Seroepidemiology of Helicobacter pylori infection in hellenic navy recruits.
To investigate the prevalence of Helicobacter pylori (HP) infection, as well as possible risk factors affecting its acquisition among young Greek adults. Sera were collected from 153 male young Hellenic Navy recruits (mean age 23.6 y.o.; range, 20-30 y.o.) at induction into the Hellenic Navy during January 1999. An enzyme-linked immunosorbent assay was used to detect HP-specific-IgG antibodies. All the subjects completed a structured questionnaire regarding demographic and socioeconomic data, as well as dietary habits, alcohol and tobacco use and gastrointestinal complaints. Statistical analysis was performed using logistic regression and the chi2 test. The observed crude seropositivity rate was 19.01%. Among the examined parameters the most important predictive variable for HP-IgG status was the current median family income (B = +0.98, SE(B) = 0.56, p = 0.08, by logistic regression), which however, did not attain adequate statistical significance. The rate of seropositivity for HP that we observed is much lower than rates reported in older studies in this narrow-aged group in Greece. Probably the changes that ensued in life-style in Greece during the last 10 years resulted in a reduction in HP seropositivity.


Streptozotocin induces brain glucose metabolic changes and alters glucose transporter expression in the Lobster cockroach; Nauphoeta cinerea (Blattodea: Blaberidae).
The development of new models to study diabetes in invertebrates is important to ensure adherence to the 3R's principle and to expedite knowledge of the complex molecular events underlying glucose toxicity. Streptozotocin (STZ)-an alkylating and highly toxic agent that has tropism to mammalian beta cells-is used as a model of type 1 diabetes in rodents, but little is known about STZ effects in insects. Here, the cockroach; Nauphoeta cinerea was used to determine the acute toxicity of 74 and 740 nmol of STZ injection per cockroach. STZ increased the glucose content, mRNA expression of glucose transporter 1 (GLUT1) and markers of oxidative stress in the head. Fat body glycogen, insect survival, acetylcholinesterase activity, triglyceride content and viable cells in head homogenate were reduced, which may indicate a disruption in glucose utilization by the head and fat body of insects after injection of 74 and 740 nmol STZ per nymph. The glutathione S-transferase (GST) activity and reduced glutathione levels (GSH) were increased, possibly via activation of nuclear factor erythroid 2 related factor as a compensatory response against the increase in reactive oxygen species. Our data present the potential for metabolic disruption in N. cinerea by glucose analogues and opens paths for the study of brain energy metabolism in insects. We further phylogenetically demonstrated conservation between N. cinerea glucose transporter 1 and the GLUT of other insects in the Neoptera infra-class.


Growth study of a nonpathogenic strain of Leishmania donovani with different nutrients.
The studies on growth pattern of a nonpathogenic Leishmania donovani, strain UR6, in different media showed that it can be regularly cultivated amd maintained in modified Ray's Medium (Agar) and three other liquid media, namely DME Medium, Medium 199 and RPMI-1640 which are manufactured in India. The well known N.N.N. Medium provided quantitatively poorer growth in comparison to these medium. Measurement of L. donovani cell concentration by optical density in a spectrophotometer has been worked out for expressing immunochemical observations on antigens in terms of cells per mililitre.


Novel use of electronic whiteboard in the operating room increases surgical team compliance with pre-incision safety practices.
Despite evidence that use of a checklist during the pre-incision time out improves patient morbidity and mortality, compliance with performing the required elements of the checklist has been low. In an effort to improve compliance, a standardized time out interactive Electronic Checklist System [iECS] was implemented in all hospital operating room (OR) suites at 1 institution. The purpose of this 12-month prospective observational study was to assess whether an iECS in the OR improves and sustains improved surgical team compliance with the pre-incision time out. Direct observational analyses of preprocedural time outs were performed on 80 cases 1 month before, and 1 and 9 months after implementation of the iECS, for a total of 240 observed cases. Three observers, who achieved high interrater reliability (kappa = 0.83), recorded a compliance score (yes, 1; no, 0) on each element of the time out. An element was scored as compliant if it was clearly verbalized by the surgical team. Pre-intervention observations indicated that surgical staff verbally communicated the core elements of the time out procedure 49.7 ± 12.9% of the time. After implementation of the iECS, direct observation of 80 surgical cases at 1 and 9 months indicated that surgical staff verbally communicated the core elements of the time out procedure 81.6 ± 11.4% and 85.8 ± 6.8% of the time, respectively, resulting in a statistically significant (P < .0001) increase in time out procedural compliance. Implementation of a standardized, iECS can dramatically increase compliance with preprocedural time outs in the OR, an important and necessary step in improving patient outcomes and reducing preventable complications and deaths.


Some considerations in using cirrhosis mortality rates as indicators of the prevalence of alcoholism.
Analysis of data on death certificates indicates that the value of P (the percentage of all deaths due to cirrhosis of the liver that can be attributed to alcoholism) in the Jellinek estimation formula is a function of sex, race and whether or not an autopsy was performed.


A search for rheumatoid arthritis-associated nuclear antigen and Epstein-Barr virus specific antigens or genomes in tissues and cells from patients with rheumatoid arthritis.
Pannus extracts and/or cells and tissues from rheumatoid arthritis (RA) patients and controls were tested for the presence of RA-associated nuclear antigen (RANA), anti-RANA, Epstein-Barr virus (EBV)-specific antigens, and EBV genomes. Using our present rather insensitive methods, RANA was rarely detected in RA pannus extracts or tissues, whereas anti-RANA was commonly found. EBV-specific antigens or genomes could not be detected in a limited number of tissues tested using our present methods. The data suggest that EBV may not be the primary event causing RA through direct infection and transformation of synovial tissues.


Spatial distribution of startup (Gojek and Grab) users in Palembang city, Indonesia.
The emergence of startups in Indonesia contributes to increasing the number of those working as startup users. Startup users define those who make use of startup services and enterprises to perform their business. This research was designed to explain the spatial distribution of startup (Gojek and Grab) users in Palembang City, Indonesia. It employed spatial analysis with inverse distance weighting and kernel density. The results indicated that startup (Gojek and Grab) users who established their business before 2020 were in densely-populated parts of the city. However, based on the interpolation of their business locations, they were variably distributed in lowly to densely-populated areas whose economic activities were dominated by trade and services. Furthermore, the nearest neighbor analysis revealed that startup (Gojek and Grab) users were close to permanent markets (including semi-permanent ones, supermarkets, restaurants, and grocery shops) and had better access to online transportation and communication with good cell phone receptions.


Bradykinin stimulation of phosphoinositide hydrolysis in guinea-pig ileum longitudinal muscle.
1. Bradykinin (BK)-induced contraction of ileal smooth muscle is assumed to be due to phosphoinositide hydrolysis but this has never been reported. We have investigated whether BK receptors are linked to this transduction mechanism in guinea-pig ileum longitudinal muscle and determined whether these receptors are equivalent to those labelled in [3H]-BK binding assays. 2. In membranes prepared from longitudinal muscle, [3H]-BK bound to a single class of sites with high affinity. Characterization of the binding with BK analogues indicated that the radioligand selectivity labelled a B2 type receptor. 3. BK significantly elevated tissue levels of [3H]-inositol phosphates in longitudinal muscle slices preincubated with [3H]-myo-inositol. The agonists potencies of BK, Lys-BK, Met-Lys-BK, Tyr5-BK and Tyr8-BK were in agreement with their relative potencies in the binding assay. The B1 receptor agonist des-Arg9-BK, did not stimulate inositol phosphate production. The response to BK was blocked by known B2 receptor antagonists but not by the B1 antagonist des-Arg9, Leu8-BK. 4. BK-induced phosphoinositide hydrolysis was unaffected by exposure of muscle slices to either atropine or indomethacin. 5. The results indicate that the B2 receptors linked to phosphoinositide turnover in ileal longitudinal muscle exhibit properties similar to those involved in contractile responses. Also, the receptor mediating the phosphoinositide response is likely to be that labelled in the [3H]-BK binding studies.


Influenza: lessons from past pandemics, warnings from current incidents.
Recent outbreaks of highly pathogenic avian influenza A virus infections (H5 and H7 subtypes) in poultry and in humans (through direct contact with infected birds) have had important economic repercussions and have raised concerns that a new influenza pandemic will occur in the near future. The eradication of pathogenic avian influenza viruses seems to be the most effective way to prevent influenza pandemics, although this strategy has not proven successful so far. Here, we review the molecular factors that contribute to the emergence of pandemic strains.


Cortical control of anticipatory postural adjustments prior to stepping.
Human bipedal balance control is achieved either reactively or predictively by a distributed network of neural areas within the central nervous system with a potential role for cerebral cortex. While the role of the cortex in reactive balance has been widely explored, only few studies have addressed the cortical activations related to predictive balance control. The present study investigated the cortical activations related to the preparation and execution of anticipatory postural adjustment (APA) that precede a step. This study also examined whether the preparatory cortical activations related to a specific movement is dependent on the context of control (postural component vs. focal component). Ground reaction forces and electroencephalographic (EEG) data were recorded from 14 healthy adults while they performed lateral weight shift and lateral stepping with and without initially preloading their weight to the stance leg. EEG analysis revealed that there were distinct movement-related potentials (MRPs) with concurrent event-related desynchronization (ERD) of mu and beta rhythms prior to the onset of APA and also to the onset of foot-off during lateral stepping in the fronto-central cortical areas. Also, the MRPs and ERD prior to the onset of APA and onset of lateral weight shift were not significantly different suggesting the comparable cortical activations for the generation of postural and focal movements. The present study reveals the occurrence of cortical activation prior to the execution of an APA that precedes a step. Importantly, this cortical activity appears independent of the context of the movement.


Finding the mental foramen.
The mental foramen and mental nerve are clinically important landmarks for clinicians across various disciplines including dentists, oral maxillofacial surgeons, emergency physicians and plastic and reconstructive surgeons. To minimize complications related to procedures in the vicinity of the mental foramen and nerve, knowledge of its anatomy and anatomical variations is cardinal to concerned clinicians. In this review, basic anatomy, procedural complications, hard and soft tissue relations, variations between population groups, asymmetry, accessory mental foramina and the use of various radiological modalities to determine the position of the mental foramen are reviewed to provide a more thorough understanding of this important landmark.


Secretion of biologically active recombinant human granulocyte-macrophage colony-stimulating factor by transduced gastric cancer cells.
Gastric cancer has the highest incidence rate among cancers in Asia. The advanced type of signet ring cell carcinoma has poor prognosis compared to other types of gastric cancer. The immuno-gene therapy with cytokine-based tumor vaccines has not yet been investigated for gastric cancer. The granulocyte macrophage colony-stimulating factor (GM-CSF)-based tumor vaccine has been demonstrated as the most potent stimulator for specific and long-lasting systemic tumor immunity. In the present study, KATO III cells, the human signet ring cell gastric carcinoma cell line, were genetically modified by the transduction with the human GM-CSF cDNA or the modified hGM-CSF in replication-deficient retroviruses. The genomic integrations and mRNA expressions of the transgenes were determined by Southern and Northern blot analyses. Wild type (wt) or modified hGM-CSF was integrated into the genome of KATO III cells. The modified hGM-CSF mRNA was more stable than that of wt. The KATO III cells with the modified hGM-CSF produced higher level of hGM-CSF (12.4-19 ng/10(6)cells/48hrs) than that with wt hGM-CSF, when determined by enzyme-linked immunosorbent assay (ELISA). The secreted recombinant hGM-CSF could support the proliferation of the GM-CSF-dependent cell line, indicating that the hGM-CSF secreted by the transduced KATO III cells has biological activities. Irradiated, transduced KATO III cells continued to secret hGM-CSF without proliferation. Our results suggest that GM-CSF secreting KATO III cells could be tested for the treatment of gastric cancer as an allogeneic tumor vaccine as a part of immunotherapeutic treatment.


Meta-Analyses Support Previous and Novel Autism Candidate Genes: Outcomes of an Unexplored Brazilian Cohort.
Large genomic databases of neurodevelopmental disorders (NDD) are helpful resources of genomic variations in complex and heterogeneous conditions, as Autism Spectrum Disorder (ASD). We evaluated the role of rare copy number variations (CNVs) and exonic de novo variants, in a molecularly unexplored Brazilian cohort of 30 ASD trios (n = 90), by performing a meta-analysis of our findings in more than 20,000 patients from NDD cohorts. We identified three pathogenic CNVs: two duplications on 1q21 and 17p13, and one deletion on 4q35. CNVs meta-analysis (n = 8,688 cases and n = 3,591 controls) confirmed 1q21 relevance by identifying duplications in other 16 ASD patients. Exome analysis led the identification of seven de novo variants in ASD genes (SFARI list): three loss-of-function pathogenic variants in CUL3, CACNA1H, and SHANK3; one missense pathogenic variant in KCNB1; and three deleterious missense variants in ATP10A, ANKS1B, and DOCK1. From the remaining 12 de novo variants in non-previous ASD genes, we prioritized PRPF8 and RBM14. Meta-analysis (n = 13,754 probands; n = 2,299 controls) identified six and two additional patients with validated de novo variants in PRPF8 and RBM14, respectively. By comparing the de novo variants with a previously established mutational rate model, PRPF8 showed nominal significance before multiple test correction (P = 0.039, P-value adjusted = 0.079, binomial test), suggesting its relevance to ASD. Approximately 60% of our patients presented comorbidities, and the diagnostic yield was estimated in 23% (7/30: three pathogenic CNVs and four pathogenic de novo variants). Our uncharacterized Brazilian cohort with tetra-hybrid ethnic composition was a valuable resource to validate and identify possible novel candidate loci. Autism Res 2020, 13: 199-206. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We believed that to study an unexplored autistic population, such as the Brazilian, could help to find novel genes for autism. In order to test this idea, with our limited budget, we compared candidate genes obtained from genomic analyses of 30 children and their parents, with those of more than 20,000 individuals from international studies. Happily, we identified a genetic cause in 23% of our patients and suggest a possible novel candidate gene for autism (PRPF8).


Emergency Laboratory Evaluations for Patients With Inborn Errors of Metabolism.
Children with inborn errors of metabolism (IEM) are at risk for metabolic crises triggered by acute illnesses. Crises are identified through laboratory evaluations. Our objective was to determine national adherence to minimum laboratory evaluations for patients with IEM in emergency departments (EDs), as well as factors associated with laboratory evaluation adherence. Using the Pediatric Health Information System, we identified visits to 48 EDs from 2012 to 2017 by children with IEM. We analyzed visits for catabolic conditions (dehydration, gastroenteritis, or vomiting) and determined variation in minimum laboratory evaluation adherence. Multivariable models were created to determine predictors of adherence. Among the visits by children with disorders of the urea cycle, organic acid metabolism, and fatty acid oxidation, 1457 (76.3%) of 1909 adhered to the minimum laboratory evaluation. Median ED-level adherence was 78.2% (interquartile range, 67.4-92.5). Factors associated with adherence were disorder [fatty acid oxidation vs urea cycle disorder; adjusted odds ratio (aOR), 9.35; 95% confidence interval (CI), 4.07-21.47], annual ED volume of patients with IEM (quartile 4 vs 1; aOR, 3.58; 95% CI, 1.51-8.49), and presence of a biochemical genetics fellowship (aOR, 0.29; 95% CI, 0.14-0.62). Patients with IEM frequently did not receive minimum laboratory evaluations for catabolic conditions. Measures to improve laboratory use in children with IEM should be undertaken.


New oral and topical approaches for the treatment of melasma.
Melasma is a common, therapeutically challenging, and universally relapsing disorder of hyperpigmentation that is most often observed in women and individuals with Fitzpatrick Skin Types III through VI. The pathogenesis of melasma is complex and protean. Contributing factors that are often implicated in the etiopathogenesis of this condition include a genetic predisposition, intense ultraviolet radiation exposure, and hormonal influences. Therapeutic interventions for melasma include a multimodality approach incorporating photoprotection agents, topical and oral skin lighteners, and resurfacing procedures. Given our expanding knowledge of the pathogenesis of melasma, new and effective treatments are expanding our therapeutic armamentarium. This article reviews new and emerging oral and topical treatments for melasma.


Levothyroxine dose following thyroidectomy is affected by more than just body weight.
To determine the factors that affect levothyroxine (LT4) requirements following thyroidectomy. Retrospective study. This study evaluated 246 participants who had undergone total thyroidectomy and were on a stable dose of LT4. Actual weight-based (AWB) and ideal body weight-based (IBWB) LT4 dose requirements were analyzed, and other confounders including adherence, concurrent medications, comorbidities, female menopausal status, and hormone replacement therapy were examined. A total of 205 women and 41 men were evaluated, with 48 (20%) benign and 198 (80%) malignant pathology findings. The mean AWB LT4 doses for men and premenopausal women were similar among members of the benign groups and similar among members of the malignant groups. There was a trend for lower dose LT4 in postmenopausal women off hormonal therapy (PM/NH) and on hormonal therapy (PM/H) in the benign group (1.4 and 1.6 μg/kg vs. 1.8 μg/kg in the men and premenopausal women) and a trend for lower dose LT4 in the PM/H women in the malignant group (1.9 μg/kg vs. 2.1 and 2.2 μg/kg in the men and premenopausal women), but they were not significant. However, PM/NH women required significantly less LT4 (1.7 μg/kg) than both the men (2.2 μg/kg) and premenopausal women (2.1 μg/kg) in the malignant group (P=.0006). The IBWB LT4 dosage was not statistically different between groups. LT4 dosage following thyroidectomy, calculated using actual body weight, can range from 1.4 to 2.2 μg/kg and is dependent on diagnosis (benign vs. malignant), goal TSH, sex, and menopausal status.


Cholera and pertussis toxins modify regulation of glucose transport activity in rat adipose cells: evidence for mediation of a cAMP-independent process by G-proteins.
Adenylyl cyclase in rat adipose cells is stimulated by ligands for Rs receptors (e.g. isoproterenol) and inhibited by ligands for Ri receptors (e.g. adenosine). In contrast, Rs receptors mediate inhibition and Ri receptors mediate augmentation of insulin-stimulated glucose transport activity by a process independent of changes in cellular cAMP-dependent protein kinase activity [Kuroda M., Honnor R. C., Cushman S. W., Londos C. and Simpson I. A. (1987) J. biol. Chem. 262, 245-253]. The present study examines the possible role of G-proteins in the regulation of insulin-stimulated glucose transport activity by Rs and Ri receptors. First, conditions were established that permit intoxication of isolated rat adipocytes by cholera and pertussis toxins without compromising cell integrity. Effectiveness of toxin treatment was monitored by examining adenylyl cyclase activity in isolated plasma membranes. Secondly, neither toxin interfered with the ability of a maximal concentration insulin to initiate the glucose transport response. Thirdly, pertussis toxin eliminated the augmenting effects of adenosine on insulin-stimulated glucose transport activity, but enhanced the inhibitory effects of isoproterenol. Findings with ligands for other Ri receptors (nicotinic acid and prostaglandin E2) mirrored those with adenosine. Finally, cholera toxin elicited a modest depression of transport activity, and only in the absence of an Ri ligand (e.g. adenosine). Furthermore, in contrast to the enhanced stimulation of adenylyl cyclase by isoproterenol and GTP, cholera toxin eliminated the inhibitory effect of isoproterenol on transport activity. The augmentative effects of adenosine on transport activity were unchanged. Measurements of (-/+cAMP) cAMP-dependent protein kinase activity ratios reinforce the notion that modulation of glucose transport activity is independent of changes in cAMP. We conclude that regulation of glucose transport activity by Rs and Ri receptors is mediated by the G-proteins, Gs and Gi (or other toxin substrates), respectively. Inasmuch as such regulation occurs at the plasma membrane and appears to be cAMP-independent, it is suggested that glucose transporters may be direct targets for receptor: G-protein interactions.


Autoreservoir computing for multistep ahead prediction based on the spatiotemporal information transformation.
We develop an auto-reservoir computing framework, Auto-Reservoir Neural Network (ARNN), to efficiently and accurately make multi-step-ahead predictions based on a short-term high-dimensional time series. Different from traditional reservoir computing whose reservoir is an external dynamical system irrelevant to the target system, ARNN directly transforms the observed high-dimensional dynamics as its reservoir, which maps the high-dimensional/spatial data to the future temporal values of a target variable based on our spatiotemporal information (STI) transformation. Thus, the multi-step prediction of the target variable is achieved in an accurate and computationally efficient manner. ARNN is successfully applied to both representative models and real-world datasets, all of which show satisfactory performance in the multi-step-ahead prediction, even when the data are perturbed by noise and when the system is time-varying. Actually, such ARNN transformation equivalently expands the sample size and thus has great potential in practical applications in artificial intelligence and machine learning.


"Game Changer": Health Professionals' Views on the Clinical Utility of Circulating Tumor DNA Testing in Hereditary Cancer Syndrome Management.
We explored health professionals' views on the utility of circulating tumor DNA (ctDNA) testing in hereditary cancer syndrome (HCS) management. A qualitative interpretive description study was conducted, using semi-structured interviews with professionals across Canada. Thematic analysis employing constant comparison was used for analysis. 2 investigators coded each transcript. Differences were reconciled through discussion and the codebook was modified as new codes and themes emerged from the data. Thirty-five professionals participated and included genetic counselors (n = 12), geneticists (n = 9), oncologists (n = 4), family doctors (n = 3), lab directors and scientists (n = 3), a health-system decision maker, a surgeon, a pathologist, and a nurse. Professionals described ctDNA as "transformative" and a "game-changer". However, they were divided on its use in HCS management, with some being optimistic (optimists) while others were hesitant (pessimists). Differences were driven by views on 3 factors: (1) clinical utility, (2) ctDNA's role in cancer screening, and (3) ctDNA's invasiveness. Optimists anticipated ctDNA testing would have clinical utility for HCS patients, its role would be akin to a diagnostic test and would be less invasive than standard screening (eg imaging). Pessimistic participants felt ctDNA testing would add limited utility; it would effectively be another screening test in the pathway, likely triggering additional investigations downstream, thereby increasing invasiveness. Providers anticipated ctDNA testing will transform early cancer detection for HCS families. However, the contrasting positions on ctDNA's role in the care pathway raise potential practice variations, highlighting a need to develop evidence to support clinical implementation and guidelines to standardize adoption.


Preparation and cytotoxicity of N-modified chitosan nanoparticles applied in curcumin delivery.
Nanoparticles (NPs) based on N,N-dimethyl chitosan (DMC) and N,N,N-trimethyl chitosan (TMC), physical crosslinked with sodium tripolyphosphate (TPP) were successful obtained, using water/benzyl alcohol emulsion system. NPs morphologies were evaluated by Scanning Electron Microscopy and Transmission Electron Microscopy. NPs were characterized by Infrared Spectroscopy (FTIR), Thermogravimetric Analysis, Zeta Potential, Differential Scanning Calorimetry and Wide-angle X-ray Scattering. Curcumin (CUR) was loaded onto NPs and controlled release studies were evaluated in simulated intestinal fluid and in simulated gastric fluid. Cytotoxicity assays showed only loaded TMC/TPP particles containing CUR were slightly cytotoxic on human cervical tumor cells (SiHa cells), concerning unloaded TMC/TPP particles. Conversely, loaded NPs (TMC/TPP/CUR and DMC/TPP/CUR), especially TMC/TPP/CUR sample presented greater biocompatibility toward healthy VERO cells than unloaded NPs (TMC/TPP and DMC/TPP).


An integrative transcriptional logic model of hepatic insulin resistance.
Abnormalities of lipid/lipoprotein and glucose metabolism are hallmarks of hepatic insulin resistance in type 2 diabetes. The former antedate the latter, but the latter become progressively refractory to treatment and contribute to therapeutic failures. It's unclear whether the two processes share a common pathogenesis and what underlies their progressive nature. In this study, we investigated the hypothesis that genes in the lipid/lipoprotein pathway and those in the glucose metabolic pathway are governed by different transcriptional regulatory logics that affect their response to physiologic (fasting/refeeding) as well as pathophysiologic cues (insulin resistance and hyperglycemia). To this end, we obtained genomic and transcriptomic maps of the key insulin-regulated transcription factor, FoxO1, and integrated them with those of CREB, PPAR-α, and glucocorticoid receptor. We found that glucose metabolic genes are primarily regulated by promoter and intergenic enhancers in a fasting-dependent manner, while lipid genes are regulated through fasting-dependent intron enhancers and fasting-independent enhancerless introns. Glucose genes also showed a remarkable transcriptional resiliency (i.e., the ability to compensate following constitutive FoxO1 ablation through an enrichment of active marks at shared PPAR-α/FoxO1 regulatory elements). Unexpectedly, insulin resistance and hyperglycemia were associated with a "spreading" of FoxO1 binding to enhancers and the emergence of unique target sites. We surmise that this unusual pattern correlates with the progressively intractable nature of hepatic insulin resistance. This transcriptional logic provides an integrated model to interpret the combined lipid and glucose abnormalities of type 2 diabetes.


Risks of caffeine residues in the environment: Necessity for a targeted ecopharmacovigilance program.
Due to the huge consumption of caffeinated food, beverages and medicines around the world, caffeine has been considered as a most representative pharmaceutically active compound (PhAC) pollutant based on its high abundance in environment and its indicator property for anthropogenic inputs of PhACs to water bodies. This review analyzed the existing literature about the bioaccumulation and environmental risks of caffeine residues in non-target organisms. There are 6 studies which were published in the last 5 years have reported the distribution of caffeine in tissues of aquatic organisms including fishes, clams, macroalgae and other aquatic plants, suggesting bioaccumulation of caffeine in organisms. The maximum detected levels of caffeine residues in tissues ranged from 1.55 to 344.9 ng/g. Importantly, definitive evidences have been provided that environmentally relevant caffeine concentrations exert adverse impacts on aquatic species and terrestrial insects, which included lethality, decreasing general stress, inducing oxidative stress and lipid peroxidation, affecting energy reserves and metabolic activity, neurotoxic effects, affecting reproduction and development, etc. In view of the severity and potential adverse impacts of caffeine pollution in the environment, we proposed that caffeine should be considered as a high-priority environmentally hazardous PhAC pollutant, and it is necessary to implement an ecopharmacovigilance (EPV) program targeting caffeine to minimize its environmental load from a pharmacy perspective.


In situ mouse carotid perfusion model: glucose and cholesterol transport in the eye and brain.
The in situ mouse brain perfusion method for measuring blood-brain barrier permeability was adapted to assess transport of solutes at the blood-brain and blood-eye barriers. The procedure was checked with radiolabeled markers in oxygenated bicarbonate-buffered fluid infused for 30 to 120 sec via a carotid artery. Vascular flow estimated with diazepam was 2.2-fold lower in the eye than in the brain. The vascular volume and the integrity markers sucrose and inulin indicated that a perfusion flow rate of 2.5 mL/min preserved the physical integrity of these organs. However, the brain vasculature integrity was more sensitive to acute perfusion pressure than the eye vasculature. The functional capacities of blood barriers were assessed with D-glucose; its transport followed Michaelis-Menten kinetics with an apparent K(m) of 7.6 mmol/L and a V(max) of 23 micromol/sec per g in the brain, and a K(m) of 22.9 mmol/L and a V(max) of 40 micromol/sec per g in the eye. The transport of cholesterol to the brain and eye was significantly enhanced by adding the Abca1 inhibitor probucol, suggesting an Abca1-mediated efflux at the mouse brain and eye blood barriers. Thus in situ carotid perfusion is suitable for elucidating transport processes at the blood-brain and blood-eye barriers.


Mechanisms affecting the gut of preterm infants in enteral feeding trials: a nested cohort within a randomised controlled trial of lactoferrin.
To determine the impact of supplemental bovine lactoferrin on the gut microbiome and metabolome of preterm infants. Cohort study nested within a randomised controlled trial (RCT). Infants across different trial arms were matched on several clinical variables. Bacteria and metabolite compositions of longitudinal stool and urine samples were analysed to investigate the impact of lactoferrin supplementation. Thirteen UK hospitals participating in a RCT of lactoferrin. 479 infants born <32 weeks' gestation between June 2016 and September 2017. 10 990 stool and 22 341 urine samples were collected. Analyses of gut microbiome (1304 stools, 201 infants), metabolites (171 stools, 83 infants; 225 urines, 90 infants) and volatile organic compounds (314 stools, 117 infants) were performed. Gut microbiome Shannon diversity at 34 weeks corrected age was not significantly different between infants in the lactoferrin (mean=1.24) or placebo (mean=1.06) groups (p=0.11). Lactoferrin receipt explained less than 1% variance in microbiome compositions between groups. Metabolomic analysis identified six discriminative features between trial groups. Hospital site (16%) and postnatal age (6%) explained the greatest variation in microbiome composition. This multiomic study identified minimal impacts of lactoferrin but much larger impacts of hospital site and postnatal age. This may be due to the specific lactoferrin product used, but more likely supports the findings of the RCT in which this study was nested, which showed no impact of lactoferrin on reducing rates of sepsis. Multisite mechanistic studies nested within RCTs are feasible and help inform trial interpretation and future trial design.


Determinants of bone mass in the Chinese old-old population.
One hundred and eighty-eight elderly men and women were included in a study of bone mass at the neck of femur and its related factors. The study subjects were a subsample of a Hong Kong wide study of the elderly population aged 70 years and above. The study variables included age, sex, body measurements of height, weight, body mass index, dietary calcium intake, grip strength, 16 feet (5 m) gait speed, smoking, drinking, and years since menopause among women. The neck of femur bone mineral density among elderly men was about 1 standard deviation higher than that of women. Subjects aged 85 years and above had about 20% lower bone mineral density at the neck of femur when compared with those in the age group 70-74 years. Mean dietary calcium intake ranged between 300 and 430 mg/day and was not associated with bone mass. Multiple regression analysis showed that body weight, 16 feet gait speed, sex and alcohol consumption explained 46% of the total variance of femoral neck bone mineral density. Body weight was the most significant predictor of bone mineral density, with a partial correlation coefficient of 0.5. The maintenance of body weight within the acceptable weight range and promotion of physical fitness may be important measures in reducing bone loss in the elderly population.


Presentation and diagnosis of primary biliary cirrhosis in the 21st century.
Primary biliary cirrhosis is a slowly progressive, cholestatic, and chronic liver disease in which the epithelium of the intrahepatic biliary tree is destroyed by a chronic inflammatory process. The origin of this disease, which mainly affects middle-aged women, is unknown but has characteristics favoring an autoimmune etiology. This article reviews the presentation and diagnosis of PBC in the 21st century.


Physostigmine: an antidote for excessive central nervous system depression or paradoxical rage reactions resulting from intravenous diazepam.
A review of the pharmacology and use of the drug physostigmine is presented. Of particular interest is the drug's capability to reverse excessive somnolence or paradoxical responses caused by intravenous diazepam (Valium®) and other clinically available benzodiazepines. Its use for the treatment of anticholinergic syndrome is discussed and incidence and characterization of side effects documented. Recommendations are made for appropriate emergency use.


Spatial distribution of total mercury and methylmercury in the sediment of a tropical coastal environment subjected to heavy urban inputs.
Jurujuba Cove is located in Guanabara Bay (adjacent to highly populated city of Rio de Janeiro, Brazil), which receives diffuse sources of contaminants along with two main freshwater inputs (the Cachoeira and Icaraí rivers), and hosts mussel farms. The main goal of this work was to evaluate the total mercury (THg) and methylmercury (MeHg) concentrations distributions in the sediments of the cove and their associations with physical and chemical parameters, thereby assessing their geochemical behavior. Twenty samples of surface sediments were collected and characterized for grain size, pH, redox potential, organic carbon, total phosphorus, THg and MeHg. Spatial distribution maps were produced for each parameter and a principal components analysis was carried out, to assess THg and MeHg behavior and their relationships with other parameters. The principal components analysis showed that grain size functions as the main diluting agent. The highest THg concentrations were observed in the mussel-farm area (656.1 ng g-1), and were related to fine grain size and elevated organic carbon values. High MeHg concentrations also occurred in the center of the cove, probably favored by high organic carbon content (low-energy environment). Total phosphorus concentrations indicate that Cachoeira River is a possible source of sewage, but little mercury seems to come from it. The results showed that although total mercury concentrations are elevated, with exception of a few locations, small methylmercury convertion rates were recorded in the sediments.


Complications of endoscopic retrograde cholangiopancreatography: an imaging review.
Endoscopic retrograde cholangiopancreatography (ERCP) has currently become an inseparable tool in the gastroenterologist's armamentarium for treatment of pancreaticobiliary disorders. Given the increase in number of therapeutic ERCP procedures today, the need for prompt and correct diagnosis of its complications is pivotal. This review discusses the mechanisms, risk factors, imaging findings and general management aspects of common and rare complications of ERCP. Furthermore, the review elaborates on imaging indications, recommended protocol and normal imaging findings post ERCP.


Bond softness sensitive bond-valence parameters for crystal structure plausibility tests.
Based on a description of bond valence as a function of valence electron density, a systematic bond softness sensitive approach to determine bond-valence parameters and related quantities such as coordination numbers is elaborated and applied to determine bond-valence parameters for 706 cation-anion pairs. While the approach is closely related to the earlier softBV parameter set, the new softNC1 parameters proposed in this work may be simpler to apply in plausibility checks of crystal structures, as they follow the first coordination shell convention. The performance of this softNC1 bond-valence parameter set is compared with that of the previously derived softBV parameter set that also factors in contributions from higher coordination shells, and with a benchmarking parameter set that has been optimized following the conventional choice of a universal value of the bond-valence parameter b. The results show that a systematic adaptation of the bond-valence parameters to the bond softness leads to a significant improvement in the bond-valence parameters, particularly for bonds involving soft anions, and is safer than individual free refinements of both R0 and b from a limited number of reference cation environments.


Trace minerals source in calf starters interacts with birth weights to affect growth performance.
The present study was conducted to investigate the effects of partial replacement of inorganic minerals (IM) with trace minerals in advance chelate components form in starter diets for calves of different birth weights on performance, health, and behavior of Holstein calves. Fifty-two calves were assigned to 1 of 4 treatments in a 2 × 2 factorial arrangement with two mineral sources (IM or advanced chelated minerals (ACMS)) and two birth weights (low or normal birth weight; LBW or NBW). Calves were weaned on d 56 and remained until d 71 of the study. Results showed that NBW calves had higher feed intake, withers and hip height, larger heart girth and lower fecal score than LBW calves throughout the study. Calves receiving ACMS tended to have higher feed intake, larger hip width, lower eye and nose scores, and lower rectal temperature throughout the study than IM calves. In addition, ACMS calves had larger abdominal girths at d 56 of the study compared to IM calves. Interactions between birth weights and mineral sources for preweaning average daily gain (ADG) and weaning and final BW showed that ACMS supplementation improved ADG and BW in LBW calves. Non-nutritive oral behavior was lower in ACMS calves compared to IM calves during all periods. Overall, ACMS feeding decreased non-nutritive oral behavior and improved calf health status during the study. In addition, feeding ACMS to dairy calves with LBW increased their ADG to a similar extent as to NBW calves, suggesting an improvement in their efficiency.


Elective cross-hand transfer: a case report with a five-year follow-up.
The elective free microvascular cross-hand transfer of the right hand to the left distal carpus was successfully performed in a 35-year old professional photographer. Traumatic loss of the left hand with preservation of a useful thumb and concomitant right upper extremity injury leaving the right hand with an amputated thumb, but paralyzed and insensate from a brachial plexus palsy 5 years before transfer, set the stage for such a reconstruction. Multiple immediate tendon transfers and primary nerve grafting provided for finger flexion and extension plus functional sensibility in this first reported case of an elective cross-hand microvascular transfer. Five years follow-up demonstrates useful and powerful flexion, and functional extension of digits in the reconstructed left hand and right upper extremity function has been improved with a below-elbow prosthesis.


Comparison of protease-resistant prion protein inhibitors in cell cultures infected with two strains of mouse and sheep scrapie.
The transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative diseases. A primary therapeutic target for TSE intervention has been a protease-resistant form of prion protein known as PrP(Sc) or PrP-res. In vitro testing of mouse scrapie-infected cell cultures has identified many PrP-res inhibitors that also have activity in vivo. Here we identify 32 new inhibitors of two strains of mouse scrapie PrP-res. Furthermore, to investigate the species-specificity of these and other PrP-res inhibitors, we have developed a high-throughput cell culture assay based on Rov9 cells chronically-infected with sheep scrapie. Of 32 inhibitors of murine PrP-res that were also tested in the Rov9 cells, only six showed inhibitory activity against sheep PrP-res. The three most potent inhibitors of both murine and ovine PrP-res formation (with 50% inhibition at < or =5 microM) were tannic acid, pentosan polysulfate and Fe(III) deuteroporphyrin 2,4-bisethyleneglycol. The latter two have anti-mouse scrapie activity in vivo. These results identify new inhibitors of murine and ovine PrP-res formation and reinforce the idea that compounds effective against PrP-res from one species or strain cannot be assumed to be active against others.


Can Guduchi (Tinospora cordifolia), a well-known ayurvedic hepato-protectant cause liver damage?
Ayurveda is a centuries old traditional medicine practiced in India even today. There are certain safe medicinal plants with well-established medicinal properties both in clinical practice as well as in modern scientific publications. Guduchi or Tinospora cordifolia (Willd.) Miers (Menispermaceae), is one such medicinal plant that has well known anti-inflammatory, immune-modulatory and other safe therapeutic applications including hepato-protection, because of which it was recommended by the Ministry of AYUSH, Government of India to be used in COVID-19 care. Therefore, Aabha Nagral's article "Herbal Immune Booster-Induced Liver Injury in the COVID-19 Pandemic-a Case Series," published in 2021, was unanticipated. The article recounted histologically documented clinical cases of six patients who developed drug-induced autoimmune-like hepatitis after reported consumption of Guduchi or Guduchi containing formulations during the COVID-19 pandemic. Since the Ayurveda practitioners vouch by the safety of T. cordifolia (TC), it was felt that the story needed to be further scrutinized. This article reviews the botanical entities, the substitutes and adulterants of species used as Guduchi, their pharmacological and toxicological properties. While the authentic botanical entity of Guduchi is TC, Tinospora sinensis and Tinospora crispa are also commonly traded in the Indian subcontinent as Guduchi or Giloy. Among these species, T. crispa is known to induce heapto-toxicity. In Nagral's article, there were variations in the reported six cases in terms of patient history and TC/TC product consumption. More importantly, the botanical authenticity of the consumed products was not investigated. A review of published literature indicates that it is unlikely that the authentic TC could have induced autoimmune-like hepatitis of the patients. It is probable that a wrong species was self-administered by the patients. It is worth following up with the cases (patients), to investigate details of the products, so that other consumers do not suffer. Nagral's article however does highlight the serious issue of adulteration in herbal markets and the need for establishing a robust pharmacovigilant system in India.


Leukotriene C4 inhibits ATP-dependent transport of glutathione S-conjugate across rat heart sarcolemma. Implication for leukotriene C4 translocation mediated by glutathione S-conjugate carrier.
Sarcolemmal vesicles prepared from rat heart exhibited ATP-dependent uptake of S-(2,4-dinitrophenyl)glutathione (DNP-SG), which obeyed Michaelis-Menten kinetics with an apparent Km of 21 microM for DNP-SG and a Vmax of 0.27 nmol.10 min-1.mg protein-1. Several model glutathione S-conjugates inhibited DNP-SG uptake, but leukotriene C4 inhibited uptake much more significantly even at lower concentrations (competitive inhibition, Ki = 1.5 microM). However, leukotrienes D4 and E4, which lack the gamma-glutamyl moiety, were less effective. The results suggest that the ATP-dependent transport system has a high affinity for leukotriene C4, and may be responsible for the translocation of this compound.


Indications and Contraindications of Full-Endoscopic Interlaminar Lumbar Decompression.
Spinal stenosis is a common disease with an increasing incidence. Narrowing of the spinal canal is caused by bone and soft tissue degeneration, such as osteophyte formation, facet and ligamentum flavum hypertrophy, and disc herniation. Various surgical techniques have been used to treat spinal canal stenosis, including open, tubular, microsurgical decompression, and fusion surgery. This article presents the technique for full-endoscopic interlaminar bilateral decompression of the lumbar spine. Surgical approach, anatomy, pathology, indications, contraindications, and surgical equipment are described. With well-chosen endoscopic equipment, surgical time can be reduced with minimal collateral damage. Clear advantages of full-endoscopic decompression over open or other minimally invasive surgery methods are demonstrated in many clinical studies. The endoscopic technique has been shown to be effective in spinal canal decompression with good to excellent clinical results. The interlaminar endoscopic approach minimizes iatrogenic injury to the stabilizing anatomic structures while achieving full unilateral and bilateral decompression. A significant improvement in pain and functional outcome scores with low complication rates has been demonstrated. This technique is safe for lumbar spinal decompression and more minimally invasive than a microendoscopic approach. However, this technique should be performed by surgeons with advanced skills. Endoscopy could become the gold standard for treatment of canal stenosis in the near future.


Effect of shear stress on intrinsic CHO culture state and glycosylation of recombinant tissue-type plasminogen activator protein.
Shear stress in suspension culture was investigated as a possible manipulative parameter for the control of glycosylation of the recombinant tissue-type plasminogen activator protein (r-tPA) produced by recombinant Chinese hamster ovary (CHO) cell culture, grown in protein-free media. Resulting fractions of partially glycosylated, Type II, and fully glycosylated, Type I, r-tPA protein were monitored as a direct function of the shear characteristics of the culture environment. The shear-induced response of CHO culture to levels of low shear stress, where exponential growth was not obtained, and to higher levels of shear stress, which resulted in extensive cell death, were examined through manipulation of the bioreactor stirring velocity. Both apparent and intrinsic cell growth, metabolite consumption, byproduct and r-tPA production, and r-tPA glycosylation, from a variable site-occupancy standpoint, were monitored throughout. Kinetic analyses revealed a shear-stress-induced alteration of cellular homeostasis resulting in a nonlinear dependency of metabolic yield coefficients and an intrinsic cell lysis kinetic constant on shear stress. Damaging levels of shear stress were used to investigate the shear dependence of cell death and lysis, as well as the effects on the intrinsic growth rate of the culture. Kinetic models were also developed on the basis of the intrinsic state of the culture and compared to traditional models. Total r-tPA production was maximized under moderate shear conditions, as was the viable CHO cell density of the culture. However, Type II r-tPA production and the fraction of Type II glycoform production ratio was maximized under damaging levels of shear stress. Analyses of biomass production yield coefficients coupled with a plug-flow reactor model of glycan addition in the endoplasmic reticulum (ER) were used to propose an overall mechanism of decreased r-tPA protein site-occupancy glycosylation with increasing shear stress. Decreased residence time of r-tPA in the ER as a result of increased protein synthesis related to shear protection mechanisms is proposed to limit contact of site Asn184 with the membrane-bound oligosaccharyltransferase enzyme in the ER.


The immunohistopathology of glomerular antigens. III. Increased mesangial actomyosin in experimental diabetes in the rat.
Antisera to rat smooth muscle actomyosin (AMY) and myosin localize in the rat glomercular mesangium. The width of mesangial staining for AMY is increased in rats diabetic for four months (p less than 0.01) and seven months (p less than 0.0005) compared with age-matched controls. Mesangial AMY staining of unilaterally nephrectomized control animals was moderately increased after seven months, whereas unilaterally nephrectomized diabetic rats had prominently increased AMY mesangial width at four months, when they were compared with intact diabetic animals (p less than 0.05). Thus, a distinctive alteration that is found in human diabetic nephropathy also occurs in experimental (streptozotocin) diabetes in the rat. Further, this alteration appears to be accelerated by the changes in nephron hemodynamics resulting from unilateral nephrectomy. While the function of mesangial AMY is unknown, it may be related to intrarenal regulation of glomerular ultrafiltration, which appears to be altered in diabetic nephropathy in man.


Successful Excision of Endobronchial Cellular Schwannoma With Right Lower Sleeve Lobectomy.
Cellular schwannoma is a rare variant of schwannoma, showing high cellularity and a low mitotic index. A 64-year-old man was admitted to our hospital with a 2-month history of productive cough. Chest computed tomography showed an endobronchial tumor with complete atelectasis of the right lower lobe. Bronchoscopy showed an endobronchial tumor occluding the intermediate bronchus that was diagnosed as a cellular schwannoma on biopsy and was successfully excised with a right lower sleeve lobectomy to preserve the middle lobe. The postoperative course was uneventful, and the patient remains well with no sign of recurrence at the 7-year follow-up.


Intracellular accumulation of potent amiloride analogues by human neutrophils.
The mechanism of uptake of a series of amiloride derivatives by human neutrophils was investigated using [14C]amiloride and the 14C-labeled 5-(1-hexahydroazepinyl)-6-bromo analogue (BrMM) which is approximately 500-fold more potent than the parent compound at inhibiting Na+/H+ exchange. At an external concentration of 2 microM, the influx of BrMM at 37 degrees C was rapid, reaching a steady state by approximately 20 min. The rate of BrMM uptake (approximately 25 mumol/liter.min) was approximately 90-fold faster than for the same concentration of amiloride, a finding which correlates with differences in lipid partitioning of the two compounds. Uptake was unrelated to specific binding to Na+/H+ exchange transport sites: influx of either drug was nonsaturable whereas amiloride- and BrMM-mediated inhibition of Na+/H+ countertransport obeyed Michaelis-Menten kinetics with apparent Ki values of approximately 75 and approximately 0.2 microM. Entry occurred exclusively via the neutral (uncharged) forms (pK'a 8.40-8.55). Influx was markedly pH-dependent: it was enhanced by extracellular alkalinization and reduced by acidification. Influx was, however, insensitive to large changes in membrane voltage, thereby implying the protonated (charged) species to be impermeant. About 75% of the total intracellular pool of amiloride, but only approximately 25% of BrMM, is contained within the lysosomes, an expected consequence of the partitioning and subsequent trapping of a weak base within this strongly acidic subcellular compartment. With BrMM, there was a relative approximately 60-fold enrichment in the internal/external water concentration ratio of the drug; the value for amiloride was much less, approximately 4. This disparity is consistent with substantial binding of BrMM to internal constituents, presumably to proteins and/or nucleic acids. Thus, it is important to recognize that potentially large intracellular accumulations of potent analogues can occur that are not directly involved in inhibition of Na+/H+ exchange. These findings sound a cautionary note in the interpretation of results using these drugs in all cells, especially those of small size with high surface-to-volume ratios.


Separation of myelin basic protein peptide 43-88 and its fragments by analytic and preparative high-performance liquid chromatography.
Reversed-phase (RP) high-performance liquid chromatography (HPLC) using a solvent mixture of triethylammonium formate buffer and methanol permitted the rapid separation of myelin basic protein peptide 43-88 and a mixture of synthetic fragments from this peptide. The elution times for some of the peptides were markedly affected by minimal changes in the solvent mixture. Attempts to separate the same peptides by gel permeation HPLC resulted in poor resolution and an aberrant elution pattern unrelated to molecular size. With the use of the volatile triethylammonium formate buffer in the RP-HPLC, material could be more readily separated and easily recovered by freeze-drying. Analysis of the components separated by this system of RP-HPLC demonstrated that the preparation of normal human BP peptide 43-88 results in an admixture of peptides 43-87 and 43-88. This procedure of RP-HPLC should make it possible to analyze the degradation of myelin basic protein peptide 43-88 and to isolate the degradation products for characterization.


The epigenetic language of circadian clocks.
Epigenetic control, which includes DNA methylation and histone modifications, leads to chromatin remodeling and regulated gene expression. Remodeling of chromatin constitutes a critical interface of transducing signals, such as light or nutrient availability, and how these are interpreted by the cell to generate permissive or silenced states for transcription. CLOCK-BMAL1-mediated activation of clock-controlled genes (CCGs) is coupled to circadian changes in histone modification at their promoters. Several chromatin modifiers, such as the deacetylases SIRT1 and HDAC3 or methyltransferase MLL1, have been shown to be recruited to the promoters of the CCGs in a circadian manner. Interestingly, the central element of the core clock machinery, the transcription factor CLOCK, also possesses histone acetyltransferase activity. Rhythmic expression of the CCGs is abolished in the absence of these chromatin modifiers. Here we will discuss the evidence demonstrating that chromatin remodeling is at the crossroads of circadian rhythms and regulation of metabolism and cellular proliferation.


Sustained virological response and its treatment predictors in hepatitis C virus genotype 4 compared to genotypes 1, 2, and 3: a meta-analysis.
Pegylated interferon and ribavirin (PEG-IFN+RBV) may be more cost-effective than direct-acting antivirals in resource-limited settings. Current literature suggests sustained virological response (SVR) in hepatitis C virus genotype 4 (HCV-4) is similar to genotype 1 (HCV-1), but worse than 2 and 3 (HCV-2/3). However, few studies have compared treatment response between these groups and these have been limited by small sample sizes with heterogeneous designs. We performed a meta-analysis of SVR predictors in HCV-4 versus HCV-1, 2, and 3 patients treated with PEG-IFN+RBV. In November 2013, we searched for 'genotype 4' in MEDLINE/EMBASE databases and scientific conferences. We included original articles with ≥25 treatment-naïve HCV-4 and comparisons to HCV-1, 2, and/or 3 patients treated with PEG-IFN+RBV. Random effects modelling was used with heterogeneity defined by Cochrane Q-test (p value<0.10) and I(2) statistic (>50%). Five studies with 20 014 patients (899 HCV-4; 12 033 HCV-1; and 7082 HCV-2/3 patients) were included. SVR was 53% (CI 43% to 62%) for HCV-4, 44% (CI 40% to 47%) for HCV-1; and 73% (CI 58% to 84%) for HCV-2/3. SVR with EVR (early virological response) was 75% (CI 61% to 86%) in HCV-4; 64% (CI 46% to 79%) in HCV-1; and 85% (CI 71% to 93%) in HCV-2/3. SVR without EVR was 10% (CI 6% to 17%) for HCV-4; 13% (CI 12% to 15%) for HCV-1; and 23% (CI 16% to 33%) for HCV-2/3. SVR rates are similar in HCV-4 (∼50%) and HCV-1 (∼40%). Lack of EVR is a good stopping rule for HCV-4 and HCV-1 since only 10% subsequently achieve SVR. In HCV-4 patients with EVR, three-quarters can expect to achieve SVR with PEG-IFN+RBV.


The neuroendocrine basis of social recognition.
All social relationships are dependent on an organism's ability to remember conspecifics. Social memory may be a unique form of memory, critical for reproduction, territorial defense, and the establishment of dominance hierarchies in a natural context. In the laboratory, social memory can be assessed reliably by measuring the reduction in investigation of a familiar partner relative to novel conspecifics. The neurohypophyseal neuropeptides oxytocin and vasopressin have been shown to influence a number of forms of social behavior, including affiliation, aggression, and reproduction. This article reviews vasopressin and oxytocin effects on social cognition, particularly the acquisition and retention of social recognition in rats and mice. Studies in rats have demonstrated that vasopressin in specific neural pathways, such as the lateral septum, is necessary for social recognition. As vasopressin facilitates recall when given after an initial encounter, the peptide appears important for the consolidation not the acquisition of a social memory. Although oxytocin has complex effects on social memory in rats, mice with a null mutation of the oxytocin gene are completely socially amnestic without other cognitive deficits evident. As oxytocin given centrally before but not after the initial encounter restores social recognition in these mutant mice, the neuropeptide appears critical for the acquisition rather than the consolidation phase of memory. Oxytocin's effects on social memory are mediated via a discrete cell population in the medial amygdala. These findings support the hypothesis that vasopressin and oxytocin are essential for social memory, although they appear to influence different cognitive processes and may modulate different neural systems. (c) Elsevier Science.


Stimulation of gp91 phagocytic oxidase and reactive oxygen species in neutrophils by an avirulent Salmonella enterica serovar infantis strain protects gnotobiotic piglets from lethal challenge with serovar Typhimurium strain F98 without inducing intestinal pathology.
Preinoculation of susceptible 5-day-old gnotobiotic piglets with Salmonella enterica serovar Infantis strain 1326/28Phi(r) stimulates neutrophil migration into the intestine, which rapidly protects the pigs against a subsequent (normally lethal) challenge with S. enterica serovar Typhimurium strain F98. Here we show that inoculation with either 1326/28Phi(r) or F98 activated reactive oxygen species (ROS) in neutrophils via NADPH pathways in vivo and in vitro and that the survival of both Salmonella strains was increased if neutrophils were cocultured with the ROS inhibitor N-acetylcysteine (captopril). Neither F98 nor 1326/28Phi(r) significantly increased reactive nitrogen species (RNS) levels in neutrophils isolated from uninfected pigs. Our results indicate the following: (i) rapid protection of highly susceptible gnotobiotic piglets against F98-induced gastroenteritis by preinoculation with 1326/28Phi(r) is likely to be due to stimulation of ROS-producing neutrophils in the intestinal epithelium prior to challenge with the lethal strain; (ii) pathological lesions of the intestine during severe gastroenteritis are not necessarily induced by neutrophil migration per se; and (iii) if neutrophil migration into the intestine is responsible for pathology, then neither increased production of ROS or RNS (in pigs inoculated with the lethal strain) nor reduced production (in protected pigs in which pathological lesions are ameliorated by preinoculation with 1326/28Phi(r)) can account for this phenomenon.


Lymecycline or doxycycline for treatment of urinary-tract infections: a comparison of attained urine concentrations.
The urine and serum concentrations of lymecycline and doxycycline were investigated in a cross-over study in ten volunteers. Both drugs were found in therapeutic serum levels but lymecycline had a mean urine concentration of 240 microgram per ml compared to 60 microgram per ml of doxycycline. The results are discussed with regard to treatment of some urinary-tract infections.


Probing CD8 T cell responses with Listeria monocytogenes infection.
CD8 T cells play a critical role in the control and eradication of intracellular pathogens. Increased understanding of CD8 T cell biology provides insight that can be translated into improved vaccination strategies. The intracellular bacterium, Listeria monocytogenes, has been used as a model organism to study every phase of the CD8 T cell response to intracellular bacterial infection. Infection of laboratory mice with L. monocytogenes has provided insight into the factors that are involved in primary T cell responses, memory CD8 T cell generation, maintenance, functionality, and diversification following repeated pathogenic challenges. In this review, we will focus on work from our laboratories utilizing the murine model of L. monocytogenes to investigate the characteristics of CD8 T cell responses to infection. This model has profoundly advanced our understanding of the CD8 T cell response to infection and is likely to continue to provide invaluable basic insights that can be translated into the development of effective vaccination strategies to protect against pathogens.


Effect of daily dosing with tiotropium against methacholine induced bronchoconstriction in asthmatics.
Loss of bronchoprotection against direct and indirect acting stimuli following regular use of inhaled beta2-agonists occurs with both short and long-acting formulations. Comparatively little is known about the development of tolerance following regular use of inhaled muscarinic receptor antagonists. Two investigations with the short-acting muscarinic receptor antagonist ipratropium bromide have reported no tolerance after regular use against inhaled methacholine. To our knowledge, there are no data regarding loss of bronchoprotection following regular use of long-acting muscarinic receptor antagonist. We therefore looked at the effect of daily dosing with tiotropium on methacholine induced bronchoconstriction in a population of mild asthmatics. We performed a randomized, double-blind, placebo-controlled cross-over study comparing tiotropium Respimat® 5 μg to placebo in adult asthmatics. Each treatment arm began with baseline methacholine challenge followed immediately by treatment administration. One hour later a post treatment methacholine challenge was performed. Participants dosed daily (two puffs) at home for the next six days and returned to the lab on Day 8 for a final dose of treatment 1 h prior to methacholine challenge. The average doubling dose increase in methacholine PD20 following a single dose of tiotropium was 3.9 doubling doses whereas that following placebo was 0.93 (p = 0.003). After regular use, methacholine PD20 was further increased to 6.4 doubling doses following tiotropium whereas that following placebo decreased by 0.57 doubling doses (p < 0.001). LAMA are indicated for use as add-on monotherapy or in triple therapy combination for poorly controlled asthma. It may be reassuring to know therefore, that regular use does not result in loss of bronchoprotection like that which occurs with beta2-agonist bronchodilators.


Successful treatment by overdrive pacing of recurrent quinidine syncope due to ventricular tachycardia.
A 54 year old patient who experienced recurrent ventricular tachycardia subsequent to quinidine administration for conversion of atrial fibrillation is described. Over a 10 hour period, 25 sustained episodes of ventricular tachycardia occurred for which electrical cardioversion was required in addition to numerous self-terminating paroxysms. Medical therapy with lidocaine, procainamide and propranolol was unsuccessful in controlling the arrhythmia. However, placement of a transvenous right ventricular pacemaker with overdrive pacing at a rate of 110 beats/min abrupty terminated all further ventricular ectopic activity during the period of quinidine elimination. Temporary overdrive pacing may be the treatment of choice for refractory, recurrent, ventricular tachycardia associated with quinidine therapy.


UV-Fenton degradation of diclofenac, sulpiride, sulfamethoxazole and sulfisomidine: Degradation mechanisms, transformation products, toxicity evolution and effect of real water matrix.
Four common refractory pharmaceuticals, diclofenac (DF), sulpiride (SP), sulfamethoxazole (SMX) and sulfisomidine (SIM) were detected in the Disc Tubular Reverse Osmosis (DTRO) concentrates with higher concentrations ranging from 0.85 to 11.57 μg/L from the local landfill. The effect of complex matrix of DTRO concentrates on the UV-Fenton degradation kinetics of DF, SP, SMX and SIM and their transformation products (TPs) were studied. All the four pharmaceuticals could be degraded more efficiently in the ultrapure water than that in the DTRO-concentrate matrix, which also had a significant negative effect on the kinetic constants of the degradation. Twenty-two out of forty-nine TPs were newly identified by HPLC-QTOF-MS and their peak-area evolution was presented. The main degradation pathways for four pharmaceuticals were identified. When assessing cytotoxicity by using HepG2 cells, there appeared to be an obvious toxicity-increase region for each of SP, SMX and SIM. Eleven TPs were identified as the potential toxicity-increase causing TPs by combination of the QSAR prediction, HepG2 cytotoxicity assessment and peak-area evolution of TPs. Therefore, UV-Fenton process was a promising method for the refractory pharmaceutical degradation even in the complex water matrix and choosing appropriate reaction parameters for the UV-Fenton could eliminate the cytotoxicity of the TPs.


Microvascular breast reconstruction and thromboembolic events in patients on hormone therapy: Audit of practice from a tertiary referral centre.
Hormonal therapy with tamoxifen and aromatase inhibitors reduces breast cancer recurrence and mortality but represents a risk factor for thromboembolic events. Therefore, most surgeons discontinue hormonal agents before microvascular surgery and for a variable period thereafter. There are no guidelines regarding when therapy should be stopped (preoperatively) or when it should be resumed (post-operatively). We, therefore, audited our hospital practice with the objective of making recommendations for microvascular breast reconstruction patients. A review was performed of all free flap breast reconstructions between 2014 and 2019. Patients were classified according to hormone medication status at operation. Timings of drug cessation and recommencement were recorded. Thrombotic events, namely flap microvascular thrombosis, deep vein thrombosis, superficial vein thrombosis and pulmonary embolism, were compared. A total of 240 patients had 275 free flaps over five years with 36 receiving hormone therapy within one month prior to surgery, which was discontinued 8.5 days (range: 0-28 days) before surgery. Intraoperative microvascular thromboses (HT 2.0%, NHT 0%, and p = 0.869) and post-operative microvascular complications/flap re-explorations (HT 6.6%, NHT 0%, and p = 0.234) were comparable between the two groups. Systemic venous thromboembolic events were also similar (HT 8.3%, NHT 6.1%, and p = 0.893). Age, BMI, smoking status and preoperative chemotherapy did not influence the incidence of thrombotic complications. Hormone therapy did not significantly increase the risk of thromboembolic events. Despite the widespread practice of withholding it for 2 weeks prior to reconstructive surgery, this study does not support such practice being beneficial in terms of thromboembolic events and flap viability. Large-scale trials are needed to establish definitive protocols.


Cavitation phenomena in mechanical heart valves: the role of squeeze flow velocity and contact area on cavitation initiation between two impinging rods.
In this study, the closing dynamics of two impinging rods were experimentally analyzed to simulate the cavitation phenomena associated with mechanical heart valve closure. The purpose of this study was to investigate the cavitation phenomena with respect to squeeze flow between two impinging surfaces and the parameter that influences cavitation inception. High-speed flow imaging was employed to visualize and identify regions of cavitation. The images obtained favored squeeze flow as an important mechanism in cavitation inception. A correlation study of the effects of impact velocities, contact areas and squeeze flow velocity on cavitation inception showed that increasing impact velocities results in an increase in the risk of cavitation. It was also shown that for similar impact velocities, regions near the point of impact were found to cavitate later for those with smaller contact areas. It was found that the decrease in contact areas and squeeze flow velocities would delay the onset and reduce the intensity of cavitation. It is also interesting to note that the squeeze flow velocity alone does not provide an indication if cavitation inception will occur. This is corroborated by the wide range of published critical squeeze flow velocity required for cavitation inception. It should be noted that the temporal acceleration of fluid, often neglected in the literature, can also play an important role on cavitation inception for unsteady flow phenomenon. This is especially true in mechanical heart valves, where for the same leaflet closing velocity, valves with a seat stop were observed to cavitate earlier. Based on these results, important inferences may be made to the design of mechanical heart valves with regards to cavitation inception.


Leaving no one behind: a neglected tropical disease indicator and tracers for the Sustainable Development Goals.
The Sustainable Development Goals (SDGs) have emerged as a global pledge to 'leave no one behind'. Under SDG 3, 'Ensure healthy lives and promote wellbeing for all', target 3.3 extends the Millennium Development Goals (MDGs) beyond HIV, TB and malaria to 'end the epidemic' of neglected tropical diseases (NTDs) by 2030. Other targets are also relevant to NTDs, especially 3.8 (Universal Health Coverage), 6.1 (water) and 6.2 (sanitation). This commentary summarises the proposed NTD indicator (3.3) and tracers (3.8 and 6.1/6.2). These will help ensure that the world's poorest and most marginalized people are prioritized at every step on the path towards SDG targets.


Reduced Exercise Capacity, Chronotropic Incompetence, and Early Systemic Inflammation in Cardiopulmonary Phenotype Long Coronavirus Disease 2019.
Mechanisms underlying persistent cardiopulmonary symptoms after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (postacute sequelae of coronavirus disease 2019 [COVID-19; PASC] or "long COVID") remain unclear. This study sought to elucidate mechanisms of cardiopulmonary symptoms and reduced exercise capacity. We conducted cardiopulmonary exercise testing (CPET), cardiac magnetic resonance imaging (CMR) and ambulatory rhythm monitoring among adults >1 year after SARS-CoV-2 infection, compared those with and those without symptoms, and correlated findings with previously measured biomarkers. Sixty participants (median age, 53 years; 42% female; 87% nonhospitalized; median 17.6 months after infection) were studied. At CPET, 18/37 (49%) with symptoms had reduced exercise capacity (<85% predicted), compared with 3/19 (16%) without symptoms (P = .02). The adjusted peak oxygen consumption (VO2) was 5.2 mL/kg/min lower (95% confidence interval, 2.1-8.3; P = .001) or 16.9% lower percent predicted (4.3%-29.6%; P = .02) among those with symptoms. Chronotropic incompetence was common. Inflammatory markers and antibody levels early in PASC were negatively correlated with peak VO2. Late-gadolinium enhancement on CMR and arrhythmias were absent. Cardiopulmonary symptoms >1 year after COVID-19 were associated with reduced exercise capacity, which was associated with earlier inflammatory markers. Chronotropic incompetence may explain exercise intolerance among some with "long COVID."


Adolescent gallstones-need for early intervention in symptomatic idiopathic gallstones.
Currently, there is a paucity of the literature describing the natural history of cholelithiasis (CL) and choledocholithiasis (CDL) in adolescent children. This study aims to analyse the changing demographics of paediatric and adolescent gallstones. Retrospective review of all children (Age 0-18 years) presenting with symptomatic gallstones over the last 15 years (2002-2017) at a single tertiary institution. Demographics, diagnostic and therapeutic information were collected, with a 5-year median follow-up. Statistics were accomplished by Chi-squared analysis of trend and Student t test. 188 children were seen with symptomatic CL. In the 0-11-year-old group, there were 13 females and 16 males (0.8: female to male ratio). There were 130 females and 29 males in the 12-18-year-old group (4.5:1 female to male ratio). The mean weight at presentation was 81.78 kg and the median age was 16 years. Idiopathic gallstones were found in 131 patients (82%). 137 required cholecystectomy (86%) and ERCP was required in 32 patients (20%). 48 adolescents (30.2%) with gallstones had an associated CDL, compared to six children (20%). All of the adolescent patients with CDL had idiopathic gallstones. Gallstone pancreatitis was noted in eighteen adolescents (11%) and one child (3%). We analysed the ideal time to operate on adolescent patients with symptomatic gallstones using the relationship between the length of delay from initial diagnosis to definitive management of CDL and incidence of complications. The analysis demonstrated that for every 10 days treatment was delayed, the risk of subsequent presentations with a symptomatic episode was increased by 5% (p = 0.0004). The current trend of gallstones in adolescent children seems to be a disease primarily of adolescent girls. Symptomatic idiopathic gallstones in adolescents are associated with high rates of common bile duct obstruction and pancreatitis and consequently warrant an early cholecystectomy for all adolescents. Level IV Treatment Study.


Clinical and Molecular Factors Associated With Histologic Response to Topical Steroid Treatment in Patients With Eosinophilic Esophagitis.
Few factors have been identified that can be used to predict response of patients with eosinophilic esophagitis (EoE) to topical steroid treatment. We aimed to determine whether baseline clinical, endoscopic, histologic, and molecular features of EoE can be used to predict histologic response. We collected data from 97 patients with EoE, from 2009 through 2015, treated with a topical steroid for 8 weeks; 59 patients had a histologic response to treatment. Baseline clinicopathologic features and gene expression patterns were compared between patients with a histologic response to treatment (<15 eos/hpf) and non-responders (≥15 eos/hpf). We performed sensitivity analyses for alternative histologic response definitions. Multivariate logistic regression was performed to identify predictive factors associated with response to therapy, which were assessed with area under the receiver operator characteristic (AUROC) curves. Baseline dilation was the only independent predictor of non-response (odds ratio [OR], 0.30; 95% CI, 0.10-0.89). When an alternate response (<1 eos/hpf) and non-response (<50% decrease in baseline eos/hpf) definition was used, independent predictors of response status were age (OR, 1.08; 95% CI, 1.02-1.14), food allergies (OR, 12.95; 95% CI, 2.20-76.15), baseline dilation (OR, 0.17; 95% CI, 0.03-0.88), edema or decreased vascularity (OR, 0.20; 95% CI, 0.04-1.03), and hiatal hernia (OR, 0.07; 95% CI, 0.01-0.66). Using these 5 factors, we developed a predictive model that discriminated complete responders from non-responders with an AUROC of 0.88. Baseline gene expression patterns were not associated with treatment response and did not change with different histologic response thresholds. In an analysis of 97 patients with EoE, we found dilation to be the only baseline factor associated with non-response to steroid treatment (<15 eos/hpf). However, a model comprising 5 clinical, endoscopic, and histologic factors identified patients with a complete response (<1 eos/hpf). A baseline gene expression panel was not predictive of treatment response at any threshold.


Growth hormone receptors.
The receptor for rabbit liver growth hormone (GH) has recently been purified and cloned. Sequencing data demonstrates that this site represents a new class of transmembrane receptor proteins containing covalently linked ubiquitin and N-linked oligosaccharides. Homology with the human GH liver receptor is estimated to be 84%. GH receptors are also present on non-liver cells, however, their function is poorly understood, and it is not yet known if there is homology with the liver site. Direct stimulation of differentiation of preadipocytes to adipocytes by GH has been demonstrated. In bone, binding of GH to the resting cell zone, but not the proliferative layers has been reported. Taken together, these data support the hypothesis of Green and colleagues that GH has a dual mechanism of action which includes direct stimulation of differentiation of precursor cells and a secondary effect of enhancing the clonal proliferative response.


Skin advanced glycation end-product accumulation is negatively associated with calcaneal osteo-sono assessment index among non-diabetic adult Japanese men.
This study aims to determine the relationship between advanced glycation end-product (AGE) accumulation in skin tissue and bone strength, assessed by quantitative ultrasound, among healthy adult Japanese men. The results of the study suggest that men with higher AGE accumulation in skin tissue have a lower osteo-sono assessment index. AGE accumulate in bone collagen with age and diabetes and decrease the mechanical properties of bone. Although increased AGE levels are associated with fractures among diabetic patients and elderly women, it is unclear whether a relationship between increased AGE levels and bone strength is present in apparently healthy adult males. The aim of this study was to determine the relationship between AGE accumulation in tissue and the mechanical properties of bone among adult Japanese men, using quantitative ultrasound as a surrogate measure of the latter. Skin autofluorescence (AF), which is a noninvasive method for measuring tissue AGEs, and osteo-sono assessment index (OSI), which is determined by quantitative ultrasound, were measured in 193 adult Japanese men (median age 43 years; interquartile range 37.0-55.0 years). Adjusted for age, BMI, calcium intake, physical activity, smoking status, and education level, log-transformed skin AF had a negative association with log-transformed OSI (β = -0.218, P < 0.01). Adjusted geometric means (95% CI) for OSI across the tertiles of skin AF were 2.81 (2.75-2.87) for the lowest tertile, 2.81 (2.74-2.87) for the middle tertile, and 2.66 (2.61-2.73) for the highest tertile; thus, OSI for the highest skin AF appeared to be 5.0% lower than that for the lowest and middle skin AF tertiles (P < 0.01). Among apparently healthy adult Japanese men, those with higher skin AF had a lower OSI, indicating a relationship between AGE accumulation and bone strength. A long-term prospective study is required to clarify the causality.


Frontotemporal dementia is the leading cause of "true" A-/T+ profiles defined with Aβ42/40 ratio.
Patients with positive tauopathy but negative Aβ42 (A-T+) in the cerebrospinal fluid (CSF) represent a diagnostic challenge. The Aβ42/40 ratio supersedes Aβ42 and reintegrates "false" A-T+ patients into the Alzheimer's disease spectrum. However, the biomarker and clinical characteristics of "true" and "false" A-T+ patients remain elusive. Among the 509 T+N+ patients extracted from the databases of three memory clinics, we analyzed T+N+ patients with normal Aβ42 and compared "false" A-T+ with abnormal Aβ42/40 ratio and "true" A-T+ patients with normal Aβ42/40 ratio, before CSF analysis and at follow-up. 24.9% of T+N+ patients had normal Aβ42 levels. Among them, 42.7% were "true" A-T+. "True" A-T+ had lower CSF tauP181 than "false" A-T+ patients. 48.0% of "true" A-T+ patients were diagnosed with frontotemporal lobar degeneration before CSF analysis and 64.0% at follow-up, as compared with 6% in the "false" A-T+ group (P < .0001). Frontotemporal lobar degeneration is probably the main cause of "true" A-T+ profiles.


Popliteal sciatic nerve block for high-risk patients undergoing lower limb angioplasty: A prospective double-blinded randomized controlled trial.
To assess the rate of conversion to general anesthesia, sedative and analgesic drug-sparing effects, and complications of popliteal sciatic nerve block (PSNB) compared with a sham block during lower limb angioplasty. A randomized, controlled, double-blinded trial of patients with chronic limb-threatening ischemia (CLTI) who receive PSNB with 0.25% levobupivacaine 20 mL compared with a sham block (control) during lower limb angioplasty. Pain scores, conversion rate to general anesthesia, amount of sedoanalgesia drug usage, complications, and satisfaction with the anesthesia technique by surgeons and patients were assessed. Forty patients were enrolled in this study. Two of 20 (10%) control group patients were converted to general anesthesia, while none of the patients in the intervention group required general anesthesia (P = .487). Pain scores before PSNB did not differ between the groups (P = .771). After the block, pain scores in the block group were lower than those in the control group: 0 (0, 1.5) (median, interquartile range) and 2.5 (0.5, 3.5), respectively (P = .024). The analgesic effect persisted until immediately after the surgery (P = .035). There was no difference in pain scores at the 24-hours follow-up visit (P = .270). The total propofol and fentanyl dosage requirements, a number of patients who required propofol and fentanyl, side effects, and satisfaction were not different between the groups. No major complications were noted. PSNB provided effective pain relief during and immediately after lower limb angioplasty, but did not statistically affect the rate of conversion to general anesthesia, sedoanalgesia drug usage, or complications.


Competition between trans-translation and termination or elongation of translation.
The effects of tRNA, RF1 and RRF on trans-translation by tmRNA were examined using a stalled complex of ribosome prepared using a synthetic mRNA and pure Escherichia coli translation factors. No endoribonucleolytic cleavage of mRNA around the A site was found in the stalled ribosome and was required for the tmRNA action. When the A site was occupied by a stop codon, alanyl-tmRNA competed with RF1 with the efficiency of peptidyl-transfer to alanyl-tmRNA for trans-translation inversely correlated to the efficiency of translation termination. The competition was not affected by RF3. A sense codon also serves as a target for alanyl-tmRNA with competition of aminoacyl-tRNA. The extent of inhibition was decreased with the length of the 3'-extension of mRNA. RRF, only at a high concentration, slightly affected peptidyl-transfer for trans-translation, although it did not affect the canonical elongation. These results indicate that alanyl-tmRNA does not absolutely require the truncation of mRNA around the A site but prefers an mRNA of a short 3'-extension from the A site and that it can operate on either a sense or termination codon at the A site, at which alanyl-tmRNA competes with aminoacyl-tRNA, RF and RRF.


Use of wire-guided (Seldinger-type) catheters in the emergency department.
The use of wire-guided catheters is a major technical advance for emergency physicians. The technique is simple, safe, and efficient, and allows tremendous flexibility in usage.


Spillover effect between carbon spot and futures market: evidence from EU ETS.
The spillover effects of European Union Allowances (EUA) spot and futures markets are important for investors in order to understand the relevance and risk management of product prices. This paper uses non-linear methods of Granger causality to test the mean spillover relationship between the two markets and then analyzes volatility spillovers between the two by the non-linear TVP-VAR spillover index. The results show that (1) the non-linear Granger causality test better reflects the mean spillover relationship between EUA spot and futures; (2) there is a bidirectional non-linear mean spillover effect between EUA spot and futures prices for the European Union Emissions Trading Scheme (EU ETS) phases II and III; and (3) volatility spillovers, appearing in EUA spot and future markets in both phases, work increasingly strong over time and are vulnerable to financial crises and extreme events.


Genome-Wide Reconstruction of Rediploidization Following Autopolyploidization across One Hundred Million Years of Salmonid Evolution.
The long-term evolutionary impacts of whole-genome duplication (WGD) are strongly influenced by the ensuing rediploidization process. Following autopolyploidization, rediploidization involves a transition from tetraploid to diploid meiotic pairing, allowing duplicated genes (ohnologs) to diverge genetically and functionally. Our understanding of autopolyploid rediploidization has been informed by a WGD event ancestral to salmonid fishes, where large genomic regions are characterized by temporally delayed rediploidization, allowing lineage-specific ohnolog sequence divergence in the major salmonid clades. Here, we investigate the long-term outcomes of autopolyploid rediploidization at genome-wide resolution, exploiting a recent "explosion" of salmonid genome assemblies, including a new genome sequence for the huchen (Hucho hucho). We developed a genome alignment approach to capture duplicated regions across multiple species, allowing us to create 121,864 phylogenetic trees describing genome-wide ohnolog divergence across salmonid evolution. Using molecular clock analysis, we show that 61% of the ancestral salmonid genome experienced an initial "wave" of rediploidization in the late Cretaceous (85-106 Ma). This was followed by a period of relative genomic stasis lasting 17-39 My, where much of the genome remained tetraploid. A second rediploidization wave began in the early Eocene and proceeded alongside species diversification, generating predictable patterns of lineage-specific ohnolog divergence, scaling in complexity with the number of speciation events. Using gene set enrichment, gene expression, and codon-based selection analyses, we provide insights into potential functional outcomes of delayed rediploidization. This study enhances our understanding of delayed autopolyploid rediploidization and has broad implications for future studies of WGD events.


Neonatal unit receives prestigious accreditation.
A NEONATAL intensive care unit in Southampton has become the first in the country to gain a family-friendly accreditation award from the charity Bliss.


Utility of an image fusion system for 3D preoperative planning and fluoroscopy in the osteosynthesis of distal radius fractures.
Recently, computerized virtual surgery planning has been increasingly applied in various orthopedic procedures. In this study, we developed an image fusion system for 3D preoperative planning and fluoroscopy for the osteosynthesis. To assess the utility of image fusion system, we evaluated the reproducibility of preoperative planning in the osteosynthesis of distal radius fractures with using the image fusion system, and compared with the reproducibility of the patients without using the image fusion system. Forty-two wrists of 42 distal radius fracture patients who underwent osteosynthesis using volar locking plates were evaluated. The patients were divided into two groups. Image fusion group utilized three-dimensional (3D) preoperative planning and image fusion system. Control group utilized only 3D preoperative planning. In both groups, 3D preoperative planning was performed in order to determine reduction, placement, and choice of implants. In the image fusion group, the outline of planned image was displayed on a monitor overlapping with fluoroscopy images during surgery. Reductions were evaluated by volar tilt and radial inclination of 3D images. Plate positions were evaluated with distance to joint surface, plate center axis position, and inclination relative to the radius axis. Screw choices were recorded for the plan and actual choices for each screw hole. Differences in the parameters between pre- and postoperative images were evaluated. Differences in reduction shape, plate positions, and screw choices were compared between groups. The differences in the distance from plate to joint surface were significantly smaller in the image fusion group compared to the control group (P < 0.01). The differences in the distal screw choices were significantly smaller in the image fusion group compared to the control group (P < 0.01). The image fusion system was useful to reproduce the planned plate position and distal screw choices in the osteosynthesis of distal radius fractures. ClinicalTrials.gov, NCT03764501.


Pneumococcal C and type polysaccharide detection in the concentrated urine of patients with bacteremia.
The C polysaccharide of Streptococcus pneumoniae was detected in the concentrated urine of 23 of 33 patients with pneumococcal bacteremia using latex agglutination. Type-specific polysaccharides were detected in the urine of 17 of these 33 patients including 4 patients lacking C polysaccharide in their urine. These 4 with the 23 detected above gave a total sensitivity of 82% (27/33). The concentrated urine from an additional 11 patients with other bacteremias were tested by C polysaccharide and type-specific reagents and were negative. C polysaccharide detection in the concentrated urine of patients may be helpful in the diagnosis of pneumococcal infections.


Mechanical properties of tricalcium phosphate single crystals grown by molten salt synthesis.
Mechanical properties of flux-grown tricalcium phosphate (TCP) single crystals ranging in size from 50 to 75microm have been characterized by performing micro- and nanoindentation on their facets. Notwithstanding the inherent brittleness and anisotropy, these single crystals exhibit nanoscale plasticity in the form of pile-up around the edges of indents. A similar plastic response was observed in hydroxyapatite (HA) single crystals during nanoindentation in an earlier study. The hardness and elastic modulus obtained during nanoindentation are discussed in comparison with the polycrystalline forms of both TCP and HA found in the literature. The indentation fracture toughness values of TCP single crystals were found to be higher than those of HA single crystals. The higher values are attributed not only to the difference in crystal structure and corresponding differences in surface energy, but also to extensive crack bridging by ligament formation across crack faces during crack propagation.


Antitracheobronchospastic interaction in vitro and in vivo between salbutamol and flunisolide.
Salbutamol and flunisolide, when administered in association, are able to potentiate their effects both in vitro and in vivo on relaxation of the tracheobronchial smooth muscle of the guinea-pig.


Evaluation of the effects of hydroxyethyl starch (130/0.4) administration as a constant rate infusion on plasma colloid osmotic pressure in hypoabluminemic dogs.
To evaluate the effects of 2 constant rate infusions of hydroxyethyl starch (HES) 130/0.4 on plasma colloid osmotic pressure (COP) in hypoalbuminemic dogs. Prospective, randomized clinical trial. A total of 24 client-owned dogs. Hypoalbuminemic euvolemic dogs (albumin < 20 g/L [<2 g/dL]) with normal perfusion parameters requiring IV fluid therapy were enrolled. In addition to crystalloid, HES 130/0.4 was administered as a constant rate infusion over 24 hours at 1 mL/kg/h (group 1, n = 15) or at 2 mL/kg/h (group 2, n = 9), in order to support plasma COP. Before infusion, a blood sample was collected to perform CBC, serum electrophoresis, and serologic tests for some infective diseases. Plasma COP, albumin concentration, PCV, and total plasma protein concentration were evaluated serially at baseline (T0) and then at 6, 12, and 24 hours after the start of infusion, and a multilevel model was performed for these parameters to detect statistically significant differences between the 2 groups. Twenty-four dogs were included. No statistically significant differences in COP were found between the 2 groups; however, a high level of variability has been identified within the single individual. Among the other laboratory analyses, PCV was significantly decreased in group 1 at T12 and T24 compared with T0 (P < 0.001) and total plasma protein concentration was significantly increased in group 2 at T12 and T24 compared with T0 (P < 0.008). No significant effect on plasma COP was found following infusion with HES 130/0.4 at doses of 1 mL/kg/h and 2 mL/kg/h for 24 hours to hypoalbuminemic dogs. The administered concomitant dose of crystalloids, underlying disease, and small sample size were all potential confounding factors.


Reduced smoke-like echo and resolved thrombus in the left atrium with rivaroxaban therapy in an acute cardioembolic stroke patient.
We report a case of a nonvalvular atrial fibrillation (NVAF) patient with acute cardioembolic stroke in whom rivaroxaban, an oral direct factor Xa inhibitor, reduced a smoke-like echo in the left atrium and resolved a thrombus in the left atrial appendage. A 71-year-old man was admitted because of the sudden onset of right hemiplegia and aphasia and was diagnosed with acute cardioembolic stroke associated with NVAF. The patient had not been treated with warfarin before admission, and rivaroxaban therapy (15 mg once daily) was initiated. Transesophageal echocardiography was performed on day 8 and a mobile thrombus was found in the left atrial appendage, accompanied by a remarkable smoke-like echo in the left atrium. Notably, the thrombus was resolved and the smoke-like echo was reduced on day 40. No recurrent ischemic stroke occurred. We describe favorable effects of rivaroxaban on the reduction of a smoke-like echo and on the resolution of a thrombus in the left atrium in an NVAF patient with acute cardioembolic stroke.