Actions of the creatine analogue beta-guanidinopropionic acid on rat heart mitochondria.
The action of the creatine analogue beta-guanidinopropionic acid (beta-GPA) was examined in rat heart mitochondria and in isolated cardiomyocytes or fibres which were permeabilized with the non-ionic detergent saponin to determine the kinetics of mitochondrial creatine kinase for beta-GPA. Fibres and myocytes were subjected to increasing [ADP] in the presence and absence of beta-GPA or creatine, whereas isolated mitochondria received a similar protocol with increasing [ATP]. In isolated mitochondria given ATP, there was a stimulation of respiration by creatine, but no significant stimulation of respiration by beta-GPA. Further studies on fibres from control and beta-GPA-fed rats also found that beta-GPA is not utilized by the mitochondria, as evidenced by a lack of beta-GPA-stimulated respiration (Km for ADP = 142 +/- 23 microM) compared with control (Km for ADP from 161 +/- 23 microM), but no significant change in Vmax. Therefore the rat heart mitochondria are not responsive to beta-GPA as compared with creatine. Interestingly, the fibres from beta-GPA-fed rats had no creatine- or beta-GPA-stimulated respiration (Km for ADP = 57.3 +/- 7.2 microM for control, 54.2 +/- 7.2 microM with creatine, and 53.5 +/- 7.8 microM with beta-GPA). The mitochondria prepared from the hearts of rats exposed for 10 weeks to 1% beta-GPA in their diet had a significant decrease in Vmax. and a significant decrease in Km for ADP. Thus the hearts from beta-GPA-fed animals may be pathologic, due to a disruption of the creatine kinase energy circuit.


Retronasal Aroma of Beef Pate Analyzed by a Chewing Simulator.
In retronasal aroma, the targeted aroma compounds are released from food during chewing. The changes in the food structures during chewing strongly influence the release of the compounds, therefore affecting the perception of food. Here, the relationship between retronasal aroma and food deliciousness based on the physicochemical properties of aroma compounds was examined. We considered the consumption of solid foods and the effect of oral parameters in elderly people. Beef pate was used as a model food sample to study the effect of the release of aroma compounds under controlled in vitro mastication and salivation conditions using a chewing simulator. We identified the effects of coexisting ingredients such as beef fat on the time course behavior of the release of aroma compounds. In particular, the release of the middle types of aromas was significantly faster with stronger chewing force, and higher with a high fat content of the sample. In addition, a larger release intensity was observed when soy proteins were partially substituted for beef proteins. Using an appropriate model saliva, a change in the salting-out effect from the saliva composition was found to be a factor, which could explain the lowering of aroma sensation in an elderly person.


Comprehensive regional and temporal gene expression profiling of the rat brain during the first 24 h after experimental stroke identifies dynamic ischemia-induced gene expression patterns, and reveals a biphasic activation of genes in surviving tissue.
In order to identify biological processes relevant for cell death and survival in the brain following stroke, the postischemic brain transcriptome was studied by a large-scale cDNA array analysis of three peri-infarct brain regions at eight time points during the first 24 h of reperfusion following middle cerebral artery occlusion in the rat. K-means cluster analysis revealed two distinct biphasic gene expression patterns that contained 44 genes (including 18 immediate early genes), involved in cell signaling and plasticity (i.e. MAP2K7, Sprouty2, Irs-2, Homer1, GPRC5B, Grasp). The first gene induction phase occurred at 0-3 h of reperfusion, and the second at 9-15 h, and was validated by in situ hybridization. Four gene clusters displayed a progressive increase in expression over time and included 50 genes linked to cell motility, lipid synthesis and trafficking (i.e. ApoD, NPC1, G3P-dehydrogenase1, and Choline kinase) or cell death-regulating genes such as mitochondrial CLIC. We conclude that a biphasic transcriptional up-regulation of the brain-derived neurotrophic factor (BDNF)-G-protein coupled receptor (GPCR)-mitogen-activated protein (MAP) kinase signaling pathways occurs in surviving tissue, concomitant with a progressive and persistent activation of cell proliferation signifying tissue regeneration, which provide the means for cell survival and postischemic brain plasticity.


Efficient identification of multiple pathways: RNA-Seq analysis of livers from 56Fe ion irradiated mice.
mRNA interaction with other mRNAs and other signaling molecules determine different biological pathways and functions. Gene co-expression network analysis methods have been widely used to identify correlation patterns between genes in various biological contexts (e.g., cancer, mouse genetics, yeast genetics). A challenge remains to identify an optimal partition of the networks where the individual modules (clusters) are neither too small to make any general inferences, nor too large to be biologically interpretable. Clustering thresholds for identification of modules are not systematically determined and depend on user-settable parameters requiring optimization. The absence of systematic threshold determination may result in suboptimal module identification and a large number of unassigned features. In this study, we propose a new pipeline to perform gene co-expression network analysis. The proposed pipeline employs WGCNA, a software widely used to perform different aspects of gene co-expression network analysis, and Modularity Maximization algorithm, to analyze novel RNA-Seq data to understand the effects of low-dose 56Fe ion irradiation on the formation of hepatocellular carcinoma in mice. The network results, along with experimental validation, show that using WGCNA combined with Modularity Maximization, provides a more biologically interpretable network in our dataset, than that obtainable using WGCNA alone. The proposed pipeline showed better performance than the existing clustering algorithm in WGCNA, and identified a module that was biologically validated by a mitochondrial complex I assay. We present a pipeline that can reduce the problem of parameter selection that occurs with the existing algorithm in WGCNA, for applicable RNA-Seq datasets. This may assist in the future discovery of novel mRNA interactions, and elucidation of their potential downstream molecular effects.


[Diagnostic approach to ischemic colitis].
Ischemic colitis is the most frequent form of intestinal ischemia and arises when the colon is temporarily deprived of blood supply. Diagnosis of this entity requires a high index of clinical suspicion. To achieve this, the chronology of the symptoms (abdominal pain followed by defecatory urgency and rectorrhagia) and the clinical context in which these symptoms appear (> 90% affect persons especially at risk for vascular accidents) must be taken into account. Although diagnosis requires early colonoscopy (< 48 h), this procedure should not be performed if peritonitis is present. In severe forms, other imaging techniques, such as Doppler ultrasound or abdominal computed tomography, provide information with diagnostic -and even prognostic- value. Angiography is reserved for patients in whom there is doubt about the presence of acute mesenteric ischemia. Thrombophilia should be investigated in persons aged less than 60 years old.


Targeting nuclear receptors in cancer-associated fibroblasts as concurrent therapy to inhibit development of chemoresistant tumors.
Most anticancer therapies to date focus on druggable features of tumor epithelia. Despite the increasing repertoire of treatment options, patient responses remain varied. Moreover, tumor resistance and relapse remain persistent clinical challenges. These observations imply an incomplete understanding of tumor heterogeneity. The tumor microenvironment is a major determinant of disease progression and therapy outcome. Cancer-associated fibroblasts (CAFs) are the dominant cell type within the reactive stroma of tumors. They orchestrate paracrine pro-tumorigenic signaling with adjacent tumor cells, thus exacerbating the hallmarks of cancer and accelerating tumor malignancy. Although CAF-derived soluble factors have been investigated for tumor stroma-directed therapy, the underlying transcriptional programs that enable the oncogenic functions of CAFs remain poorly understood. Nuclear receptors (NRs), a large family of ligand-responsive transcription factors, are pharmacologically viable targets for the suppression of CAF-facilitated oncogenesis. In this study, we defined the expression profiles of NRs in CAFs from clinical cutaneous squamous cell carcinoma (SCC) biopsies. We further identified a cluster of driver NRs in CAFs as important modifiers of CAF function with profound influence on cancer cell invasiveness, proliferation, drug resistance, energy metabolism and oxidative stress status. Importantly, guided by the NR profile of CAFs, retinoic acid receptor β and androgen receptor antagonists were identified for concurrent therapy with cisplatin, resulting in the inhibition of chemoresistance in recurred SCC:CAF xenografts. Our work demonstrates that treatments targeting both the tumor epithelia and the surrounding CAFs can extend the efficacy of conventional chemotherapy.


Passing MRCP (UK) PACES: a cross-sectional study examining the performance of doctors by sex and country.
There is much discussion about the sex differences that exist in medical education. Research from the United Kingdom (UK) and United States has found female doctors earn less, and are less likely to be senior authors on academic papers, but female doctors are also less likely to be sanctioned, and have been found to perform better academically and clinically. It is also known that international medical graduates tend to perform more poorly academically compared to home-trained graduates in the UK, US, and Canada. It is uncertain whether the magnitude and direction of sex differences in doctors' performance is variable by country. We explored the association between doctors' sex and their performance at a large international high-stakes clinical examination: the Membership of the Royal Colleges of Physicians (UK) Practical Assessment of Clinical Examination Skills (PACES). We examined how sex differences varied by the country in which the doctor received their primary medical qualification, the country in which they took the PACES examination, and by the country in which they are registered to practise. Seven thousand six hundred seventy-one doctors attempted PACES between October 2010 and May 2013. We analysed sex differences in first time pass rates, controlling for ethnicity, in three groups: (i) UK medical graduates (N = 3574); (ii) non-UK medical graduates registered with the UK medical regulator, the General Medical Council (GMC), and thus likely to be working in the UK (N = 1067); and (iii) non-UK medical graduates without GMC registration and so legally unable to work or train in the UK (N = 2179). Female doctors were statistically significantly more likely to pass at their first attempt in all three groups, with the greatest sex effect seen in non-UK medical graduates without GMC registration (OR = 1.99; 95% CI = 1.65-2.39; P < 0.0001) and the smallest in the UK graduates (OR = 1.18; 95% CI = 1.03-1.35; P = 0.02). As found in a previous format of this examination and in other clinical examinations, female doctors outperformed male doctors. Further work is required to explore why sex differences were greater in non-UK graduates, especially those without GMC registration, and to consider how examination performance may relate to performance in practice.


Differential motif enrichment analysis of paired ChIP-seq experiments.
Motif enrichment analysis of transcription factor ChIP-seq data can help identify transcription factors that cooperate or compete. Previously, little attention has been given to comparative motif enrichment analysis of pairs of ChIP-seq experiments, where the binding of the same transcription factor is assayed under different conditions. Such comparative analysis could potentially identify the distinct regulatory partners/competitors of the assayed transcription factor under different conditions or at different stages of development. We describe a new methodology for identifying sequence motifs that are differentially enriched in one set of DNA or RNA sequences relative to another set, and apply it to paired ChIP-seq experiments. We show that, using paired ChIP-seq data for a single transcription factor, differential motif enrichment analysis identifies all the known key transcription factors involved in the transformation of non-cancerous immortalized breast cells (MCF10A-ER-Src cells) into cancer stem cells whereas non-differential motif enrichment analysis does not. We also show that differential motif enrichment analysis identifies regulatory motifs that are significantly enriched at constrained locations within the bound promoters, and that these motifs are not identified by non-differential motif enrichment analysis. Our methodology differs from other approaches in that it leverages both comparative enrichment and positional enrichment of motifs in ChIP-seq peak regions or in the promoters of genes bound by the transcription factor. We show that differential motif enrichment analysis of paired ChIP-seq experiments offers biological insights not available from non-differential analysis. In contrast to previous approaches, our method detects motifs that are enriched in a constrained region in one set of sequences, but not enriched in the same region in the comparative set. We have enhanced the web-based CentriMo algorithm to allow it to perform the constrained differential motif enrichment analysis described in this paper, and CentriMo's on-line interface (http://meme.ebi.edu.au) provides dozens of databases of DNA- and RNA-binding motifs from a full range of organisms. All data and output files presented here are available at http://research.imb.uq.edu.au/t.bailey/supplementary\_data/Lesluyes2014.


Ion pumps in epithelial cells: sorting, stabilization, and polarity.
The P-type family of ion-transporting ATPases includes all of the isoforms of Na(+)-K(+)-adenosinetriphosphatase (ATPase), the plasma membrane and organellar Ca(2+)-ATPases, gastric H(+)-K(+)-ATPase, and the recently characterized nongastric H(+)-K(+)-ATPases, among others. In epithelial cells, members of this pump family generate the cation gradients responsible for vectorial fluid and solute transport. To carry out this function, each P-type ATPase must be restricted to a specific membrane domain. Newly synthesized ion pumps must be sorted to their appropriate destinations and retained there after their delivery. Recently, progress has been made toward understanding the signals and targeting pathways that epithelial cells employ to generate anisotropic pump distributions. The mechanisms involved in generating these pump distributions may serve as well to regulate pump function.


Periodically Grafted Amphiphilic Copolymers: Effects of Steric Crowding and Reversal of Amphiphilicity.
Two series of periodically clickable polyesters were prepared; one of them carries alkylene segments along its backbone, whereas the other carries poly(ethylene glycol) (PEG) segments. These polyesters were clicked with either MPEG-350 azide or docosyl (C22) azide to yield periodically grafted amphiphilic copolymers (PGACs) carrying either flexible hydrophilic or crystallizable hydrophobic backbone segments. The immiscibility between hydrocarbon and PEG segments causes both of these systems to fold in either a zigzag or hairpin-like conformation; the hairpin-like conformation appears to be preferred when flexible PEG segments are present in the backbone. The folded chains further reorganize in the solid state to develop a lamellar morphology that permits the collocation of the PEG and hydrocarbon (HC) segments within alternate domains; evidence for the self-segregation was gained from DSC, SAXS, and AFM studies. SAXS studies revealed the formation of an extended lamellar structure, whereas AFM images showed uniform layered morphology with layer heights that matched reasonably well with the interlamellar spacing obtained from the SAXS study. Labeling one representative PGAC, carrying crystallizable long alkylene segments in the backbone and pendant PEG-350 side chains, with a small mole fraction of pyrene fluorophore permitted the examination of the conformational transition that occurs upon going from a good to a poor solvent; this single-chain folded conformation, we postulate, is the intermediate that organizes into the lamellar morphology.


Identification of the synthetic surfactant nonylphenol ethoxylate: a P-glycoprotein substrate in human urine.
P-glycoprotein (Mdr1p) is an ATP-dependent drug efflux pump that is overexpressed in multidrug-resistant cells and some cancers. Mdr1p is also expressed in normal tissues like the kidney, where it can mediate transepithelial drug transport. A human urinary compound that reverses multidrug resistance and blocks [3H]azidopine photolabeling of P-glycoprotein was purified to homogeneity and identified by 1H-NMR and mass spectrometry as the synthetic surfactant nonylphenol ethoxylate (NPE). Multidrug-resistant Chinese hamster ovary (CHO) C5 cells accumulated less [3H]NPE than parental drug-sensitive Aux-B1 cells, and Mdr1p substrates, verapamil and cyclosporin A, increased this surfactant's accumulation in C5 cells. NPE blocked the net transepithelial transport (basolateral to apical) of [3H]cyclosporin A in epithelia formed by Madin-Darby canine kidney (MDCK) cells. Net transepithelial transport (basal to apical) of [3H]NPE was demonstrated in MDCK cells and was inhibited by cyclosporin A. These findings show NPE is a Mdr1p substrate excreted into urine by kidney P-glycoprotein. NPE is a widely used surfactant and a known hormone disrupter that is readily absorbed orally or topically. The current findings indicate the function of kidney Mdr1p may be to eliminate exogenous compounds from the body.


The Changes in Levels and Barriers of Physical Activity Among Community-Dwelling Older Adults During and After the Fifth Wave of COVID-19 Outbreak in Hong Kong: Repeated Random Telephone Surveys.
COVID-19 has had an impact on physical activity (PA) among older adults; however, it is unclear whether this effect would be long-lasting, and there is a dearth of studies assessing the changes in barriers to performing PA among older adults before and after entering the "postpandemic era." The aim of this study was to compare the levels and barriers of PA among a random sample of community-dwelling older adults recruited during (February to April 2022) and after the fifth wave of the COVID-19 outbreak (May to July 2022) in Hong Kong. In addition, we investigated factors associated with a low PA level among participants recruited at different time points. This study involved two rounds of random telephone surveys. Participants were community-dwelling Chinese-speaking individuals aged 65 years or above and having a Hong Kong ID card. Household telephone numbers were randomly selected from the most updated telephone directories. Experienced interviewers carried out telephone interviews between 6 PM and 10 PM on weekdays and between 2 PM and 9 PM on Saturdays to avoid undersampling of working individuals. We called 3900 and 3840 households in the first and second round, respectively; for each round, 640 and 625 households had an eligible older adult and 395 and 370 completed the telephone survey, respectively. As compared to participants in the first round, fewer participants indicated a low level of PA in the second round (28.6% vs 45.9%, P<.001). Participants in the second round had higher metabolic equivalent of tasks-minutes/week (median 1707.5 vs 840, P<.001) and minutes of moderate-to-vigorous PA per week (median 240 vs 105, P<.001) than those in the first round. After adjustment for significant background characteristics, participants who perceived a lack of physical capacity to perform PA (first round: adjusted odds ratio [AOR] 3.34, P=.001; second round: 2.92, P=.002) and believed that PA would cause pain and discomfort (first round: AOR 2.04, P=.02; second round: 2.82, P=.001) were more likely to have a low level of PA in both rounds. Lack of time (AOR 4.19, P=.01) and concern about COVID-19 infection during PA (AOR 1.73, P=.02) were associated with a low level of PA among participants in the first round, but not in the second round. A perceived lack of space and facility to perform PA at home (AOR 2.03, P=.02) and unable to find people to do PA with (AOR 1.80, P=.04) were associated with a low PA level in the second round, but not in the first round. The level of PA increased significantly among older adults after Hong Kong entered the "postpandemic era." Different factors influenced older adults' PA level during and after the fifth wave of the COVID-19 outbreak. Regular monitoring of the PA level and its associated factors should be conducted to guide health promotion and policy-making.


[Early ischemic lesions of hippocampus neurons in experimental status epilepticus].
The ischaemic changes in the hippocampus reported here were observed during a series of experiments in which the effect of ionized and non-ionized intracortically injected contrast media were investigated. Only the group with ionized contrast medium showed early ischaemic lesions in the hippocampal neurons. Our model is comparable with the final status epilepticus. Generalized spike activity of more than 2 1/2 hours, without a recovery phase, is involved. Our findings thus indicate that under certain conditions, i.e. in this case, generalized activity lasting for a long time, ischaemic lesions can occur. However, in view of the ultrastructural features, the changes can still be considered reversible.


Solution of disordered microphases in the Bethe approximation.
The periodic microphases that self-assemble in systems with competing short-range attractive and long-range repulsive (SALR) interactions are structurally both rich and elegant. Significant theoretical and computational efforts have thus been dedicated to untangling their properties. By contrast, disordered microphases, which are structurally just as rich but nowhere near as elegant, have not been as carefully considered. Part of the difficulty is that simple mean-field descriptions make a homogeneity assumption that washes away all of their structural features. Here, we study disordered microphases by exactly solving a SALR model on the Bethe lattice. By sidestepping the homogenization assumption, this treatment recapitulates many of the key structural regimes of disordered microphases, including particle and void cluster fluids as well as gelation. This analysis also provides physical insight into the relationship between various structural and thermal observables, between criticality and physical percolation, and between glassiness and microphase ordering.


Limpet teeth microstructure unites auxeticity with extreme strength and high stiffness.
Materials displaying negative Poisson's ratio, referred to as auxeticity, have been found in nature and created in engineering through various structural mechanisms. However, uniting auxeticity with high strength and high stiffness has been challenging. Here, combining in situ nanomechanical testing with microstructure-based modeling, we show that the leading part of limpet teeth successfully achieves this combination of properties through a unique microstructure consisting of an amorphous hydrated silica matrix embedded with bundles of single-crystal iron oxide hydroxide nanorods arranged in a pseudo-cholesteric pattern. During deformation, this microstructure allows local coordinated displacement and rotation of the nanorods, enabling auxetic behavior while maintaining one of the highest strengths among natural materials. These findings lay a foundation for designing biomimetic auxetic materials with extreme strength and high stiffness.


Perinatal manifestations of congenital disorders of glycosylation-A clue to early diagnosis.
N-glycosylation defects-isolated or mixed with other glycosylation defects-are the most frequent congenital disorders of glycosylation and present mostly in childhood, with a specific combination of non-specific phenotypic features. The diagnosis, however, is often delayed. The aim of this study is to describe the perinatal phenotype of congenital disorders of N-glycosylation. We present an analysis of perinatal symptoms in a group of 24 one-center Polish patients with N-glycosylation defects-isolated or mixed. The paper expands the perinatal phenotype of CDGs and shows that some distinctive combinations of symptoms present in the perinatal period should raise a suspicion of CDGs in a differential diagnosis.


Campylobacter jejuni Response When Inoculated in Bovine In Vitro Fecal Microbial Consortia Incubations in the Presence of Metabolic Inhibitors.
Infection with the foodborne pathogen Campylobacter is the leading bacterial cause of human foodborne illness in the United States. The objectives of this experiment were to test the hypothesis that mixed microbial populations from the bovine rumen may be better at excluding Campylobacter than populations from freshly voided feces and to explore potential reasons as to why the rumen may be a less favorable environment for Campylobacter than feces. In an initial experiment, C. jejuni cultures inoculated without or with freshly collected bovine rumen fluid, bovine feces or their combination were cultured micro-aerobically for 48 h. Results revealed that C. jejuni grew at similar growth rates during the first 6 h of incubation regardless of whether inoculated with the rumen or fecal contents, with rates ranging from 0.178 to 0.222 h-1. However, C. jejuni counts (log10 colony-forming units/mL) at the end of the 48 h incubation were lowest in cultures inoculated with rumen fluid (5.73 log10 CFUs/mL), intermediate in cultures inoculated with feces or both feces and rumen fluid (7.16 and 6.36 log10 CFUs/mL) and highest in pure culture controls that had not been inoculated with the rumen or fecal contents (8.32 log10 CFUs/mL). In follow-up experiments intended to examine the potential effects of hydrogen and hydrogen-consuming methanogens on C. jejuni, freshly collected bovine feces, suspended in anaerobic buffer, were incubated anaerobically under either a 100% carbon dioxide or 50:50 carbon dioxide/hydrogen gas mix. While C. jejuni viability decreased <1 log10 CFUs/mL during incubation of the fecal suspensions, this did not differ whether under low or high hydrogen accumulations or whether the suspensions were treated without or with the mechanistically distinct methanogen inhibitors, 5 mM nitrate, 0.05 mM 2-bromosulfonate or 0.001 mM monensin. These results suggest that little if any competition between C. jejuni and hydrogen-consuming methanogens exists in the bovine intestine based on fecal incubations.


Health state utilities in non-small cell lung cancer: An international study.
Quality of life weights (utilities) are an important input in economic evaluation and evidence suggests that there can be important differences between countries. This study was designed to capture utilities for metastatic non-small cell lung cancer and common grade III/IV toxicities associated with treatment from local populations in the United Kingdom, Australia, France, China, Taiwan, and Korea. Toxicities included neutropenia, febrile neutropenia, fatigue, diarrhea, nausea and vomiting, rash, bleeding, hypertension, and hair loss. Existing health state descriptions of non-small cell lung cancer were adapted to represent descriptions of patients on first-line treatment. Twenty-three states were translated and assessed in cognitive debrief content validation interviews with oncologists in each country. Seventy-five respondents per country completed a time trade-off interview to evaluate the states. Variation between countries for all states was explored with a Generalized Estimating Equations model. The mean utility for "stable disease and no side effects" (base state) varied between 0.84 (United Kingdom) and 0.54 (Taiwan). The largest utility decrements were found for febrile neutropenia (0.47) and neutropenia (0.35) across all countries. Asian countries regarded bleeds as a severe toxicity whereas non-Asian countries did not and valued diarrhea and fatigue as more severe. Significant differences in utilities between countries emerged with the Taiwanese population in particular rating states as significantly worse than other countries. This study improves our understanding of how utilities for the same states can vary across countries. The study shows the importance of capturing utilities that reflect the preferences of the local population.


Role of cysteine residues and disulfide bonds in the activity of a legume root nodule-specific, cysteine-rich peptide.
The root nodules of certain legumes including Medicago truncatula produce >300 different nodule-specific cysteine-rich (NCR) peptides. Medicago NCR antimicrobial peptides (AMPs) mediate the differentiation of the bacterium, Sinorhizobium meliloti into a nitrogen-fixing bacteroid within the legume root nodules. In vitro, NCR AMPs such as NCR247 induced bacteroid features and exhibited antimicrobial activity against S. meliloti. The bacterial BacA protein is critical to prevent S. meliloti from being hypersensitive toward NCR AMPs. NCR AMPs are cationic and have conserved cysteine residues, which form disulfide (S-S) bridges. However, the natural configuration of NCR AMP S-S bridges and the role of these in the activity of the peptide are unknown. In this study, we found that either cysteine replacements or S-S bond modifications influenced the activity of NCR247 against S. meliloti. Specifically, either substitution of cysteines for serines, changing the S-S bridges from cysteines 1-2, 3-4 to 1-3, 2-4 or oxidation of NCR247 lowered its activity against S. meliloti. We also determined that BacA specifically protected S. meliloti against oxidized NCR247. Due to the large number of different NCRs synthesized by legume root nodules and the importance of bacterial BacA proteins for prolonged host infections, these findings have important implications for analyzing the function of these novel peptides and the protective role of BacA in the bacterial response toward these peptides.


Peripherally inserted central venous catheters and central venous catheters related thrombosis in post-critical patients.
Peripherally inserted central venous catheters (PICC) have been proposed as an alternative to central venous catheters (CVC). The aim of this study was to determine the thrombosis rate in relation to PICC placement in patients discharged from the intensive care unit (ICU). Data of patients admitted to the ICU (Careggi Teaching Hospital, Florence, Italy; January-August 2008) and discharged with a central venous device were sequentially studied. During the first 4 months, CVCs were used (CVC group), whereas during the last 4 months, PICCs were used (PICC group). Demographic/clinical and catheter-related data were collected. Intensivists performed Doppler examination at ICU discharge and 7, 15, and 30 days after placement. Data of 239 patients were analyzed (125 of CVC group, 114 of PICC group). A total of 2,747 CVC-days and 4,024 PICC-days of observation were included. Patient characteristics were comparable between groups. Patients with PICC had a significantly higher incidence rate of deep venous thrombosis (DVT) than patients with CVC (27.2 vs. 9.6%, P = 0.0012). The rate of DVT/1,000 catheter days was 4.4 for CVCs and 7.7 for PICCs. Eighty percent of DVTs occurred within 2 weeks after insertion. Binary logistic analysis showed a two-fold increased risk for women and a three-fold increased risk when using the left basilic vein in the PICC group. In our post-critically ill population, PICCs were associated with a higher rate of DVT complications than CVCs. Routine ultrasound surveillance for the first 2 weeks after patient discharge from the ICU with a PICC and preferential use of CVC for these patients may be warranted.


Angioplasty for renovascular hypertension in 78 children.
To evaluate the outcome of percutaneous transluminal angioplasty (PTA) in children with renovascular hypertension (RVH) treated at a single centre over 29 years. A retrospective study of the medical charts of all children with RVH who underwent PTA between 1984 and 2012. The primary outcome measurement was blood pressure (BP) achieved after the procedure. The BP before the procedure was compared with that at last available follow-up, 6 (range 0.6-16) years after the initial procedure. Seventy-eight children with median (range) age of 6.5 (0.5-17) years were studied. Twenty-three (29.5%) had an underlying syndrome, 35 (44.9%) children had bilateral renal artery stenosis (RAS), 18 (23%) intrarenal disease and 11(14%) showed bilateral RAS and intrarenal disease. Twenty (25.6%) children had mid-aortic syndrome and 14 (17.9%) cerebrovascular disease. One hundred and fourteen PTA procedures were carried out including 31 stent insertions. Following PTA, BP was improved in 49 (62.8%) children and of those 18 (23.1%) were cured. Children with involvement of only the main renal arteries showed improved BP control in 79.9% of the children with cure in 39.5%. BP was intentionally maintained above the 95th centile for age and height in four children with coexistent cerebrovascular disease. No change in BP was seen in 18 children despite observed technical success of the PTA, and in seven children due to technical failure of the procedure. PTA provided a clinical benefit in 62.8% of children with RVH.


[Levels of fatty acid binding protein before and after direct current cardioversion of atrial fibrillation or flutter in patients without acute coronary syndrome].
It is not known whether FABP suggested as an early marker of myocardial necrosis increases after direct current cardioversion (DCC). Moreover there are no data on FABP levels in patients with atrial fibrillation (AF) and flutter. To find out whether DCC induces acute changes of FABP levels in patients with AF or flutter without acute coronary syndrome. Serum FABP and troponin I (TnI) were measured in 63 pts treated with DCC (monophasic shocks) because of AF (n=45, 71.4%) or atrial flutter (n=18, 28.6%). Initial energy was 50J for atrial flutter and 200J for AF. Median total energy was 200J, max 660J. Blood was sampled before DCC and in 30, 60 min, 3, 6 h after first shock. TnI and FABP were measured with single-step sandwich method ("Hytest" Finland). Upper limit of normal range (ULN) for TnI was 0.4 ng/ml (recommended by manufacturer). Serum FABP was measured in healthy volunteers and 95th percentile was used as ULN (4.67 ng/ml). Most pts (n=40, 63.5%) had baseline FABP > ULN (median for all pts--5.55 ng/ml). In 11 pts (17.4%) baseline FABP was > 2 ULN. No relationship was found between baseline FABP and age, sex, duration of arrhythmia, concomitant ECG changes, and presence of overt coronary heart disease or clinical signs of heart failure. Median FABP level increased after DCC (p for trend 0.00014). FABP levels after DCC correlated with total delivered energy. Delivery of > or = 2 shocks compared with 1 shock was associated with higher FABP (median 60 min--9.65 and 5.24 ng/ml, p=0.009; 3 h--12.41 and 5.84 ng/ml, p=0.01, respectively). Median TnI levels were below ULN at each study point. After DCC TnI did not exceed ULN in 61 pts and remained unchanged in 2 pts with baseline TnI above ULN. Unexpectedly most pts with AF and atrial flutter had elevated FABP at baseline. After DCC FABP increased in proportion with total delivered energy. Elevations of FABP levels were not associated with rapid increases of TnI so skeletal muscle damage can be a likely cause of elevated FABP. AF, atrial flutter and DCC for these arrhythmias should be considered as sources of false positive results when FABP is used for diagnosis of acute myocardial infarction.


Management of anal canal cancer.
Chemoradiotherapy has replaced radical surgery as the initial treatment of choice for anal canal cancer. The roles of these therapeutic modalities are discussed and recommendations on management of anal canal cancer are made based on currently available evidence. Areas for further studies also are identified. Literature on management of anal canal cancer from January 1970 to July 2003 obtained via MEDLINE was reviewed. Reports on anal margin cancers were excluded. Randomized, prospective, Phase 3 trials in Europe and the United States showed that chemoradiotherapy with 5-fluorouracil and mitomycin C was superior in local control, colostomy-free rate, progression-free survival, and cancer-specific survival compared with radiation alone. In larger tumors, the addition of mitomycin C to radiotherapy and 5-fluorouracil improves local control, colostomy-free, and disease-free survival but is associated with more acute hematologic toxicity. Chemoradiotherapy, including Cisplatin and 5-fluorouracil, appeared to be equal or superior to surgery as salvage therapy in patients with residual disease six weeks after initial nonsurgical treatment. To improve treatment outcomes and reduce treatment-related toxicities, further studies are required to elucidate the optimal drug combination and doses, optimal radiation field, total dose, and fraction sizes. Randomized, multicenter trials are needed to define the treatment protocol that provides the highest rate of sphincter preservation with acceptable toxicity. Few studies addressed the treatment of metastatic disease, which remains a major cause of mortality.


A change in taste: the role of microRNAs in altering hedonic value.
The mechanisms associated with neophobia and anhedonia remain largely unknown. Neuropsychological disorders such as depression and schizophrenia are associated with excessive fear and anhedonia, and have been linked to microRNA 137. We hypothesized that microRNAs (miRNAs) in the snail Lymnaea stagnalis are important for regulating feeding behaviour through either preventing neophobia or establishing hedonic value. To test these hypotheses, we used an injection of poly-l-lysine (PLL) to inhibit miRNA biogenesis and observed its effects on feeding behaviour. We repeated these experiments with pre-exposure to novel stimuli capable of eliciting neophobia to disentangle the processes predicted to regulate feeding behaviour. Next, we exposed snails to food stimuli of high hedonic value after PLL injection to reset their hedonic value for that food. Finally, we consolidated our results with previous research by examining the effect of PLL injection on a one-trial appetitive classical conditioning procedure (1TT) to induce long-term memory (LTM). We found that miRNAs are likely not required for preventing neophobia. Moreover, we discovered that snails experienced anhedonia in response to inhibition of miRNA biogenesis, resulting in diminished feeding behaviour for food stimuli with a previously high hedonic value. Snails showed diminished feeding behaviour for multiple food stimuli of high hedonic value post-1TT with PLL injection. This finding suggests that PLL causes anhedonia rather than an impairment of LTM formation following the 1TT procedure. This is the first evidence suggesting that inhibiting the biogenesis of miRNAs contributes to anhedonia in L. stagnalis.


Primary healthcare clinicians.
The objective of the study was to measure implementation of telehealth for client consultations from Allied Health and Community Health clinicians' perspectives during the COVID-19 pandemic. Purposeful sampling was used to invite allied and community health clinicians to complete the survey. An online survey design, underpinned by normalisation process theory, utilising the NoMAD tool, which consists of 19 implementation assessment items. Descriptive statistics are reported. A 66% (n=24) response rate was obtained. Fifty-two percent indicated they were using telehealth for the first time. Despite the rapid implementation of telehealth for client consultations due to the pandemic crisis, participants reported positive perceptions of the use of telehealth when measured using the NoMAD. Fifty-eight percent (n=14) of respondents agreed or strongly agreed that telehealth will become a normal part of their work. Despite unplanned and under-resourced implementation of telehealth, Allied Health and Community Health clinicians reported very positive perceptions. However, further education and training to ensure 'normalisation' of this model may be required.


Common-path interferometric detection of protein monolayer on the BioCD.
The bio-optical compact disk (BioCD) is an optical biosensor that performs common-path molecular interferometry of patterned proteins on a disk spinning at high speed. The common-path configuration makes it ultrastable and allows surface height precision below 10 pm. In this paper we show that two complementary interferometric quadrature conditions exist simultaneously that convert the modulus and phase of the reflection coefficient, modulated by protein patterns on the disk surface, into intensity modulation at the detector. In the far field they separate into spatially symmetric and antisymmetric intensity modulation in response to the local distribution of protein. The antisymmetric response is equivalent to differential phase-contrast detection, and the symmetric response is equivalent to in-line (IL) common-path interferometry. We measure the relative sensitivities of these orthogonal channels to printed protein patterns on disk structures that include thermal oxide on silicon and Bragg dielectric stacks. The scaling mass sensitivity of the IL channel on oxide on silicon was measured to be 0.17 pg/mm.


On the location of gamma-aminobutyrate and benzodiazepine receptors in the cerebellum of the normal C3H and Lurcher mutant mouse.
Binding of gamma-aminobutyrate and benzodiazepine receptor ligands has been studied in the cerebellum of adult normal (C3H) and Lurcher mutant mice. The adult mutant has lost all Purkinje cells and more than 90% of the granule cells in the cerebellar cortex. When compared with their normal littermates Lurcher mice displayed large decreases in the number of high-affinity binding sites for [3H]muscimol, a synaptic gamma-aminobutyrate receptor ligand, in washed cerebellar homogenates. This observation was consistent with the extensive loss of gamma-aminobutyrate receptive Purkinje and granule cells from the Lurcher cerebellum. However, specific binding of the benzodiazepine-receptor ligand [3H]flunitrazepam to Lurcher cerebellum remained unchanged. Indeed quantitative autoradiography, employing [3H]flunitrazepam as a photoaffinity label, showed no significant differences in the density of labelling between Lurcher and normal littermate mice in any region of the cerebellum. These benzodiazepine binding sites in washed homogenates or tissue sections displayed a gamma-aminobutyrate-induced enhancement of [3H]flunitrazepam binding which occurred to the same extent in both Lurcher and normal cerebellum, a facilitatory effect which could be blocked by the addition of bicuculline methobromide. Our results suggest that a large proportion of the high-affinity, specific benzodiazepine binding sites in mouse cerebellum are not coupled to the synaptic gamma-aminobutyrate receptors thought to be labelled by high affinity [3H]muscimol binding. Further, that benzodiazepine binding sites do not appear to be enriched on either the soma or dendrites of Purkinje cells, as has been suggested from previous studies. Investigations at the electron microscope level are now required to elucidate the cellular location of benzodiazepine binding sites in the cerebellar cortex and to examine whether or not they are likely to be exposed to gamma-aminobutyrate in vivo.


Testing social-cognitive theory to explain physical activity change in adolescent girls from low-income communities.
The aim of this study was to test the hypothesized structural paths in Bandura's social-cognitive theory (SCT) model on adolescent girls' physical activity following a 12-month physical activity and dietary intervention to prevent obesity. We conducted a 12-month follow-up study of 235 adolescent girls (M(age) = 13.2 years, SD = 0.4) from 12 secondary schools located in low-income communities. At baseline, participants completed SCT scales related to physical activity (i.e., self-efficacy, intention, parental support, and outcome expectations). At baseline and 12-month follow-up (postintervention), participants wore accelerometers for 7 days. Structural equation modeling was used to determine if Time 1 measures predicted physical activity at 12-month follow-up after adjusting for baseline activity. The model explained 28% and 34% of the variance in physical activity and intention, respectively. Model fit indexes indicated the data were a good fit to the model; however, only self-efficacy was associated with physical activity at 12 months. There was no support for intention or outcome expectations as proximal determinants of behavior. Self-efficacy was associated with outcome expectations and parental support; however, only outcome expectations predicted intention. Current findings indicate a large proportion of the variance for physical activity and intention remains unexplained and that the proposed pathways in the SCT model were not fully supported. Future model testing may need to consider augmentation or integration of theoretical models, which may include ecological components if we are to advance our understanding of physical activity behavior in this subgroup of the adolescent population.


Evolution of endoscopic surgical therapy for Zenker's diverticulum.
Zenker's diverticulum is a rare anatomic defect that physicians have confronted for almost 250 years. Its location at the interface of the pharynx, neck, and mediastinum makes surgical access difficult and risks severe morbidity. Minimally invasive endoscopic surgical repair of Zenker's diverticulum has been attempted for more than a century as an alternative to reduce morbidity of an open transcervical approach. However, limitations due to available antibiotics, instrumentation, and laryngoscopes, as well as a general discomfort with a sutureless closure of the mucosal excision, have delayed widespread adoption of minimally invasive repair until the last 10 to 15 years. This manuscript will detail the historical evolution of endoscopic surgical therapy for Zenker's diverticulum and highlight the work of two otolaryngologists, Chevalier Jackson and Gosta Dohlman, who were critical in advancing the surgical technique and reducing morbidity. Lastly, this manuscript will analyze the delay in widespread application of endoscopic surgical repair of Zenker's diverticulum.


Focal Segmental Glomerulosclerosis Associated with Chronic Progressive External Ophthalmoplegia and Mitochondrial DNA A3243G Mutation.
Focal segmental glomerulosclerosis (FSGS) is caused by various etiologies, with mitochondrial dysfunction being one of the causes. FSGS is known to be associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), which is a subclass of mitochondrial disease. However, it has rarely been reported in other mitochondrial disease subclasses. Here, we reported a 20-year-old man diagnosed with FSGS associated with chronic progressive external ophthalmoplegia (CPEO) due to mitochondrial DNA (mtDNA) 3243A>G mutation. He presented with left ptosis, short stature, mild sensorineural deafness, and cardiac conduction block. A renal biopsy sample showed segmental sclerosis and adhesions between capillaries and Bowman's capsule, indicating FSGS. Electron microscopy demonstrated abnormal aggregated mitochondria in podocytes, and the basement membrane and epithelial cells of Bowman's capsule. Skeletal muscle biopsy also showed accumulation of abnormal mitochondria. mtDNA analysis identified heteroplasmic mtDNA 3243A>G mutation with no large-scale deletions. From these findings, we diagnosed the case as CPEO with multi-organ involvement including FSGS. Our report demonstrates that CPEO, as well as MELAS, can be associated with FSGS. Because mitochondrial disease presents with a variety of clinical symptoms, atypical cases with non-classical manifestations are observed. Thus, mitochondrial disease should be considered as an underlying cause of FSGS with systemic manifestations even with atypical phenotypes.


Serological and Molecular Investigation of Batai Virus Infections in Ruminants from the State of Saxony-Anhalt, Germany, 2018.
Arthropod-borne Batai virus (BATV) is an Orthobunyavirus widely distributed throughout European livestock and has, in the past, been linked to febrile diseases in humans. In Germany, BATV was found in mosquitoes and in one captive harbor seal, and antibodies were recently detected in various ruminant species. We have, therefore, conducted a follow-up study in ruminants from Saxony-Anhalt, the most affected region in Eastern Germany. A total of 325 blood samples from apparently healthy sheep, goats, and cattle were tested using a BATV-specific qRT-PCR and SNT. Even though viral RNA was not detected, the presence of antibodies was confirmed in the sera of all three species: sheep (16.5%), goats (18.3%), and cattle (41.4%). Sera were further analyzed by a glycoprotein Gc-based indirect ELISA to evaluate Gc-derived antibodies as a basis for a new serological test for BATV infections. Interestingly, the presence of neutralizing antibodies was not directly linked to the presence of BATV Gc antibodies. Overall, our results illustrate the high frequency of BATV infections in ruminants in Eastern Germany.


The Effect of Dexamethasone Intravitreal Implant on Retinal Nerve Fiber Layer in Patients Diagnosed with Branch Retinal Vein Occlusion.
To evaluate the effect of a single dose of intravitreal dexamethasone (DEX) implant on retinal nerve fiber layer (RNFL) thickness in patients with branch retinal vein occlusion (BRVO) in a 6-month period. This retrospective observational study included the patients with BRVO who received intravitreal DEX implant and whose assessment included the baseline RNFL thickness measurements. The data of 26 eyes of 24 patients were retrospectively analyzed. Spectral domain optic coherence tomography was used to measure peripapillary RNFL thickness in six regional subfields. Intraocular pressure (IOP) values at each visit were recorded. The data of single dose DEX implant during 6 months were assessed. The mean preoperative and postoperative 6th month nasal RNFL values were 85.4 ± 23.0 μm and 82.1 ± 17.6 μm, respectively, and the difference between the measurements was not statistically significant (p = 0.372). There was a slight decrease in the mean RNFL values postoperatively compared to the baseline values in all quadrants except supero-temporal quadrant; however, none of them reached statistically significant level (p > 0.05). The mean IOP values before and 6 months after implantation were 15.7 ± 2.9 mmHg and 16.5 ± 4.2 mmHg, respectively. The difference between the 6th month IOP values and baseline IOP values was not statistically significant (p = 0.236). Intravitreal DEX implant seems to have no adverse effect on RNFL thickness in BRVO patients in a 6-month period.


MArVD2: a machine learning enhanced tool to discriminate between archaeal and bacterial viruses in viral datasets.
Our knowledge of viral sequence space has exploded with advancing sequencing technologies and large-scale sampling and analytical efforts. Though archaea are important and abundant prokaryotes in many systems, our knowledge of archaeal viruses outside of extreme environments is limited. This largely stems from the lack of a robust, high-throughput, and systematic way to distinguish between bacterial and archaeal viruses in datasets of curated viruses. Here we upgrade our prior text-based tool (MArVD) via training and testing a random forest machine learning algorithm against a newly curated dataset of archaeal viruses. After optimization, MArVD2 presented a significant improvement over its predecessor in terms of scalability, usability, and flexibility, and will allow user-defined custom training datasets as archaeal virus discovery progresses. Benchmarking showed that a model trained with viral sequences from the hypersaline, marine, and hot spring environments correctly classified 85% of the archaeal viruses with a false detection rate below 2% using a random forest prediction threshold of 80% in a separate benchmarking dataset from the same habitats.


Dietary intakes of dioxins and polychlorobiphenyls (PCBs) and breast cancer risk in 9 European countries.
Dioxins and polychlorobiphenyls (PCBs) are persistent organic pollutants that have demonstrated endocrine disrupting properties. Several of these chemicals are carcinogenic and positive associations have been suggested with breast cancer risk. In general population, diet represents the main source of exposure. Associations between dietary intake of 17 dioxins and 35 PCBs and breast cancer were evaluated in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort from nine European countries using multivariable Cox regressions. The present study included 318,607 women (mean ± SD age: 50.7 ± 9.7) with 13,241 incident invasive breast cancers and a median follow-up of 14.9 years (IQR = 13.5-16.4). Dietary intake of dioxins and PCBs was assessed combining EPIC food consumption data with food contamination data provided by the European Food Safety Authority. Exposure to dioxins, dioxins + Dioxin-Like-PCBs, Dioxin-Like-PCBs (DL-PCBs), and Non-Dioxin-Like-PCBs (NDL-PCBs) estimated from reported dietary intakes were not associated with breast cancer incidence, with the following hazard ratios (HRs) and 95% confidence intervals for an increment of 1 SD: HRdioxins = 1.00 (0.98 to 1.02), HRdioxins+DL-PCB = 1.01 (0.98 to 1.03), HRDL-PCB = 1.01 (0.98 to 1.03), and HRNDL-PCB = 1.01 (0.99 to 1.03). Results remained unchanged when analyzing intakes as quintile groups, as well as when analyses were run separately per country, or separating breast cancer cases based on estrogen receptor status or after further adjustments on main contributing food groups to PCBs and dioxins intake and nutritional factors. This large European prospective study does not support the hypothesis of an association between dietary intake of dioxins and PCBs and breast cancer risk.


Chronic Therapy-Resistant Neck Pain in a Fifty-Year-Old Man: The Role of Partially Impacted Third Molars - Case Report and New Pathophysiological Insights.
Inflammatory and mechanical stimuli in tooth/jaw pathologies can have far-reaching consequences via trigeminal and autonomic circuitry and can cause systemic (e.g., autoimmune) diseases and pain conditions outside the tooth/jaw region. In addition to a case report, we also describe new pathophysiological findings. We report on a patient with chronic, therapy-resistant neck pain whose cause lied in the tooth/jaw region, specifically, in wisdom teeth with space problems, and partially impacted. The tooth/jaw area itself was not painful; however, neck pain developed via the nucleus spinalis n. trigemini which extends into the cervical medulla. Surgical restoration of the wisdom teeth and subsequent neural therapy treatment of the extraction scars provided permanent pain relief. In case of therapy-resistant neck pain (among others), it is worthwhile to look for pathologies in the dental/jaw area, possibly allowing for a causal therapy.


Prepared for Mission? A Survey of Medical Personnel Training Needs Within the International Committee of the Red Cross.
Humanitarian organizations such as the International Committee of the Red Cross (ICRC) provide worldwide protection and medical assistance for victims of disaster and conflict. It is important to gain insight into the training needs of the medical professionals who are deployed to these resource scarce areas to optimally prepare them. This is the first study of its kind to assess the self-perceived preparedness, deployment experiences, and learning needs concerning medical readiness for deployment of ICRC medical personnel. All enlisted ICRC medical employees were invited to participate in a digital questionnaire conducted during March 2017. The survey contained questions about respondents' personal background, pre-deployment training, deployment experiences, self-perceived preparedness, and the personal impact of deployment. The response rate (consisting of nurses, surgeons, and anesthesiologists) was 54% (153/284). Respondents rated their self-perceived preparedness for adult trauma with a median score of 4.0 on a scale of 1 (very unprepared) to 5 (more than sufficient); and for pediatric trauma with a median score of 3.0. Higher rates of self-perceived preparedness were found in respondents who had previously been deployed with other organizations, or who had attended at least one master class, e.g., the ICRC War Surgery Seminar (p < 0.05). Additional training was requested most frequently for pediatrics (65/150), fracture surgery (46/150), and burns treatment (45/150). ICRC medical personnel felt sufficiently prepared for deployment. Key points for future ICRC pre-deployment training are to focus on pediatrics, fracture surgery, and burns treatment, and to ensure greater participation in master classes.


The use of drains following thyroid and parathyroid surgery: a meta-analysis.
The use of suction drains following thyroid and parathyroid surgery is controversial. Although there have been several prospective and retrospective studies carried out on this subject, no paper had sufficient power to provide a suitable answer to whether or not drains should be used routinely. We present the first formal meta-analysis of the data from eight randomized controlled trials on this subject. The result of the meta-analysis showed that there is no difference in complication rates between patients in whom drains have been used routinely and those in whom they have not.


Fentanyl for neuropathic pain in adults.
Opioid drugs, including fentanyl, are commonly used to treat neuropathic pain, and are considered effective by some professionals. Most reviews have examined all opioids together. This review sought evidence specifically for fentanyl, at any dose, and by any route of administration. Other opioids are considered in separate reviews. To assess the analgesic efficacy of fentanyl for chronic neuropathic pain in adults, and the adverse events associated with its use in clinical trials. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase from inception to June 2016, together with the reference lists of retrieved articles, and two online study registries. We included randomised, double-blind studies of two weeks' duration or longer, comparing fentanyl (in any dose, administered by any route, and in any formulation) with placebo or another active treatment in chronic neuropathic pain. Two review authors independently searched for studies, extracted efficacy and adverse event data, and examined issues of study quality and potential bias. We did not carry out any pooled analyses. We assessed the quality of the evidence using GRADE. Only one study met our inclusion criteria. Participants were men and women (mean age 67 years), with postherpetic neuralgia, complex regional pain syndrome, or chronic postoperative pain. They were experiencing inadequate relief from non-opioid analgesics, and had not previously taken opioids for their neuropathic pain. The study used an enriched enrolment randomised withdrawal design. It was adequately blinded, but we judged it at unclear risk of bias for other criteria.Transdermal fentanyl (one-day fentanyl patch) was titrated over 10 to 29 days to establish the maximum tolerated and effective dose (12.5 to 50 µg/h). Participants who achieved a prespecified good level of pain relief with a stable dose of fentanyl, without excessive use of rescue medication or intolerable adverse events ('responders'), were randomised to continue with fentanyl or switch to placebo for 12 weeks, under double-blind conditions. Our prespecified primary outcomes were not appropriate for this study design, but the measures reported do give an indication of the efficacy of fentanyl in this condition.In the titration phase, 1 in 3 participants withdrew because of adverse events or inadequate pain relief, and almost 90% experienced adverse events. Of 258 participants who underwent open-label titration, 163 were 'responders' and entered the randomised withdrawal phase. The number of participants completing the study (and therefore continuing on treatment) without an increase of pain by more than 15/100 was 47/84 (56%) with fentanyl and 28/79 (35%) with placebo. Because only 63% responded sufficiently to enter the randomised withdrawal phase, this implies that only a maximum of 35% of participants entering the study would have had useful pain relief and tolerability with transdermal fentanyl, compared with 22% with placebo. Almost 60% of participants taking fentanyl were 'satisfied' and 'very satisfied' with their treatment at the end of the study, compared with about 40% with placebo. This outcome approximates to our primary outcome of moderate benefit using the Patient Global Impression of Change scale, but the group was enriched for responders and the method of analysis was not clear. The most common adverse events were constipation, nausea, somnolence, and dizziness.There was no information about other types of neuropathic pain, other routes of administration, or comparisons with other treatments.We downgraded the quality of the evidence to very low because there was only one study, with few participants and events, and there was no information about how data from people who withdrew were analysed. There is insufficient evidence to support or refute the suggestion that fentanyl works in any neuropathic pain condition.


RWJF's future of nursing's campaign for action: A content analysis of social determinants of health activities.
The RWJF-sponsored 2010 report, The Future of Nursing: Leading Change, Advancing Health (FoN), fostered creation of the Campaign for Action (Campaign) as a mechanism to monitor and enact the FoN report's recommendations. Influenced by RWJF's Culture of Health initiative, Campaign efforts refocused to include the social determinants of health (SDOH), with an additional action area entitled "Building Healthier Communities" (BHC). This study describes nursing activities in the BHC action area relative to the six initial FoN core action areas and assesses the extent to which nursing actions in the BHC action area align with public health conceptions of the SDOH. A content analysis was conducted of the RWJF's Campaign issue blog posts on 51 state Action Coalition websites from January 2011 to August 2018. Results demonstrate a decline in blog posts among the six FoN action areas over time compared to an increase in the BHC action area. BHC blog posts of nursing activities included predominantly stories and events, with few interventions. Although the Campaign's definition of the SDOH aligns with definitions from public health, posted actions do not. Re-evaluation of the Campaign' tagging process is needed so system-level conceptualizations can be integrated into the Campaign's next iteration for categorizing SDOH-driven interventions.


Cross-education of muscle strength is greater with stimulated than voluntary contractions.
Cross-education enhances the performance of muscles not directly involved in the chronic conditioning of the muscles in a remote limb. Substantial cross-education occurs after training with eccentric contractions or with contractions evoked by electromyostimulation (EMS). Since during EMS and eccentric contractions, skin and muscle afferents are activated that have excitatory effects on contralateral homologous muscles, it was hypothesized that exercise training with stimulated vs. voluntary eccentric contractions would lead to greater cross-education. Thirty-two women were randomly assigned to a voluntary (Vol), an EMS, or remote EMS (rEMS) exercise group and performed 840 voluntary or stimulated eccentric contractions over 6 weeks. All subjects, including nonexercising controls (Con), were tested pre- and posttraining for maximal voluntary and stimulated isometric and eccentric quadriceps strength. Ipsilateral voluntary and stimulated forces increased in all groups. Changes in EMG activity paralleled those in voluntary force in each limb. No changes occurred in grip strength. The great contra- and ipsilateral strength gains after EMS training were most likely related to an additive effect of EMS and muscle lengthening.


Guishaozichuan granules can attenuate asthma in rats via the MUC5AC/EGFR signaling pathway.
Background: Guishaozichuan (GSZC) granules are a traditional Chinese medicine formulation created by Professor Li (Chinese-Japanese Friendship Hospital, Beijing, China) we studied the effect of GSZC granules in rats suffering from asthma. Methods: Specific pathogen-free Sprague-Dawley rats were divided randomly into seven groups. Ovalbumin (OVA) and Al (OH)3 gel were used to create an asthma model. On day 1, rats were injected with OVA (10 mg) and an Al(OH)3 gel suspension (100 mg). One week later, rats were sensitized again. On day 15, rats were given aerosolized OVA (1%) for 30 min/day for 10 days. Gastric administration of OVA was 1 h before nebulization. At 24 h after the last stimulation, changes in airway resistance (RI) and dynamic compliance (Cdyn) in rat lungs were measured after challenge with methacholine at increasing concentrations. The contents of immunoglobulin (Ig)E, interleukin (IL)-4, IL-5, IL-13, and IL-17 in serum were measured by enzyme-linked immunosorbent assays. The percentage of eosinophils (EOS) and the white blood cell (WBC) count in bronchoalveolar lavage fluid (BALF) were counted under an optical microscope. Pathologic alterations in lung tissue were evaluated by optical microscopy, and lung injury score calculated. Expression of mucin 5AC, oligomeric mucus/gel-forming (MUC5AC) and epidermal growth factor receptor (EGFR) in lung tissue was measured by immunohistochemistry. mRNA expression of MUC5AC and EGFR in lung tissue was measured by real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Results: GSZC granules reduced RI markedly and improved Cdyn, decreased serum levels of IgE, IL-4, IL-5, IL-13, IL-17, %EOS and the WBC count in BALF. GSZC granules alleviated lung-tissue damage, diminished the Inflammation Score, and reduced mRNA and protein expression of MUC5AC and EGFR in lung tissue. Conclusion: GSZC granules could improve bronchial hyperresponsiveness, bronchial inflammation, and histopathologic damage in the lungs of rats suffering from asthma. This phenomenon may be related to its regulation of cytokine levels and the MUC5AC/EGFR signaling pathway.


[Clinical study of catamenial epilepsy: significance of the presence of a previous cerebral lesion].
Four hundred thirty one epileptic patients, aged 10 years or more old, have been studied in the neurology clinic of Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da U.S.P., from February to July, 1981. The authors selected 119 patients aged between 13 to 45 years, that presented periodic menstrual bleeding and at least, one epileptic seizure a month. The patients were divided in two groups, the first constituted of 36 patients with catamenial seizures and the second one with 83 patients showing non catamenial seizures. The authors compare the number of pictures suggestive of "organic lesions" found in both groups. The statistical analysis shows that there are no differences between the two groups. The authors registered the EEG findings of these patients.


Advancement in the research on vascular endothelial growth inhibitor (VEGI).
Vascular endothelial growth inhibitor (VEGI), also known as tumor necrosis factor superfamily member 15 or TNF ligand-related molecule 1, is identified as one kind of antiangiogenic cytokine that belongs to the tumor necrosis factor superfamily. VEGI includes three isoforms: VEGI-174, VEGI-192, and VEGI-251. VEGI can activate multiple signaling pathways including nuclear factor-kappaB, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase. Moreover, it suppresses endothelial cell proliferation, angiopoiesis, and tumor growth. Genetic engineering techniques have been used to produce recombinant human vascular endothelial growth inhibitor, and great progress has been made in its application for curing cancer. VEGI could serve as a potential target in the development of angiogenesis-based cancer therapy, and this paper briefly summarizes the progress of the research on VEGI.


On the Bumpy Road to the Dominant Mode.
Maximum likelihood estimation in many classical statistical problems is beset by multimodality. This article explores several variations of deterministic annealing that tend to avoid inferior modes and find the dominant mode. In Bayesian settings, annealing can be tailored to find the dominant mode of the log posterior. Our annealing algorithms involve essentially trivial changes to existing optimization algorithms built on block relaxation or the EM or MM principle. Our examples include estimation with the multivariate t distribution, Gaussian mixture models, latent class analysis, factor analysis, multidimensional scaling and a one-way random effects model. In the numerical examples explored, the proposed annealing strategies significantly improve the chances for locating the global maximum.


Genesis of home care in Brazil at the start of the twentieth century.
Objective to discuss the conditions that enabled home care at the beginning of the twentieth century. Method study of the genealogic inspiration on home care. The empirical material consisted of legal documents on the subject that were published in the Official Journal. The documents were studied using analytical tools, such as Power, Discipline and Biopolitics, which were inspired in Foucault. Results two analytical categories were established, "home inspection: visiting nurses and tuberculosis" and "records: political and economic apparatus". Final considerations tuberculosis, the new profession of visiting nurses, inspection records and the detailed analysis of the cities grant home care a nature of surveillance, inspection and control to conduct the behaviour of individuals.


Association of Barrett's esophagus with type II Diabetes Mellitus: results from a large population-based case-control study.
Central obesity could increase the risk for Barrett's esophagus (BE) and esophageal adenocarcinoma by mechanical and/or metabolic mechanisms, such as hyperinsulinemia. We performed an epidemiologic study to determine whether prior type 2 diabetes mellitus (DM2) is associated with BE. We performed a population-based case-control study using the General Practice Research Database, a UK primary care database that contains information on more than 8 million subjects, to identify cases of BE (using previously validated codes; n = 14,245) and matched controls without BE (by age, sex, enrollment date, duration of follow-up evaluation, and practice region by incidence density sampling; n = 70,361). We assessed the association of a prior diagnosis of DM2 with BE using conditional univariate and multivariable regression analysis. Confounders assessed included smoking, obesity measured by body mass index (BMI), and gastroesophageal reflux disease. BE cases were more likely than controls to have smoked (52.4% vs 49.9%), have a higher mean BMI (27.2 vs 26.9), and a higher prevalence of DM2 than controls (5.8% vs 5.3%). On multivariable analysis, DM2 was associated with a 49% increase in the risk of BE, independent of other known risk factors (odds ratio, 1.49; 95% confidence interval, 1.16-1.91). This association was stronger in women than men. Results remained stable with sensitivity analyses. In a large population-based case-control study, DM2 was a risk factor for BE, independent of obesity (as measured by BMI) and other risk factors (smoking and gastroesophageal reflux disease). These data suggest that metabolic pathways related to DM2 should be explored in BE pathogenesis and esophageal carcinogenesis.


Sodium glucose co-transporter 2 inhibitors and cardiovascular event protections: how applicable are clinical trials and observational studies to real-world patients?
This study evaluated the characteristics of new users of sodium glucose co-transporter 2 inhibitors (SGLT2i) in clinical practice to assess the applicability of the findings from clinical trials (Empagliflozin, Cardiovascular Outcomes and Mortality in Type 2 Diabetes (EMPA-REG OUTCOME) trial, Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 trial, Canagliflozin Cardiovascular Assessment Study (CANVAS) program and the Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes (VERTIS-CV) trial) and multinational observational studies (CVD-REAL Nordic study and CVD-REAL 2 study). We conducted a retrospective cohort study using the largest electronic medical records database from seven hospitals in Taiwan. We included adult patients with type 2 diabetes initiating canagliflozin, dapagliflozin and empagliflozin between 1 January 2018 and 31 August 2019. We compared the patient characteristics with SGLT2i to examine the data representativeness of clinical trials and to evaluate channeling uses between canagliflozin, dapagliflozin and empagliflozin. We identified a cohort of 11 650 patients newly initiating SGLT2i, 49.9% of whom received empagliflozin. However, only 18.7%, 19.2%, 50.4% and 57.3% of real-world SGLT2i new users were included in the EMPA-REG OUTCOME trial, VERTIS-CV trial, DECLARE-TIMI 58 trial and CANVAS program, respectively. Reasons for exclusion were largely reduced cardiovascular disease risks in real-world patients, namely 72.8%, 73.6% and 34.2% for EMPA-REG OUTCOME trial, VERTIS-CV trial and DECLARE-TIMI 58 trial and CANVAS program, respectively. However, hemoglobin A1c out of range accounted for the most frequent reason (25.0%) for exclusion of real-world patients from the CANVAS program. We found channeling uses in different SGLT2i, for example, more patients receiving empagliflozin (15.3%) and canagliflozin (19.6%) had poorer renal functions (eg, estimated glomerular filtration rate <60 mL/min/1.73 m2), compared with dapagliflozin (9.3%). The findings provide clear evidence that results from current studies may be less applicable to real-world patients. Further studies are required to support the concept of real-world cardiovascular event protection through SGLT2i.


Epidemiology of thrombotic-hemostatic factors and their associations with cardiovascular disease.
Abundant evidence proves that thrombosis is involved in the acute presentation of coronary, cerebrovascular, and peripheral vascular diseases. However, the role of thrombotic factors in the development of the atherosclerotic lesions themselves has been more difficult to prove. This difficulty has been due, at least in part, to several methodologic issues in the study of hemostatic factors and cardiovascular disease (CVD). These include the possibility that associations between CVD and hemostatic factors may not be causal but rather due to confounding by other factors, acting as part of an extended causal pathway or requiring interaction with other risk factors or atherosclerotic disease, or may result from disease rather than causing the disease. In addition, several challenges remain in the measurement of hemostatic factors. Nonetheless, a growing number of studies have examined the association of CVD with coagulation factors (fibrinogen, factor VII, factor VIII, and platelet aggregability) and fibrinolytic factors [tissue plasminogen activator, plasminogen activator inhibitor 1, lipoprotein(a), and plasminogen or global fibrinolytic activity]. Of these, only for fibrinogen is there significant, strong, and consistent evidence of a causal association. Given the preliminary nature of these associations, any association between dietary factors and hemostatic factors other than fibrinogen is difficult to invoke as evidence for a deleterious effect of diet on CVD risk via thrombogenic mechanisms.


[Impaction of button batteries in the esophagus: a potentially fatal surgical emergency in infancy].
With the recent popularization of button batteries, the incidence of cases of children who ingest them has risen. Unlike other foreign bodies, button batteries are more likely to develop severe complications due to the possibility of early injury to the tissues in direct contact with them. We present the case of a 22-month-old boy who ingested a button battery which subsequently became lodged in the cervical esophagus. The endoscopic attempt to remove the battery failed, requiring an open esophagotomy for its extraction. In the postoperative period, he presented an esophagocutaneous fistula that closed spontaneously, and an esophageal stricture that was treated successfully with endoscopic balloon dilations. We reviewed the literature analyzing the recommendations recently outlined and contrasted them with our own protocol for management of ingested foreign bodies. In addition, measures aimed at reducing the risk of button battery ingestion in small children are proposed to the electronics manufacturing industry.


The Need for School Nursing in Spain: A Mixed Methods Study.
Background: Teachers are not trained or feel prepared for urgent action. Nevertheless, the presence of children with health problems is relevant. We identified vital health risk problems and complications among students, as well as the related training and perception of teachers. Methods: An explanatory sequential design was employed. The study sample consisted of a cross-sectional study of an intentional nonprobabilistic sample of 3246 teachers in the quantitative phase, and a total of 16 semistructured interviews were conducted in its qualitative phase. Results: 56.6% (1837) of teachers show high concern about facing such situations and only 0.6% (19) feel appropriately trained. For 81.8% (2556), the existence of school nursing would be quite relevant. The presence of nursing professionals in schools could lead to an improvement in the quality of life of both the students and teachers. Conclusions: There is a significant percentage of children with diseases that often require specific care and there is a high probability that teachers, throughout their professional lives, have to deal with situations of vital urgency. The presence of professionals in educational centres seems to be a relevant option. These data suggest that it is necessary for nurses to establish a pilot programme for the incorporation of professional nurses in educational centres to determine its implications, benefits in health prevention and promotion issues, as well as costs.


Point-of-care anti-CD19 chimeric antigen receptor T-cell therapy for relapsed/refractory follicular lymphoma.
Patients with relapsed/refractory follicular lymphoma (R/R-FL) often require multiple treatment lines. We performed a phase 1b/2 single-center clinical trial of autologous point-of-care anti-CD19 chimeric antigen receptor (CAR) T-cells in R/R-FL patients treated patients with ≥ 2 treatment lines. All 26 patients enrolled received CAR T-cell infusion at a median of 11 days after leukapheresis. Seventy-seven percent of patients had POD24. At enrollment, disease stage was III-IV in 85% of the patients, 77% had high-risk FLIPI score, and 77% had progressive disease. Grade III-IV cytokine release and immune effector cell-associated neurotoxicity syndromes occurred in 12% and 16% of the patients, respectively. Overall response rate at 1-month was 88%. The median follow-up was 15.4 months. One-year overall and progression-free survival were 100% and 63%, respectively. In conclusion, point-of-care CAR T-cell, manufactured within 11 days, induced a high response rate with an acceptable safety profile in patients with high-risk R/R-FL.


[Effect of the culture technic on results following corneal preservation].
Organ culture of human donor material extends post mortem storage times up to 4 weeks. If dextrane is omitted from the medium, as in the authors' current technique, a stromal swelling occurs which can be reserved preoperatively. The authors also report on their experience with organ culture of donor material in a culture medium containing dextrane. Short-term incubation of donor tissue in culture medium at 32 degrees C containing dextrane may be possible as an alternative to the MK technique, in which the donor tissue is kept at 4 degrees C. All methods have specific advantages and disadvantages, not only in laboratory handling but also in the postoperative development of the graft.


Lyplal1 is dispensable for normal fat deposition in mice.
Genome-wide association studies (GWAS) have detected association between variants in or near the Lysophospholipase-like 1 (LYPLAL1) locus and metabolic traits, including central obesity, fatty liver and waist-to-hip ratio. LYPLAL1 is also known to be upregulated in the adipose tissue of obese patients. However, the physiological role of LYPLAL1 is not understood. To investigate the function of Lyplal1 in vivo we investigated the phenotype of the Lyplal1tm1a(KOMP)Wtsi homozygous mouse. Body composition was unaltered in Lyplal1 knockout mice as assessed by dual-energy X-ray absorptiometry (DEXA) scanning, both on normal chow and on a high-fat diet. Adipose tissue distribution between visceral and subcutaneous fat depots was unaltered, with no change in adipocyte cell size. The response to both insulin and glucose dosing was normal in Lyplal1tm1a(KOMP)Wtsi homozygous mice, with normal fasting blood glucose concentrations. RNAseq analysis of liver, muscle and adipose tissue confirmed that Lyplal1 expression was ablated with minimal additional changes in gene expression. These results suggest that Lyplal1 is dispensable for normal mouse metabolic physiology and that despite having been maintained through evolution Lyplal1 is not an essential gene, suggesting possible functional redundancy. Further studies will be required to clarify its physiological role.


Relationship of Maxillary Sinus Mucosal Thickening and Residual Alveolar Ridge Height: A CBCT Analysis.
Objectives: Maxillary sinus pathological conditions, like thickening of the Schneiderian membrane, can influence the outcomes of augmentation procedures and implant treatment. The present study aimed to evaluate the relationship between the residual ridge height and maxillary sinus membrane thickening. Materials and Methods: A total of 240 cone-beam computed tomography (CBCT) images of the maxillary sinus of 141 patients (62.1% males and 37.9% females, bilateral in 99 patients and unilateral in 42 patients) who were candidates for implant placement were evaluated. The CBCT scans were subsequently assessed for the following variables: residual ridge height, sinus membrane thickening at future implant(s) site(s), the ostium patency, and presence of periapical lesion adjacent to the edentulous area. Results: The total prevalence of sinus membrane thickening (66.2%) was sub-classified as follows: flat in 53.7%, polypoid in 12.1%, and complete opacification in 0.4%. The prevalence of sinus membrane thickening was higher in male participants. It was revealed that age had no significant relationship with presence of a periapical lesion or sinus membrane thickening (P>0.05). Membrane thickening was detected in all sinuses with obstructed ostium. Reduced residual ridge height was significantly associated with higher sinus membrane thickening at the second premolar and first molar sites (P<0.05). Conclusion: Maxillary sinus membrane thickening (mostly with flat appearance) is frequently observed on CBCT scans taken prior to augmentation and implant placement. This, in return, may trigger a reduction in ridge height.


[Preauricular tags: prevalence, clinical characteristics and maternal risk factors].
To determine prevalence and maternal risk factors associated with preauricular tags. A case-control study of 254 newborns with isolated preauricular tags not considered part of a syndrome and their controls, and who were delivered at the Hospital Civil de Guadalajara Dr. Juan I. Menchaca between 1990 and 2003. The maternal risk factors were demonstrated by means of a direct interview with the mother. The prevalence of the isolated preauricular tags was 1.96 per 1,000 newborns alive, in a 1.2 men for each woman. The history of another affected relative was strongly associated with preauricular tags (OR 19.28; 95% CI: 4.44-117.60). Infants with preauricular tags frequently showed parents consanguinity (OR 3.04; 95% CI: 0.28-76.26), maternal age > or =35 years (OR 1.14; 95% CI: 0.53-2.48), exposure to some disease (OR: 1.23, 95% CI: 0.72-2.12), and drugs use in the first trimester of pregnancy (OR: 1.11; 95% CI: 0.65-1.92). No associations were found for the frequency of abortion, exposure to organic solvents and maternal occupation. The prevalence of isolated preauricular tags in this population was similar to that reported in other regions of Latin America, but lower to the prevalences in Sweden and Israel. This malformation has an important hereditary component; however, it is probably that some teratogenic factors, such as diabetes mellitus, can increase its frequency.


Zygomycotic lymphadenitis in slaughtered feedlot cattle.
During the 12 months of 2006, zygomycotic lymphadenitis was diagnosed in 194 of 198 feedlot steers (0.04% of cattle slaughtered during that period) in a California slaughterhouse as part of bovine tuberculosis surveillance. Mesenteric lymph nodes were involved in 190 cases. Affected lymph nodes were enlarged (2 to 42 cm in greatest dimension), firm, and mottled gray-white to yellow with multiple granular or caseocalcareous foci. Histologically, nodal architecture was effaced by necrosis, granulomatous inflammation, and fibrosis. In approximately 20% of the cases, granulomas were mainly restricted to subcapsular sinuses and afferent lymphatic vessels, causing granulomatous lymphangitis. Nonseptate, irregularly branching hyphae with nonparallel walls and bulbous enlargements were common in necrotic areas and within the cytoplasm of multinucleated giant cells. Fungal cultures were performed on 124 affected lymph nodes using 7 media, but no zygomycetes were cultured. Fungal DNA was amplified from 20 lymph nodes. Amplicons from 16 nodes had nearly 100% homology with sequences for Rhizomucor pusillus; 4 amplicons had (> 98%) homology with Absidia corymbifera sequences. Zygomycosis should be considered in the differential diagnosis for granulomatous lymphadenitis in feedlot steers.


Metformin repositioning as antitumoral agent: selective antiproliferative effects in human glioblastoma stem cells, via inhibition of CLIC1-mediated ion current.
Epidemiological and preclinical studies propose that metformin, a first-line drug for type-2 diabetes, exerts direct antitumor activity. Although several clinical trials are ongoing, the molecular mechanisms of this effect are unknown. Here we show that chloride intracellular channel-1 (CLIC1) is a direct target of metformin in human glioblastoma cells. Metformin exposure induces antiproliferative effects in cancer stem cell-enriched cultures, isolated from three individual WHO grade IV human glioblastomas. These effects phenocopy metformin-mediated inhibition of a chloride current specifically dependent on CLIC1 functional activity. CLIC1 ion channel is preferentially active during the G1-S transition via transient membrane insertion. Metformin inhibition of CLIC1 activity induces G1 arrest of glioblastoma stem cells. This effect was time-dependent, and prolonged treatments caused antiproliferative effects also for low, clinically significant, metformin concentrations. Furthermore, substitution of Arg29 in the putative CLIC1 pore region impairs metformin modulation of channel activity. The lack of drugs affecting cancer stem cell viability is the main cause of therapy failure and tumor relapse. We identified CLIC1 not only as a modulator of cell cycle progression in human glioblastoma stem cells but also as the main target of metformin's antiproliferative activity, paving the way for novel and needed pharmacological approaches to glioblastoma treatment.


Time course and zonal variations of ischemia-induced myocardial cationic electrolyte derangements.
Myocardial cationic electrolytes were determined at regular time intervals up to 24 hours after coronary artery ligation in the dog. Replicate electrolyte ratios were computed for different areas of the heart at each time interval. For purposes of statistical analysis, ratios from two border areas and four areas remote from the infarct were pooled as values for ZONE B and ZONE N, respectively, and compared with those from the infarct proper, ZONE I. Ischemia-induced tissue Mg++/Ca++ changes paralleled those of K+/Na+ with respect to time course and zonal variations. In ZONE I, both K+/Na+ and Mg++/Ca++ fell precipitously during the first hour, and the falls became more gradual thereafter, approac hing those of extracellular fluid at 24 hours. Changes in ZONE B, which appeared normal histologically, followed a similar downward trend but differed in magnitude from those in ZONE I (P smaller than 0.01). Changes in ZONE N were small but did not always overlap values in sham-operated dogs. It was concluded that lowered tissue K+/Na+ and Mg++/Ca++ were sensitive, but not specific, indices of myocardial ishemia, and multiple samplings of ionic ratios were essential for proper interpretation of ischemia-induced myocardial electrolyte derangements.


The white world of nursing homes: the myriad barriers to access facing today's elderly minorities.
In this note, Ms. Aeschleman explores the cultural, social, and economic barriers faced by elderly minorities in need of nursing home care. Ms. Aeschleman argues that minority elders face greater economic barriers to nursing home access than Whites because of factors such as lower average incomes and a lack of access to and assistance with government programs. Culturally, Ms. Aeschleman argues that minorities face barriers to nursing home care because of language differences, the location of nursing homes within communities, traditions, and both overt and indirect acts of discrimination from nursing home staff, administrators, and White clients. Following a discussion of these barriers, Ms. Aeschleman suggests options to give elderly minorities equal access to nursing homes through federal and state incentives, as well as community-based activism and awareness campaigns.


Immune dysfunction in COVID-19 and judicious use of antirheumatic drugs for the treatment of hyperinflammation
In the Wuhan province of China, almost two years ago, in December 2019, the novel Coronavirus 2019 has caused a severe involvement of the lower respiratory tract leading to an acute life-threatening respiratory syndrome, coronavirus disease-19 (COVID-19). Subsequently, coronavirus 2 (SARS-CoV-2) rapidly spread to the entire world causing a pandemic and affected every single person on earth either directly or indirectly with destroying all facets of social life and economy. Since the announcement of COVID-19 as a global pandemic, we have witnessed tremendous scientific work on all aspects of COVID-19 across the globe, which has never been witnessed before. The most remarkable achievement would be the introduction of vaccines, which provide protection from the severe infection and is the only premise for the control of disease. However, despite the tremendous work, the number of treatments either antiviral or immunomodulatory for infected patients are considerably limited, yet disease is causing substantial morbidity and mortality. COVID-19 follows heterogenous disease course among infected individuals, and dysregulated immune system is primarily responsible for the worse outcomes. Immune deficiency, being on corticosteroids for inflammatory diseases, delayed interferon response and advanced age adversely influence prognosis with impairing viral clearance. On the other hand, exuberant immune response with features of cytokine storm is the leading cause of death, which can be alleviated by use of either general immunosuppression with corticosteroids or selective neutralization of potent pro-inflammatory cytokines such as interleukin (IL)-1 and IL-6. Herein, we summarized the potential effective immunomodulatory treatments emphasizing in which patient population it is the most suitable, which dose should be administered, and which is the most appropriate timepoint to administer the drug during the course of the disease.


[Radiothermometry in intracavitary hyperthermia].
The potentialities of microwave radiometry application have been considered as an adjuvant to invasive thermometry to control temperature during local MWF-hyperthermia. An increasing role of radiometric monitoring in intracavitary hyperthermia has been shown in experiments on heating rectal tumors. Technical aspects of radiometric temperature measurements combined with MWF-hyperthermia are discussed.


The treatment of painful osseous metastases with phosphorus-32-labeled phosphates.
32P orthophosphate administered in a wide range of activity reduces or relieves the pain from osteoblastic metastases in approximately 80% of patients treated. The efficacy of this agent is equal to that of newer agents and of wide field radiotherapy, as documented in a literature review of 28 series reporting the use of 32P orthophosphate over a 50-year period. There is no dose-response relationship between the activity of 32P given and the percentage of patients experiencing pain reduction who received that activity. Only one death has been attributed to this radiopharmaceutical.


[The experience of the patient and the registered nurse during tuberculosis education].
This article focused on the problem that patients suffering from tuberculosis often stop taking their prescribed medicine and become defaulters. Although various factors could possibly contribute to the non compliance of the patients, this research had focused only on the teaching-learning situation. The experience of both the primary health nurse and the patient suffering from tuberculosis, during the teaching-learning situation in tuberculosis education, has been explored and described within the context of the North West Province. Phenomenological interviews were conducted with primary health nurses and defaulting patients suffering from tuberculosis. Interviews were recorded on tape and transcribed verbatim. The method of content analysis was used. The research has proven that adult-teaching principles have not been established in the teaching-learning situation and that the parent-child ego state predominates in communication.


A single institution study evaluating outcomes of PD-L1 high KRAS-mutant advanced non-small cell lung cancer (NSCLC) patients treated with first line immune checkpoint inhibitors.
This study aimed to evaluate the impact of KRAS status on the efficacy of first-line immune checkpoint inhibitors (ICI) in patients with advanced non-small cell lung cancer (NSCLC). Patients with advanced incurable or metastatic NSCLC with PD-L1 ≥50% treated with palliative-intent, single-agent PD-1/PD-L1 inhibitors at the Cancer Centre of Southeastern Ontario were included. KRAS mutation status was determined via massively parallel sequencing. Primary study outcome was median overall survival (mOS). Seventy-eight patients (59 non-squamous, 19 squamous) were identified; only non-squamous patients were included in KRAS mutation analyses. Thirty patients (51%) were KRAS-MT (mutant), with G12C (19%), G12V (15%), and G12D (13%) accounting for the most common KRAS mutation subtypes. There was no difference in mOS between KRAS-MT and KRAS-WT (wild-type) patients (12.9 vs. 19.3 months, p = 0.879). There was a non-significant trend towards worse mOS in KRAS G12C patients compared to non-G12C and KRAS-WT patients (11.4 vs. 44.9 vs. 19.3 months, p = 0.772). On multivariable analysis, KRAS-MT status was not associated with mOS (HR 0.901, 95%CI 0.417-1.946, p = 0.791). ECOG≥2 was an independent prognostic factor for worse mOS (HR 2.853, 95%CI 1.237-6.583, p = 0.014). Immune-related adverse events did not differ between KRAS-MT and KRAS-WT groups (48% vs. 52%, p = 1.000). KRAS mutation status did not have a significant impact on ICI efficacy or safety. However, a non-significant trend towards worse survival was noted in patients treated with ICI whose tumours harboured the KRAS G12C variant. This study provides valuable information for comparative analysis in the future.


Association between low level of physical activity and mobility limitation in older adults: evidence from the SABE study.
Several studies are limited by verifying the level of physical activity with questionnaires and not through objective measurement in older adults. This article aims to analyze the association between a low level of physical activity with accelerometry) and mobility limitation in older adults. A population-based cross-sectional study conducted with 543 older adults. Multiple regression analysis was performed using hierarchical analysis, grouping the variables into two blocks ordered according to the precedence with which they acted on the outcomes. Among the evaluated older adults, 13.7% presented mobility limitations and among these 60.39% were in the low level of physical activity group. Older adults with a low level of physical activity (OR = 3.49 [2.0 - 6.13]), aged 75 and over (OR = 1.97 [1.03 - 3.72]), living without a partner (OR = 2.01 [1.09 - 3.68]), having difficulty performing basic (OR = 2.49 [1.45 - 4.28]) and instrumental (OR = 2.28) [1.18 - 4.36]) activities of daily life, and multimorbidity (OR = 2.06 [1.04 - 4.08]) were independently associated with mobility limitation. A low level of physical activity increases the chance of mobility limitation in older adults, regardless of sociodemographic and clinical variables.