A whispering bat that screams: bimodal switch of foraging guild from gleaning to aerial hawking in the desert long-eared bat.
Echolocating bats have historically been classified as either loud aerial hawkers or whispering gleaners. Some bat species can forage in multiple ways and others have demonstrated limited flexibility in the amplitude of their echolocation calls. The desert long-eared bat, Otonycteris hemprichii, has been said to be a passive gleaning whispering bat preying on terrestrial arthropods such as scorpions. Using an acoustic tracking system, we recorded individuals flying at foraging and drinking sites and compared their flight height, flight speed, call duration, pulse interval and source levels with those of gleaning individuals previously recorded using the same setup. We found differences in all variables with the strongest difference in source levels, where bats called at a mean of 119 dB peSPL (compared with 75 dB peSPL when gleaning). Bat faecal analysis indicated that their diet differed from previous studies and that prey species were capable of flight. We conclude that the bats switched from passive gleaning to capturing airborne insects (aerial hawking). Although whispering bats have been known to opportunistically catch insects on the wing, in the present study we show a full bimodal switch between foraging guilds with the respective changes in source level to those typical of a true aerial hawker.


Stable correction of a genetic deficiency in human cells by an episome carrying a 115 kb genomic transgene.
Persistent expression of a transgene at therapeutic levels is required for successful gene therapy, but many small vectors with heterologous promoters are prone to vector loss and transcriptional silencing. The delivery of genomic DNA would enable genes to be transferred as complete loci, including regulatory sequences, introns, and native promoter elements. These elements may be critical to ensure prolonged, regulated, and tissue-specific transgene expression. Many studies point to considerable advantages to be gained by using complete genomic loci in gene expression. Large-insert vectors incorporating elements of the bacterial artificial chromosome (BAC) cloning system, and the episomal maintenance mechanisms of Epstein-Barr virus (EBV), can shuttle between bacteria and mammalian cells, allowing large genomic loci to be manipulated conveniently. We now demonstrate the potential utility of such vectors by stably correcting a human genetic deficiency in vitro. When the complete hypoxanthine phosphoribosyltransferase (HPRT) locus of 115 kilobases (kb) was introduced into deficient human cells, the transgene was both maintained as an episome and expressed stably for six months in rapidly dividing cell cultures. The results demonstrate for the first time that gene expression from an episomal genomic transgene can correct a cell culture disease phenotype for a prolonged period.


Anaphylaxis.
Anaphylaxis is an acute, potentially fatal systemic allergic reaction with varied mechanisms and clinical presentations. Although prompt recognition and treatment of anaphylaxis are imperative, both patients and healthcare professionals often fail to recognize and diagnose early signs and symptoms of the condition. Clinical manifestations vary widely; however, the most common signs are cutaneous symptoms, including urticaria, angioedema, erythema and pruritus. Immediate intramuscular administration of epinephrine into the anterolateral thigh is first-line therapy, even if the diagnosis is uncertain. The mainstays of long-term management include specialist assessment, avoidance measures, and the provision of an epinephrine auto-injector and an individualized anaphylaxis action plan. This article provides an overview of the causes, clinical features, diagnosis and acute and long-term management of this serious allergic reaction.


Surface roughness influences the protein corona formation of glycosylated nanoparticles and alter their cellular uptake.
Recently the role of protein absorption in nanoparticle drug delivery has gathered significant attention as the protein corona can significantly decide on the fate of nanoparticles in the body. Although it is known that the surface chemistry will significantly influence the amount and type of bound protein, there is little known about the effect of surface roughness and surface topography on the interaction. In this work, we show how patchy nanoparticles can noticeably reduce the adsorption of proteins compared to spherical nanoparticles with a smooth surface as demonstrated using six ABC triblock terpolymers based on glucose, mannose and galactose. To obtain patchy nanoparticles, poly(2-d-sugar ethyl acrylate)-b-poly (n-butyl acrylate)-b-poly(4-vinyl pyridine) (PSugEA-b-PBuA-b-P4VP) was prepared by reversible addition-fragmentation chain-transfer (RAFT) polymerization and assembled into nanoparticles with a patch-like appearance and a hydrodynamic diameter of around 130-160 nm. As control, smooth nanoparticles were prepared from poly(2-d-sugar ethyl acrylate)-b-poly (n-butyl acrylate)-b-polystyrene (PSugEA-b-PBuA-b-PS). The patchy nanoparticles displayed significantly reduced protein absorption when exposed to serum-supplemented cell culture media, as observed using dynamic light scattering. The smooth particles, however, supported the formation of a large protein corona. Additionally, an enrichment of haemoglobin was observed in the corona compared to the serum protein in solution. The amount of albumin on the surface was observed to be dependent on the type of sugar with glucose resulting in the highest absorption. The protein corona led to cellular uptake that was unrelated to the underlying sugar, which was supposed to help targeting specific cell lines. This example demonstrated how the protein corona can override any attempts to target receptor expressing cells.


High-precision tracking of sperm swimming fine structure provides strong test of resistive force theory.
The shape of the flagellar beat determines the path along which a sperm cell swims. If the flagellum bends periodically about a curved mean shape then the sperm will follow a path with non-zero curvature. To test a simple hydrodynamic theory of flagellar propulsion known as resistive force theory, we conducted high-precision measurements of the head and flagellum motions during circular swimming of bull spermatozoa near a surface. We found that the fine structure of sperm swimming represented by the rapid wiggling of the sperm head around an averaged path is, to high accuracy, accounted for by resistive force theory and results from balancing forces and torques generated by the beating flagellum. We determined the anisotropy ratio between the normal and tangential hydrodynamic friction coefficients of the flagellum to be 1.81+/-0.07 (mean+/-s.d.). On time scales longer than the flagellar beat cycle, sperm cells followed circular paths of non-zero curvature. Our data show that path curvature is approximately equal to twice the average curvature of the flagellum, consistent with quantitative predictions of resistive force theory. Hence, this theory accurately predicts the complex trajectories of sperm cells from the detailed shape of their flagellar beat across different time scales.


Task-switching deficits and repetitive behaviour in genetic neurodevelopmental disorders: data from children with Prader-Willi syndrome chromosome 15 q11-q13 deletion and boys with Fragile X syndrome.
Prader-Willi syndrome (PWS) and Fragile X syndrome (FraX) are associated with distinctive cognitive and behavioural profiles. We examined whether repetitive behaviours in the two syndromes were associated with deficits in specific executive functions. PWS, FraX, and typically developing (TD) children were assessed for executive functioning using the Test of Everyday Attention for Children and an adapted Simon spatial interference task. Relative to the TD children, children with PWS and FraX showed greater costs of attention switching on the Simon task, but after controlling for intellectual ability, these switching deficits were only significant in the PWS group. Children with PWS and FraX also showed significantly increased preference for routine and differing profiles of other specific types of repetitive behaviours. A measure of switch cost from the Simon task was positively correlated to scores on preference for routine questionnaire items and was strongly associated with scores on other items relating to a preference for predictability. It is proposed that a deficit in attention switching is a component of the endophenotypes of both PWS and FraX and is associated with specific behaviours. This proposal is discussed in the context of neurocognitive pathways between genes and behaviour.


Outcomes of universal germline testing for men with prostate cancer in an Australian tertiary center.
The role of germline testing in prostate cancer is evolving and knowledge of an individual's genetic profile may be used to guide not only an assessment of their familial risk but also have prognostic and therapeutic implications. Although international guidelines have incorporated recommendations for germline testing in prostate cancer, there is little Australian data to guide referrals. The aim of this study is to review the frequency of relevant pathogenic mutations in an Australian center, their associated clinical factors and clinical impact. We conducted a single-center retrospective review of men with prostate cancer that undertook prospective germline testing using a targeted next generation sequencing panel. Results for 100 men were analyzed. Median age at diagnosis was 62 years (range 43-84); 92% had metastatic disease at referral. A pathogenic mutation was confirmed in 9%, a likely pathogenic variant in 2% and a variant of uncertain significance in 15%. Age ≤60 years was associated with an increased risk for a pathogenic germline variant (P = 0.0096). Two of the nine (22%) with pathogenic variants went on to receive targeted treatment. In this single center study, the incidence of germline mutations in genes associated with DNA-repair was consistent with rates seen previously published international series of men with metastatic disease. A pathogenic variant was only seen in one patient >60 years of age and no man referred solely on the basis of age or high-risk localized disease had a relevant finding.


Blindness and visual impairment in an American urban population. The Baltimore Eye Survey.
Data on the prevalence of blindness and visual impairment in multiracial urban populations of the United States are not readily available. The Baltimore Eye Survey was designed to address this lack of information and provide estimates of prevalence in age-race subgroups that had not been well studied in the past. A population-based sample of 5300 blacks and whites from east Baltimore, Md, received an ophthalmologic screening examination that included detailed visual acuity measurements. Blacks had, on average, a twofold excess prevalence of blindness and visual impairment than whites, irrespective of definition. Rates rose dramatically with age for all definitions of vision loss, but there was no difference in prevalence by sex. More than 50% of subjects improved their presenting vision after refractive correction, with 7.5% improving three or more lines. Rates in Baltimore are as high or higher than those reported from previous studies. National projections indicate that greater than 3 million persons are visually impaired, 890,000 of whom are bilaterally blind by US definitions.


HPV16 and increased risk of recurrence after treatment for CIN.
Addition of high-risk human papillomavirus (hrHPV) testing to post-treatment monitoring policies of women treated for high-grade cervical intraepithelial neoplasia (CIN) may improve the effectiveness of detecting recurrent/residual disease. Recent studies have shown that HPV type 16 confers an increased risk of high-grade CIN and cervical cancer. This study aimed to find out whether the post-treatment CIN3 rate is increased in HPV16-positive women treated for CIN3. We included 229 hrHPV-positive women treated for CIN3. HPV typing was performed by GP5+/6+-PCR followed by reverse line blotting on a cervical scrape taken before treatment. HPV typing data were related to the occurrence of post-treatment CIN3 within a median follow-up time of 20.1 months (range 3-85.4 months) following treatment. Twenty nine of the 151 (19%) HPV16-positive women versus 6 of the 78 (8%) women with other hrHPV types had recurrent/residual CIN3. Post-treatment CIN3 rate was significantly increased in women with HPV16 compared to those harboring other hrHPV types (p=0.03). None of the other hrHPV types were associated with higher post-treatment CIN3 rates. Women treated for HPV16 containing CIN3 should be monitored more intensively because of their increased risk of post-treatment CIN3. Thus, the HPV genotype should be considered in post-treatment monitoring policies.


Human papillomavirus testing for triage of women with cytologic evidence of low-grade squamous intraepithelial lesions: baseline data from a randomized trial. The Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesions Triage Study (ALTS) Group.
Human papillomavirus (HPV) infections appear to be central to the development of cervical cancer. This study addresses the question of whether testing women who have low-grade squamous intraepithelial lesions (LSILs) of the uterine cervix for HPV DNA is useful as a triage strategy. Four clinical centers in different areas of the United States participated in a randomized clinical trial of the use of HPV DNA testing in women with cytologic evidence of atypical squamous cells of undetermined significance (ASCUS) or LSIL. The study sample in this article consists only of women who had LSIL at enrollment. Within 6 months of an LSIL diagnosis (based on a Pap smear read by a community-based cytopathologist), women who were 18 years of age or older completed a standardized questionnaire and underwent a pelvic examination that included collection of cervical specimens for HPV DNA testing by Hybrid Capture II (HCII)(R) assay. Among the 642 women referred with LSIL who had analyzable test results, the mean chronologic age and age at first coitus were similar among the four clinical centers, despite the centers' ethnic and geographic diversity. Overall, HPV DNA was detected in cervical samples from 532 (82.9%) of the 642 women (95% confidence interval = 79.7%-85.7%). This high frequency of HPV positivity was confirmed by polymerase chain reaction (PCR) assays in a subset of 210 paired specimens tested by HCII and PCR (81.4% were positive by both methods). Because a very high percentage of women with an LSIL diagnosis from Pap smears are positive for HPV DNA by HCII testing, there is limited potential for this assay to direct decisions about the clinical management of women with LSIL. The role of HPV testing in the management of women with ASCUS is still under study.


Noise beating in hybrid phase-sensitive amplifier systems.
We investigate the effect of noise loading in a hybrid phase-sensitive amplifier system, analyzing the effect of noise beating between the signal and idler waves coupled in a parametric amplifier. Through analyzing input and output optical signal to noise ratios, we find that system performance of a phase-sensitive amplifier is 3 to 6 dB improved over a phase-insensitive amplifier, depending on the ratio of loaded noise power to that of vacuum fluctuations.


Neonatal calf infection with respiratory syncytial virus: drawing parallels to the disease in human infants.
Respiratory syncytial virus (RSV) is the most common viral cause of childhood acute lower respiratory tract infections. It is estimated that RSV infections result in more than 100,000 deaths annually worldwide. Bovine RSV is a cause of enzootic pneumonia in young dairy calves and summer pneumonia in nursing beef calves. Furthermore, bovine RSV plays a significant role in bovine respiratory disease complex, the most prevalent cause of morbidity and mortality among feedlot cattle. Infection of calves with bovine RSV shares features in common with RSV infection in children, such as an age-dependent susceptibility. In addition, comparable microscopic lesions consisting of bronchiolar neutrophilic infiltrates, epithelial cell necrosis, and syncytial cell formation are observed. Further, our studies have shown an upregulation of pro-inflammatory mediators in RSV-infected calves, including IL-12p40 and CXCL8 (IL-8). This finding is consistent with increased levels of IL-8 observed in children with RSV bronchiolitis. Since rodents lack IL-8, neonatal calves can be useful for studies of IL-8 regulation in response to RSV infection. We have recently found that vitamin D in milk replacer diets can be manipulated to produce calves differing in circulating 25-hydroxyvitamin D3. The results to date indicate that although the vitamin D intracrine pathway is activated during RSV infection, pro-inflammatory mediators frequently inhibited by the vitamin D intacrine pathway in vitro are, in fact, upregulated or unaffected in lungs of infected calves. This review will summarize available data that provide parallels between bovine RSV infection in neonatal calves and human RSV in infants.


Biogenesis of cytosolic ribosomes requires the essential iron-sulphur protein Rli1p and mitochondria.
Mitochondria perform a central function in the biogenesis of cellular iron-sulphur (Fe/S) proteins. It is unknown to date why this biosynthetic pathway is indispensable for life, the more so as no essential mitochondrial Fe/S proteins are known. Here, we show that the soluble ATP-binding cassette (ABC) protein Rli1p carries N-terminal Fe/S clusters that require the mitochondrial and cytosolic Fe/S protein biogenesis machineries for assembly. Mutations in critical cysteine residues of Rli1p abolish association with Fe/S clusters and lead to loss of cell viability. Hence, the essential character of Fe/S clusters in Rli1p explains the indispensable character of mitochondria in eukaryotes. We further report that Rli1p is associated with ribosomes and with Hcr1p, a protein involved in rRNA processing and translation initiation. Depletion of Rli1p causes a nuclear export defect of the small and large ribosomal subunits and subsequently a translational arrest. Thus, ribosome biogenesis and function are intimately linked to the crucial role of mitochondria in the maturation of the essential Fe/S protein Rli1p.


Nerve growth factor (NGF) prevents the shift in ocular dominance distribution of visual cortical neurons in monocularly deprived rats.
The hypothesis that NGF could play a role in the plasticity of the developing mammalian visual cortex was tested in monocularly deprived (MD) rats. In particular, we have asked whether an exogenous supply of NGF could prevent the changes in ocular dominance distribution induced by monocular deprivation. Hooded rats were monocularly deprived for 1 month, starting at postnatal day 14 (P14), immediately before eye opening, by means of eyelid suture. In eight rats, only monocular deprivation was performed; in eight rats, monocular deprivation was combined with intraventricular injections of beta-NGF, and in three rats, with intraventricular injections of cytochrome C. Injections (2 microliters) were given every other day for a period of 1 month. Single neuron activity was recorded in the primary visual cortex of MD rats, MD rats treated with NGF, and MD rats treated with cytochrome C at the end of the deprivation period, and in normal rats of the same age. We found that monocular deprivation caused a striking change in the ocular dominance distribution of untreated MD rats, reducing binocular cells by a factor of two and increasing by a factor of eight the number of cells dominated by the nondeprived eye. In MD NGF-treated rats, the ocular dominance distribution was indistinguishable from the normal. Cytochrome C treatment was completely ineffective in preventing the ocular dominance shift induced by monocular deprivation. To test whether NGF affected cortical physiology or interfered with transmission of visual information, we evaluated in NGF-treated rats the spontaneous discharge and the orientation selectivity. We found these functional properties to be in the normal range. We conclude that NGF is effective in preventing the effects of monocular deprivation in the rat visual cortex and suggest that NGF is a crucial factor in the competitive processes leading to the stabilization of functional geniculocortical connections during the critical period.


Evaluation of a fast method of EPID-based dosimetry for intensity-modulated radiation therapy.
Electronic portal imaging devices (EPIDs) could potentially be useful for intensity-modulated radiation therapy (IMRT) QA. The data density, high resolution, large active area, and efficiency of the MV EPID make it an attractive option. However, EPIDs were designed as imaging devices, not dosimeters, and as a result they do not inherently measure dose in tissue equivalent media. EPIDose (Sun Nuclear, Melbourne, FL) is a tool designed for the use of EPIDs in IMRT QA that uses raw MV EPID images (no additional build-up and independent of gantry angle, but with dark and flood field corrections applied) to estimate absolute dose planes normal to the beam axis in a homogeneous media (i.e. similar to conventional IMRT QA methods). However, because of the inherent challenges of the EPID-based dosimetry, validating and commissioning such a system must be done very carefully, by exploring the range of use cases and using well-proven "standards" for comparison. In this work, a multi-institutional study was performed to verify accurate EPID image to dose plane conversion over a variety of conditions. Converted EPID images were compared to 2D diode array absolute dose measurements for 188 fields from 28 clinical IMRT treatment plans. These plans were generated using a number of commercially available treatment planning systems (TPS) covering various treatment sites including prostate, head and neck, brain, and lung. The data included three beam energies (6, 10, and 15 MV) and both step-and-shoot and dynamic MLC fields. Out of 26,207 points of comparison over 188 fields analyzed, the average overall field pass rate was 99.7% when 3 mm/3% DTA criteria were used (range 94.0-100 per field). The pass rates for more stringent criteria were 97.8% for 2mm/2% DTA (range 82.0-100 per field), and 84.6% for 1 mm/1% DTA (range 54.7-100 per field). Individual patient-specific sites as well, as different beam energies, followed similar trends to the overall pass rates.


Molecular Origins of Functional Diversity in Benzylisoquinoline Alkaloid Methyltransferases.
O- and N-methylations are ubiquitous and recurring features in the biosynthesis of many specialized metabolites. Accordingly, the methyltransferase (MT) enzymes catalyzing these modifications are directly responsible for a substantial fraction of the vast chemodiversity observed in plants. Enabled by DNA sequencing and synthesizing technologies, recent studies have revealed and experimentally validated the trajectories of molecular evolution through which MTs, such as those biosynthesizing caffeine, emerge and shape plant chemistry. Despite these advances, the evolutionary origins of many other alkaloid MTs are still unclear. Focusing on benzylisoquinoline alkaloid (BIA)-producing plants such as opium poppy, we review the functional breadth of BIA N- and O-MT enzymes and their relationship with the chemical diversity of their host species. Drawing on recent structural studies, we discuss newfound insight regarding the molecular determinants of BIA MT function and highlight key hypotheses to be tested. We explore what is known and suspected concerning the evolutionary histories of BIA MTs and show that substantial advances in this domain are within reach. This new knowledge is expected to greatly enhance our conceptual understanding of the evolutionary origins of specialized metabolism.


Cardiovascular and sympathetic response to exercise after long-term beta-adrenergic blockade.
The response to dynamic exercise was investigated in 21 patients receiving long-term treatment with beta-adrenoceptor antagonists and 22 controls. An electrocardiogram (ECG) and blood pressure were recorded before and after treadmill exercise, and plasma dopamine-beta-hydroxylase (DBH) activity was measured as an index of changes in sympathetic activity. Heart rate and blood pressure were lower at rest and throughout exercise in treated patients, although the pressor effect of exercise was not reduced. The ECG P-R interval was lengthened, and in addition the Q-T interval was prolonged. After exercise, plasma DBH activity was significantly increased in controls but not in treated patients. We conclude that long-term administration of beta-adrenergic blockers increases myocardial repolarisation time and reduces sympathetic nervous activity. These actions may contribute to the antiarrhythmic and hypotensive effects of long-term beta-blockade.


Commensal bacteria modulate cullin-dependent signaling via generation of reactive oxygen species.
The resident prokaryotic microflora of the mammalian intestine influences diverse homeostatic functions of the gut, including regulation of cellular growth and immune responses; however, it is unknown how commensal prokaryotic organisms mechanistically influence eukaryotic signaling networks. We have shown that bacterial coculture with intestinal epithelial cells modulates ubiquitin-mediated degradation of important signaling intermediates, including beta-catenin and the NF-kappaB inhibitor IkappaB-alpha. Ubiquitination of these proteins as well as others is catalyzed by the SCF(betaTrCP) ubiquitin ligase, which itself requires regulated modification of the cullin-1 subunit by the ubiquitin-like protein NEDD8. Here we show that epithelia contacted by enteric commensal bacteria in vitro and in vivo rapidly generate reactive oxygen species (ROS). Bacterially induced ROS causes oxidative inactivation of the catalytic cysteine residue of Ubc12, the NEDD8-conjugating enzyme, resulting in complete but transient loss of cullin-1 neddylation and consequent effects on NF-kappaB and beta-catenin signaling. Our results demonstrate that commensal bacteria directly modulate a critical control point of the ubiquitin-proteasome system, and suggest how enteric commensal bacterial flora influences the regulatory pathways of the mammalian intestinal epithelia.


Soft cellulose II nanospheres: sol-gel behaviour, swelling and material synthesis.
High axial aspect crystalline nanomaterials have emerged as polymeric building blocks for the construction of supermaterials. In contrast to this form, amorphous nanospheres have remained largely untapped. This is especially peculiar in the context of material assembly, due to the wide range of opportunities they offer by virtue of their soft particle characteristics, high volume ratio at low solid content and their highly swollen and accessible structure. In the context of cellulose, these colloids represent a new field in the family of nanocelluloses. We report an organic solvent-free, heterogeneous and simple synthesis of spherical carboxylated nanoparticles bearing a distinctive, amorphous outer shell structure. The particle shape is evaluated by atomic force microscopy, cryo-transmission electron microscopy, dynamic light scattering and small-angle X-ray scattering. The soft shell structure of the particles and their responsiveness to ionic strength and pH are quantified by the combination of quartz-crystal microgravimetry and atomic force microscopy. Aqueous dispersions of the nanocolloids feature distinctive sol/gel behaviour: at solid content <2 wt% they behave as a low viscous liquid (sol state), whereas at higher concentrations the shells dominate the interparticle interactions, causing an exponential increase in viscosity, typical of a gel state (hydrogel). Gelation is reversible and can be triggered alternatively by protonation of the carboxylate groups under acidic conditions. Supercritical drying of the hydrogels yields a highly porous, isotropic aerogel composed of aggregated nanoparticles. In contrast, ambient drying results in an anisotropic, fully transparent film. These colloids will allow the study of the interaction between soft cellulose and rigid matter, and have high potential as toughening additives in composites. Furthermore, the amorphous nature of this new class of cellulose nanocolloids makes them attractive as support materials for catalysts and enzymes.


Ropivacaine 0.2% versus bupivacaine 0.1% with fentanyl: a double blind comparison for analgesia during labour.
We have performed a randomized, double-blind comparison of two epidural drug regimens for analgesia in labour. In the bupivacaine group (BUPIV), 101 healthy parturients received 0.1% bupivacaine with fentanyl 2 microg ml(-1). In the ropivacaine group (ROPIV), 102 women received 0.2% ropivacaine. Both groups received an initial loading dose of 15 ml, a continuous infusion of 8 ml h(-1), and top-ups of 10 ml. Breakthrough pain not responding to a routine top-up was treated with an 'escape' top-up of 10 ml 0.25% bupivacaine. The two groups were compared for complete analgesia at 30 min, routine and 'escape' top-up requirements, midwife assessment of analgesic efficacy, delivery mode, patient visual analogue scores (VAS) for first and second stage analgesia, overall satisfaction, and patient assessment of motor blockade. Patients receiving ropivacaine received fewer routine top-ups (median 1.0 vs. 2.0, P=0.001) and fewer escape top-ups (9.8% vs. 21.8%, P=0.02). The ropivacaine group was more likely to be pain free in the first stage (51% vs. 33.7%, P=0.01). There were no significant differences in patients' assessment of motor block or mode of delivery between the groups. Pain relief and satisfaction scores from midwives and patients were consistently better in the ropivacaine group, but did not reach statistical significance.


Characterization of a replication-incompetent pseudorabies virus mutant lacking the sole immediate early gene IE180.
The alphaherpesvirus pseudorabies virus (PRV) encodes a single immediate early gene called IE180. The IE180 protein is a potent transcriptional activator of viral genes involved in DNA replication and RNA transcription. A PRV mutant with both copies of IE180 deleted was constructed 20 years ago (S. Yamada and M. Shimizu, Virology 199:366-375, 1994, doi:10.1006/viro.1994.1134), but propagation of the mutant depended on complementing cell lines that expressed the toxic IE180 protein constitutively. Recently, Oyibo et al. constructed a novel set of PRV IE180 mutants and a stable cell line with inducible IE180 expression (H. Oyibo, P. Znamenskiy, H. V. Oviedo, L. W. Enquist, A. Zador, Front. Neuroanat. 8:86, 2014, doi:10.3389/fnana.2014.00086), which we characterized further here. These mutants failed to replicate new viral genomes, synthesize immediate early, early, or late viral proteins, and assemble infectious virions. The PRV IE180-null mutant did not form plaques in epithelial cell monolayers and could not spread from primary infected neurons to second-order neurons in culture. PRV IE180-null mutants lacked the property of superinfection exclusion. When PRV IE180-null mutants infected cells first, subsequent superinfecting viruses were not blocked in cell entry and formed replication compartments in epithelial cells, fibroblasts, and neurons. Cells infected with PRV IE180-null mutants survived as long as uninfected cells in culture while expressing a fluorescent reporter gene. Transcomplementation with IE180 in epithelial cells restored all mutant phenotypes to wild type. The conditional expression of PRV IE180 protein enables the propagation of replication-incompetent PRV IE180-null mutants and will facilitate construction of long-term single-cell-infecting PRV mutants for precise neural circuit tracing and high-capacity gene delivery vectors. Pseudorabies virus (PRV) is widely used for neural tracing in animal models. The virus replicates and spreads between synaptically connected neurons. Current tracing strains of PRV are cytotoxic and kill infected cells. Infected cells exclude superinfection with a second virus, limiting multiple virus infections in circuit tracing. By removing the only immediate early gene of PRV (called IE180), the mutant virus will not replicate or spread in epithelial cells, fibroblasts, or neurons. The wild-type phenotype can be restored by transcomplementation of infected cells with IE180. The PRV IE180-null mutant can express fluorescent reporters for weeks in cells with no toxicity; infected cells survive as long as uninfected cells. Infection with the mutant virus allows superinfection of the same cell with a second virus that can enter and replicate. The PRV IE180-null mutant will permit conditional long-term tracing in animals and is a high-capacity vector for gene delivery.


The interaction between personality and health policy: Empirical evidence from the UK smoking bans.
We investigate whether responses to the UK public places smoking ban depend on personality. Drawing on individual level panel data from the British Household Panel Survey (BHPS) we exploit variation in the timing and location of these bans to establish their overall effect on smoking outcomes, and how this differs by personality. We measure personality using the Big Five personality traits. We are particularly interested in conscientiousness, given the evidence that it is a good proxy for self-control. Overall, we find that a one standard deviation increase in conscientiousness leads to a 1.4 percentage point reduction in the probability of smoking after the ban. Notably, this is the only Big Five personality trait that interacts with the smoking ban. This finding is very robust to different specifications.


Vascular graft infections.
Vascular procedures are rarely complicated by infection, but if prosthetic vascular graft infection (PVGI) occurs, morbidity and mortality are high. Several patient-related, surgery-related and postoperative risk factors are reported, but they are not well validated. PVGI is due to bacterial colonisation of the wound and the underlying prosthetic graft, generally as a result of direct contamination during the operative procedure, mainly from the patient's skin or adjacent bowel. There is no consensus on diagnostic criteria or on the best management of PVGI. On the basis of reported clinical studies and our own experience, we advocate a surgical approach combining repeated radical local debridement, with graft preservation whenever possible or partial excision of the infected graft, depending on its condition, plus simultaneous negative-pressure wound therapy (NPWT). In addition, antimicrobial therapy is recommended, but there is no consensus on which classes of agent are adequate for the treatment of PVGI and whether certain infections may be treated by means of NPWT alone. Since staphylococci and Gram-negative rods are likely to be isolated, empirical treatment might include a penicillinase-resistant beta-lactam or a glycopeptide, plus an aminoglycoside, the latter for Gram-negative coverage and synergistic treatment of Gram-positive cocci. Additionally, empirical treatment might include rifampicin since it penetrates well into biofilms.


Efficacy and safety of 121 injections of the greater occipital nerve in episodic and chronic cluster headache.
Infiltration of the greater occipital nerve (GON) with local anaesthetics and corticosteroids is a treatment option for cluster headache. We retrospectively analysed the efficacy and safety of 121 GON injections in 60 patients with episodic or chronic cluster headache over a period of 4 years. Almost 80% of the infiltrations were at least partially effective (reduction of attack frequency, duration or severity) and 45% resulted in a complete response (no further attacks). The effect was maintained for 3.5 weeks on average in chronic cluster headache. In episodic cluster headache, the effect lasted for most of the bout. In 18 infiltrations, transient side effects were reported, such as local pain, steroid effects (facial oedema, sleeping disorders, acne), bradycardia or syncope. Our data show that GON infiltration is a valuable and safe option in the clinical setting to treat patients suffering from cluster headache, especially for the episodic form of the disorder.


Toxicity evaluation of two typical surfactants to Dunaliella bardawil, an environmentally tolerant alga.
Sodium dodecyl benzene sulfonate (SDBS) and cetyl trimethyl ammonium chloride (CTAC) are two kinds of surfactants widely applied in various industries. The tremendous direct discharge of these surfactants into natural waters has posed a significant threat to ecosystems. Dunaliella bardawil was employed in the present research to test the toxic effects of SDBS, CTAC, and their mixture on cell growth, cellular morphology, β-carotene accumulation, and enzymatic activities of superoxide dismutase (SOD) and catalase (CAT). The results showed that SDBS at 200, 550, 900, 1,350, 1,800, and 2,400 mg/L and CTAC at 0.4, 0.7, 1.0, 1.3, 2.8, and 3.5 mg/L inhibited algal growth and β-carotene accumulation, both of which declined and then increased. In particular, CTAC (median inhibitory concentration at 10 days [IC50](10 d) = 2.8 ± 1.49 mg/L) was more hazardous than SDBS (IC50(10 d) = 2,044 ± 637.3 mg/L). The additive index (AI) calculated from carotene content data was (-4.10, -1.67) < 0, indicating an antagonistic effect between SDBS and CTAC. Algae cultivated at level 6 of the binary system showed hormesis due to the mitigated toxicity; SDBS at 2,400 mg/L, CTAC at 3.5 mg/L, and combined surfactants at level 6 exerted lethal effects on D. bardawil. Both SOD and CAT activities showed similar associations with varied concentrations of surfactants: SOD was significantly promoted by 550 to 1,800 mg/L SDBS, 0.7 to 1.3 mg/L CTAC, and mixtures at levels 2 to 4; CAT was clearly promoted by 900 mg/L SDBS, 0.4 to 1.3 mg/L CTAC, and mixtures at levels 2 to 4.


Dynamic quadripolar radiofrequency treatment of vaginal laxity/menopausal vulvo-vaginal atrophy: 12-month efficacy and safety.
Twelve-month extension of a previous spontaneous exploratory study investigating safety and efficacy of a new low-energy dynamic quadripolar radiofrequency (DQRF) device in: A) premenopausal women with symptoms of vaginal laxity, with special reference to dysuria, urinary incontinence and unsatisfactory sexual life (vaginal laxity arm of the study); B) postmenopausal women with vulvovaginal atrophy/genitourinary syndrome of menopause (VVA/GSM) and VVA/GSM-related symptoms (VVA/GSM arm of the study). DQRF treatment schedule in both study arms: 4 to 6 procedures of 15 to 20 min every 14 days (vaginal laxity, range 12-17 days; VVA/GSM, range 13-16). Operative temperatures in vaginal target tissues during procedure: vaginal laxity, 42 °C (range 40-43 °C); VVA/GSM, 40 °C (range 40-42 °C). In the vaginal laxity arm of the study, 25 women with subjective sensation of vaginal introital laxity (very to slightly loose). Assessment of urinary incontinence, satisfaction with sexual relationship and contribution of pelvic organ prolapse: Vaginal Laxity Questionnaire (VLQ, Italian certified translation) and short form of the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12, Italian certified translation). Further evaluation of sexual gratification: Sexual Satisfaction Questionnaire (SSQ). In the VVA/GSM arm of the study, 32 women with objective evidence of VVA and vaginal dryness and/or dyspareunia as most bothersome symptoms. Assessment of VVA/GSM symptoms and overall satisfaction with sexual life: specifically designed 10-cm visual analogue scales. All 4 to 6 planned DQRF sessions were well tolerated in both the vaginal laxity and VVA/GSM arms of the study, with no troubling pain, thermal injury or other immediate adverse effects during all the procedures. All screened women completed the planned DQRF treatment sessions in both arms of the extension study. There was no participant attrition with only a few occasionally missing visits over the 12-month follow-up period. Improvements were rapid in self-perception of introital looseness and related symptoms like dysuria/urinary incontinence and unrewarding sexual relationship (vaginal laxity patients) and atrophy-related symptoms including painful and unsatisfactory sexual activity (VVA/GSM patients). Participating women consistently reported wide-spectrum strong clinical improvements by the end of the planned DQRF sessions. Clinical improvements remained steady for the whole follow-up period in postmenopausal women; a statistically non-significant tendency to slight deterioration in VLQ, PISQ-12 and SSQ mean scores was detected after 6 to 9 months of follow-up in the vaginal laxity arm of the study. Safety was excellent during all DQRF procedures and over the 12 months following the end of the treatment sessions. VLQ, PISQ-12 and SSQ scores (women with vaginal laxity), VAS self-evaluation of VVA/GSM symptoms and overall satisfaction with sexual life (women with VVA/GSM symptoms) improved rapidly, reaching almost normal levels by the last DQRF session and suggesting rapid, but also persistent, vaginal rejuvenation in both indications. A late tendency to some slight deterioration in women treated for vaginal laxity suggests such women might benefit from new DQRF treatments 6 to 9 months after the previous cycle.


Novel, Family-Centered Intervention to Improve Nutrition in Patients Recovering From Critical Illness: A Feasibility Study.
Critically ill patients are at increased risk of developing malnutrition-related complications because of physiological changes, suboptimal delivery, and reduced intake. Strategies to improve nutrition during critical illness recovery are required to prevent iatrogenic underfeeding and risk of malnutrition. The purpose of this study was to assess the feasibility and acceptability of a novel family-centered intervention to improve nutrition in critically ill patients. A 3-phase, prospective cohort feasibility study was conducted in 4 intensive care units (ICUs) across 2 countries. Intervention feasibility was determined by patient eligibility, recruitment, and retention rates. The acceptability of the intervention was assessed by participant perspectives collected through surveys. Participants included family members of the critically ill patients and ICU and ward healthcare professionals (HCPs). A total of 75 patients and family members, as well as 56 HCPs, were enrolled. The consent rate was 66.4%, and 63 of 75 (84%) of family participants completed the study. Most family members (53/55; 98.1%) would recommend the nutrition education program to others and reported improved ability to ask questions about nutrition (16/20; 80.0%). Family members viewed nutrition care more positively in the ICU. HCPs agreed that families should partner with HCPs to achieve optimal nutrition in the ICU and the wards. Health literacy was identified as a potential barrier to family participation. The intervention was feasible and acceptable to families of critically ill patients and HCPs. Further research to evaluate intervention impact on nutrition intake and patient-centered outcomes is required.


The wavelength of light governing intraocular immune reactions.
Injection of antigen into the anterior chamber of the eye results in the induction of suppressed systemic cell-mediated responses as measured by delayed-type hypersensitivity or contact hypersensitivity (CHS). Previous studies from the author's laboratories have determined that this response is governed by exposure of the eye to visible light during the initial intraocular encounter between T cells and antigen. To more fully understand the role of light, as well as to begin to understand the molecular mediators involved, the authors chose to explore the properties of light governing the effect. Neutral density filter were used to demonstrate that the minimum amount of light required to induce suppression of CHS following anterior chamber injection of antigen is 1-2 lux (lumens/meter2). With narrow band filters, the wavelengths responsible for suppression were shown to be 500-510 nm. The results show that the effect of light extends beyond the hapten-derivatized spleen cell system to other antigens placed in the anterior chamber of the eye. Studies also show that the retina and the pineal gland, two light absorbing structures, may not be involved. The results in this report show that light of very restricted wavelengths controls intraocular immune reactions.


Ultrasound measurement of optic nerve sheath diameter in patients with a clinical suspicion of raised intracranial pressure.
To assess if ultrasound measurement of the optic nerve sheath diameter (ONSD) can accurately predict the presence of raised intracranial pressure (ICP) and acute pathology in patients in the emergency department. This 3-month prospective observational study used ultrasound to measure the ONSD in adult patients who required CT from the emergency department. The mean ONSD from both eyes was measured using a 7.5 MHz ultrasound probe on closed eyelids. A mean ONSD value of >0.5 cm was taken as positive. Two radiologists independently assessed CT scans from patients in the study population for signs of raised ICP and signs of acute pathology (cerebrovascular accident, subarachnoid, subdural or extradural haemorrhage and tumour). Specificity, sensitivity and κ values, for interobserver variability between reporting radiologists, were generated for the study data. In all, 26 patients were enrolled into the study. The ONSD measurement was 100% specific (95% CI 79% to 100%) and 86% sensitive (95% CI 42% to 99%) for raised ICP. For any acute intracranial abnormality the value of ONSD was 100% specific (95% CI 76% to 100%) and 60% sensitive (95% CI 27% to 86%). κ Values were 0.91 (95% CIs 0.73 to 1) for identification of raised ICP on CT and 0.84 (95% CIs 0.62 to 1) for any acute pathology on CT, between the radiologists. This study shows that ultrasound measurement of ONSD is sensitive and specific for raised ICP in the emergency department. Further observational studies are needed but this emerging technique could be used to focus treatment in unstable patients.


Influence of wetting conditions on drainage in porous media: a microfluidic study.
This paper presents some experimental results on two-phase flows in model two-dimensional (2D) porous media with different wetting properties. Standard microfluidic techniques are used to fabricate the 2D micromodels that consist of a network of straight microchannels having heterogeneous sizes. The invasion mechanism is analyzed quantitatively for partial and total wetting conditions, and for various stable viscosity ratios and capillary pressure heterogeneity. For capillary numbers ranging from 10(-7) to 10(-2), we observe a transition between capillary fingering and a stable front. The capillary fingering regime exhibits differences between partial and complete wetting systems: The front width in complete wetting is larger. Simple models are proposed to account for these regimes and indicate that the differences between the systems are likely to be due to the flow of the displaced fluid in the complete wetting situation.


A role for neutrophils in intermittent allergic rhinitis.
In patients with intermittent allergic rhinitis, allergen challenge may induce both early- and late-phase responses. The aim of this study was to examine the correlation between inflammatory cells in the nasal lavage fluid and clinical parameters following pollen challenge. Nasal lavage fluids were obtained from 29 patients with intermittent allergic rhinitis before and 1 and 6 h after allergen provocation, representing the control, early and late phases, respectively. Symptom and rhinoscopic scores were registered on the same occasions. Inflammatory cells were determined in the nasal fluid. The early phase was characterized by increased symptom scores, rhinoscopic signs of oedema and secretion and neutrophilia. In the late phase, symptom scores had diminished, but the signs of ongoing secretion remained. Both the total nasal symptom score and the secretion score correlated with the number of neutrophils in lavage fluids at 1 h. The eosinophil count did not increase during the early or late phases. A single allergen provocation induces an early-phase response dominated by neutrophils, with secretion being the only clinical sign remaining during the late phase. The increase in neutrophil numbers correlated with the registration of secretory symptoms. The presented data indicate a role for neutrophils in intermittent allergic rhinitis and their relation with secretory parameters makes it intriguing to speculate that neutrophils may function as promoters of nasal secretion.


Modelling the fate of hydrophobic organic contaminants in a boreal forest catchment: a cross disciplinary approach to assessing diffuse pollution to surface waters.
The fate of hydrophobic organic compounds (HOCs) in soils and waters in a northern boreal catchment was explored through the development of a chemical fate model in a well-characterised catchment system dominated by two land types: forest and mire. Input was based solely on atmospheric deposition, dominated by accumulation in the winter snowpack. Release from soils was governed by the HOC concentration in soil, the soil organic carbon fraction and soil-water DOC content. The modelled export of selected HOCs in surface waters ranged between 11 and 250 ng day(-1) during the snow covered period, compared to 200 and 9600 ng/d during snow-melt; highlighting the importance of the snow pack as a source of these chemicals. The predicted levels of HOCs in surface water were in reasonable agreement to a limited set of measured values, although the model tended to over predict concentrations of HOCs for the forested sub-catchment, by over an order of magnitude in the case of hexachlorobenzene and PCB 180. This possibly reflects both the heterogeneity of the forest soils and the complicated and changing hydrology experienced between the different seasons.


Modulation of lower urinary tract smooth muscle contraction and relaxation by the urothelium.
The epithelial inner layer of the lower urinary tract, i.e., the urothelium, and other parts of the mucosa are not just a passive barrier but play an active role in the sensing of stretching, neurotransmitters, paracrine mediators, hormones, and growth factors and of changes in the extracellular environment. We review the molecular and cellular mechanisms enabling the urothelium to sense such inputs and how this leads to modulation of smooth muscle contraction and relaxation. The urothelium releases various mediators including ATP, acetylcholine, prostaglandins, nitric oxide, and nerve growth factor. These may affect function and growth of smooth muscle cells and afferent nerves. However, the molecular identity of the urothelium-derived mediator directly modulating contractile and relaxant responses of isolated bladder strips has remained elusive. The morphology and function of the urothelium undergo changes with aging and in many pathophysiological conditions. Therefore, the urothelium may contribute to the therapeutic effects of established drugs to treat lower urinary tract dysfunction and may also serve as a target for novel therapeutics. However, therapeutics may also change urothelial function, and it is not always easy to determine whether such changes are part of the therapeutic response or reflect secondary alterations.


Post-discharge outcomes of failed car seat tolerance screens: A case-control and follow-up study.
Despite widespread implementation, limited data exists relating morbidity or adverse outcomes to Car Seat Tolerance Screen (CSTS) result in preterm and low birth weight (LBW) neonates. The objective of this study was to determine longer term post-discharge outcomes of infants who failed a CSTS. We performed a case control study evaluating outcomes of infants born over one year who failed vs. passed an initial CSTS, utilizing both retrospective medical record review and parental survey data 2-3 years after discharge. Subjects were matched one case of failed CSTS to two controls who passed CSTS based on sex, gestational age, and BW. We performed bivariate analysis of clinical and demographic risk factors comparing those who passed vs. failed CSTS. We identified 19 subjects who failed and matched to 37 controls. Cases were significantly more likely to be diagnosed with obstructive sleep apnea (p = 0.027), asthma (p = 0.016), and be treated with albuterol (p = 0.008). We did not find differences in frequency of urgent care visits or hospital admissions between the groups. Although more of the cases were noted to have developmental delays, the difference was not statistically significant. This is the first study to evaluate longer term post-discharge outcomes of subjects having undergone CSTS. Subjects who failed CSTS had significantly increased incidence of respiratory diagnoses such as OSA and asthma than matched controls by 2-3 years after discharge. Larger studies are necessary to further evaluate these findings, but this does provide data that CSTS may be useful in identifying at risk neonates.


A qualitative study of rural primary care clinician views on remote monitoring technologies.
Remote monitoring technologies (RMTs) may improve the quality of care, reduce access barriers, and help control medical costs. Despite the role of primary care clinicians as potential key users of RMTs, few studies explore their views. This study explores rural primary care clinician interest and the resources necessary to incorporate RMTs into routine practice. We conducted 15 in-depth interviews with rural primary care clinician members of the Oregon Rural Practice-based Research Network (ORPRN) from November 2011 to April 2012. Our multidisciplinary team used thematic analysis to identify emergent themes and a cross-case comparative analysis to explore variation by participant and practice characteristics. Clinicians expressed interest in RMTs most relevant to their clinical practice, such as supporting chronic disease management, noting benefits to patients of all ages. They expressed concern about the quantity of data, patient motivation to utilize equipment, and potential changes to the patient-clinician encounter. Direct data transfer into the clinic's electronic health record (EHR), availability in multiple formats, and review by ancillary staff could facilitate implementation. Although participants acknowledged the potential system-level benefits of using RMTs, adoption would be difficult without payment reform. Adoption of RMTs by rural primary care clinicians may be influenced by equipment purpose and functionality, implementation resources, and payment. Clinician and staff engagement will be critical to actualize RMT use in routine primary care.


Differences in beta 3-adrenergic receptor cardiovascular regulation in conscious primates, rats and dogs.
The goal of our study was to compare the effects of two beta 3-adrenergic receptor agonists, i.e., BRL37344 (BRL) and CL316243 (CL), in conscious dogs, rats and nonhuman primates, instrumented with aortic and atrial catheters, ascending aortic flow probes and left ventricular (LV) pressure gauges. In conscious dogs, CL, 10 micrograms/kg, i.v., reduced, P < .05, mean arterial pressure by 8 +/- 4% and total peripheral resistance by 51 +/- 4% and increased, P < .05, LV dP/dt by 79 +/- 10% and heart rate by 88 +/- 8%. These responses were similar to those induced by BRL, 8.3 micrograms/kg, i.v. After autonomic blockade (beta 1/beta 2-adrenergic, cholinergic and ganglionic), CL still reduced total peripheral resistance by 49 +/- 4%, and increased LV dP/dt by 21 +/- 4%, without an effect on heart rate. In conscious rats, 10 times the dose of CL 100 micrograms/kg, i.v., reduced, P < .05, total peripheral resistance by 18 +/- 4%, without major effects on LV dP/dt and heart rate. BRL, 83 micrograms/kg i.v., reduced total peripheral resistance similarly by 31 +/- 3%, and increased heart rate (25 +/- 3%) and LV dP/dt (27 +/- 5%) more, P < .05. In conscious monkeys and baboons, CL, 100 micrograms/kg, i.v., did not induce significant effects, whereas BRL, 83 micrograms/kg, i.v., increased heart rate (36 +/- 6%), LV dP/dt (85 +/- 9%) and decreased total peripheral resistance (30 +/- 2%). After beta 1/beta 2-adrenergic receptor blockade in rats and primates, there were almost no differences between BRL and CL, i.e., in primates there were almost no significant cardiovascular effects with either compound. Both CL and BRL increased circulating free fatty acids in the dog, but not in the baboon. Thus, CL appears to be a more specific beta 3-adrenergic receptor agonist than BRL. More importantly, beta 3-adrenergic receptor stimulation was most profound in dogs, where even a direct effect on LV contractility was identified, was diminished but still significant in rats, and essentially absent in primates.


Blunted hemodynamic response and reduced oxygen delivery with exercise in anemic heart failure patients with systolic dysfunction.
Anemic heart failure patients with systolic dysfunction are known to have reduced exercise capacity. Whether this is related to poor hemodynamic adaptation to anemia is not known. Peak exercise oxygen consumption (VO2) and hemodynamics at rest and peak exercise were assessed among 209 patients and compared among those who were (n=90) and were not (n=119) anemic. Peak VO2 was significantly lower among anemic patients (11.7+/-3.3 mL/min/kg vs 13.4+/-3.1 mL/min/kg; P=.01). At rest, right atrial pressure was higher (10+/-5 mm Hg vs 8+/-4 mm Hg; P=.02) and venous oxygen saturation lower (62%+/-8% vs 58%+/-10%; P<.01) among anemic patients. At peak exercise, anemic patients had a higher wedge pressure (27+/-9 mm Hg vs 24+/-10 mm Hg; P=.04). No significant differences in stroke volume, cardiac index, systemic vascular resistance, or oxygen saturation were noted between the 2 groups. In conclusion, the relative hemodynamic response to exercise among anemic heart failure patients appears blunted and may contribute to worse exercise tolerance.


Effect of Ames dwarfism and caloric restriction on spontaneous DNA mutation frequency in different mouse tissues.
Genetic instability has been implicated as a causal factor in cancer and aging. Caloric restriction (CR) and suppression of the somatotroph axis significantly increase life span in the mouse and reduce multiple symptoms of aging, including cancer. To test if in vivo spontaneous mutation frequency is reduced by such mechanisms, we crossed long-lived Ames dwarf mice with a C57BL/6J line harboring multiple copies of the lacZ mutation reporter gene as part of a plasmid that can be recovered from tissues and organs into Escherichia coli to measure mutant frequencies. Four cohorts were studied: (1) ad lib wild-type; (2) CR wild-type; (3) ad lib dwarf; and (4) CR dwarf. While both CR wild-type and ad lib dwarf mice lived significantly longer than the ad lib wild-type mice, under CR conditions dwarf mice did not live any longer than ad lib wild-type mice. While this may be due to an as yet unknown adverse effect of the C57BL/6J background, it did not prevent an effect on spontaneous mutation frequencies at the lacZ locus, which were assessed in liver, kidney and small intestine of 7- and 15-month-old mice of all four cohorts. A lower mutant frequency in the ad lib dwarf background was observed in liver and kidney at 7 and 15 months of age and in small intestine at 15 months of age as compared to the ad lib wild-type. CR also significantly reduced spontaneous mutant frequency in kidney and small intestine, but not in liver. In a separate cohort of lacZ-C57BL/6J mice CR was also found to significantly reduce spontaneous mutant frequency in liver and small intestine, across three age levels. These results indicate that two major pro-longevity interventions in the mouse are associated with a reduced mutation frequency. This could be responsible, at least in part, for the enhanced longevity associated with Ames dwarfism and CR.


The tip-sample water bridge and light emission from scanning tunnelling microscopy.
The light emission spectrum from a scanning tunnelling microscope (LESTM) is investigated as a function of relative humidity and shown to provide a novel and sensitive means for probing the growth and properties of a water meniscus on the nanometre scale. An empirical model of the light emission process is formulated and applied successfully to replicate the decay in light intensity and spectral changes observed with increasing relative humidity. The modelling indicates a progressive water filling of the tip-sample junction with increasing humidity or, more pertinently, of the volume of the localized surface plasmons responsible for light emission; it also accounts for the effect of asymmetry in structuring of the water molecules with respect to the polarity of the applied bias. This is juxtaposed with the case of a non-polar liquid in the tip-sample nanocavity where no polarity dependence of the light emission is observed. In contrast to the discrete detection of the presence/absence of a water bridge in other scanning probe experiments through measurement of the feedback parameter for instrument control, LESTM offers a means of continuously monitoring the development of the water bridge with sub-nanometre sensitivity. The results are relevant to applications such as dip-pen nanolithography and electrochemical scanning probe microscopy.


Establishing a standard protocol for the voiding cystourethrography.
The voiding cystourethrogram (VCUG) is a frequently performed test to diagnose a variety of urologic conditions, such as vesicoureteral reflux (VUR). The test results determine whether continued observation or an interventional procedure is indicated. VCUGs are ordered by many specialists and primary care providers, including pediatricians, family practitioners, nephrologists, hospitalists, emergency room physicians, and urologists. Current protocols for performing and interpreting a VCUG are based on the International Reflux Study in 1985. However, more recent information provided by many national and international institutions suggests a need to refine those recommendations. The lead author of the 1985 study, R.L. Lebowitz, agreed to and participated in the current protocol. In addition, a recent survey directed to the chairpersons of pediatric radiology of 65 children's hospitals throughout the United States and Canada showed that VCUG protocols vary substantially. Recent guidelines from the American Academy of Pediatrics (AAP) recommend a VCUG for children between 2 and 24 months of age with urinary tract infections but did not specify how this test should be performed. To improve patient safety and to standardize the data obtained when a VCUG is performed, the AAP Section on Radiology and the AAP Section on Urology initiated the current VCUG protocol to create a consensus on how to perform this test.


Quality of Life in a Randomized Breast Cancer Prevention Trial of Low-Dose Tamoxifen and Fenretinide in Premenopausal Women.
Menopausal symptoms are the main reason for withdrawal in tamoxifen prevention trials. Here, we present Menopause Quality of Life (MenQoL) assessment within a randomized 2 × 2 phase II clinical trial of low-dose tamoxifen and the synthetic retinoid fenretinide. A total of 235 premenopausal women at higher risk for breast cancer were randomized to either tamoxifen 5 mg daily, fenretinide 200 mg daily, their combination, or placebo. Climacteric symptoms were investigated using the MenQoL questionnaire which was self-administered at each visit for 2 years of treatment and for 1 year of follow-up. CYP2D6 was genotyped in subjects taking tamoxifen to study the association with menopausal symptoms. The MenQoL effect size analysis showed no statistically significant difference among the four treatment arms for all four domains (vasomotor, physical, psychosocial, and sexual). Vasomotor symptoms only slightly increased under tamoxifen, with a score at year two of 1.45, 1.21, 0.58, and 1.17 in the combined, tamoxifen, fenretinide, and placebo arms, respectively. Compared with the slow metabolizers, a higher percentage of subjects with CYP2D6 extensive metabolizer genotype complained of a ≥3 score in the vasomotor, psychosocial, and sexual domain in the tamoxifen arms (P value = 0.01, 0.007, and 0.007, respectively). QoL in premenopausal or perimenopausal women was not significantly worsened by low-dose tamoxifen or fenretinide. Our findings suggest that a low dose of tamoxifen may increase its acceptability for breast cancer prevention.


The reversal of xylazine hydrochloride by yohimbine and 4-aminopyridine in goats.
Yohimbine, 4-aminopyridine, and a combination of the 2 drugs were studied to assess their potential as antagonists to xylazine in goats. Twenty-four small East African goats were divided randomly into 4 groups of 6 goats each in a placebo-controlled study. They were all treated with intramuscular xylazine at 0.44 mg/kg. At the time of maximum sedation, sterile water was administered intravenously to the control group, 0.15% 4-aminopyridine at 0.4mg/kg to Group 2, 0.1% yohimbine at 0.25 mg/kg to Group 3, and the combination of the 2 drugs at the same dose rates to Group 4. The yohimbine/4-aminopyridine combination was also used to antagonise xylazine at 0.88mg/kg in 6 goats. The heart rate, respiratory rate and rate of ruminal movements, the pedal and palpebral reflexes as well as the reaction to noxious stimuli, the standing time and the total recovery time were established and evaluated to assess the effects of the treatments. The drugs reversed the xylazine-induced decrease in the heart rate, respiratory rate and rate of ruminal movements, and also rapidly restored the reflexes as well as the reaction to noxious stimulation. In addition, they significantly (P < 0.05) decreased the mean standing time. The mean total recovery time was decreased significantly (P < 0.05) by 4-aminopyridine and the yohimbine/4-aminopyridine combination, but non-significantly (P > 0.05) by yohimbine. No relapse in sedation occurred. Overall, the combination of yohimbine and 4-aminopyridine produced better responses than the individual drugs, and may therefore be used for rapid reversal of xylazine-induced sedation in goats. Yohimbine or 4-aminopyridine may also be useful for this purpose but recovery may be prolonged.


Expression and purification of Z protein from Junín virus.
Arenaviridae comprises 23 recognized virus species with a bipartite ssRNA genome and an ambisense coding strategy. The virions are enveloped and include nonequimolar amounts of each genomic RNA species, designated L and S, coding for four ORFs (N, GPC, L, and Z). The arenavirus Junín (JUNV) is the etiological agent of Argentine Hemorrhagic Fever, an acute disease with high mortality rate. It has been proposed that Z is the functional counterpart of the matrix proteins found in other negative-stranded enveloped RNA viruses. Here we report the optimized expression of a synthetic gene of Z protein, using three expression systems (two bacterial and a baculoviral one). One of these recombinant proteins was used to generate antibodies. A bioinformatic analysis was made where Z was subdivided into three domains. The data presented contributes methodologies for Z recombinant production and provides the basis for the development of new experiments to test its function.


[Anesthesia in a patient with Marshall-Smith syndrome: case report].
The Marshall-Smith Syndrome is a rare disease characterized by facial dysmorphism, accelerated osseous maturation, retarded neuropsychomotor development, and abnormalities of the airways. Patients with this syndrome have a high risk of developing anesthetic complications, especially concerning the maintenance of the airways. There are very few data in the anesthetic literature regarding this syndrome. The objective of this report was to show the difficulties and anesthetic management in a 28-day old child with this syndrome, who underwent surgery for correction of choanal atresia under general anesthesia. A male child, 28 days old, weighing 2.8 kg, undergoing general anesthesia for surgical correction of choanal atresia. The child presented the typical manifestations of the Marshall-Smith syndrome, with a narrow thorax, pectus excavatum, large hands and feet, long neck, facial dysmorphism, high and arched palate, and accelerated osseous maturation. Anesthetic induction was done with a mask with 100% O2 associated with sevoflurane. Due to the possibility of a difficult intubation, tracheal intubation with a fibrobronchoscope was scheduled. After tracheal intubation and assisted manual ventilation, 1.5 mg of rocuronium were administered and, after ten minutes, the patient developed bradycardia (80 bpm), severe hypoxemia (O2 saturation of 30%), and manual ventilation through the tracheal tube became impossible. An urgent tracheostomy was done and the surgical procedure was cancelled. In cases of anesthetic-surgical emergencies, in which the child does not ventilate and tracheal intubation is not possible, there is desaturation and bradycardia, requiring fast and appropriate decision making to guarantee adequate pulmonary ventilation. These patients need careful evaluation of the airways to identify upper and lower airways obstruction. During anesthesia, spontaneous ventilation should be maintained during induction until control of the airways is possible, avoiding the use of neuromuscular blockers.


Adolescents' alcohol use and strength of policy relating to youth access, trading hours and driving under the influence: findings from Australia.
To determine (i) whether the strength of Australian alcohol control policy in three domains (youth access, trading hours and drink driving) changed during the 2000s; and (ii) estimate associations between these policies and adolescent drinking after adjusting for television alcohol advertising exposures, alcohol outlet density, alcohol price changes, exposure to negative articles about alcohol in daily newspapers and adult drinking prevalence. Repeated cross-sectional surveys conducted triennially from 2002 to 2011. Multi-level modelling examined the association between alcohol control policies and drinking prevalence after adjusting for covariates. Four Australian capital cities between 2002 and 2011. Students aged 12-17 years participating in a triennial national representative school-based survey (sample size range/survey: 9805-13 119). Outcome measures were: past month drinking and risky drinking (5+ drinks on a day) in the past 7 days. Policy strength in each of three domains (youth access, trading hours, drink-driving) were the key predictor variables. Covariates included: past 3-month television alcohol and alcohol-control advertising, alcohol outlet density, alcohol price change, negatively framed newspaper alcohol articles, adult drinking prevalence and student demographic characteristics. During the study period, the strength of youth access policies increased by 10%, trading hours policies by 14% and drink-driving policies by 58%. Past-month and risky drinking prevalence decreased (e.g. past-month: 2002: 47.4% to 2011: 26.3%). Multivariable analyses that included all policy variables and adjusted for year, student and other covariates showed past-month drinking to be associated inversely with stronger trading hours policies [odds ratio (OR) = 0.80, 95% confidence interval (CI) = 0.69, 0.94], but not youth access (OR = 0.92 95% CI = 0.81, 1.04) or drink-driving (OR = 1.00, 95% CI = 0.93, 1.09). Risky drinking was associated inversely with stronger youth access policies (OR = 0.82, 95% CI = 0.69, 0.98), but not trading hours (OR = 0.85, 95% CI = 0.66, 1.09) or drink-driving (OR = 1.02, 95% CI = 0.90, 1.14) policies. Population-directed policies designed to reduce alcohol availability and promotion may reduce adolescents' alcohol use.


A nonlinear mechanics model of bio-inspired hierarchical lattice materials consisting of horseshoe microstructures.
Development of advanced synthetic materials that can mimic the mechanical properties of non-mineralized soft biological materials has important implications in a wide range of technologies. Hierarchical lattice materials constructed with horseshoe microstructures belong to this class of bio-inspired synthetic materials, where the mechanical responses can be tailored to match the nonlinear J-shaped stress-strain curves of human skins. The underlying relations between the J-shaped stress-strain curves and their microstructure geometry are essential in designing such systems for targeted applications. Here, a theoretical model of this type of hierarchical lattice material is developed by combining a finite deformation constitutive relation of the building block (i.e., horseshoe microstructure), with the analyses of equilibrium and deformation compatibility in the periodical lattices. The nonlinear J-shaped stress-strain curves and Poisson ratios predicted by this model agree very well with results of finite element analyses (FEA) and experiment. Based on this model, analytic solutions were obtained for some key mechanical quantities, e.g., elastic modulus, Poisson ratio, peak modulus, and critical strain around which the tangent modulus increases rapidly. A negative Poisson effect is revealed in the hierarchical lattice with triangular topology, as opposed to a positive Poisson effect in hierarchical lattices with Kagome and honeycomb topologies. The lattice topology is also found to have a strong influence on the stress-strain curve. For the three isotropic lattice topologies (triangular, Kagome and honeycomb), the hierarchical triangular lattice material renders the sharpest transition in the stress-strain curve and relative high stretchability, given the same porosity and arc angle of horseshoe microstructure. Furthermore, a demonstrative example illustrates the utility of the developed model in the rapid optimization of hierarchical lattice materials for reproducing the desired stress-strain curves of human skins. This study provides theoretical guidelines for future designs of soft bio-mimetic materials with hierarchical lattice constructions.


Gibberellin as a factor in floral regulatory networks.
Gibberellins (GAs) function not only to promote the growth of plant organs, but also to induce phase transitions during development. Their involvement in flower initiation in long-day (LD) and biennial plants is well established and there is growing insight into the mechanisms by which floral induction is achieved. The extent to which GAs mediate the photoperiodic stimulus to flowering in LD plants is, with a few exceptions, less clear. Despite evidence for photoperiod-enhanced GA biosynthesis in leaves of many LD plants, through up-regulation of GA 20-oxidase gene expression, a function for GAs as transmitted signals from leaves to apices in response to LD has been demonstrated only in Lolium species. In Arabidopsis thaliana, as one of four quantitative floral pathways, GA signalling has a relatively minor influence on flowering time in LD, while in SD, in the absence of the photoperiod flowering pathway, the GA pathway assumes a major role and becomes obligatory. Gibberellins promote flowering in Arabidopsis through the activation of genes encoding the floral integrators SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 (SOC1), LEAFY (LFY), and FLOWERING LOCUS T (FT) in the inflorescence and floral meristems, and in leaves, respectively. Although GA signalling is not required for floral organ specification, it is essential for the normal growth and development of these organs. The sites of GA production and action within flowers, and the signalling pathways involved are beginning to be revealed.


Synthesis and antibacterial activity of novel curcumin derivatives containing heterocyclic moiety.
A series of curcumin derivatives containing heterocyclic moiety have been synthesized and evaluated for their antibacterial activities. The chemical structures of the synthesized compounds were verified on the basis of spectral data and elemental analyses. Investigation of antimicrobial activity of the derivatives demonstrated the ability to inhibit Gram-positive microorganisms with zone of inhibition ranging from 14-18 mm, MIC ranging between 0.0625 and 0.25 mg/mL. Among all tested derivatives, diazepine 4 exhibited remarkable potency against Gram-positive bacteria S. aureus. An extensive study is underway to optimize the effectiveness of diazepine type of compounds and to determine their mode of action.


Comprehensive molecular characterization of gastric adenocarcinoma.
Gastric cancer is a leading cause of cancer deaths, but analysis of its molecular and clinical characteristics has been complicated by histological and aetiological heterogeneity. Here we describe a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project. We propose a molecular classification dividing gastric cancer into four subtypes: tumours positive for Epstein-Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also known as PD-L2); microsatellite unstable tumours, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signalling proteins; genomically stable tumours, which are enriched for the diffuse histological variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; and tumours with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases. Identification of these subtypes provides a roadmap for patient stratification and trials of targeted therapies.


Clinical Performance and Future Potential of Magnetic Resonance Thermometry in Hyperthermia.
Hyperthermia treatments in the clinic rely on accurate temperature measurements to guide treatments and evaluate clinical outcome. Currently, magnetic resonance thermometry (MRT) is the only clinical option to non-invasively measure 3D temperature distributions. In this review, we evaluate the status quo and emerging approaches in this evolving technology for replacing conventional dosimetry based on intraluminal or invasively placed probes. First, we define standardized MRT performance thresholds, aiming at facilitating transparency in this field when comparing MR temperature mapping performance for the various scenarios that hyperthermia is currently applied in the clinic. This is based upon our clinical experience of treating nearly 4000 patients with superficial and deep hyperthermia. Second, we perform a systematic literature review, assessing MRT performance in (I) clinical and (II) pre-clinical papers. From (I) we identify the current clinical status of MRT, including the problems faced and from (II) we extract promising new techniques with the potential to accelerate progress. From (I) we found that the basic requirements for MRT during hyperthermia in the clinic are largely met for regions without motion, for example extremities. In more challenging regions (abdomen and thorax), progress has been stagnating after the clinical introduction of MRT-guided hyperthermia over 20 years ago. One clear difficulty for advancement is that performance is not or not uniformly reported, but also that studies often omit important details regarding their approach. Motion was found to be the common main issue hindering accurate MRT. Based on (II), we reported and highlighted promising developments to tackle the issues resulting from motion (directly or indirectly), including new developments as well as optimization of already existing strategies. Combined, these may have the potential to facilitate improvement in MRT in the form of more stable and reliable measurements via better stability and accuracy.


Hearing shapes our perception of time: temporal discrimination of tactile stimuli in deaf people.
Confronted with the loss of one type of sensory input, we compensate using information conveyed by other senses. However, losing one type of sensory information at specific developmental times may lead to deficits across all sensory modalities. We addressed the effect of auditory deprivation on the development of tactile abilities, taking into account changes occurring at the behavioral and cortical level. Congenitally deaf and hearing individuals performed two tactile tasks, the first requiring the discrimination of the temporal duration of touches and the second requiring the discrimination of their spatial length. Compared with hearing individuals, deaf individuals were impaired only in tactile temporal processing. To explore the neural substrate of this difference, we ran a TMS experiment. In deaf individuals, the auditory association cortex was involved in temporal and spatial tactile processing, with the same chronometry as the primary somatosensory cortex. In hearing participants, the involvement of auditory association cortex occurred at a later stage and selectively for temporal discrimination. The different chronometry in the recruitment of the auditory cortex in deaf individuals correlated with the tactile temporal impairment. Thus, early hearing experience seems to be crucial to develop an efficient temporal processing across modalities, suggesting that plasticity does not necessarily result in behavioral compensation.


Justins v The Queen: assisted suicide, juries and the discretion to prosecute.
Juries are often a crucial protection for citizens against unjust or highly controversial laws. The decision whether to proceed with a prosecution rests on the discretionary powers of prosecutors. In cases where the community is deeply divided over right and wrong, it appears that there is, at times, a transference from the public of thwarted law reform aspirations which can create difficult tensions and expectations. This case commentary considers an appeal by Shirley Justins following her conviction for manslaughter by gross criminal negligence as a result of her involvement in the mercy killing of her partner, Mr Graeme Wylie. The morally unsettled nature of the charges brought against her, her own initial plea, the directions given to the jury by the trial judge and even the basis of her appeal resulted in a convoluted and complicated legal case. Spigelman CJ and Johnson J ordered a new trial, Spigelman CJ stating that it was open for a new jury to consider (a) if Mr Wylie lacked capacity; and (b) whether there was criminal involvement by one person in another's death. Simpson J found that further prosecution on the count of manslaughter would amount to an abuse of process and that an acquittal should be entered. This case highlights how fundamentally unsettled are the publicly much debated and persistently contentious issues of euthanasia, assisted suicide, the right of a person to die a dignified death and the way their capacity in that respect should be assessed. It perhaps asks us to reconsider the role of juries and the exercise of discretion by Directors of Public Prosecutions in areas of law where the community and law-makers are deeply and intractably divided.


A charge-suppressing strategy for probing protein methylation.
Methylation of arginine and lysine (RK) residues play essential roles in epigenetics and the regulation of gene expression. However, research in this area is often hindered by the lack of effective tools for probing the protein methylation. Here, we present an antibody-free strategy to capture protein methylation on RK residues by using chemical reactions to eliminate the charges on un-modified RK residues and peptide N-termini. Peptides containing methylated RK residues remain positively charged and are then enriched by strong cation exchange chromatography, followed by high-resolution mass spectrometry identification.


Pentraxin 3 overexpression accelerated tumor metastasis and indicated poor prognosis in hepatocellular carcinoma via driving epithelial-mesenchymal transition.
As a pattern recognition receptor, pentraxin 3 (PTX3) has been found to exert the pleiotropic roles on a variety of cancers. However, the accurate clinical significance of PTX3 in hepatocellular carcinoma (HCC) has not been well defined. The aim of the present investigation was to determine the expression characteristics, prognostic significance, and the relevant biological effect of PTX3 in HCC. The expression of PTX3 was evaluated in tumor and adjacent liver tissues from 210 HCC patients using immunohistochemistry staining. And it was found that a marked up-regulation in the expression of PTX3 in the HCC specimens, which was remarkably correlated with high serum AFP level (P = 0.006), larger tumor size (P <0.001), liver cirrhosis (P = 0.004), advanced TNM stage (P = 0.022), PVTT (P = 0.010), intra-hepatic metastases (P = 0.019), and MVI (P <0.001). PTX3 was identified as an independent predictive factor of poor prognosis by multivariate analysis. Ectopic expression of PTX3 enhanced proliferation, migration, invasion capacities of Huh7 cells and induced EMT phenotype. Silencing PTX3 obtained the opposite results. Moreover, the in vivo experiments confirmed PTX3 induced EMT and promoted proliferation and growth of HCC cells. Collectivelly, these data indicated that PTX3 could accelerate HCC progression through activating EMT and served as a potential predictive factor and therapeutic target for HCC.


Preliminary experience with cryoablation of renal lesions smaller than 4 centimeters.
Nephron-sparing surgical techniques represent an attractive treatment approach for small renal lesions that are limited only by potential operative morbidity. This study tests the hypothesis that an alternative strategy of in situ cryoablation of these lesions may further reduce the incidence of complications with similar efficacy. Beginning August 1996,17 patients were enrolled in an institutional review board-approved protocol for open renal cryoablation for lesions smaller than 4 cm in diameter. The median age was 62 years (range, 35-75 years). The median preoperative lesion size was 2.0 cm (range, 1.1-4.2 cm) determined with either computed tomography or magnetic resonance imaging. A double freeze-thaw technique to -180 degrees C was used under direct intraoperative ultrasound monitoring. The median length of follow-up was 30 months (range, 10-60 months), with 8 patients followed up for more than 20 months. The procedure was accomplished in 3 hours (range, 2.25-4.25 hours) through a 5-cm to 7-cm subcostal incision. The median blood loss was 100 mL, and the median hospital stay was 2 days (range, 2-8 days). The median intraoperative lesion was 2.4 cm, which was not statistically different from preoperative measurements. Postoperative serum creatinine levels were unchanged except for a transient increase from 5.5 mg/dL to 7.0 mg/dL in one patient. Follow-up magnetic resonance imaging scans have demonstrated infarction and a reduction of lesion size in 15 of 16 cases. The size of one patient's mass was unchanged after 3 months. Renal cryoablation via an open approach is associated with few complications and represents a viable alternative to extirpative surgical techniques. The open exposure provides an accurate assessment of the renal unit with definitive ultrasound visualization.


The Impact of Polydispersity and Molecular Weight on the Order-Disorder Transition in Poly(3-hexylthiophene).
Conjugated poly(3-hexylthiophene) (P3HT) chains are known to exist at least in two distinct conformations: a coiled phase and a better ordered aggregated phase. Employing steady state absorption and fluorescence spectroscopy, we measure the course of aggregation of P3HT in tetrahydrofuran (THF) solution within a temperature range of 300 K to 170 K. We show that aggregation is a temperature controlled process, driven by a thermodynamic order-disorder transition. The transition temperature increases with the molecular weight of the chains and can be rationalized in the theory of Sanchez. This implies a smearing out of the phase transition in samples with increasing polydispersity and erodes the signature of a first order phase transition. The detection of a hysteresis when undergoing cooling/heating cycles further substantiates this reasoning.


Balancing benefit against risk in the choice of therapy for coronary artery disease. Lesson from prospective, randomized, clinical trials of percutaneous coronary intervention and coronary artery bypass graft surgery.
The ageing world population faces a coming pandemic of high-risk coronary artery disease (CAD). Patients with CAD have 3 therapeutic options, which are based on objective clinical outcome: medical therapy and risk factor modification (Medicine), and 2 forms of revascularization, coronary artery bypass graft surgery (CABG), and percutaneous coronary intervention (PCI). More than 50 large (>100 patients), multicenter, prospective, randomized clinical trials (RCT) have compared these treatment options in terms of clinical benefits and patient risks. The randomized trials which demonstrated hard outcome (survival, myocardial infarction, stroke) benefits from statins, angiotensin-converting enzyme inhibition and thienopyridines have all been completed subsequent to the publication of most Medicine versus revascularization trials. These medical therapies, plus aspirin, beta-blockers, and risk factor modification, should be made available to patients regardless of the decision to revascularize, or the decision by what means (CABG or PCI). This review integrates the information from these trials, comparing the clinical benefits against the risks inherent in the 3 therapeutic options. The results of our review show that: trials of medicine versus revascularization (either CABG or PCI) support the revascularization paradox, in that the patients at highest risk of adverse outcome, from myocardial ischemia, have a hard outcome benefit (survival, MI, or stroke) from revascularization. This paradox, first seen in the Medicine versus CABG trials of the 1970s, is evident in the trials comparing fibrinolysis and other medicines, with primary PCI for ST-elevation myocardial infarction (MI). The paradox is evident in the conservative versus invasive strategy trials of non-ST-elevation MI and unstable angina, where the benefit of revascularization occurs only in high-risk subsets. The paradox often results in sicker patients, who have more to gain from revascularization, being denied it because of the elevated perception of risk (comparable to a reperfusion paradox in ST-elevation MI, where patients most likely to benefit from thrombolytics are denied them because of the perception of risk). Trials that compared medicine with revascularization for the treatment of acute MI support the use of PCI as the preferred early stabilization strategy (90% of all PAMI trial patients). The majority of the PCI versus CABG trials enrolled populations that were at relatively low risk for ischemic clinical events. These trials demonstrated few hard outcome (survival, MI, or stroke) differences between CABG and PCI. On the basis of the results obtained the following conclusions may be drawn: medicines are the primary options for stable, low-risk CAD, and should be given to all CAD patients. Medically refractory is a useful high-risk marker of potential benefit from revascularization. CABG continues to be the complete revascularization option for patients with multivessel, multi-lesion CAD, in part because of its application to chronic occlusions. PCI is the acute stabilization method of choice for patients with on-going ischemia and acute MI, especially among patients with hemodynamic compromise, and/or major comorbidity.


Force production parameters as behavioural measures for anger expression and control: The Method of Stamp Strike Shout.
This study presents first test results of a new performance-based, psychomotor method to measure anger expression and control, based on voice expression and physical force production in directional movement of arms and legs, called the Method of Stamp Strike Shout (MSSS). Recorded are the standardized impact of stamping on a force plate, hitting a punching bag, and the amplitude of shouting in a microphone at various force levels. The premise is, that these body behaviours stand for the 'urge to act or shout' that belongs to anger-related emotions. The MSSS is meant to be applied in addition to potentially biased self-report questionnaires and has been designed for diagnostic as well as therapeutic purposes in clinical practice. First, this paper focusses on the instrumentation, internal structure and reliability of the MSSS. An explorative study in a student sample (n = 104) shows correlation patterns between increasing and decreasing levels of force production within each subtest (Stamp, Strike and Shout) and between the three subtests. We found excellent internal consistency of the three subtests and high test-retest reliability. The parameters of increasing and decreasing force levels form the slopes of what we call a force pyramid. To adjust for the clustering within persons, aggregated outcomes were calculated: sum scores per subtest as an indication of total force produced, two linear contrast scores to indicate the rate of increase / decrease, and two quadratic contrast scores as measures of the curvature of the slopes. On all subtests, all aggregated scores showed differences between men and women, also when controlled for weight. To test the validity of the MSSS, the second part of the paper examines the relationship between force parameters and anger coping style, measured by the Self-Expression and Control Scale (SECS). The results suggest that the Shout subtest was the most sensitive indicator for anger coping style, showing negative correlations with Anger In, for women as well as men. For women, higher amplitude was also associated with higher Anger Out and lower amplitude with higher Anger Control. The Stamp subtest showed weak positive correlations with the Anger In subscales, whereas no correlations were found on the Strike subtest. Further, a more robust comparison was made between two groups of participants who reported to have an internalizing versus an externalizing anger coping style. Results indicated that internalizing women as well as men used less force than externalizing participants on all three subtests, especially on the Shout subtest. This was confirmed by lower mean sum scores on the Shout subtest for internalizing women compared with externalizing women. No differences in linear contrast scores were shown between internalizing and externalizing participants. The quadratic contrast scores suggested differences of the curvation of the slopes between women with more or less anger control when stamping, and men with more or less anger control when striking. As this is an explorative study, findings should be interpreted with caution.


A longitudinal analysis of estimation, counting skills, and mathematical ability across the first school year.
In response to claims that the quality (and in particular linearity) of children's mental representation of number acts as a constraint on number development, we carried out a longitudinal assessment of the relationships between number line estimation, counting, and mathematical abilities. Ninety-nine 5-year-olds were tested on 4 occasions at 3 monthly intervals. Correlations between the 3 types of ability were evident, but while the quality of children's estimations changed over time and performance on the mathematical tasks improved over the same period, changes in one were not associated with changes in the other. In contrast to the earlier claims that the linearity of number representation is potentially a unique contributor to children's mathematical development, the data suggest that this variable is not significantly privileged in its impact over and above simple procedural number skills. We propose that both early arithmetic success and estimating skill are bound closely to developments in counting ability.


Changes in gait symmetry, gait velocity and self-reported function following total hip replacement.
To investigate the magnitude of change at different time points in measures of gait symmetry, gait velocity and self-reported function following total hip replacement. Longitudinal with test occasions pre-surgery and 3, 6 and 12 months post-surgery. Thirty-four patients with hip osteoarthritis (mean age 63 years, standard deviation 11 years). Subjects walked back and forth along a 7-m walkway at slow, preferred and fast speed. Anteroposterior, vertical and mediolateral trunk symmetry was assessed by accelerometry, while single support symmetry, step-length symmetry and gait velocity was simultaneously assessed by an electronic walkway. Self-reported function was assessed by Hip disability and Osteoarthritis Outcome Score. Gait symmetry data were normalized for gait velocity. Changes between test occasions were reported as effect size. All measures showed effect sizes > 0.30 from pre-operative to 12-months postoperative assessments, and improvements were significant (p < 0.05) in all measures, except mediolateral symmetry. In general, gait symmetry and gait velocity improved most 6 and 12 months postoperatively, while self-reported function improved most 3 months postoperatively. Early improvements were seen in self-reported function, suggesting immediate relief from stiffness and pain, while gait symmetry and velocity improved later postoperatively, suggesting that gait quality and performance require prolonged rehabilitation with postoperative guidance, muscular strengthening and motor relearning.