Electrocoagulation versus chemical coagulation: coagulation/flocculation mechanisms and resulting floc characteristics.
Electrocoagulation (EC) and chemical coagulation (CC) are employed in water treatment for particle removal. Although both are used for similar purposes, they differ in their dosing method - in EC the coagulant is added by electrolytic oxidation of an appropriate anode material, while in CC dissolution of a chemical coagulant is used. These different methods in fact induce different chemical environments, which should impact coagulation/flocculation mechanisms and subsequent floc formation. Hence, the process implications when choosing which to apply should be significant. This study elucidates differences in coagulation/flocculation mechanisms in EC versus CC and their subsequent effect on floc growth kinetics and structural evolution. A buffered kaolin suspension served as a representative solution that underwent EC and CC by applying aluminum via additive dosing regime in batch mode. In EC an aluminum anode generated the active species while in CC, commercial alum was used. Aluminum equivalent doses were applied, at initial pH values of 5, 6.5 and 8, while samples were taken over pre-determined time intervals, and analyzed for pH, particle size distribution, ζ potential, and structural properties. EC generated fragile flocs, compared to CC, over a wider pH range, at a substantially higher growth rate, that were prone to restructuring and compaction. The results suggest that the flocculation mechanism governing EC in sweep floc conditions is of Diffusion Limited Cluster Aggregation (DCLA) nature, versus a Reaction Limited Cluster Aggregation (RLCA) type in CC. The implications of these differences are discussed.


Fat-body brummer lipase determines survival and cardiac function during starvation in Drosophila melanogaster.
The cross talk between adipose tissue and the heart has an increasing importance for cardiac function under physiological and pathological conditions. This study characterizes the role of fat body lipolysis for cardiac function in Drosophila melanogaster. Perturbation of the function of the key lipolytic enzyme, brummer (bmm), an ortholog of the mammalian ATGL (adipose triglyceride lipase) exclusively in the fly's fat body, protected the heart against starvation-induced dysfunction. We further provide evidence that this protection is caused by the preservation of glycerolipid stores, resulting in a starvation-resistant maintenance of energy supply and adequate cardiac ATP synthesis. Finally, we suggest that alterations of lipolysis are tightly coupled to lipogenic processes, participating in the preservation of lipid energy substrates during starvation. Thus, we identified the inhibition of adipose tissue lipolysis and subsequent energy preservation as a protective mechanism against cardiac dysfunction during catabolic stress.


Trypanosoma cruzi: explant organ cultures from mice with chronic Chagas' disease.
Explants of 13 different organs obtained from C3H/HEN, Swiss-Webster, and C57Bl/6 mice chronically infected with Trypanosoma cruzi (Y strain) were cocultivated with mouse embryo fibroblasts to determine the organs that contain T. cruzi during the chronic infection. Explant cultures frequently yielded T. cruzi as late as 12 months after infection. Spleen and skeletal muscle were most frequently positive; heart cultures were rarely positive in any mouse strain. C3H/HEN mice had significantly more cultures positive than Swiss-Webster mice, as expected from relative susceptibility of C3H/HEN mice to acute infection. In contrast, C57Bl/6 mice, relatively resistant to acute infection, had significantly more cultures positive at 12 months of infection than Swiss-Webster mice. Also, C57Bl/6 mice had a significant increase in the number of positive cultures at 12 months of infection compared to 6 months of infection. These results show that organisms can be recovered routinely from some tissues during the chronic infection, that murine susceptibility to infection should differentiate between acute and chronic infection, and that C57Bl/6 mice may lose control of infection during the chronic infection.


A comparative evaluation of the efficacy between skeletal traction and skin traction in pre-operative management of femur shaft fractures in Korle Bu Teaching Hospital.
This study is to compare the outcomes of pre-operative skeletal and skin traction in adult femoral shaft fractures awaiting surgical fixation within two weeks of presentation to the Accident Center of Korle Bu Teaching Hospital. This study was a clinical trial on 86 recruited patients with closed femoral shaft fractures sustained within 24 hours of presentation grouped into 2 groups. Descriptive and inferential statistics comprising frequency, percentage, Chi-square, independent sample t-test and Mann-Whitney U test were used in analysing the data. Of the total number of patients involved in the study, 74% (n=64) were males and 26% (n=22) were females with a mean age of 39.49 (SD ±15). There was no statistically significant difference in the mean visual analogue scale (VAS) pain assessment between the Skin traction group and Trans-tibia skeletal traction group after traction. With regards to complications, the difference between the Skin traction group and the Skeletal traction group was statistically significant (P=0.001). Moreover, the mean blood loss compared with the open type of reduction in the Transtibia skeletal traction group was significantly less than the Skin traction group (p=0.000). This study has shown that both Skeletal traction and Skin traction were equally effective in controlling pre-operative pain in adult patients with femoral shaft fractures and does not affect intra-operative blood loss and post-operative management. Therefore, pre-operative Skin traction can be considered a useful and cost-effective method of maintaining alignment and pain relief in adult femoral shaft fractures. Personal Funding.


Trends in the incidence of lower limb amputation after implementation of a Multidisciplinary Diabetic Foot Unit.
Incidence of lower extremity amputations (LEA) in the population with and without diabetes mellitus (DM) was assessed after implementation of a Multidisciplinary Diabetic Foot Unit (MDFU) during 2008. Non-traumatic LEA were analyzed, and those performed before (2001-2007) and after (2008-2014) introduction of the MDFU were compared. LEA were grouped by age and sex. Their incidence was expressed as a rate per 100,000 population per year, adjusted to the standard European population. A total of 664 LEA were performed during the 2001-2014 period, 486 (73%) of them in patients with DM. Total LEA incidence was 11.2/105 population in DM versus 3.9/105 in the population without DM. Incidence of major LEA in patients with DM significantly decreased from 6.1/105 population in the 2001-2007 period to 4.5/105 in the 2008-2014 period (p=.03). Joinpoint regression analysis also showed a reduction in the trend of incidence of major LEA in patients with DM, with an annual percentage change of -3.3% [95% CI, -6.2-0.3] (p=.025). No significant differences were found for all other incidences and trends in the diabetic and non-diabetic populations. Implementation of a MDFU has been shown to be associated with a significant reduction in major amputation rate in the diabetic population, although the results are not optimal yet. Both results and work at the MDFU should be improved.


Evidence-based medicine V: how to use in clinical practice.
In this penultimate installment in the educational series on evidence-based medicine, the Research Committee of the European Society of Pediatric Urology will focus on clinical application. In previous communications, optimizing medical decisions was focused on through the use of well-conducted research publications, and the topics of background, hierarchy of evidence, information acquisition, and critical appraisal tools were covered. The goal is to guide the clinician in using evidentiary tools for setting up a clinical question, finding appropriate information, searching appropriate databases, and evaluating the results with the patient in mind.


Prevalence and impact of migraine among university students in Bangladesh: findings from a cross-sectional survey.
Migraine is one of the main causes of long-term morbidity, and it is one of the major contributors of all types of headaches in worldwide. Despite its disruptive effect, it is frequently underdiagnosed and undertreated in Bangladesh. The aim of the present study was to determine the prevalence of migraines and its impact on daily life of university students in Bangladesh. This cross-sectional study was conducted among 2,352 students of Rajshahi University and Jahangirnagar University during March 2020 through a self-administered online survey. ID Migraine™ scale and HIT-6 scale were used to screen migraine and its impact respectively. Frequency distribution, Chi-square test and t-test along with multiple logistic regressions model were used to determine the prevalence and associated factors of migraine respectively. The overall prevalence of migraine among the participants was 21.4%. The prevalence was higher among females (29%) than males (12%). A multivariable logistic regression model provided the following eight risk factors of migraine: (i) gender (p < 0.01), (ii) family income (p < 0.01), (iii) marital status (p < 0.01), (iv) infrequent exercise (p < 0.01), (v) family history of headache (p < 0.01), (vi) high screen time (p < 0.05), (vii) depressive symptoms (p < 0.05) and (viii) anxiety disorder (p < 0.01). More than two-thirds of the people with migraines reported more than five attacks during the past month with moderate to severe intense headache. Stress was the most reported trigger of migraine among university students (71%) followed by irregular sleep (47%), academic pressure (33%), and external noise (28%). Almost 37% of the participants who had migraines reported that headache caused severe impact in their day to day life. The prevalence of migraine among university students of Bangladesh is alarmingly high. Frequent migraine attacks and severe intensity of headache cause a substantial level of impact among the sufferers. Cautious avoidance of the triggering factors through appropriate interventions and prophylactic medication can mitigate the negative impact of migraine as well as improve the quality of life.


A novel peripherin gene (PRPH) mutation identified in one sporadic amyotrophic lateral sclerosis patient.
Motor neurons in amyotrophic lateral sclerosis (ALS) are characterized by the presence of inclusion bodies composed of intermediate filament (IF) proteins. Peripherin protein is as components of these inclusions and rare mutations in peripherin gene (PRPH) were identified in sporadic ALS cases. The aim of this study was to further define the spectrum of PRPH mutations in a cohort of 122 Italian ALS patients. We screened the coding sequence, the exon/intron boundaries, and the 5'-3' un-translated regions (UTRs) in 122 ALS patients. Eighteen sequence variations were detected. Seven variants were not identified in a panel of at least 245 matched controls, including 2 missense variations, namely p.R133P and p.D141Y, each identified in one heterozygous patient. p.R133P was newly identified whereas p.D141Y was previously described in one homozygous sporadic ALS patient. These 2 variants were predicted to have a deleterious effect on protein structure or function. This work contributes to determine the role of PRPH gene variants in ALS. Further studies are necessary to define the mechanisms through which the mutant peripherin could cause ALS phenotype.


Induction of lysophosphatidic acid receptor-3 by 12-O-tetradecanoylphorbol-13-acetate stimulates cell migration of rat liver cells.
12-O-tetradecanoylphorbol-13-acetate (TPA) which is one of tumor promoting agents stimulates cell migration ability of several tumor cells. In the present study, we investigated whether lysophosphatidic acid (LPA) receptors are involved in cell migration of rat liver cells stimulated by TPA. The rat liver epithelial WB-F344 and hepatoma RH7777 cells were treated by TPA for 48h. The expression levels of LPA receptor genes in those cells were measured by real-time reverse transcription (RT)-polymerase chain reaction (PCR) analysis. The expressions of the LPA receptor-3 (Lpar3) gene were significantly elevated in WB-F344 and RH7777 cells treated by TPA, but not Lpar1 and Lpar2 genes. In cell migration assay, TPA treatment showed markedly high cell migration in both cells. The pretreatment with inhibitors of Gi protein suppressed those migration abilities. We next generated the Lpar3 knockdown cells from WB-F344 cells and investigated the effect on cell migration. Interestingly, the cell migration of the knockdown cells was not stimulated by TPA. These results suggest that TPA-stimulated cell migration of rat liver cells may be mainly dependent on the LPA(3)-mediated effect.


Protective effects of anthocyanins on the ectonucleotidase activity in the impairment of memory induced by scopolamine in adult rats.
We investigated whether the treatment with anthocyanins prevents the scopolamine-induced memory deficits and whether ectonucleotidase activities and purine levels are altered in the cerebral cortex (CC) and hippocampus (HC) in this model of mnemonic deficit in rats. The animals were divided into 4 experimental groups: control (vehicle), anthocyanins (Antho), scopolamine (SCO), and scopolamine plus anthocyanins (SCO+Antho). After seven days of treatment, they were tested in the inhibitory avoidance task and open field test and submitted to euthanasia. The CC and the HC were collected for biochemical assays. The effect of treatment with Antho (200 mgkg(-1), i.p.) was investigated in rats trained to a stable level of performance and post-treated with SCO (1 mgkg(-1), i.p. 30 min after training). The treatment with SCO decreased the step-down latency in inhibitory avoidance task. Antho prevented the scopolamine-induced memory impairment and also the increase of NTPDase activity in the CC and HC. Furthermore, the treatment with anthocyanins prevents the decrease in 5'-nucleotidase activity and the increase in adenosine deaminase activity induced by SCO in HC. In addition, the treatment with Antho prevented the decrease in ATP levels induced by SCO in the CC and HC. Our results show that scopolamine may affect purinergic enzymatic cascade or cause alterations in energy metabolism inducing loss of memory. In contrast Antho could reverse these changes, suggesting a neuroprotective effect of Antho on ectonucleotidase activities and neuronal energetic metabolism.


Branched reaction mechanism for the Na/K pump as an alternative explanation for a nonmonotonic current vs. membrane potential response.
Nonmonotonic velocity vs. membrane potential curves are often taken as evidence that two steps involve charge movement through the electric field. However, a branched reaction scheme in which only one step involves charge movement per cycle can lead to a nonmonotonic response. A similar case occurs in enzyme kinetics: nonmonotonic velocity vs. substrate curves are often taken as evidence for two different substrate-binding sites. However, a branched reaction scheme in which only one substrate binds per complete cycle can lead to a nonmonotonic response (see Segel, I.H. 1975, Enzyme Kinetics, pp. 657-659. John Wiley & Sons, New York). Some analytical constraints on the relative sizes of the rate constants of a branched reaction mechanism that give rise to nonmonotonic responses are derived. There are two necessary conditions. (i) The rate of at least one step in the branched pathway must be less than the rate of the step after the branch. (ii) The rate of the pathway in which S binds first must be slower than the rate of the other pathway. Analogous cases give rise to nonmonotonic current vs. membrane potential curves. A branched mechanism for the Na/K pump provides an alternative explanation for a nonmonotonic pump current vs. membrane potential relationship.


Cerebral hemodynamics and metabolism in postoperative cerebral vasospasm and treatment with hypertensive therapy.
A 24-year-old woman developed subarachnoid hemorrhage from an aneurysm at the bifurcation of the right internal carotid artery. Following successful clipping of the aneurysm she developed a left hemiplegia associated with focal cerebral vasospasm, which markedly improved when systemic blood pressure was raised with intravenous dopamine infusion. Regional cerebral blood flow and oxygen utilization were significantly depressed in both cerebral hemispheres, while blood volume was significantly elevated only on the side with vasospasm. Oxygen extraction was significantly elevated in both hemispheres, indicating a generalized impairment in oxygen delivery to the brain.


Characterization of a Chromobacterium haemolyticum population from a natural tropical lake.
To study genetic diversity of Chromobacterium haemolyticum isolates recovered from a natural tropical lake. A set of 31 isolates were recovered from a bacterial freshwater community by conventional plating methods and subjected to genetic and phenotypic characterization. The 16S ribosomal RNA (rRNA) gene phylogeny revealed that the isolates were related most closely with C. haemolyticum. In addition to the molecular data, our isolates exhibited strong β-haemolytic activity, were nonviolacein producers and utilized i-inositol, D-mannitol and D-sorbitol in contrast with the other known chromobacteria. Evaluation of the genetic diversity in the 16S rRNA gene, tRNA intergenic spacers (tDNA) and 16S-23S internal transcribed spacers (ITS) unveiled different levels of genetic heterogeneity in the population, which were also observed with repetitive extragenic palindromic (rep)-PCR genomic fingerprinting using the BOX-AR1 primer. tDNA- and ITS-PCR analyses were partially congruent with the 16S rRNA gene phylogeny. The isolates exhibited high resistance to β-lactamic antibiotics. The population genetic heterogeneity was revealed by 16S rRNA gene sequence, ITS and BOX-PCR analysis. This study provides for the first time an insight into the genetic diversity of phylogenetically close isolates to C. haemolyticum species.


l-glycine and l-glutamic acid protect Pediococcus pentosaceus R1 against oxidative damage induced by hydrogen peroxide.
The effects of l-glycine (Gly) and l-glutamic acid (Glu) on oxidative damage induced by hydrogen peroxide (H2O2) in Pediococcus pentosaceus R1 were investigated. Gly and Glu significantly reduce the production of intracellular reactive oxygen species and the levels of malondialdehyde and carbonylated proteins and concomitantly increase ATP levels in P. pentosaceus R1 under H2O2-induced stress (P < 0.05). Transmission electron microscopy and atomic force microscopy of bacteria under H2O2-induced stress revealed that Gly and Glu suppress bacterial membrane deformation and cell damage. Gly exhibited stronger ferrous ion-chelating ability, whereas Glu has higher radical scavenging activities and reducing power (P < 0.05). The abilities of Gly and Glu to inhibit lipid peroxidation are comparable. Gly and Glu significantly enhance the activities of superoxide dismutase and glutathione peroxidase, respectively, and increase the total antioxidant capacity of bacteria (P < 0.05). These findings indicate that Gly and Glu alleviate H2O2-induced oxidative stress via direct antioxidant effects and increase the activities of bacterial antioxidant enzyme.


Advances in dietary pattern analysis in nutritional epidemiology.
It used to be a common practice in the field of nutritional epidemiology to analyze separate nutrients, foods, or food groups. However, in reality, nutrients and foods are consumed in combination. The introduction of dietary patterns (DP) and their analysis has revolutionized this field, making it possible to take into account the synergistic effects of foods and to account for the complex interaction among nutrients and foods. Three approaches of DP analysis exist: (1) the hypothesis-based approach (based on prior knowledge regarding the current understanding of dietary components and their health relation), (2) the exploratory approach (solely relying on dietary intake data), and (3) the hybrid approach (a combination of both approaches). During the recent past, complementary approaches for DP analysis have emerged both conceptually and methodologically. We have summarized the recent developments that include incorporating the Treelet transformation method as a complementary exploratory approach in a narrative review. Uses, peculiarities, strengths, limitations, and scope of recent developments in DP analysis are outlined. Next, the narrative review gives an overview of the literature that takes into account potential relevant dietary-related factors, specifically the metabolome and the gut microbiome in DP analysis. Then the review deals with the aspect of data processing that is needed prior to DP analysis, particularly when dietary data arise from assessment methods other than the long-established food frequency questionnaire. Lastly, potential opportunities for upcoming DP analysis are summarized in the outlook. Biological factors like the metabolome and the microbiome are crucial to understand diet-disease relationships. Therefore, the inclusion of these factors in DP analysis might provide deeper insights.


A testimony to the history of heart and lung transplantation: English translation of Demikhov's paper, "Transplantation of the Heart, Lungs and other Organs".
Vladimir Petrovich Demikhov, a Soviet physiologist and surgeon, made meticulous attempts at reviving heart and lung transplantation in the last century. Herein, we present an English translation of Demikhov's 1969 paper of Transplantation of the Heart, Lungs and other Organs (published in Eksperimental'naia Khirurgiia i Anesteziologiia), which represented a synopsis of his experiences with experimental transplantation. A brief account of Demikhov's life and contributions to transplant medicine is also given.


The ionization of phenolic amines, including apomorphine, dopamine and catecholamines and an assessment of zwitterion constants.
The dissociation constants of many phenolic amines, including benzylamines, phenethylamines, phenylethanolamines, phenylpropylamines, catecholamines, and apomorphine have been measured by potentiometric titration at 25 degrees C. Measurements have also been made with many of their methoxy derivatives and with series of phenolic quaternary ammonium salts. Some compounds were also studied at 37 degrees C. 2 Usually at least five titrations were made with each compound and Debye--Hückel theory was applied to convert concentrations to activities but the estimates of pKa were not constant and found to increase with increasing concentration. The range studied was usually 5-15 mM and a least-squares line-fit, based on the empirical assumption that pKa varies with (concentration)1/2, has been used to calculate values for 10 mM solutions and to extrapolate to infinite dilution and to 100 mM. The dependence of pKa on concentration was much less at 37 degrees C than at 25 degrees C. 3 At 37 degrees C the pKa values of many biologically interesting compounds in the group, dopamine, noradrenaline, adrenaline and isoprenaline, coryneine (the trimethylammonium derivative of dopamine) and apomorphine are within 1 log unit of physiological pH, indicating the presence of a significant proportion of either the zwitterion or of the uncharged phenolic amine. 4 Zwitterion constants have been estimated from the pKa values of the phenolic amines and those of their methoxy and quaternary trimethylammonium analogues. Zwitterion formation does not appear to be associated with activity at alpha-adrenoceptors and probably not with activity at beta-receptors. The active species seems likely to contain the unionised phenolic group but at dopamine receptors this may be in the uncharged phenolic amine rather than in the phenolic ammonium salt.


Selective adsorption of antiphospholipid and anti-dsDNA autoantibodies on histidine based pseudobioaffinity adsorbent from sera of patients with systemic lupus erythematosus (SLE).
Systemic lupus erythematosus (SLE) is an autoimmune diseases characterized by the presence of antiphospholipid and anti-dsDNA autoantibodies in the sera of patients. These autoantibodies and their subclasses have received increasing attention by medical community due to their association with recurrent venous thrombosis, fetal loss and thrombocytopenia. In particular, attention has been paid to IgG subclasses in SLE. The biological and functional properties together with the subclass distribution might therefore influence the course of SLE. The separation and elimination of these autoantibodies from sera of patients can be effective in clinical therapy. In the present study, histidine based pseudobioaffinity adsorbents have been used for the selective adsorption and separation of anti-double stranded DNA (anti-dsDNA), anticardiolipin (aCL) and anti-β2-glycoprotein-I (anti-β2-GPI) antibodies from sera of patients with SLE. For this purpose histidine acting as a pseudobiospecific ligand has been coupled to bisoxirane activated sepharose CL-6B for the adsorption and separation of these autoantibodies. The removal of autoantibodies was carried out under gentle adsorption and elution chromatographic conditions at pH values 7.0 and 8.0. Autoantibodies isotypes and subclasses distribution in the separated fractions were studied by enzyme-linked immune-sorbent assay. The obtained results showed that the separated anticardiolipin and anti-β2-glycoprotein-I autoantibodies belong to IgG1, IgG2 and IgG3subclasses, while those of anti-dsDNA belong to IgM isotype and were shown to have a DNA hydrolyzing activity that hydrolyzes plasmid DNA. The results also indicate a total IgM and IgG recovery superior to 90% of the fraction loaded at pH 7.4 and pH 8.0 respectively.


Anesthetic Management of Children and Adolescents With Giant Axonal Neuropathy: A Large Case Series.
Giant axonal neuropathy (GAN) is a rare autosomal recessive neurodegenerative disorder caused by mutations in the GAN gene, which encodes for gigaxonin, a protein involved in intermediate filament processing in neural cells and fibroblasts. We report on 14 GAN patients who underwent 77 anesthetics during the conduct of an intrathecal gene transfer clinical trial from April 2015 to August 2020. We observed only a few nonsignificant perianesthetic complications. Our data expand the knowledge regarding safety of anesthesia for patients with this rare and potentially fatal disease and highlights the tolerability of shorter procedural sedation and anesthesia.


Murine mesenchymal and embryonic stem cells express a similar Hox gene profile.
Using degenerate oligonucleotide primers targeting the homeobox domain, we amplified by PCR and sequenced 723 clones from five murine cell populations and lines derived from embryonic mesoderm and adult bone marrow. Transcripts from all four vertebrate Hox clusters were expressed by the different populations. Hierarchical clustering of the data revealed that mesenchymal stem cells (MSCs) and the embryonic stem (ES) cell line D3 shared a similar Hox expression profile. These populations exclusively expressed Hoxb2, Hoxb5, Hoxb7, and Hoxc4, transcripts regulating self-renewal and differentiation of other stem cells. Additionally, Hoxa7 transcript quantified by real-time PCR strongly correlated (r2=0.89) with the number of Hoxa7 clones identified by sequencing, validating that data from the PCR screen reflects differences in Hox mRNA abundance between populations. This is the first study to catalogue Hox transcripts in murine MSCs and by comparative analyses identify specific Hox genes that may contribute to their stem cell character.


Oxidative degradations of reactive blue 4 dye by different advanced oxidation methods.
The degradations of an anthraquinone dye, the reactive blue 4 (RB4), were studied by wet air oxidation (WAO), wet peroxide oxidation (WPO), photocatalytic oxidation, and electro-Fenton (EF) advanced oxidation. The RB4 oxidation was evaluated by the decrease in total organic carbon (TOC) content and concentration. The most efficient method for mineralization of RB4 was WPO, but in all methods TOC removal efficiency was above 75% after 60 min of treatment.


The influence of implant design on accuracy of postoperative refraction.
To assess the degree of accuracy of postoperative refraction that may be achieved with modern techniques and a new lens of modern design. Five hundred eyes underwent refraction at one week and one month following phacoemulsification and implantation of the Centerflex lens (Rayner Intraocular Lenses Ltd style 570H). Results were compared with the target that had been computerised at the time of surgery, using the Hoffer Q formula for axial lengths less than 22.0 mm, the SRK-T for lengths greater than 24.5 mm and a mean of the two formulae for lengths between 22.0 and 24.5 mm. Statistical analysis used Fisher's exact and one way ANOVA tests. At one month 97% of refractions were within 1.0 D spherical equivalent (SE) of target and 81% within 0.5 SE. The mean absolute error was 0.37 +/- 0.39 SD. 75.8% of all eyes achieved 6/12 unaided and 88.6% achieved 6/9 with correction. In only 1.2% the refraction between one week and one month had altered by 0.5 D or more. The Centerflex when combined with modern methods of power calculation, can be associated with a high degree of accuracy in postoperative refraction.


The association of HDL cholesterol concentration with the -629C>A CETP promoter polymorphism is not fully explained by its relationship with plasma cholesteryl ester transfer.
HDL cholesterol is associated with the -629C>A cholesteryl ester transfer protein (CETP) promoter polymorphism. This relationship may in part be explained via effects on plasma cholesteryl ester transfer (CET), which reflects the activity of CETP in the context of endogenous lipoproteins, but also via CET independent pathways involved in HDL metabolism. In this study, we determined the contributions of the CETP -629 C>A genotype, plasma CETP mass and cholesteryl ester transfer to HDL cholesterol. The -629 C>A CETP gene promoter polymorphism, plasma CETP mass, CET, HDL cholesterol, lipids and apolipoprotein (apo) A-I were measured in 220 non-diabetic men without cardiovascular disease. Plasma CETP mass (p<0.001) and CET (p<0.001) were higher, whereas HDL cholesterol (p<0.05) and plasma apo A-I levels (p<0.05) were lower in CC compared to AA carriers. Univariate regression analysis showed that plasma CET was related to the CETP genotype (p = 0.004), plasma CETP mass (p<0.001) and triglycerides (p<0.001). In a multiple linear regression model, HDL cholesterol was related to CETP genotype (p = 0.04) and plasma triglycerides (p<0.001) without independent contributions of plasma CETP mass and CET (p>0.20 for both). This study suggests that, despite a relationship between a common CETP gene variation and plasma cholesteryl ester transfer, the association between CETP gene and HDL cholesterol appears to be at least in part unexplained by the plasma cholesteryl ester transfer process.


Stabilization of bromthymol blue colour in lecithin-sphingomyelin ratio determinations in amniotic fluid.
Amniotic fluid lecithin and sphingomyelin areas after extraction and chromatography are rendered permanently visible by the use of bromthymol blue dye buffered to a pH of 11-3.


Co-Administration of Multiple Childhood Vaccines - Guangdong Province, 2019.
What is already known about this topic? The Co-Administration of Multiple Vaccines were implemented in many countries and have been shown to significantly reduce many times of visiting the vaccination clinic. What is added by this report? It is the first time to calculate the cost of visiting vaccination clinic from transportation and work-absence for children's families in Guangdong. What are the implications for public health practice? We demonstrated the importance of Co-Administration of Multiple Vaccines that reduce the vaccination cost of children's families. The policy should be promoted as soon as possible.


Evaluation of aortocoronary venous bypass grafting for prevention of cardiac arrhythmias.
The influence of ACB on cardiac arrhythmias was examined in 27 patients. Eight-hour Holter monitoring was performed 8 days preoperatively and 100 days postoperatively. Arrhythmias were divided into 3 groups (Class I: NSR +/- occasional APBs; Class II: less than five unifocal VPBs per minute; Class II: more than five VPBs per minute, multifocal VPBs, VPBs in a row or VT). Preoperative classification disclosed that 13 patients (48.1 per cent) were in Class I, six patients (22.2 per cent) were in Class II, and eight patients (29.6 per cent) were in Class III. The corresponding values after surgery were 10 patients (37.0 per cent), 13 patients (48.1 per cent), and four patients (14.8 per cent). These differences were not statistically significant (p less than 0.1). In view of the tendency of arrhythmias of Class III to improve after ACB, we feel that further investigations in this area are needed. At the present time ventricular arrhythmias alone constitute no indication for bypass surgery.


Simulations of arterial pressure pulses using a transmission line model.
Transmission of pressure pulses from the aorta to the central retinal artery is studied under normal and stenotic conditions. A convenient model for the study is obtained by replacing the arteries with a network of distributed electrical transmission lines. By using boundary conditions and a voltage-pressure analogy, the transmitted pulse is obtained. Stenosis of varying degrees were simulated at different locations and the characteristics of the transmitted pulse was studied by examining its peak value, the dicrotic notch and the systolic slope. The dependence of the characteristics of the transmitted pulse on the physical parameters were also studied.


Promiscuous honey bee queens increase colony productivity by suppressing worker selfishness.
Queen monogamy is ancestral among bees, ants, and wasps (Order Hymenoptera), and the close relatedness that it generates within colonies is considered key for the evolution of eusociality in these lineages. Paradoxically, queens of several eusocial species are extremely promiscuous, a derived behavior that decreases relatedness among workers and fitness gained from rearing siblings but benefits queens by enhancing colony productivity and inducing workers to rear queens' sons instead of less related worker-derived males. Selection for promiscuity would be especially strong if productivity in a singly inseminated queen's colony declined because selfish workers invested in personal reproduction at the expense of performing tasks that contribute to colony productivity. We show in honey bees that workers' ovaries are more developed when queens are singly rather than multiply inseminated and that increasing ovary activation is coupled with reductions in task performance by workers and colony-wide rates of foraging and waggle-dance recruitment. Increased investment in reproductive physiology by selfish workers might result from greater incentive for them to favor worker-derived males or because low mating frequency signals a queen's diminished quality or future fecundity. Either possibility fosters selection for queen promiscuity, revealing a novel benefit of it for eusocial insects.


Long-Term Benefits of Tailored Exercise in Severe Sarcoidosis: A Case Report.
We studied the effects of a supervised, structured exercise program in a severe sarcoidosis patient. After being clinically stable for two years, a 52-year-old woman (stage IV, American Thoracic Society) who originally had irreversible lung fibrosis, pulmonary arterial hypertension (PAH), mild mitral insufficiency, and atrial dilatation, and was candidate for lung transplant, performed a combined high-intensity interval, high load resistance, and inspiratory muscle training for 4.5 years, and was tested (cardiopulmonary exercise testing and dual X-ray absorptiometry) every six months. Cardiorespiratory fitness (CRF) and maximal pulmonary ventilation increased by 44% and 60%, respectively. Ventilatory efficiency also improved (decrease in the ventilatory equivalent for oxygen by 32% and 14% at the ventilatory threshold and respiratory compensation point, respectively). She improved New York Heart Association (NYHA) class (from III to II), and cardiac alterations as well as PAH reversed so that she was not in need of lung transplantation anymore. Likewise, she suffered no more episodes of hemoptysis. Bone health was overall maintained despite the post-menopausal status and the corticoid treatment. A long-term combined exercise intervention safely contributed-at least partly-to improve CRF and NYHA class in a patient with severe sarcoidosis, suggesting a potential coadjuvant effect to attenuate clinical manifestations.


Physiological concentration of calcium inhibits elastase-induced cleavage of a functional recombinant fragment of surfactant protein D.
Surfactant protein D (SP-D) plays an important role in lung host defence. SP-D levels have been shown to be depleted in cystic fibrosis (CF) patients. A recombinant fragment of the human SP-D (rfhSP-D) which consist of a hydrophobic neck and a CRD has been shown to be active in vivo and partially reverses the symptoms of the SP-D deficiency in the lungs when administered to SP-D knock-out mice. In this paper we studied the in vitro effect of different proteolytic enzymes commonly found in CF patients lungs, such as neutrophil elastase, cathepsin G and protease 3 as well as Pseudomonas elastase, on rfhSP-D. It was also shown that cleavage was inhibited by physiological concentration of calcium. When Western blot was compared with ELISA, we show that an anti-SP-D ELISA is a not a reliable assay of functional SP-D levels since non-functional fragments of SP-D are also detected. Thus, ELISA cannot be used as a reliable "diagnostic" tool for SP-D deficiency. Finally, we observe that SP-D is not cleaved in control patients but is degraded in about half the samples from cystic fibrosis patients, indicating that degradation of endogenous SP-D, by enzymes present in CF bronchioalveolar lavage fluid (BALF), may lead to deficiency of the protein as seen in CF and therefore rfhSP-D may be a useful future therapy.


Effect of supplementing pomegranate peel infusion on body growth, feed efficiency, biochemical metabolites and antioxidant status of broiler chicken.
Pomegranate fruit peel is a great source of natural polyphenols. The objective of the present study was to evaluate efficacy of pomegranate peel infusion (PPI) on growth characteristics, feed efficiency, blood metabolites and antioxidant profile of broiler chicken. A total of 200 broiler chickens were randomly assigned to 4 treatments with 5 replicates of 10 birds. Pomegranate peel infusion was supplemented in drinking water to 3 treatment groups in a graded dose. At the end of the trial (42 days), 2 broiler chickens from each pen were sampled for serum and liver tissue. Results revealed that low-dose (50 mL/L) PPI influenced (L: P < 0.001) final body weight, daily body weight gain, and feed conversion ratio. Quadratic effect (Q: P < 0.001) was found in overall body weight, average daily gain in body weight, and average daily feed intake. It was also observed that PPI had significant (L: P < 0.05) hypo-lipidaemic effect. PPI supplementation reduced (L: P < 0.01) lipid peroxidation in all supplemented birds. Reduced glutathione and catalase in the liver tissue was also increased linearly (L: P < 0.05) by PPI supplementation, suggesting that natural polyphenols present in the PPI can stimulate antioxidant defence system. Thus, it could be concluded that low-dose supplementation of pomegranate peel infusion could be of great benefits in broiler chickens as a source of natural antioxidants.


Comparative evaluation of 2-isopropyl-3-methoxypyrazine, 2-isobutyl-3-methoxypyrazine, and 2,4,6-trichloroanisole degradation by ultraviolet/chlorine and ultraviolet/hydrogen peroxide processes.
2-Isopropyl-3-methoxypyrazine (IPMP), 2-Isobutyl-3-methoxypyrazine (IBMP), and 2,4,6-Trichloroanisole (TCA) are the primary emerging taste and odor (T&O) compounds in water systems with low thresholds (ng L-1). The selected T&O compounds are known to be difficult to remove using conventional water treatment processes. In this study, we compared the removal characteristics of the three T&O compounds using UV/Cl2 and UV/H2O2. The removal rates of the three compounds by direct photolysis at 254 nm were less than 10%, even at a high UV dose (approximately 1000 mJ cm-2). Under conditions of an oxidant injection volume of 5 mg L-1 and UV dose of 1000 mJ cm-2, the degradation rate of the target compounds in the UV/H2O2 process exceeded that of the UV/Cl2 process. Moreover, the results revealed that pH has a significant impact on the removal of the T&O compounds during the UV/Cl2 process. The IPMP, IBMP, and TCA were found to be more reactive with hydroxyl radicals than reactive chlorine species (RCS). A predictive tool was developed to determine the optimal operating condition using the generalized reduced gradient (GRG) nonlinear solver. In the UV/H2O2 process, the EED value for 90% removing rate was 0.156 kWh m-3 for the IPMP, 0.135 kWh m-3 for the IBMP, and 0.154 kWh m-3 for the TCA, respectively. In case of the UV/Cl2, the EED value for 50% removing rate was 0.174 kWh m-3 for the IPMP, 0.138 kWh m-3 for the IBMP, and 0.169 kWh m-3 for the TCA, respectively.


Preparation of site-specifically labeled fluorinated proteins for 19F-NMR structural characterization.
A straightforward protocol for the site-specific incorporation of a 19F label into any protein in vivo is described. This is done using a plasmid containing an orthogonal aminoacyl-tRNA synthetase/tRNA(CUA) that incorporates L-4-trifluoromethylphenylalanine in response to the amber codon UAG. This method improves on other in vivo methods because the 19F label is incorporated into only one location on the protein of interest and that protein can easily be produced in large quantities at low cost. The protocol for producing 19F-labeled protein is similar to expressing protein in Escherichia coli and takes 4 d to obtain pure protein starting from the appropriate vectors.


Complexation between rice starch and cellulose nanocrystal from black tea residues: Gelatinization properties and digestibility in vitro.
In this work, cellulose nanocrystal (CNC) was extracted from black tea waste and its effects on the physicochemical properties of rice starch were explored. It was revealed that CNC improved the viscosity of starch during pasting and inhibited its short-term retrogradation. The addition of CNC changed the gelatinization enthalpy and improved the shear resistance, viscoelasticity, and short-range ordering of starch paste, which meant that CNC made the starch paste system more stable. The interaction of CNC with starch was analyzed using quantum chemistry methods, and it was demonstrated that the hydrogen bonds were formed between starch molecules and the hydroxyl groups of CNC. In addition, the digestibility of starch gels containing CNC was significantly decreased because CNC could dissociate and act as an inhibitor of amylase. This study further expanded the understanding of the interactions between CNC and starch during processing, which could provide a reference for the application of CNC in starch-based foods and the development of functional foods with a low glycemic index.


ELISA for diagnosis of ocular toxocariasis.
The enzyme-linked immunosorbed assay test was positive in 37 of 41 patients (90%) suspected of having clinical Toxocara infections. The antigen used in this test is prepared from the Toxocara egg and is felt to be extremely specific in making the diagnosis. The prevalence of Toxocara infection is much greater than previously believed. It is hoped that this test will help the surgeon fell more secure in not enucleating eyes containing masses suggestive of Toxocara infection.


Social robots and therapeutic adherence: A new challenge in pediatric asthma?
Social Robots are used in different contexts and, in healthcare, they are better known as Socially Assistive Robots. In the context of asthma, the use of Socially Assistive Robots has the potential to increase motivation and engagement to treatment. Other positive roles proposed for Socially Assistive Robots are to provide education, training regarding treatments, and feedback to patients. This review evaluates emerging interventions for improving treatment adherence in pediatric asthma, focusing on the possible future role of social robots in the clinical practice.


Ethical Considerations of Wearable Technologies in Human Research.
Wearable technologies hold great promise for disease diagnosis and patient care. Despite the flourishing research activities in this field, only a handful of wearable devices are commercialized and cleared for medical usage. The successful translation of current proof-of-concept prototypes requires extensive in-human testing. There is a lag between current standards and operation protocols to guide the responsible and ethical conduct of researchers in such in-human studies and the rapid development of the field. This essay presents relevant ethical concerns in early-stage human research from a researcher's perspective.


Antiarrhythmic and electrophysiological effects in-vivo of the major metabolite of Org 7797 found in canine and rodent liver homogenate preparations.
Org 20781, the major metabolite of Org 7797 found in in-vitro experiments was examined for antiarrhythmic and electrophysiological effects in-vivo. Org 20781 (0.5-2.0mg kg-1, i.v.) inhibited the development of early ischaemia-induced arrhythmias in rats, suppressed spontaneous ventricular tachycardia (VT) in conscious dogs with 24-h old infarcts, and prevented electrical induction of VT in dogs with 5-6 day old infarcts, actions associated with slowing of conduction at all levels of the myocardium. Cardiac refractory periods were only modestly prolonged whilst repolarization was unchanged. Peak plasma levels of the parent compound (infused to total doses of 2-4 mg kg-1) associated with suppression of late arrhythmias were 6-18 microM, whilst the mean plasma elimination half-life (in normal dogs) was 107 min. It was concluded that the major metabolite has a similar antiarrhythmic and electrophysiological profile to the parent compound, is at least half as potent and may contribute to the therapeutic effects of Org 7797 administration.


Enhanced firing of locus coeruleus neurons and SK channel dysfunction are conserved in distinct models of prodromal Parkinson's disease.
Parkinson's disease (PD) is clinically defined by the presence of the cardinal motor symptoms, which are associated with a loss of dopaminergic nigrostriatal neurons in the substantia nigra pars compacta (SNpc). While SNpc neurons serve as the prototypical cell-type to study cellular vulnerability in PD, there is an unmet need to extent our efforts to other neurons at risk. The noradrenergic locus coeruleus (LC) represents one of the first brain structures affected in Parkinson's disease (PD) and plays not only a crucial role for the evolving non-motor symptomatology, but it is also believed to contribute to disease progression by efferent noradrenergic deficiency. Therefore, we sought to characterize the electrophysiological properties of LC neurons in two distinct PD models: (1) in an in vivo mouse model of focal α-synuclein overexpression; and (2) in an in vitro rotenone-induced PD model. Despite the fundamental differences of these two PD models, α-synuclein overexpression as well as rotenone exposure led to an accelerated autonomous pacemaker frequency of LC neurons, accompanied by severe alterations of the afterhyperpolarization amplitude. On the mechanistic side, we suggest that Ca2+-activated K+ (SK) channels are mediators of the increased LC neuronal excitability, as pharmacological activation of these channels is sufficient to prevent increased LC pacemaking and subsequent neuronal loss in the LC following in vitro rotenone exposure. These findings suggest a role of SK channels in PD by linking α-synuclein- and rotenone-induced changes in LC firing rate to SK channel dysfunction.


Recent Advances in KEAP1/NRF2-Targeting Strategies by Phytochemical Antioxidants, Nanoparticles, and Biocompatible Scaffolds for the Treatment of Diabetic Cardiovascular Complications.
Significance: Modulation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-mediated antioxidant response is a key aspect in the onset of diabetes-related cardiovascular complications. With this review, we provide an overview of the recent advances made in the development of Nrf2-targeting strategies for the treatment of diabetes, with particular attention toward the activation of Nrf2 by natural antioxidant compounds, nanoparticles, and oxidative stress-modulating biocompatible scaffolds. Recent Advances: In the past 30 years, studies addressing the use of antioxidant therapies to treat diabetes have grown exponentially, showing promising but yet inconclusive results. Animal studies and clinical trials on the Nrf2 pathway have shown promising results, suggesting that its activation can delay or reverse some of the cardiovascular impairments in diabetes. Critical Issues: Hyperglycemia- and oscillating glucose levels-induced reactive oxygen species (ROS) accumulation is progressively emerging as a central factor in the onset and progression of diabetes-related cardiovascular complications, including endothelial dysfunction, retinopathy, heart failure, stroke, critical limb ischemia, ulcers, and delayed wound healing. In this context, accumulating evidence suggests a central role for Nrf2-mediated antioxidant response, one of the most studied cellular defensive mechanisms against ROS accumulation. Future Directions: Innovative approaches such as tissue engineering and nanotechnology are converging toward targeting oxidative stress in diabetes. Antioxid. Redox Signal. 36, 707-728.


Reward Processing Deficits During a Spatial Attention Task in Patients With ADHD: An fMRI Study.
In this study, we aimed to explore how cues signaling rewards and feedbacks about rewards are processed in ADHD. Inside the scanner, 16 healthy children and 19 children with ADHD completed a spatial attention paradigm where cues informed about the availability of reward and feedbacks were provided about the earned reward. In ventral anterior thalamus (VA), the controls exhibited greater activation in response to reward-predicting cues, as compared with no-reward cues, whereby in the ADHD group, the reverse pattern was observed (nonreward > reward). For feedbacks; absence of rewards produced greater activation than presence in the left caudate and frontal eye field for the control group, whereas for the ADHD group, the reverse pattern was again observed (reward > nonreward). The present findings indicate that ADHD is associated with difficulty integrating reward contingency information with the orienting and regulatory phases of attention.


Widening the boundaries of the production effect.
Words that are read aloud are more memorable than words that are read silently. The boundaries of this production effect (MacLeod, Gopie, Hourihan, Neary, & Ozubko, Journal of experimental psychology: learning, memory, and cognition, 36, 671-685, 2010) have been found to extend beyond speech. MacLeod and colleagues demonstrated that mouthing also facilitates memory, leading them to speculate that any distinct, item-specific response should result in a production effect. In experiment 1, we found support for this conjecture: Relative to silent reading, three unique productions-spelling, writing, and typing-all boosted explicit memory. In experiment 2, we tested the sensitivity of the production effect. Although mouthing, writing, and whispering all improved explicit memory when compared to silent reading, these other production modalities were not as beneficial as speech. We argue that the enhanced distinctiveness of speech relative to other productions-and of other productions relative to silent reading-underlies this pattern of results.


Acute Pain Predictors of Remote Postoperative Pain Resolution After Hand Surgery.
Chronic postsurgical pain (CPSP) is a global issue with high prevalence. This study compared acute pain descriptors among patients undergoing carpal tunnel release (CTR) or trigger finger release (TFR). We hypothesized worst pain intensity on postoperative day (POD) 10 would be best to predict the time to pain resolution. In this secondary analysis of a negative, randomized, double-blind placebo-controlled trial, adult veterans undergoing CTR or TFR were enrolled January 2012-January 2014, with data analysis February 2020-October 2020. Participants were randomized to receive minocycline 200 mg or placebo 2 h prior to the operation, then minocycline 100 mg or placebo twice daily for 5 days. The Brief Pain Inventory, assessed daily, captured three pain scores: average and worst pain over the past 24 h, and current pain intensity. Fifteen acute pain descriptors based on the pain scores (clusters, mean, median, pain scores on POD 10, and linear slopes) were compared as predictors of time to pain resolution. Of 131 randomized participants, 114 (83 CTR, 31 TFR) were included. Average pain over the last 24 h reported on POD 10 best predicted time to pain cessation. Every one-point increase in the average pain score was associated with a 36.0% reduced rate of pain cessation (HR, 0.64, 95% CI 0.55-0.74, p < 0.001). Average pain on POD 10 was significantly associated with the development of CPSP at 90 days (OR 1.74, 95% CI 1.30-2.33, p value < 0.001). The optimal cutoff score for the high-risk group was determined as average pain on POD 10 ≥ 3. This study validates prior work and demonstrates the importance of assessing pain severity on POD 10 to identify patients at high risk for CPSP who are most likely to benefit from early pain intervention. Future research in diverse surgical cohorts is needed to further validate pain assessment on POD 10 as a significant predictor of CPSP.


Radiologic assessment of femoral and tibial tunnel placement based on anatomic landmarks in arthroscopic single bundle anterior cruciate ligament reconstruction.
Accurate tibial and femoral tunnel placement has a significant effect on outcomes after anterior cruciate ligament reconstruction (ACLR). Postoperative radiographs provide a reliable and valid way for the assessment of anatomical tunnel placement after ACLR. The aim of this study was to examine the radiographic location of tibial and femoral tunnels in patients who underwent arthroscopic ACLR using anatomic landmarks. Patients who underwent arthroscopic ACLR from January 2014 to March 2016 were included in this retrospective cohort study. 45 patients who underwent arthroscopic ACLR, postoperative radiographs were studied. Femoral and tibial tunnel positions on sagittal and coronal radiographic views, graft impingement, and femoral roof angle were measured. Radiological parameters were summarized as mean ± standard deviation and proportions as applicable. Interobserver agreement was measured using intraclass correlation coefficient. The position of the tibial tunnel was found to be at an average of 35.1% ± 7.4% posterior from the anterior edge of the tibia. The femoral tunnel was found at an average of 30% ± 1% anterior to the posterior femoral cortex along the Blumensaat's line. Radiographic impingement was found in 34% of the patients. The roof angle averaged 34.3° ± 4.3°. The position of the tibial tunnel was found at an average of 44.16% ± 3.98% from the medial edge of the tibial plateau. The coronal tibial tunnel angle averaged 67.5° ± 8.9°. The coronal angle of the femoral tunnel averaged 41.9° ± 8.5°. The femoral and tibial tunnel placements correlated well with anatomic landmarks except for radiographic impingement which was present in 34% of the patients.


TRPV1 drugs alter core body temperature via central projections of primary afferent sensory neurons.
TRPV1, a capsaicin- and heat-activated ion channel, is expressed by peripheral nociceptors and has been implicated in various inflammatory and neuropathic pain conditions. Although pharmacological modulation of TRPV1 has attracted therapeutic interest, many TRPV1 agonists and antagonists produce thermomodulatory side effects in animal models and human clinical trials, limiting their utility. These on-target effects may result from the perturbation of TRPV1 receptors on nociceptors, which transduce signals to central thermoregulatory circuits and release proinflammatory factors from their peripheral terminals, most notably the potent vasodilative neuropeptide, calcitonin gene-related peptide (CGRP). Alternatively, these body temperature effects may originate from the modulation of TRPV1 on vascular smooth muscle cells (vSMCs), where channel activation promotes arteriole constriction. Here, we ask which of these pathways is most responsible for the body temperature perturbations elicited by TRPV1 drugs in vivo. We address this question by selectively eliminating TRPV1 expression in sensory neurons or vSMCs and show that only the former abrogates agonist-induced hypothermia and antagonist-induced hyperthermia. Furthermore, lesioning the central projections of TRPV1-positive sensory nerve fibers also abrogates drug-mediated thermomodulation, whereas eliminating CGRP has no effect. Thus, TRPV1 drugs alter core body temperature by modulating sensory input to the central nervous system, rather than through peripheral actions on the vasculature. These findings suggest how mechanistically distinct TRPV1 antagonists may diminish inflammatory pain without affecting core body temperature.


Influence of antiresorptive/antiangiogenic therapy on the extension of experimentally induced peri-implantitis lesions.
To investigate the extension of experimentally induced peri-implantitis lesions under various antiresorptive and antiangiogenic medications. Fourty-eight albino rats had randomly received the following medications (dual application, n = 8 each): (1) amino-bisphosphonate (zoledronate) (Zo), (2) RANKL inhibitor (denosumab) (De), (3) antiangiogenic (bevacizumab) (Be), (4) Zo+Be, (5) De+Be, or (6) no medication (Co). Ligature- and lipopolysaccharide-induced peri-implantitis lesions were established at 2 maxillary implants over a period of 16 weeks. Histological (e.g., apical extension and surface area of the inflammatory cell infiltrate-aICT, ICT; defect length; defect width; CD68 positive cells) and bone micromorphometric (μCT) outcomes were assessed. The animal was defined as a statistical unit. A total of n = 38 animals (Zo = 6, De = 6, Be = 8, Zo + Be = 6, De + Be = 5, Co = 7) were analyzed. ICT's were commonly marked by a positive CD68 antigen reactivity. Comparable median aICT (lowest-Zo: 0.53 mm; highest-Be: 1.22 mm), ICT (lowest-De + Be: 0.00 mm2; highest-Co: 0.49 mm2), defect length (lowest-Zo: 0.90 mm; highest-Co: 1.93 mm) and defect width (lowest-De+Be: 1.27 mm; highest-Be: 1.80 mm) values were noted in all test and control groups. Within an inner (diameter: 0.8 mm) cylindric volume of interest, the bone microstructure did not significantly differ between groups. The present analysis did not reveal any marked effects of various antiresorptive/ antiangiogenic medications on the extension of experimentally induced peri-implantitis lesions. The extension of peri-implantitis lesions may not be facilitated by the antiresorptive and antiangiogenic medications investigated.


Experience with a questionnaire administered by emergency medical service for pre-hospital identification of patients with acute stroke.
We prospectively verified whether an ad-hoc questionnaire administered by phone supports pre-hospital suspicion of stroke in order to reduce the time before care is given. From June 1996 to May 1997, physicians of the Emergency Medical Service in the area of Bergamo, Italy asked all people calling for a patient with symptoms and signs suggesting a cerebral vascular injury to immediately answer some questions on common symptoms and signs of stroke. The medical records of the patients hospitalized at Ospedali Riuniti of Bergamo were reviewed at the end of the study by a single neurologist, skilled in stroke management and blinded to the questionnaires. Sensitivity and specificity, in addition to positive and negative predictive values, of single questions versus final diagnosis were assessed. Logistic regression analysis was also performed to identify those questions useful to suspect strokes. We collected 143 valid questionnaires, related to 63 men and 80 women, aged 34-99 years (mean, 71.8 years). The question concerning headache had the lowest sensitivity and specificity, respectively 57.1% and 36.5%, and the question concerning leg palsy had the highest sensitivity and specificity, respectively 82.0% and 52.4%. Multivariate analysis identified questions on facial and leg palsy as independent predictors of a final diagnosis of stroke. A few questions on motor deficits proposed by emergency medical service operators may be useful in the pre-hospital identification of stroke patients. Concordance of any questions versus final diagnosis of stroke was, however, far to be satisfying. Thus, our experience supports the need for an educational program to improve the efficiency of a pre-hospital diagnosis of stroke.


Characterization of somatostatin receptor subtypes mediating inhibition of nutrient-stimulated gastric acid and gastrin in dogs.
Five somatostatin receptor subtypes (SSTR) have been cloned and characterized in various tissues, including the gastrointestinal tract. This study examined which receptor subtypes mediate the inhibitory actions of somatostatin on gastric acid secretion and gastrin release in conscious dogs. Peptide agonists with relatively high specificity for SSTR1-5 (somatostatin-14), SSTR2 (MK-678), SSTR3 (L-362823), and SSTR5 (L-362855) were infused i.v. after nutrient-stimulated gastric acid secretion and gastrin release with intraduodenal perfusions of 8% peptone and after secretagogue-stimulated acid secretion with gastrin (75 pmol kg-1 h-1) or histamine (20 micrograms kg-1 h-1). At 1000 pmol kg-1 h-1, the SSTR2 agonist inhibited peptone-stimulated acid output to baseline (P < 0.001), whereas the SSTR3 agonist decreased acid output by 58 +/- 6% (P < 0.01): the SSTR5 agonist was without effect. The SSTR2 agonist at 100 pmol kg-1 h-1 also abolished the rise of plasma gastrin. At 50 pmol kg-1 h-1 i.v. infusions of S-14, to simulate circulating S-14 rises after nutrients, decreased peptone-stimulated acid secretion by 58 +/- 8% (P < 0.01), whereas the SSTR2 agonist inhibited gastric acid by 96 +/- 2% (P < 0.001); the SSTR3 agonist was without effect. S-14 or the agonists at 50 pmol kg-1 h-1 did not alter elevations of plasma gastrin. S-14 and the SSTR2 agonist at 50 pmol kg-1 h-1 decreased gastrin-stimulated acid secretion by 42 +/- 8% (P < 0.01) and 78 +/- 4% (P < 0.001), respectively but the SSTR3 and SSTR5 agonists were without effect. In contrast, histamine-stimulated acid secretion was not altered by 1000 pmol kg-1 h-1 S-14 or the agonists. These results in conscious dogs suggest that the inhibitory actions of circulating S-14 on nutrient and gastrin-stimulated acid secretion include activation of the SSTR-2 subtype. Regulation of gastrin release by S-14 may also occur via SSTR-2, but not through an endocrine mechanism. Factors in addition to gastrin and histamine modulate intestinal protein-stimulated acid secretion yet include peripheral S-14 inhibition via SSTR2 activation.


Aryl hydrocarbon receptor-dependent induction of apoptosis by 2,3,7,8-tetrachlorodibenzo-p-dioxin in cerebellar granule cells from mouse.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a prototypical environmental contaminant with neurotoxic properties that alters neurodevelopment and behavior. TCDD is a ligand of the aryl hydrocarbon receptor (AhR), which is a key signaling molecule to fully understand the toxic and carcinogenic properties of dioxin. Much effort is underway to unravel the molecular mechanisms and the signaling pathways involved in TCDD-induced neurotoxicity, and to define its molecular targets in neurons. We have used cerebellar granule cells (CGC) from wild-type (AhR+/+) and AhR-null (AhR-/-) mice to characterize the cell death that takes place in neurons after TCDD toxicity. TCDD induced cell death in CGC cultures from wild-type mice with an EC(50) of 127±21 nM. On the contrary, when CGC neurons from AhR-null mice were treated with TCDD no significant cell death was observed. The role of AhR in TCDD-induced death was further assessed by using the antagonists resveratrol and α-naphtoflavone, which readily protected against TCDD toxicity in AhR+/+ CGC cultures. AhR+/+ CGC cultures treated with TCDD showed nuclear fragmentation, DNA laddering, and increased caspase 3 activity, similarly to what was found by the use of staurosporine, a well-established inducer of apoptosis. Finally, the AhR pathway was active in CGC because TCDD could induce the expression of the target gene cytochrome P450 1A2 in AhR+/+ CGC cultures. All together these results support the hypothesis that TCDD toxicity in CGC neurons involves the AhR and that it takes place mainly through an apoptotic process. AhR could be then considered a novel target in neurotoxicity and neurodegeneration whose down-modulation could block certain xenobiotic-related adverse effects in CNS.


L-ascorbic acid 2-phosphate, a phosphate derivative of L-ascorbic acid, enhances the growth of cultured rabbit keratocytes.
We examined the effect of L-ascorbic acid 2-phosphate (P-Asc) on the proliferation of cultured rabbit keratocytes. P-Asc is a phosphate derivative of L-ascorbic acid and has more prolonged vitamin C activity in solution than does L-ascorbic acid. The proliferation of cultured keratocytes was promoted by the presence of P-Asc in culture medium. Transmission electron microscopic observations revealed that cells were more multi-layered after culture in the presence of P-Asc (0.1 mM) for 30 days than were those cultured in the absence of P-Asc. The effect of P-Asc was abrogated by L-azetidine 2-carboxylic acid, which is an analogue of proline that inhibits the production and secretion of collagen. Our observations support a therapeutic role for P-Asc in the repair of corneal stromal damage such as that caused by a corneal chemical burn.


Pharmacokinetics of 4-demethoxydaunorubicin in cancer patients.
The clinical pharmacokinetics of 4-demethoxy-daunorubicin was investigated in 28 cancer patients who received the drug orally. The majority of the patients were elderly (median age, 72 years). Nine of them also received an i.v. dose, and the bioavailability of the oral dose ranged between 9% and 39%. 4-Demethoxydaunorubicin peak levels were achieved 2-4 h after the oral dose in most patients. The drug was rapidly and extensively metabolized to 4-demethoxy-13-hydroxydaunorubicin, which is probably as active as the parent drug. The metabolite levels were much higher and longer lasting than the parent drug, suggesting that it may play an important role in the drug's pharmacological effects.


Robots have grasped and manipulated the imagination since 1839.
Science fiction was prescient about many aspects of grasping and manipulation, but can it keep up with new advances?


Attempts at correlation of the radiolytic species of irradiated solid-state captopril studied by multi-frequency EPR and HPLC.
The purpose of this study was to provide insight into the processes that occur after the irradiation of solid-state drugs. Electron paramagnetic resonance (EPR) experiments were performed at two different frequencies, X-band (about 9.5 GHz) and Q-band (about 34 GHz), to identify the radicals present in irradiated captopril. The results confirmed that an irradiated drug can trap several main radicals. Moreover, the radical composition varied as a function of the treatment. In addition, non-volatile final products were studied by liquid chromatography coupled to UV and to mass spectrometry (LC-MS). The variation of the radical composition did not influence the profile of the final products; this appears to indicate that, in the case of captopril, the trapped radicals observed by EPR are not the main precursors of the final products. Finally, high-performance liquid chromatography data appear to indicate that radiosterilization of captopril is feasible.


Complications after pancreaticoduodenectomy are associated with higher amounts of intra- and postoperative fluid therapy: A single center retrospective cohort study.
Perioperative mortality after pancreaticoduodenectomy has decreased significantly in high-volume centers, but morbidity remains high. Restrictive perioperative fluid management may contribute to reduced complication rates after various surgical procedures. The aim of this study was to determine whether there is a correlation between the amount of fluid administered and postoperative complications. We hypothesized that higher amounts of intra- and total fluid is associated with greater postoperative morbidity. We retrospectively examined data of 553 patients who underwent pancreaticoduodenectomy at University of Freiburg Medical Center between 2001 and 2013. Data on intra - and postoperative fluid administration (until postoperative day 5) were obtained from anesthesiological and surgical records. Data on complications were retrieved from our institutional pancreatic database. The median values for intra- and total fluid administered were 6000 ml (range 400-15,000 ml) and 13,600 ml (range 5000-57,700 ml), respectively. The overall in-hospital mortality was 1.9% (no correlation with fluid administration). Patients who received more than 6000 ml intraoperative fluid had more wound infections (P = 0.049), intra-abdominal abscesses (P = 0.020) and postoperative interventions (P = 0.007). In patients who received more than 14000 ml fluid until postoperative day 5 all evaluated types of postoperative complications (infectious, fistula, delayed gastric emptying, bleeding) and re-interventions occurred significantly more frequently than in patients who received less than 14,000 ml (P < 0.05-0.001). Higher amounts of fluids may contribute to postoperative complications. More studies are needed to adequately assess the use of intra/postop fluid therapy.


Improving women's experiences of perineal suturing: A pragmatic qualitative analysis of what is helpful and harmful.
Perineal trauma requiring suturing is increasing, along with the associated physiological and psychological morbidities for women. Provider training appears to focus more on technical aspects rather than respectful, relational care for women. Studies exploring women's experiences have identified that how women are cared for can significantly impact upon overall experiences. To identify areas of improvement to the perineal suturing process and provide robust recommendations for urgent change by investigating what aspects are most traumatic to women and which are most supportive. A pragmatic qualitative analysis of data generated from 15 in-depth interviews with women who were sutured following birth. Regardless of tear severity, what was identified as helpful included anything that made the process better by increasing feelings of trust and reassurance, and providing women with a sense of being seen and heard. Harmful experiences were identified as those that worsened the experience, by increasing feelings of fear and vulnerability and leaving women with a sense of being disregarded or disrespected. The study confirmed that how the suturing process is conducted can have a significant detrimental impact upon women's short- and longer-term physical and psychological well-being. An improved experience for women is most likely with kind professionals who explain the process as it goes along, check-in regularly and validate how the women feel. Women prefer to be sutured by a known professional, only if this provider is also kind and respectful.


Effects of nitrogen application rate and a nitrification inhibitor dicyandiamide on ammonia oxidizers and N2O emissions in a grazed pasture soil.
Ammonia oxidizers, including ammonia oxidizing bacteria (AOB) and ammonia oxidizing archaea (AOA) are important drivers of a key step of the nitrogen cycle - nitrification, which affects the production of the potent greenhouse gas, nitrous oxide (N2O). A field experiment was conducted to determine the effect of nitrogen application rates and the nitrification inhibitor dicyandiamide (DCD) on the abundance of AOB and AOA and on N2O emissions in a grazed pasture soil. Nitrogen (N) was applied at four different rates, with urea applied at 50 and 100 kg N ha(-1) and animal urine at 300 and 600 kg N ha(-1). DCD was applied to some of the N treatments at 10 kg ha(-1). The results showed that the AOB amoA gene copy numbers were greater than those of AOA. The highest ratio of the AOB to AOA amoA gene copy numbers was 106.6 which occurred in the urine-N 600 treatment. The AOB amoA gene copy numbers increased with increasing nitrogen application rates. DCD had a significant impact in reducing the AOB amoA gene copy numbers especially in the high nitrogen application rates. N2O emissions increased with the N application rates. DCD had the most significant effect in reducing the daily and total N2O emissions in the highest nitrogen application rate. The greatest reduction of total N2O emissions by DCD was 69% in the urine-N 600 treatment. The reduction in the N2O emission factor by DCD ranged from 58% to 83%. The N2O flux and NO3(-)-N concentrations were significantly correlated to the growth of AOB, rather than AOA. This study confirms the importance of AOB in nitrification and the effect of DCD in inhibiting AOB growth and in decreasing N2O emissions in grazed pasture soils under field conditions.


Vascular endothelial growth factor receptors in osteoclast differentiation and function.
Osteoclasts are derived from haematopoietic stem cell precursors of the monocyte/macrophage cell lineage, through interaction with factors that are believed to include M-CSF and RANKL. VEGF is a proangiogenic cytokine that has been shown to promote osteoclast differentiation and survival. In this study, we assessed the role of VEGF and its receptors in osteoclastogenesis, in vitro, by culturing osteoclast precursors in the presence of VEGF, VEGF receptor-specific ligands, and blocking antibodies to VEGF receptors. Activation of VEGFR1 in the presence of RANKL induces osteoclast differentiation. Stimulating the receptors individually induced increased resorption by osteoclasts compared to controls but not to the level observed when stimulating both receptors simultaneously. We have shown that VEGF induces osteoclast differentiation through its action on VEGFR1. The way in which VEGF mediates its effect on mature osteoclast activity, however, may be through its interaction with both receptor subtypes.


The IPGA1-ANGUSTIFOLIA module regulates microtubule organisation and pavement cell shape in Arabidopsis.
Plant cells continuously experience mechanical stress resulting from the cell wall that bears internal turgor pressure. Cortical microtubules align with the predicted maximal tensile stress direction to guide cellulose biosynthesis and therefore results in cell wall reinforcement. We have previously identified Increased Petal Growth Anisotropy (IPGA1) as a putative microtubule-associated protein in Arabidopsis, but the function of IPGA1 remains unclear. Here, using the Arabidopsis cotyledon pavement cell as a model, we demonstrated that IPGA1 forms protein granules and interacts with ANGUSTIFOLIA (AN) to cooperatively regulate microtubule organisation in response to stress. Application of mechanical perturbations, such as cell ablation, led to microtubule reorganisation into aligned arrays in wild-type cells. This microtubule response to stress was enhanced in the IPGA1 loss-of-function mutant. Mechanical perturbations promoted the formation of IPGA1 granules on microtubules. We further showed that IPGA1 physically interacted with AN both in vitro and on microtubules. The ipga1 mutant alleles exhibited reduced interdigitated growth of pavement cells, with smooth shape. IPGA1 and AN had a genetic interaction in regulating pavement cell shape. Furthermore, IPGA1 genetically and physically interacted with the microtubule-severing enzyme KATANIN. We propose that the IPGA1-AN module regulates microtubule organisation and pavement cell shape.


Response of end bud cells from immature rat mammary gland to hormones when cultured in collagen gel.
End buds from 4- to 5-week-old rat mammary glands were isolated and cultured within a rat tail tendon collagen gel matrix. Media containing equine serum or porcine serum and cholera toxin promoted growth, but not the production of casein or thioesterase II, nor did they induce a state of differentiation as assessed by cell ultrastructure. Medium supplemented with only 5% porcine serum, insulin and cholera toxin did not support growth or differentiation. However, when prolactin, estradiol, progesterone and hydrocortisone were added to this medium, growth was stimulated greatly and a differentiated state was induced as assessed by the production of casein and thioesterase and by the appearance of a highly secretory ultrastructure.


New aporphine alkaloids with selective cytotoxicity against glioma stem cells from Thalictrum foetidum.
Seven new isoquinoline alkaloids, 9-(2'-formyl-5', 6'-dimethoxyphenoxy)-1, 2, 3, 10-tetramethoxy dehydroaporphine (1), 9-(2'-formyl-5', 6'-dimethoxyphenoxy)-1, 2, 3, 10-tetramethoxy oxoaporphine (2), 3-methoxy-2'-formyl oxohernandalin (3), (-)-9-(2'-methoxycarbonyl-5', 6'-dimethoxyphenoxy)-1, 2, 3, 10-tetramethoxy aporphine (4), (-)-2'-methoxycarbonyl thaliadin (5), (-)-9-(2'-methoxyethyl-5', 6'-dimethoxyphenoxy)-1, 2, 3, 10-tetramethoxy aporphine (6), (-)-3-methoxy hydroxyhernandalinol (7), together with six known isoquinoline alkaloids (8-13) were isolated from the roots of Thalictrum foetidum. Their structures were elucidated by extensive spectroscopic measurements. Compounds 1 and 2 showed significant selective cytotoxicity against glioma stem cells (GSC-3# and GSC-18#) with IC50 values ranging from 2.36 to 5.37 μg·mL-1.


Occludin S408 phosphorylation regulates tight junction protein interactions and barrier function.
Although the C-terminal cytoplasmic tail of the tight junction protein occludin is heavily phosphorylated, the functional impact of most individual sites is undefined. Here, we show that inhibition of CK2-mediated occludin S408 phosphorylation elevates transepithelial resistance by reducing paracellular cation flux. This regulation requires occludin, claudin-1, claudin-2, and ZO-1. S408 dephosphorylation reduces occludin exchange, but increases exchange of ZO-1, claudin-1, and claudin-2, thereby causing the mobile fractions of these proteins to converge. Claudin-4 exchange is not affected. ZO-1 domains that mediate interactions with occludin and claudins are required for increases in claudin-2 exchange, suggesting assembly of a phosphorylation-sensitive protein complex. Consistent with this, binding of claudin-1 and claudin-2, but not claudin-4, to S408A occludin tail is increased relative to S408D. Finally, CK2 inhibition reversed IL-13-induced, claudin-2-dependent barrier loss. Thus, occludin S408 dephosphorylation regulates paracellular permeability by remodeling tight junction protein dynamic behavior and intermolecular interactions between occludin, ZO-1, and select claudins, and may have therapeutic potential in inflammation-associated barrier dysfunction.


Improving access to HCV treatment: external jugular venepuncture can overcome problems with difficult venous access.
Many patients requiring antiviral treatment of chronic hepatitis C (HCV) have a background of significant injection drug use (IDU). In a proportion of patients, IDU results in difficulty with blood collection from conventional sites. We audited patients from the Liver Clinics and Drug Health Pharmacotherapy Service of The Royal Prince Alfred Hospital (RPAH) to determine the incidence of difficulty with blood collection. This survey identified the need for an innovative venous access strategy to better manage this group of patients. An external jugular venepuncture (EJV) protocol and education package was developed in collaboration with the Department of Anaesthetics, Gastroenterology and Liver Centre and HCV clinical nurse consultants (CNC). RPAH policy and procedure committee approved the protocol and patient information sheet. Patients with a history of difficulty with blood collection were eligible for the protocol. Patient satisfaction surveys were conducted. The initial survey of patients from the liver clinics and pharmacotherapy service identified that 48 percent had difficulty with blood collection from conventional sites. In the period October 2002 to July 2006, 29 patients (89 percent with history of IDU) were referred for EJV assessment. Major indications for EJV were for blood testing for initiation and monitoring of antiviral therapy and ongoing assessment of HCV infected patients. No adverse events resulted from the procedure. All patients surveyed report high levels of satisfaction with the technique compared to previous venous access attempts. EJV improves access to antiviral therapy and is a safe and effective technique for patients with difficult venous access (DVA). In addition, we have utilised EJV for post-transplant care of patients and used external jugular vein cannulation as vascular access for contrast imaging in hepatocellular carcinoma (HCC) assessment.


Cholangiocarcinoma with metastasis in a captive Adelie penguin (Pygoscelis adeliae).
A captive male Adelie penguin (Pygoscelis adeliae), wild caught in 1976, died unexpectedly. Necropsy revealed cholangiocarcinoma with metastases to lung, pancreas, mesentery, and cloaca, the first known case of a penguin hepatic tumor.


Stabilin-1/CLEVER-1, a type 2 macrophage marker, is an adhesion and scavenging molecule on human placental macrophages.
Stabilin-1/common lymphatic endothelial and vascular endothelial receptor-1 (CLEVER-1) is a multidomain protein present in lymphatic and vascular endothelial cells and type 2 immunosuppressive macrophages. In adults, stabilin-1/CLEVER-1 is a scavenging receptor and an adhesion molecule, but much less is known about its role during development. Here, we studied the expression and functions of macrophage stabilin-1/CLEVER-1 in human placenta and during human ontogeny. Using newly generated mAbs, we found that stabilin-1/CLEVER-1 is expressed on virtually all macrophages in term placenta, both in the decidua and in the placental villi. Placental stabilin-1/CLEVER-1 was involved in the scavenging of Ac-LDL (acetylated low density lipoprotein) and in the uptake of fluorescently labeled model antigen OVA. siRNA-mediated suppression of stabilin-1/CLEVER-1 altered the cytokine profile produced by placental macrophages. Stabilin-1/CLEVER-1 on placental macrophages mediated their adhesion to placental vessels and supported their transmigration through vascular endothelium. Finally, we found that stabilin-1/CLEVER-1 is induced very early in fetal macrophages, high endothelial venules, and lymphatic vessels in multiple lymphatic organs. Together, these data suggest that macrophage stabilin-1/CLEVER-1 can potentially regulate leukocyte migration and scavenging during the development of the placenta and fetus.


In-situ fabrication of zirconium entrenched biopolymeric hybrid membrane for the removal of toxic anions from aqueous medium.
The eutrophication of water bodies resulting from the excessive amounts of phosphate and nitrate ions in the water systems will cause serious environmental problems. This study deals with the adsorptive removal of toxic anions from aqueous medium using zirconium entrenched chitosan-starch membrane (Zr-CS-ST). The optimization of several influencing key factors like adsorbent dosage, shaking time, solution pH, aggressive ions, zero point charge and temperature were examined by batch mode adsorption experiments. In addition, Freundlich isotherm model showed an outstanding fit with the experimental data's, yielding the maximum adsorption capacities of 86.28 and 70.88 mg/g for phosphate and nitrate, respectively. Thermodynamic parameters, including the Gibbs free energy, entropy and enthalpy change indicated that the removal of both anions by Zr-CS-ST membrane was feasible, spontaneity and endothermic in nature. The diffusion and reaction based kinetic models were exposed to study about the kinetics and adsorption process were followed by pseudo-second-order and intra-particle diffusion kinetic models. The removal mechanism involved by different types of interactions such as complexation, ion exchange and electrostatic interaction, which were adopted for the removal mechanisms. We exposed that, Zr-CS-ST was successfully developed and will be effectively employed for the remediation of phosphate and nitrate ions in field/practical applications.


Long-term tracking of cardiovascular risk factors among men and women in a large population-based health system: the Vorarlberg Health Monitoring & Promotion Programme.
To document tracking patterns, if any, over time, of classical cardiovascular risk factors in men and women participants in the Vorarlberg Health Monitoring and Promotion Programme (VHM&PP) METHODS AND RESULTS: 67,413 men and 82,237 women underwent a total of 45,4448 standardised examinations in the 15 year period 1985-1999. Measures included were systolic and diastolic blood pressure, height, weight and fasting sample for total cholesterol, triglycerides, gamma-gt and blood glucose. Tracking coefficients were calculated by multivariable regression models using the GEE estimation method. All variables showed evidence of significant tracking over time, whether estimated in 10-year age bands or among individuals categorized as being at high risk using cut-points proposed by international guidelines. Effects were most marked for body mass index (0.87, SE0.005 in men and 0.89, SE0.003 in women), and were also associated with increasing age. Women who died during follow-up showed stronger tracking patterns for triglycerides and gamma-gt and weaker effects for blood pressure, but there was no effect on patterns according to survival in men. Tracking coefficients were weaker among initially high-risk individuals. This is the largest study yet of adults to demonstrate significant tracking effects of cardiovascular risk factors over time. The strength of this effect should be considered in assessing effectiveness of risk factor modification programmes. The study is novel too in highlighting more fully differences according to gender and social circumstances and in taking account of the impact on long-term survival.


Anterior cervical interbody fusion with a titanium box cage: early radiological assessment of fusion and subsidence.
The use of stand-alone cervical interbody cages in anterior cervical discectomy with fusion (ACDF) has become popular, but high subsidence rates have been reported in the literature. The authors present short-term radiological results of a titanium box cage with regard to fusion and subsidence. Reliable fusion and lack of subsidence may influence long-term clinical results. Early radiological data are necessary before implementation of this device on a larger scale can be accepted. Retrospective radiological quality assessment study. ACDF using the titanium cage was performed in 71 consecutive patients at 106 levels. Diagnoses included cervical disc disease (57) and cervical spinal stenosis (14) after failed conservative treatment. Subsidence and kyphosis were assessed on lateral cervical radiographs made directly postoperative and at 3- and 6-month follow-up. At 6-month follow-up, lateral flexion-extension radiographs were made to assess fusion. Subsidence of the cage was defined as a decrease in total vertical height of the two fused vertebral bodies as measured on the lateral cervical radiographs made 3 and 6 months postoperatively compared with the directly postoperative radiographs. Segmental kyphosis was measured as the angle between the posterior borders of the two vertebral bodies on the lateral radiograph. No patients were lost to follow-up. Fusion was achieved after 6 months in all patients. At 3 and 6 months postoperative the same 10 cages (each in a different patient) had subsided. The C6-C7 level was significantly more frequently involved compared with all other levels. A segmental kyphotic alignment was observed in five patients at the C6-C7 level and in one patient at the C4-C5 level. For patients with cervical disc disease, the high subsidence tendency of the cage into the end plate of predominantly C7 is a disturbing phenomenon found in this study. A modified cage design that improves and extends contact with the inferior surface could be expected to reduce subsidence into C7.


Red blood cell mannoses as phagocytic ligands mediating both sickle cell anaemia and malaria resistance.
In both sickle cell disease and malaria, red blood cells (RBCs) are phagocytosed in the spleen, but receptor-ligand pairs mediating uptake have not been identified. Here, we report that patches of high mannose N-glycans (Man5-9GlcNAc2), expressed on diseased or oxidized RBC surfaces, bind the mannose receptor (CD206) on phagocytes to mediate clearance. We find that extravascular hemolysis in sickle cell disease correlates with high mannose glycan levels on RBCs. Furthermore, Plasmodium falciparum-infected RBCs expose surface mannose N-glycans, which occur at significantly higher levels on infected RBCs from sickle cell trait subjects compared to those lacking hemoglobin S. The glycans are associated with high molecular weight complexes and protease-resistant, lower molecular weight fragments containing spectrin. Recognition of surface N-linked high mannose glycans as a response to cellular stress is a molecular mechanism common to both the pathogenesis of sickle cell disease and resistance to severe malaria in sickle cell trait.


TNF-α renders macrophages resistant to a range of cancer chemotherapeutic agents through NF-κB-mediated antagonism of apoptosis signalling.
The abundance of macrophages is an independent negative prognostic factor in a range of cancer types, linked to the actions of macrophage products on vasculogenesis and cancer cell survival, motility and metastasis. TNF-α is a macrophage product and a product of some cancer cell types that is also associated with adverse prognosis in clinical and experimental cancers, through enhanced tumour cell growth, survival and metastasis. Macrophages are important targets of TNF-α. We observed that TNF-α partly substituted for the macrophage growth factor, M-CSF, in maintaining macrophage survival by protecting cells from apoptosis. We found that TNF-α afforded similar protection to chemotherapeutic agents and related cytotoxic drugs that acted through a range of apoptosis-initiating pathways, but not where protein synthesis was inhibited. Protection was dependent on intact NF-κB signalling. In addition to NF-κB-dependent factors previously identified as anti-apoptotic, we found an absolute requirement for very early antagonism of mitochondrial cytochrome C release, which sufficed to prevent apoptosis in the face of activation of a range of upstream apoptosis pathways, including p53, DISC-linked, mitochondrial depolarisation and calcium-sensitive pathways. The capacity of TNF-α to preserve macrophage numbers in the face of chemotherapy drugs is a potential contributor to prognosis in TNF-α-expressing cancers, encouraging further testing of anti-TNF-α treatments in these patients.


Oxidative and antioxidative stress markers in keratoconus: a systematic review and meta-analysis.
To conduct a systematic review and meta-analysis on the levels of oxidative stress markers and antioxidants in keratoconus compared to healthy subject. The PubMed, Cochrane Library, Embase, Science Direct and Google Scholar databases were searched on 1st June 2020 for studies reporting oxidative and antioxidative stress markers in keratoconus and healthy controls. Main meta-analysis was stratified by type of biomarkers, type of samples (tears, cornea, aqueous humour and blood) and type of corneal samples (stromal cells, epithelium and endothelium). We included 36 articles, for a total of 1328 keratoconus patients and 1208 healthy controls. There is an overall increase in oxidative stress markers in keratoconus compared with healthy controls (standard mean deviation (SMD) = 0.94, 95% confidence interval (95% CI) 0.55-1.33), with a significant increase in reactive oxygen and nitrogen species (1.09, 0.41-1.78) and malondialdehyde (1.78, 0.83-2.73). There is an overall decrease in antioxidants in keratoconus compared with healthy controls (-0.63, -0.89 to -0.36), with a significant decrease in total antioxidant capacity/status (-1.65, -2.88 to -0.43), aldehyde/NADPH dehydrogenase (-0.77, -1.38 to -0.17), lactoferrin/transferrin/albumin (-1.92, -2.96 to -0.89) and selenium/zinc (-1.42, -2.23 to -0.61). Oxidative stress markers were higher in tears and in cornea of keratoconus than in aqueous humour, and antioxidants were decreased in tears, aqueous humour and blood without difference between sample type. Oxidative stress markers increased in stromal cells and antioxidants decreased in endothelium. Oxidative stress markers and antioxidants were dysregulated in keratoconus, involving an imbalance of redox homeostasis in tears, cornea, aqueous humour and blood.


Touch imprint cytology evaluation of sentinel lymph node in breast cancer.
Most centers use lymphoscintiscan for identification of a sentinel lymph node (SLN) and frozen section for its evaluation. The aim of the present study was to assess the accuracy of peritumoral methylene blue dye injection for SLN identification and the technique of touch imprint cytology (TIC) for its evaluation. One hundred and eight fine needle aspiration cytology (FNAC)-proven breast cancer patients with clinically N0 axilla were recruited for the study. Prior to the induction of anesthesia, 5 ml of 1% methylene blue was injected in the peritumoral region to stain the sentinel node, following which conventional modified radical mastectomy was performed. Touch imprint cytology was obtained from the cut surface of the SLN, and then the SLN along with all nonsentinel nodes were sent for histopathology. Intraoperative identification of a blue node was possible in 102 of 108 patients (94%). Touch imprint cytology had a sensitivity of 88%, specificity of 98%, and overall diagnostic accuracy of 94% for diagnosing metastasis in the SLN. The false positive rate for malignancy of TIC versus histology was 2.5% and the false negative rate 7.8%. Blue dye lymphatic mapping by peritumoral injection of methylene blue was found to be accurate and cost effective for SLN identification. It avoids the expenses of lymphoscintiscanning, which requires special infrastructure and expertise with a significant learning curve. The identified SLN can, with reasonable accuracy, be assessed for metastasis by TIC. The frequently used method of frozen section requires a cryostat and a pathologist trained in the technique. Additionally scanty SLN tissue can be wasted in the cryostat and freezing artifacts can be introduced in the imprint, both of which are avoided by TIC.


Chronic cortisol elevation restricts glucose uptake but not insulin responsiveness in zebrafish skeletal muscle.
Although teleosts show an elevated insulin response to hyperglycemia, the circulating glucose levels are not normalized as rapidly as in mammals. While this may suggest a lack of target tissue insulin responsiveness, the underlying mechanisms are unclear. We investigated whether changes in skeletal muscle insulin sensitivity and glucose uptake underlie the cortisol-mediated elevated blood glucose levels. Adult zebrafish (Danio rerio) were exposed to water-borne cortisol for 3 days followed by an intraperitoneal injection of glucose with or without insulin. Cortisol treatment resulted in a temporal delay in the reduction in blood glucose levels, and this corresponded with a reduced glucose uptake capacity and lower glycogen content in the skeletal muscle. The transcript abundance of slc2a1b (which encodes for GLUT1b) and a suite of genes encoding enzymes involved in muscle glycogenesis and glycolysis were upregulated in the cortisol group. Both the control and cortisol groups showed higher whole body insulin expression in response to blood glucose elevation, which also resulted in enhanced insulin-stimulated phosphorylation of AKT in the skeletal muscle. The insulin-mediated phosphorylation of S6 kinase was lower in the cortisol group. Altogether, chronic cortisol stimulation restricts glucose uptake and enhances the glycolytic capacity without affecting insulin responsiveness in zebrafish skeletal muscle.


The matricellular protein SPARC induces inflammatory interferon-response in macrophages during aging.
The risk of chronic diseases caused by aging is reduced by caloric restriction (CR)-induced immunometabolic adaptation. Here, we found that the matricellular protein, secreted protein acidic and rich in cysteine (SPARC), was inhibited by 2 years of 14% sustained CR in humans and elevated by obesity. SPARC converted anti-inflammatory macrophages into a pro-inflammatory phenotype with induction of interferon-stimulated gene (ISG) expression via the transcription factors IRF3/7. Mechanistically, SPARC-induced ISGs were dependent on toll-like receptor-4 (TLR4)-mediated TBK1, IRF3, IFN-β, and STAT1 signaling without engaging the Myd88 pathway. Metabolically, SPARC dampened mitochondrial respiration, and inhibition of glycolysis abrogated ISG induction by SPARC in macrophages. Furthermore, the N-terminal acidic domain of SPARC was required for ISG induction, while adipocyte-specific deletion of SPARC reduced inflammation and extended health span during aging. Collectively, SPARC, a CR-mimetic adipokine, is an immunometabolic checkpoint of inflammation and interferon response that may be targeted to delay age-related metabolic and functional decline.