Schistosoma mansoni: suppression of carbamoyl phosphate synthetase (ammonia) and ornithine carbamoyltransferase activities in the liver of infected mice.
ICR female mice infected with cercariae of Schistosoma mansoni exhibited a significant decrease in both total and specific activities of carbamoyl-phosphate synthetase (ammonia) (EC 188.8.131.52) and ornithine carbamoyltransferase (EC 18.104.22.168), and also in the serum urea level. Intraperitoneal administration of the S. mansoni egg granulomas or 15,000g X 30 min supernatant fluid of their extract into the uninfected, normal mice also significantly decreased the total and specific activities of both enzymes without any appreciable histopathological influence on their livers. S. mansoni viable eggs caused a significant decrease in the total and specific activities of carbamoyl phosphate synthetase (ammonia) alone as well as active intraperitoneal inflammation when inoculated into the normal mice by the same route. There was no difference in the amount of food intake between the control and these experimental mice. These findings suggest that the granuloma or inflammatory cells induced by schistosome eggs produce some factor(s) which may be responsible for reduction of these enzymatic activities in experimental schistosomiasis mansoni.


Iron deficiency anemia among Alaska Natives may be due to fecal loss rather than inadequate intake.
To define more fully the nature of a persistently high prevalence of iron deficiency anemia observed among Alaska Native children, we examined dietary iron intake, hemoglobin concentrations, and storage iron (serum ferritin) based on multiple cross-sectional surveys of Alaska Natives between 1983 and 1989. Approximately 30 to 50% of the children studied < 12 y of age had depleted iron stores. Anemia and depleted iron stores also were prevalent among adult men and women, about twice as prevalent as in the U.S. population based on the Second National Health and Nutrition Examination Survey (NHANES II). The higher rate of iron deficiency, occurring even when the dietary assessment found Alaska Native iron intake to be higher than the U.S. average with an ample intake of food high in bioavailable iron, suggests blood loss as a possible cause of the unusual pattern of iron deficiency observed. In a pilot study of stool blood loss in two villages, 65% of the samples had a significantly elevated stool heme concentration. Further investigation of iron deficiency due to gastrointestinal blood loss for the Alaska Native is warranted.


Hindbrain leptin stimulation induces anorexia and hyperthermia mediated by hindbrain melanocortin receptors.
Of the central nervous system receptors that could mediate the energy balance effects of leptin, those of the hypothalamic arcuate nucleus receive the greatest attention. Melanocortin receptors (MC-Rs) contribute to the feeding and energetic effects of hypothalamically delivered leptin. Energy balance effects of leptin are also mediated by extrahypothalamic neurons including the hindbrain nucleus tractus solitarius. Hindbrain leptin receptors play a role in leptin's anorectic effects, but their contribution to its energetic effects and their functional interaction with melanocortin systems within the hindbrain remains unexplored. Here rats implanted with telemetric devices for recording energetic/cardiovascular responses were examined to determine whether: 1) hindbrain (fourth ventricular) leptin receptor stimulation triggers energetic and cardiovascular effects, 2) these effects are altered by a 6-wk high-fat diet maintenance, and 3) hindbrain MC-Rs mediate the thermogenic, cardiovascular, and anorexic effects of hindbrain leptin delivery. Results show that hindbrain leptin receptor stimulation produced long-lasting (>6 h) increases in core temperature and heart rate and also decreased food intake and body weight. These responses were not altered by high-fat maintenance, in contrast to what has been reported for forebrain leptin delivery. Fourth ventricular pretreatment with MC-R antagonist SHU 9119 completely abolished the hyperthermia, anorexia, and body weight loss seen with hindbrain-directed leptin but had no effects of its own. These data highlight a role for hindbrain leptin receptors in the initiation of energetic and anorexic responses and show that MCRs are part of the downstream mediation of hindbrain leptin-induced energy balance effects, paralleling effects observed for hypothalamic leptin receptors.


The evolution of solvation symmetry and composition in Zn halide aqueous solutions from dilute to extreme concentrations.
The emergence of cation-anion species, or contact ion pairs, is fundamental to understanding the physical properties of aqueous solutions when moving from the ideal, low-concentration limit to the manifestly non-ideal limits of very high solute concentration or constituent ion activity. We focus here on Zn halide solutions both as a model system and also as an exemplar of the applications spanning from (i) electrical energy storage via the paradigm of water in salt electrolyte (WiSE) to (ii) the physical chemistry of brines in geochemistry to (iii) the long-standing problem of nucleation. Using a combination of experimental and theoretical approaches we quantify the halide coordination number and changing coordination geometry without embedded use of theoretical equilibrium constants. These results and the associated methods, notably including the use of valence-to-core X-ray emission spectroscopy, provide new insights into the Zn halide system and new research directions in the physical chemistry of concentrated electrolytes.


A biobank management model applicable to biomedical research.
The work of Research Ethics Boards (REBs), especially when involving genetics research and biobanks, has become more challenging with the growth of biotechnology and biomedical research. Some REBs have even rejected research projects where the use of a biobank with coded samples was an integral part of the study, the greatest fear being the lack of participant protection and uncontrolled use of biological samples or related genetic data. The risks of discrimination and stigmatization are a recurrent issue. In light of the increasing interest in biomedical research and the resulting benefits to the health of participants, it is imperative that practical solutions be found to the problems associated with the management of biobanks: namely, protecting the integrity of the research participants, as well as guaranteeing the security and confidentiality of the participant's information. We aimed to devise a practical and efficient model for the management of biobanks in biomedical research where a medical archivist plays the pivotal role as a data-protection officer. The model had to reduce the burden placed on REBs responsible for the evaluation of genetics projects and, at the same time, maximize the protection of research participants. The proposed model includes the following: 1) a means of protecting the information in biobanks, 2) offers ways to provide follow-up information requested about the participants, 3) protects the participant's confidentiality and 4) adequately deals with the ethical issues at stake in biobanking. Until a governmental governance body is established in Quebec to guarantee the protection of research participants and establish harmonized guidelines for the management of biobanks in medical research, it is definitely up to REBs to find solutions that the present lack of guidelines poses. The model presented in this article offers a practical solution on a day-to-day basis for REBs, as well as researchers by promoting an archivist to a pivotal role in the process. It assures protection of all participants who altruistically donate their samples to generate and improve knowledge for better diagnosis and medical treatment.


Cellular prion protein is expressed on peripheral blood mononuclear cells but not platelets of normal and scrapie-infected sheep.
Transmissible spongiform encephalopathies (TSEs) including sheep scrapie are characterized by the conversion of a normal, cellular prion protein (PrPc) to an abnormal protease-resistant form (PrPSc). Like human peripheral blood, the peripheral blood of scrapie-infected sheep remains one possible source of disease transmission. As a first step in understanding the disease requirements in the natural scrapie host, the presence of PrPc was evaluated in peripheral blood cells from five normal and five scrapie-infected Suffolk sheep. Live peripheral blood cells from normal and scrapie-infected sheep were analyzed for the presence of PrP using flow cytometry and reverse transcriptase-polymerase chain reaction (RT-PCR). PrP mRNA was detected in peripheral blood mononuclear cells (PBMC) but not in platelets or granulocytes. Consistent with PrP mRNA expression, cell-surface expressed PrP was detected on PBMC, but was not detected on granulocytes, platelets, or erythrocytes. Two-color flow cytometric analysis of PBMC specific phenotypes revealed that regardless of scrapie-status, expression of PrP was significantly higher on B2 positive B-lymphocytes than on CD4, CD8, WC1 positive T-lymphocytes or CD14 positive monocytes. In addition, PrP expressed on PBMC from normal and scrapie-infected sheep was sensitive to proteinase K (PK)and phosphatidylinositol-specific phospholipase C (PIPLC). Regardless of the scrapie-status of the sheep, resting PBMC transcribe PrPc and express PrPc as a cell-surface protein sensitive to both PK and PIPLC. Because of the abundance of PrPc on PBMC, future diagnostic tests using PK and PIPLC to discriminate between protease sensitive and resistant PrP must be carefully evaluated.


Transfibular total ankle arthroplasty : a new reliable procedure at five-year follow-up.
This study reports updates the previously published two-year clinical, functional, and radiological results of a group of patients who underwent transfibular total ankle arthroplasty (TAA), with follow-up extended to a minimum of five years. We prospectively evaluated 89 patients who underwent transfibular TAA for end-stage osteoarthritis. Patients' clinical and radiological examinations were collected pre- and postoperatively at six months and then annually for up to five years of follow-up. Three patients were lost at the final follow-up with a total of 86 patients at the final follow-up. A total of 86 patients were evaluated at a mean follow-up of 65.4 months (60 to 90). At five-year follow-up, statistically significant improvements (p < 0.001) were found in the mean American Orthopaedic Foot & Ankle Society Ankle Hindfoot Score (from 33.8 (SD 14.3) to 86.1 (SD 8.8)), visual analogue scale for pain (from 8.5 (SD 1.7) to 1.5 (SD 1.2)), Short Form-12 Physical and Mental Component Scores (from 29.9 (SD 6.7) and 43.3 (SD 8.6) to 47.3 (SD 7.5) and 52.2 (SD 8.0), respectively), and mean ankle dorsiflexion and plantarflexion (from 6.2° (SD 5.5°) and 9.6° (SD 5.8°) to 23.9° (SD 7.7°) and 16.9° (SD 7.2°), respectively). Radiologically, the implants maintained neutral alignment without subsidence. Tibial or talar radiolucency was found in eight patients, but none of these patients was symptomatic. At five-year follow up, 97.7% of implants (95% confidence interval 91.2 to 99.4) were free from revision or removal with 84 implants at risk. We recorded two cases (2.3%) of failure for septic loosening. Transfibular TAA is safe and effective with a high survival rate at mid-term follow-up and satisfactory clinical and radiological results. Further studies are required to determine the long-term performance of these implants. Cite this article: Bone Joint J 2022;104-B(4):472-478.


Hot flashes: epidemiology and physiology.
A review of the literature illustrates the many questions about hot flashes that remain unanswered. My survey addresses some of these questions. The prospective and retrospective descriptions of hot flashes provide a more detailed profile of the hot flash than has previously been available. Further, data from this survey demonstrate that while the patterns of hot flashes may be varied, there are commonalities in hot flash physiology and subjective manifestation. The data indicate that hot flashes may start much earlier and continue far longer than is commonly recognized by physicians or acknowledged in textbooks of gynecology. Studies of hot flash duration must control for age or age at hot flash onset, since the older the subjects, the more potential years of hot flashes and the greater the probability of encompassing the entire period of hot flashes. Hot flashes are not static; patterns may change with time. For some women, hot flashes become less frequent and less intense; for others, hot flashes may continue at hourly intervals well into old age. How common these experiences are for women of all ages still needs to be discovered. As expounded by Kaufert, McKinlay, Goodman, and many others, a greater effort must be made to standardize definitions and question formats as well as to improve methodology in epidemiologic investigations to facilitate comparability between studies and insure that proffered conclusions indeed reflect the questions being asked. Physiological studies are critical counterparts to the epidemiology; yet such studies have been too few. My work, by examining the physiology and psychophysiology of hot flashes, has raised additional questions about central and peripheral inputs that may affect the subjective experience of hot flashes. A more complete understanding of the thermoregulatory, cardiovascular, and psychophysiology of women with hot flashes are compared to women without will facilitate the prediction of who is most likely to be affected and the identification of additional approaches to the management of hot flashes.


Critical Care Simulation Education Program During the COVID-19 Pandemic.
Coronaviruses are important emerging human and animal pathogens. SARS-CoV-2, the virus that causes COVID-19, is responsible for the current global pandemic. Early in the course of the pandemic, New York City became one of the world's "hot spots" with more than 250,000 cases and more than 15,000 deaths. Although medical providers in New York were fortunate to have the knowledge gained in China and Italy before it came under siege, the magnitude and severity of the disease were unprecedented and arguably under appreciated. The surge of patients with significant COVID-19 threatened to overwhelm health care systems, as New York City health systems realized that the number of specialized critical care providers would be inadequate. A large academic medical system recognized that rapid redeployment of noncritical providers into such roles would be needed. An educational gap was therefore identified: numerous providers with minimal critical care knowledge or experience would now be required to provide critical-level patient care under supervision of intensivists. Safe provision of such high level of patient care mandated the development of "educational crash courses." The purpose of this special article is to summarize the approach adopted by the Institute for Critical Care Medicine and Department of Anesthesiology, Perioperative and Pain Medicine's Human Emulation, Education, and Evaluation Lab for Patient Safety and Professional Study Simulation Center in developing a training program for noncritical care providers in this novel disease. Using this joint approach, we were able to swiftly educate a wide range of nonintensive care unit providers (such as surgical, internal medicine, nursing, and advanced practice providers) by focusing on refreshing critical care knowledge and developing essential skillsets to assist in the care of these patients. We believe that the practical methods reviewed here could be adopted by any health care system that is preparing for an unprecedented surge of critically ill patients.


Concentration-dependent toxicity of iron oxide nanoparticles mediated by increased oxidative stress.
Iron oxide nanoparticles with unique magnetic properties have a high potential for use in several biomedical, bioengineering and in vivo applications, including tissue repair, magnetic resonance imaging, immunoassay, drug delivery, detoxification of biologic fluids, cell sorting, and hyperthermia. Although various surface modifications are being done for making these nonbiodegradable nanoparticles more biocompatible, their toxic potential is still a major concern. The current in vitro study of the interaction of superparamagnetic iron oxide nanoparticles of mean diameter 30 nm coated with Tween 80 and murine macrophage (J774) cells was undertaken to evaluate the dose- and time-dependent toxic potential, as well as investigate the role of oxidative stress in the toxicity. A 15-30 nm size range of spherical nanoparticles were characterized by transmission electron microscopy and zeta sizer. MTT assay showed >95% viability of cells in lower concentrations (25-200 μg/mL) and up to three hours of exposure, whereas at higher concentrations (300-500 μg/mL) and prolonged (six hours) exposure viability reduced to 55%-65%. Necrosis-apoptosis assay by propidium iodide and Hoechst-33342 staining revealed loss of the majority of the cells by apoptosis. H₂DCFDDA assay to quantify generation of intracellular reactive oxygen species (ROS) indicated that exposure to a higher concentration of nanoparticles resulted in enhanced ROS generation, leading to cell injury and death. The cell membrane injury induced by nanoparticles studied using the lactate dehydrogenase assay, showed both concentration- and time-dependent damage. Thus, this study concluded that use of a low optimum concentration of superparamagnetic iron oxide nanoparticles is important for avoidance of oxidative stress-induced cell injury and death.


First Report of Phomopsis longicolla Causing Stem Canker of Eggplant in Guangdong, China.
Eggplant (Solanum melongena L.) is an economically important vegetable crop worldwide. In August 2012, severe stem cankers were observed on eggplant at the early stage of maturation in several fields in Guangdong Province, China. Diseased plants raised cankers on the stems and branches, which resulted in wilting and stunting. No symptoms developed on eggplant fruit. Disease incidence was as high as 40% within affected fields. By using routine fungal-isolation methods and single-spore purification technique, five single-conidial isolates were obtained from each diseased stem. Colonies were grayish-white, circular, and got yellow pigmentation when placed in acidified potato dextrose agar (PDA) in an incubator at pH 4.5 and 25°C with a 12-h photoperiod. Stromata were black, large, and spreading in a concentric pattern. Conidiomata were pycnidial, and the pycnidia were round, oblate, triangular or irregular, and unilocular. Conidiophores were colorless, separated, dichotomous, and 10.0 to 18.0 × 1.5 to 2.0 μm. Alpha conidia were single-celled, ellipsoidal to fusiform, guttulate, and 6.0 to 8.0 × 2.0 to 2.5 μm. Beta conidia, produced on oat meal agar in 2 weeks at 25°C in the dark, were filiform, hamate, and 16.0 to 28.0 × 0.7 to 1.0 μm. Based on these morphological characters, the fungus was identified as Phomopsis longicolla Hobbs (1). The ITS-rDNA sequence (GenBank Accession No. KC886605) of the isolate EPPL1 of this fungus (P. longicolla EPPL1) was obtained by using universal primers ITS5/ITS4 (1). BLAST searches showed a 98% homology with the sequence of the ITS region of rDNA of P. longicolla. Phylogenetic analysis showed that P. longicolla EPPL1 clustered with P. longicolla SYJM15 and formed a distinct clade distantly related to P. vexans PV3 (GU373630), a well-known pathogen of eggplant. Digestion of PCR-amplified DNA with Alu I yielded two restriction fragments of sizes consistent with those reported for P. longicolla (2). Pathogenicity tests were performed on 30-day-old plants of cv. Yuefengzihongqie grown in a plastic pot (1 liter) in a greenhouse by using mycelial plugs and conidial suspensions of isolate EPPL1 as inocula. A mycelial plug (4 mm in diameter) from a 7-day-old PDA culture was placed on stems of both wounded and non-wounded plants and covered with sterile absorbent cotton moistened with sterile distilled water. Both wounded and non-wounded plants were inoculated with 0.5 ml of conidial suspension (1 × 106 conidia ml-1) dropped onto sterile absorbent cotton covering the stems. Control assays were performed with agar plugs and sterile distilled water only. Inoculated plants were placed in a greenhouse with a 12-h photoperiod at 28°C. Each treatment was replicated on five plants, and the test was repeated. Twenty-five days after inoculation, both wounded and non-wounded plants inoculated with either method showed raised cankers at the points of inoculation and canker lesions similar to those observed in the field expanded up and down the stems to reach lengths of 15 to 30 mm. Later, sparse, small, black pycnidia formed on the surface of the lesions. The inoculated plants exhibited stunting and premature senescence compared to controls. P. longicolla was re-isolated from the infected stems of inoculated plants. Control plants were asymptomatic. To our knowledge, this is the first report of P. longicolla causing stem canker in eggplant in Guangdong, China. Considering the economic importance of eggplant in Guangdong Province and throughout the world, further study of phomopsis stem canker of eggplant is warranted. References: (1) T. W. Hobbs et al. Mycologia 77:535, 1985. (2) A. W. Zhang et al. Plant Dis. 81:1143, 1997.


Post-obstructive diuresis after posterior urethral valve treatment in neonates: a retrospective cohort study.
The management of posterior urethral valve (PUV) in neonates requires close monitoring in the intensive care unit because of the risk of post-obstructive diuresis (POD). Our aim was to describe the incidence and factors associated with POD in newborns treated for PUV. Retrospective analysis of the medical records of all neonates who underwent surgical intervention for PUV in our neonatal intensive care unit between January 2014 and April 2021. Of the 40 patients included, 15 (37.5%) had POD defined by urine output > 6 ml.kg-1.h-1 during the first 24 h following urinary tract obstruction relief. At prenatal ultrasound examinations, oligohydramnios was more common in the group with POD than in the group without (53.3% vs. 8%, p = 0.002). Preterm birth was more frequent in neonates with POD (66.7% vs. 8%; p < 0.001). Median serum creatinine (212 [137-246] vs. 95 [77-125] µmol.l-1; p < 0.001) and urea (8.5 [5.2-12.2] vs. 4.1 [3.5-4.7] mmol.l-1; p < 0.001) concentrations on the day of obstruction relief were significantly higher in the group with POD than in the group without. After adjustment for prematurity, logistic regression models confirmed correlation between the occurrence of POD and the severity of the consequences of urethral obstruction (i.e., oligohydramnios and serum creatinine levels; ß = 2.90 [0.88; 5.36], p = 0.013 and ß = 0.014 [0.003; 0.031], p = 0.034, respectively). In neonates, POD is common after the relief of PUV-related obstruction. Our findings may help to identify patients at highest risk. A higher resolution version of the Graphical abstract is available as Supplementary information.


Applications of bacterial ghosts in biomedicine.
Bacterial Ghosts (BG) are empty cell envelopes of Gram-negative bacteria which have been produced by E-mediated lysis. BG are devoid of cytoplasmic content and in combination with the expression of the nuclease SNUC, BG are also devoid of chromosomal and plasmid DNA. Proof of concept and proof of principle studies showed that BG candidate vaccines are highly immunogenic and in many instances induce protective immunity against lethal challenge in animal models. Due to their nature of being bacterial envelope complexes, BG are endowed with intrinsic natural adjuvant activity. BG are able to stimulate the innate and adaptive immune system without any addition of exogenous adjuvants. Although the use of plasmid encoded genetic information is essential for the final make up of BG, BG are not to be considered as genetically manipulated organisms (GMO), as they are nonliving and devoid of genetic information. The latter aspect is of great importance for safety, as no pathogenic islands or antibiotic resistance cassettes can be transferred to other bacteria by horizontal gene transfer. This is an important difference to other chemical-, heat- and pressure- or radiation-inactivated vaccine candidates, which also very often need artificial adjuvants to be added to improve their immunogenicity. The final BG vaccine preparations are freeze dried and are stable for many years at ambient temperature. BG can also be used as carrier and delivery vehicles for drugs or active substances in tumor therapy and due to specific targeting of tumor cells allow a higher specificity of treatment and a reduction of the total amount of drug per application. As carrier of enzymatic activity BG can be used for a new concept of probiotics which can synthesise active compounds from substrates of the environment where they are applied with a certain preference for the gut system. Thus, BG represent a promising technology platform for novel vaccines including combination or DNA vaccines, as drug carriers for therapeutic approaches in tumor treatment and as novel probiotics.


Deployment of nursing students to assist in CLABSI and CAUTI prevention bundle audits and interventions during the COVID-19 pandemic.
The COVID-19 pandemic exacerbated previously existing health care challenges related to hospital-acquired infections. Nursing students were deployed to augment staffing shortages and mitigate incidences of catheter-associated urinary tract infections and catheter-associated bloodstream infections. Nursing students' use as an adjunct to infection prevention measures facilitated success in sustaining low rates of catheter-associated bloodstream infections and catheter-associated urinary tract infections.


Spread of activation and deactivation in the brain: does age matter?
Cross-sectional aging functional MRI results are sometimes difficult to interpret, as standard measures of activation and deactivation may confound variations in signal amplitude and spread, which however, may be differentially affected by age-related changes in various anatomical and physiological factors. To disentangle these two types of measures, here we propose a novel method to obtain independent estimates of the peak amplitude and spread of the BOLD signal in areas activated (task-positive) and deactivated (task-negative) by a Sternberg task, in 14 younger and 28 older adults. The peak measures indicated that, compared to younger adults, older adults had increased activation of the task-positive network, but similar levels of deactivation in the task-negative network. Measures of signal spread revealed that older adults had an increased spread of activation in task-positive areas, but a starkly reduced spread of deactivation in task-negative areas. These effects were consistent across regions within each network. Further, there was greater variability in the anatomical localization of peak points in older adults, leading to reduced cross-subject overlap. These results reveal factors that may confound the interpretation of studies of aging. Additionally, spread measures may be linked to local connectivity phenomena and could be particularly useful to analyze age-related deactivation patterns, complementing the results obtained with standard peak and region of interest analyses.


Resistance and immune response in scabies-infested hosts immunized with Dermatophagoides mites.
Seventy-one percent of rabbits immunized with a mixed (50:50) Dermatophagoides farinae and D. pteronyssinus house dust mite extract were resistant to infestation by Sarcoptes scabiei var. canis. The resistance was evidenced by a marked reduction in parasite load. All immunized hosts developed similar immunogen-specific antibody titers that were independent of the levels of scabies infestation that developed when the hosts were infested with scabies. Resistant hosts exhibited significantly lower scabies-specific immunoglobulin titers and produced antibody to fewer scabies antigens than did nonresistant hosts. All infested hosts (resistant and nonresistant) showed a cellular infiltrate in the scabietic lesions that was composed of neutrophils, plasma cells, macrophages, and mononuclear cells. Resistant hosts were characterized by fewer plasma cells in the infiltrate than were observed for non-resistant hosts. Resistant hosts exhibited a gradual increase in the number of infiltrating neutrophils, followed by a decrease that correlated with a decrease in the mite burden. Nonresistant hosts exhibited an early rapid increase, a decrease, and then a gradual increase in the concentration of neutrophils as the mite load increased. These results clearly showed that D. farinae/D. pteronyssinus antigens/epitopes can sensitize the hosts to scabies mites and induce protective immunity. The lower circulating antibody levels and generally stronger inflammatory cell-mediated response of resistant hosts compared with nonresistant hosts suggested that the mechanism by which immunization with Dermatophagoides mites induces immunity to scabies mites involved a down-regulated T helper cell type 2 (Th2) response with reduced antibody production but an up-regulated and stronger Th1 (inflammatory cell-mediated) response to scabies.


Comparison of gene expression profiles of the jejunum of broilers supplemented with a yeast cell wall-derived mannan oligosaccharide versus bacitractin methylene disalicylate.
1. The addition of yeast cell wall (YCW) mannan fractions or low concentrations of antibiotics to the diet of broilers positively affects gut health by improving intestinal cell morphology and improves feed efficiency and performance; however the exact mechanisms are unclear. Based on these production responses, the objective of this study was to compare the effects of supplementing YCW and bacitracin methylene disalicylate (BMD) in the diet on mRNA levels in the jejunum of 6-week-old broilers. 2. Dietary treatments were a maize-soya control diet and the control diet with the addition of YCW or BMD. Birds (n = 7) from each dietary treatment were randomly selected and killed at d 42. Whole jejunum (with serosa) samples were collected for RNA isolation. Gene expression analysis was performed using the AffymetrixGeneChip Chicken Genome Array (Santa Clara, CA, USA). 3. Supplementation with YCW resulted in 928 genes that were significantly changed (456 down-regulated, 472 up-regulated) and supplementation with BMD resulted in 857 genes that significantly changed (408 down-regulated, 449 up-regulated). In addition, 316 genes were significantly changed by both YCW and BMD (146 down-regulated, 170 up-regulated). 4. BMD increased the expression of genes involved in lipid and carbohydrate metabolism and decreased expression of genes associated with T-helper cell pathways. Gene expression profiles from birds fed on diets containing YCW showed changes on a genomic level that correspond to slower gut cell turnover and therefore increased energy preservation for growth. 5. In conclusion, supplementation with BMD or YCW had similar influences on the number of differentially expressed genes in the jejunum. Biological functions common to both YCW and BMD with positive activation scores included antiviral response and antimicrobial response. Genes that were affected by BMD or YCW classified into both different and common biological functions and pathways related to improved metabolism and health in the jejunum.


Rhodococcus fascians infection accelerates progression of tobacco BY-2 cells into mitosis through rapid changes in plant gene expression.
* To characterize plant cell cycle activation following Rhodococcus fascians infection, bacterial impact on cell cycle progression of tobacco BY-2 cells was investigated. * S-phase-synchronized BY-2 cells were cocultivated with R. fascians and cell cycle progression was monitored by measuring mitotic index, cell cycle gene expression and flow cytometry parameters. Cell cycle alteration was further investigated by cDNA-AFLP (amplified fragment length polymorphism). * It was shown that cell cycle progression of BY-2 cells was accelerated only upon infection with bacteria whose virulence gene expression was induced by a leafy gall extract. Thirty-eight BY-2 genes showed a differential expression within 6 h post-infection. Among these, seven were previously associated with specific plant cell cycle phases (in particular S and G2/M phases). Several genes also showed a differential expression during leafy gall formation. * R. fascians-infected BY-2 cells provide a simple model to identify plant genes related to leafy gall development. R. fascians can also be regarded as a useful biotic agent to alter cell cycle progression and, thereby, gain a better understanding of cell cycle regulation in plants.


The First Decade of Web-Based Sports Injury Surveillance: Descriptive Epidemiology of Injuries in US High School Boys' Soccer (2005-2006 Through 2013-2014) and National Collegiate Athletic Association Men's Soccer (2004-2005 Through 2013-2014).
The advent of Web-based sports injury surveillance via programs such as the High School Reporting Information Online system and the National Collegiate Athletic Association Injury Surveillance Program has aided the acquisition of boys' and men's soccer injury data. To describe the epidemiology of injuries sustained in high school boys' soccer in the 2005-2006 through 2013-2014 academic years and collegiate men's soccer in the 2004-2005 through 2013-2014 academic years using Web-based sports injury surveillance. Descriptive epidemiology study. Online injury surveillance from soccer teams of high school boys (annual average = 100) and collegiate men (annual average = 41). Boys' or men's soccer players who participated in practices and competitions during the 2005-2006 through 2013-2014 academic years in high school and the 2004-2005 through 2013-2014 academic years in college, respectively. Athletic trainers collected time-loss (≥24 hours) injury and exposure data. Injury rates per 1000 athlete-exposures (AEs), injury rate ratios (IRRs) with 95% confidence intervals (CIs), and injury proportions by body site and diagnosis were calculated. High School Reporting Information Online documented 2912 time-loss injuries during 1 592 238 AEs; the National Collegiate Athletic Association Injury Surveillance Program documented 4765 time-loss injuries during 686 918 AEs. The injury rate was higher in college than in high school (6.94 versus 1.83/1000 AEs; IRR = 3.79; 95% CI = 3.62, 3.97). Injury rates increased with smaller school size for high schools and were higher in Division I than in Divisions II and III. The injury rate was higher during competitions than during practices in both high school (IRR = 3.55; 95% CI = 3.30, 3.83) and college (IRR = 3.45; 95% CI = 3.26, 3.65). Most injuries were to the lower extremity. However, concussion was a common injury, particularly in collegiate goalkeepers and at all positions for high school players. Concussions accounted for more than one-fifth of injuries in high school games. Injury-prevention interventions should be tailored to reflect variations in the incidence and type of injury by level of competition, event type, and position.


Associations between symptoms of attention deficit hyperactivity disorder, depression, and suicide in Korean female adolescents.
The objective of this study was to examine the associations between symptoms of attention-deficit/hyperactivity disorder (ADHD), depression, and suicide in Korean female adolescents. It was hypothesized that the relationship between ADHD symptoms and suicidal ideation would be mediated by the level of depressive symptoms. Seven hundred and eighty-eight high school girls completed the Conners/Wells Adolescent Self-Report Scale: Short Form, Children's Depression Inventory, and Reynolds Suicidal Ideation Questionnaire. Path analyses were conducted using the statistical program, AMOS version 4.0, to determine the best fitting model. The conduct, cognitive, and hyperactivity problems of the ADHD symptoms in each domain were associated positively with the depressive symptoms, with the depressive symptoms being associated with suicidal ideation. This initially proposed model represented an acceptable fit to the data (root mean square error of approximation, RMSEA=0.077; normed fit index, NFI=0.998; non-NFI, NNFI=0.990; comparative fit index, CFI=0.998). The inclusion of a direct path from the conduct problems of ADHD symptoms to suicidal ideation significantly improved the model fit (RMSEA=0, NFI=1, NNFI=1, CFI=1). The results of our study suggest that depressive symptoms partially mediate the relationship between ADHD symptoms and suicidal ideation, and that the conduct problems of ADHD symptoms are associated with suicidal ideation both directly and indirectly via the depressive symptoms in Korean female adolescents.


Some comments on the formation of murine hemopoietic colonies grown in vivo and in vitro: quantitative analysis.
Experimental distributions of in vitro colonies are analyzed and compared to numerically calculated distributions. The experimental data are those of Nakahata et al. [J. Cell. Physiol., 113, 455-458, 1982], who studied the development of primary and secondary murine hemopoietic colonies in vitro. The cumulative probability distributions of the secondary colonies are simulated by a simple proliferation tree model. The model consists of four subsequent generations of distinct cells undergoing self-renewal and differentiation governed by an unspecified control process. It is assumed only that the control mechanism is so complex that the resulting commitment can be well described by probabilistic formalism. The calculated and experimental distributions are found to be in reasonable agreement. Furthermore, 25 additional experimental distributions have been examined, corresponding to various sets of in vitro and spleen-grown colonies reported in the literature. It is shown that most of the cumulative distributions analyzed are well approximated by the exponential function f(n) = exp(alpha n), where f(n) is the relative number of originating elements (e.g., cells or clones) producing groups having at least n members. A formula is suggested relating the exponent alpha and the probability of self-renewal for a simple single-generation case.


Mechanisms of Chronic Muscle Wasting and Dysfunction after an Intensive Care Unit Stay. A Pilot Study.
Critical illness survivors often experience permanent functional disability due to intensive care unit (ICU)-acquired weakness. The mechanisms responsible for long-term weakness persistence versus resolution are unknown. To delineate cellular mechanisms underlying long-term weakness persistence in ICU survivors. We conducted a nested, prospective study of critically ill patients mechanically ventilated for 7 days or longer. The patients were recruited from the RECOVER program and serially assessed over 6 months after ICU discharge. Twenty-seven of 82 patients consented to participate; 15 and 11 patients were assessed at 7 days and 6 months after ICU discharge, respectively. We assessed motor functional capacity, quadriceps size, strength, and voluntary contractile capacity and performed electromyography, nerve conduction studies, and vastus lateralis biopsies for histologic, cellular, and molecular analyses. Strength and quadriceps cross-sectional areas were decreased 7 days after ICU discharge. Weakness persisted to 6 months and correlated with decreased function. Quadriceps atrophy resolved in 27% patients at 6 months. Muscle mass reconstitution did not correlate with resolution of weakness, owing to persistent impaired voluntary contractile capacity. Compared with Day 7, increased ubiquitin-proteasome system-mediated muscle proteolysis, inflammation, and decreased mitochondrial content all normalized at 6 months. Autophagy markers were normal at 6 months. Patients with sustained atrophy had decreased muscle progenitor (satellite) cell content. Long-term weakness in ICU survivors results from heterogeneous muscle pathophysiology with variable combinations of muscle atrophy and impaired contractile capacity. These findings are not explained by ongoing muscle proteolysis, inflammation, or diminished mitochondrial content. Sustained muscle atrophy is associated with decreased satellite cell content and compromised muscle regrowth, suggesting impaired regenerative capacity.


Transforming growth factor-beta 1 down-regulates basal and polycyclic aromatic hydrocarbon-induced cytochromes P-450 1A1 and 1A2 in adult human hepatocytes in primary culture.
The effects of interleukin (IL)-1 beta, IL-4, IL-6, tumor necrosis factor (TNF)-alpha, interferon (IFN)-alpha, IFN-gamma, and transforming growth factor (TGF)-beta 1 on cytochrome P-450 (CYP) 1A expression and polycyclic aromatic hydrocarbon (PAH)-mediated induction in primary human hepatocyte cultures were determined. Most cytokines that were previously found to decrease basal CYP expression could counteract PAH induction of CYP1A mRNA and its associated ethoxyresorufin-O-deethylation (EROD) activity. IL-1 beta and TNF-alpha blocked 3-methylcholanthrene (3-MC)-induced EROD activity by up to 25 and 44%, respectively. IFN-alpha and IFN-gamma antagonized EROD induction by up to 61 and 70%, respectively. TGF-beta 1 proved to be the most effective cytokine, because 72 hr of treatment with 2 ng/ml TGF-beta 1 produced nearly 100% inhibition of 3-MC- and benzo(a)pyrene-induced CYP1A1 and CYP1A2 mRNAs and EROD activity. Treatment with cycloheximide in combination with 3-MC led to superinduction of CYP1A mRNA, under which conditions TGF-beta 1 did not block induction, suggesting the requirement for protein synthesis for the suppressive effect of the cytokine. In addition, TGF-beta 1 augmented AP-1-binding activity, suggesting that fos and/or jun protooncogene products could be implicated in the response. Our results demonstrate that IL-1 beta, TNF-alpha, and IFNs antagonized PAH-mediated induction of CYP1A gene expression in human hepatocytes. In addition, we report the finding of a novel effect of TGF-beta 1, which was able to prevent CYP1A1 and -1A2 induction by two different PAHs.


Climbing the Jaynes-Cummings ladder and observing its nonlinearity in a cavity QED system.
The field of cavity quantum electrodynamics (QED), traditionally studied in atomic systems, has gained new momentum by recent reports of quantum optical experiments with solid-state semiconducting and superconducting systems. In cavity QED, the observation of the vacuum Rabi mode splitting is used to investigate the nature of matter-light interaction at a quantum-mechanical level. However, this effect can, at least in principle, be explained classically as the normal mode splitting of two coupled linear oscillators. It has been suggested that an observation of the scaling of the resonant atom-photon coupling strength in the Jaynes-Cummings energy ladder with the square root of photon number n is sufficient to prove that the system is quantum mechanical in nature. Here we report a direct spectroscopic observation of this characteristic quantum nonlinearity. Measuring the photonic degree of freedom of the coupled system, our measurements provide unambiguous spectroscopic evidence for the quantum nature of the resonant atom-field interaction in cavity QED. We explore atom-photon superposition states involving up to two photons, using a spectroscopic pump and probe technique. The experiments have been performed in a circuit QED set-up, in which very strong coupling is realized by the large dipole coupling strength and the long coherence time of a superconducting qubit embedded in a high-quality on-chip microwave cavity. Circuit QED systems also provide a natural quantum interface between flying qubits (photons) and stationary qubits for applications in quantum information processing and communication.


Current updates on protein as biomarkers for diabetic kidney disease: a systematic review.
In the past decade, researchers have been focused on discovering protein biomarkers for diabetic kidney disease. This paper aims to search for, analyze, and synthesize current updates regarding the development of these efforts. We systematically searched the ScienceDirect, SpringerLink, and PubMed databases for observational studies of protein biomarkers in patients with diabetes mellitus. We included studies published between January 2018 and April 2020, that were based on a population of patients with type-1 or type-2 diabetes mellitus aged ⩾18 years, with an observational design such as cross-sectional, case-control, or cohort studies. The dependent variable of the research results was in the form of protein biomarkers from urine, plasma, or serum. Following the screening process, 20 research articles with available full text met the inclusion criteria. These could be categorized as glomerular biomarkers (ANGPTL4, beta-2 microglobulin, Smad1, and glypican-5); inflammatory biomarkers (MCP-1 and adiponectin); and tubular biomarkers (NGAL, VDBP, megalin, sKlotho, and KIM-1). The development of a panel of biomarkers showed more promising results than those for a single biomarker in diagnosing diabetic kidney disease. All the biomarkers discussed in this review showed promising results for predicting diabetic kidney disease because they correlate with albuminuria, eGFR, or both. However, of the 11 protein biomarkers, none have prognostic value beyond albuminuria and eGFR.


An inhibitory mechanism for suppressing high salt intake in Drosophila.
High concentrations of dietary salt are harmful to health. Like most animals, Drosophila melanogaster are attracted to foods that have low concentrations of salt, but show strong taste avoidance of high salt foods. Salt in known on multiple classes of taste neurons, activating Gr64f sweet-sensing neurons that drive food acceptance and 2 others (Gr66a bitter and Ppk23 high salt) that drive food rejection. Here we find that NaCl elicits a bimodal dose-dependent response in Gr64f taste neurons, which show high activity with low salt and depressed activity with high salt. High salt also inhibits the sugar response of Gr64f neurons, and this action is independent of the neuron's taste response to salt. Consistent with the electrophysiological analysis, feeding suppression in the presence of salt correlates with inhibition of Gr64f neuron activity, and remains if high salt taste neurons are genetically silenced. Other salts such as Na2SO4, KCl, MgSO4, CaCl2, and FeCl3 act on sugar response and feeding behavior in the same way. A comparison of the effects of various salts suggests that inhibition is dictated by the cationic moiety rather than the anionic component of the salt. Notably, high salt-dependent inhibition is not observed in Gr66a neurons-response to a canonical bitter tastant, denatonium, is not altered by high salt. Overall, this study characterizes a mechanism in appetitive Gr64f neurons that can deter ingestion of potentially harmful salts.


Associations of childhood adiposity and changes in adiposity status from childhood to adulthood with pregnancy hypertension.
To investigate the associations between adiposity in childhood, and adiposity change from childhood to adulthood, with pregnancy hypertension. The study followed-up 985 girls from the 1985 Australian Schools Health and Fitness Survey (aged 9-15 years) who were ever pregnant in 2004-2006 and/or 2009-2011. In childhood, overweight and obesity were defined by age-sex-specific international standard for body mass index (BMI) and in adulthood as BMI ≥ 25 kg/m2. Childhood and adult abdominal obesity were defined as waist-to-height ratio (WHtR) ≥ 0.5. A subsample of adults had abdominal obesity measures (n = 549). Pregnancy hypertension was self-reported as having had high blood pressure during or due to pregnancy. Childhood overweight/obesity (relative risk [RR] = 1.66, 95% confidence interval [CI]:1.07-2.52) and abdominal obesity (RR = 2.55, 95% CI:1.34-4.85) were associated with higher risks of pregnancy hypertension after adjustment for age, socioeconomic status and parity. Further adjustment for adult BMI attenuated the association for childhood overweight/obesity which was no longer statistically significant (RR = 1.28, 95% CI:0.79-2.07). The association with childhood abdominal obesity persisted after adjustment for adult WHtR (RR = 2.15, 95% CI:1.10-4.20). Compared to participants with persistently normal BMI or WHtR, those who were overweight/obese in adulthood only (RR = 1.49, 95% CI:1.10-2.02), persistently overweight/obese (RR = 2.06, 95% CI:1.29-3.29) or persistently abdominally obese (RR = 3.09, 95% CI:1.54-6.20) had increased risks of pregnancy hypertension. Childhood adiposity was associated with increased risk of pregnancy hypertension, with the association of childhood abdominal obesity independent of adult abdominal obesity. Women who were persistently overweight/obese or abdominally obese since childhood had the highest risk of pregnancy hypertension.


[Patient management after splenectomy in 2015: state of the art and recommendations].
Spleen gathers numerous functions and plays a critical role in immunity against encapsulated bacteria. Anatomical injuries or physiological spleen dysfunctions can lead to complete (asplenism) or partial (hyposplenism) functional deficits and expose the patient to the risk of fulminant sepsis, as well as to thromboembolic complications. The purpose of this article is to provide the primary care physician with the tools needed to identify functional disorders of the spleen and to prevent their complications. The latest recommendations for antibiotic prophylaxis and immunization are also addressed.


Loss of heterochromatin protein 1 (HP1) chromodomain function in mammalian cells by intracellular antibodies causes cell death.
The chromodomain (CD) is a highly conserved motif present in a variety of animal and plant proteins, and its probable role is to assemble a variety of macromolecular complexes in chromatin. The importance of the CD to the survival of mammalian cells has been tested. Accordingly, we have ablated CD function using two single-chain intracellular Fv (scFv) fragments directed against non-overlapping epitopes within the HP1 CD motif. The scFv fragments can recognize both CD motifs of HP1 and Polycomb (Pc) in vitro and, when expressed intracellularly, interact with and dislodge the HP1 protein(s) from their heterochromatin localization in vivo. Mouse and human fibroblasts expressing anti-chromodomain scFv fragments show a cell-lethal phenotype and an apoptotic morphology becomes apparent soon after transfection. The mechanism of cell death appears to be p53 independent, and the cells are only partly rescued by incubation with the wide spectrum caspase inhibitor Z-VAD fmk. We conclude that expression of anti-chromodomain intracellular antibodies is sufficient to trigger a p53-independent apoptotic pathway that is only partly dependent on the known Z-VAD-inhibitable caspases, suggesting that CD function is essential for cell survival.


Trigger-specific risk factors and response to therapy in long QT syndrome type 2.
Cardiac events in patients with long QT syndrome type 2 (LQT2) are predominately associated with sudden arousal. However, exercise-induced events also occur in this population. The purpose of this study was to test the hypothesis that risk factors show a trigger-specific association with cardiac events in LQT2 patients. The study population consisted of 634 genetically confirmed LQT2 patients from the U.S. portion of the International LQTS Registry. Multivariate Cox proportional hazards regression analysis was used to determine the independent contribution of clinical and genetic risk factors to the first occurrence of trigger-specific cardiac events, categorized as arousal, exercise-induced, and nonarousal/nonexercise, from birth through age 40 years. Study patients experienced 204 cardiac events during follow-up, of which 44% were associated with arousal triggers, 13% with exercise activity, and 43% with nonexercise/nonarousal triggers. Risk factors for arousal-triggered cardiac events included gender (female:male > 13 years: hazard ratio [HR] 9.10, P < .001) and the presence of pore-loop mutations (HR 2.19, P = .009). In contrast, non-pore-loop transmembrane mutations were the predominant risk factor for exercise-triggered events (HR 6.84, P < .001), whereas gender was not a significant risk factor for this endpoint. Nonexercise/nonarousal events were associated with heterogeneous causes. Risk factors for this endpoint included gender, mutation location and type, and prolonged QTc (≥ 500 m) Beta-blocker therapy was associated with a pronounced reduction in the risk for exercise-triggered events (HR 0.29, P < .01) but had a nonsignificant effect on the risk for arousal and nonexercise/nonarousal events. The study findings suggest that management of patients with the LQT2 genotype should use a trigger-specific approach to risk assessment and medical therapy.


Granzyme B Contributes to Barrier Dysfunction in Oxazolone-Induced Skin Inflammation through E-Cadherin and FLG Cleavage.
Atopic dermatitis (AD) is the most common inflammatory skin condition. Skin barrier dysfunction is of major importance in AD because it facilitates allergen sensitization and systemic allergic responses. Long regarded as a pro-apoptotic protease, emerging studies indicate granzyme B (GzmB) to have extracellular roles involving the proteolytic cleavage of extracellular matrix, cell adhesion proteins, and basement membrane proteins. Minimally expressed in normal skin, GzmB is elevated in AD and is positively correlated with disease severity and pruritus. We hypothesized that GzmB contributes to AD through extracellular protein cleavage. A causative role for GzmB was assessed in an oxazolone-induced murine model of dermatitis, comparing GzmB-/- mice with wild-type mice, showing significant reductions in inflammation, epidermal thickness, and lesion formation in GzmB-/- mice. Topical administration of a small-molecule GzmB inhibitor reduced disease severity compared with vehicle-treated controls. Mechanistically, GzmB impaired epithelial barrier function through E-cadherin and FLG cleavage. GzmB proteolytic activity contributes to impaired epidermal barrier function and represents a valid therapeutic target for AD.


Tumbling, an interactive way to move forward.
The migration of Drosophila border cells has become a powerful model with which to genetically identify guidance cues that control the directed migration of a group of interconnected cells. During oogenesis, border cells delaminate from an epithelial layer and move collectively toward the oocyte. In vivo observation has been added to the impressive experimental toolkit available to study border cell migration. These studies reveal two previously unknown migratory behaviors: one in which cells within the border cell cluster constantly change their position, and another called "tumbling," by which the entire border cell cluster rotates forward. Unexpectedly, the same receptor tyrosine kinases control these different modes of migration through separate downstream pathways. An early mode is mediated by the actin regulatory proteins ELMO and Mbc and resembles cellular polarization during individual cell migration; whereas during a later phase, communication between cells, facilitated by mitogen-activated protein kinase and phospholipase C-gamma, organizes the polarity of the entire cluster.


Studies on kinetics of [3H]beta-funaltrexamine binding to mu opioid receptor.
beta-Funaltrexamine (beta-FNA) was shown to be a reversible kappa agonist and an irreversible mu antagonist. [3H]beta-FNA at low concentrations (less than 10 nM) covalently binds to mu but not delta or kappa opioid receptors in brain membranes. The interaction between beta-FNA and mu opioid receptors was thought to involve two steps; a reversible ligand-receptor complex is formed before the formation of an irreversible complex, based on observations in bioassays in vitro. In this study, we investigated whether such a two-step process occurred in binding using bovine striatal membranes and determined the kinetic parameters by examining the time courses of both reversible and irreversible binding of [3H]beta-FNA to mu opioid receptors. Specific binding was defined as the difference between binding in the presence of levorphanol and dextrorphan (1 microM). Reversible binding was determined as the difference between membrane (reversible and irreversible) binding and irreversible binding. At 25 degrees, the rate of formation of irreversible [3H]beta-FNA-receptor complex increased as the concentration increased and reached a plateau at 2 nM; further increase in [3H]beta-FNA concentration did not enhance the rate of formation, indicating that the rate saturation effect exists for irreversible binding of [3H]beta-FNA to mu opioid receptors. At 10 degrees and low concentrations (less than 1 nM) of [3H]beta-FNA, appreciable reversible binding to opioid receptors occurred before any irreversible [3H]beta-FNA-receptor complex could be detected. These observations support the notion that reversible binding occurs before alkylation of the receptor. The binding of [3H]beta-FNA to mu opioid receptors was thus modeled to allow for such a two-step process: (formula; see text) A mathematical analysis method was derived to allow determination of all kinetic parameters (k+1, k-1, k2, and Kd) of such a two-step reaction. Values of k2, k+1, k-1, and Kd were determined at 10 degrees for 0.5, 0.25, and 0.125 nM [3H]beta-FNA and were found to be very similar among these three concentrations. Raising the incubation temperature from 10 degrees to 37 degrees greatly enhanced the values of k+1, k-1, and k2 without affecting Kd. At 37 degrees incubation without 200 mM NaCl significantly decreased the values of k+1, k-1, and k2 without affecting Kd. NaCl increased the irreversible binding, probably by shifting the equilibrium towards a conformation that binds more easily with beta-FNA. Under all conditions examined, the value of k-1 was found to be at least 5-fold greater than k2, indicating that the majority of the reversible complex dissociates and only a small portion proceeds to form irreversible complex. This finding is consistent with published observations that only a portion of beta-FNA binding to mu opioid receptors is irreversible. In conclusion, [3H]beta-FNA binds reversibly to mu opioid receptors before forming covalent bonding...


Does integrative medicine enhance balance in aging adults? Proof of concept for the benefit of electroacupuncture therapy in Parkinson's disease.
Postural balance and potentially fall risk increases among older adults living with neurological diseases, especially Parkinson's disease (PD). Since conventional therapies such as levodopa or deep brain stimulation may fail to alleviate or may even worsen balance, interest is growing in evaluating alternative PD therapies. The purpose of the current study was to assess improvement in postural balance in PD patients following electroacupuncture (EA) as an alternative therapy. 15 aging adults (71.2 ± 6.3 years) with idiopathic PD and 44 healthy age-matched participants (74.6 ± 6.5 years) were recruited. The PD participants were randomly assigned (at a ratio of 2:1) to an intervention (n = 10) or to a control group (n = 5). The intervention group received a 30-min EA treatment on a weekly basis for 3 weeks, while the control group received a sham treatment. Outcomes were assessed at baseline and after the final therapy. Measurements included balance assessment, specifically the ratio of medial-lateral (ML) center-of-gravity (COG) sway to anterior-posterior (AP) sway (COGML/AP) and ankle/hip sway during eyes-open, eyes-closed, and eyes-open dual-task trials, the Unified Parkinson's Disease Rating Scale (UPDRS), as well as quality of life, concerns for fall, and pain questionnaires. No difference was observed for the assessed parameters between the intervention and the control group at baseline. After treatment, an improvement in balance performance was observed in the intervention group. Compared with the healthy population, PD patients prior to treatment had larger COGML/AP sway with more dependency on upper-body movements for maintaining balance. Following EA therapy, COGML/AP sway was reduced by 31% and ankle/hip sway increased by 46% in the different conditions (p = 0.02 for the dual-task condition). The clinical rating revealed an overall improvement (p < 0.01) in mentation, behavior, and mood (UPDRS part I, 49%), activities of daily living (UPDRS part II, 46%), and motor examination (UPDRS part III, 40%). There was a significant reduction (p < 0.02) in the specific items regarding UPDRS fall status (67%) and rigidity (48%). Changes were small and nonsignificant in the controls (p > 0.29). This pilot study demonstrates improvement in rigidity and balance following EA. These preliminary results suggest EA could be a promising alternative treatment for balance disturbance in PD.


Metabolic profiling in nutrition and metabolic disorders.
Nutrients exert potent effects on metabolism through a variety of regulatory mechanisms, resulting in local and systemic changes in metabolite levels. Numerous studies have focused on mechanisms by which nutrients and disease states regulate metabolism at the gene or protein levels using genomic and proteomic approaches, respectively. However, few studies have investigated nutritional regulation of the whole metabolome. Thus, metabolomic approaches have recently emerged to complement the genomics and proteomics research and to help identify biologically meaningful metabolites and metabolic networks that control cellular responses to genetic and environmental factors, including diet, and to identify metabolic diseases that are influenced by genetic and dietary factors. These large-scale studies expedite our ability to develop targeted treatments. The goal of this symposium was to provide a forum to introduce the metabolomics field to nutrition researchers. An overview of the state-of-the-art metabolomic technologies used was provided. The impact of some specific nutrients, disease states, or genetic variations and their interaction with the metabolome was discussed by the speakers. Our objectives were as follows: 1) to educate the audience about the use of metabolomics as an innovative tool for linking changes in cell metabolites and genetic variations to nutrient metabolism, energy balance, and the overlying effects on health and disease; 2) to understand the concept of metabolomics and describe the analytical tools and resources available in this area; 3) to introduce the potential application of metabolomics in the field of nutrition research; and 4) to provide specific nutrition-relevant metabolomics study examples in investigating regulation of the metabolic network or metabolic changes resulting from disease states by dietary factors.


The relaxed crossbridge pattern in isolated rabbit psoas muscle thick filaments.
Rabbit muscle is a major source of material for biochemical experiments and spin labelling studies of contraction, and so it is important to establish how closely this material resembles the frog and fish muscles usually used for structural studies. Previous studies have shown that relaxed rabbit muscle thick filaments lose the characteristic order of their crossbridges when they are cooled below about 15-19 degrees C, whereas the order of fish and frog muscles is retained above 0 degrees C. The lack of order has frustrated attempts to examine rabbit thick filament structure and has raised questions about how closely they might resemble other thick filaments. We have therefore developed a procedure for preserving the crossbridge order in isolated filaments. Electron microscopy of these thick filaments after either negative staining or metal shadowing has shown that the crossbridge pattern has a 43 nm axial repeat and is based on three near-helical strands. Computed transforms of either type of image show a series of layer lines confirming that the native relaxed pattern has been preserved, and computer reconstructions show the individual crossbridges lying on a slightly perturbed 3-stranded lattice. These data indicate an unexpectedly high degree of similarity between the rabbit and frog patterns and indicate that, in fully preserved material, there is little structural difference between the two thick filaments at the temperature at which each normally functions.(ABSTRACT TRUNCATED AT 250 WORDS)


Folliculosebaceous Cystic Hamartoma Mimicking Preauricular Sinus Cyst.
Folliculosebaceous cystic hamartoma (FSCH) is a rare cutaneous hamartoma that consists of follicular, sebaceous, and mesenchymal elements. These lesions are mostly seen on the central face and scalp of adults and mostly present as single 0.5-1.5 cm papules or exophytic nodules. A 17-year-old female patient presented at our clinic with the complaint of swelling, pain and discharge in front of the left ear, which had been recurrent since childhood. The lesion was clinically suspected to be an infected preauriculer sinus cyst. After the medical treatment, the patient was operated on with a pre-diagnosis of preauricular sinus cyst. Histopathological findings revealed FSCH. To the best of our knowledge, this is the first reported case of FSCH originating from the preauricular region, located subcutaneously.


[A preliminary study of human Y chromosome specific short tandem repeat loci].
To understand the allele structure and reveal genetic polymorphism of Y chromosome specific short tandem repeat (Y-specific STR) loci in Chinese Han population. The authors used a set of five Y-specific STR loci which were tetrameric tandem repeat loci chosen from the Genome Database. EDTA-blood specimens were collected from the unrelated individuals. DNA was extracted by Chelex method and amplified by the polymerase chain reaction (PCR). The PCR products were analyzed using both the PAGE horizontal electrophoresis with discontinuous buffer system and the automated fluorescence detection approach. The authors observed that the alleles at the five Y-specific STR loci were composed of some complex repeat structures. They successfully prepared a set of human allele ladders for the typing of the five Y-specific STRs and demonstrated the polymorphisms at the five Y-specific STR loci in Chinese Han population. Y-specific STRs are good genetic markers for the purpose of analysis of genetic relationship between populations. This preliminary study not only reveals allele frequencies and haplotype distribution of Y-specific STR in Chinese Han population, but also indicates a reference population for detecting male migration events and for reconstructing paternal history.


Strong stability and host specific bacterial community in faeces of ponies.
The horse, as a hindgut fermenter, is reliant on its intestinal bacterial population for efficient diet utilisation. However, sudden disturbance of this population can result in severe colic or laminitis, both of which may require euthanasia. This study therefore aimed to determine the temporal stability of the bacterial population of faecal samples from six ponies maintained on a formulated high fibre diet. Bacterial 16S rRNA terminal restriction fragment length polymorphism (TRFLP) analyses of 10 faecal samples collected from 6 ponies at regular intervals over 72 hour trial periods identified a significant pony-specific profile (P<0.001) with strong stability. Within each pony, a significantly different population was found after 11 weeks on the same diet (P<0.001) and with greater intra-individual similarity. Total short chain fatty acid (SCFA) concentration increased in all ponies, but other changes (such as bacterial population diversity measures, individual major SCFA concentration) were significant and dependent on the individual. This study is the first to report the extent of stability of microbes resident in the intestinal tract as represented with such depth and frequency of faecal sampling. In doing so, this provides a baseline from which future trials can be planned and the extent to which results may be interpreted.


Planarian flatworms as a new model system for understanding the epigenetic regulation of stem cell pluripotency and differentiation.
Planarian flatworms possess pluripotent stem cells (neoblasts) that are able to differentiate into all cell types that constitute the adult body plan. Consequently, planarians possess remarkable regenerative capabilities. Transcriptomic studies have revealed that gene expression is coordinated to maintain neoblast pluripotency, and ensure correct lineage specification during differentiation. But as yet they have not revealed how this regulation of expression is controlled. In this review, we propose that planarians represent a unique and effective system to study the epigenetic regulation of these processes in an in vivo context. We consolidate evidence suggesting that although DNA methylation is likely present in some flatworm lineages, it does not regulate neoblast function in Schmidtea mediterranea. A number of phenotypic studies have documented the role of histone modification and chromatin remodelling complexes in regulating distinct neoblast processes, and we focus on four important examples of planarian epigenetic regulators: Nucleosome Remodeling Deacetylase (NuRD) complex, Polycomb Repressive Complex (PRC), the SET1/MLL methyltransferases, and the nuclear PIWI/piRNA complex. Given the recent advent of ChIP-seq in planarians, we propose future avenues of research that will identify the genomic targets of these complexes allowing for a clearer picture of how neoblast processes are coordinated at the epigenetic level. These insights into neoblast biology may be directly relevant to mammalian stem cells and disease. The unique biology of planarians will also allow us to investigate how extracellular signals feed into epigenetic regulatory networks to govern concerted neoblast responses during regenerative polarity, tissue patterning, and remodelling.


Neuronal involvement in muscular atrophy.
The innervation of skeletal myofibers exerts a crucial influence on the maintenance of muscle tone and normal operation. Consequently, denervated myofibers manifest atrophy, which is preceded by an increase in sarcolemma permeability. Recently, de novo expression of hemichannels (HCs) formed by connexins (Cxs) and other none selective channels, including P2X7 receptors (P2X7Rs), and transient receptor potential, sub-family V, member 2 (TRPV2) channels was demonstrated in denervated fast skeletal muscles. The denervation-induced atrophy was drastically reduced in denervated muscles deficient in Cxs 43 and 45. Nonetheless, the transduction mechanism by which the nerve represses the expression of the above mentioned non-selective channels remains unknown. The paracrine action of extracellular signaling molecules including ATP, neurotrophic factors (i.e., brain-derived neurotrophic factor (BDNF)), agrin/LDL receptor-related protein 4 (Lrp4)/muscle-specific receptor kinase (MuSK) and acetylcholine (Ach) are among the possible signals for repression for connexin expression. This review discusses the possible role of relevant factors in maintaining the normal functioning of fast skeletal muscles and suppression of connexin hemichannel expression.


Kinetics of antigen expression and epitope presentation during virus infection.
Current knowledge about the dynamics of antigen presentation to T cells during viral infection is very poor despite being of fundamental importance to our understanding of anti-viral immunity. Here we use an advanced mass spectrometry method to simultaneously quantify the presentation of eight vaccinia virus peptide-MHC complexes (epitopes) on infected cells and the amounts of their source antigens at multiple times after infection. The results show a startling 1000-fold range in abundance as well as strikingly different kinetics across the epitopes monitored. The tight correlation between onset of protein expression and epitope display for most antigens provides the strongest support to date that antigen presentation is largely linked to translation and not later degradation of antigens. Finally, we show a complete disconnect between the epitope abundance and immunodominance hierarchy of these eight epitopes. This study highlights the complexity of viral antigen presentation by the host and demonstrates the weakness of simple models that assume total protein levels are directly linked to epitope presentation and immunogenicity.


Incorporation of pentacyclic triterpenes into mitochondrial membrane--studies on the interactions in model 2D lipid systems.
Three representatives of naturally occurring pentacyclic triterpenes (PTs) were subjected to comprehensive studies aimed at the analysis of their interactions with phospholipids found naturally in mitochondrial membrane. To reach this goal, the selected compounds--α-amyrin (AMalf), betulinic acid (BAc), and ursolic acid (Urs)--were incorporated into two-component and multicomponent Langmuir monolayers acting as a model of mitochondrial membrane. As the lipids characteristic for mitochondria, phosphatidylcholine (POPC), phosphatidylethanolamine (POPE), and cardiolipin (BHCL) were chosen. Our studies were motivated by the fact that, according to the literature, the anticancer activity of PTs is correlated with their ability to incorporate into mitochondrial membrane and modify its properties. The undertaken studies were based on the surface pressure (π)-molecular area (A) isotherm registration complemented with the thermodynamic analysis and BAM visualization. It was found that all three terpenes with the exception of high betulinic acid proportion (30 and 50%) interact beneficially with POPC in two-component monolayers, while incorporation of BAc and Urs into POPE film is energetically unfavorable. As far as the model mitochondrial membrane composed of POPC/POPE/BHCL is concerned, the largest destructive influence (high positive values of ΔG(Exc) and decrease of the model monolayer condensation) was found in the case of terpene acids, while the effect of α-amyrin was energetically favorable. We postulated that the origin of the observed findings is connected with the specific interactions between bolaamphlilic terpene acids and POPE, known from its propensity to form intermolecular hydrogen bonds.


Twintrons are not unique to the Euglena chloroplast genome: structure and evolution of a plastome cpn60 gene from a cryptomonad.
Introns within introns (twintrons) are known only from the Euglena chloroplast genome. Twintrons are group II or III introns, into which another group II or III intron has been transposed. In this paper we describe a non-Euglena twintron structure within a plastid-encoded chaperone gene (cpn60) of the cryptomonad alga Pyrenomonas salina. In addition, the evolutionary relationships between members of the Cpn60 protein family are determined. Our findings permit the inclusion of cryptomonad plastomes in phylogenetic studies of intron evolution and present further evidence for the origin of modern plastids from a cyanobacterial ancestor.


[Effect of laser exposure on hemostatic parameters in the preagonal and post-resuscitation period].
Effects of intravascular low-intensive laser exposure of the blood on the hemostasis during acute blood loss and the early postresuscitation period after 4-min clinical death were studied on narcotized dogs (8-17 kg) of both sexes with different initial levels of heparin. During the preagonal period laser exposure caused hypercoagulation in animals with initial heparin content below 60 micrograms/ml. This acceleration of blood clotting prevented a drop in the activity of antithrombin III and hypercoagulation by the third hour of postresuscitation period. In animals with initial heparin content more than 60 micrograms/ml laser exposure caused hypocoagulation in the presence of reduced activity of antithrombin III by the third hour of the resuscitation period.


Clinical Usefulness of Linked Color Imaging for Detection and Characterization of UndifferentiatedType Early Gastric Cancer.
Linked color imaging is based on the bioluminescent imaging technique, which enhances differences in mucosal color allowing for contrast-based detection of lesions. There have been reports which have investigated the usefulness of linked color imaging for assessing color values in endoscopy for early gastric cancer cases. However, these primarily focused on differentiated early gastric cancer. This study aimed to assess the efficacy of linked color imaging in analyzing the color differences between cancerous and noncancerous areas in undifferentiated-type early gastric cancer patients compared with conventional white light imaging. Forty-six patients were prospectively enrolled with undifferentiated-type early gastric cancer from 3 academic hospitals. All lesions were observed first by white light imaging followed by linked color imaging. An additional biopsy was taken from the surrounding mucosa to check for intestinal metaplasia, and test for Helicobacter pylori was performed. Color difference was measured in accordance with the International Commission on Illumination details. The color difference value with linked color imaging was significantly higher, being more than twice that of white light imaging (26.82 ± 14.18 and 12.60 ± 6.42, P < .001), and this difference appeared to be similar in cases of accompanying Helicobacter pylori infection or intestinal metaplasia. In the subgroup analysis, color difference of poorly differentiated adenocarcinoma was notable in linked color imaging compared to white light imaging. Conversely, no statistically significant finding was present in signet ring cell carcinoma or mixed-type histology. Linked color imaging provides a significantly greater color difference between cancerous lesions and background noncancerous mucosa in undifferentiated-type early gastric cancer. Moreover, linked color imaging may differentiate between pathologic subgroups of undifferentiated-type early gastric cancer possibly due to characteristic cellular growth pattern.


Personal barriers to addressing intimate partner abuse: a qualitative meta-synthesis of healthcare practitioners' experiences.
Healthcare practitioners (HCPs) play a crucial role in recognising, responding to, and supporting female patients experiencing intimate partner abuse (IPA). However, research consistently identifies barriers they perceive prevent them from doing this work effectively. These barriers can be system-based (e.g. lack of time or training) or personal/individual. This review of qualitative evidence aims to synthesise the personal barriers that impact HCPs' responses to IPA. Five databases were searched in March 2020. Studies needed to utilise qualitative methods for both data collection and analysis and be published between 2010 and 2020 in order to qualify for inclusion; however, we considered any type of healthcare setting in any country. Article screening, data extraction and methodological appraisal using a modified version of the Critical Appraisal Skills Program checklist for qualitative studies were undertaken by at least two independent reviewers. Data analysis drew on Thomas and Harden's thematic synthesis approach. Twenty-nine studies conducted in 20 countries informed the final review. A variety of HCPs and settings were represented. Three themes were developed that describe the personal barriers experienced by HCPs: I can't interfere (which describes the belief that IPA is a "private matter" and HCPs' fears of causing harm by intervening); I don't have control (highlighting HCPs' frustration when women do not follow their advice); and I won't take responsibility (which illuminates beliefs that addressing IPA should be someone else's job). This review highlights the need for training to address personal issues in addition to structural or organisational barriers. Education and training for HCPs needs to: encourage reflection on their own values to reinforce their commitment to addressing IPA; teach HCPs to relinquish the need to control outcomes so that they can adopt an advocacy approach; and support HCPs' trust in the critical role they can play in responding. Future research should explore effective ways to do this within the context of complex healthcare organisations.


Transforming schools into communities of thinking and learning about serious matters.
In this article, a program of research known as Fostering Communities of Learners is described. This program is in place in several schools and classrooms serving inner-city students from 6 to 12 years of age. Based on theoretical advances in cognitive and developmental psychology, the program is successful at improving both literacy skills and domain-area subject matter knowledge (e.g., environmental science and biology). Building on young children's emergent strategic and metacognitive knowledge, together with their skeletal biological theories, the program leads children to discover the deep principles of the domain and to develop flexible learning and inquiry strategies of wide applicability.


The NH(2)-terminus of norepinephrine transporter contains a basolateral localization signal for epithelial cells.
When expressed in epithelial cells, dopamine transporter (DAT) was detected predominantly in the apical plasma membrane, whereas norepinephrine transporter (NET) was found in the basolateral membrane, despite 67% overall amino acid sequence identity. To identify possible localization signals responsible for this difference, DAT-NET chimeras were expressed in MDCK cells and localized by immunocytochemistry and transport assays. The results suggested that localization of these transporters in MDCK cells depends on their highly divergent NH(2)-terminal regions. Deletion of the first 58 amino acids of DAT (preceding TM1) did not change its apical localization. However, the replacement of that region with corresponding sequence from NET resulted in localization of the chimeric protein to the basolateral membrane, suggesting that the NH(2)-terminus of NET, which contains two dileucine motifs, contains a basolateral localization signal. Mutation of these leucines to alanines in the context of a basolaterally localized NET/DAT chimera restored transporter localization to the apical membrane, indicating that the dileucine motifs are critical to the basolateral localization signal embodied within the NET NH(2)-terminal region. However, the same mutation in the context of wild-type NET did not disrupt basolateral localization, indicating the presence of additional signals in NET directing its basolateral localization within the plasma membrane.


[Reconsideration of prevention in mental health in post-industrial society/culture].
The paradigmatic shift in medicine and in psychiatry (the introduction of the bio-psycho-social model) as well as its interaction with certain aspects of the postindustrial society influence both the theory and practice of mental health prevention. The targets of prevention are high risk situations which are defined according to empirical and theoretical criteria. New preventive technics in line with the above mentioned aspects are described. The great importance of adequate education of those who are taking part in mental health prevention is stressed.


Human norovirus occurrence and diversity in the Llobregat river catchment, Spain.
Human noroviruses (NoV) were quantified and characterized in an 18 month survey conducted along the Llobregat river catchment in Spain. Sample types included freshwater, untreated and treated wastewater and drinking water. High NoV genome copy numbers were reported, reaching up to 10(6) l(-1) and 10(9) l(-1) in freshwater and raw sewage respectively. In both types of samples, GII NoV genome copies outnumbered those of GI, although without significance. All samples of semi-treated and treated drinking water were negative for NoV. A clear seasonality of NoV occurrence was observed both in river water and sewage samples, with significantly higher genome copy numbers in the cold than in the warm months period. Mean NoV log reduction rates after biological treatment of sewage were 2.2 and 3.1 for GI and GII respectively. A total of 77 NoV strains isolated in the Llobregat river catchment could be phylogenetically characterized, 44 belonging to GI and 33 to GII. The most prevalent genotype was GI.4, followed by GII.4 and GII.21. Several variants of the pandemic GII.4 strain were detected in the environment, corroborating their circulation among the population.


Family Factors and HIV-Related Risk Behaviors Among Adolescent Sexual Minority Males in Three United States Cities, 2015.
Purpose: We examined the relationship between family factors and HIV-related sexual risk behaviors among adolescent sexual minority males (ASMM) who are affected disproportionately by HIV. Methods: We analyzed results from the National HIV Behavioral Surveillance among Young Men Who Have Sex with Men. Adolescent males ages 13-18 who identified as gay or bisexual, or who reported attraction to or sex with males were interviewed in 2015 in Chicago, New York City, and Philadelphia. Separate log-linked Poisson regression models were used to estimate associations between family factors and sexual risk behaviors. Results: Of the 569 ASMM, 41% had condomless anal intercourse in the past 12 months, 38% had ≥4 male sex partners in the past 12 months, and 23% had vaginal or anal sex before age 13. ASMM who had ever been kicked out of their house or run away, those who were out to their mother, and those who were out to their father, were more likely to engage in sexual risk behaviors. ASMM who were currently living with parents or guardians and those who received a positive reaction to their outness by their mother were less likely to engage in sexual risk behaviors. Conclusion: Our findings highlight the important role of family factors in HIV risk reduction among ASMM. A better understanding of the complex dynamics of these families will help in developing family-based interventions.


Standards for model-based early bactericidal activity analysis and sample size determination in tuberculosis drug development.
Background: A critical step in tuberculosis (TB) drug development is the Phase 2a early bactericidal activity (EBA) study which informs if a new drug or treatment has short-term activity in humans. The aim of this work was to present a standardized pharmacometric model-based early bactericidal activity analysis workflow and determine sample sizes needed to detect early bactericidal activity or a difference between treatment arms. Methods: Seven different steps were identified and developed for a standardized pharmacometric model-based early bactericidal activity analysis approach. Non-linear mixed effects modeling was applied and different scenarios were explored for the sample size calculations. The sample sizes needed to detect early bactericidal activity given different TTP slopes and associated variability was assessed. In addition, the sample sizes needed to detect effect differences between two treatments given the impact of different TTP slopes, variability in TTP slope and effect differences were evaluated. Results: The presented early bactericidal activity analysis approach incorporates estimate of early bactericidal activity with uncertainty through the model-based estimate of TTP slope, variability in TTP slope, impact of covariates and pharmacokinetics on drug efficacy. Further it allows for treatment comparison or dose optimization in Phase 2a. To detect early bactericidal activity with 80% power and at a 5% significance level, 13 and 8 participants/arm were required for a treatment with a TTP-EBA0-14 as low as 11 h when accounting for variability in pharmacokinetics and when variability in TTP slope was 104% [coefficient of variation (CV)] and 22%, respectively. Higher sample sizes are required for smaller early bactericidal activity and when pharmacokinetics is not accounted for. Based on sample size determinations to detect a difference between two groups, TTP slope, variability in TTP slope and effect difference between two treatment arms needs to be considered. Conclusion: In conclusion, a robust standardized pharmacometric model-based EBA analysis approach was established in close collaboration between microbiologists, clinicians and pharmacometricians. The work illustrates the importance of accounting for covariates and drug exposure in EBA analysis in order to increase the power of detecting early bactericidal activity for a single treatment arm as well as differences in EBA between treatments arms in Phase 2a trials of TB drug development.


Nuclear GRP78 Promotes Metabolic Reprogramming and Therapeutic Resistance in Pancreatic Ductal Adenocarcinoma.
Stromal fibrosis limits nutritional supply and disarrays metabolism in pancreatic cancer (PDA, pancreatic ductal adenocarcinoma). Understanding of the molecular basis underlying metabolic cues would improve PDA management. The current study determined the interaction between glucose-regulated proteins 78 (GRP78) and hypoxia-inducible factor 1α (HIF-1α) and its mechanistic roles underlying PDA response to oxygen and glucose restrains. Gene expression and its association with clinicopathologic characteristics of patients with PDA and mouse models were analyzed using IHC. Protein expression and their regulation were measured by Western blot and immunoprecipitation analyses. Protein interactions were determined using gain- and loss-of-function assays and molecular methods, including chromatin immunoprecipitation, co-immunoprecipitation, and dual luciferase reporter. There was concomitant overexpression of both GRP78 and HIF-1α in human and mouse PDA tissues and cells. Glucose deprivation increased the expression of GRP78 and HIF-1α, particularly colocalization in nucleus. Induction of HIF-1α expression by glucose deprivation in PDA cells depended on the expression of and its own interaction with GRP78. Mechanistically, increased expression of both HIF-1α and LDHA under glucose deprivation was caused by the direct binding of GRP78 and HIF-1α protein complexes to the promoters of HIF-1α and LDHA genes and transactivation of their transcriptional activity. Protein complex of GRP78 and HIF-1α directly binds to HIF-1α own promoter and LDHA promoter, enhances the transcription of both HIF-1α and LDHA, whereas glucose deprivation increases GRP78 expression and further enhances HIF-1α and LDHA transcription. Therefore, crosstalk and integration of hypoxia- and hypoglycemia-responsive signaling critically impact PDA metabolic reprogramming and therapeutic resistance.


Th1, Th17, and Th9 effector cells induce experimental autoimmune encephalomyelitis with different pathological phenotypes.
Experimental autoimmune encephalomyelitis (EAE) is a model of human multiple sclerosis induced by autoreactive Th cells that mediate tissue inflammation and demyelination in the CNS. Initially, IFN-gamma-producing Th1 cells and, more recently, IL-17-producing Th17 cells with specificity for myelin Ags have been implicated in EAE induction, but whether Th17 cells are encephalitogenic has been controversial. Moreover, a new effector T cell subset, Th9 cells, has been identified; however, the ability of this T cell subset to induce EAE has not been investigated. Here, we have developed protocols to generate myelin oligodendrocyte glycoprotein-specific Th17, Th1, Th2, and Th9 cells in vitro, so that we could directly compare and characterize the encephalitogenic activity of each of these subsets upon adoptive transfer. We show that myelin oligodendrocyte glycoprotein-specific Th1, Th17, and Th9 cells but not Th2 cells induce EAE upon adoptive transfer. Importantly, each T cell subset induced disease with a different pathological phenotype. These data demonstrate that different effector T cell subsets with specificity for myelin Ags can induce CNS autoimmunity and that the pathological heterogeneity in multiple sclerosis lesions might in part be due to multiple distinct myelin-reactive effector T cells.


Evaluating the noise in electrically evoked compound action potential measurements in cochlear implants.
Electrically evoked compound action potentials (ECAPs) are widely used to study the excitability of the auditory nerve and stimulation properties in cochlear implant (CI) users. However, ECAP detection can be difficult and very subjective at near-threshold stimulation levels or in spread of excitation measurements. In this study, we evaluated the statistical properties of the background noise (BN) and the postaverage residual noise (RN) in ECAP measurements in order to determine an objective detection criterion. For the estimation of the BN and the RN, a method currently used in auditory brainstem response measurements was applied. The potential benefit of using weighted (Bayesian) averages was also examined. All estimations were performed with a set of approximately 360 ECAP measurements recorded from five human CI users of the CII or HiRes90K device (advanced bionics). Results demonstrated that the BN was normally distributed and the RN decreased according to the square root of the number of averages. No additional benefit was observed by using weighted averaging. The noise was not significantly different either at different stimulation intensities or across recording electrodes along the cochlea. The analysis of the statistical properties of the noise indicated that a signal-to-noise ratio of 1.7 dB as a detection criterion corresponds to a false positive detection rate of 1% with the used measurement setup.


[End-results of resection for distal gastric cancer].
End-results of surgery for stomach cancer conducted at the Institute Clinic have been evaluated. In 1982-2002, 260 patients with gastrointestinal tumors underwent subtotal distal resection of the stomach (Billroth-1) and another 220--Billroth-2. Functional outcome was assessed in 122 (46.9%) (Billroth-1) and 78 (Billroth-2). The end-results appeared to be identical: 5- and 10-year survival rate after Billroth-1 was 65.1 and 24.7%, and Billroth-2--63.4 and 27.1%, respectively.


Active control of strong plasmon-exciton coupling in biomimetic pigment-polymer antenna complexes grown by surface-initiated polymerisation from gold nanostructures.
Plexcitonic antenna complexes, inspired by photosynthetic light-harvesting complexes, are formed by attachment of chlorophylls (Chl) to poly(cysteine methacrylate) (PCysMA) scaffolds grown by atom-transfer radical polymerisation from gold nanostructure arrays. In these pigment-polymer antenna complexes, localised surface plasmon resonances on gold nanostructures are strongly coupled to Chl excitons, yielding hybrid light-matter states (plexcitons) that are manifested in splitting of the plasmon band. Modelling of the extinction spectra of these systems using a simple coupled oscillator model indicates that their coupling energies are up to twice as large as those measured for LHCs from plants and bacteria. Coupling energies are correlated with the exciton density in the grafted polymer layer, consistent with the collective nature of strong plasmon-exciton coupling. Steric hindrance in fully-dense PCysMA brushes limits binding of bulky chlorophylls, but the chlorophyll concentration can be increased to ∼2 M, exceeding that in biological light-harvesting complexes, by controlling the grafting density and polymerisation time. Moreover, synthetic plexcitonic antenna complexes display pH- and temperature-responsiveness, facilitating active control of plasmon-exciton coupling. Because of the wide range of compatible polymer chemistries and the mild reaction conditions, plexcitonic antenna complexes may offer a versatile route to programmable molecular photonic materials.


A prospective, randomized, blinded study of continuous ropivacaine infusion in the median sternotomy incision following cardiac surgery.
The aim of this prospective, randomized, double-blind, placebo controlled trial was to evaluate the safety and efficacy of continuous ropivacaine infusion of into the sternal wound. We planned to enroll 200 patients scheduled for various cardiac surgical procedures into the study. Patients, in a double-blind randomized fashion, were given either normal saline or 0.3% ropivacaine through 2 subcutaneous multiport catheters placed on either side of the sternal split at an infusion rate of 4 mL/h for 64 hours. The efficacy outcomes measured were time to extubation of the trachea, intensive care unit and hospital stay duration, pain scores, and narcotic usage. The safety outcomes measured were systemic local anesthetic toxicity, major cardiac complications, and wound infection. The data safety monitoring board stopped the study after enrolling 85 patients because of excessive sternal wound infections (9%, n = 44) in the ropivacaine group. This rate of infection was not statistically different from the control group (0%, n = 41, P = 0.12), but it was statistically different from our historical incidence of sternal wound infection (1.9%, no = 6381, P = 0.002). There was also a lack of evidence of efficacy for time to extubation of the trachea, narcotic usage, and pain control. The phase III trial did not show improvement in time to extubation of the trachea or pain control in the 0.3% ropivacaine group, but it was stopped early by the data safety monitoring board.