction (one of two studies) and improved organisational efficiency (four of five studies). Conclusions A stronger research culture appears to be associated with benefits to patients, staff and the organisation. What is known about this topic? Research investment in the health workforce can increase research productivity of the health workforce. In addition, investment in clinical research can lead to positive health outcomes. However, it is not known whether a positive research culture among the health workforce is associated with improved organisational performance. What does this paper add? The present systematic review of the literature provides evidence that a positive research culture and interventions directed at the health workforce are associated with patient, staff and organisational benefits. What are the implications for practitioners? For health service managers and policy makers, one interpretation of the results could be to provide support for initiatives directed at the health workforce to increase a research culture in health services. However, because association does not imply causation, managers need to interpret the results with caution and evaluate the effect of any initiatives to increase the research culture of the health workforce on the performance of their organisation.


Properties of binding of Escherichia coli endotoxin to various matrices.
Binding of Escherichia coli O127:B8 endotoxin to a variety of resins and column materials was investigated by measuring the beta-hydroxy myristic acid content (a major component of the lipid A moiety) of endotoxin after hydrolysis by selected ion-monitoring gas chromatography-mass spectrometry. More than 80% of the endotoxin was bound to hydroxylapatite, polystyrene, Dowex 1-X2, and charcoal. The binding of endotoxin to these materials was markedly reduced by the addition of normal or delipidated serum. Phenyl- and octyl-Sepharose bound 56 and 50% of the endotoxin from saline solutions, respectively. Their percent binding was increased significantly in 1 M ammonium sulfate solutions, indicating hydrophobic interactions between endotoxin and phenyl- and octyl-Sepharose. Only 5% of the endotoxin was bound to plastic polymer PSI-HAP-100 beads, and no binding was observed with concanavalin A- and heparin-Sepharose. Study of the in vitro binding of endotoxin to the above material in the presence of serum suggests that the use of these materials in removing circulating endotoxin in vivo is limited.


Frequency and factors related to not receiving acute reperfusion therapy in patients with ST elevation myocardial infarction; a single specialty cardiac center.
To determine the frequency of no reperfusion therapy, its reasons, hospital management and intermediate-term outcome s of ST- elevation my ocardial in farction patients . The retrospective ambi-directional observational study was conducted at Tabba Heart Institute, Karachi, and comprised record of ST-elevation myocardial infarction patients without immediate reperfusion therapy with symptom onset time of 12 hours who presented between January 2013 and December 2017. Prospective follow-up of all patients was performed till June 2018. Coronary angiography, non-invasive stress tests, medications and late revascularisation were explored. Predictors of hospital mortality and major adverse cardiovascular events at follow-up were analysed. Data was analysed using SPSS 19. Of the 1977 records evaluated, 218(11%) patients of mean age 60.3±12.4 years did not receive immediate reperfusion therapy. Coronary angiography was done in 163(74.7%) patients of whom 45(27.6%) were taken for immediate procedure. Besides, 26 (11.9%) patients died during hospital stay. Predictors of hospital mortality were no revascularisation (odds ratio: 24.1, 95% confidence interval: 1.3-500), cardiogenic shock (odds ratio: 65, 95% confidence interval: 5.7-745) and tachycardia (odds ratio: 17, 95% confidence interval: 1.2-254.5) at presentation. Predictor of major adverse cardiovascular events was guideline-directed medical therapy (hazard ratio 2.6, 95% confidence interval: 1.16-6.2) at discharge, while revascularisation was not a significant predictor (p>0.05). A huge number of salvageable ST-elevation myocardial infarction patients failed to receive reperfusion therapy. There is a huge potential of improvement in ST-elevation myocardial infarction care in terms of increasing community awareness, prompt reperfusion therapy and usage of optimal medical therapy.


Long Noncoding RNA KCNQ1OT1 is a Prognostic Biomarker and mediates CD8+ T cell exhaustion by regulating CD155 Expression in Colorectal Cancer.
Background: Long noncoding RNA KCNQ1 opposite strand/antisense transcript 1 (lncRNA KCNQ1OT1) is abnormally expressed in various solid tumors. The purpose of this study was to explore the prognostic value and potential functional role of lncRNA KCNQ1OT1 across cancers. Methods: We performed a meta-analysis of published literature to evaluate the prognostic value of lncRNA KCNQ1OT1 across cancers. Verification, functional analysis, and genomic variation analysis were performed using the GEPIA, TIMER, and LnCeVar databases. According to the immune cell infiltration level, we established a prognostic model of lncRNA KCNQ1OT1 expression using public datasets of TIMER. We used quantitative real-time polymerase chain reaction (RT-qPCR) and western blot to detect the expression levels of lncRNA KCNQ1OT1 and the CD155 protein in colorectal cancer (CRC) tissues and cell lines. Then, a lncRNA KCNQ1OT1-knockdown cell line was cocultured to explore the role of lncRNA KCNQ1OT1 and CD155 in the T cell response by flow cytometric analysis. Results: Our results showed that the high expression of lncRNA KCNQ1OT1 was significantly related to poor overall survival across cancers, especially CRC. Interestingly, we found that COAD patients with high lncRNA KCNQ1OT1 expression and high CD8+ T cell infiltration levels had a worse prognosis than those with low lncRNA KCNQ1OT1 expression and high CD8+ T cell infiltration levels. Moreover, lncRNA KCNQ1OT1 and CD155 showed significantly higher expression in CRC tissue than in normal tissue, and lncRNA KCNQ1OT1 expression was positively correlated with CD155 expression in CRC. Finally, knockdown of lncRNA KCNQ1OT1 reduced CD155 expression in HCT116 and SW620 cells and enhanced the immune response in coculture with CD8+ T cells. Conclusions: High lncRNA KCNQ1OT1 expression is significantly correlated with poor prognosis of CRC patients and mediates the CD8+ T cell response in CRC. These findings indicate that lncRNA KCNQ1OT1 is a prognostic biomarker and potential immune therapeutic target for enhancing the CD8+ T cell response in CRC.


Self-guiding interlocking intramedullary nail.
A critical step in closed interlocking intramedullary nailing is the insertion of the proximal and distal screws under fluoroscopic control. An intramedullary nailing system is described that does not require the use of direct fluoroscopic control for distal screw insertion. With the SG interlocking intramedullary nail, the location and fixation of the distal screw is achieved by keying in on a transversely placed guide pin, with imaging required only to confirm the alignment and final placement of the instrumentation.


True phosphorus digestibility and the endogenous phosphorus outputs associated with brown rice for weanling pigs measured by the simple linear regression analysis technique.
The objectives of this study were to determine true phosphorus (P) digestibility, degradability of phytate-P complex and the endogenous P outputs associated with brown rice feeding in weanling pigs by using the simple linear regression analysis technique. Six barrows with an average initial body weight of 12.5 kg were fitted with a T-cannula and fed six diets according to a 6 × 6 Latin-square design. Six maize starch-based diets, containing six levels of P at 0.80, 1.36, 1.93, 2.49, 3.04, and 3.61 g/kg per kg dry-matter (DM) intake (DMI), were formulated with brown rice. Each experimental period lasted 10 days. After a 7-day adaptation, all faecal samples were collected on days 8 and 9. Ileal digesta samples were collected for a total of 24 h on day 10. The apparent ileal and faecal P digestibility values of brown rice were affected ( P < 0.01) by the P contents in the assay diets. The apparent ileal and faecal P digestibility values increased from - 48.0 to 36.7% and from - 35.6 to 40.0%, respectively, as P content increased from 0.80 to 3.61 g/kg DMI. Linear relationships ( P < 0.05), expressed as g/kg DMI, between the apparent ileal and faecal digestible P and dietary levels of P, suggested that true P digestibility and the endogenous P outputs associated with brown rice feeding could be determined by using the simple regression analysis technique. There were no differences ( P>0.05) in true P digestibility values (57.7 ± 5.4 v. 58.2 ± 5.9%), phytate P degradability (76.4 ± 6.7 v. 79.0 ± 4.4%) and the endogenous P outputs (0.812 ± 0..096 v. 0.725 ± 0.083 g/kg DMI) between the ileal and the faecal levels. The endogenous faecal P output represented 14 and 25% of the National Research Council (1998) recommended daily total and available P requirements in the weanling pig, respectively. About 58% of the total P in brown rice could be digested and absorbed by the weanling pig. Our results suggest that the large intestine of the weanling pigs does not play a significant role in the digestion of P in brown rice. Diet formulation on the basis of total or apparent P digestibility with brown rice may lead to P overfeeding and excessive P excretion in pigs.


Idiopathic gingival fibromatosis: a review of the literature and a case report.
Gingival fibromatosis is characterized by localized or generalized fibrous enlargement of the gingivae, mainly around permanent teeth. Gingival fibromatosis affects only the masticatory mucosa and does not extend beyond the muco-gingival junction. This article describes an unusual case of idiopathic gingival fibromatosis with delayed eruption of permanent teeth in an 8 year-old boy. The pathogenic mechanisms that bring about gingival fibromatosis are discussed.


Chemiomics: network reconstruction and kinetics of port wine aging.
Network reconstruction (NR) has proven to be useful in the detection and visualization of relationships among the compounds present in a Port wine aging data set. This view of the data provides a considerable amount of information with which to understand the kinetic contexts of the molecules represented by peaks in each chromatogram. The aim of this study was to use NR together with the determination of kinetic parameters to extract more information about the mechanisms involved in Port wine aging. The volatile compounds present in samples of Port wines spanning 128 years in age were measured with the use of GC-MS. After chromatogram alignment, a peak matrix was created, and all peak vectors were compared to one another to determine their Pearson correlations over time. A correlation network was created and filtered on the basis of the resulting correlation values. Some nodes in the network were further studied in experiments on Port wines stored under different conditions of oxygen and temperature in order to determine their kinetic parameters. The resulting network can be divided into three main branches. The first branch is related to compounds that do not directly correlate to age, the second branch contains compounds affected by temperature, and the third branch contains compounds associated with oxygen. Compounds clustered in the same branch of the network have similar expression patterns over time as well as the same kinetic order, thus are likely to be dependent on the same technological parameters. Network construction and visualization provides more information with which to understand the probable kinetic contexts of the molecules represented by peaks in each chromatogram. The approach described here is a powerful tool for the study of mechanisms and kinetics in complex systems and should aid in the understanding and monitoring of wine quality.


How common is diabetic nephropathy?
In a study of 1,356 diabetic patients attending a clinic in a 12 month period, 28 (2.1%) were considered to have definite diabetic nephropathy by strict diagnostic criteria. This suggests that the prevalence of overt nephropathy is less than has been previously reported. This may be because many patients with microalbuminuria or early proteinuria do not survive to develop the syndrome of established diabetic nephropathy.


New frontiers for mid-infrared sensors: towards deep sea monitoring with a submarine FT-IR sensor system.
A sub-sea deployable fiber-optic sensor system for the continuous determination of a range of environmentally relevant volatile organic compounds in seawater has been developed. The prototype of a robust, miniaturized Fourier transform infrared (FT-IR) spectrometer for in situ underwater pollution monitoring was designed, developed, and built in our research group. The assembled instrument is enclosed in a sealed aluminium pressure vessel and is capable of maintenance-free operation in an oceanic environment down to depths of at least 300 m. The whole system can be incorporated either in a tow frame or a remotely operated vehicle (ROV). A suitable fiber-optic sensor head was developed, optimized in terms of sensitivity and hydrodynamics, and connected to the underwater FT-IR spectrometer. Due to a modular system design, various other sensor head configurations could be realized and tested, ensuring facile adaptation of the instrument to future tasks. The sensor system was characterized in a series of laboratory and simulated field tests. The sensor proved to be capable of quantitatively detecting a range of chlorinated hydrocarbons and monocyclic aromatic hydrocarbons in seawater down to the low ppb (microg/L) concentration range, including mixtures of up to 6 components. It has been demonstrated that varying amounts of salinity, turbidity, or humic acids, as well as interfering seawater pollutants, such as aliphatic hydrocarbons or phenols, do not significantly influence the sensor characteristics. In addition, the sensor exhibits sufficient long-time stability and a low susceptibility to sensor fouling.


[A fact-free medicine? Report by Dutch Council for Public Health and Society is slap in the face].
A recently released report by the Dutch Council for Public Health and Society ('Raad voor Volksgezondheid en Samenleving') is subtitled "About the illusion of evidence-based practice in healthcare". The author argues that this report is a sign of the times, a period of "post-truth medicine" and "alternative facts", in which "science offers nothing but a reduction". Although the report rightly - but superfluously - argues that having an evidence base is insufficient for delivering quality care (no decisions without considering context), its depiction of the illusory nature of evidence-based practice represents a brutal slap in the face of all those who turn to sound clinical and biomedical research to back up or refute claims about the effectiveness of healthcare interventions.


Nonsense-mediated decay enables intron gain in Drosophila.
Intron number varies considerably among genomes, but despite their fundamental importance, the mutational mechanisms and evolutionary processes underlying the expansion of intron number remain unknown. Here we show that Drosophila, in contrast to most eukaryotic lineages, is still undergoing a dramatic rate of intron gain. These novel introns carry significantly weaker splice sites that may impede their identification by the spliceosome. Novel introns are more likely to encode a premature termination codon (PTC), indicating that nonsense-mediated decay (NMD) functions as a backup for weak splicing of new introns. Our data suggest that new introns originate when genomic insertions with weak splice sites are hidden from selection by NMD. This mechanism reduces the sequence requirement imposed on novel introns and implies that the capacity of the spliceosome to recognize weak splice sites was a prerequisite for intron gain during eukaryotic evolution.


BGP-15 Protects against Oxaliplatin-Induced Skeletal Myopathy and Mitochondrial Reactive Oxygen Species Production in Mice.
Chemotherapy is a leading intervention against cancer. Albeit highly effective, chemotherapy has a multitude of deleterious side-effects including skeletal muscle wasting and fatigue, which considerably reduces patient quality of life and survivability. As such, a defense against chemotherapy-induced skeletal muscle dysfunction is required. Here we investigate the effects of oxaliplatin (OXA) treatment in mice on the skeletal muscle and mitochondria, and the capacity for the Poly ADP-ribose polymerase (PARP) inhibitor, BGP-15, to ameliorate any pathological side-effects induced by OXA. To do so, we investigated the effects of 2 weeks of OXA (3 mg/kg) treatment with and without BGP-15 (15 mg/kg). OXA induced a 15% (p < 0.05) reduction in lean tissue mass without significant changes in food consumption or energy expenditure. OXA treatment also altered the muscle architecture, increasing collagen deposition, neutral lipid and Ca2+ accumulation; all of which were ameliorated with BGP-15 adjunct therapy. Here, we are the first to show that OXA penetrates the mitochondria, and, as a possible consequence of this, increases mtROS production. These data correspond with reduced diameter of isolated FDB fibers and shift in the fiber size distribution frequency of TA to the left. There was a tendency for reduction in intramuscular protein content, albeit apparently not via Murf1 (atrophy)- or p62 (autophagy)- dependent pathways. BGP-15 adjunct therapy protected against increased ROS production and improved mitochondrial viability 4-fold and preserved fiber diameter and number. Our study highlights BGP-15 as a potential adjunct therapy to address chemotherapy-induced skeletal muscle and mitochondrial pathology.


Predicting factors of depression in patients with primary hypertension: a community-based study.
OBJECTIVE To investigate the factors that may predict the occurrence of depression in patients with primary hypertension. METHODS We conducted a cross-sectional survey on 891 hypertensive patients and 651 normal subjects (control group) from a single community. Zung self-rating depression scale (SDS) was applied to evaluate the symptoms of depression, which was diagnosed when the SDS score was >41. RESULTS There was no significant difference in gender distribution (female, 48.5 vs. 47.6%) and age (65.3±9.2 vs. 64.0±7.9 years) between the hypertensive control groups (P>0.05). Depression was diagnosed in 139 hypertensive patients (15.6%) and 27 (4.2%) control subjects (P<0.01). The average SDS score was higher in patients with hypertension duration of more than 3 years (33.3±9.0 vs. 30.6±7.6, P<0.001), in patients with severe hypertension (44.0±7.8 vs. 28.9±4.9, P<0.001) and in patients with a history of hospitalization for cardiovascular disorders (38.1±9.3 vs. 32.0±8.4, P<0.001). Multivariate regression analysis showed that the degree and the duration of hypertension, as well as hospitalization history, were independent predictors of depression in the hypertensive patients. CONCLUSIONS Hypertension is associated with a higher prevalence of depression that can be predicted by the duration and severity of hypertension as well as a history of hospitalization.


[Isolation and identification of Malassezia spp. In pytiriasis versicolor, seborrheic dermatitis and healthy skin.].
The taxonomy of the genus Malassezia has been recently revised and enlarged to include seven distinct species. The aim of the study was to analyse the prevalence of these species in the cutaneous lesions of pityriasis versicolor and dermatitis seborrhoeica, as well as in the normal skin. Seventy-five patients with pityriasis versicolor, 75 of dermatitis seborrhoeica, and 150 samples of normal skin (75 from the forehead and 75 from the shoulders) were studied. A direct microscopy with KOH + Parker ink was carried out in the pityriasis versicolor and dermatitis seborrhoeica samples. All the samples were inoculated in plates containing modified Dixon medium and incubated at 31 degrees C. The yeasts isolated were identified by its morphological and physiological characteristics, upon the scheme published by Guillot et al. In pityriasis versicolor, Malassezia globosa was found in 84% of cases, alone or associated with Malassezia sympodialis, which was by far the commonest species in normal skin (91.7% of isolates, predominating in the trunk skin). In dermatitis seborrhoeica, Malassezia restricta was the commonest species (63.9%), often associated with M. globosa and/or Malassezia sympodialis. M. globosa was also very common in this disease (54.4%), where Malassezia slooffiae and Malassezia furfur could be detected in less than 5% of the samples. These results support that M. globosa, in its mycelial phase, plays a predominant role in the aetiology of pityriasis versicolor. In dermatitis seborrhoeica, the significance of the presence of different species, mainly M. restricta and M. globosa in its yeast phase, remains unclear. Further studies are needed to establish appropriately the pathogenicity of the lipophilic skin mycoflora.


Optical signatures of energy-level statistics in a disordered quantum system
Time-resolved measurements of the resonant Rayleigh scattering from quantum well excitons are shown to provide information on the energy-level statistics of the localized exciton states. The signal transients are reproduced by a microscopic quantum model of the exciton two-dimensional motion in presence of spatially correlated disorder. This model allows quantitative determination of the average energy separation between the localized states. Here this quantity turns out to be only a few times smaller than the average disorder amplitude, proving that spatial correlation and quantum mechanics are equally important in the description of the exciton localization process.


Designing quality brochures.
Many formulas may be used to create a brochure. The main goal is to entice people to read the material. Designing and preparing brochures in house offers a great deal of flexibility and is generally less expensive than having them designed outside. Brochures can be produced very creatively, and they give the education department yet another opportunity to develop professionally.


New perspectives and strategy research biomarkers for hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Cirrhosis caused by hepatitis B virus, hepatitis C virus or chronic alcohol intake is associated with major risk. Systematic screening for HCC of asymptomatic patients with cirrhosis is needed for earlier detection of small tumors requiring treatment (liver transplantation, surgical resection, percutaneous techniques). The recommended screening strategy among cirrhotic patients is based on regular liver ultrasonography associated with serum alpha-fetoprotein (AFP) assay. As the performance of AFP is not satisfactory, additional tumoral markers are proposed (des-gamma-carboxyprothrombin, glycosylated AFP-L3 fraction). Currently, diagnosis of HCC in cirrhotic patients includes non-invasive tests (imaging after contrast administration, AFP assay); diagnostic biopsy is performed when imaging is limited. After treatment, tumor recurrence is assessed by regular follow-up (AFP assay and imaging). Despite the lack of accurate markers, recent developments in genomic and proteomic approaches will allow the discovery of new biomarkers for primary tumors, as well as for recurrence. This review summarizes the current state of biomarkers for screening, diagnosis and follow-up of HCC, and highlights new perspectives in the field.


Calponin and h-caldesmon in soft tissue tumors: consistent h-caldesmon immunoreactivity in gastrointestinal stromal tumors indicates traits of smooth muscle differentiation.
Currently, the immunohistochemical evaluation of smooth muscle differentiation is usually based on desmin, which also reacts with skeletal muscle and is not present in all smooth muscle tumors, and alpha-smooth muscle actin, which reacts with myoepithelial cells. Neither marker typically reacts with gastrointestinal stromal tumors (GISTs), previously classified as smooth muscle tumors or presently often classified as smooth muscle/stromal tumors. Two cytoskeleton-associated actin-binding proteins, calponin (CALP) and h-caldesmon (HCD), are putative smooth muscle markers that also react with myoepithelia. These markers are of particular interest in the immunohistochemical analysis of tumors; neither of them has been extensively documented in soft tissue tumors. In this study, we evaluated selected normal and reactive tissues and more than 250 mesenchymal tumors for CALP and HCD. Both markers were expressed in parenchymal and vascular smooth muscle cells in various organs and in myoepithelial cells. CALP also reacted with myofibroblasts of desmoplastic stroma. All of our 25 benign smooth muscle tumors from various locations were positive for CALP and HCD, as were most of the retroperitoneal and uterine leiomyosarcomas. HCD was more specific, because CALP also reacted with myofibroblastic lesions. The common reactivity of malignant fibrous histiocytomas with CALP and HCD suggests a combination of myofibroblastic and smooth muscle differentiation in these tumors. The GISTs (c-kit positive, usually actin negative) showed nearly consistent HCD reactivity, suggesting traits of smooth muscle differentiation. GISTs were usually CALP negative and showed a CALP expression pattern similar to that of alpha-smooth muscle actin. Although nonmuscle, nonmyofibroblastic tumors were negative for CALP and HCD, synovial sarcomas showed streaks of CALP-positive cells of unknown significance. CALP and HCD should be explored as markers to identify myofibroblastic and smooth muscle cell differentiation in mesenchymal tumors.


A powerful combinatorial screen to identify high-affinity terbium(III)-binding peptides.
Lanthanide-binding tags (LBTs) are protein fusion partners consisting of encoded amino acids that bind lanthanide ions with high affinity. Herein, we present a new screening methodology for the identification of new LBT sequences with high affinity for Tb(3+) ions and intense luminescence properties. This methodology utilizes solid-phase split-and-pool combinatorial peptide synthesis. Orthogonally cleavable linkers allow an efficient two-step screening procedure. The initial screen avoids the interference caused by on-bead screening by photochemically releasing a portion of the peptides into an agarose matrix for evaluation. The secondary screen further characterizes each winning sequence in a defined aqueous solution. Employment of this methodology on a series of focused combinatorial libraries yielded a linear peptide sequence of 17 encoded amino acids that demonstrated a 140-fold increase in affinity (57 nM dissociation constant, K(D)) over previously reported lanthanide-binding peptides. This linear sequence was macrocyclized by introducing a disulfide bond between flanking cysteine residues to produce a peptide with a 2-nM apparent dissociation constant for Tb(3+) ions.Supporting information for this article is available on the WWW under http://www.chemphyschem.org or from the author.


Sub-ms dynamics of the instability onset of electrospinning.
Electrospun polymer jets are imaged for the first time at an ultra-high rate of 10,000 frames per second, investigating the process dynamics, and the instability propagation velocity and displacement in space. The polymer concentration, applied voltage bias and needle-collector distance are systematically varied, and their influence on the instability propagation velocity and on the jet angular fluctuations is analyzed. This allows us to unveil the instability formation and cycling behavior, and its exponential growth at the onset, exhibiting radial growth rates of the order of 10(3) s(-1). Allowing the conformation and evolution of polymeric solutions to be studied in depth, high-speed imaging at the sub-ms scale shows significant potential for improving the fundamental knowledge of electrified jets, leading to finely controllable bending and solution stretching in electrospinning, and consequently better designed nanofiber morphologies and structures.


The importance of supervisor-nurse relationships, teamwork, wellbeing, affective commitment and retention of North American nurses.
Using Social Exchange Theory, this study examines links between supervisor-nurse relationships, teamwork, psychological wellbeing and turnover intentions for nurses in the USA. Nurses in the USA comprise the biggest workforce of any country in the world. However, nurses continue to be in short supply even with an aggressive campaign to attract foreign nurses. The shortage of qualified registered nurses has negative implications for patient care and mortality because it affects problem-solving and teamwork as a result of poor communication among nurses. The study uses a cross-sectional design and 730 completed surveys were obtained using a self-report strategy. The findings indicate that supervisor-nurse relationships, teamwork and wellbeing explain almost half of nurses' commitment to their hospital and their intentions to leave. Further, there was evidence of a generational effect in that Baby Boomer nurses perceived higher levels of wellbeing and commitment, and lower intention to leave. These findings suggest that management must focus on improving the quality of workplace relationship as a first step in retaining skilled nurses. It may be time for management to embed performance indicators for all levels of management, linked to ensuring effective workplace relationships.


Local motifs in proteins combine to generate global functional moves.
Literature on the topological properties of folded proteins that has emerged as a field in its own right in the past decade is reviewed. Physics-based construction of coarse-grained models of proteins from knowledge of all-atom coordinates of the average structure is discussed. Once network is thus obtained with the node and link information, local motifs provide plethora of information on protein function. The hierarchical structure of the proteins manifested in the interrelations of local motifs is emphasized. Motifs are also related to modularity of the structure, and they quantify shifts in the landscapes upon conformational changes induced by, e.g. ligand binding. Redundancy emerges as a balance between local and global network descriptors and is related to the collectivity of the protein motions. Introducing weight on links followed by sequential removal of least cohesive contacts allows interactions in proteins to be represented as the superposition of essential and redundant sets. Lack of the former makes the network non-functional, while the latter ensures robust functioning under a wide range of perturbation scenarios.


A rigorous evaluation of optimal peptide targets for MS-based clinical diagnostics of Coronavirus Disease 2019 (COVID-19).
The Coronavirus Disease 2019 (COVID-19) global pandemic has had a profound, lasting impact on the world's population. A key aspect to providing care for those with COVID-19 and checking its further spread is early and accurate diagnosis of infection, which has been generally done via methods for amplifying and detecting viral RNA molecules. Detection and quantitation of peptides using targeted mass spectrometry-based strategies has been proposed as an alternative diagnostic tool due to direct detection of molecular indicators from non-invasively collected samples as well as the potential for high-throughput analysis in a clinical setting; many studies have revealed the presence of viral peptides within easily accessed patient samples. However, evidence suggests that some viral peptides could serve as better indicators of COVID-19 infection status than others, due to potential misidentification of peptides derived from human host proteins, poor spectral quality, high limits of detection etc. METHODS: In this study we have compiled a list of 636 peptides identified from Sudden Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) samples, including from in vitro and clinical sources. These datasets were rigorously analyzed using automated, Galaxy-based workflows containing tools such as PepQuery, BLAST-P, and the Multi-omic Visualization Platform as well as the open-source tools MetaTryp and Proteomics Data Viewer (PDV). Using PepQuery for confirming peptide spectrum matches, we were able to narrow down the 639-peptide possibilities to 87 peptides that were most robustly detected and specific to the SARS-CoV-2 virus. The specificity of these sequences to coronavirus taxa was confirmed using Unipept and BLAST-P. Through stringent p-value cutoff combined with manual verification of peptide spectrum match quality, 4 peptides derived from the nucleocapsid phosphoprotein and membrane protein were found to be most robustly detected across all cell culture and clinical samples, including those collected non-invasively. We propose that these peptides would be of the most value for clinical proteomics applications seeking to detect COVID-19 from patient samples. We also contend that samples harvested from the upper respiratory tract and oral cavity have the highest potential for diagnosis of SARS-CoV-2 infection from easily collected patient samples using mass spectrometry-based proteomics assays.


Dentigerous cyst formation following trauma to the primary incisors: A case report.
Although usually considered to be of developmental origin, dentigerous cysts (DCs) have been reported to form in response to chronic periapical inflammation associated with primary teeth that have necrotic, infected pulps. This article describes the management of a DC associated with tooth 21 in a seven-year-old Caucasian child with a history of multiple TDIs to the primary maxillary incisors. Chronic periapical inflammation associated with a necrotic pulp in tooth 61 was identified as the likely cause of the lesion. Initial conservative management involved marsupialization of the lesion by extracting the necrotic tooth 61. Following significant decompression of the cyst, surgical enucleation was carried out under general anaesthesia and an orthodontic attachment was bonded to the crown of the unerupted tooth 21 to facilitate traction. Histopathological assessment of the enucleated tissue confirmed it to be a DC. Two years after the initial presentation, teeth 21 and 22 had erupted into the oral cavity, improving patient aesthetics. However, the root of tooth 22 was transposed with the crown of the unerupted tooth 23. This case highlights the undesirable sequelae that may occur following delayed and inappropriate management of TDIs.


Volatile organic compounds and pulmonary function in the Third National Health and Nutrition Examination Survey, 1988-1994.
Volatile organic compounds (VOCs) are present in much higher concentrations indoors, where people spend most of their time, than outdoors and may have adverse health effects. VOCs have been associated with respiratory symptoms, but few studies address objective respiratory end points such as pulmonary function. Blood levels of VOCs may be more indicative of personal exposures than are air concentrations; no studies have addressed their relationship with respiratory outcomes. We examined whether concentrations of 11 VOCs that were commonly identified in blood from a sample of the U.S. population were associated with pulmonary function. We used data from 953 adult participants (20-59 years of age) in the Third National Health and Nutrition Examination Survey (1988-1994) who had VOC blood measures as well as pulmonary function measures. Linear regression models were used to evaluate the relationship between 11 VOCs and measures of pulmonary function. After adjustment for smoking, only 1,4-dichlorobenzene (1,4-DCB) was associated with reduced pulmonary function. Participants in the highest decile of 1,4-DCB concentration had decrements of -153 mL [95% confidence interval (CI) , -297 to -8] in forced expiratory volume in 1 sec and -346 mL/sec (95% CI, -667 to -24) in maximum mid-expiratory flow rate, compared with participants in the lowest decile. Exposure to 1,4-DCB, a VOC related to the use of air fresheners, toilet bowl deodorants, and mothballs, at levels found in the U.S. general population, may result in reduced pulmonary function. This common exposure may have long-term adverse effects on respiratory health.


Hypoxia Has a Lasting Effect on Fast-Startle Behavior of the Tropical Fish Haemulon plumieri.
Anthropogenic activities and climate change have resulted in an increase of hypoxic conditions in nearshore ecosystems worldwide. Depending on the persistence of a hypoxic event, the survival of aquatic animals can be compromised. Temperate fish exposed to hypoxia display a reduction in the probability of eliciting startle responses thought to be important for escape from predation. Here we examine the effect of hypoxia on the probability of eliciting fast-startle responses (fast-starts) of a tropical fish, the white grunt (Haemulon plumieri), and whether hypoxia has a prolonged impact on behavior once the fish are returned to normoxic conditions. White grunts collected from the San Juan Bay Estuary in Puerto Rico were exposed to an oxygen concentration of 2.5 mg L-1 (40% dissolved oxygen). We found a significant reduction in auditory-evoked fast-starts that lasted for at least 24 hours after fish were returned to normoxic conditions. Accessibility to the neuronal networks that underlie startle responses was an important motivator for this study. Mauthner cells are identifiable neurons found in most fish and amphibians, and these cells are known to initiate fast-starts in teleost fishes. The assumption that most of the short-latency responses in this study are Mauthner cell initiated provided the impetus to characterize the white grunt Mauthner cell. The identification of the cell provides a first step in understanding how low oxygen levels may impact a single cell and its circuit and the behavior it initiates.


Catechol-O-methyltransferase inhibition increases the uptake of 11C-3-(3,4-dihydroxyphenyl)-L-alanine in the rat pancreas.
The objective of the present investigation was to evaluate the uptake and metabolism of 3-(3,4-dihydroxyphenyl-L-alanine) (L-DOPA) in the rat pancreas. The procedure included intravenous injection of the positron-emitting radiotracer L-[beta-11C] DOPA (DOP) into unanaesthetized male Sprague-Dawley rats and evaluation of uptake of radioactivity in organs in animals only given the tracer and in animals given therapeutic doses of three different catechol-O-methyltransferase (COMT) inhibitors, OR-486, OR-611, or Ro 41-0960. Selected pancreati were homogenized, and the chemical form bearing the radioactivity was analysed with high-performance liquid chromatography (HPLC). The main finding was that the tracer uptake in the pancreas increased fourfold when the rats were pretreated with COMT inhibitors. Half maximum effect of OR-486 was found at a dose of 0.2 mg/kg. HPLC analysis showed that with COMT inhibitor, the radioactivity in the pancreas consisted of 90% DOPAC. When administering MAO-A and COMT inhibitor together, the pancreas radioactivity corresponded to dopamine. Also in the pig pancreas a significant increase of DOP was observed after COMT inhibition. This study has shown a high turnover of L-DOPA in the rat pancreas, which can be modulated to give enhanced levels of DOPAC or dopamine by COMT and MAO inhibition.


[Placebo, placebo effect and clinical trials].
Recent studies have begun to unveil some of the biochemical bases of the placebo effect. Thus, while placebo analgesia is related to the release of endogenous opioids, placebo-induced dopamine release leads to motor improvement in Parkinson's disease. A theory proposes that the placebo effect is mediated by the activation of the reward circuitry. These biochemical findings indicate that the placebo effect is real, and suggest that many ethical arguments and controversies regarding the use of placebos should perhaps be reconsidered. While it may be advisable to minimize the placebo effect in clinical trials in order to estimate the pure effect of the active treatment, acting in the patient's best interest may require maximizing the placebo effect in the usual clinical setting.


Light-Induced Nanoscale Deformation in Azobenzene Thin Film Triggers Rapid Intracellular Ca2+ Increase via Mechanosensitive Cation Channels.
Epithelial cells are in continuous dynamic biochemical and physical interaction with their extracellular environment. Ultimately, this interplay guides fundamental physiological processes. In these interactions, cells generate fast local and global transients of Ca2+ ions, which act as key intracellular messengers. However, the mechanical triggers initiating these responses have remained unclear. Light-responsive materials offer intriguing possibilities to dynamically modify the physical niche of the cells. Here, a light-sensitive azobenzene-based glassy material that can be micropatterned with visible light to undergo spatiotemporally controlled deformations is used. Real-time monitoring of consequential rapid intracellular Ca2+ signals reveals that the mechanosensitive cation channel Piezo1 has a major role in generating the Ca2+ transients after nanoscale mechanical deformation of the cell culture substrate. Furthermore, the studies indicate that Piezo1 preferably responds to shear deformation at the cell-material interphase rather than to absolute topographical change of the substrate. Finally, the experimentally verified computational model suggests that Na+ entering alongside Ca2+ through the mechanosensitive cation channels modulates the duration of Ca2+ transients, influencing differently the directly stimulated cells and their neighbors. This highlights the complexity of mechanical signaling in multicellular systems. These results give mechanistic understanding on how cells respond to rapid nanoscale material dynamics and deformations.


Generation of tumor-reactive CTL against the tumor-associated antigen HER2 using retrovirally transduced dendritic cells derived from CD34+ hemopoietic progenitor cells.
Ag-specific CD8+ CTL are crucial for effective tumor rejection. Attempts to treat human malignancies by adoptive transfer of tumor-reactive CTL have been limited due to the difficulty of generating and expanding autologous CTL with defined Ag specificity. The current study examined whether human CTL can be generated against the tumor-associated Ag HER2 using autologous dendritic cells (DC) that had been genetically engineered to express HER2. DC progenitors were expanded by culturing CD34+ hemopoietic progenitor cells in the presence of the designer cytokine HyperIL-6. Proliferating precursor cells were infected by a retroviral vector encoding the HER2 Ag and further differentiated into CD83+ DC expressing high levels of MHC, adhesion, and costimulatory molecules. Retroviral transduction of DC resulted in the expression of the HER2 molecule with a transduction efficiency of 15%. HER2-transduced DC correctly processed and presented the Ag, because HLA-A*0201-positive DC served as targets for CTL recognizing the HLA-A*0201-binding immunodominant peptide HER2(369-377). HER2-transduced DC were used as professional APCs for stimulating autologous T lymphocytes. Following repetitive stimulation, a HER2-specific, HLA-A*0201-restricted CTL line was generated that was capable of lysing HLA-A*0201-matched tumor cells overexpressing HER2. A CD8+ T cell clone could be generated that displayed the same specificity pattern as the parenteral CTL line. The ability to generate and expand HER2-specific, MHC class I-restricted CTL clones using HER2-transduced autologous DC in vitro facilitates the development of adoptive T cell transfer for patients with HER2-overexpressing tumors without the requirement of defining immunogenic peptides.


[Use of tykveol in the treatment of impaired biliary tract function in patients with chronic non-calculous cholecystitis].
The therapeutic efficacy of tykveol was evaluated in 22 patients with chronic non-calculous cholecystitis and/or dyskinesia of the biliary tract (BT) concurrent with gallbladder deformity (GD). Supplementation of tykveol to the combined therapy in the patients with chronic non-calculous cholecystitis concurrent with GD was shown to exert a pronounced therapeutic effect. This caused positive changes in clinical symptoms and BT function, diminished the lithogenic propertes of bile. With the use of tykveol, recovery of neurohumoral regulation is an important factor that improves biliary tract function, as evidenced by decreased gastrin secretion.


Emergence of Neuronal Synchronisation in Coupled Areas.
One of the most fundamental questions in the field of neuroscience is the emergence of synchronous behaviour in the brain, such as phase, anti-phase, and shift-phase synchronisation. In this work, we investigate how the connectivity between brain areas can influence the phase angle and the neuronal synchronisation. To do this, we consider brain areas connected by means of excitatory and inhibitory synapses, in which the neuron dynamics is given by the adaptive exponential integrate-and-fire model. Our simulations suggest that excitatory and inhibitory connections from one area to another play a crucial role in the emergence of these types of synchronisation. Thus, in the case of unidirectional interaction, we observe that the phase angles of the neurons in the receiver area depend on the excitatory and inhibitory synapses which arrive from the sender area. Moreover, when the neurons in the sender area are synchronised, the phase angle variability of the receiver area can be reduced for some conductance values between the areas. For bidirectional interactions, we find that phase and anti-phase synchronisation can emerge due to excitatory and inhibitory connections. We also verify, for a strong inhibitory-to-excitatory interaction, the existence of silent neuronal activities, namely a large number of excitatory neurons that remain in silence for a long time.


Aggression Prevention Training for Individuals With Dementia and Their Caregivers: A Randomized Controlled Trial.
International appeals call for interventions to prevent aggression and other behavioral problems in individuals with dementia (IWD). Aggression Prevention Training (APT), based on intervening in three contributors to development of aggression (IWD pain, IWD depression, and caregiver-IWD relationship problems) aims to reduce incidence of aggression in IWD over 1 year. Randomized, controlled trial. Three clinics that assess, diagnose, and treat dementia. Two hundred twenty-eight caregiver-IWD dyads who screened positive for IWD pain, IWD depression, or caregiver-IWD relationship problems randomized to APT or Enhanced Usual Primary Care (EU-PC). APT, a skills-based intervention delivered over 3 months to address pain/depression/caregiver-IWD relationship issues. EU-PC included printed material on dementia and community resources; and eight brief, weekly support calls. The primary outcome was incidence of aggression over 1 year, determined by the Cohen Mansfield Agitation Inventory-Aggression Subscale. Secondary outcomes included pain, depression, caregiver-IWD relationship, caregiver burden, positive caregiving, behavior problems, and anxiety. Aggression incidence and secondary outcomes did not differ between groups. However, in those screening positive for IWD depression or caregiver-IWD relationship problems, those receiving EU-PC had significant increases in depression and significant decreases in quality of the caregiver-IWD relationship, whereas those receiving APT showed no changes in these outcomes over time. The cost to patients, family, and society of behavioral problems in IWD, along with modest efficacy of most pharmacologic and nonpharmacologic interventions, calls for more study of novel preventive approaches.


Galantamine, a cholinesterase inhibitor that allosterically modulates nicotinic receptors: effects on the course of Alzheimer's disease.
Despite the proven efficacy of acetylcholinesterase inhibitors in Alzheimer's disease, there is a need for new and more effective treatments. Galantamine is a novel treatment for Alzheimer's disease that inhibits acetylcholinesterase and modulates nicotinic receptors. In randomized, double-blind, placebo-controlled studies of up to 6 months duration, galantamine significantly improved cognitive function. Galantamine also had beneficial effects on instrumental and basic activities of daily living, and postponed the progression of behavioral symptoms. Patients who completed one of the 6-month, placebo-controlled studies were eligible to enter a 6-month, open-extension study of the 24-mg/day dose of galantamine. At the end of 12 months, cognitive function and activities of daily living were preserved in those patients who had been treated throughout the study with galantamine 24 mg/day. At 12 months, this group of patients had significantly better cognitive functions than patients who had been treated with a placebo for 6 months before receiving galantamine. These studies indicate that galantamine postpones the progression of symptoms in Alzheimer's disease. Since galantamine shows the greatest benefits when treatment is started early, its long-term benefits may result from an effect on the underlying disease process; such an effect might be mediated by galantamine's concomitant action on nicotinic receptors.


Omalizumab treatment in Samter's triad: case series and review of the literature.
Samter's triad is the combination of asthma, aspirin sensitization, and nasal polyposis. Few data are available on the use of omalizumab in this disease. The study aimed to describe the impact of omalizumab on clinical and functional parameters and the quality of life of a series of patients with Samter's triad. Moreover, we aimed to provide a review of the literature on this topic. We retrospectively described four patients with Samter's triad undergoing omalizumab therapy. Clinical, functional, and immunological data of these patients were collected at baseline and follow-up. Reduction of asthma exacerbations and salbutamol rescue therapy were observed in all patients after anti-IgE treatment together with an improvement in the quality of life. A significant improvement in FEV1, FVC, and FEF25-75 was observed. No major side-effects were observed. A total of 14 studies regarding omalizumab in aspirin-exacerbated respiratory diseases were included in the review, comprising 78 patients. All studies reported a good efficacy in improving asthma control; restoration of aspirin tolerance was repeatedly reported. The results of our case series and review of the literature suggest that omalizumab effectively improves asthma control, lung function tests, and quality of life in patients with Samter's triad.


Multivariate MIMO FIR inverses.
The problem of computing exact finite impulse response (FIR) inverses for multivariate multiple-input multiple-output (MIMO) FIR systems is considered. Necessary and sufficient conditions for invertibility are given, along with computation techniques. Random systems and structured systems are defined. Necessary and sufficient conditions for the almost sure invertibility of structured random systems are derived. Bounds on the orders of the inverse filters are computed.


The physiological effects and quality of chest compressions during CPR at sea level and high altitude.
Rescuers that undergo acute ascent without acclimatization can experience acute mountain sickness. Although performing cardiopulmonary resuscitation (CPR) for a short period requires intensive effort at sea level, performing CPR at high altitude is even more exhausting and can endanger the rescuer. Therefore, we conducted a pilot study to compare the quality of resuscitation in health professionals at high altitude (3100 m) and that at sea level. Thirty-eight participants were asked to performed continuous chest compression CPR (CCC-CPR) for 5 minutes at sea level and at high altitude. Cardiopulmonary resuscitation recording technology was used to objectively quantify the quality of the chest compressions (CCs), including the depth and rate thereof. At high altitude, rescuers showed a statistically significant decrease in blood oxygen saturation and an increase in systolic blood pressure, diastolic blood pressure, heart rate, and fatigue, as measured with the Borg score, after CCC-CPR compared with resting levels. The analysis of the time-dependent deterioration in the quality of CCC-CPR showed that the depth of CCs declined from the mean depth of the first 30 seconds after CCC-CPR to that at more than 120 seconds after CCC-CPR at both sea level and high altitude. The average number of effective CCs declined after CCC-CPR was performed for 1 minute at sea level and high altitude. The quality of CC rapidly declined at high altitude. At high altitude, the average number of effective CC decreases; and this decrease became significant after continuous CCs had been performed for 1 minute.


Crystallization of Amino Acids on a 21-well Circular PMMA Platform using Metal-Assisted and Microwave-Accelerated Evaporative Crystallization.
We describe the design and the use of a circular poly(methyl methacrylate) (PMMA) crystallization platform capable of processing 21 samples in Metal-Assisted and Microwave-Accelerated Evaporative Crystallization (MA-MAEC). The PMMA platforms were modified with silver nanoparticle films (SNFs) to generate a microwave-induced temperature gradient between the solvent and the SNFs due to the marked differences in their physical properties. Since amino acids only chemisorb on to silver on the PMMA platform, SNFs served as selective and heterogeneous nucleation sites for amino acids. Theoretical simulations for electric field and temperature distributions inside a microwave cavity equipped with a PMMA platform were carried out to determine the optimum experimental conditions, i.e., temperature variations and placement of the PMMA platform inside a microwave cavity. In addition, the actual temperature profiles of the amino acid solutions were monitored for the duration of the crystallization experiments carried out at room temperature and during microwave heating. The crystallization of five amino acids (L-threonine, L-histidine, L-leucine, L-serine and L-valine HCl) at room temperature (control experiment) and using MA-MAEC were followed by optical microscopy. The induction time and crystal growth rates for all amino acids were determined. Using MA-MAEC, for all amino acids the induction times were significantly reduced (up to ~8-fold) and the crystal growth rates were increased (up to ~50-fold) as compared to room temperature crystallization, respectively. All crystals were characterized by Raman spectroscopy and powder x-ray diffraction, which demonstrated that the crystal structures of all amino acids grown at room temperature and using MA-MAEC were similar.