Molecular epidemiologic techniques in analysis of epidemic and endemic Shigella dysenteriae type 1 strains.
During 1988 the number of Shigella dysenteriae type 1 infections reported in the United States increased fivefold. To determine if recent isolates from Mexico were related to those that caused epidemics of dysentery worldwide, Southern hybridization analysis was done with Shiga toxin and ribosomal RNA gene probes. Western hemisphere and Eastern Hemisphere strains differed by the size of a single EcoRI fragment carrying the Shiga toxin genes. Three ribosomal DNA (rDNA) patterns were observed, which correlated with the strain's continental origin for 81 of 83 isolates tested. Together the Shiga toxin and rDNA probe results indicated that recent Mexican isolates were chromosomally similar to earlier Central American isolates and distinct from Asian and African strains. This suggests there has been no significant exchange of organisms between continents in recent decades and that the 1988 outbreak in Mexico was caused by strains present in Central America since at least 1962.


Simulation of tuning graphene plasmonic behaviors by ferroelectric domains for self-driven infrared photodetector applications.
We demonstrate a tunable longwave infrared photodetector with ultra-high sensitivity based on graphene surface plasmon polaritons controlled by ferroelectric domains. The simulated results show that the photodetector shows a tunable absorption peak, modulated by periodically polarized ferroelectric domains at the nanoscale, with an ultra-high responsivity up to 7.62 × 106 A W-1 and a detectivity of ∼6.24 × 1013 Jones (Jones = cm Hz1/2 W-1) in the wavelengths ranging from 5 to 20 μm at room temperature. The potential mechanism for the prominent performances of the proposed photodetector can be attributed to the highly confined graphene surface plasmons excited by the local electrical field across the interface of the graphene and ferroelectric layer resonant to the incident wavelength, which could be easily controlled by the features of the ferroelectric domains. Compared with the silicon-based graphene plasmonic photodetector using a complex process of micro-nano fabrication, the proposed photodetector provides the advantages of a more convenient and controllable technique without the need for patterning graphene, and lower energy consumption due to the non-volatile properties of the ferroelectrics without an additional contact electrode. The tunable spectral response and the ultra-high responsivity make the graphene plasmonic photodetector tuned by the ferroelectric domains promising in practical applications of micro-spectrometers and other light sensing devices.


Complement: a critical test of its biological importance.
The biological activities of the more than 30 proteins that comprise the complement system have been elucidated in parallel lines of investigation that resulted in the purification of the proteins and studies of their function in vitro. Twenty years ago, the first complement cDNA clones were generated. Subsequently the structure and chromosomal localization of the complement genes and the primary sequences of their gene products were revealed. For some, even their higher order structure was solved. This work, coupled with studies of complement gene expression, biosynthesis, post-synthetic processing and secretion, contributed to an analysis of the relatively rare naturally occurring genetic deficiencies of complement proteins discovered fortuitously in humans sand experimental animals. Not until the past 5 years, with the application of methods for manipulating genes in vivo (targeted deletion and overexpression), has it been possible to definitively assign specific functions to complement proteins and to assess their importance in the intact organism. These relatively recent studies have confirmed the in vitro work or revealed unexpected roles for complement effector and regulatory proteins in host defenses, specific immunity, immunopathology, metabolism and reproductive biology This work is reviewed and the implications for understanding human diseases and the design of novel pharmaceutical agents are discussed. The promise of this line of investigation is certain but the context imposed by gender, developmental stage, other genes and environment must be taken into account before the practical implications of this deeper understanding of complement biology are fully realized.


Prevalence of infection with herpes simplex virus types 1 and 2 in Australia: a nationwide population based survey.
Studies demonstrating previous herpes simplex virus (HSV) type 2 infection as a risk factor for HIV transmission, and the development of a HSV vaccine candidate, have emphasised the need for worldwide population based studies of HSV seroprevalence. The only nationwide seroprevalence studies have been conducted in the United States. An Australia-wide, population based study of HSV-1 and HSV-2 seroprevalence was conducted, using serum and sociodemographic data collected between 1999-2000, for a representative study of risk factors for diabetes in over 11 000 adults. A stratified random sample of 4000 was tested for HSV-2 and 1000 for HSV-1, with sampling and weighting for various demographic factors. Seroprevalence of HSV-2 in Australian adults was 12%. Prevalence in women (16%) was twice that in men (8%). Rural populations had a lower prevalence (9%) than metropolitan (13%), and Indigenous had a higher prevalence (18%) than the non-Indigenous populations (12%). The seroprevalence of HSV-1 was 76% with significant differences by age group, sex and Indigenous status. These are the first nationwide data to compare with US studies. HSV-2 infection is less common in Australia than the United States, and this will allow planning for combating HIV transmission in high prevalence populations in northern Australia. In addition, the high HSV-1 seroprevalence will be important for future deployment of genital herpes vaccines.


A Retrospective Study of Letrozole Treatment Prior to Human Chorionic Gonadotropin in Women with Polycystic Ovary Syndrome Undergoing In Vitro Fertilization at Risk of Ovarian Hyperstimulation Syndrome.
BACKGROUND Women with polycystic ovary syndrome (PCOS) undergoing in vitro fertilization (IVF) are given letrozole before a trigger injection of human chorionic gonadotropin (hCG) to lower estrogen (E2) levels, but can experience ovarian hyperstimulation syndrome (OHSS). The aim of this study was to evaluate the effect of oral letrozole, prior to administration of hCG, on the outcome of IVF and development of OHSS. MATERIAL AND METHODS Retrospective clinical review included 181 cases of women with PCOS who underwent IVF cycles with intracytoplasmic sperm injection (ICSI) and embryo transfer (ET) (IVF/ICSI-ET). The day before the use of hCG, cases were divided into a letrozole-treated group (N=78) and a non-letrozole group (N=103). An oral dose of 2.5 mg qd of letrozole was given when the peak level of E2 was ≥4000 pg/ml during ovarian stimulation and ceased before the day of egg retrieval. RESULTS The letrozole-treated group had a significant increase in the number of retrieved oocytes, viable embryos, and fresh ET rate (P>0.05); peak levels of E2, and E2 levels on the day of the egg retrieval, were significantly higher, and the fertilization rate was significantly lower (P<0.001). No significant differences were found in the rates of pregnancy, abortion, or ectopic pregnancy between the two groups (P>0.05). The incidence OHSS was lower in the letrozole-treated group, but this difference did not reach statistical significance (P>0.05). CONCLUSIONS Women with PCOS who underwent IVF, oral treatment with letrozole a day prior to treatment with hCG lowered E2 levels, but did not significantly reduce the incidence of OHSS.


Modulation of Huh7.5 spheroid formation and functionality using modified PEG-based hydrogels of different stiffness.
Physical cues, such as cell microenvironment stiffness, are known to be important factors in modulating cellular behaviors such as differentiation, viability, and proliferation. Apart from being able to trigger these effects, mechanical stiffness tuning is a very convenient approach that could be implemented readily into smart scaffold designs. In this study, fibrinogen-modified poly(ethylene glycol)-diacrylate (PEG-DA) based hydrogels with tunable mechanical properties were synthesized and applied to control the spheroid formation and liver-like function of encapsulated Huh7.5 cells in an engineered, three-dimensional liver tissue model. By controlling hydrogel stiffness (0.1-6 kPa) as a cue for mechanotransduction representing different stiffness of a normal liver and a diseased cirrhotic liver, spheroids ranging from 50 to 200 μm were formed over a three week time-span. Hydrogels with better compliance (i.e. lower stiffness) promoted formation of larger spheroids. The highest rates of cell proliferation, albumin secretion, and CYP450 expression were all observed for spheroids in less stiff hydrogels like a normal liver in a healthy state. We also identified that the hydrogel modification by incorporation of PEGylated-fibrinogen within the hydrogel matrix enhanced cell survival and functionality possibly owing to more binding of autocrine fibronectin. Taken together, our findings establish guidelines to control the formation of Huh7.5 cell spheroids in modified PEGDA based hydrogels. These spheroids may serve as models for applications such as screening of pharmacological drug candidates.


POLYOMA VIRUS GENETIC MATERIAL IN A VIRUS-FREE POLYOMA-INDUCED TUMOR.
The DNA-agar technique for homology studies was used to investigate of the viral genetic material. Complemetary found between the polyoma DNA and the DNA of several mammalian species. The increased complementarity of the polyoma DNA to the DNA of polyoma-induced tumor reflects an increased frequency of common poly-nucleotide sequences in the tumor DNA.


Subcloning the RBL-2H3 mucosal mast cell line reduces Ca2+ response heterogeneity at the single-cell level.
Ca2+ imaging experiments have revealed that for a wide variety of cell types, including RBL-2H3 mucosal mast cells, there are considerable cell-to-cell differences of the Ca2+ responses of individual cells. This heterogeneity is evident in both the shape and latency of the responses. Mast cells within a single microscopic field of view, which have experienced identical culture conditions and experimental preparation, display a wide variety of responses upon antigen stimulation. We have subcloned the RBL-2H3 mucosal mast cell line to test the hypothesis that genetic heterogeneity within the population is the cause of the Ca2+ response heterogeneity. We found that cell-to-cell variability was significantly reduced in four of five clonal lines. The response heterogeneity remaining within the clones was not an experimental artifact caused by differences in the amount of fura-2 loaded by individual cells. Factors other than genetic heterogeneity must partly account for Ca2+ response heterogeneity. It is possible that the complex shapes and variability of the Ca2+ responses are reflections of the fact that there are multiple factors underlying the Ca2-response to antigen stimulation. Small differences from cell to cell in one or more of these factors could be a cause of the remaining Ca2+ response heterogeneity.


Comparison of smoking-related DNA methylation between newborns from prenatal exposure and adults from personal smoking.
Aim: Cigarette smoking influences DNA methylation genome wide, in newborns from pregnancy exposure and in adults from personal smoking. Whether a unique methylation signature exists for in utero exposure in newborns is unknown. Materials & methods: We separately meta-analyzed newborn blood DNA methylation (assessed using Illumina450k Beadchip), in relation to sustained maternal smoking during pregnancy (9 cohorts, 5648 newborns, 897 exposed) and adult blood methylation and personal smoking (16 cohorts, 15907 participants, 2433 current smokers). Results & conclusion: Comparing meta-analyses, we identified numerous signatures specific to newborns along with many shared between newborns and adults. Unique smoking-associated genes in newborns were enriched in xenobiotic metabolism pathways. Our findings may provide insights into specific health impacts of prenatal exposure on offspring.


The Perceived Social Context Modulates Rule Learning in Autism.
This study examines how the awareness of social situation affects rule learning in children with autism spectrum disorders (ASD) using computer-based distrust and deception games. Twenty-eight 4- to 7-year-old children with ASD and 28 age- and IQ-matched typically developing (TD) peers learned the distrusting and deceptive rules in a non-social condition, in which they were playing with a computer, or a social condition with another person pretending to interact via a computer. Results showed intact rule-learning ability in the ASDs in the non-social condition, but poorer overall performance and slower learning process than TD children when they thought that they interacted with a human opponent. Rule learning in ASD was affected by their beliefs about the social context.


[Expert consensus on microbiome sequencing and analysis].
In the past ten years, the research and application of microbiome has continued to increase. The microbiome has gradually become the research focus in the fields of life science, environmental science, and medicine. Meanwhile, many countries and organizations around the world are launching their own microbiome projects and conducting a multi-faceted layout, striving to gain a strategic position in this promising field. In addition, whether it is scientific research or industrial applications, there has been a climax of research and a wave of investment and financing, accordingly, products and services related to the microbiome are constantly emerging. However, due to the rapid development of microbiome sequencing and analysis related technologies and methods, the research and application from various countries have not yet unified on the standards of technology, programs, and data. Domestic industry participants also have insufficient understanding of the microbiome. New methods, technologies, and theories have not yet been fully accepted and used. In addition, some of the existing standards and guidelines are too general with poor practicality. This not only causes obstacles in the integration of scientific research data and waste of resources, but also gives related companies unfair competition opportunity. More importantly, China still lacks national standards related to the microbiome, and the national microbiome project is still in the process of preparation. In this context, the experts and practitioners of the microbiome worked together and developed the consensus of experts. It can not only guide domestic scientific research and industrial institutions to regulate the production, learning and research of the microbiome, the application can also provide reference technical basis for the relevant national functional departments, protect the scale and standardized corporate company's interests, strengthen industry self-discipline, avoid unregulated enterprises from disrupting the market, and ultimately promote the benign development of microbiome-related industries.


Fluorescence polarization immunoassay for theophylline modified for use with dried blood spots on filter paper.
We used dried blood spots successfully as alternative specimens for quantifying concentrations of theophylline in the circulation by a modified fluorescence polarization immunoassay (FPIA) with the Abbott TDx instrument. The method described is simple, rapid, and acceptably precise. More importantly, it can provide results comparable with those of the conventional serum assay. Results for 64 pairs of dried blood spots (y) and serum (x) specimens analyzed by the respective FPIA methods yielded the following regression parameters: y = 0.94x + 0.71, r = 0.988, and Sxy = 0.92. A major advantage of FPIA is that it requires only basic laboratory skills. When coupled with the use of dried blood spots, this system can be effective in remote theophylline monitoring, particularly suited for domiciliary care.


Induction of labor by endocervical application of prostaglandins and intravenous infusion of oxytocin in postterm pregnancy.
The study compares two contemporary modes of labor induction: intravenous application of Syntocinon and endocervical application of prostaglandins and examines their efficacy and safety. Ninety women were divided according to the degree of cervical maturation (shown by Bishop score) into two groups. In group I there were 60 women with unripe cervix (Bishop score < or = 5) and induction was performed by endocervical application of 0.5 mg Dinoprostone, and in group II there were 30 women with ripe cervix (Bishop score < or = 6) in which the induction was performed by intravenous application of Syntocinon (500 ml of 5% glycose with 10 iu of Syntocinon). After three hours the initially significantly different Bishop score values were equalized and it was possible to correlate the duration of the labor (Group I 545 min, Group II 338 min). The correlation of initial Bishop score values and the total duration of the labor was negative and high in both groups. All the neonates from both groups were in good condition and no serious complication was noted. Both methods of labor induction appear similarly effective and safe both for the fetus and the mother.


Merits of sponge-like PLGA microspheres as long-acting injectables of hydrophobic drug.
Our study was initiated to challenge the preconception that nonporous PLGA microspheres with compact matrices should be used to develop long-acting depot injectables of hydrophobic drugs. A simple, new oil-in-water emulsion technique was utilized to produce porous PLGA microspheres with a sponge-like skeleton. Then, their applicability to developing sustained-release depots of hydrophobic drugs was explored in this study. As control, nonporous microspheres with a compact matrix were produced following a typical solvent evaporation process. Both microsphere manufacturing processes used non-halogenated isopropyl formate and progesterone as a dispersed solvent and a model hydrophobic drug, respectively. Various attempts were made to evaluate critical quality attributes of the porous microspheres and the nonporous ones. Surprisingly, the former displayed interesting features from the viewpoints of manufacturability and microsphere quality. For example, the spongy microspheres improved drug encapsulation efficiency and particle size uniformity, inhibited drug crystallization during microencapsulation, and minimized the residual solvent content in microspheres. Furthermore, the porous microspheres provided continual drug release kinetics without a lag time and much faster drug release than the non-porous microspheres did. In summary, the porous and sponge-like PLGA microspheres might find lucrative applications in developing sustained release dosage forms of hydrophobic drugs.


Management of stable chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease (COPD) is a common condition. There are an estimated 3 million cases in the UK. Of these, 2 million have not got a formal diagnosis. Community nurses meet patients with COPD frequently, although COPD may not be the primary reason for the encounter, or the COPD may be present but undiagnosed. The number of patients with COPD is believed to be increasing and, with increased awareness of the condition and an emphasis on improving diagnosis, the number of cases is expected to rise. Community nurses are well placed to raise concerns that a patient in their care may have undiagnosed COPD; if the condition is subsequently diagnosed and appropriate treatment is given, outcomes will improve for that individual. Community nurses can also support patients and their families to manage the condition through all stages of the disease trajectory, from diagnosis to the end-of-life phase.


Arbutus unedo leaf extracts as potential dairy preservatives: case study on quark cheese.
The plant kingdom is an endless source of molecules that can be applied in almost all realms of society. The food industry has profited from the use of plants and their derived materials for many decades. Recently, the food industry has been looking into plants to find different ways of either preserving, coloring or sweetening foods. In this work, leaf extracts of Arbutus unedo L. obtained by dynamic maceration and ultrasound assisted extraction with prior optimization of their extraction conditions through the response-surface methodology, were incorporated in quark cheese as natural preservatives and analyzed over 8 days of shelf-life. Both extracts showed antioxidant activity with no toxicity towards primary cell lines at the maximum tested concentration, as well as antibacterial activity, especially against Gram-positive strains. After their incorporation in quark cheese, no significant changes were observed in the nutritional profile and physical traits of the quark cheeses, while the microbial load was highly reduced in the cheese, especially using the extracts obtained from dynamic maceration. Thus, leaf extracts of A. unedo can be promising candidates for use in the food industry as natural preservatives.


CBirTox is a selective antigen-specific agonist of the Treg-IgA-microbiota homeostatic pathway.
Cultivating an environment of mutualism between host cells and the microbiota is vital, and dysregulation of this relationship is associated with multiple immune disorders including metabolic and skin diseases, asthma, allergy, and Inflammatory Bowel Disease (IBD). One prominent mechanism for maintaining homeostasis is the protective regulatory T cell (Treg)- Immunoglobulin A (IgA) pathway toward microbiota antigens, in which Tregs maintain homeostasis and provide critical survival factors to IgA+ B cells. In order to amplify the Treg-IgA pathway, we have generated a fusion protein, CBirTox, comprised of a portion of the carboxy terminus of CBir1, a microbiota flagellin, genetically coupled to Cholera Toxin B subunit (CTB) via the A2 linker of CT. Both dendritic cells (DCs) and B cells pulsed with CBirTox selectively induced functional CD4+Foxp3+ Tregs in vitro, and CBirTox augmented CD4+Foxp3+ cell numbers in vivo. The induced Foxp3 expression was independent of retinoic acid (RA) signaling but was inhibited by neutralization of TGF-β. CBirTox treatment of B cells downregulated mammalian target of rapamycin (mTOR) signaling. Furthermore, CBirTox-pulsed DCs induced substantial production of IgA from naïve B cells. Collectively these data demonstrate that CBirTox represents a novel approach to bolstering the Treg-IgA pathway at the host-microbiota interface.


Man-made mineral fibers and health. Answered and unanswered questions.
An overall assessment of the epidemiologic evidence from 23 published studies on workers' health in the industry producing man made mineral fibers (MMMF) (21 studies) and in the user industry (2 studies) is presented. Three major studies recently published, one cross-sectional and two of the historical cohort type, conducted in the producer industry, have been singled out for closer examination and discussion. The combined evidence from the epidemiologic studies indicates that causal associations between MMMF occupational exposure, as it occurred in past decades, and lung cancer and chronic respiratory diseases cannot be excluded, neither does it offer clear support for such associations. Experimental data indicate clearly that a fibrogenic effect can be obtained by the intratracheal administration of MMMF and a carcinogenic effect by the intratracheal, intrapleural, and intraperitoneal administration of MMMF, while no appreciably fibrogenic nor carcinogenic effects have been detected in inhalation experiments. While it can be stated that no long-term pathological effects have been observed in MMMF workers in the first 20 years or so after first employment, the key scientific issue of whether MMMF are fibrogenic and/or carcinogenic in man when inhaled remains still open.


Self-reported recent testing and diagnosis for sexually transmitted infections among regular ecstasy users in Australia, 2011-2012.
Previous studies suggest that people who consume alcohol and drugs are at increased risk of sexually transmitted infections (STI). We examined the prevalence and predictors of self-reported STI testing and diagnosis among self-reported regular ecstasy users (REU). Nine hundred and fifty-five REUs from the 2011 and 2012 Ecstasy and Related Drugs Reporting System were included in the analysis. Bivariate and multivariate Poisson regression were used to identify predictors of recent STI testing, and logistic regression was used to identify predictors of recent STI diagnosis. Forty-four per cent of REUs reported having a recent STI test, and 5% reported a recent diagnosis. Of the 421 REUs who reported a recent test, 10% reported a recent STI diagnosis. In multivariate analysis, REUs were more likely to report a recent STI test if they were female versus male [risk ratio (RR) = 1.56; 95% confidence interval (CI) = 1.36-1.80], aged 25-29 years versus 16-19 years (RR = 1.34; 95% CI = 1.05-1.72), or reported ≥2 casual sex partners versus no casual partners (RR = 1.48; 95% CI = 1.01-2.14). REUs reporting cannabis use in the past six months were 0.78 times less likely to report a recent STI test (95% CI = 0.66-0.94). There were no significant predictors associated with STI diagnosis. Encouragingly, REUs who reported having multiple casual partners in the past six months were more likely to report a recent test. However, younger REUs aged 16-19 years were least likely to test, suggesting health promotion needs to be directed to this age group. Further research is required to explain the lower testing among cannabis users.


A qualitative study of women's feelings about future childbirth: dread and delight.
There is extensive knowledge about expectations of and thoughts about childbirth among women who have not given birth. When it comes to women who have given birth to at least 1 child, on the other hand, knowledge about their expectations for a future birth is limited. The purpose of this study is thus to describe the emotions of this group concerning future childbirth. Participants were 908 women in Sweden who had given birth to at least 1 child. This study is based on responses to the following request in the questionnaire sent out to women 4 to 7 years after they had given birth vaginally: "Please describe your feelings when you think about giving birth in the future." One-third of the women responded that they were mostly frightened of future childbirth, while the remaining two-thirds had mostly positive feelings. The qualitative analysis resulted in 3 categories and 8 subcategories and an overall theme: a mixture of dread and delight. Even with negative feelings/fears about future childbirth, many women want to give birth to more children. Despite experiences of severe pain or complications during a previous birth, many women nonetheless looked forward to future childbirth, primarily since they were motivated by having another child and encouraged by having been given good support by the midwife.


SVachra: a tool to identify genomic structural variation in mate pair sequencing data containing inward and outward facing reads.
Characterization of genomic structural variation (SV) is essential to expanding the research and clinical applications of genome sequencing. Reliance upon short DNA fragment paired end sequencing has yielded a wealth of single nucleotide variants and internal sequencing read insertions-deletions, at the cost of limited SV detection. Multi-kilobase DNA fragment mate pair sequencing has supplemented the void in SV detection, but introduced new analytic challenges requiring SV detection tools specifically designed for mate pair sequencing data. Here, we introduce SVachra - Structural Variation Assessment of CHRomosomal Aberrations, a breakpoint calling program that identifies large insertions-deletions, inversions, inter- and intra-chromosomal translocations utilizing both inward and outward facing read types generated by mate pair sequencing. We demonstrate SVachra's utility by executing the program on large-insert (Illumina Nextera) mate pair sequencing data from the personal genome of a single subject (HS1011). An additional data set of long-read (Pacific BioSciences RSII) was also generated to validate SV calls from SVachra and other comparison SV calling programs. SVachra exhibited the highest validation rate and reported the widest distribution of SV types and size ranges when compared to other SV callers. SVachra is a highly specific breakpoint calling program that exhibits a more unbiased SV detection methodology than other callers.


[Study on the stability of chicken egg yolk immunoglobulin (IgY) modified with mPEG].
The objective of the present paper was to study the effect of monomethoxypolyethlene glycol (mPEG) modification on the stability of chicken IgY and compare the stability of the modification products by Fourier transform infrared spectroscopy (FTIR), CD spectrooscopy and fluorescence spectroscopy. NHS-mPEG was used to modify IgY after mPEG was activated with N-hydroxysuccinimide (NHS). The optimal reaction condition for modification was 1:10 molar rate of IgY to mPEG at pH 7, reaction for 1 h, and the product was obtained with modification rate of 20.56% and activity reservation of 87. 62%. In addition, the thermal and pH stability of IgY and mPEG-IgY was compared by spectroscopic methods. The results showed that the alpha-helix, beta-sheet, beta-turn, and random content of IgY changed from 14.5%, 42.1%, 6.2% and 37.2% to 1.6%, 55.25%, 5.8% and 37.5%, while mPEG changed from 12.9%, 42.7%, 6.3% and 38. 1% to 3.1%, 50.5%, 7.2% and 39.2%, respectively, after incubating for 120 min at 70 degrees C. For the treatment with acid-base, similarly, the structure changes of mPEG-IgY were smaller than IgY. Thus, it is indicated that IgY modified by mPEG had greater stable properties.


[Comparative morphological and insulin-producing characteristics of cellular cultures of the islands of Langerhans in experimental animals].
The pancreas from cattle and pigs (5--6-month-old), newborn rats, and guinea pits (1--1.5-month-old) was subjected to combined with trypsin and Wersen solutions and collagenase. Morphological changes and the insulin-producing activity of the primary cultures of the islet cells from these pancreas were studied. B- and A-cells were identified histologically. Concentration of insulin produced in the culture medium was determined immunoradiologically. The culture studied proved to preserve the morphological and functional differentiation for 4 to 5 weeks from the growth onset; their morphological changes during growth were similar. The level of the insulin produced depended on the cell composition and functional state of the culture. Increased glucse concentration (300 mg %) stimulated insulin secretion.


Maternal antenatal anxiety, postnatal stroking and emotional problems in children: outcomes predicted from pre- and postnatal programming hypotheses.
Mothers' self-reported stroking of their infants over the first weeks of life modifies the association between prenatal depression and physiological and emotional reactivity at 7 months, consistent with animal studies of the effects of tactile stimulation. We now investigate whether the effects of maternal stroking persist to 2.5 years. Given animal and human evidence for sex differences in the effects of prenatal stress we compare associations in boys and girls. From a general population sample of 1233 first-time mothers recruited at 20 weeks gestation we drew a random sample of 316 for assessment at 32 weeks, stratified by reported inter-partner psychological abuse, a risk indicator for child development. Of these mothers, 243 reported at 5 and 9 weeks how often they stroked their infants, and completed the Child Behavior Checklist (CBCL) at 2.5 years post-delivery. There was a significant interaction between prenatal anxiety and maternal stroking in the prediction of CBCL internalizing (p = 0.001) and anxious/depressed scores (p < 0.001). The effects were stronger in females than males, and the three-way interaction prenatal anxiety × maternal stroking × sex of infant was significant for internalizing symptoms (p = 0.003). The interactions arose from an association between prenatal anxiety and internalizing symptoms only in the presence of low maternal stroking. The findings are consistent with stable epigenetic effects, many sex specific, reported in animal studies. While epigenetic mechanisms may be underlying the associations, it remains to be established whether stroking affects gene expression in humans.


The utility of solid-phase microextraction in evaluating polycyclic aromatic hydrocarbon bioavailability during habitat restoration with dredged material at moderately contaminated sites.
The over- or underprediction of risk in moderately contaminated sediments can have a large impact on the nature of applied management strategies given that concentrations border on being toxic or not toxic. Project managers should give significant consideration as to how moderate levels of contaminants in native sediments and dredged material used for restoration will impact recovery of habitat. Total solid-phase (Ctotal ) and porewater (Cfree ) polycyclic aromatic hydrocarbons (PAHs) were quantified in native sediments and dredged material to determine if the predictions of risk from Ctotal are consistent with those based on Cfree . The sediment matrix phase in which PAHs were quantified resulted in disparate conclusions regarding the predicted reduction in contamination following restoration. Total solid-phase PAH concentrations suggested a significant decrease following restoration, whereas little to no change was observed in measured Cfree . Risk metrics based on Ctotal gave inconclusive estimates for toxicity, whereas measured Cfree suggested toxicity is unlikely, a conclusion consistent with toxicity testing. The incorporation of black carbon (BC) into model estimates for Cfree gave predictions more consistent with measured Cfree , suggesting that geochemical conditions (especially BC) play an important part in predicting toxicity at moderately contaminated sites. In addition to the use of Cfree in toxicity evaluation, in-situ Cfree measurements provided a constraint on diffusive PAH loads from sediment relative to ongoing stream loads. If passive sampling had been employed during the sampling designs and site evaluations, the costs of toxicity testing would not have been incurred, given that Cfree suggested little to no toxicity. The results from the project highlight the benefits to be gained by moving beyond inconclusive, screening-level Ctotal metrics and implementing more sensitive and accurate Cfree metrics in assessments of risk in moderately contaminated sediments. Integr Environ Assess Manag 2018;14:212-223. © 2017 SETAC.


[The significance of the chordal apparatus of the heart in forming "innocent" murmurs (clinical echocardiographic research)].
Clinical and echocardiographic studies were carried out in 100 young men (mean age 18.0 +/- 3.0 years) with "harmless" murmur (HM). 20 young men (mean age 17.0 +/- 2.0 years) were examined as control. In these men, murmur could not be detected both at rest and after 15 squattings and the hyperventilation test. No relationship was discovered between the murmur intensity and gravity of heart hyperdynamia, although in persons with HM, the predominance of hyperdynamia could be observed. It is believed that the intensity of HM is due to the morphofunctional features of the cardiac structures. The chordal apparatus of the heart is viewed as one of them. In 37% of persons with HM, echocardiography revealed a phenomenon of the "fluttering" chorda, which lies in diastolic-systolic hypermobility of one of the commonly attached chordae of the mitral valve because of its excessive length and weak tonic tension. That phenomenon is usually associated with so-called Steele's murmur. It is concluded that via the phenomenon of the "fluttering" of the chorda of the mitral valve there may occur labile and, in some cases, of "musical" non-regurgitation systolic murmur in local dysfunction of the papillary muscles.


Point mutation in the MITF gene causing Waardenburg syndrome type II in a three-generation Indian family.
Waardenburg syndrome (WS) is an autosomal-dominant neural crest cell disorder phenotypically characterized by hearing impairment and disturbance of pigmentation. A presence of dystopia canthorum is indicative of WS type 1, caused by loss of function mutation in the PAX3 gene. In contrast, type 2 WS (WS2) is characterized by normally placed medial canthi and is genetically heterogeneous; mutations in MITF (microphthalmia associated transcription factor) associated with WS2 have been identified in some but not all affected families. Here, we report on a three-generation Indian family with a point mutation in the MITF gene causing WS2. This mutation, initially reported in a Northern European family, creates a stop codon in exon 7 and is predicted to result in a truncated protein lacking the HLH-Zip or Zip structure necessary for normal interaction with its target DNA motif. Comparison of the phenotype between the two families demonstrates a significant difference in pigmentary disturbance of the eye. This family, with the first documented case of two unrelated WS2 families harboring identical mutations, provides additional evidence for the importance of genetic background on the clinical phenotype.


Mitochondrial DNA variants in schizophrenia: association studies.
The frequency of three selected mitochondrial DNA variations was compared between cases with schizophrenia and two groups of unrelated controls: screened adults and neonates. The comparisons were conducted separately among Caucasians and African-Americans. No significant differences were detected, suggesting that the variants may not be associated with schizophrenia. Limitations of the study are discussed.


Visualization of spatial distribution of gamma-aminobutyric acid in eggplant (Solanum melongena) by matrix-assisted laser desorption/ionization imaging mass spectrometry.
We applied imaging mass spectrometry (IMS) to determine the spatial distribution of gamma-aminobutyric acid (GABA). We found that GABA had a specific localization in seeds. We also visualized various biomolecules as well as GABA with higher spatial resolution than in the previous report. Our work suggests that IMS might be a powerful tool for exploring functional food factors, investigating the specific distribution of nutrients in unused natural resources, and evaluating the quality of functional foods.


Genomic adaptation of Burkholderia anthina to glyphosate uncovers a novel herbicide resistance mechanism.
Glyphosate (GS) specifically inhibits the 5-enolpyruvyl-shikimate-3-phosphate (EPSP) synthase that converts phosphoenolpyruvate (PEP) and shikimate-3-phosphate to EPSP in the shikimate pathway of bacteria and other organisms. The inhibition of the EPSP synthase depletes the cell of the EPSP-derived aromatic amino acids as well as of folate and quinones. A variety of mechanisms (e.g., EPSP synthase modification) has been described that confer GS resistance to bacteria. Here, we show that the Burkholderia anthina strain DSM 16086 quickly evolves GS resistance by the acquisition of mutations in the ppsR gene. ppsR codes for the pyruvate/ortho-Pi dikinase PpsR that physically interacts and regulates the activity of the PEP synthetase PpsA. The mutational inactivation of ppsR causes an increase in the cellular PEP concentration, thereby abolishing the inhibition of the EPSP synthase by GS that competes with PEP for binding to the enzyme. Since the overexpression of the Escherichia coli ppsA gene in Bacillus subtilis and E. coli did not increase GS resistance in these organisms, the mutational inactivation of the ppsR gene resulting in PpsA overactivity is a GS resistance mechanism that is probably unique to B. anthina.


Microchimeric fetal cells are recruited to maternal kidney following injury and activate collagen type I transcription.
Fetal cells enter the maternal circulation from the early first trimester of pregnancy, where they persist in tissue decades later. We investigated in mice whether fetal microchimeric cells (FMCs) can be detected in maternal kidney, and whether they play a role in kidney homeostasis. FMCs were identified in vivo in two models: one an adaptive model following unilateral nephrectomy, the other an injury via unilateral renal ischaemia reperfusion. Both models were carried out in mothers that had been mated with transgenic mice expressing luciferase transgene under the control of collagen type I, and had given birth to either 1 or 3 litters. FMCs were detected by Y-probe fluorescent in situ hybridization (FISH) and bioluminescence, and the cell number quantified by real-time polymerase chain reaction. In the adaptive model, the remaining kidney showed more cells by all 3 parameters compared with the nephrectomized kidney, while ischaemia reperfusion resulted in higher levels of FMC participation in injured compared to contralateral kidneys. Bioluminescence showed that FMCs switch on collagen type I transcription implicating mesenchymal lineage cells. After injury, Y-probe in situ hydridization was found mainly in the tubular epithelial network. Finally, we compared FMCs with bone marrow cells and found similar dynamics but altered distribution within the kidney. We conclude that FMCs (1) are long-term sequelae of pregnancy and (2) are recruited to the kidney as a result of injury or adaptation, where they activate the transcriptional machinery of matrix proteins.


Cangrelor Bridge Therapy for Gastroduodenal Biopsy.
Dual antiplatelet therapy (DAPT) is the key for secondary prevention of acute coronary syndromes and percutaneous coronary intervention with stent placement. Premature discontinuation of DAPT can result in an increase in cardiac ischemic events and death. If early interruption of DAPT for urgent procedures or surgery is necessary, then ischemic and bleed risks must be balanced with bridging therapy. To date, no medications have a Food and Drug Administration indication for antiplatelet bridge therapy. We present a case of a woman with a history of gastrointestinal bleeding on DAPT for a drug-eluting stent who received cangrelor as bridge therapy prior to gastroduodenal biopsy.


Effects of acute and chronic denervation on human myotonia.
A 32-year-old man with myotonia congenita (Becker type) sustained multiple gunshot wounds. These produced a partial thoracic spinal cord injury and a severe sciatic nerve injury. Six days following the incident, clinical (percussion) and electrophysiologic (EMG) myotonia could be elicited in paretic leg muscles resulting both from the myelopathy and peripheral nerve disruption. Eight months later, the myotonia was no longer present in denervated muscles from the sciatic nerve injury, but was still noted in muscles with upper-motor neuron weakness from the myelopathy. Although myotonia is related principally to abnormalities in the muscle fiber itself, it appears that it is also dependent upon the structural integrity of the peripheral nerve supply to the muscle for myotonia to continue to occur. The findings in this patient suggest that myotonia may well have diminished and disappeared in muscles shortly after the nerves had undergone Wallerian degeneration. Myotonia does not recur if there is no significant reinnervation.


Understanding the Needs of Female Veterans.
This commentary attempts to frame the article, "Safer Housing for Homeless Women Veterans," in a wider context. It defines female veterans, homelessness, and military sexual trauma. This commentary also tackles a question that often confuses civilian providers regarding who has access to care at the Veterans Health Administration. It does not repeat in detail all of the recommendations in the article, but it advocates their broader use in shelters and transitional housing. Finally, I close with some thoughts about a new generation of young, homeless, female veterans who may have children and how to accommodate their needs.


What is the meaning of ANCA positivity in IgG4-related disease?
To evaluate the prevalence and meaning of antineutrophil cytoplasmic antibodies (ANCA) positivity in a cohort of IgG4-related disease (IgG4-RD). We identified patients with ANCA determination from a retrospective cohort of 69 patients with IgG4-RD. ANCA were measured by indirect immunofluorescence microscopy (IIF) and/or proteinase 3 (PR3)-ANCA and MPO-ANCA by ELISA. IIF patterns were classified as perinuclear (P-ANCA), cytoplasmic (C-ANCA) and atypical (X-ANCA). We compared the ANCA-positive vs the ANCA-negative IgG4-RD group. Out of 69 patients, 31 IgG4-RD patients had an ANCA determination. Four patients with concomitant systemic autoimmune diseases were excluded. We found positive ANCA by IIF in 14 (56%) of 25 patients tested. The most common IIF pattern was C-ANCA in eight (57.1%), followed by dual C-ANCA/X-ANCA in four (28.6%) and P-ANCA and dual C-ANCA/P-ANCA in one each (7.1%). Of the 20 patients with ANCA determination by both IIF and ELISA, four have positive ANCA by ELISA (three for MPO-ANCA and one for PR3-ANCA). Of the two patients with only ELISA determination, one was positive for MPO-ANCA. The prevalence of ANCA positivity by ELISA was 22.7% (5 out of 22 patients). ANCA was more frequent in the Mikulizc/systemic phenotype (42.9%) compared with other phenotypes (P = 0.04). ANCA-positive IgG4-RD patients had more frequently lymph node and kidney involvement, high IgG1 levels and erythrocyte sedimentation rate, and positive antinuclear antibodies. ANCA are found in a significant number of patients with IgG4-RD and differed from the ANCA-negative group in terms of clinical and serological features.


Oxidative damage to mitochondrial complex I due to peroxynitrite: identification of reactive tyrosines by mass spectrometry.
There is growing evidence that oxidative phosphorylation (OXPHOS) generates reactive oxygen and nitrogen species within mitochondria as unwanted byproducts that can damage OXPHOS enzymes with subsequent enhancement of free radical production. The accumulation of this oxidative damage to mitochondria in brain is thought to lead to neuronal cell death resulting in neurodegeneration. The predominant reactive nitrogen species in mitochondria are nitric oxide and peroxynitrite. Here we show that peroxynitrite reacts with mitochondrial membranes from bovine heart to significantly inhibit the activities of complexes I, II, and V (50-80%) but with less effect upon complex IV and no significant inhibition of complex III. Because inhibition of complex I activity has been a reported feature of Parkinson's disease, we undertook a detailed analysis of peroxynitrite-induced modifications to proteins from an enriched complex I preparation. Immunological and mass spectrometric approaches coupled with two-dimensional PAGE have been used to show that peroxynitrite modification resulting in a 3-nitrotyrosine signature is predominantly associated with the complex I subunits, 49-kDa subunit (NDUFS2), TYKY (NDUFS8), B17.2 (17.2-kDa differentiation associated protein), B15 (NDUFB4), and B14 (NDUFA6). Nitration sites and estimates of modification yields were deduced from MS/MS fragmentograms and extracted ion chromatograms, respectively, for the last three of these subunits as well as for two co-purifying proteins, the beta and the d subunits of the F1F0-ATP synthase. Subunits B15 (NDUFB4) and B14 (NDUFA6) contained the highest degree of nitration. The most reactive site in subunit B14 was Tyr122, while the most reactive region in B15 contained 3 closely spaced tyrosines Tyr46, Tyr50, and Tyr51. In addition, a site of oxidation of tryptophan was detected in subunit B17.2 adding to the number of post-translationally modified tryptophans we have detected in complex I subunits (Taylor, S. W., Fahy, E., Murray, J., Capaldi, R. A., and Ghosh, S. S. (2003) J. Biol. Chem. 278, 19587-19590). These sites of oxidation and nitration may be useful biomarkers for assessing oxidative stress in neurodegenerative disorders.


[Neurochemical mechanisms of a novel Alzheimer's disease therapeutics on improvement of cognition and depressive behavior].
Loss of cholinergic neurons and/or dysfunction of the glutamatergic system in the central nervous system cause learning impairment in experimental Alzheimer's (Alz) disease animals and Alz patients. Furthermore, the impaired cholinergic system is likely implicated in depressive behaviors in Alz patients. Neurogenesis persistently occurs in the forebrain subventricular zone (SVZ) and hippocampal subgranular zone (SGZ) in rodent and human brains. Notably, impaired neurogenesis in those regions is implicated not only in memory deficits but also in depressive behaviors. We have recently found that olfactory bulbectomized (OBX) mice reveal memory impairment and depressive behaviors. Using this attractive OBX mice model, we discovered a novel cognitive enhancer, spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one (ZSET1446/ST101), that is a new azaindolizinone derivative without inhibitory action on acetylcholine esterase (AChE). Interestingly, ZSET1446 improved learning and memory by potentiating nicotine-induced ACh release in the hippocampus of amyloid-beta infused rats. In addition, ZSET1446 restored OBX-induced cognitive deficits in mice. Furthermore, chronic ZSET1446 administration significantly rescues decreased neuronal precursor cell proliferation seen in the dentate gyrus of OBX mice. Consistent with enhanced neurogenesis, chronic ZSET1446 administration improved depressive behavior assessed using the tail suspension test in OBX mice. Protein kinase B (Akt) and extracellular signal-regulated kinase pathways likely mediate ZSET1446-induced neurogenesis. These results suggest that ZSET1446 action via stimulation of the cholinergic system elicits improvement of the depression and cognitive impairment observed in Alz disease patients.


Water replacement hypothesis in atomic details: effect of trehalose on the structure of single dehydrated POPC bilayers.
We present molecular dynamics (MD) simulations to study the plausibility of the water replacement hypothesis (WRH) from the viewpoint of structural chemistry. A total of 256 2-oleoyl-1-palmitoyl-sn-glycero-3-phosphocholine (POPC) lipids were modeled for 400 ns at 11.7 or 5.4 waters/lipid. To obtain a single dehydrated bilayer relevant to the WRH, simulations were performed in the NP(xy)h(z)T ensemble with h(z) > 8 nm, allowing interactions between lipids in the membrane plane and preventing interactions between neighboring membranes via periodic boundary conditions. This setup resulted in a stable single bilayer in (or near) the gel state. Trehalose caused a concentration-dependent increase of the area per lipid (APL) accompanied by fluidizing the bilayer core. This mechanism has been suggested by the WRH. However, dehydrated bilayers in the presence of trehalose were not structurally identical to fully hydrated bilayers. The headgroup vector was in a more parallel orientation in dehydrated bilayers with respect to the bilayer plane and maintained this orientation in the presence of trehalose in spite of APL increase. The total dipole potential changed sign in dehydrated bilayers and remained slightly positive in the presence of trehalose. The model of a dehydrated bilayer presented here allows the study of the mechanisms of membrane protection against desiccation by different compounds.


Both piston-like and rotational motions are present in bacterial chemoreceptor signaling.
Bacterial chemotaxis signaling is triggered by binding of chemo-effectors to the membrane-bound chemoreceptor dimers. Though much is known about the structure of the chemoreceptors, details of the receptor dynamics and their effects on signaling are still unclear. Here, by using molecular dynamics simulations and principle component analysis, we study the dynamics of the periplasmic domain of aspartate chemoreceptor Tar dimer and its conformational changes when binding to different ligands (attractant, antagonist, and two attractant molecules). We found two dominant components (modes) in the receptor dynamics: a relative rotation of the two Tar monomers and a piston-like up-and-down sliding movement of the α4 helix. These two modes are highly correlated. Binding of one attractant molecule to the Tar dimer induced both significant piston-like downward movements of the α4 helix and strong relative rotations of the two Tar monomers, while binding of an antagonist or the symmetric binding of two attractant molecules to a Tar dimer suppresses both modes. The anti-symmetric effects of the relative rotation mode also explained the negative cooperativity between the two binding pockets. Our results suggest a mechanism of coupled rotation and piston-like motion for bacterial chemoreceptor signaling.


Nitro-benzylideneoxymorphone, a bifunctional mu and delta opioid receptor ligand with high mu opioid receptor efficacy.
Introduction: There is a major societal need for analgesics with less tolerance, dependence, and abuse liability. Preclinical rodent studies suggest that bifunctional ligands with both mu (MOPr) and delta (DOPr) opioid peptide receptor activity may produce analgesia with reduced tolerance and other side effects. This study explores the structure-activity relationships (SAR) of our previously reported MOPr/DOPr lead, benzylideneoxymorphone (BOM) with C7-methylene-substituted analogs. Methods: Analogs were synthesized and tested in vitro for opioid receptor binding and efficacy. One compound, nitro-BOM (NBOM, 12) was evaluated for antinociceptive effects in the warm water tail withdrawal assay in C57BL/6 mice. Acute and chronic antinociception was determined, as was toxicologic effects on chronic administration. Molecular modeling experiments were performed using the Site Identification by Ligand Competitive Saturation (SILCS) method. Results: NBOM was found to be a potent MOPr agonist/DOPr partial agonist that produces high-efficacy antinociception. Antinociceptive tolerance was observed, as was weight loss; this toxicity was only observed with NBOM and not with BOM. Modeling supports the hypothesis that the increased MOPr efficacy of NBOM is due to the substituted benzylidene ring occupying a nonpolar region within the MOPr agonist state. Discussion: Though antinociceptive tolerance and non-specific toxicity was observed on repeated administration, NBOM provides an important new tool for understanding MOPr/DOPr pharmacology.


17(R),18(S)-epoxyeicosatetraenoic acid, a potent eicosapentaenoic acid (EPA) derived regulator of cardiomyocyte contraction: structure-activity relationships and stable analogues.
17(R),18(S)-epoxyeicosatetraenoic acid [17(R),18(S)-EETeTr], a cytochrome P450 epoxygenase metabolite of eicosapentaenoic acid (EPA), exerts negative chronotropic effects and protects neonatal rat cardiomyocytes against Ca(2+)-overload with EC(50) ≈ 1-2 nM. Structure-activity studies revealed that a cis-Δ(11,12)- or Δ(14,15)-olefin and a 17(R),18(S)-epoxide are minimal structural elements for antiarrhythmic activity whereas antagonist activity was often associated with the combination of a Δ(14,15)-olefin and a 17(S),18(R)-epoxide. Compared with natural material, the agonist and antagonist analogues are chemically and metabolically more robust and several show promise as templates for future development of clinical candidates.


[Functional morphology of the myocardium and carotid paraganglion of dogs during electrical stimulation of the carotid sinus nerve in experimental stenocardia].
Histochemical methods demonstrated the recovery of the glycogen content, the activity of succinate dehydrogenase and alpha-glycerophosphate dehydrogenase as well as increased fluorescence of catecholaminergic nerves in short-term ischemized myocardium (experimental angina pectoris) after stimulation of the carotid sinus nerve. At the same time, a decrease in the number of cells containing catecholamines in the carotid paraganglion was observed which might indicate their discharge into the blood. Normalization of the histochemical values in ischemized myocardium after stimulation of the carotid sinus nerve allows this method to recommend for investigations in clinical practice.


Melanoma of glans penis and urethra: A case report and systematic review of the literature of a rare and complex neoplasm.
To evaluate the features and prognosis of melanoma of glans penis and urethra, with the presentation of a significant case report. A systematic literature review was performed using the MEDLINE (PubMed) and Cochrane Libraries databases to identify all cases of male mucosal melanoma reported. Two hundred fifty-two patients with male mucosal primary melanoma were found. Glans penis and fossa navicularis as primary site includes the 81.6% of all lesions considered. Median Breslow's depth is 2.1 mm, whereas nine in situ melanomas have been reported. At the diagnosis, the disease was at a non-localized stage in 21.4% for glans penis melanomas and 11.7% urethral lesions, respectively. The 2 and 5-year survival for glans melanoma is 62.5% and 38.4%; higher rates were observed in the 2012-2020 period (76% and 58.8%, respectively). Two-year survival for urethral melanomas is 66.7%, while 5-year survival is 12.5%. 22 patients survived over 5 years with a Breslow's depth reported always < 3.3 mm. Melanoma of the glans penis and urethra is a rare neoplasm associated with a poor prognosis, however recent reports show higher survival rates. Surgery remains the mainstay for a localized disease. Taking into account the small number of cases reported, topical imiquimod seems to be a valid non-surgical alterative for melanoma in situ. The use of immunotherapy and targeted therapy should be considered only in an adjuvant setting according to the recommendations of cutaneous melanoma; however, additional clinical data on male mucosal melanoma are needed to draw definitive conclusions.


Health Equity Ratings of US Burn Centers-Does For-Profit Status Matter?
Achieving health equity is forefront in national discussions on health care structuring. Burn injuries transcend racial and socioeconomic boundaries. Burn center funding ranges from safety-net to for-profit without an understanding of how funding mechanisms translate into equity outcomes. We hypothesized that health equity would be highest at safety-net facilities and lowest at for-profit centers. All verified and non-verified American Burn Association burn centers were collated in 2022. Safety-net status, for-profit status, and health equity rating were extracted from national datasets. Equity ratings were compared across national burn centers and significance was determined with comparative statistics and ordinal logistic regression. On an equity grade of A to D (A is the best), 27.6% of centers were rated A, 27.6% rated B, 41.5% rated C, and 3.3% rated D. 17.1% of all burn centers were designated as for-profit compared to 21.1% of centers that were safety-net. 73.1% of safety-net centers scored an A rating, and 14.3% of for-profit centers scored an A rating. Safety-net centers were 21.8 times more likely (p<0.001) to have the highest equity score compared to non-safety-net centers. There was an 80% decrease in the odds of having a rating of A for for-profit centers compared to non-profit centers (p=0.04). Safety-net centers had the highest equity ratings while for-profit burn centers scored the lowest. For-profit funding mechanisms may lead to the delivery of less equitable burn care. Burn centers should focus on health equity in the triage and management of their patients.


Open versus laparoscopic pelvic lymph node dissection in early stage cervical cancer: no difference in surgical or disease outcome.
This study aimed to investigate in a retrospective study the effect of laparoscopic surgery, introduced in our center in 1994 as part of the standard treatment of early stage cervical cancer, on surgical and disease outcomes. A total of 169 women with cervical carcinoma stage IB1 (n = 150) or IB2 (n = 19) were included in the study. Seventy-six patients who underwent laparoscopic pelvic lymph node dissection (LPLND), followed either by open radical hysterectomy (n = 63) or, in case of positive lymph nodes, by primary chemoradiation (n = 13), were compared with an historic cohort of 93 patients who underwent a fully open, traditional Wertheim-Meigs procedure (WM). Recorded clinical characteristics of patients included age, International Federation of Gynecology and Obstetrics stage, histologic diagnosis, differentiation grade, tumor diameter, lymph node status, and adjuvant therapy. Operation time; lymph node yield; intraoperative, early, and late complications; site of recurrences; and disease-free and overall survival rates were analyzed and compared between groups. Clinical characteristics did not differ between groups. Duration of total surgery time was longer in patients with LPLND followed by open radical hysterectomy compared with that in the WM group (P < 0.001). In patients with negative lymph nodes (n = 129), the number of resected nodes was higher (P = 0.002) in the LPLND (median, 26 nodes; range, 8-55 nodes) than in the WM group (median, 21 nodes; range, 7-50 nodes). In patients with positive lymph nodes (n = 40), no significant difference in the number of resected lymph nodes between the 2 groups (P = 0.904) was found. Intraoperative, early, and late complications did not differ between the 2 surgical procedures. The number of locoregional recurrences, but not of distant metastases, was significantly higher (P = 0.018) in the WM group compared with the LPLND group. No difference in disease-free or disease-specific survival was found between the LPLND and WM group, neither with nor without adjuvant or primary (chemo)radiation. A benefit in disease-free survival (P = 0.044), but not in disease-specific survival (P = 0.070), was found in the LPLND compared with the WM group in those patients who received adjuvant therapy or primary chemoradiation. Introduction of a laparoscopic procedure in the surgical staging and treatment of cervical cancer patients did not have a detrimental effect on surgical or disease outcome, and this can be safely applied to the treatment of early stage cervical cancer.


Effects of omega-3 polyunsaturated fatty acids supplementation for patients with cardiovascular disease risks: a dose-response meta-analysis.
Previous studies assessing the impact of omega-3 polyunsaturated fatty acids (ω-3 PUFA) have shown conflicting results in regard to the cardiovascular mortality. It is likely that higher dose of ω-3 PUFA would have a greater effect on the major adverse cardiovascular events (MACEs). Therefore, we performed a dose-response meta-analysis to explore the potential protective effect of ω-3 PUFA, with the increase of daily intake and extension of the intervention period, on patients with cardiovascular disease risks. Outcomes included major adverse cardiovascular events, cardiovascular and all-cause mortality. A systematic literature search of PubMed, Embase and the Cochrane Library from inception to September 31, 2019 was conducted to identify the randomized controlled trails (RCTs) of ω-3 PUFA supplementation, which reported cardiovascular events or deaths and recruited no less than 500 participants. We evaluated the effect of ω-3 PUFA through the pooled relative risks (RR) and 95% confidence intervals (95% CI), and further carried out subgroup analysis and dose-response meta-analysis. Fourteen trials including 87718 individuals were reviewed. By conventional statistical significance, there was no apparent difference between the two groups on major adverse cardiovascular effects (RR 0.94, 95% CI 0.84-1.04) and all-cause mortality (RR 0.96, 95% CI 0.91-1.00), but there was an effect on the cardiovascular mortality (RR 0.93, 95% CI 0.88-0.99). However, with the dose increased and intervention period prolonged (daily dose × intervention period > 8 grams/day × years), subgroup analyses showed a more obvious reduction of MACEs (RR 0.79, 95% CI 0.65-0.95) and all-cause mortality (RR 0.93, 95% CI 0.85-1.03). Furthermore, the dose-response meta-analysis presented a 13.05% reduction of MACEs and 8.99% reduction of all-cause mortality with 10 grams/day × years increments. Updated with the newly published RCTs, this meta-analysis indicated that large dose and long period of interventions with ω-3 PUFA supplementation produce a close association with MACEs and cardiovascular or all-cause mortality. A dose-response beneficial effect was preliminarily established.


Detection of altered collagen fiber alignment in the cervical facet capsule after whiplash-like joint retraction.
The cervical facet joint has been identified as the source of pain in patients with whiplash-associated disorders, but most clinical studies report no radiographic evidence of tissue injury in these disorders. The goal of this study was to utilize quantitative polarized light imaging to assess the potential for altered collagen fiber alignment in human cadaveric cervical facet capsule specimens (n = 8) during and after a joint retraction simulating whiplash exposure. Although no evidence of ligament damage was detected during whiplash-like retraction, mechanical and microstructural changes were identified after loading. Retraction produced significant decreases in ligament stiffness (p = 0.0186) and increases in laxity (p = 0.0065). In addition, image analysis indicated that 21.1 ± 17.1% of the capsule sustained principal strains that were unrecovered immediately after retraction. Altered collagen fiber alignment was detected in 32.7 ± 22.9% of the capsule after retraction. The capsule regions with unrecovered strain and altered fiber alignment after retraction were significantly co-localized with each other (p < 0.0001), suggesting the altered mechanical function may relate to a change in the tissue's fiber organization. The identification of altered fiber alignment in this ligament following retraction without any tears implicates the whiplash kinematic as a potential cause of microstructural damage that is not detectable using standard clinical imaging techniques.


Programs, models, theories, and reality.
The question "Are 'biorobots' good models of biological behaviour?" can be seen as a specific instance of a more general question about the relation between computer programs and models, between models and theories, and between theories and reality. This commentary develops a personal view of these relations, from an antirealism perspective. Programs, models, theories and reality are separate and distinct entities which may converge in particular cases but should never be confused.


Adolescents' Contraceptive Use with School-Discordant Partners: Exploring Individual- and Relationship-Level Characteristics.
Heterosexual adolescents are less likely to use contraceptives when their partners are of different backgrounds or social circles. It is unclear why risky behaviors are more common within these relationships, and characteristics associated with school-discordant partners-that is, partners who do not attend the adolescent's school-are particularly understudied. Characteristics of romantic relationships and contraceptive use were examined among 1,043 female and 961 male respondents in Waves 1 (1994-1995) and 2 (1996) of the National Longitudinal Study of Adolescent to Adult Health. Generalized linear regression and structural equation models identified individual- and relationship-level characteristics that were associated with school-discordant relationships and contraceptive use. For females, the likelihood of ever having used a condom with a partner was reduced when that partner had not attended her school at the start of the relationship (odds ratio, 0.5) or when he was two or more years older (0.6). Notably, however, having a school- or age-discordant partner was not associated with ever having used hormonal or dual methods for females, or with any contraceptive measures for males. For females, lower emotional intimacy with school-discordant partners was positively associated with ever having used condoms with such partners (1.2). Characteristics of school-discordant relationships are correlated with condom use in varying and sometimes countervailing ways. Future research examining the mechanisms linking school discordance to decreased condom use, particularly for females, would deepen understanding of the emotional and psychosocial processes involved in adolescents' sexual and contraceptive behavior.


[Evaluation of Malaria Cases that Were Detected in Kocaeli Province During 2008 Through 2013].
Malaria is still a serious public health problem around the world and in our country. In this study, we examined the epidemiology of malaria cases retrorespectively by using the surveillance data provided by the Malaria Control Unit of the Infectious Disease Division of Kocaeli Health Directory, from the years of 2008 to 2013. Our aim was to compare our findings with the findings of the past studies and provide support to the future surveillance studies. A total of 10008 periferic blood samples were examined in this surveillance based study. The cases were evaluated according to age groups, gender, month during which the infection was detected and the origin of district. The species of malaria parasites were detected in 27 samples of which 51.9 % (n=14) was Plasmodium vivax and 48.1% (n=13) was Plasmodium falciparum. Among 27 cases 77.8% (n=21) of the cases were male and 22.2% (n=6) were female. 96.3% of the cases were above the age of 15. All cases of Plasmodium vivax were consisted of the workers who came to Kocaeli from Southeastern Anatolia Region. Malaria cases detected in our region have displayed a relatively meaningful decrease in comparison to past. While Plasmodium vivax was dominating infecting agent in the past, in recent years Plasmodium falciparum appeared to be infecting nearly half of the cases. These cases were imported cases coming to Kocaeli from other countries. It is important to take the necessary precautions for timely diagnosis of imported cases and to prevent its spread in the area.


Functional MRI in investigating cognitive impairment in multiple sclerosis.
There is increasing evidence that the severity of the clinical manifestations of multiple sclerosis (MS) does not simply result from the extent of tissue destruction, but it rather represents a complex balance between tissue damage, tissue repair, and cortical reorganization. Functional magnetic resonance imaging (fMRI) provides information about the plasticity of the human brain. Therefore, it has the potential to provide important pieces of information about brain reorganization following MS-related structural damage. When investigating cognitive systems, fMRI changes have been described in virtually all patients with MS and different clinical phenotypes. These functional changes have been related to the extent of brain damage within and outside T2-visible lesions as well as to the involvement of specific central nervous system structures. It has also been suggested that a maladaptive recruitment of specific brain regions might be associated with the appearance of clinical symptoms in MS, such as fatigue and cognitive impairment. fMRI studies from clinically (and cognitively) impaired MS patients may be influenced by different task performances between patients and controls. As a consequence, new strategies have been introduced to assess the role, if any, of brain reorganization in severely impaired patients, including the analysis of resting-state networks. The enhancement of any beneficial effects of this brain adaptive plasticity should be considered as a potential target of therapy for MS.


Identification of novel testing matrices for African swine fever surveillance.
African swine fever (ASF) is a devastating viral disease of pigs and wild boar, and it threatens global food security. We aimed to identify suitable sample matrices for use in ASF surveillance programs. Six pigs inoculated with ASFV were sampled at postmortem. Blood, bone marrow, ear biopsies, and oral, nasal, and rectal swabs were taken from all pigs. All samples were analyzed using 3 real-time PCR (rtPCR) assays and a LAMP assay. ASFV was detected at > 107 genome copies/mL in blood; bone marrow was found to provide the highest viral load. Ct values provided by the rtPCR assays were correlated, and ASFV was detected in all oral, nasal, and rectal swabs and in all ear biopsy samples irrespective of the location from which they were taken. The LAMP assay had lower sensitivity, and detected ASFV in 54 of 66 positive samples, but delivered positive results within 17 min. We identified additional sample matrices that can be considered depending on the sampling situation: bone marrow had a high probability of detection, which could be useful for decomposed carcasses. However, ear biopsies provide an appropriate, high-throughput sample matrix to detect ASFV and may be useful during surveillance programs.


[Two ways of formate oxidation in methylotrophic bacteria].
The cells of Achromobacter parvulus, strain 1T, when grown in a methanol-containing medium, have two formate dehydrogenases, i.e. NAD-linked formate dehydrogenase and the formate dehydrogenase reducing the ferricyanide and tetrazolia. Only the latter enzyme was found in the cells grown in a medium with glycerol as a carbon source. These enzymes differ with respect to Km for formate and antigenic specificity. Km for formate oxidation by the cells of A. parvulus is lower than for formate of the NAD-dependent formate dehydrogenase and is equal to Km for the enzyme reducing artificial electron acceptors. The results obtained are discussed in terms of the existence of two cytochrome oxidase systems in the methylotrophic bacteria, differing in their sensitivities to the inhibition by formate.


Motivation in ultra-marathon runners.
In ultra-marathon running the proper motivation of the athlete is one of the milestones, not only during the races, but also during the practice sessions, which are long and very exhausting. The aim of this study was to examine the relationship of sport experience (expressed as number of finishes in ultra-marathons) with motivation characteristics of ultra-marathon runners. The Motivation of Marathoners Scale examined the motivation of ultra-marathon runners compared to endurance runners of shorter distances (control group). Participants were 1,539 Polish runners, 382 women (24.7%) and 1,157 men (75.3%). Ultra-marathoners (N=425; 26.7%) finished at least one ultra-marathon, whereas the control group consisted of runners of shorter distances (N=1,114, 72.3%). Ultra-marathoners had higher scores in affiliation (3.55±1.60 vs 3.34±1.62, P<0.05), life meaning (4.20±1.40 vs 4.03±1.44, P<0.05) and lower in the areas of weight concern (4.33±1.68 vs 4.64±1.65, P<0.01), personal goal achievement (5.09±1.25 vs 4.64±1.65, P<0.001) and self-esteem (4.44±1.36 vs 4.68±1.38, P<0.01), than runners in the control group. The number of completed ultra-marathons was negatively related to the personal goal achievement, competition and recognition scale. The level of training experience was negatively correlated with the personal goal achievement scale in all participants, and with the self-esteem scale in the control group. In summary, ultra-marathoners had different motivations compared to runners of shorter race distance. These findings should be considered by sport psychologists and other professionals to develop performance-tailored interventions for ultra-marathoners.


Chronic pruritic papular dermatitis in adult men: a variant of prurigo.
Chronic recurrent pruritic papular eruptions in which a specific diagnosis cannot be established becomes a baffling experience to the dermatologist. We have met adult male patients with chronic recurrent pruritic papular eruptions, but their clinicopathological features are not described in English language textbooks. Our purpose was to study the clinical and histological features of this entity and review the various existing taxonomy. We conducted a study of 20 patients over a six year period by taking histories, performing skin biopsies, screening patch tests, and doing immunofluoresence studies. The eruptions occurred exclusively in male adults and had a predilection for the trunk and proximal extremities. The lesions were characterized by severely pruritic, nonfollicular, monomorphic, erythematous urticarial papules. There was no evidence of atopic diathesis or history of insect bite. Most patients had normal levels of serum eosinophils and IgE. The predominant histopathologic finding was a presence of perivascular infiltration of mononuclear cells with eosinophils. The patients followed a chronic course of at least six months with waxing and waning; systemic corticosteroids were the only effective treatment. Finally, all other pruritic erythematous papular dermatoses were ruled out. These cases comprise a distinct entity that has previously been mentioned in a few reports. Clear definition of this entity with an appropriate designation is in order to avoid confusion among dermatologists, and we propose the disease name "chronic papular dermatitis in adult men" as a variant of prurigo.


Iron uptake by rabbit intestinal brush border membrane vesicles involves movement through the outer surface, membrane interior, inner surface and aqueous interior.
Iron uptake in rabbit brush border membrane vesicles was measured in the presence of nitrilotriacetate. The complexes formed ranged from stable mononuclear species to hydrolyzed polynuclear complexes and are considered as a good model for nutritional iron compounds with respect to their chemical reactivity. Uptake includes both binding to and penetration through the membrane. A strategy was developed to localize iron in the following four compartments: outer membrane surface, membrane interior, inner membrane surface and aqueous phase within the vesicles. Both surfaces as well as the membrane interior revealed a high metal binding capacity. After an incubation for 10 min with 182 mumol/L iron and 364 mumol/L nitrilotriacetate, 35% of total vesicle iron was found to be bound to the outer membrane surface, 34% to the inner membrane surface, and 23% was not accessible to EDTA. Thus, by adsorption of polynuclear iron complexes to the outer surface, the residence time of iron may be prolonged. The remaining 8% of total iron was in the aqueous phase within the vesicles. Nitrilotriacetate enters the rabbit vesicles in a concentration-dependent manner. As a consequence, iron concentration in the aqueous phase within the vesicles will be driven to the medium equilibrium concentration.


Pan-Canadian assessment of pandemic immunization data collection: study methodology.
The collection of individual-level pandemic (H1N1) 2009 influenza immunization data was considered important to facilitate optimal vaccine delivery and accurate assessment of vaccine coverage. These data are also critical for research aimed at evaluating the new vaccine's safety and effectiveness. Systems used to collect immunization data include manual approaches in which data are collected and retained on paper, electronic systems in which data are captured on computer at the point of vaccination and hybrid systems which are comprised of both computerized and manual data collection components. This study's objective was to compare the efficiencies and perceptions of data collection methods employed during Canada's pandemic (H1N1) 2009 influenza vaccination campaign. A pan-Canadian observational study was conducted in a convenience sample of public health clinics and healthcare institutions during the H1N1 vaccination campaign in the fall of 2009. The study design consisted of three stages: Stage 1 involved passive observation of the site's layout, processes and client flow; Stage 2 entailed timing site staff on 20 clients through five core immunization tasks: i) client registration, ii) medical history collection, iii) medical history review, iv) vaccine administration record keeping and v) preparation of proof of vaccine administration for the client; in Stage 3, site staff completed a questionnaire regarding perceived usability of the site's data collection approach. Before the national study began, a pilot study was conducted in three seasonal influenza vaccination sites in Ontario, to both test that the proposed methodology was logistically feasible and to determine inter-rater reliability in the measurements of the research staff. Comparative analyses will be conducted across the range of data collection methods with respect to time required to collect immunization data, number and type of individual-level data elements collected, and clinic staff perceptions of the usability of the method employed at their site, using analysis of variance (ANOVA). Various data collection methods were employed at immunization sites across Canada during the pandemic (H1N1) 2009 influenza vaccination campaign. Our comparison of methods can facilitate planning an efficient, coordinated approach for collecting immunization data in future influenza seasons.


Hemorrhagic Meckel's diverticulum. Interest of the digestive pertechnetate scintigraphy.
Meckel's diverticulum is the most prevalent congenital abnormality of the gastrointestinal tract. Clinical symptoms can result in pain, bleeding and perforation caused by peptic ulceration. Among all imaging modalities, Tc-99m pertechnetate scintigraphy is the most sensitive method for Meckel's diverticulum diagnosis, but only mentioned in a few publications. We report the case of a young child with rectal bleeding related hemorrhagic Meckel's diverticulum. Endoscopy and ultrasound were normal. The diagnosis was done by scintigraphy with technetium revealing an accumulation of radiotracer by mucous cells in ectopic gastric mucosa, which allows a detection of Meckel's diverticulum. Our case illustrates the importance of this exam to the diagnosis of gastrointestinal bleeding with normal endoscopy.


Decreased cord blood estradiol levels in related to mothers with gestational diabetes.
Recent studies have revealed a link between estradiol (E2) and glucose homeostasis. We aimed to assess the association between cord blood hormone levels and the risk of gestational diabetes mellitus (GDM).A total of 204 pregnant women with GDM and 204 pregnant women without GDM (control) were included in the study. Maternal GDM were diagnosed using a 75 g oral glucose tolerance test at 24 to 26 weeks of gestation. Cord blood samples from neonates were collected immediately post delivery. Controls, which were randomly selected from the study population, were matched (cases to controls ratio: 1:1) to cases by age, sex of fetus, and gestational week.Pregravid body mass index (BMI) (mean ± standard deviation) was (GDM vs. control): 24.5 ± 2.1 versus 22.8 ± 2.4 (P = .001). Cord blood estradiol in the GDM group was significantly lower than in the control group (P < .05). Pregravid BMI in the GDM group was significantly higher than in the control group (P < .05). Estradiol concentrations in cord blood were negatively correlated with birth weight (r = -0.121, P < .05). Conditional logistic regressions showed pregravid BMI, cord blood estradiol, and parity independently and positively predicted GDM. Multivariable regression splines characterize a nonlinear relationship between cord blood estradiol and GDM risk.These results demonstrate a relationship between cord blood estradiol levels and GDM. Estradiol might be involved in the pathophysiology of GDM. Further studies are needed to explore potential mechanism.


Quantification of viable Giardia cysts and Cryptosporidium oocysts in wastewater using propidium monoazide quantitative real-time PCR.
Real-time PCR (qPCR) is a rapid tool to quantify pathogens in the aquatic environment; however, it quantifies all pathogens, including both viable and nonviable. Propidium monoazide (PMA) is a membrane-impairment dye that penetrates only membrane-damaged cells. Once inside the cell, PMA is covalently cross-linked to DNA through light photoactivation, and PCR amplification is strongly inhibited. The goal of this study was to evaluate PMA-qPCR assays for rapid quantification of viable and heat-treated Giardia cysts and Cryptosporidium oocysts in wastewater. We observed a reduction in detection of heat-treated Giardia duodenalis cysts of 83.2, 89.9, 98.2, or 97% with PMA-qPCR assays amplifying a 75 base-pair (bp) β-giardin target, 77-bp triosephosphate isomerase (tpi), 133-bp glutamate dehydrogenase (GDH), and 143-bp β-giardin gene target, respectively. Thus, the exclusion of dead cysts was more effective when qPCR assays that produced larger amplicons were used. The PMA treatment of Cryptosporidium oocysts plus/minus heat treatment abolished the fluorescent signal for dead oocysts with a PMA-qPCR assay amplifying a Cryptosporidium parvum (150-bp) oocyst wall protein (COWP) gene. The PMA-qPCR 143-bp β-giardin assay for Giardia and the PMA-qPCR 150-bp COWP assay for Cryptosporidium accurately quantified live oo(cysts), and failed to detect dead oo(cysts), when phosphate-buffered saline and tertiary effluent wastewater were spiked with concentrations of 10(3) or 10(2) dead oo(cysts), respectively. Therefore, these assays are suitable for the detection of viable parasites that are typically present in tertiary wastewater effluents at concentrations of <10(3) oo(cysts)/l and can provide rapid risk assessments of environmental water.


Anandamide and delta 9-THC dilation of cerebral arterioles is blocked by indomethacin.
Anandamide (AN, arachidonyl ethanolamide) has been isolated from the brain and shown to be an endogenous ligand for the delta 9-tetrahydrocannabinol (delta 9-THC) receptor. The purpose of these studies was to determine whether AN or delta 9-THC can affect the cerebral circulation. With the use of the closed cranial window AN and delta 9-THC (10(-13)-10(-3) M) were topically applied to rabbit cerebral arterioles and effects on diameter were measured with a microscope. AN and delta 9-THC similarly induced a dose-dependent dilation starting at concentrations as low as 10(-12) M. Maximum dilation for AN was 25% and that for delta 9-THC 22%. Topical coapplication of indomethacin, a cyclooxygenase inhibitor, completely blocked dilation, whereas the free radical scavengers superoxide dismutase and catalase or the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) had no effect on AN-induced dilation. The cerebrospinal fluid level of prostaglandin E2 increased only in response to 10(-7) M and greater AN and was not affected by delta 9-THC. [3H]AN superfused through the cranial window was 20% converted to arachidonic acid. These results show that AN and delta 9-THC can modulate cerebral arterioles, likely by stimulating release and metabolism of endogenous arachidonic acid. Whether dilation is due to vasodilator eicosanoids, or other vasoactive agents whose synthesis or release is cyclooxygenase dependent, is uncertain.


An adapted clinical global Impression of improvement for use in Angelman syndrome: Validation analyses utilizing data from the NEPTUNE study.
Angelman Syndrome (AS) is a rare, severe neurogenetic disorder that causes symptoms such as intellectual disability and motor impairments and is typically diagnosed in early childhood. The complexity and heterogeneity of AS confound characterization of disease severity and pose unique challenges when determining an individual's response to treatment. There is therefore a substantial unmet need for rating scales specifically designed for complex conditions such as AS. To address this, the Clinical Global Impressions (CGI) scale, which has components for both symptom severity (CGI-S) and improvement (CGI-I) was specifically adapted to measure severity (CGI-S-AS) and improvement (CGI-I-AS) in AS. The modified CGI-S/I-AS was used in the NEPTUNE trial of gaboxadol for the treatment of AS. Here we report on the validation of the CGI-I-AS using data from NEPTUNE and discuss insights for its potential use in future trials. Improvements in the CGI-I-AS rating tended to be consistent with changes on other relevant rating scales. Sleep-related symptoms were particularly well represented, while communication-related symptoms were not. Our validation analysis of the CGI-I-AS demonstrates its usefulness along with possible areas of improvement. The CGI-I-AS is a potential tool for use in other trials of AS drug candidates, and the process for its development can serve as a road map for the development of assessment tools for other neuropsychiatric disorders with similar complexities and heterogeneity.


Estimating the impact of a diffuse technology on the running costs of a hospital. A case study of a picture archiving and communication system.
This paper considers the methodological problems that arise in conducting cost analyses in economic evaluations where only observational (rather than experimental) data are available and where the technology being evaluated is diffuse, such that the unit of analysis has to be the institution rather than the patient. A case study is reported that concerns the application of computer technology in radiology: picture archiving and communication systems (PACS). A range of different approaches were used to estimate changes in running costs, including time series analyses of routine data and direct observation of resource use. The analysis illustrates some of the difficulties involved in costing the introduction of a diffuse technology. Nevertheless, it provides a firm indication that, overall, the introduction of PACS was found to be associated with a significant increase in hospital costs, suggesting that the initial expectations of financial savings were unduly optimistic. The research demonstrates that, using multiple methods, it is possible to estimate cost changes within a single hospital. In addition, the paper discusses the nature of the uncertainties in such analyses and possible ways of representing such uncertainty in terms of confidence intervals.


A predictive tool particularly designed for elderly myeloma patients presenting with spinal cord compression.
This study was performed to design a predictive tool that allows the estimation of overall survival (OS) of elderly myeloma patients (aged ≥ 65 years) presenting with myeloma-induced spinal cord compression (SCC). One-hundred-and-sixteen patients irradiated for motor deficits of the legs due to myeloma-induced spinal cord compression were retrospectively evaluated. Ten characteristics were analyzed for OS including age, interval between myeloma diagnosis and radiotherapy, other osseous myeloma lesions, myeloma type, gender, time developing motor deficits, number of affected vertebrae, ECOG-PS, pre-radiotherapy ambulatory status, and fractionation regimen. Characteristics that achieved significance on multivariate analysis were included in the predictive tool. The score for each characteristic was obtained from the 1-year OS rate divided by 10. The sum of these scores represented the prognostic score for each patient. On multivariate analysis, myeloma type (hazard ratio 3.31; 95%-confidence interval 1.75-6.49; p < 0.001), ECOG-PS (HR 5.33; 95%-CI 2.67-11.11; p < 0.001), ambulatory status (HR 2.71; 95% CI 1.65-4.57; p < 0.001), and age (HR 1.95; 95% CI 1.03-3.78; p = 0.040) were significantly associated with survival. Sum scores ranged from 18 to 32 points. Based on the sum scores, three prognostic groups were designed: 18-19, 21-28 and 29-32 points. The corresponding 1-year survival rates were 0, 43 and 96%, respectively (p < 0.001). This new predictive tool has been specifically designed for elderly myeloma patients with SCC. It allows estimating the survival prognosis of this patient group and supports the treating physicians when looking for the optimal treatment approach for an individual patient.


Selling yourself in a tough health care market.
Physician executives are vying for top positions in health care organizations. With so many qualified candidates in the marketplace, how can you differentiate yourself as a strong contender? Recruiters search through hundreds of résumés, not the ten or 20 that many hospital and HMO CEOs have seen. Recruiters--the people who actually find specific candidates--were interviewed to find out what they are looking for. Here are the top items on their checklists: Articulated focus, documented results, competitive intelligence, professional growth, good references, appearance and social skills, responsive and timely, and technical skills.


TRPC6 channels promote dendritic growth via the CaMKIV-CREB pathway.
The canonical transient receptor potential channels (TRPCs) are Ca(2+)-permeable nonselective cation channels with various physiological functions. Here, we report that TRPC6, a member of the TRPC family, promotes hippocampal neuron dendritic growth. The peak expression of TRPC6 in rat hippocampus was between postnatal day 7 and 14, a period known to be important for maximal dendritic growth. Overexpression of TRPC6 increased phosphorylation of Ca(2+)/calmodulin-dependent kinase IV (CaMKIV) and cAMP-response-element binding protein (CREB) and promoted dendritic growth in hippocampal cultures. Downregulation of TRPC6 by short hairpin RNA interference against TRPC6 suppressed phosphorylation of both CaMKIV and CREB and impaired dendritic growth. Expressing a dominant-negative form of CaMKIV or CREB blocked the TRPC6-induced dendritic growth. Furthermore, inhibition of Ca(2+) influx suppressed the TRPC6 effect on dendritic growth. Finally, in TRPC6 transgenic mice, the phosphorylation of CaMKIV and CREB was enhanced and the dendritic growth was also increased. In conclusion, TRPC6 promoted dendritic growth via the CaMKIV-CREB pathway. Our results thus revealed a novel role of TRPC6 during the development of the central nervous system (CNS).


A viable isolated tissue system: a tool for detailed MR measurements and controlled perturbation in physiologically stable tissue.
In vivo magnetic resonance imaging (MRI) assessment of neuronal tissue is prone to artifacts such as movement, pulsatile flow, and tissue susceptibility. Furthermore, stable in vivo scans of over 3 h are difficult to achieve, experimental design is therefore limited. Using isolated tissue maintained in a viable physiological state can mitigate many of these in vivo issues. This work describes the fabrication and validation of an MRI compatible viable isolated tissue maintenance chamber. Parameters measured from maintained rat optic nerves did not change significantly over 10 h: (i) mean axon radius [electron microscopy--0 h: 0.75±0.46; 5 h: 0.74±0.35; 10 h: 0.76±0.35 μm (P>>0.05, t-test], (ii) action potentials [grease-gap electrophysiology--4.89±0.16 mv, (P>>0.05, Pearson test], and (iii) diffusion tensor imaging parameters [fractional anisotropy: 0.86±0.02 (P>>0.05, Pearson test), mean diffusivity: 1.48E-06±9.74E-08 cm2/s, (P>>0.05, Pearson test)]. In addition, a thorough diffusion-weighted MR protocol demonstrated the comparable stability of viable isolated and chemically fixed rat optic nerve. This MRI compatible viable isolated tissue system allows researchers to probe neuronal physiology in a controlled environment by limiting in vivo artifacts and allowing extended MRI acquisitions.


Enhancing the sialylation of recombinant EPO produced in CHO cells via the inhibition of glycosphingolipid biosynthesis.
Sialylation regulates the in vivo half-life of recombinant therapeutic glycoproteins, affecting their therapeutic efficacy. Levels of the precursor molecule cytidine monophospho-N-acetylneuraminic acid (CMP-Neu5Ac) are considered a limiting factor in the sialylation of glycoproteins. Here, we show that by reducing the amount of intracellular CMP-Neu5Ac consumed for glycosphingolipid (GSL) biosynthesis, we can increase the sialylation of recombinant human erythropoietin (rhEPO) produced in CHO cells. Initially, we found that treating CHO cells with a potent inhibitor of GSL biosynthesis increases the sialylation of the rhEPO they produce. Then, we established a stable CHO cell line that produces rhEPO in the context of repression of the key GSL biosynthetic enzyme UDP-glucose ceramide glucosyltransferase (UGCG). These UGCG-depleted cells show reduced levels of gangliosides and significantly elevated levels of rhEPO sialylation. Upon further analysis of the resulting N-glycosylation pattern, we discovered that the enhanced rhEPO sialylation could be attributed to a decrease in neutral and mono-sialylated N-glycans and an increase in di-sialylated N-glycans. Our results suggest that the therapeutic efficacy of rhEPO produced in CHO cells can be improved by shunting intracellular CMP-Neu5Ac away from GSL biosynthesis and toward glycoprotein sialylation.


Testing legal assumptions regarding the effects of dancer nudity and proximity to patron on erotic expression.
A field experiment was conducted in order to test the assumptions by the Supreme Court in Barnes v. Glen Theatre, Inc. (1991) and the Ninth Circuit Court of Appeals in Colacurcio v. City of Kent (1999) that government restrictions on dancer nudity and dancer-patron proximity do not affect the content of messages conveyed by erotic dancers. A field experiment was conducted in which dancer nudity (nude vs. partial clothing) and dancer-patron proximity (4 feet; 6 in.; 6 in. plus touch) were manipulated under controlled conditions in an adult night club. After male patrons viewed the dances, they completed questionnaires assessing affective states and reception of erotic, relational intimacy, and social messages. Contrary to the assumptions of the courts, the results showed that the content of messages conveyed by the dancers was significantly altered by restrictions placed on dancer nudity and dancer-patron proximity. These findings are interpreted in terms of social psychological responses to nudity and communication theories of nonverbal behavior. The legal implications of rejecting the assumptions made by the courts in light of the findings of this study are discussed. Finally, suggestions are made for future research.