Suppression of inflammatory cytokine production by carbon monoxide involves the JNK pathway and AP-1.
The stress-inducible protein heme oxygenase-1 provides protection against oxidative stress and modulates pro-inflammatory cytokines. As the sepsis syndrome results from the release of pro-inflammatory mediators, we postulated that heme oxygenase-1 and its enzymatic product CO would protect against lethality in a murine model of sepsis. Mice treated with a lethal dose of lipopolysaccharide (LPS) and subsequently exposed to inhaled CO had significantly better survival and lower serum interleukin (IL)-6 and IL-1beta levels than their untreated counterparts. In vitro, mouse macrophages exposed to LPS and CO had significantly attenuated IL-6 production; this effect was concentration-dependent and occurred at a transcriptional level. The same effect was seen with increased endogenous CO production through overexpression of heme oxygenase-1. Mutation within the AP-1-binding site in the IL-6 promoter diminished the effect of CO on promoter activity, and treatment of macrophages with CO decreased AP-1 binding in an electrophoretic mobility shift assay. Electrophoretic mobility supershift assay indicated that the JunB, JunD, and c-Fos components of AP-1 were particularly affected. Upstream of AP-1, CO decreased JNK phosphorylation in murine macrophages and lung endothelial cells. Mice deficient in the JNK pathway had decreased serum levels of IL-6 and IL-1beta in response to LPS compared with control mice, and no effect of CO on these cytokine levels was seen in Jnk1 or Jnk2 genedeleted mice. In summary, these results suggest that CO provides protection in a murine model of sepsis through modulation of inflammatory cytokine production. For the first time, the effect of CO is shown to be mediated via the JNK signaling pathway and the transcription factor AP-1.


High-abundance protein depletion: comparison of methods for human plasma biomarker discovery.
Affinity depletion of abundant proteins from human plasma has become a routine sample preparation strategy in proteomics used prior to protein identification and quantitation. To date, there have been limited published studies comparing the performance of commercially available depletion products. We conducted a thorough evaluation of six depletion columns using 2-DE combined with sophisticated image analysis software, examining the following criteria: (i) efficiency of high-abundance protein depletion, (ii) non-specific removal of other than the targeted proteins and (iii) total number of protein spots detected on the gels following depletion. From all the products investigated, the Seppro IgY system provided the best results. It displayed the greatest number of protein spots on the depleted plasma gels, minimal non-specific binding and high efficiency of abundant protein removal. Nevertheless, the increase in the number of detected spots compared with the second best performing and cheaper multiple affinity removal column (MARC) was not shown to be statistically significant. The ProteoPrep spin column, considered to be the "deepest" depletion technique available at the time of conducting the study, surprisingly displayed significantly fewer spots on the flow-through fraction gels compared with both the Seppro and the MARC. The spin column format and low plasma capacity were also found to be impractical for 2-DE. To conclude, we succeeded in providing an overview of the depletion columns performances with regard to the three examined areas. Our study will serve as a reference to other scientists when deciding on the optimal product for their particular projects.


The antimicrobial sensitivity of Streptococcus mutans and Streptococcus sangius to colloidal solutions of different nanoparticles applied as mouthwashes.
Metal nanoparticles have been recently applied in dentistry because of their antibacterial properties. This study aimed to evaluate antibacterial effects of colloidal solutions containing zinc oxide (ZnO), copper oxide (CuO), titanium dioxide (TiO2) and silver (Ag) nanoparticles on Streptococcus mutans and Streptococcus sangius and compare the results with those of chlorhexidine and sodium fluoride mouthrinses. After adding nanoparticles to a water-based solution, six groups were prepared. Groups I to IV included colloidal solutions containing nanoZnO, nanoCuO, nanoTiO2 and nanoAg, respectively. Groups V and VI consisted of 2.0% sodium fluoride and 0.2% chlorhexidine mouthwashes, respectively as controls. We used serial dilution method to find minimum inhibitory concentrations (MICs) and with subcultures obtained minimum bactericidal concentrations (MBCs) of the solutions against S. mutans and S. sangius. The data were analyzed by analysis of variance and Duncan test and P < 0.05 was considered as significant. The sodium fluoride mouthrinse did not show any antibacterial effect. The nanoTiO2-containing solution had the lowest MIC against both microorganisms and also displayed the lowest MBC against S. mutans (P < 0.05). The colloidal solutions containing nanoTiO2 and nanoZnO showed the lowest MBC against S. sangius (P < 0.05). On the other hand, chlorhexidine showed the highest MIC and MBC against both streptococci (P < 0.05). The nanoTiO2-containing mouthwash proved to be an effective antimicrobial agent and thus it can be considered as an alternative to chlorhexidine or sodium fluoride mouthrinses in the oral cavity provided the lack of cytotoxic and genotoxic effects on biologic tissues.


Indomethacin and flurbiprofen speed recovery of rat bronchial epithelium after exposure to cigarette smoke.
The cigarette smoke-induced rat model of chronic bronchitis was used to study the time course of the return of cigarette smoke-induced secretory cell hyperplasia to the normal and the capacity of two non-steroidal anti-inflammatory drugs to speed this recovery. Cigarette smoke alone significantly increased (P less than 0.05) the number of secretory cells in all of the eight airway levels studied to between 52-225% above control values. After cessation of exposure, recovery was complete by 9 days in the trachea, between 10-21 days in 'proximal' intrapulmonary airways and 43-84 days in distal bronchioli. Indomethacin and flurbiprofen, given by intraperitoneal injection at 4 mg/kg body weight for 21 days of the recovery period, significantly reduced the time taken for recovery to between 4 and 9 days in intrapulmonary airways but had no effect in the trachea.


Deaf and Hearing American Sign Language-English Bilinguals: Typical Bilingual Language Development.
Some studies have concluded that sign language hinders spoken language development for deaf and hard-of-hearing (DHH) children even though sign language exposure could protect DHH children from experiencing language deprivation. Furthermore, this research has rarely considered the bilingualism of children learning a signed and a spoken language. Here we compare spoken English development in 2-6-year-old deaf and hearing American Sign Language-English bilingual children to each other and to monolingual English speakers in a comparison database. Age predicted bilinguals' language scores on all measures, whereas hearing status was only significant for one measure. Both bilingual groups tended to score below monolinguals. Deaf bilinguals' scores differed more from monolinguals, potentially because of later age of and less total exposure to English, and/or to hearing through a cochlear implant. Overall, these results are consistent with typical early bilingual language development. Research and practice must treat signing-speaking children as bilinguals and consider the bilingual language development literature.


Diagnosis and Treatment of Eosinophilic Esophagitis.
Eosinophilic esophagitis (EoE) is a new disease. It is caused by a T-helper type 2 cell response to food antigens in contact with the esophageal mucosa. Although no single feature defines EoE, a constellation of compatible demographic, clinical, endoscopic, and histologic findings establish the diagnosis. Children present with symptoms and endoscopic patterns characteristic of inflammation, whereas adolescents and adults have manifestations of fibrosis and gross esophageal strictures. Clinical and endoscopic scoring systems have helped to standardize diagnosis. There is controversy in EoE research over the optimal endpoint for treatment. Although the most common endpoint is a reduced number of eosinophils in biopsies, changes in symptoms and endoscopic features are becoming important targets of therapy. We should improve our understanding of EoE progression and the need for maintenance therapy, and continue development of diagnostic tools that avoid endoscopy and biopsy analyses to more easily monitor disease activity.


Association of hostility with sleep duration and sleep disturbances in an employee population.
Sleep disturbances are common among the general population, and hostile persons have been proposed to be at greater risk of several serious health problems and diseases. This study examined the relationships between hostility, sleep disturbances, and sleep duration in a large non-clinical sample of 5,433 employees working in 12 Finnish hospitals. Data were collected by questionnaire surveys in 1998 and 2000. Higher hostility was cross-sectionally associated with increased sleep disturbances but not with sleep duration after adjustment for gender, age, marital status, education, shift work, smoking, alcohol consumption, physical activity, body mass index, psychiatric morbidity, and somatic disease. A stratified analysis distinguishing individuals with stable hostility across the two measurements and those with transient hostility (> 0.5 SD difference between measurements) replicated the association with increased sleep disturbance in both groups, but among those with transient hostility, there additionally was a cross-sectional association between higher hostility and shorter sleep duration. Our evidence suggests that hostility is an independent risk factor for sleep disturbances and that transient hostility may also predispose shorter sleep duration. However, the effect sizes for all these associations were small, suggesting limited clinical significance for our findings.


Arabidopsis AtSPL14, a plant-specific SBP-domain transcription factor, participates in plant development and sensitivity to fumonisin B1.
The recessive Arabidopsis thalianafumonisin B1-resistant (fbr6) mutant was identified by its ability to survive in the presence of a programmed cell death (PCD)-inducing fungal toxin FB1. The fbr6 mutant also displays altered plant architecture in the absence of FB1, most notably elongated petioles and enhanced leaf margin serration. These phenotypes are a result of a T-DNA insertion in the SQUAMOSA promoter binding protein (SBP) domain gene, AtSPL14. AtSPL14 encodes a plant-specific protein with features characteristic of a transcriptional regulator, including a nuclear localization signal sequence, a plant-specific DNA binding domain (the SBP box), and a protein interaction motif (ankyrin repeats). A transiently expressed fusion of the AtSPL14 protein to green fluorescent protein is directed to the plant nucleus. DNA sequences immediately upstream of the translation start site direct expression of the beta-glucuronidase reporter gene primarily in the vascular tissues, consistent with the phenotypes of the fbr6 mutant. AtSPL14 activates transcription in yeast, with a transactivation domain residing within the N-terminal region of the protein. Recombinant AtSPL14 protein binds A. thaliana genomic DNA in vitro in the absence of other proteins. These results indicate that FBR6/SPL14 functions as a transcriptional regulator that plays a role not only in sensitivity to FB1, but also in the development of normal plant architecture.


A novel gene, MALT1 at 18q21, is involved in t(11;18) (q21;q21) found in low-grade B-cell lymphoma of mucosa-associated lymphoid tissue.
The t(11;18) (q21;q21) translocation is a characteristic chromosomal aberration in low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type. We previously identified a YAC clone y789F3, which includes the breakpoint at 18q21 in a MALT lymphoma patient. BAC and PAC contigs were constructed on the YAC, and BAC 193f9 was found to encompass the breakpoint region. In the present study, we further narrowed down the breakpoint region at 18q21 in five MALT lymphoma patients by means of FISH and Southern blot analyses using the plasmid contig constructed from BAC 193f9. The breakpoints at 18q21 in three of the five MALT lymphoma patients were found to be clustered approximately within the 20 kb region. By using exon amplification and cDNA library screening, we identified a novel cDNA spanning the breakpoint region that exhibited aberrant mRNA signals in four of the five MALT lymphoma patients. The nucleotide sequence predicted an 813 amino acid protein that shows significant sequence similarity to the CD22beta and laminin 5 alpha3b subunit. We refer to the gene encoding this transcript as MALT1 (Mucosa-Associated Lymphoid Tissue lymphoma translocation gene 1). The alteration of MALT1 by translocation strongly suggests that this gene plays an important role in the pathogenesis of MALT lymphoma.


Isolation, characterization and screening of actinomycetes associated with fijian ant-plant symbioses.
In the search for novel therapeutics to combat the ongoing antimicrobial resistance crisis, scientists are turning to underexplored environments. Defensive mutualisms between hymenopteran insects and actinomycetes represent important reservoirs for bioactive compounds. In this study, we examined the association between actinomycetes and Squamellaria ant-plants spanning three different ant and plant species combinations (Squamellaria imberbis-Philidris nagasau, Squamellaria tenuiflora- Technomyrmex vitiensis, and Squamellaria tenuiflora-Tetramorium insolens). Eight Squamellaria plants were sampled including four containing T. vitiensis, three containing P. nagasau, and a single plant containing T. insolens. A total of 47 actinomycetes were obtained from the sampled material, with 5, 16, and 26 isolates originating from cuticle, tissue, and nest samples, respectively. Cross-streaking tests showed that 12 out of 47 isolates inhibited bacterial pathogens. The most frequently inhibited pathogens in the cross-streaking tests were S. aureus and E. coli while S. enterica was the least inhibited. Among the three primary screening media used, ISP2 agar was the most suitable for secondary metabolism as more isolates exhibited antibacterial activity when grown on the medium. TFS2010 and TFS2003, which matched to Streptomyces gramineus (>99% similarity), were the most bioactive isolates in cross-streaking tests. TFS2010 displayed the strong antibacterial on Nutrient agar, Mueller Hinton agar, and ISP2 agar while TFS2003 only exhibited strong antibacterial activity on Nutrient agar. Furthermore, a difference in potency of extracts based on batch culture medium was noted in TFS2010. DNA was extracted from 19 isolates and followed by 16SrRNA gene sequencing. Analysis of sequence data revealed the presence of six genera, including Amycolatopsis, Asanoa, Jiangella, Nocardia, Nocardiopsis, and Streptomyces, with the latter being the most abundant taxon. Among these, three isolates (PNS3002, PNS3005, and TFS3001) are likely to represent new species while one (TFS2015) is likely to be a member of a novel genus. Our work represents the first attempt to study actinomycetes from Squamellaria-ant mutualisms.


Quantitative evaluation of microstructural changes and their relations with some physical characteristics of food during drying.
Drying is known to affect various quality attributes of a food product, especially its physical properties. However, changes of physical properties or characteristics are generally due to changes of the product microstructure. Nevertheless, not much quantitative information, as opposed to abundant qualitative information, is available to describe in detail relationships between microstructural and physical changes of food undergoing drying. The present study, thus, aimed at studying quantitative relationships between microstructural and selected physical changes of a test material, that is, carrot, undergoing hot air drying at 60 and 80 °C. The microstructural changes were represented quantitatively in terms of the normalized changes of the fractal dimension (ΔFD/FD(0)) of microstructural images of the samples as well as the normalized changes of the sample average cell diameter (ΔD/D(0)), while the physical changes of interest were shrinkage and hardness. The results showed that during an earlier period of drying ΔFD/FD(0) as well as ΔD/D(0) tended to increase with decreasing moisture content; deformation of the microstructures (represented either in terms of ΔFD/FD(0) or ΔD/D(0)) led to increased shrinkage and hardness. On the other hand, deformation of the microstructures existed, while the moisture content did not change much during the final stage of drying. The relationships between ΔFD/FD(0) and both physical changes were quite well established; ΔD/D(0)were also found to correlate well with the physical changes. Either ΔFD/FD(0) or ΔD/D(0)could thus be used as a tool to monitor the apparent physical changes (shrinkage and hardness) of a sample during drying. Either the normalized changes of the fractal dimension of microstructural images of a sample or the normalized changes of the sample average cell diameter can be a useful tool in monitoring the drying process by 1st assessing the product volumetric shrinkage, which can be assessed easily on-line and on a real-time basis by such techniques as image analysis, and then relating the obtained results through microstructural changes to other apparent physical changes, including the product texture.


[The use of large doses of retabolil and support loads for prevention of osteopenia in male rats during suspension].
The histological and histomorphometric techniques were used to evaluate effects of anabolic steroid rhetabolil and graded support loads on the osteopenia progress in suspended rats. Thirty-day head-down tail suspension was found to inhibit body mass gain, induce a moderate stress reaction, dampen the longitudinal bone growth and provoke osteopenia in the spongy metaphysis of rats' tibiae. Rhetabolil injection at a total dose of 10 mg per 100 g of the body mass (a large dose) prevented tibial osteopenia, and yet it hampered bone growth in length. Daily 3-hr. support loads also inhibited osteopenia in the suspended rats, especially when combined with the rhetabolil injections. The unfavorable side-effect of the dose was virtually complete thymus aplasia in all animals. Hence, large rhetabolil doses as a means against osteopenia in the inadequately loaded locomotor system should be given with great care and require further investigations.


Canadian Rheumatology Association Meeting Fairmont The Queen Elizabeth Montreal, Quebec, Canada February - March 2, 2019.
The 73rd Annual Meeting of The Canadian Rheumatology Association was held at the Fairmont The Queen Elizabeth, Montreal, Quebec, Canada February 27 - March 2, 2019. The program consisted of presentations covering original research, symposia, awards, and lectures. Highlights of the meeting include the following 2019 Award Winners: Distinguished Rheumatologist, Edward Keystone; Distinguished Investigator, Diane Lacaille; Teacher-Educator, Shirley Tse; Emerging Investigator, Glen Hazlewood; Best Abstract on SLE Research by a Trainee - Ian Watson Award, Alexandra Legge; Best Abstract on Clinical or Epidemiology Research by a Trainee - Phil Rosen Award, Lauren King; Best Abstract on Basic Science Research by a Trainee, Remy Pollock; Best Abstract for Research by an Undergraduate Student, Andrea Carboni-Jimènez; Best Abstract on Research by a Rheumatology Resident, May Choi; Best Abstract by a Medical Student, Leonardo Calderon; Best Abstract by a Post-Graduate Research Trainee, Carolina Munoz-Grajales; Best Abstract by a Rheumatology Post-Graduate Research Trainee, Andre Luquini; Best Abstract on Quality Care Initiatives in Rheumatology, Cheryl Barnabe and Ines Colmegna; Best Abstract on Research by Young Faculty, Bindee Kuriya; Practice Reflection Award, Gold, Jason Kur; Practice Reflection Award, Silver, May Choi. Lectures and other events included Keynote Lecture by Andre Picard: Quirky Past, Uncertain Future: The State of Medicare in Canada; Keynote Address by Diane Lacaille, Distinguished Investigator Awardee: Time to Re-Label Comorbidities in RA - Coexisting or Complications; State of the Art Lecture by Mark Roberts: Myositis and its Mimics; Dunlop-Dottridge Lecture by Gilles Boire: The 4-H of Biomarkers in Arthritis: A lot of Help, Potential Harm, Some Hype, Increasing Hope; and the Great Debate: Be it Resolved that Competency-based Medical Education will Result in Improved Quality of Care for Patients vs the "Old Way" of Training Rheumatologists. Arguing for: Mercedes Chan and Marie-Paule Morin, and against: Beth Hazel and Heather McDonald-Blumer. Topics including rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, Sjögren syndrome, psoriatic arthritis, spondyloarthritis, vasculitis, osteoarthritis, fibromyalgia, and their respective diagnoses, treatments, and outcomes are reflected in the abstracts, which we are pleased to publish in this issue of The Journal.


Enhancement of Bone Augmentation in Osteoporotic Conditions by the Intermittent Parathyroid Hormone: An Animal Study in the Calvarium of Ovariectomized Rat.
Intermittent parathyroid hormone (PTH) is the commonly used therapeutic approach for patients with severe osteoporosis. The goal of this study was to elucidate the effect of the intermittent PTH treatment on guided bone augmentation (GBA) in the calvarium of ovariectomized (OVX) rats. Surgical ovariectomy on 14 rats and sham surgery on 7 rats were conducted on all rats as the first surgery. GBA surgery was conducted 8 weeks following the first surgery in the rat calvarium by placing 5-mm-diameter cylindrical plastic caps. Following surgery, rats were treated with 40 μg/kg PTH (OVX-PTH) or saline (Sham-Saline, OVX-Saline) via intraperitoneal injection three times per week during the all-observational period. Longitudinal microcomputed tomography (micro-CT) imaging was performed every 2 weeks following the GBA surgery without euthanasia, and the amount of newly generated bone volume (BV) was calculated. All rats were euthanized 12 weeks after GBA surgery, and histology was obtained. Sections stained with hematoxylin and eosin were used for the quantitative analysis of newly generated tissue, and immunohistology was used to visualize Runx2-positive cells and TRAP-positive cells. Throughout the monitoring period, the BVs of OVX rats without PTH treatment (OVX-Saline) were significantly lower than that of the other two groups at weeks 8 and 12 in micro-CT analysis. During all experimental periods, the BV was highest in the OVX rats that were treated with PTH (OVX-PTH). Histologic analysis confirmed the result of micro-CT, and determined that the OVX-PTH presented a greater number of Runx2-positive cells. The number of TRAP-positive multinucleated osteoclasts was highest in OVX-PTH rats; there were no significant differences between the other two groups. The results of this study suggest that treatment with intermittent PTH was associated with increased newly regenerated bone volume in ovariectomized rat calvarial bone augmentation, which may have important clinical implications.


Arabidopsis MYB26/MALE STERILE35 regulates secondary thickening in the endothecium and is essential for anther dehiscence.
The Arabidopsis thaliana MYB26/MALE STERILE35 (MS35) gene is critical for the development of secondary thickening in the anther endothecium and subsequent dehiscence. MYB26 is localized to the nucleus and regulates endothecial development and secondary thickening in a cell-specific manner in the anther. MYB26 expression is seen in anthers and also in the style and nectaries, although there is no effect on female fertility in the ms35 mutant. MYB26 expression in anthers occurs early during endothecial development, with maximal expression during pollen mitosis I and bicellular stages, indicating a regulatory role in specifying early endothecial cell development. Overexpression of MYB26 results in ectopic secondary thickening in both Arabidopsis and tobacco (Nicotiana tabacum) plants, predominantly within the epidermal tissues. MYB26 regulates a number of genes linked to secondary thickening, including IRREGULAR XYLEM1 (IRX1), IRX3, IRX8, and IRX12. Changes in expression were also detected in two NAC domain genes, NAC SECONDARY WALL-PROMOTING FACTOR1 (NST1) and NST2, which have been linked to secondary thickening in the anther endothecium. These data indicate that MYB26 regulates NST1 and NST2 expression and in turn controls the process of secondary thickening. Therefore, MYB26 appears to function in a regulatory role involved in determining endothecial cell development within the anther and acts upstream of the lignin biosynthesis pathway.


Semisynthesis of 5-O-ester derivatives of renieramycin T and their cytotoxicity against non-small-cell lung cancer cell lines.
The semisynthesis of 5-O-ester derivatives of renieramycin T was accomplished through the photoredox reaction of renieramycin M (1), a bistetrahydroisoquinolinequinone alkaloid isolated from the Thai blue sponge Xestospongia sp. This process led to the conversion of compound 1 to renieramycin T (2), which was subsequently subjected to Steglich esterification with appropriate acylating agents containing linear alkyl, N-tert-butoxycarbonyl-L-amino, and heterocyclic aromatic substituent. Notably, the one-pot transformation, combining the photoredox reaction and esterification led to the formation of 7-O-ester derivatives of renieramycin S due to hydrolysis. Subsequently, the in vitro cytotoxicity of the 17 semisynthesized derivatives against human non-small-cell lung cancer (NSCLC) cells in parallel with normal cell lines was evaluated. Among the tested compounds, 5-O-(3-propanoyl) ester of renieramycin T (3b) exhibited potent cytotoxic activity with half-maximal inhibitory concentration (IC50) values at 33.44 and 33.88 nM against H292 and H460 cell lines, respectively. These values were within the same range as compound 1 (IC50 = 34.43 and 35.63 nM) and displayed twofold higher cytotoxicity compared to compound 2 (IC50 = 72.85 and 83.95 nM). The steric characteristics and aromatic orientation of the 5-O-ester substituents played significant roles in their cytotoxicity. Notably, derivative 3b induced apoptosis with minimal necrosis, in contrast to the parental compound 1. Hence, the relationship between the structure and cytotoxicity of renieramycin-ecteinascidin hybrid alkaloids was investigated. This study emphasizes the potential of the series of 5-O-ester derivatives of renieramycin T as promising leads for the further development of potential anti-NSCLC agents.


[The need to teach research methodology in the career of medical surgeon].
A survey on the interest in doing medical research, present or previous involvement in it, and opinions on the need for a research course in the medical doctor and surgeon degree program was administered to 310 persons. The participants were divided into seven groups in accordance with their main lines of work: professors, administrative personnel, doctors at the primary, secondary and tertiary care level, residents, and medical students. The participants were in favor of research: 93.5% felt that they would have profited from a research course during their undergraduate studies and 94.8% were of the opinion that an introductory course in scientific research was needed in the graduate program; although 23.5% of the administrative personnel (a figure significantly different from the other groups, p less than 0.05) thought that the course was unnecessary. From the data obtained, the authors consider that an introductory course in scientific research should be included in the medical doctor and surgeon degree program.


Any Role of High-Dose Vitamin C for Septic Shock in 2021?
While the use of vitamin C as a therapeutic agent has been investigated since the 1950s, there has been substantial recent interest in the role of vitamin C supplementation in critical illness and particularly, sepsis and septic shock. Humans cannot synthesize vitamin C and rely on exogenous intake to maintain a plasma concentration of approximately 70 to 80 μmol/L. Vitamin C, in healthy humans, is involved with antioxidant function, wound healing, endothelial function, and catecholamine synthesis. Its function in the human body informs the theoretical basis for why vitamin C supplementation may be beneficial in sepsis/septic shock.Critically ill patients can be vitamin C deficient due to low dietary intake, increased metabolic demands, inefficient recycling of vitamin C metabolites, and loss due to renal replacement therapy. Intravenous supplementation is required to achieve supraphysiologic serum levels of vitamin C. While some clinical studies of intravenous vitamin C supplementation in sepsis have shown improvements in secondary outcome measures, none of the randomized clinical trials have shown differences between vitamin C supplementation and standard of care and/or placebo in the primary outcome measures of the trials. There are some ongoing studies of high-dose vitamin C administration in patients with sepsis and coronavirus disease 2019; the majority of evidence so far does not support the routine supplementation of vitamin C in patients with sepsis or septic shock.


Cesarean section: an answer to the House of Horne.
The incidence of cesarean delivery in the United States has at least tripled in the past 20 years, and this has generated a great deal of concern within the profession, by the government, and by the consumer. Recent data from the National Maternity Hospital in Dublin, Ireland, from which a stable 5% cesarean section rate was reported, have led those investigators to conclude that more frequent delivery by cesarean section in the United States was due in part to less aggressive management of labor in nulliparous patients. In this report, we compare obstetric practices and outcomes during 1983 for Parkland Memorial Hospital with those of the National Maternity Hospital. The overall cesarean delivery rate was 18% in Dallas and 6% in Dublin, and racial population differences along with an increased number of nulliparous patients likely account for a higher incidence of primary cesarean sections for dystocia in Dallas. Importantly, when we compared the results in Dublin with our own, more liberal use of cesarean delivery for presumed fetal jeopardy in Dallas was associated with a sevenfold decreased incidence of intrapartum fetal death and a twofold decrease in infants with seizures. From these data, we advise caution before one attempts to emulate, on faith alone, someone else's low and seemingly safe cesarean delivery rate.


Emergency and urgent operations for ulcerative colitis. The procedure of choice.
Eighty consecutive emergency and urgent colectomies for ulcerative colitis were performed. One-stage total proctocolectomy was performed in 37 patients, with a 9.1% mortality; ileostomy with subtotal colectomy was performed in 43, with a 7.0% mortality. The overall mortality was 7.5%. Postoperative morbidity after total proctocolectomy (mean postoperative hospitalization, 27.6 days; nonseptic complication rate, 29.4%; septic complication rate, 29.4%) was not substantially different from that after subtotal colectomy (postoperative hospitalization, 33.3 days; nonseptic complications, 45.0%; septic complications, 35.0%). Survivors of subtotal colectomy required abdominal-perineal resection of the colorectal remnant in 75.7% of patients, and no patient had successful subsequent ileorectal anastomosis. It is suggested that one-stage total proctocolectomy be adopted as the surgical procedure of choice in emergency or urgent operations for ulcerative colitis.


Selection for increased voluntary wheel-running affects behavior and brain monoamines in mice.
Selective-breeding of house mice for increased voluntary wheel-running has resulted in multiple physiological and behavioral changes. Characterizing these differences may lead to experimental models that can elucidate factors involved in human diseases and disorders associated with physical inactivity, or potentially treated by physical activity, such as diabetes, obesity, and depression. Herein, we present ethological data for adult males from a line of mice that has been selectively bred for high levels of voluntary wheel-running and from a non-selected control line, housed with or without wheels. Additionally, we present concentrations of central monoamines in limbic, striatal, and midbrain regions. We monitored wheel-running for 8 weeks, and observed home-cage behavior during the last 5 weeks of the study. Mice from the selected line accumulated more revolutions per day than controls due to increased speed and duration of running. Selected mice exhibited more active behaviors than controls, regardless of wheel access, and exhibited less inactivity and grooming than controls. Selective-breeding also influenced the longitudinal patterns of behavior. We found statistically significant differences in monoamine concentrations and associated metabolites in brain regions that influence exercise and motivational state. These results suggest underlying neurochemical differences between selected and control lines that may influence the observed differences in behavior. Our results bolster the argument that selected mice can provide a useful model of human psychological and physiological diseases and disorders.


Notch pathway activation can replace the requirement for Wnt4 and Wnt9b in mesenchymal-to-epithelial transition of nephron stem cells.
The primary excretory organ in vertebrates is the kidney, which is responsible for blood filtration, solute homeostasis and pH balance. These functions are carried out by specialized epithelial cells organized into tubules called nephrons. Each of these cell types arise during embryonic development from a mesenchymal stem cell pool through a process of mesenchymal-to-epithelial transition (MET) that requires sequential action of specific Wnt signals. Induction by Wnt9b directs cells to exit the stem cell niche and express Wnt4, which is both necessary and sufficient for the formation of epithelia. Without either factor, MET fails, nephrons do not form and newborn mice die owing to kidney failure. Ectopic Notch activation in stem cells induces mass differentiation and exhaustion of the stem cell pool. To investigate whether this reflected an interaction between Notch and Wnt, we employed a novel gene manipulation strategy in cultured embryonic kidneys. We show that Notch activation is capable of inducing MET in the absence of both Wnt4 and Wnt9b. Following MET, the presence of Notch directs cells primarily to the proximal tubule fate. Only nephron stem cells have the ability to undergo MET in response to Wnt or Notch, as activation in the closely related stromal mesenchyme has no inductive effect. These data demonstrate that stem cells for renal epithelia are uniquely poised to undergo MET, and that Notch activation can replace key inductive Wnt signals in this process. After MET, Notch provides an instructive signal directing cells towards the proximal tubule lineage at the expense of other renal epithelial fates.


The role of the sedimentary regime in shaping the distribution of subtidal sandbank environments and the associated meiofaunal nematode communities: an example from the southern North Sea.
We combined sediment and faunal data to explore the role of the sedimentary regime in shaping the distribution of subtidal sandbank environments and the associated meiofaunal nematode communities at Broken Bank and Swarte Bank, in the southern North Sea. A variety of sediment transport processes occur in the area, differing in the frequency and magnitude of sediment mobility, and the continuum between erosion, translation and sediment accumulation. The seabed contained a variety of bedforms, including longitudinal furrows, and small to very large sandwaves. The bed sediments were dominated by fine and medium sands, with admixtures of silt and gravel. Based on sedimentary bedforms and grain size analysis, a total of 11 sedimentary facies were delineated, of which 8 were analysed in detail for their relationships with the meiofauna. The sedimentary facies fell clearly into groups of facies, respectively representing high, high-moderate and moderate, and episodic sediment mobility. For those sedimentary facies where daily movement of sediments and bedforms occurred ('high' sediment mobility), the resulting spatially homogeneous environments were dominated by an impoverished nematode community comprising small deposit feeders and large predators. Resistance to sediment movement and the ability to exploit alternative food sources were prominent functional features of the successful colonisers. Those facies characterised by relatively infrequent sediment mobility ('episodic' and 'high-moderate and moderate' sediment mobility) comprised a heterogeneous suite of benthic habitats, containing taxonomically and functionally diverse assemblages of nematodes of various sizes, feeding types and reproductive potential. Faunal distribution patterns here indicated trade-offs between the resistance to sediment movement, environmental tolerance and competitive abilities. Our focus on diverse assemblages of organisms with high turnover times, inhabiting highly dynamic sedimentary environments, has revealed new animal-sediment relationships of relevance to pure and applied science.


In vivo analysis of vascularization and biocompatibility of electrospun polycaprolactone fibre mats in the rat femur chamber.
In orthopaedic medicine, connective tissues are often affected by traumatic or degenerative injuries, and surgical intervention is required. Rotator cuff tears are a common cause of shoulder pain and disability among adults. The development of graft materials for bridging the gap between tendon and bone after chronic rotator cuff tears is essentially required. The limiting factor for the clinical success of a tissue engineering construct is a fast and complete vascularization of the construct. Otherwise, immigrating cells are not able to survive for a longer period of time, resulting in the failure of the graft material. The femur chamber allows the observation of microhaemodynamic parameters inside implants located in close vicinity to the femur in repeated measurements in vivo. We compared a porous polymer patch (a commercially available porous polyurethane-based scaffold from Biomerix™) with electrospun polycaprolactone (PCL) fibre mats and chitosan (CS)-graft-PCL modified electrospun PCL (CS-g-PCL) fibre mats in vivo. By means of intravital fluorescence microscopy, microhaemodynamic parameters were analysed repetitively over 20 days at intervals of 3 to 4 days. CS-g-PCL modified fibre mats showed a significantly increased vascularization at Day 10 compared with Day 6 and at Day 14 compared with the porous polymer patch and the unmodified PCL fibre mats at the same day. These results could be verified by histology. In conclusion, a clear improvement in terms of vascularization and biocompatibility is achieved by graft-copolymer modification compared with the unmodified material.


Follicle-stimulating hormone within and secreted from anterior pituitaries of female golden hamsters during the estrous cycle and after ovariectomy.
Anterior pituitary (AP) glands were removed from groups of female golden hamsters at 0900 h on estrus (E), diestrus I (DI), and diestrus II (DII) and at 1200 h and 1500 h on proestrus (P12 and P15), as well as at 0900 h from ovariectomized hamsters (OVX). Hemipituitaries were incubated in culture medium with or without 10(-8) M luteinizing hormone-releasing hormone (LHRH) for 3 h at 37 degrees C to determine the magnitude of basal and LHRH-stimulated follicle-stimulating hormone (FSH) release. All samples were assessed for FSH activity by radioimmunoassay and radioreceptor assay. In a second set of experiments, AP were removed from E, DII, and OVX hamsters and bisected. One hemipituitary was homogenized in 10 mM Tris-HCl and the other half was incubated for 3 h. Follicle-stimulating hormone forms present within pituitary extracts or secreted into medium were separated by an isoelectric focusing technique, chromatofocusing. Basal FSH release was lowest in AP collected on DII and P12, higher in AP collected on E and DI, and highest in AP from OVX. Luteinizing hormone-releasing hormone-stimulated release of FSH was highest in AP obtained on DII and P12, lower in AP collected on E and DI, and lowest in AP from OVX. Radio-receptor-to-radioimmunoassay ratio of secreted FSH was greatest when basal FSH secretion was low and LHRH sensitivity was high (DII and P12) and least when basal FSH secretion was high and LHRH sensitivity low (E and after OVX).(ABSTRACT TRUNCATED AT 250 WORDS)


Aging: a portrait from gene expression profile in blood cells.
The availability of reliable biomarkers of aging is important not only to monitor the effect of interventions and predict the timing of pathologies associated with aging but also to understand the mechanisms and devise appropriate countermeasures. Blood cells provide an easily available tissue and gene expression profiles from whole blood samples appear to mirror disease states and some aspects of the aging process itself. We report here a microarray analysis of whole blood samples from two cohorts of healthy adult and elderly subjects, aged 43±3 and 68±4 years, respectively, to monitor gene expression changes in the initial phase of the senescence process. A number of significant changes were found in the elderly compared to the adult group, including decreased levels of transcripts coding for components of the mitochondrial respiratory chain, which correlate with a parallel decline in the maximum rate of oxygen consumption (VO2max), as monitored in the same subjects. In addition, blood cells show age-related changes in the expression of several markers of immunosenescence, inflammation and oxidative stress. These findings support the notion that the immune system has a major role in tissue homeostasis and repair, which appears to be impaired since early stages of the aging process.


Clouds of venus: particle size distribution measurements.
Data from the Pioneer Venus cloud particle size spectrometer experiment has revealed the Venus cloud system to be a complicated mixture of particles of various chemical composition distinguishable by their multimodal size distributions. The appearance, disappearance, growth, and decay of certain size modes has aided the preliminary identification of both sulfuric acid and free sulfur cloud regions. The discovery of large particles > 30 micrometers, significant particle mass loading, and size spectral features suggest that precipitation is likely produced; a peculiar aerosol structure beneath the lowest cloud layer could be residue from a recent shower.


Background light produces a recoverin-dependent modulation of activated-rhodopsin lifetime in mouse rods.
The Ca(2+)-binding protein recoverin is thought to regulate rhodopsin kinase and to modulate the lifetime of the photoexcited state of rhodopsin (Rh*), the visual pigment of vertebrate rods. Recoverin has been postulated to inhibit the kinase in darkness, when Ca(2+) is high, and to be released from the disk membrane in light when Ca(2+) is low, accelerating rhodopsin phosphorylation and shortening the lifetime of Rh*. This proposal has remained controversial, in part because the normally rapid turnoff of Rh* has made Rh* modulation difficult to study in an intact rod. To circumvent this problem, we have made mice that underexpress rhodopsin kinase so that Rh* turnoff is rate limiting for the decay of the rod light response. We show that background light speeds the decay of Rh* turnoff, and that this no longer occurs in mice that have had recoverin knocked out. This is the first demonstration in an intact rod that light accelerates Rh* inactivation and that the Ca(2+)-binding protein recoverin may be required for the light-dependent modulation of Rh* lifetime.


Connexin Gap Junctions and Hemichannels Link Oxidative Stress to Skeletal Physiology and Pathology.
The goal of this review is to provide an overview of the impact and underlying mechanism of oxidative stress on connexin channel function, and their roles in skeletal aging, estrogen deficiency, and glucocorticoid excess associated bone loss. Connexin hemichannel opening is increased under oxidative stress conditions, which confers a cell protective role against oxidative stress-induced cell death. Oxidative stress acts as a key contributor to aging, estrogen deficiency, and glucocorticoid excess-induced osteoporosis and impairs osteocytic network and connexin gap junction communication. This paper reviews the current knowledge for the role of oxidative stress and connexin channels in the pathogenesis of osteoporosis and physiological and pathological responses of connexin channels to oxidative stress. Oxidative stress decreases osteocyte viability and impairs the balance of anabolic and catabolic responses. Connexin 43 (Cx43) channels play a critical role in bone remodeling, mechanotransduction, and survival of osteocytes. Under oxidative stress conditions, there is a consistent reduction of Cx43 expression, while the opening of Cx43 hemichannels protects osteocytes against cell injury caused by oxidative stress.


[Recommendations and evidence synthesis: guidelines on antibiotic prophylaxis and choice of antiseptics for women in instrumental vaginal delivery or cesarean sectionSíntese de evidências e recomendações: diretrizes para a profilaxia antibiótica e a escolha de antissépticos em mulheres submetidas a parto vaginal operatório ou cesariana].
Maternal sepsis and infections during or after childbirth increase maternal mortality, leading to a high burden of disease in the Region of the Americas. The risk of infection after a cesarean section or instrumental vaginal delivery can be reduced with the appropriate skin antiseptic agents and antibiotic prophylaxis. To synthesize World Health Organization (WHO) recommendations to improve the quality of care and health outcomes related to routine antibiotic prophylaxis in women during instrumental vaginal delivery; routine use of antibiotic prophylaxis in women having a cesarean section; the choice of antiseptics and skin preparation methods before a cesarean; and vaginal irrigation with antiseptics in women undergoing a cesarean. The WHO guidelines were based on the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology as described in the WHO Handbook for Guideline Development. Recommendations contained in four WHO guidelines were synthesized and a systematic search for studies carried out in the Region of the Americas was conducted in PubMed, Lilacs, Health Systems Evidence, Epistemonikos, and gray literature to identify barriers, facilitators, and implementation strategies. Five recommendations were made on the routine use of antibiotic prophylaxis in women undergoing instrumental vaginal delivery, routine use of antibiotic prophylaxis in women having a cesarean section, the choice of antiseptics and skin preparation prior to a cesarean section, and vaginal irrigation with antiseptics during a cesarean section. Implementation barriers and facilitators were identified, and indicators were created to assess adherence and outcomes. The formulated recommendations aim to provide guidance on how to improve quality of care and outcomes related to antibiotic prophylaxis and the choice of antiseptics in women undergoing instrumental vaginal delivery or a cesarean section.


Insertional inactivation of streptolysin S expression in Streptococcus pyogenes.
The inactivation of a genetic determinant critical for streptolysin S production was accomplished by transfer and insertion of the transposon Tn916 into the DNA of a group A streptococcal strain. The group D strain CG110 was able to efficiently transfer Tn916 into the group A strain CS91 when donor and recipient cells were concentrated and incubated together on membrane filters. Among tetracycline-resistant transconjugants, nonhemolytic mutants that no longer produced streptolysin S and retained the capacity to produce streptolysin O were discovered. Hemolytic revertants from these mutants regained tetracycline sensitivity; other revertants still retained a tetracycline resistance phenotype. Hybridization studies employing Tn916 DNA located Tn916 sequences in EcoRI and HindIII fragments of DNA from mutants devoid of streptolysin S; one carried a single copy of Tn916, and the other two carried multiple copies of the transposon.


Video-capture virtual reality system for patients with paraplegic spinal cord injury.
This article presents results from a feasibility study of a video-capture virtual reality (VR) system used with patients who have paraplegic spinal cord injury (SCI) and who need balance training. The advantages of the VR system include providing the user with natural control of movements, the ability to use as many parts of the body as are deemed suitable within the context of therapeutic goals, and flexibility in the way the system can be adapted to suit specific therapeutic objectives. Thirteen participants with SCI experienced three virtual environments (VEs). Their responses to a Short Feedback Questionnaire showed high levels of presence. We compared performance in the environments with a group of 12 nondisabled participants. Response times for the patient group were significantly higher and percentage of success was significantly lower than that for the nondisabled group. In addition, significant moderate correlations were found between performance within a VE and static balance ability as measured by the Functional Reach Test. This study is a first step toward future studies aimed at determining the potential of using this VR system during the rehabilitation of patients with SCI.


Disease-associated mutations cause premature oligomerization of myelin proteolipid protein in the endoplasmic reticulum.
Pelizaeus-Merzbacher disease (PMD) is a dysmyelinating disease caused by mutations, deletions, or duplications of the proteolipid protein (PLP) gene. Mutant forms of PLP are retained in the endoplasmic reticulum (ER), and the resulting accumulation of mutant protein is thought to be a direct cause of oligodendrocyte cell death, which is the primary clinical feature of PMD. The molecular mechanisms underlying the toxicity of mutant PLP are however currently unknown. We report here that PMD-linked mutations of PLP are associated with the accelerated assembly of the protein into stable homooligomers that resemble mature, native PLP. Thus although WT PLP forms stable oligomers after an extended maturation period, most likely at the cell surface, mutant forms of PLP rapidly assemble into such oligomers at the ER. Using PLP mutants associated with diseases of varying severity, we show that the formation of stable oligomers correlates with the development of PMD. Based on these findings, we propose that the premature oligomerization of PLP in the ER of oligodendrocytes contributes to the pathology of PMD.


Development of a PCR-free electrochemical point of care test for clinical detection of methicillin resistant Staphylococcus aureus (MRSA).
An MRSA assay requiring neither labeling nor amplification of target DNA has been developed. Sequence specific binding of fragments of bacterial genomic DNA is detected at femtomolar concentrations using electrochemical impedance spectroscopy (EIS). This has been achieved using systematic optimisation of probe chemistry (PNA self-assembled monolayer film on gold electrode), electrode film structure (the size and nature of the chemical spacer) and DNA fragmentation, as these are found to play an important role in assay performance. These sensitivity improvements allow the elimination of the PCR step and DNA labeling and facilitate the development of a simple and rapid point of care test for MRSA. Assay performance is then evaluated and specific direct detection of the MRSA diagnostic mecA gene from genomic DNA, extracted directly from bacteria without further treatment is demonstrated for bacteria spiked into saline (10(6) cells per mL) on gold macrodisc electrodes and into human wound fluid (10(4) cells per mL) on screen printed gold electrodes. The latter detection level is particularly relevant to clinical requirements and point of care testing where the general threshold for considering a wound to be infected is 10(5) cells per mL. By eliminating the PCR step typically employed in nucleic acid assays, using screen printed electrodes and achieving sequence specific discrimination under ambient conditions, the test is extremely simple to design and engineer. In combination with a time to result of a few minutes this means the assay is well placed for use in point of care testing.


Pathogenesis of nonimmune hydrops fetalis caused by intrauterine B19 infection.
Intrauterine human parvovirus B19 infection is related to non-immune hydrops fetalis and fetal death. First, we performed epidemiological studies to determine the critical period during which maternal infection led to hydrops fetalis. The studies showed that the hepatic period of hematopoietic activity was correlated with the critical period of maternal infection, which suggested that B19 might have affinity for erythroid lineage cells at the stage of hematopoiesis. We next established an in vitro infection experimental system of B19 using erythroid lineage cells derived from fetal liver cells. We demonstrated that the erythroid lineage cells proved to be appropriate targets for B19 virus and that B19 infection could induce apoptosis of infected cells. The massive destruction of erythroid lineage cells through apoptosis seems to cause severe anemia and to result in heart failure of the fetus. To analyze the cytotoxic mechanism in more detail, we established a stringent regulatory expression system of the NS1 protein encoded by the B19 genome and indicated that the apoptosis induced by B19 was directly caused by the NS1 protein. Experiments using mutations engineered in the ATP-binding domain of NS1 indicated that this domain played a critical role for the apoptosis induction. The present studies may contribute to a better understanding of the pathogenesis of hydrops fetalis associated with B19 infection during pregnancy.


Implant rehabilitation of the edentulous posterior atrophic mandible: the sandwich osteotomy revisited.
Treatment of the posterior atrophic mandible has long been a challenge in implant dentistry and maxillofacial surgery. The objective of this study was to reevaluate the safety and efficacy of the sandwich osteotomy and bone grafting in patients with moderate to severe posterior mandibular atrophy. This retrospective study included patients with an edentulous posterior mandible in which there was not enough bone above the dental nerve to insert implants at least 10 mm in length; patients with adequate bone volume but with an excessive interocclusal distance at the posterior occlusal region were also included. Twenty-three patients with 30 sites of moderate to severe posterior atrophy were treated using a sandwich osteotomy above the mental nerve and an interpositioned block of autologous or allogeneic bone. Success criteria were based on the possibility of implant insertion after bone grafting. The average gain in height was 5.3 mm (range, 2 to 10 mm). Partial loss of alveolar height was observed in only one patient from the allogeneic graft group. Patients were followed for 12 to 93 months after bone grafting. No signs of infection were observed. Minor dehiscence of the surgical wound occurred in four segments, but healing ultimately occurred in every patient. Sixty-five implants were placed, and none were lost during follow-up. Insertion of implants of 10 mm or more in length was successfully achieved in 90.8% of the sites, and partial success (ie, bone segments suitable for insertion of shorter implants) was seen in the remaining sites. Moderate to severe posterior mandibular atrophy can be successfully treated by interpositional sandwich osteotomy and bone grafting, allowing for the subsequent placement of implants and fixed prostheses in all segments.


Quick reference guide to apixaban.
Direct oral anticoagulants (DOACs) are being increasingly used in the clinical setting for patients at risk of venous thromboembolism (VTE) and/or stroke. These medications offer valued benefits for long-term use, including a fast onset of anticoagulation, fixed anticoagulation profile (and consequent prescription of specified doses) and no requirement for routine monitoring. Apixaban is a selective factor Xa inhibitor, approved for use in the prevention of stroke in patients with nonvalvular atrial fibrillation and in the prevention and treatment of acute VTE. Like many of the DOACs, it has a fast onset of action and works to deliver predictable coagulation results. Multiple randomized controlled trials including ARISTOTLE and AMPLIFY have shown apixaban to be noninferior to vitamin K antagonists in the prevention of stroke and VTE, with a good safety profile. This article aims to review the use of apixaban for the prevention and treatment of thromboembolic disease, highlighting the key study results that have led to its current licensing and use.


A new anesthesia protocol enabling longitudinal lung-function measurements in neonatal rabbits by micro-CT.
Micro-computed tomography (micro-CT) imaging is an emerging technology with many applications in small animals, for example, the study of pulmonary diseases, although clear guidelines and critical mass of evidence are still missing in the preclinical literature. The neonatal rabbit is a valuable model for studying pulmonary development. However, the longitudinal monitoring of lung function by micro-CT can be challenging. Distinctive datasets corresponding to the end-inspiration and end-expiration phases need to be generated and analyzed to derive lung-functional parameters. The quality of CT scans and the reliability of parameters obtained remain highly dependent on the anesthesia protocol used. Three different anesthetic protocols were tested. The combination of dexmedetomidine 0.25 mg/kg injected intraperitoneally followed by 1% isoflurane was found to facilitate CT imaging at 4 and 11 days after birth. Contrarily, isoflurane and ketamine-xylazine were found unsuitable and thus not investigated further. Total lung volumes significantly increased at day 11 compared with baseline in both respiratory phases, whereas lung tissue remained constant. As expected, functional residual capacity, air-to-tissue ratio, and minute ventilation were significantly increased at day 11 in each animal. Those parameters were correlated with inspiratory capacity, compliance, elastance, and resistance of both respiratory system and tissue component, as measured by flexiVent. Lung development was also evaluated by histomorphometric analyses. In conclusion, we have identified a safe and suitable anesthesia protocol for micro-CT imaging in neonatal rabbits. Moreover, the possibility to longitudinally measure lung function in the same subject dramatically reduced the intraexperimental variability.


Psychosocial origins of obesity stigma: toward changing a powerful and pervasive bias.
Widespread bias and discrimination based on weight have been documented in key areas of living, including education, employment, and health care. This paper examines the social and psychological origins of this bias through a review and critique of theoretical and empirical literatures, and proposes how the field might best advance in the area of reducing stigma. Explanations for the development and reduction of weight stigma are examined with different theoretical approaches, including attribution theory and a social consensus model. Individual and sociocultural contributors to bias suggested by these approaches are highlighted. New directions are discussed in both the understanding and prevention of weight bias.


Comparison of regional blood flow values measured by radioactive and fluorescent microspheres.
Fluorescent microspheres (FM) have become an attractive alternative to radioactive microspheres (RM) for the measurement of regional blood flow (RBF). The aim of the present study was to investigate the comparability of both methods by measuring RBF with FM and RM. Eight anaesthetised pigs received simultaneous, left atrial injections of FM and RM with a diameter of 15 microm at six different time points. Blood reference samples were collected from the descending aorta. RBF was determined in tissue samples of the myocardium, spleen and kidneys of all 8 animals. After radioactivity of the tissue samples was determined, the samples were processed automatically for measuring fluorescence using a recently developed filter device (SPU). RBF was calculated with both the isotope and spectrometric data of both methods for each sample resulting in a total of 10,512 blood flow values. The comparison of the RBF values yielded high linear correlation (mean r(2) = 0.95 +/- 0.03 to 0.97 +/- 0.02) and excellent agreement (bias 5.4-6.7%, precision 9.9- 16.5%) of both methods. Our results indicate the validity of MS and of the automated tissue processing technique by means of the SPU.


Asia-Pacific Working Group consensus on non-variceal upper gastrointestinal bleeding.
Upper gastrointestinal bleeding (UGIB), especially peptic ulcer bleeding, remains one of the most important cause of hospitalisation and mortality world wide. In Asia, with a high prevalence of Helicobacter pylori infection, a potential difference in drug metabolism, and a difference in clinical management of UGIB due to variable socioeconomic environments, it is considered necessary to re-examine the International Consensus of Non-variceal Upper Gastrointestinal Bleeding with emphasis on data generated from the region. The working group, which comprised experts from 12 countries from Asia, recommended the use of the Blatchford score for selection of patients who require endoscopic intervention and which would allow early discharge of patients at low risk. Patients' comorbid conditions should be included in risk assessment. A pre-endoscopy proton pump inhibitor (PPI) is recommended as a stop-gap treatment when endoscopy within 24 h is not available. An adherent clot on a peptic ulcer should be treated with endoscopy combined with a PPI if the clot cannot be removed. Routine repeated endoscopy is not recommended. High-dose intravenous and oral PPIs are recommended but low-dose intravenous PPIs should be avoided. COX-2 selective non-steroidal anti-inflammatory drugs combined with a PPI are recommended for patients with very high risk of UGIB. Aspirin should be resumed soon after stabilisation and clopidogrel alone is no safer than aspirin plus a PPI. When dual antiplatelet agents are used, prophylactic use of a PPI reduces the risk of adverse gastrointestinal events.


Effect of varicocele on chromatin condensation and DNA integrity of ejaculated spermatozoa using cytochemical tests.
Varicocele occurs in approximately 15% to 20% of the general male population and it is the most common cause of poor semen production and decreased semen quality. It has been demonstrated that patients with varicocele have a significantly higher DNA fragmentation index (DFI) and spermatozoa with nuclear anomalies than healthy fertile men. Therefore, the aim of this study was to evaluate sperm chromatin integrity in these patients. Sixty men referring to the andrology laboratory were categorised into three different groups: 20 infertile men with varicocele, 20 infertile men with abnormal semen parameters and 20 fertile men who had normal spermatogram were considered as control group. Semen analysis was performed according to WHO criteria. To evaluate sperm chromatin quality and DNA integrity, after fixation of sperm smears, aniline blue, toluidine blue, chromomycin A(3) and acridine orange staining were applied in three groups. The slides were analysed by light and fluorescent microscopy and to determine the percentage of mature or immature spermatozoa, 200 spermatozoa were counted in each slide. The results showed that the rates of aniline blue-reacted spermatozoa were significantly higher in infertile and varicocele patients than in the normal group (P < 0.001). In addition, with regard to chromomycin A(3), acridine orange and toluidine blue staining, there was a significant difference between the three groups (P < 0.001). The results showed that the varicocele samples contain a higher proportion of spermatozoa with abnormal DNA and immature chromatin than those from fertile men as well as infertile men without varicocele. Therefore, varicocele results in the production of spermatozoa with less condensed chromatin and this is one of the possible causes of infertility due to varicocele.


Solubility-modulated asymmetric membrane tablets of triprolidine hydrochloride: statistical optimization and evaluation.
The aim of the present study was to develop asymmetric membrane (AM) tablets for controlled delivery of highly water-soluble antihistaminic drug triprolidine hydrochloride. The solubility of triprolidine hydrochloride was modulated through the incorporation of coated sodium chloride crystals encapsulated with asymmetric membrane coating polymer, cellulose acetate butyrate. Formulation of AM tablets was based on a 2(3) factorial design to study the effect of formulation variables, namely, polymer concentration, level of pore former, and amount of osmogen on the in vitro release. Core tablets prepared by wet granulation and coated with asymmetric membrane by a dip coating method were evaluated. Statistical analysis was done with the Design Expert Software 8.0.2 (USA), and the polynomial equation generated by Pareto charts was used for validation of the experimental design. The interaction chart and response surface plots deduced the simultaneous effect of independent variables on in vitro drug release. The in vitro drug release was inversely proportional and directly related to the level(s) of polymer and pore former in the membrane, respectively. The level of osmogen not only increased the osmotic pressure but also controlled the drug release due to a common ion effect. The drug release of the optimized formulation (F6) followed zero-order kinetics, which would be capable of reducing the administration, and was stable over 3 months. SEM photographs revealed asymmetry in membrane structure.


Antiretroviral therapy for initial human immunodeficiency virus/AIDS treatment: critical appraisal of the evidence from over 100 randomized trials and 400 systematic reviews and meta-analyses.
There have been over 100 randomized clinical trials (RCTs) of diverse regimens of antiretroviral therapy for treatment-naïve human immunodeficiency virus-positive patients. A further 400 systematic reviews and meta-analyses are informed by these trials. There are, however, difficulties in using systematic reviews and meta-analyses of this clinical evidence to inform guidelines and clinical practice. Several issues can make the interpretation of comparative effectiveness challenging. In this article, we review the key challenges in interpreting multiple trials in this population. We specifically examine the network geometry of the clinical trial comparisons, the predominance of non-inferiority trial designs, issues related to potential class effects, heterogeneous documentation of adverse events, and a relative lack of RCTs that reflect specific current clinical guideline recommendations. We conclude with recommendations for future clinical trials and meta-analyses.


[Our experience with management of inherited thrombophilia during pregnancy. Preliminary report].
It has become clear in the recent years that inherited thrombophilias (IT) are associated with serious abnormalities during pregnancy. This includes miscarriage, still birth, placental abruption, praeclamcspia and intrauterine fetal growth restriction. The aim of this study is to share our experience in the field. 38 patients with medical history of abnormal pregnancies (miscarriage, still birth, placental abruption, praeclamcspia and intrauterine fetal growth reastriction). They were all tested for the following gene alterations: V Laidon-R506Q/phiVL-R506Q/, protrombin G/A 20210 /Pi pG/A20210/, Plasminogen activator inhibitor- PAI- 4G/4G/PAI 4G/5G/). IT were diagnosed in 24 patients. They were all treated by: Aspirin 75 mg form prior to conception and low molecular Heparin after detection of fetal heart movement. Due to the observed NRDS in some of the newborns, the low molecular heparin intake was discontinued 30 days prior to expected delivery. keeping up to the therapeutic scheme, 70% (17) of women with IT gave birth to a term baby, and 30% (7)-to a preterm one, all pregnancies were successful. Amongst the patients with medical history of miscarriage, 72% were diagnosed with IT and 87.5% of them gave birth to a term newborn as a result of the anticoagulant treatment. Undiagnosed IT is a common cause of adverse pregnancy outcome. Uninterrupted anticoagulant treatment of these patients is very successful. The whole pregnancy should be followed up closely. Due to the higher risk of respiratory complications in the infants, delivery should be performed in a specialized hospital with neonatology department, capable of newborn resuscitation.


Evaluation of burden felt by caregivers of patients with schizophrenia and bipolar disorder.
It can be a difficult task to provide care to the patients living with mental health issues, especially with chronic diseases such as schizophrenia and bipolar disorder where the patient loses touch with reality. The current study was aimed to assess the of burden of care that caregivers feel while giving care to the patients of schizophrenia and bipolar disorder and to compare the difference in burden between these two conditions. The study also evaluated the factors affecting the caregiver's burden. This was a cross-sectional interview-based study conducted at the psychiatry department of a tertiary care hospital in Gujarat among caregivers of schizophrenia and bipolar disorder. Each caregiver was given the Zarit-Burden Interview scale in vernacular language and asked to rate each statement from 0 to 4 where 0: never, 1: rarely, 2: sometimes, 3: quite frequently, and 4: nearly always. The final score was calculated and interpreted as: 0-21 - little or no burden, 41-60 - moderate to severe burden, and 61-88 - severe burden. Data of the burden score were expressed as mean and standard deviation and compared using unpaired t-test. Pearson's correlation coefficient was used for correlation between burden score and variables such as age, years of education, and duration of illness. The analysis was done using GraphPad version 3.0 and Microsoft Excel 2016. A total of 210 caregivers reported the interview scale completely, of which 105 caregivers belonged to schizophrenia group and 105 were related to bipolar disorder. Average of burden score was 64.89 ± 15.7 and 59.11 ± 17.8 (maximum score: 88) in schizophrenia and bipolar group, respectively, and difference between the group was statistically significant. In both the groups, it was found that, with increase in the age of patients, caregiver's burden significantly increased. Caregivers of schizophrenia and bipolar disorder patients feel a considerable burden of care with more burden felt by the caregivers of schizophrenia. The more vulnerable to burden are females, elderly, low-income groups, and patients in whom longer duration of care is required. The caregivers should receive an adequate support for maintaining their own mental health. they should be provided support for maintaining their mental health. Particularly, vulnerable are females, elderly, low-income groups, and longer duration of care. They should be provided with adequate support.


SLFN11 Expression in Advanced Prostate Cancer and Response to Platinum-based Chemotherapy.
Expression of the DNA/RNA helicase schlafen family member 11 (SLFN11) has been identified as a sensitizer of tumor cells to DNA-damaging agents including platinum chemotherapy. We assessed the impact of SLFN11 expression on response to platinum chemotherapy and outcomes in patients with metastatic castration-resistant prostate cancer (CRPC). Tumor expression of SLFN11 was assessed in 41 patients with CRPC treated with platinum chemotherapy by RNA sequencing (RNA-seq) of metastatic biopsy tissue (n = 27) and/or immunofluorescence in circulating tumor cells (CTC; n = 20). Cox regression and Kaplan-Meier methods were used to evaluate the association of SLFN11 expression with radiographic progression-free survival (rPFS) and overall survival (OS). Multivariate analysis included tumor histology (i.e., adenocarcinoma or neuroendocrine) and the presence or absence of DNA repair aberrations. Patient-derived organoids with SLFN11 expression and after knockout by CRISPR-Cas9 were treated with platinum and assessed for changes in dose response. Patients were treated with platinum combination (N = 38) or platinum monotherapy (N = 3). Median lines of prior therapy for CRPC was two. Median OS was 8.7 months. Overexpression of SLFN11 in metastatic tumors by RNA-seq was associated with longer rPFS compared with those without overexpression (6.9 vs. 2.8 months, HR = 3.72; 95% confidence interval (CI), 1.56-8.87; P < 0.001); similar results were observed for patients with SLFN11-positive versus SLFN11-negative CTCs (rPFS 6.0 vs. 2.2 months, HR = 4.02; 95% CI, 0.77-20.86; P = 0.002). A prostate-specific antigen (PSA) decline of ≥50% was observed in all patients with SLFN11 overexpression. No association was observed between SLFN11 expression and OS. On multivariable analysis, SLFN11 was an independent factor associated with rPFS on platinum therapy. Platinum response of organoids expressing SLFN11 was reduced after SLFN11 knockout. Our data suggest that SLFN11 expression might identify patients with CRPC with a better response to platinum chemotherapy independent of histology or other genomic alterations. Additional studies, also in the context of PARP inhibitors, are warranted.


Theodore E. Woodward award: non-pharmaceutical interventions employed by major American cities during the 1918-19 influenza pandemic.
A critical question in pandemic influenza planning is the role that non-pharmaceutical interventions (NPI) such as isolation and quarantine, social distancing, and school closure, might play in delaying the temporal impact of a pandemic, reducing the overall and peak attack rate, and reducing the number of cumulative deaths. Such measures could potentially provide valuable time for pandemic-strain vaccine and antiviral medication production and distribution. Optimally, appropriate NPI implementation would decrease the burden on healthcare services and critical infrastructure. These public health measures, however, are often associated with enormous social and economic costs. Therefore, it is imperative to assess past applications of NPIs in order to better understand how they might (or might not) be employed during future pandemics in an effective, legal, ethical manner that inspires confidence and compliance in the public at large.


Diastolic Augmentation Index Improves Radial Augmentation Index in Assessing Arterial Stiffness.
Arterial stiffness is an important risk factor for cardiovascular events. Radial augmentation index (AI r ) can be more conveniently measured compared with carotid-femoral pulse wave velocity (cfPWV). However, the performance of AI r in assessing arterial stiffness is limited. This study proposes a novel index AI rd , a combination of AI r and diastolic augmentation index (AI d ) with a weight α, to achieve better performance over AI r in assessing arterial stiffness. 120 subjects (43 ± 21 years old) were enrolled. The best-fit α is determined by the best correlation coefficient between AI rd and cfPWV. The performance of the method was tested using the 12-fold cross validation method. AI rd (r = 0.68, P < 0.001) shows a stronger correlation with cfPWV and a narrower prediction interval than AI r (r = 0.61, P < 0.001), AI d (r = -0.17, P = 0.06), the central augmentation index (AI c ) (r = 0.61, P < 0.001) or AI c normalized for heart rate of 75 bpm (r = 0.65, P < 0.001). Compared with AI r (age, P < 0.001; gender, P < 0.001; heart rate, P < 0.001; diastolic blood pressure, P < 0.001; weight, P = 0.001), AI rd has fewer confounding factors (age, P < 0.001; gender, P < 0.001). In conclusion, AI rd derives performance improvement in assessing arterial stiffness, with a stronger correlation with cfPWV and fewer confounding factors.


Ultraprocessed Products as Food Fortification Alternatives: A Critical Appraisal from Latin America.
Ultraprocessed products (UPPs), associated with obesity and non-communicable diseases (NCDs), are becoming predominant on the global market and a target for market-driven fortification initiatives. The aim of this article is to describe the implications of adding micronutrients to UPPs with excessive amounts of critical nutrients associated with NCDs and provide recommendations for legislation and policies. UPPs with added micronutrients such as breakfast cereals, sugar-sweetened beverages, powder beverages, fruit juices, sauces, and bouillon cubes, among others, are commonly available and heavily promoted in Latin American countries. Misleading advertising of UPPs with added micronutrients and with excessive content of sugar, fat, and salt might increase the consumption of such products, giving them a "health halo effect" that leads consumers to overestimate their nutritional quality and healthfulness. Although international collections of standards such as the Codex Alimentarius provide some guidelines on this matter, countries need to implement national legislations, through a food systems approach, to regulate the marketing and labeling of UPPs. Lastly, there is still the need to foster research to close knowledge gaps and help countries to guide the process of food fortification strategies from a regulatory standpoint.


Risk of retinal detachment following cataract extraction: results from the International Cataract Surgery Outcomes Study.
To estimate the risk of retinal detachment (RD) following cataract extraction in Denmark, and to compare the risk with that following cataract extraction in the USA, and with that in a sample of Danish patients who did not have ocular surgery. A sample was created from the administrative Danish Hospital Register and included 19,252 patients who underwent first eye cataract surgery between 1985 and 1987, and who were 50 years of age or older. The patients were then followed for 4-6 years using the register data. The design and definition of events were identical to the US National Study of Cataract Outcomes. In Denmark a 4 year cumulative risk of hospitalisation for RD of 0.93% (95% confidence interval (CI) 0.71-1.16) was observed following an extracapsular cataract extraction with a lens implant. A similar cumulative risk of RD was reported from the US study. Thus, no difference in outcomes concerning risk of RD was shown between Denmark and the USA. In a multivariate analysis younger age, male sex, and intracapsular cataract extraction were all associated with higher risk of postoperative RD. A reference group of 7636 people not undergoing any ocular surgery was created and the incidence of RD in this group was calculated. During the sixth year following cataract surgery, the incidence of RD in the cataract group was still 7.5 (95% CI 1.6-22.0) times higher than that observed in the reference group.


Differential localization of HPV16 E6 splice products with E6-associated protein.
High-risk Human Papillomavirus (HPV) is the etiological agent associated with the majority of anogenital cancers. The primary HPV oncogenes, E6 and E7, undergo a complex splicing program resulting in protein products whose purpose is not fully understood. Previous mouse studies have confirmed the existence of a translated product corresponding to the E6*I splice product. In terms of function, the translated E6*I protein has been shown to bind to E6 protein and to E6 associated protein (E6AP). E6*I has an inhibitory effect on E6-mediated p53 degradation in E6 expressing cells. In order to analyze the relationship between E6*I and full-length E6 in relation to localization, we created a series of green fluorescent protein (GFP) fusion products. The localization of these proteins with reference to E6AP in vivo remains unclear. Therefore, we investigated the cellular distribution of different forms of E6 with reference to E6AP. E6 and E6*I proteins, expressed from a wild type E6 gene cassette, were dispersed in the nucleus and the cytoplasm. Whereas, the E6 splice donor mutant (E6MT) was primarily localized to the nucleus. E6*I protein and E6AP were found to co-localize mainly to the cytoplasm, whereas the co-localization of full-length E6 protein and E6AP, if at all, was found mainly at the perinuclear region. These results suggest a functional relationship between the E6*I and full-length E6 protein which correlates with their localization and likely is important in regulation of the E6-E6AP complex.


Novel functional proteins coded by the human genome discovered in metastases of melanoma patients.
In the advanced stages, malignant melanoma (MM) has a very poor prognosis. Due to tremendous efforts in cancer research over the last 10 years, and the introduction of novel therapies such as targeted therapies and immunomodulators, the rather dark horizon of the median survival has dramatically changed from under 1 year to several years. With the advent of proteomics, deep-mining studies can reach low-abundant expression levels. The complexity of the proteome, however, still surpasses the dynamic range capabilities of current analytical techniques. Consequently, many predicted protein products with potential biological functions have not yet been verified in experimental proteomic data. This category of 'missing proteins' (MP) is comprised of all proteins that have been predicted but are currently unverified. As part of the initiative launched in 2016 in the USA, the European Cancer Moonshot Center has performed numerous deep proteomics analyses on samples from MM patients. In this study, nine MPs were clearly identified by mass spectrometry in MM metastases. Some MPs significantly correlated with proteins that possess identical PFAM structural domains; and other MPs were significantly associated with cancer-related proteins. This is the first study to our knowledge, where unknown and novel proteins have been annotated in metastatic melanoma tumour tissue.


Fiducial-aided on-machine positioning method for precision manufacturing of optical freeform surfaces.
There are still significant challenges in the accurate positioning of optical freeform surfaces on the machine tool and the measurement instrument due to the high accuracy requirement and their complex shapes. This paper proposes a Fiducial-aided On-machine Positioning method (FAOPM) that combines on-machine measurement and off-machine measurement to precisely position optical freeform surfaces during the precision manufacturing cycle including rough machining, fine machining, measurement, and error compensation. The FAOPM makes use of fiducials which are firstly measured on a coordinate measuring machine with nanometric accuracy to generate a Fiducial-aided Computer Aided Design (FA-CAD) of the designed optical surface, then the developed on-machine measuring device obtains the accurate positions of the fiducials after remounting in the machining coordinate system. Finally the relative position of the workpiece is identified so that the associated cutting paths and compensation tool path can be easily generated. Several optical freeform surfaces were experimentally machined to prove the capability of the proposed method. The results indicate that the positions of the workpiece during the precision manufacturing and measurement cycle were precisely achieved and the form accuracy of the optical freeform surfaces was remarkable improved based on the FAOPM.


The impact of i-PUSH on maternal and child health care utilization, health outcomes, and financial protection: study protocol for a cluster randomized controlled trial based on financial and health diaries data.
Universal Health Coverage ensures access to quality health services for all, with no financial hardship when accessing the needed services. Nevertheless, access to quality health services is marred by substantial resource shortages creating service delivery gaps in low-and middle-income countries, including Kenya. The Innovative Partnership for Universal Sustainable Healthcare (i-PUSH) program, developed by AMREF Health Africa and PharmAccess Foundation (PAF), aims to empower low-income women of reproductive age and their families through innovative digital tools. This study aims to evaluate the impact of i-PUSH on maternal and child health care utilization, women's health including their knowledge, behavior, and uptake of respective services, as well as women's empowerment and financial protection. It also aims to evaluate the impact of the LEAP training tool on empowering and enhancing community health volunteers' health literacy and to evaluate the impact of the M-TIBA health wallet on savings for health and health insurance uptake. This is a study protocol for a cluster randomized controlled trial (RCT) study that uses a four-pronged approach-including year-long weekly financial and health diaries interviews, baseline and endline surveys, a qualitative study, and behavioral lab-in-the-field experiments-in Kakemega County, Kenya. In total, 240 households from 24 villages in Kakamega will be followed to capture their health, health knowledge, health-seeking behavior, health expenditures, and enrolment in health insurance over time. Half of the households live in villages randomly assigned to the treatment group where i-PUSH will be implemented after the baseline, while the other half of the households live in control village where i-PUSH will not be implemented until after the endline. The study protocol was reviewed and approved by the AMREF Ethical and Scientific Review Board. Research permits were obtained from the National Commission for Science, Technology and Innovation agency of Kenya. People in low-and middle-income countries often suffer from high out-of-pocket healthcare expenditures, which, in turn, impede access to quality health services. Saving for healthcare as well as enrolment in health insurance can improve access to healthcare by building capacities at all levels-individuals, families, and communities. Notably, i-PUSH fosters savings for health care through the mobile-phone based "health wallet," it enhances enrolment in subsidized health insurance through the mobile platform-M-TIBA-developed by PAF, and it seeks to improve health knowledge and behavior through community health volunteers (CHVs) who are trained using the LEAP tool-AMREF's mHealth platform. The findings will inform stakeholders to formulate better strategies to ensure access to Universal Health Coverage in general, and for a highly vulnerable segment of the population in particular, including low-income mothers and their children. Registered with Protocol Registration and Results System (protocol ID: AfricanPHRC; trial ID: NCT04068571 : AEARCTR-0006089 ; date: 29 August 2019) and The American Economic Association's registry for randomized controlled trials (trial ID: AEARCTR-0006089; date: 26 June 2020).


Second-generation integrated genetic linkage/radiation hybrid maps of the domestic cat (Felis catus).
We report construction of second-generation integrated genetic linkage and radiation hybrid (RH) maps in the domestic cat (Felis catus) that exhibit a high level of marker concordance and provide near-full genome coverage. A total of 864 markers, including 585 coding loci (type I markers) and 279 polymorphic microsatellite loci (type II markers), are now mapped in the cat genome. We generated the genetic linkage map utilizing a multigeneration interspecies backcross pedigree between the domestic cat and the Asian leopard cat (Prionailurus bengalensis). Eighty-one type I markers were integrated with 247 type II markers from a first-generation map to generate a map of 328 loci (320 autosomal and 8 X-linked) distributed in 47 linkage groups, with an average intermarker spacing of 8 cM. Genome coverage spans approximately 2,650 cM, allowing an estimate for the genetic length of the sex-averaged map as 3,300 cM. The 834-locus second-generation domestic cat RH map was generated from the incorporation of 579 type I and 255 type II loci. Type I markers were added using targeted selection to cover either genomic regions underrepresented in the first-generation map or to refine breakpoints in human/feline synteny. The integrated linkage and RH maps reveal approximately 110 conserved segments ordered between the human and feline genomes, and provide extensive anchored reference marker homologues that connect to the more gene dense human and mouse sequence maps, suitable for positional cloning applications.


Impact of antimicrobial stewardship by infection control team in a Japanese teaching hospital.
The objective of this study is to investigate an effect on the antimicrobial appropriate use of the antimicrobial stewardship. We investigated the consumption of injectable antimicrobials from 2001 to 2007 and the administration period of specific antimicrobials (carbapenems, fourth-generation cephalosporins, anti-methicillin-resistant Staphylococcus aureus (MRSA) agents) in the individual patient. Since September 2004, the infection control team at Osaka University Hospital has been promoting appropriate use of antimicrobials through consultation, education, and weekly surveillance of specific antimicrobial usage. We obtained the amount of all antimicrobial injections as titer from the medical information database of the electronic medical chart system retrospectively. Antimicrobial use densities (AUD) were evaluated by measuring the number of doses administered/1000 patient-days. Although the number of inpatient admissions and operations increased 1.53- and 1.39-fold, respectively, in the seven years from 2001 to 2007, the expenditure on specific antimicrobials decreased markedly with AUD of specific antimicrobials decreasing from 39.6 to 29.2. The percentage of inpatients receiving specific antimicrobials decreased from 19.8% to 9.8%, and the ratio of the number of inpatients administered a specific antimicrobial within seven days to the number of inpatients administered each specific antimicrobial increased to over 60%. This led to reduction in the total expenditure of antimicrobials by about 100 million yen annually. The incidence of hospital-associated MRSA (HA-MRSA) infection decreased from 0.93% (2003) to 0.68% (2007). We can reduce the expenditure of antimicrobials without increasing incidence of the HA-MRSA by antimicrobial stewardship, and we think that appropriate use of antimicrobials is achieved progressively.


Lifelong exposures and the potential for stroke prevention: the contribution of cigarette smoking, exercise, and body fat.
To examine the potential for stroke prevention by avoidance of hazards related to lifestyle. Assessment of the lifelong contribution of both individual and combined exposures was a particular feature of the study. An estimate was sought of the proportion (population attributable risk fraction) of strokes likely to be caused by one or a combination of cigarette smoking, lack of exercise, and obesity. Case-control study. Eleven general practices in west Birmingham. Altogether 125 men and women who had just had their first stroke and were aged 35-74 and 198 controls frequency matched for age and sex recruited over 24 months during 1988-90. The hazards of cigarette smoking for stroke were confirmed and noted to persist for one to two decades after stopping smoking. Cigarette smoking was estimated to have caused 49% (95% confidence level 22, 67%) of the strokes in this population with roughly equal contributions from current and former smoking. Combinations of cigarette smoking (current and former) with lack of exercise or previous obesity apparently caused 62% and 72% of the strokes respectively. If cigarette smoking, lack of exercise and obesity were all avoided, 79% (32, 94%) of the strokes could potentially have been prevented. No stroke patient reported a combination of never smoking, taking regular exercise aged 15 to 25, and avoidance of overweight (body mass index > 25 kg/m2). Taken together, the combination of cigarette smoking, excessive body fat, and lack of exercise accounted for a major proportion of stroke cases in the population studied. It appears that these easily identifiable factors related to lifestyle are a major and possibly predominant cause of stroke, at least until the age of 75.


Co-Processed Excipients for Dispersible Tablets-Part 1: Manufacturability.
Co-processed excipients may enhance functionality and reduce drawbacks of traditional excipients for the manufacture of tablets on a commercial scale. The following study aimed to characterise a range of co-processed excipients that may prove suitable for dispersible tablet formulations prepared by direct compression. Co-processed excipients were lubricated and compressed into 10.5-mm convex tablets using a Phoenix compaction simulator. Compression profiles were generated by varying the compression force applied to the formulation and the prepared tablets were characterised for hardness, friability, disintegration and fineness of dispersion. Our data indicates that CombiLac, F-Melt type C and SmartEx QD100 were the top 3 most suitable out of 16 co-processed excipients under the conditions evaluated. They exhibited good flow properties (Carr's index ˂ 20), excellent tabletability (tensile strength > 3.0 MPa at 0.85 solid fraction), very low friability (< 1% after 15 min), rapid disintegration times (27-49 s) and produced dispersions of ideal fineness (< 250 μm). Other co-processed excipients (including F-Melt type M, Ludiflash, MicroceLac, Pharmaburst 500 and Avicel HFE-102) may be appropriate for dispersible tablets produced by direct compression providing the identified disintegration and dispersion risks were mitigated prior to commercialisation. This indicates that robust dispersible tablets which disintegrate rapidly could be manufactured from a range of co-processed excipients.


Water splitting on semiconductor catalysts under visible-light irradiation.
Sustainable hydrogen production is a key target for the development of alternative, future energy systems that will provide a clean and affordable energy supply. The Sun is a source of silent and precious energy that is distributed fairly all over the Earth daily. However, its tremendous potential as a clean, safe, and economical energy source cannot be exploited unless the energy is accumulated or converted into more useful forms. The conversion of solar energy into hydrogen via the water-splitting process, assisted by photo-semiconductor catalysts, is one of the most promising technologies for the future because large quantities of hydrogen can potentially be generated in a clean and sustainable manner. This Minireview provides an overview of the principles, approaches, and research progress on solar hydrogen production via the water-splitting reaction on photo-semiconductor catalysts. It presents a survey of the advances made over the last decades in the development of catalysts for photochemical water splitting under visible-light irradiation. The Minireview also analyzes the energy requirements and main factors that determine the activity of photocatalysts in the conversion of water into hydrogen and oxygen using sunlight. Remarkable progress has been made since the pioneering work by Fujishima and Honda in 1972, but he development of photocatalysts with improved efficiencies for hydrogen production from water using solar energy still faces major challenges. Research strategies and approaches adopted in the search for active and efficient photocatalysts, for example through new materials and synthesis methods, are presented and analyzed.


Relaxation of surface tension in the free-surface boundary layer of simple Lennard-Jones liquids.
In this paper we use molecular dynamics to answer a classical question: how does the surface tension on a liquid/gas interface appear? After defining surface tension from the first principles and performing several consistency checks, we perform a dynamic experiment with a single simple liquid nanodroplet. At time zero, we remove all molecules of the interfacial layer, creating a fresh bare interface with the bulk arrangement of molecules. After that the system evolves towards equilibrium, and the expected surface tension is re-established. We found that the system relaxation consists of three distinct stages. First, the mechanical balance is quickly re-established. During this process the notion of surface tension is meaningless. In the second stage, the surface tension equilibrates, and the density profile broadens to a value which we call "intrinsic" interfacial width. During the third stage, the density profile continues to broaden due to capillary wave excitations, which does not however affect the surface tension. We have observed this scenario for monatomic Lennard-Jones (LJ) liquid as well as for binary LJ mixtures at different temperatures, monitoring a wide range of physical observables.