Impact of the duration of hormonal therapy following radiotherapy for localized prostate cancer.
External-beam radiotherapy (EBRT) combined with androgen deprivation therapy (ADT) is known to provide improved survival outcomes compared with EBRT alone in the treatment of prostate cancer; however, the use of ADT has been reported to be associated with adverse events. Accordingly, the aim of the present study was to clarify the adequate duration of ADT when combined with EBRT to treat patients with high-risk localized prostate cancer, with consideration of survival outcomes and toxicity. Between 2001 and 2011, 173 patients with high-risk localized prostate cancer received ADT combined with EBRT, at a median dose of 69.6 Gy. Of these, 54 (31%) underwent short-term ADT (<36 months) and 119 (69%) underwent long-term ADT (≥36 months). During the median follow-up period of 54 months, the five-year progression-free survival rate of patients receiving short-term ADT (72.9%) was significantly lower than that of patients receiving long-term ADT (92.8%) (P<0.01). Furthermore, the incidence of cardiovascular toxicity at grade II or above was significantly higher amongst patients treated with short-term ADT compared with patients treated with long-term ADT (P<0.01). Thus, the present study determined that ADT for ≥36 months combined with EBRT significantly improved the progression-free survival of patients with high-risk localized prostate cancer and exhibited an acceptable toxicity profile.


[Acute abdomen in the elderly].
Nearly 10% of emergency consultations are due to acute abdominal pain. In people over 65 years old, it can have atypical presentations, that retard the correct diagnosis and worsens prognosis. To study the causes, evolution and prognosis of acute abdomen in the elderly. Prospective study of 45 patients aged more than 65 years old (mean age+/-SD, 75.7+/-7.7, 51% men) and 221 patients of less than 65 years old (mean age+/-SD, 36.7+/-14.0, 48% men), consulting for acute abdomen in the emergency room. Sixty six percent of elderly patients had concomitant diseases, that were multiple in 63%. In this age group, the causes accounting for 71% of acute abdominal pain were bilio-pancreatic diseases (31.1%), intestinal adhesive obstruction (17.7%), complicated abdominal wall hernia (13.7%), and complications of peptic ulcer disease (8.9%). Sixty four percent required surgical treatment and, in almost 50% the surgical risk was classified in ASA III or IV, according to the American Society of Anesthesiology. Thirty one percent had postoperative complications. Compared with their younger counterparts, elderly patients required significantly (p<0.05) more admissions to intensive care units (2.7 and 24.2% respectively), more connections to mechanical ventilation (1.4 and 8.9% respectively) and longer hospital stays (5.4+/-7.4 and 12.4+/-10.9 days, respectively). In this series overall mortality was 6.7%, being 0.6% for young patients and 11.1% for the surgical group over 65 years old. Acute abdomen in the elderly has a high rate of complications and mortality. According to the causes of acute abdomen in this group, evaluation in the emergency setting with an ultrasonography may be very useful. In the elderly, elective correction of potential causes of acute abdomen should be done.


Enteroviral ribonucleic acid. I. Recovery from virus and assimilation by cells.
A relatively sensitive and adequately reproducible assay of infectious enteroviral RNA was obtained by exposing calf serum-grown HeLa cells to RNA suspended in 2 M magnesium sulfate solution. Highly purified enteroviral preparations yielded RNA exhibiting more than 0.1 per cent of the infectivity of whole original virus and infectivity regressed linearly with dilution. Radioisotope experiments with P(32)-labeled RNA and spectrophotometric studies demonstrated that Gierer-Schramm phenol extraction permits almost quantitative recovery of high molecular weight RNA from poliovirus. Intact chromatography-purified type 2 poliovirus in the analytical ultracentrifuge showed a sharp boundary and a sedimentation coefficient of S(20, w) = 147 +/- 5S. Phenol-extracted poliovirus RNA exhibited a heterodisperse sedimentation pattern with a large proportion of homogeneous, rapidly sedimenting material having a coefficient of S(20, w) = 37 +/- 2S. Although the bulk of extracted poliovirus RNA as measured by radiophosphorus labeling was not taken up by cells, the infectious fraction of RNA was adsorbed rapidly by HeLa-cell or L strain mouse fibroblast monolayers, indicating a possible dissimilarity between the bulk of extracted virus RNA and a relatively small fraction responsible for infectivity. Enhancement of poliovirus RNA infectivity for HeLa cells by high ionic-strength magnesium sulfate solution appeared due partly to an effect of hypertonicity on cells, and partly to an effect of high-concentration divalent cation on RNA itself, but not to enhancement of adsorption. Poliovirus RNA adsorbed by HeLa cells apparently was rapidly received within the cells since it became quickly insusceptible to ribonuclease. Heterologous nucleic acids and degradation products to the level of oligoribonucleotides inhibited infectivity of poliovirus RNA for HeLa cells. This inhibitory activity appeared due to intermolecular complexing, since exposure of cells to heterologous RNA immediately before or after exposure to virus RNA failed to reduce infectivity. Ultraviolet absorption spectra demonstrated that the RNA within intact poliovirus is more hypochromic (and thus more extensively hydrogen-bonded) than is the same RNA isolated by phenol extraction, and suspended in 0.02 M phosphate buffer.


Probiotics for Prevention of Severe Necrotizing Enterocolitis: Experience of New Zealand Neonatal Intensive Care Units.
Introduction: Necrotizing enterocolitis (NEC) affects mainly preterm infants, has a multifactorial etiology and is associated with intestinal dysbiosis and disordered immunity. Use of probiotics for prophylaxis is beneficial with studies indicating reduction in NEC ≥ stage 2, late onset sepsis (LOS) and mortality. However, not all studies have shown a reduction, there are questions regarding which probiotic to use, whether infants <1,000 g benefit and the risk of probiotic sepsis. All neonatal intensive care units in New Zealand (NZ) use probiotics and contribute to an international database (Australian and New Zealand Neonatal Network or ANZNN). Objective: To use ANZNN data to investigate the experience of NZ neonatal units with probiotics for NEC prevention in a setting where the baseline incidence of severe NEC was low, to compare results of 2 commonly used probiotic regimes and report on the extremely low birth weight subgroup. Method: Outcomes before (Pre group 2007-2010) and after (Probiotic group 2013-2015) starting routine probiotics for preterm infants <1,500 g or <32 weeks were compared. Clinicians reviewed cases to ensure they met database criteria. Five units used Infloran (Bifidobacterium bifidum and Lactobacillus acidophilus) and 1 unit used Lactobacillus GG (LGG) and bovine lactoferrin (bLF). Results: Four thousand five hundred and twenty nine infants were included and Pre and Probiotic groups were well-balanced with regard to gestation, birth weight and gender. The incidence of NEC in the Probiotic group was 1.6 and 2.7% in the pre group (corrected OR 0.62 CI 0.41-0.94). There was one case of probiotic sepsis. There was no significant difference between the Infloran and LGG/bLF combinations in regard to observed NEC rates. Late onset sepsis rates were significantly lower in the Probiotic group (p < 0.01). Conclusions: Introduction of probiotics for preterm infants in NZ has been associated with significant reductions in NEC and late onset sepsis.


Antibacterial activity of ceftolozane/tazobactam alone and in combination with other antimicrobial agents against MDR Pseudomonas aeruginosa.
Broad-spectrum antimicrobial resistance in Pseudomonas aeruginosa (PSA) isolates is a growing concern as our therapeutic options have become significantly limited. Although ceftolozane/tazobactam (C/T) has been shown to be highly active against MDR PSA pathogens, combination regimens are often employed in real-world settings. To assist the clinical decision-making process regarding the selection of combination antibiotics and dosages for this pathogen, we performed time-kill studies assessing clinical free peak and trough C/T concentrations alone and in combination with eight anti-pseudomonal agents against four clinical MDR PSA isolates. Time-kill analyses were performed over 24 h in duplicate using C/T concentrations reflective of the free peak concentrations of a 3 g dose every 8 h (q8h; 120/25.2 mg/L) and the peak and trough of a 1.5 g q8h dose (60/12.6 and 7.5/1.6 mg/L) in humans. The activity of C/T 120, 60 and 7.5 mg/L alone and C/T 7.5 mg/L in combination with free peak and trough concentrations of clinical doses for cefepime, ciprofloxacin, colistin, aztreonam, meropenem, piperacillin/tazobactam, fosfomycin and amikacin was tested for all isolates. C/T 3 and 1.5 g q8h peak concentrations demonstrated killing against the MDR PSA. Colistin and fosfomycin were synergistic with C/T as dual therapy and triple therapy regimens. As a result of escalating resistance, PSA is an increasingly challenging pathogen in the clinical setting. Our findings aid in the identification of novel treatment options using achievable drug exposures for the treatment of MDR PSA.


Interpopulation differences in male reproductive effort drive the population dynamics of a host exposed to an emerging fungal pathogen.
Compensatory recruitment is a key demographic mechanism that has allowed the coexistence of populations of susceptible amphibians with Batrachochytrium dendrobatidis (Bd), a fungus causing one of the most devastating emerging infectious disease ever recorded among vertebrates. However, the underlying processes (e.g. density-dependent increase in survival at early life stages, change in reproductive traits) as well as the level of interpopulation variation in this response are poorly known. We explore potential mechanisms of compensatory recruitment in response to Bd infection by taking advantage of an amphibian system where male reproductive traits are easy to quantify in free-living populations. The Southern Darwin's frog Rhinoderma darwinii is a vocal sac-brooding species that exhibits a high susceptibility to lethal Bd infection. Using a 7-year capture-recapture study at four populations with contrasting Bd infection status (one high prevalence, one low prevalence and two Bd-free populations), we evaluated whether Bd-positive populations exhibited a higher adult recruitment and a higher male reproductive effort than Bd-negative populations. We also estimated population growth rates to explore whether recruitment compensated for the negative impacts of Bd on the survival of adults. In addition, we evaluated a potential demographic signal of compensatory recruitment (i.e. positive relationship between the proportion of juveniles and Bd prevalence) in response to Bd infection using raw count data from 13 R. darwinii populations. The high Bd prevalence population exhibited the highest male reproductive effort and the highest recruitment among the four monitored populations. This led to a growing population during the study period despite high mortality of adult hosts. In contrast, males from the population with low Bd prevalence had a low reproductive effort and this population, which had the lowest adult recruitment, was declining during the study period despite adults having a higher survival in comparison to the high Bd prevalence population. We also found a demographic signal of compensatory recruitment in response to Bd infection in our broader analysis of 13 R. darwinii populations. Our study underlines the importance of interpopulation variation in life-history strategies on the fate of host populations after infectious disease emergence. Our results also suggest that an increase in reproductive effort can be one of the processes underlying compensatory recruitment in populations of Bd-susceptible amphibians.


Genes as Cues of Relatedness and Social Evolution in Heterogeneous Environments.
There are many situations where relatives interact while at the same time there is genetic polymorphism in traits influencing survival and reproduction. Examples include cheater-cooperator polymorphism and polymorphic microbial pathogens. Environmental heterogeneity, favoring different traits in nearby habitats, with dispersal between them, is one general reason to expect polymorphism. Currently, there is no formal framework of social evolution that encompasses genetic polymorphism. We develop such a framework, thus integrating theories of social evolution into the evolutionary ecology of heterogeneous environments. We allow for adaptively maintained genetic polymorphism by applying the concept of genetic cues. We analyze a model of social evolution in a two-habitat situation with limited dispersal between habitats, in which the average relatedness at the time of helping and other benefits of helping can differ between habitats. An important result from the analysis is that alleles at a polymorphic locus play the role of genetic cues, in the sense that the presence of a cue allele contains statistical information for an organism about its current environment, including information about relatedness. We show that epistatic modifiers of the cue polymorphism can evolve to make optimal use of the information in the genetic cue, in analogy with a Bayesian decision maker. Another important result is that the genetic linkage between a cue locus and modifier loci influences the evolutionary interest of modifiers, with tighter linkage leading to greater divergence between social traits induced by different cue alleles, and this can be understood in terms of genetic conflict.


[Childhood bacterial meningitis trends in Japan from 2005 to 2006].
We surveyed pediatric bacterial meningitis epidemiology from January 2005 to December 2006 in Japan, with the following results. Bacterial meningitis cases numbered 246 -138 boys and 108 girls-, equivalent to 1.7-1.72 children of 1,000 hospitalized in pediatrics per year. The age distribution for infection was highest in those under 1 year of age and decreased with increasing age, Haemophilus influenzae was the most common infection causing the pathogen, followed by Streptococcus pneumoniae, group B streptococcus, and Escherichia coli. The relationship between causative pathogens and age distribution was as follows: group B streptococcus and E. coli were major pathogens in patients under 4 months old and H. influenzae and S. pneumoniae in those over 4 months old. Susceptibility tests at individual facilities showed 59.3% of H. influen- zae isolates and 69.3% of S. pneumoniae isolates in 2004 to be drug-resistant. Ampicillin and cephem antibiotics are effective against GBS, E. coli, and Listeria, so combined of ampicillin and cephem antibiotics are used as first-line antibiotics in many facilities in patients under 4 month old and combined of carbapenem antibiotics effective against PRSP and cephem effective against H. influenzae were the first choice against childhood bacterial meningitis in patients over 4 month old.


(Benzoyl-acetonato-κ(2) O,O')dicarbonyl-rhodium(I).
In the title compound, [Rh(C10H9O2)(CO)2], a distorted square-planar coordination geometry is observed around the Rh(I) atom, formed by the O atoms of the bidentate ligand and two C atoms from the carbonyl ligands. The Rh(I) atom is displaced from the plane through the surrounding atoms by 0.017 Å. In the crystal, C-H⋯O inter-action is observed between a methyl group of the bidentate ligand and a carbonyl O atom. Metallophilic inter-actions [3.308 (3) and 3.461 (3) Å] between neighbouring Rh(I) atoms are encountered in the crystal, resulting in the formation of a metal chain along the b-axis direction.


Gene activation cascade triggered by a single photoperiodic cycle inducing flowering in Sinapis alba.
Molecular genetic analyses in Arabidopsis disclosed a genetic pathway whereby flowering is induced by the photoperiod. This cascade is examined here within the time course of floral transition in the long-day (LD) plant Sinapis alba induced by a single photoperiodic cycle. In addition to previously available sequences, the cloning of CONSTANS (SaCO) and FLOWERING LOCUS T (SaFT) homologues allowed expression analyses to be performed to follow the flowering process step by step. A diurnal rhythm in SaCO expression in the leaves was observed and transcripts of SaFT were detected when light was given in phase with SaCO kinetics only. This occurred when day length was extended or when a short day was shifted towards a 'photophile phase'. The steady-state level of SaFT transcripts in the various physiological situations examined was found to correlate like a rheostat with floral induction strength. Kinetics of SaFT activation were also consistent with previous estimations of translocation of florigen out of leaves, which could actually occur after the inductive cycle. In response to one 22-h LD, initiation of floral meristems by the shoot apical meristem (SAM) started about 2 days after activation of SaFT and was marked by expression of APETALA1 (SaAP1). Meanwhile, LEAFY (SaLFY) was first up-regulated in leaf primordia and in the SAM. FRUITFULL (SaFUL) was later activated in the whole SAM but excluded from floral meristems. These patterns are integrated with previous observations concerning upregulation of SUPPRESSOR OF OVEREXPRESSION OF CO1 (SaSOC1) to provide a temporal and spatial map of floral transition in Sinapis.


Large and rapid melt-induced velocity changes in the ablation zone of the Greenland Ice Sheet.
Continuous Global Positioning System observations reveal rapid and large ice velocity fluctuations in the western ablation zone of the Greenland Ice Sheet. Within days, ice velocity reacts to increased meltwater production and increases by a factor of 4. Such a response is much stronger and much faster than previously reported. Over a longer period of 17 years, annual ice velocities have decreased slightly, which suggests that the englacial hydraulic system adjusts constantly to the variable meltwater input, which results in a more or less constant ice flux over the years. The positive-feedback mechanism between melt rate and ice velocity appears to be a seasonal process that may have only a limited effect on the response of the ice sheet to climate warming over the next decades.


The beta 3-adrenergic receptor gene Trp64Arg mutation is overrepresented in obese women. Effects on weight, BMI, abdominal fat, blood pressure, and reproductive history in an elderly Australian population.
A tryptophan to arginine (Trp64Arg) mutation in the beta 3-adrenergic receptor (beta 3-AR) gene has been implicated in diabetes and obesity. We investigated the relationship of the beta 3-AR gene mutation with total body weight, BMI, central abdominal fat, blood pressure (BP), and reproductive history in 686 elderly subjects (429 women, 257 men; mean age 69.8 +/- 6.9 [+/-SD] years) from a cross section of a normal population in Australia. About 14% of the test population were heterozygote carriers of the Trp64Arg mutation; however, significant effects on clinical parameters were only observed in women. The frequency of the mutation was significantly increased in obese women compared with lean women (BMI > or = 27: 20% compared with BMI < 27: 11%, P = 0.02). Significantly higher total body weight (67.5 +/- 12.9 vs. 64.1 +/- 12.2 kg, P = 0.03) and BMI (26.3 +/- 4.7 vs. 25.1 +/- 4.5 kg/m2, P = 0.03) was observed in heterozygote women compared with normal subjects (homozygous for tryptophan). Central abdominal fat was not significantly different, except in women under 70 years, where heterozygotes had 16% higher abdominal fat compared with normal subjects. Female heterozygotes had significantly higher diastolic BP, even after adjustment for age and BMI (88.9 +/- 11.1 vs. 84.2 +/- 10.8 mmHg, P = 0.003) and a longer reproductive life, with an earlier menarche (12.8 +/- 1.3 vs. 13.4 +/- 1.5 years, P = 0.006), a higher gravidity (4.4 +/- 2.4 vs. 3.5 +/- 2.1, P = 0.01), and higher parity (3.8 +/- 2.0 vs. 3.0 +/- 1.9, P = 0.005). Clearly, the beta 3-AR mutation has pleiotrophic effects on a number of physiological systems, including BMI, BP, and reproductive history, perhaps suggesting evolutionary reasons for its maintenance in the population.


The evolutionary path to terminal differentiation and division of labor in cyanobacteria.
A common trait often associated with multicellularity is cellular differentiation, which is a spatial separation of tasks through the division of labor. In principle, the division of labor does not necessarily have to be constrained to a multicellular setting. In this study, we focus on the possible evolutionary paths leading to terminal differentiation in cyanobacteria. We develop mathematical models for two developmental strategies. First, of populations of terminally differentiated single cells surviving by the exchange of common goods. Second, of populations exhibiting terminal differentiation in a multicellular setting. After testing the two strategies against the effect of disruptive mutations (i.e. "cheater" mutants), we assess the effects of selection on the optimization of the ratio of vegetative (carbon fixing) to heterocystous (nitrogen fixing) cells, which in turn leads to the maximization of the carrying capacity for the population density. In addition, we compare the performance of differentiated populations to undifferentiated ones that temporally separate tasks in accordance to a day/night cycle. We then compare some predictions of our model with phylogenetic relationships derived from analyzing 16S rRNA sequences of different cyanobacterial strains. In line with studies indicating that group or spatial structure are ways to evolve cooperation and protect against the spread of cheaters, our work shows that compartmentalization afforded by multicellularity is required to maintain the vegetative/heterocyst division in cyanobacteria. We find that multicellularity allows for selection to optimize the carrying capacity. These results and the phylogenetic analysis indicates that terminally differentiated cyanobacteria evolved after undifferentiated species. In addition, we show that, in regimes of short daylight periods, terminally differentiated species perform worse than undifferentiated species that follow the day/night cycle; indicating that undifferentiated species have an evolutionary advantage in regimes of short daylight periods.


Structures, energetics, and dynamics of helium adsorbed on isolated fullerene ions.
Helium adsorbed on C(60)(+) and C(70)(+) exhibits phenomena akin to helium on graphite. Mass spectra suggest that commensurate layers form when all carbon hexagons and pentagons are occupied by one He each, but that the solvation shell does not close until 60 He atoms are adsorbed on C(60)(+), or 62 on C(70)(+). Molecular dynamics simulations of C(60)He(n)(+) at 4 K show that the commensurate phase is solid. Helium added to C(60)He(32)(+) will displace some atoms from pentagonal sites, leading to coexistence of a registered layer of immobile atoms interlaced with a nonregistered layer of mobile atoms.


Association of androgenetic alopecia and hypertension.
Androgenetic alopecia is considered to be associated with coronary heart disease but the explanation of this association remains unknown. Hypertension is highly prevalent in patients with coronary heart disease. Essential hypertension is linked to hyperaldosteronism and spironolactone, an antihypertensive drug which is a mineralocorticoid receptor antagonist, has been used for a long time in the treatment of androgenic alopecia. We recently observed in a double transgenic mouse model that overexpression of a mineralocorticoid receptor targeted to the skin induced the development of alopecia. We prospectively studied the association of hypertension and androgenetic alopecia in Caucasian men. Two hundred and fifty Caucasian men aged 35-65 years were consecutively recruited by 5 general practitioners (50 per practitioner). Data collected included age, androgenetic alopecia score with a simplified Norwood's score (0-4), blood pressure or history of hypertension, smoking, history of diabetes mellitus or hyperlipidemia, familial history of androgenetic alopecia, and treatment. Chi-square, Fisher exact tests and linear regression model were used for statistical analysis. Hypertension was strongly associated to androgenetic alopecia (p < 0.001). Linear regression tests confirmed that this association was independent of age : odds ratio was 2.195 (95% CI : 1.1-4.3). Familial history of androgenetic alopecia was also strongly associated with androgenetic alopecia : odds ratio was 10.870 (95% CI : 4.3-27.1). Other variables (diabetes mellitus, hyperlipidemia, smoking, treatment) were not associated with androgenetic alopecia. We were limited by a relatively small study sample but in this study androgenetic alopecia was strongly associated with hypertension. Association of androgenetic alopecia and hyperaldosteronism warrants additional studies. The use of specific mineralocorticoid receptor antagonists could be of interest in the treatment of androgenetic alopecia.


Development and validation of a generalizable model for predicting major transfusion during spine fusion surgery.
Surgery for posterior spine instrumentation often requires major transfusion. The aim of this study was to develop and test the validity of a model for predicting intraoperative major transfusion (>4 U total red blood cells), based on preoperative patient and surgical variables, that was applicable to adult patients undergoing cervical, thoracic, and/or lumbar spine deformity surgery with and without osteotomies. The perioperative data from 548 patients who underwent ≥ 3 levels of posterior spinal fusion with instrumentation between January 1, 2003 and May 30, 2009, were retrospectively collected to create a model for predicting major blood transfusion. The validity of the model was retrospectively tested with a separate data set of 95 patients who underwent surgery from June 1, 2009 through September 30, 2010. There was a 59.5% incidence of major transfusion in the derivation set of patients. Independent predictors of major transfusion were operation duration, number of posterior levels instrumented, surgical complexity score, and preincision hemoglobin. This model was able to predict major transfusion significantly better than a previously published model (ROCAUC=0.89; 99% confidence interval, 0.80-0.90; P<0.001). Our model has an increased accuracy for predicting the probability of major transfusion compared with a previously published model. In addition, our model is applicable to all types of spine fusion surgery and accounts for the complexity of surgical instrumentation, the number of levels instrumented, and the predicted duration of surgery as independent variables.


Balloons in endovascular neurosurgery: history and current applications.
The use of balloons in the field of neurosurgery is currently an essential part of our clinical practice. The field has evolved over the last 40 years since Serbinenko used balloons to test the feasibility of occluding cervical vessels for intracranial pathologies. Since that time, indications have expanded to include sacrificing cervical and intracranial vessels with detachable balloons, supporting the coil mass in wide-necked aneurysms (balloon remodeling technique), and performing intracranial and cervical angioplasty for atherosclerotic disease, as well as an adjunct to treat arteriovenous malformations. With the rapid expansion of endovascular technologies, it appears that the indications and uses for balloons will continue to expand. In this article, we review the history of balloons, the initial applications, the types of balloons available, and the current applications available for endovascular neurosurgeons.


Initial route of antigen administration alters the T-cell cytokine profile produced in response to the mouse pneumonitis biovar of Chlamydia trachomatis following genital infection.
A Th1-type response develops following vaginal infection with the mouse pneumonitis biovar of Chlamydia trachomatis (MoPn). Since the type of response, i.e., Th1 versus Th2, can be influenced by factors present during T-cell activation, we examined the effects of different routes of MoPn administration on the cytokine profile and resistance against infection following a MoPn vaginal challenge. A dominant Th1-type cytokine profile developed in mice given live MoPn via the intranasal, oral, and vaginal routes with ratios of gamma interferon-secreting cells to interleukin 4-secreting cells greater than 10. In contrast, mice injected subcutaneously produced a Th2-type profile with a gamma interferon/interleukin 4 ratio of only 0.7. These mice also had significantly higher anti-MoPn immunoglobulin G1 serum titers, confirming a Th2-type cytokine profile. Exposure of mice to live MoPn, by any route prior to vaginal challenge, resulted in a shortened course of infection. However, the subcutaneous group resolved the vaginal infection more slowly, with 60% (6 of 10 mice) of the mice still isolation positive 12 days after challenge compared with only 20% of mice given live MoPn by other routes. Administration of UV-inactivated MoPn did not provide protection against a vaginal challenge. The decreased ability to clear infection was not associated with a shift in the cytokine profile, since intranasal and oral administration of UV-inactivated MoPn resulted in a predominant Th1-type response. Taken together, these data indicate that the initial route of MoPn administration can direct the type of response produced after a local MoPn infection and thus influence the ability of the immune response to protect against subsequent infection.


Predicting Take-All Severity in Second-Year Wheat Using Soil DNA Concentrations of Gaeumannomyces graminis var. tritici Determined with qPCR.
The lack of accurate detection of Gaeumannomyces graminis var. tritici inoculum in soil has hampered efforts to predict the risk of severe take-all for wheat growers. The current study used a molecular method to quantify soil G. graminis var. tritici concentrations in commercial wheat fields in New Zealand and to compare them with the proportion of crops surpassing the thresholds for visible and moderate to severe take-all over three growing seasons. The study evaluated a soil G. graminis var. tritici DNA-based take-all prediction system developed in Australia, with four take-all risk categories. These categories were found to be useful for predicting disease severity in second wheat but did not clearly separate risk between fields in medium- and high-risk categories. A sigmoidal relationship was identified between inoculum concentration and the proportion of fields exceeding the two disease thresholds. A logistic response curve was used to further examine this relationship and evaluate the boundaries between take-all risk categories. G. graminis var. tritici boundaries between medium- and high-risk categories were clustered near or within the upper plateau of the relationship. Alternative G. graminis var. tritici boundaries for a three-category system were identified that provided better separation of take-all risk between categories. This information could improve prediction of the risk of severe take-all.


Averrhoa bilimbi fruits attenuate hyperglycemia-mediated oxidative stress in streptozotocin-induced diabetic rats.
Hyperglycemia-mediated oxidative stress plays a major role in the development of diabetic complications. Averrhoa bilimbi Linn. (Oxalidaceae) is a medicinal plant with fruits reported to possess antidiabetic activity. This study evaluated the beneficial effects of the ethyl acetate fraction of A. bilimbi fruit (ABAEE) on the antioxidant/oxidant status in diabetes mellitus. Diabetic rats were treated orally with the ethyl acetate fraction of A. bilimbi fruits at a dose of 25 mg/kg body weight for 60 days. Serum glucose, glycated hemoglobin, plasma insulin, hepatic toxicity markers, antioxidant enzymes, lipid peroxidation products, and liver histopathology were assayed checked after 60 days of extract treatment. Diabetic rats administered ABAEE showed a significant decline in serum glucose, glycated hemoglobin, and also significantly increases the level of plasma insulin, as well as a notable attenuation in thiobarbituric acid-reactive substances, conjugated dienes, and hydroperoxides. ABAEE also modulated hepatic antioxidant potential by significantly increasing the activities of catalase, glutathione peroxidase, glutathione reductase, superoxide dismutase, and reducing glutathione content. The results associated with ABAEE were more significant than those observed following treatment with the standard drug metformin. Histopathological observations showed that ABAEE effectively rescued hepatocytes from oxidative damage without affecting cellular function and structural integrity. High-performance liquid chromatography analysis of ABAEE indicated the presence of phenolic compound, quercetin, indicating that the antidiabetic effect of the extract might be related to quercetin. These results demonstrated the potential beneficial effect of ABAEE on streptozotocin-induced diabetes in rats.


EXPERIMENTAL STUDIES ON THE ADMINISTRATION OF SALVARSAN BY MOUTH TO ANIMALS AND MAN.
Salvarsan in capsule and in solution in doses varying from 0.1 to 0.6 of a gram was administered by mouth to seven patients suffering from syphilis. Five patients were given full doses of 0.6 of a gram. One patient (case 3) received in the aggregate within four weeks 2.4 grams without loss of weight or any disturbing effects. An ulcerating gumma of the knee was practically healed after a period of five weeks. This was the only patient of the seven, however, in whom notable improvement in the cutaneous manifestations followed the administration of the drug. This ulceration would probably have healed as soon, or possibly sooner, under the influence of mercury and the iodids. From the above observations, it would appear that salvarsan administered by mouth up to the full dose of 0.6 of a gram, has a perceptible though feeble therapeutic effect on cutaneous syphilitic manifestations. We should naturally expect the influence of any drug to be more evident in the case of a gumma, in which spirochaetes are only sparsely present, than in the secondary syphilides in which the spirochaetes are present in enormous numbers. Cutaneous gummata are readily healed at times by very small doses of mercury or iodids. It is interesting to note that the administration of the full dose of the drug by mouth does not appear to give rise to symptoms of systemic arsenical poisoning, unless the vomiting and diarrhea be regarded as such. After some of the full dose administrations, there was neither vomiting nor diarrhea. As salvarsan contains 34 per cent. of arsenic, these patients received the equivalent of five grains of arsenic. In case 3, in the course of four weeks the patient took by mouth the equivalent of over twelve grains of arsenic, without vomiting or having diarrhea, and with no loss of weight or disturbance of health. The urine of this patient was entirely normal. It would seem, therefore, that salvarsan is not converted in the gastro-intestinal tract into an organotropic arsenical compound, and it is possible that it may remain practically unchanged.


Strengthening participation by young women sex workers in HIV programs: reflections on a study from Bangkok, Thailand.
Participation is an accepted means of increasing the effectiveness of public health programs, and as such, it is considered an important component of HIV interventions targeting at-risk youth. The situation of young women sex workers in Thailand is alarming on many fronts, including that of HIV risk. As a result, HIV programs in Thailand are the key interventions undertaken in relation to young women sex workers' health. A small-scale study used semistructured interviews to explore the participation reports of five young women sex workers, as well as the related views of two community support workers, who lived and worked in Bangkok, Thailand. This study is considered in the light of current research on - as well as new opportunities and challenges offered for - participation by vulnerable groups in the context of digital society. Thematic analysis of the interview data identified barriers to participation, including the illegality of sex work, fear, and lack of trust of the authorities, as well as widespread social stigma. Such barriers resulted in young women seeking anonymity. Yet, promisingly, young women positioned themselves as experts; they are involved in peer education and are supportive of greater involvement in HIV programs, such as further educational initiatives and collective actions. There is a need for a more empowerment-oriented participation practice positioning young women sex workers as expert educators and codecision makers within a model of participation that is also accountable, such as including young women as members of program boards. Beyond current norms, there are new opportunities emerging because of the increasing availability of smartphone/Internet technology. These can support activist and codesign participation by young women sex workers in HIV programs. However, any developments in participation must maximize opportunities carefully, taking into consideration the difficult social environment faced by young women sex workers as well as the need for strategies to address illegality and stigma.


Synthetic glycopolymers as modulators of protein aggregation: influences of chemical composition, topology and concentration.
Novel drug excipients are required to achieve stable formulations of protein drug candidates. Synthetic glycopolymers have been shown in some cases to improve protein formulation stability, although their structure-function relationship remains unknown. Here we report the synthesis of linear or 4-arm star glycopolymers with different molecular topology and chemical composition, with mannose, galactose, arabinose, N-acetyl glucosamine, lactose and trehalose pendant units - and investigate their modulation of conformational stability and aggregation propensity of a model monoclonal antibody (mAb1). Mono-and di-saccharides with free reducing ends are not frequently utilised as protein stabilisers, due to potential reactivity with protein's amine group. In this study, this was circumvented through the use of a stable acetal linker connecting the polymer backbone to the sugar pendant residues, which made the latter virtually non-reactive with amines. The general destabilisation of the antibody was determined as an unfolding transition temperature (Tm) of CH2 and Fab structural domains, and aggregation temperature (Tagg). The most prominent effect of the glycopolymers on a temperature induced stress in low concentration solutions was a decrease in Tm and Tagg, regardless of the sugar composition or glycopolymer topology - in contrast to the stabilising effect of the corresponding mono- and di-saccharide constituents. The exceptions of linear-lactose and star-trehalose glycopolymers, which increased Tm of the mAb Fab region and Tagg, however, highlight a more complex structure-function relationship. Accelerated stability studies of the highly concentrated mAb solutions (50 mg mL-1) revealed that the increased glycopolymer concentrations generally decreased the mAb stability, as judged by the amount of mAb1 'monomer' molecules in solution, with star- and linear-trehalose glycopolymers further generating visible aggregates. Interestingly the latter effect could not have been predicted from the Tm or Tagg experiments conducted in a low concentration regime. Taken together, the data demonstrate the influence of a complex interplay of sugar chemistry and molecular topology of the synthetic glycopolymers on their modulation of protein conformational stability and aggregation propensity. The solution concentration was also an important parameter contributing to the stability modulation, and suggests that the stabilising properties of a sugar as a mono- or di-saccharide cannot be extrapolated to the corresponding glycopolymers.


Behaviour of acid secretion, gastrin release, serum pepsinogen I, and gastric emptying of liquids over six months from eradication of helicobacter pylori in duodenal ulcer patients. A controlled study.
The behaviour of basal and stimulated acid secretion, gastrin release, serum pepsinogen I, and gastric emptying of liquids was studied in 19 consecutive patients with Helicobacter pylori positive duodenal ulcer, over a follow up period of six months. Eleven patients were studied before and at three and six months after eradication with lansoprazole plus amoxicillin and tinidazole (case group), whereas the remainder, with persistent H pylori infection, were studied before and after three and six months from ulcer healing, thus constituting the control group. In the case group, three months after eradication, fasting serum pepsinogen I fell from (mean (SEM)) 91.9 (6.9) (pretreatment) to 72.2 (5.1) ng/l and the integrated gastrin response to a meal reduced from 11,470 (1174) (pretreatment) to 8130 (608) pg/ml/h (p < 0.05). Fasting serum gastrin concentrations and maximal acid output reduced significantly only six months after eradication. In contrast, no significant change of any of these measurements was seen in the control group either at three or six months from healing compared with the pretreatment values. Gastric emptying of liquids did not change over the entire period of follow up in both study groups. In conclusion, eradication of H pylori in duodenal ulcer patients is accompanied by a rapid fall in serum pepsinogen I and plasma gastrin concentrations, whereas a slight but significant reduction of maximal acid secretion takes place later on. In contrast, gastric emptying of liquids does not seem to be influenced by H pylori status.


The person-based development and realist evaluation of a summary report for GP consultations [version 1; peer review: 2 approved].
Use of telephone, video and e-consultations is increasing. These can make consultations more transactional. This study aimed to develop a complex intervention to address patients' concerns more comprehensively in general practice and test the feasibility of this in a cluster-randomised framework.The complex intervention used two technologies: a patient-completed pre-consultation form used at consultation opening and a doctor-provided summary report provided at consultation closure. This paper reports on the development and realist evaluation of the summary report. A person-based approach was used to develop the summary report. An electronic protocol was designed to automatically generate the report after GPs complete a clinical template in the patient record. This was tested with 45 patients in 3 rounds each, with iterative adjustments made based on feedback after each round. Subsequently, an intervention incorporating the pre-consultation form with the summary report was then tested in a cluster-randomised framework with 30 patients per practice in six practices: four randomised to intervention, and two to control. An embedded realist evaluation was carried out. The main feasibility study results are reported elsewhere. Intervention Development: 15 patients were recruited per practice. Eight patients and six GPs were interviewed and 18 changes made. The summary report improved substantially; GPs and patients in the final practice were more satisfied with the report than the first practice.Realist evaluation: The summary was most useful for consultations when safety-netting advice was important or with multiple complex follow-up steps in patients who have difficulty remembering or communicating. It generated greater clarity on the follow-up and greater patient empowerment and reassurance. The person-based approach was successful. The summary report creates clarity, empowerment and reassurance in certain consultations and patients. As it takes a few minutes per patient, GPs prefer to select patients who will benefit most.


Liquid crystal dynamics in a photonic crystal cavity created by selective microfluidic infiltration.
A microfluidic double heterostructure cavity is created in a silicon planar photonic crystal waveguide by selective infiltration of a liquid crystal. The spectral evolution of the cavity resonances probed by evanescent coupling reveals that the liquid crystal evaporates, even at room temperature, despite its relatively low vapor pressure of 5 × 10(-3) Pa. We explore the infiltration and evaporation dynamics of the liquid crystal within the cavity using a Fabry-Perot model that accounts for the joint effects of liquid volume reduction and cavity length variation due to liquid evaporation. While discussing how the pattern of the infiltrated liquid can be optimized to restrict evaporation, we find that the experimental behavior is consistent with basic microfluidic relations considering the small volumes of liquids and large surface areas present in our structure.


MIF synergizes with Trypanosoma cruzi antigens to promote efficient dendritic cell maturation and IL-12 production via p38 MAPK.
Macrophage migration inhibitory factor (MIF) has been found to be involved in host resistance to several parasitic infections. To determine the mechanisms of the MIF-dependent responses to Trypanosoma cruzi, we investigated host resistance in MIF⁻/⁻ mice (on the BALB/c background) during an intraperitoneal infection. We focused on the potential involvement of MIF in dendritic cell (DC) maturation and cytokine production. Following a challenge with 5 x 10(3)T. cruzi parasites, wild type (WT) mice developed a strong IL-12 response and adequate maturation of the draining mesenteric lymph node DCs and were resistant to infection. In contrast, similarly infected MIF⁻/⁻ mice mounted a weak IL-12 response, displayed immature DCs in the early phases of infection and rapidly succumbed to T. cruzi infection. The lack of maturation and IL-12 production by the DCs in response to total T. cruzi antigen (TcAg) was confirmed by in vitro studies. These effects were reversed following treatment with recombinant MIF. Interestingly, TcAg-stimulated bone marrow-derived DCs from both WT and MIF⁻/⁻ mice had increased ERK1/2 MAPK phosphorylation. In contrast, p38 phosphorylation was only upregulated in WT DCs. Reconstitution of MIF to MIF⁻/⁻ DCs upregulated p38 phosphorylation. The MIF-p38 pathway affected MHC-II and CD86 expression as well as IL-12 production. These findings demonstrate that the MIF-induced early DC maturation and IL-12 production mediates resistance to T. cruzi infection, probably by activating the p38 pathway.


Radiative decay engineering: the role of photonic mode density in biotechnology.
Fluorescence detection is a central technology in biological research and biotechnology. A vast array of fluorescent probes are available with diverse spectral properties. These properties were 'engineered' into fluorophores by modification of the chemical structures. Essentially, all present uses of fluorescence rely on the radiation of energy into optically transparent media, the free space which surrounds the fluorophores. In this paper, we summarize an opportunity for novel fluorescence technology based on modification of the photonic mode density around the fluorophore and thus control of its spectral properties. This modification can be accomplished by proximity of fluorophores to metallic particles of gold, silver and possibly others. By engineering the size and shape of the metal particles, and the location of the fluorophores relative to the surfaces, fluorophores can be quenched, display increases in quantum yield, and changes in lifetime. Fluorophore-metal surface combinations can even display directional rather than isotropic emission. We describe recent experimental results and suggest potential biomedical applications of fluorophore-metal particle interactions.


Thumb-Sucking, Nail-Biting, and Atopic Sensitization, Asthma, and Hay Fever.
The hygiene hypothesis suggests that early-life exposure to microbial organisms reduces the risk of developing allergies. Thumb-sucking and nail-biting are common childhood habits that may increase microbial exposures. We tested the hypothesis that children who suck their thumbs or bite their nails have a lower risk of developing atopy, asthma, and hay fever in a population-based birth cohort followed to adulthood. Parents reported children's thumb-sucking and nail-biting habits when their children were ages 5, 7, 9, and 11 years. Atopic sensitization was defined as a positive skin-prick test (≥2-mm weal) to ≥1 common allergen at 13 and 32 years. Associations between thumb-sucking and nail-biting in childhood, and atopic sensitization, asthma, and hay fever at these ages were assessed by using logistic regression with adjustments for sex and other potential confounding factors: parental atopy, breastfeeding, pet ownership, household crowding, socioeconomic status, and parental smoking. Thirty-one percent of children were frequent thumb-suckers or nail-biters at ≥1 of the ages. These children had a lower risk of atopic sensitization at age 13 years (odds ratio 0.67, 95% confidence interval 0.48-0.92, P = .013) and age 32 years (odds ratio 0.61, 95% confidence interval 0.46-0.81, P = .001). These associations persisted when adjusted for multiple confounding factors. Children who had both habits had a lower risk of atopic sensitization than those who had only 1. No associations were found for nail-biting, thumb-sucking, and asthma or hay fever at either age. Children who suck their thumbs or bite their nails are less likely to have atopic sensitization in childhood and adulthood.


Spatial distribution of power coupling in self-pumped photorefractive reflection gratings.
The spatial distribution of the power transfer achieved by contradirectional two-beam coupling using self-pumped photorefractive reflection gratings is investigated in two materials with different photorefractive gain coefficients, LiNbO3:Fe and KNbO3:Fe. Incremental portions of the volume grating are erased optically by inducing thin optical damage planes, reducing the overall two-beam coupling efficiency. By monitoring the effect of local grating disruption, the distribution of power transfer is spatially resolved throughout the crystal, and the results are found to be in agreement with our theoretical predictions.


Comparison of the genomes of the wild-type French viscerotropic strain of yellow fever virus with its vaccine derivative French neurotropic vaccine.
The French neurotropic vaccine, or FNV, was used extensively in Africa to control yellow fever (YF). Although efficacious, the vaccine caused an unacceptable rate of post-vaccinal complications in children and was subsequently replaced by the 17D vaccine. Here we report that the genomes of the wild-type YF virus French viscerotropic virus and its attenuated vaccine derivative, FNV virus from the Institut Pasteur, Paris, (FNV-IP) differ by 77 nucleotides encoding 35 amino acid substitutions. Comparison of FNV-IP and three other isolates of FNV with other YF vaccine strains (17D-204 and 17DD derived from wild-type strain Asibi) revealed that during the two attenuation processes two common nucleotide changes arose that encode two amino acid substitutions: one is in the membrane protein at amino acid 35 (M-35), the other in non-structural (NS) protein 4B at NS4B-95. These common substitutions may be important in the process of attenuation of viscerotropic disease for humans and monkeys, and/or may be involved in loss of mosquito competence of the vaccine viruses.


Responses of hydrophobic and hydrophilic groups in Nafion differentiated by least squares modeling of infrared spectra recorded during thin film hydration.
Least squares modeling was applied to gain insights into changes that occur in the structure of Nafion polymer membrane during hydration. Transmission infrared spectra followed changes in the strong polymer bands in the range of 1400-950 cm(-1) during water uptake by initially dry membrane upon exposure to 100% relative humidity atmosphere. Spectra recorded during hydration were fit to a rate equation that modeled the loss of a dry state accompanied by the development of a hydrated state. The evolution of the two states was described by an equation for diffusion in a cylindrical pore in the long time limit. Comparison of the experimental spectra in a data set to spectra calculated from the pure components derived by least squares modeling gave an excellent match for bands of the -CF2 and C-O-C group modes, but agreement was not as close for bands arising from modes of the hydrophilic -SO3(-) group and (modeled separately) water. The differences are discussed in terms of the likelihood that the -SO3(-) groups have stronger interactions with bulk-like water condensed in the membrane and therefore undergo more complex changes than do more hydrophobic polymer regions during hydration. A different model is necessary to describe the evolution of spectral features for water and -SO3(-) end groups during water uptake into Nafion thin films.


Epileptic seizures and occupational exposure to solvents: a cases series.
Organic solvents (OS) are substances with well-known nervous system tropism. Long-term exposure can cause several neurological and neuropsychic manifestations (mainly toxic encephalopathy). A potential causal relation between epileptic seizures and exposure to OS remains controversial. We report seven cases of patients with no neurological history who had been professionally exposed to OS and who had at least one epileptic seizure after exposure. Selection of these cases was based on medical records of patients who were referred to the occupational health department of Charles Nicolle Hospital of Tunis during the period from January 1, 2010 to December 31, 2014. Cases studies concerned five men and two women aged between 29 and 46. Professional seniority ranged from 2 to 31 years. In all cases, epileptic seizures occurred after exposure to a mixture of solvents. It was concluded, according to workplace inspections, that there was an important daily and direct OS exposure. Working conditions were considered as defective. Six cases had generalized seizures, one patient presented with status epilepticus. Illness onset occurred between one and nine years after the beginning of exposure to OS. These cases suggest a possible relationship between OS exposure and onset of epilepsy.


Nutrition Education in Portuguese Medical Students: Impact on the Attitudes and Knowledge.
Nutrition has been underrepresented in the curriculum of many medical schools and therefore physicians do not feel adequately prepared to provide dietary counselling. The aim of the present study is to determine the impact of a Nutrition and Metabolism curricular unit on nutrition attitudes, knowledge and confidence on future clinical practice of medical students. All the students enrolled in the curricular unit (2017/2018) were invited to complete a questionnaire assessing their nutritional knowledge and eating habits at the beginning and at the end of the semester (n = 310). Initially, students reported good eating habits and nutrition knowledge. These aspects improved at the end of the study. Moreover, students reported that they felt more confident to do dietary counselling after intervention. Most medical students answered affirmatively to all questions related with good habits or eating behaviours, and the acquisition of knowledge had an impact in specific attitudes. After the Nutrition and Metabolism classes the students felt able to provide dietary counselling in different clinical settings, but none of the students felt extremely confident about their competencies for dietary counselling. This can be due to the fact that the students involved were in the first year of the integrated master's degree in medicine, which is a preclinical year, and thus distant from the medical reality and from contact with patients. Nutrition education can have a positive impact on attitudes and eating behaviours, knowledge and in the perception of competencies for dietary counselling.


The Vulnerable Attachment Style Questionnaire (VASQ): an interview-based measure of attachment styles that predict depressive disorder.
The Vulnerable Attachment Style Questionnaire (VASQ) was developed to provide a brief self-report tool to assess adult attachment style in relation to depression and validated against an existing investigator-based interview (Attachment Style Interview--ASI). This paper describes the development and scoring of the VASQ and its relationship to poor support and major depression. Items for the VASQ reflected behaviours, emotions and attitudes relating to attachment relationship style, drawn directly from the ASI. The VASQ was validated against the ASI for 262 community-based subjects. Test-retest was determined on 38 subjects. Factor analysis derived two factors, labelled 'insecurity' and 'proximity-seeking'. The VASQ insecurity dimension had highest mean scores for those with interview-based Angry-dismissive and Fearful styles and was significantly correlated with degree of interview-based insecurity. The proximity-seeking VASQ scores had highest mean for those with Enmeshed interview attachment style and was uncorrelated with ASI insecurity. VASQ scores were highly correlated with a well-known self-report measure of insecure attachment (Relationship Questionnaire) and text-retest reliability of the VASQ was satisfactory. The total VASQ score and the insecurity subscale proved highly related to poor support and to depressive disorder. This was not the case for the proximity-seeking subscale. The VASQ is a brief self-report measure that distinguishes individuals with attachment styles vulnerable for depressive disorder. The use of the measure for screening in research and clinical contexts is discussed.


Potentiation of cyclic adenosine monophosphate production by thrombin in the human erythroleukemia cell line, HEL.
The human erythroleukemia cell line (HEL) has been used as a model system for studying signal transduction processes as they might relate to platelet/megakaryocyte function. We were interested in examining the role of thrombin in the regulation of adenylyl cyclase in this cell line. As opposed to its predominantly inhibitory effects on cyclic AMP production in platelets or in membranes from HEL cells, our initial experiments in intact HEL cells revealed that thrombin markedly potentiated the cyclic AMP response to prostaglandin E1 (2.9 +/- 0.2-fold), prostacyclin (1.9 +/- 0.2-fold) and carbacyclin (2.5 +/- 0.5-fold), measured either by radioimmunoassay or by the [3H]adenine preloading procedure. Thrombin, although ineffective alone, also potentiated cyclic AMP production stimulated by vasoactive intestinal peptide (1.6 +/- 0.2-fold), cholera toxin (3.0 +/- 0.6-fold) and AIF4- (2.3 +/- 0.6-fold), but not by forskolin (0.9 +/- 0.1-fold). The thrombin effect 1) produced an increase in the efficacy of the prostaglandins with no change in potency; 2) was long-lived; 3) required the proteolytic activity of thrombin; 4) was insensitive to pertussis toxin; and 5) was at least partially mimicked by trypsin, extracellular ATP and UTP, platelet activating factor and activators of protein kinase C. Down-regulation of protein kinase C or pre-exposure to the protein kinase inhibitor staurosporine blocked the potentiating effect. Together, these results suggest that in HEL cells, the mechanism of thrombin potentiation of cyclic AMP production may involve alterations in the interaction between stimulatory guanine nucleotide binding protein and the catalytic subunit of adenylyl cyclase, possibly involving protein kinase C-mediated phosphorylation.


2011 nutritional assessment guidelines.
Careful assessment of nutritional needs of dogs and cats must be taken into consideration in order to maintain optimum health, be part of a treatment regimen for a diseased state, or to maximise the quality of life in all animals. Therefore, the goal of these WSAVA Guidelines is that a nutritional assessment and specific nutritional recommendation be made on every patient on every visit. This will become known as the 5th Vital Assessment (5VA), following the four vital assessments of temperature, pulse, respiration and pain that are already addressed on each patient interaction. Routinely doing a brief screening evaluation of the nutritional status during history taking and the physical examination can be seamlessly performed as part of every patient exam. Nutrition-related risk factors that can be easily identified from the history and physical examination include age (growing or old), suboptimal body condition score (overweight or thin), muscle loss, atypical or homemade diet, medical conditions, or changes in appetite. An extended evaluation would follow, if one or more risk factors is identified on screening. These guidelines provide criteria to evaluate the animal and the diet, as well as key feeding and environmental factors. In addition, recommendations for interpretation, analysis, and action are included so that a plan for optimising the animal's nutritional status can be instituted. Client compliance with nutritional recommendations requires input from the veterinarian, veterinary technicians/nurses, and the hospital staff. A team approach to continuous nutritional education, implementation of appropriate protocols, and focused client communication, utilising these WSAVA Nutritional Guidelines, are key components to reach this 5VA goal.


Enhancing access to the Bibliome: the TREC 2004 Genomics Track.
The goal of the TREC Genomics Track is to improve information retrieval in the area of genomics by creating test collections that will allow researchers to improve and better understand failures of their systems. The 2004 track included an ad hoc retrieval task, simulating use of a search engine to obtain documents about biomedical topics. This paper describes the Genomics Track of the Text Retrieval Conference (TREC) 2004, a forum for evaluation of IR research systems, where retrieval in the genomics domain has recently begun to be assessed. A total of 27 research groups submitted 47 different runs. The most effective runs, as measured by the primary evaluation measure of mean average precision (MAP), used a combination of domain-specific and general techniques. The best MAP obtained by any run was 0.4075. Techniques that expanded queries with gene name lists as well as words from related articles had the best efficacy. However, many runs performed more poorly than a simple baseline run, indicating that careful selection of system features is essential. Various approaches to ad hoc retrieval provide a diversity of efficacy. The TREC Genomics Track and its test collection resources provide tools that allow improvement in information retrieval systems.


Giant two-dimensional gel electrophoresis: methodological update and comparison with intermediate-format gel systems.
Two-dimensional (2-D) gel electrophoresis methods for separating complex mixtures of proteins have not changed fundamentally since their original description in the late 1970's. Nevertheless, 2-D gel resolution has improved substantially as a result of a series of incremental modifications. One of these was the development of the "giant-gel" format, using gels measuring at least 30 x 30 cm to provide the highest resolution 2-D gel system available. As originally described, this procedure has several important limitations: it requires custom-built equipment; it is expensive in terms of time, reagents, film and support matrices; and it generates gels which are difficult to manupulate, particularly for silver staining. This report describes modifications in the giant gel procedure to permit use of a commercially available gel apparatus and to obtain giant gels of improved mechanical strength suitable for silver staining. The resolution of giant gels is compared with that obtained using two systems currently being marketed for use by laboratories performing large numbers of 2-D gel analyses. The smaller format gels resolved fewer proteins, by 30-40%, compared with the giant gels. This difference in resolving power suggests that giant gels will continue to be useful in selected applications.


Sociocultural tailoring of a healthy lifestyle intervention to reduce cardiovascular disease and type 2 diabetes risk among Latinos.
Suboptimal lifestyle factors in combination with genetic susceptibility contribute to cardiovascular disease and type 2 diabetes risk among Latinos. We describe a community-academic collaboration that developed and explored the feasibility of implementing a socioculturally tailored, healthy lifestyle intervention integrating genomics and family history education to reduce risk of cardiovascular disease and type 2 diabetes among Latinos. The community-based participatory research was conducted with communities in Kentucky, which has a rapidly growing Latino population. This growth underscores the need for socioculturally appropriate health resources. Su Corazon, Su Vida (Your Heart, Your Life) is a Spanish-language, healthy lifestyle educational program to reduce cardiovascular disease and type 2 diabetes risk among Latinos. Twenty natural leaders from an urban Latino community in Kentucky participated in sociocultural tailoring of the program and development of a genomics and family history module. The tailored program was presented to 22 participants to explore implementation feasibility and assess appropriateness for community use. Preintervention and postintervention assessments of genomic knowledge and lifestyle behaviors and qualitative postintervention evaluations were conducted. Postintervention improvements in health-promoting lifestyle choices and genomic knowledge specific to cardiovascular disease and type 2 diabetes suggested that the program may be effective in reducing risk. Feedback indicated the program was socioculturally acceptable and responsive to community needs. These findings indicated that a tailored healthy lifestyle program integrating genomics and family history education was socioculturally appropriate and may feasibly be implemented to reduce cardiovascular disease and type 2 diabetes risk in a Latino community with limited health care resources. The project highlights contributions of community-based processes in tailoring interventions that are appropriate for community contexts.


2016 Updated American Society of Clinical Oncology/Oncology Nursing Society Chemotherapy Administration Safety Standards, Including Standards for Pediatric Oncology.
Purpose To update the ASCO/Oncology Nursing Society (ONS) Chemotherapy Administration Safety Standards and to highlight standards for pediatric oncology. Methods The ASCO/ONS Chemotherapy Administration Safety Standards were first published in 2009 and updated in 2011 to include inpatient settings. A subsequent 2013 revision expanded the standards to include the safe administration and management of oral chemotherapy. A joint ASCO/ONS workshop with stakeholder participation, including that of the Association of Pediatric Hematology Oncology Nurses and American Society of Pediatric Hematology/Oncology, was held on May 12, 2015, to review the 2013 standards. An extensive literature search was subsequently conducted, and public comments on the revised draft standards were solicited. Results The updated 2016 standards presented here include clarification and expansion of existing standards to include pediatric oncology and to introduce new standards: most notably, two-person verification of chemotherapy preparation processes, administration of vinca alkaloids via minibags in facilities in which intrathecal medications are administered, and labeling of medications dispensed from the health care setting to be taken by the patient at home. The standards were reordered and renumbered to align with the sequential processes of chemotherapy prescription, preparation, and administration. Several standards were separated into their respective components for clarity and to facilitate measurement of adherence to a standard. Conclusion As oncology practice has changed, so have chemotherapy administration safety standards. Advances in technology, cancer treatment, and education and training have prompted the need for periodic review and revision of the standards. Additional information is available at http://www.asco.org/chemo-standards .


Surfactant changes during experimental pneumocystosis are related to Pneumocystis development.
Pneumocystosis-related surfactant changes have been reported in both humans and corticosteroid-treated experimental hosts. As corticosteroids induce an increase in pulmonary surfactant, some findings could be considered as controversial. The aim of this study was to investigate whether the surfactant composition changes during experimental pneumocystosis were related to the Pneumocystis development. In this work two corticosteroid-untreated animal models were used: rabbits, which develop spontaneous pneumocystosis at weaning; and severe combined immunodeficiency mice, which were intranasally inoculated with Pneumocystis carinii. Surfactant phospholipid and protein content was explored by bronchoalveolar lavage. The in vitro effect of surfactant on P. carinii growth was also explored. In the two models, the surfactant phospholipid/protein ratio was significantly increased, whereas parasite rates were low. This ratio decreases with the slope increase of the parasite growth curve. These early surfactant changes suggested that Pneumocystis proliferation requires alveolar lining fluid changes, and that normal surfactant is not suitable for parasite development. In this way, in vitro experiments presented here have revealed an inhibitory effect of synthetic or seminatural surfactants on the P. carinii growth. Further studies are needed to determine how Pneumocystis induces the reported early modifications of the surfactant, and why the parasite development is inhibited by pulmonary surfactant.


Dental workplace exposure and effect on fertility.
This study assessed occupational exposure in dental surgeries on the basis of the reported use of dental materials and techniques and applied waiting-time-to-pregnancy methodology to study fertility in relation to the occupational exposure. Data were collected retrospectively using a self-administered postal questionnaire addressing the occupational and reproductive history of the participants. The study groups consisted of 558 female dental surgeons and 450 high school teachers that had given birth in Norway to at least 1 living child. The present study comprised data from a total of 1408 pregnancies. The effects of practicing dentistry and of the given workplace exposure on fertility were analyzed with the discrete proportional hazard regression method. Most of the female dental surgeons were using amalgam for fillings during the period they tried to conceive, and 1/3 placed more than 50 fillings a week. Tooth-colored fillings were in limited use. Prior to 75% of the pregnancies, the dental surgeons reported handling chloroform-based root canal sealers. Forty percent of the dental surgeons were daily exposed to disinfectants containing ethanol and benzene. No difference was found in fertility between the dental surgeons and the high school teachers. Exposure to mercury, chloroform, and benzene was not associated with decreased fertility, except for a possible effect of mercury in the last pregnancy of multiparous dental surgeons. Occupational exposures had no clear adverse effects on fertility among the female dental surgeons studied.


Physicians' perceptions of the effect of nonclinical factors on coronary revascularization.
The main objective of this study was to determine if physicians perceive that extracardiac or nonclinical factors such as patients' financial status, lifestyle, or trust in the physician impact coronary revascularization decisions. A self-administered questionnaire was developed and mailed to a random sample of 1200 family physicians, internists, cardiologists, and cardiothoracic surgeons who were active members of well-respected medical organizations in the United States. Survey questions were rated on a 4- and 5-point Likert scale to determine whether physicians perceive that nonclinical factors impede or facilitate coronary revascularization, respectively. The survey response rate was 70%. Family physicians were most likely to perceive that unhealthy lifestyle (51%), financial barriers (48%), and lack of social support (31%) probably or definitely precluded revascularization. White physicians (52%) were more likely to perceive that distrust in the physician affected revascularization, compared with black (33%), Hispanic (38%) and Asian (40%) physicians. Mean responses regarding how often (1 = rarely to 5 = most of the time) nonclinical factors facilitate revascularization revealed that women and Hispanic physicians were more likely to perceive male patients had easier access to the procedure (mean response, 2.8 for women versus 2.1 for men; 2.8 for Hispanics versus 2.4 for blacks and 2.1 for whites). Physicians perceived that nonclinical factors influence decision making for coronary revascularization. What needs to be further explored is whether such factors affect actual patient outcomes or contribute to disparities in the utilization of cardiac interventions.


Hospital discharge of respiratory-technology-dependent children: role of a dedicated respiratory care discharge coordinator.
Preparation of respiratory-technology-dependent children for hospital discharge presents many challenges. Adequate training and education of parental caregivers, discharge planning, and coordination with the durable-medical-equipment and home-nursing companies must be completed. A process using multiple respiratory therapists (RTs) to achieve this may not be efficient. We evaluated our model, in which a dedicated RT discharge coordinator provides education and coordinates discharge planning of respiratory-technology-dependent pediatric patients. This system provides a single contact for caregivers and outside agencies, a single respiratory-care educator for the caregivers, and a clinical pathway that involves the entire multidisciplinary team. Patient length of stay and customer satisfaction were evaluated before and after implementation of the discharge-coordinator program. Our dedicated-RT-discharge-coordinator model was associated with rapid initiation of frequent family-training sessions. Durable-medical-equipment-company personnel reported that they had increased satisfaction with the quality of training of the family caregivers. The members of the hospital multidisciplinary team had increased satisfaction with the discharge process. Patient length of stay nonsignificantly decreased after the implementation of the discharge-coordinator program. There are several advantages to using a dedicated RT-discharge-coordinator system for home-discharge preparation of respiratory-technology-dependent children.


High mobility group box 1 and adenosine are both released by endothelial cells during hypothermic preservation.
Hypothermic preservation of solid allografts causes profound damage of vascular endothelial cells. This, in turn, might activate innate immunity. In the present study we employed an in vitro model to study to what extent supernatants of damaged endothelial cells are able to activate innate immunity and to study the nature of these signals. The expression of high mobility group box 1 (HMGB1) and adhesion molecules on human umbilical vein endothelial cell was studied by immunofluorescence, fluorescence activated cell sorter and Western blotting. Cytokine production was performed by enzyme-linked immunosorbent assay. HMGB1 expression was lost completely in endothelial cells after hypothermic preservation. This was associated with cell damage as it occurred only in untreated endothelial cell but not in cells rendered resistant to hypothermia-mediated damage by dopamine treatment. Only supernatants from hypothermia susceptible cells up-regulated the expression of interleukin (IL)-8 and adhesion molecules in cultured endothelial cells in an HMGB1-dependent manner. In whole blood assays, both supernatants of hypothermia susceptible and resistant cells inhibited tumour necrosis factor (TNF)-alpha production concomitantly with an increased IL-10 secretion. The activity of the supernatants was already found after 6 h of hypothermic preservation, and paralleled the decrease in intracellular adenosine triphosphate (ATP) levels. Modulation of TNF-alpha and IL-10 production by these supernatants was abrogated completely by prior treatment with adenosine deaminase and was similar to the response of an A2R agonist. Our study demonstrates that both HMGB1 and adenosine are released during hypothermic preservation. While release of HMGB1 is caused by cell damage, release of adenosine seems to be related to ATP hydrolysis, occurring in both susceptible and resistant cells.


Profiling the humoral immune response of acute and chronic Q fever by protein microarray.
Antigen profiling using comprehensive protein microarrays is a powerful tool for characterizing the humoral immune response to infectious pathogens. Coxiella burnetii is a CDC category B bioterrorist infectious agent with worldwide distribution. In order to assess the antibody repertoire of acute and chronic Q fever patients we have constructed a protein microarray containing 93% of the proteome of Coxiella burnetii, the causative agent of Q fever. Here we report the profile of the IgG and IgM seroreactivity in 25 acute Q fever patients in longitudinal samples. We found that both early and late time points of infection have a very consistent repertoire of IgM and IgG response, with a limited number of proteins undergoing increasing or decreasing seroreactivity. We also probed a large collection of acute and chronic Q fever patient samples and identified serological markers that can differentiate between the two disease states. In this comparative analysis we confirmed the identity of numerous IgG biomarkers of acute infection, identified novel IgG biomarkers for acute and chronic infections, and profiled for the first time the IgM antibody repertoire for both acute and chronic Q fever. Using these results we were able to devise a test that can distinguish acute from chronic Q fever. These results also provide a unique perspective on isotype switch and demonstrate the utility of protein microarrays for simultaneously examining the dynamic humoral immune response against thousands of proteins from a large number of patients. The results presented here identify novel seroreactive antigens for the development of recombinant protein-based diagnostics and subunit vaccines, and provide insight into the development of the antibody response.


Measuring forces at the leading edge: a force assay for cell motility.
Cancer cells become mobile by remodelling their cytoskeleton to form migratory structures. This transformation is dominated by actin assembly and disassembly (polymerisation and depolymerisation) in the cytoplasm. Synthesis of filamentous actin produces a force at the leading edge that pushes the plasma membrane forward. We describe an assay to measure the restoring force of the membrane in response to forces generated within the cytoplasm adjacent to the membrane. A laser trap is used to form a long membrane nanotube from a living cell and to measure the axial membrane force at the end of the tube. When the tube, resembling a filopodium, is formed and in a relaxed state the axial membrane force exhibits a positive stationary value. This value reflects the influence of the cytoskeleton that acts to pull the tube back to the cell. A dynamic sawtooth force that rides upon the stationary value is also observed. This force is sensitive to a toxin that affects actin assembly and disassembly, but not affected by agents that influence microtubules and myosin light chain kinase. We deduce from the magnitude and characteristics of dynamic force measurements that it originates from depolymerisation and polymerisation of F-actin. The on- and off-rates, the number of working filaments, and the force per filament (2.5 pN) are determined. We suggest the force-dependent transitions are thermodynamically uncoupled as both the on- and off-rates decrease exponentially with a compressive load. We propose kinetic schemes that require attachment of actin filaments to the membrane during depolymerisation. This demonstrates that actin kinetics can be monitored in a living cell by measuring force at the membrane, and used to probe the mobility of cells including cancer cells.


Identification of hairy cell leukemia subset defining p35 as the human homologue of Ii.
A molecule defining a subset of patients with hairy cell leukemia (HCL) on the basis of being abundantly labeled with [35S]methionine, was demonstrated to be the human homologue of murine Ii, a glycoprotein which lacks alloantigenic variation and is associated non-covalently with Ia antigens. In one-dimensional SDS-polyacrylamide gradient gel electrophoresis, the HCL-subset-defining molecule migrated with HLA-DR molecules which were immunoprecipitated with a specific heteroantiserum. These molecules were further defined in two-dimensional, SDS and non-equilibrium pH gradient electrophoresis of either membrane preparations or immunoprecipitates formed with various antibodies. [35S]methionine-labeling of the HCL-subset-defining molecule was greater in hairy leukemic cells than in lymphoblastoid cell lines. The subset-defining species was associated non-covalently with HLA-DR alpha and beta chains and ran electrophoretically at a position described for murine and human Ii molecules (in terms of pI and weight). Metabolic labeling of HLA-A,-B and -DR was also increased in HCL cells relative to lymphoblastoid cell lines. A separate protein, of 41,000 mol. wt and pI of 7-8, resembled another Ii-associated molecule which has been described in murine and human studies.


Drug-induced sleep endoscopy as a selection tool for mandibular advancement therapy by oral device in patients with mild to moderate obstructive sleep apnoea.
Nowadays oral appliance therapy is recognised as an effective therapy for many patients with primary snoring and mild to moderate obstructive sleep apnoea (OSA), as well as those with more severe OSA who cannot tolerate positive airway pressure (PAP) therapies. For this reason, it is important to focus on objective criteria to indicate which subjects may benefit from treatment with a mandibular advancement device (MAD). Various anthropometric and polysomnographic predictors have been described in the literature, whereas there are still controversies about the role of drug-induced sleep endoscopy (DISE) and advancement bimanual manoeuvre as predictor factors of treatment outcome by oral device. Herein, we report our experience in treatment of mild moderate OSA by oral appliance selected by DISE. We performed a single institution, longitudinal prospective evaluation of a consecutive group of mild moderate patients with obstructive sleep apnoea syndrome who underwent DISE. During sleep endoscopy, gentle manoeuvre of mandibular advancement less than 5 mm was performed. In 30 of 65 patients (46.2%) we obtained an unsuccessful improvement of airway patency whereas in 35 of 65 patients (53.8%) the improvement was successful and patients were considered suitable for oral device application. Because 7 of 35 patients were excluded due to conditions interfering with oral appliance therapy, we finally treated 28 patients. After 3 months of treatment, we observed a significant improvement in the Epworth medium index [(7.35 ± 2.8 versus 4.1 ± 2.2 (p < 0.05)], in mean AHI [(21.4 ± 6 events per hour versus 8.85 ± 6.9 (p < 0.05)] and in mean ODI [(18.6 ± 8 events per hour to 7 ± 5.8 (p < 0.05)]. We observed that the apnoea/hypopnoea index (AHI) improved by up to 50% from baseline in 71.4% of patients selected after DISE for MAD therapy. In the current study, mandibular advancement splint therapy was successfully prescribed on the basis not only of severity of disease, as determined by the subject's initial AHI, but also by DISE findings combined with results of gentle mandibular advancement manoeuvre allowing direct view of the effects of mandibular protrusion on breathing spaces in obstruction sites, and showing good optimisation of selection of patients for oral device treatment.


Balloon kyphoplasty compared to vertebroplasty and nonsurgical management in patients hospitalised with acute osteoporotic vertebral compression fracture: a UK cost-effectiveness analysis.
The purpose of the study was to estimate the cost-effectiveness of balloon kyphoplasty compared to nonsurgical management and vertebroplasty for the treatment of hospitalised osteoporotic vertebral compression fractures in the UK. A cost-effectiveness model was constructed and used for analysis. Balloon kyphoplasty may be cost-effective compared to relevant alternatives. The objective of this study was to estimate the cost-effectiveness of balloon kyphoplasty (BKP) for the treatment of patients hospitalised with acute osteoporotic vertebral compression fracture (OVCF) compared to percutaneous vertebroplasty (PVP) and nonsurgical management (NSM) in the UK. A Markov simulation model was developed to evaluate treatment with BKP, NSM and PVP in patients with symptomatic OVCF. Data on health-related quality of life (HRQoL) with acute OVCF were derived from the FREE and VERTOS II randomised clinical trials (RCTs) and normalised to the NSM arm in the FREE trial. Estimated differences in mortality among the treatments and costs for NSM were obtained from the literature whereas procedure costs for BKP and PVP were obtained from three National Health Service hospitals. It was assumed that BKP and PVP reduced hospital length of stay by 6 days compared to NSM. The incremental cost-effectiveness ratio was estimated at Great Britain Pound Sterling (GBP) 2,706 per quality-adjusted life year (QALY) and GBP 15,982 per QALY compared to NSM and PVP, respectively. Sensitivity analysis showed that the cost-effectiveness of BKP vs. NSM was robust when mortality and HRQoL benefits with BKP were varied. The cost-effectiveness of BKP compared to PVP was particularly sensitive to changes in the mortality benefit. BKP may be a cost-effective strategy for the treatment of patients hospitalised with acute OVCF in the UK compared to NSM and PVP. Additional RCT data on the benefits of BKP and PVP compared to simulated sham surgery and further data on the mortality benefits with BKP compared to NSM and PVP would reduce uncertainty.


Tropical and subtropical Asia's valued tree species under threat.
Tree diversity in Asia's tropical and subtropical forests is central to nature-based solutions. Species vulnerability to multiple threats, which affect provision of ecosystem services, is poorly understood. We conducted a region-wide, spatially explicit assessment of the vulnerability of 63 socioeconomically important tree species to overexploitation, fire, overgrazing, habitat conversion, and climate change. Trees were selected for assessment from national priority lists, and selections were validated by an expert network representing 20 countries. We used Maxent suitability modeling to predict species distribution ranges, freely accessible spatial data sets to map threat exposures, and functional traits to estimate threat sensitivities. Species-specific vulnerability maps were created as the product of exposure maps and sensitivity estimates. Based on vulnerability to current threats and climate change, we identified priority areas for conservation and restoration. Overall, 74% of the most important areas for conservation of these trees fell outside protected areas, and all species were severely threatened across an average of 47% of their native ranges. The most imminent threats were overexploitation and habitat conversion; populations were severely threatened by these factors in an average of 24% and 16% of their ranges, respectively. Our model predicted limited overall climate change impacts, although some study species were likely to lose over 15% of their habitat by 2050 due to climate change. We pinpointed specific natural areas in Borneo rain forests as hotspots for in situ conservation of forest genetic resources, more than 82% of which fell outside designated protected areas. We also identified degraded areas in Western Ghats, Indochina dry forests, and Sumatran rain forests as hotspots for restoration, where planting or assisted natural regeneration will help conserve these species, and croplands in southern India and Thailand as potentially important agroforestry options. Our results highlight the need for regionally coordinated action for effective conservation and restoration.


Detecting silent seizures by their sound.
The traditional approach to interpreting electroencephalograms (EEGs) requires physicians with formal training to visually assess the waveforms. This approach can be less practical in critical settings where a trained EEG specialist is not readily available to review the EEG and diagnose ongoing subclinical seizures, such as nonconvulsive status epilepticus. We have developed a novel method by which EEG data are converted to sound in real time by letting the underlying electrophysiological signal modulate a voice tone that is in the audible range. Here, we explored whether individuals without any prior EEG training could listen to 15-second sonified EEG and determine whether the EEG represents seizures or nonseizure conditions. We selected 84 EEG samples to represent seizures (n = 7), seizure-like activity (n = 25), or nonperiodic, nonrhythmic activity (normal or focal/generalized slowing, n = 52). EEGs from single channels in the left and right hemispheres were then converted to sound files. After a 4-minute training video, medical students (n = 34) and nurses (n = 30) were asked to designate each audio sample as "seizure" or "nonseizure." We then compared their performance with that of EEG-trained neurologists (n = 12) and medical students (n = 29) who also diagnosed the same EEGs on visual display. Nonexperts listening to single-channel sonified EEGs detected seizures with remarkable sensitivity (students, 98% ± 5%; nurses, 95% ± 14%) compared to experts or nonexperts reviewing the same EEGs on visual display (neurologists, 88% ± 11%; students, 76% ± 19%). If the EEGs contained seizures or seizure-like activity, nonexperts listening to sonified EEGs rated them as seizures with high specificity (students, 85% ± 9%; nurses, 82% ± 12%) compared to experts or nonexperts viewing the EEGs visually (neurologists, 90% ± 7%; students, 65% ± 20%). Our study confirms that individuals without EEG training can detect ongoing seizures or seizure-like rhythmic periodic patterns by listening to sonified EEG. Although sonification of EEG cannot replace the traditional approaches to EEG interpretation, it provides a meaningful triage tool for fast assessment of patients with suspected subclinical seizures.


Sensitivity of a Large and Representative Sample of Antarctic Marine Invertebrates to Metals.
There are limited data on the sensitivity to contaminants of marine organisms in polar regions. Consequently, assessments of the risk of contaminants to marine biota in polar environments typically include extrapolations from temperate and/or tropical species. This is problematic because the taxonomic composition of organisms differs between polar and temperate/tropical waters, and both the toxicity of chemicals and the physiology of organisms are very different at the stable low temperatures experienced in polar marine systems. Collecting high-quality sensitivity data for a wide range of marine polar organisms using traditional toxicity assessment approaches is a time-consuming and difficult process, especially in remote and hostile environments. We applied a rapid toxicity testing approach, which allowed a much larger number of species to be tested than would be possible with traditional toxicity test methods, albeit with lower replications and fewer exposure concentrations. With this rapid approach, sensitivity estimates are less precise, but more numerous. This is important when constructing species sensitivity distributions (SSDs), which aim to represent the sensitivity of communities. We determined the approximate sensitivity (4- and 10-d median lethal concentration [LC50] values) of a large and representative sample of Antarctic marine invertebrates to copper (Cu), zinc (Zn), and cadmium (Cd). Up to 88 LC50 values (from 88 different taxa) were used in the construction of SSDs. The hazardous concentrations for 1% of taxa (HC1) based on 10-d LC50 values were 37, 346, and 792 μg/L for Cu, Zn, and Cd, respectively. Our results provide a basis for estimating the risk of exposure to metals for a large representative sample of marine polar invertebrates. Environ Toxicol Chem 2019;38:1560-1568. © 2019 SETAC.


Factor XII inhibition reduces thrombus formation in a primate thrombosis model.
The plasma zymogens factor XII (fXII) and factor XI (fXI) contribute to thrombosis in a variety of mouse models. These proteins serve a limited role in hemostasis, suggesting that antithrombotic therapies targeting them may be associated with low bleeding risks. Although there is substantial epidemiologic evidence supporting a role for fXI in human thrombosis, the situation is not as clear for fXII. We generated monoclonal antibodies (9A2 and 15H8) against the human fXII heavy chain that interfere with fXII conversion to the protease factor XIIa (fXIIa). The anti-fXII antibodies were tested in models in which anti-fXI antibodies are known to have antithrombotic effects. Both anti-fXII antibodies reduced fibrin formation in human blood perfused through collagen-coated tubes. fXII-deficient mice are resistant to ferric chloride-induced arterial thrombosis, and this resistance can be reversed by infusion of human fXII. 9A2 partially blocks, and 15H8 completely blocks, the prothrombotic effect of fXII in this model. 15H8 prolonged the activated partial thromboplastin time of baboon and human plasmas. 15H8 reduced fibrin formation in collagen-coated vascular grafts inserted into arteriovenous shunts in baboons, and reduced fibrin and platelet accumulation downstream of the graft. These findings support a role for fXII in thrombus formation in primates.


The immunomodulation of endotoxin-induced acute lung injury by hesperidin in vivo and in vitro.
To investigate the modulation of lung local immune responses of hesperidin (HES) on the acute lung inflammation induced by LPS in vivo. Mice were challenged with intratracheal lipopolysaccharide (100 microg) 30 min before with treatment hesperidin (200 mg/kg oral administration) or vehicle. After 4 and 24 h, bronchoalveolar lavage fluid was obtained to measure proinflammatory (TNF-alpha, IL-1 beta, IL-6), anti-inflammatory (IL-10, IL-4, IL-12) cytokines, chemokines (KC, MCP-1 and MIP-2), total cell counts, nitric oxide production, and proteins. Lung histology was performed in inflated-fixed lungs. Hesperidin downregulate the LPS-induced expression of TNF-alpha, IL-1 beta, IL-6, KC, MIP-2, MCP-1, and IL-12. It also enhanced the production of IL-4, IL-10. Total leukocyte counts; nitric oxide production, iNOS expression, and proteins were significantly decreased by hesperidin. In vitro, HES suppressed the expression of IL-8 on A549 cells and THP-1 cells, the expression of TNF-alpha, IL-1 beta, and IL-6 on THP-1 cells, the expression of ICAM-1 and VCAM-1 on A549 cells which effect cell adhesion function. The suppression of those molecules is controlled by NF-kappaB and AP-1, which are activated by I kappa B and MAPK pathways. HES inhibits those pathways, thereby suppressing the expression of IL-8, TNFalpha, IL-1 beta, IL-6, IL-12, ICAM-1 and VCAM-1. This study indicates that HES had a markedly immunomodulatory effect in a clinically relevant model of ARDS. Nevertheless, further investigations are required to determine the potential clinical usefulness of HES in the adjunctive therapy of ARDS.


Role of carbonic anhydrases in the progression of renal cell carcinoma subtypes: proposal of a unified hypothesis.
Renal cell carcinoma (RCC) has the highest rate of occurrence within the US when compared with other countries. Recent advances in the basic research and molecular diagnostics of this malignancy have revealed that RCC is not a single disease, but it is a mixture of several types of malignancies with unique molecular mechanisms and pathological attributes. RCC is now divided into clear cell carcinoma (80% of all kidney cancers), papillary type 1 and papillary type 2 neoplasms (10-15% of all RCC patients) and RCC with chromophobic and oncocytic features, called the Birt-Hogg-Dube (BHD) subtype, in roughly 5% of all patients. Apart from these, neoplasms such as the tuberous sclerosis (TSC) syndrome may occur with a mixed pathological features with a renal presentation. In this review, molecular evidence, both direct and indirect, published so far on all these RCC subtypes have been analyzed to find out whether there is any common thread that could run through these disparate malignancies that happen to occur in a single organ, i.e., the kidney. We believe that the role played by the expression and certain non-traditional activities of the cabonic anhydrase (CA) family members, along with the differing levels of hypoxia induced within these tumors may be the most common denominators. Evidence is presented focusing on how the CA family members could participate in the genesis and progression of each and every one of these RCC subtypes and how their function could be influenced by hypoxia, activities of receptor type protein tyrosine kinases and certain other pre-disposing factors. These rationalizations point towards a unified hypothesis that may help explain the occurrence of all these RCC subtypes in a molecular manner. We hope that these analyses would a) stimulate further studies aimed toward a better understanding of the role played by carbonic anhydrases in RCC subtypes and b) would pave way to a better and rationally designed therapies to interfere with their function to benefit patients with RCC and possibly other cancers.