Quercetin induces apoptosis and enhances 5-FU therapeutic efficacy in hepatocellular carcinoma.
Quercetin (Q), a flavonoid compound, which is obtained in variety of fruits, seeds, and vegetables, has been reported to possess many pharmacological properties including cancer-preventive and anticancer effects. However, studies on the anticancer effects and underlying mechanisms of Q in human hepatocellular carcinoma (HCC) are still limited. The present study is conducted to investigate the anticancer efficacy and adjuvant chemotherapy action of Q in HCC. HCC cell lines HepG2 and SMCC-7721 were treated with different concentrations of Q. The antiproliferative effects of Q were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and the apoptosis and cell cycle dynamics were assessed by flow cytometry; the expression of apoptosis-associated proteins were evaluated by Western blot and immunohistochemistry staining; the tumor growth in vivo was evaluated in a xenograft mouse model. Our results showed that Q effectively inhibited human HCC cell proliferation and induced apoptosis by upregulating the expression of Bad and Bax and downregulating the expression of Bcl-2 and Survivin in vitro. Furthermore, Q obviously inhibited the tumor growth and enhanced the 5-fluorouracil (5-FU) therapeutic efficacy in vitro and in vivo. Taken together, our findings highlight that Q effectively inhibited the growth of tumor and enhanced the sensitivity to thermotherapy, indicating Q is a potential treatment option for HCC.


Functional rehabilitation interventions for chronic ankle instability: a systematic review.
Functional rehabilitation is often employed for ankle instability, but there is little evidence to support its efficacy, especially in those with chronic ankle instability (CAI). To review studies using both functional rehabilitation interventions and functional measurements to establish the effectiveness of functional rehabilitation for both postural control and self-reported outcomes in those with CAI. The databases of Medline, SPORTDiscus, and PubMed were searched between the years 1988 and 2008. Inclusion criteria required articles to have used a clinical research trial involving at least 1 functional rehabilitation intervention, have at least 1 outcome measure of function and/or functional performance, and to have used at least 1 group of subjects who reported either repeated lateral ankle sprains or episodes of "giving way." The term functional was operationally defined as dynamic, closed-kinetic-chain activity other than quiet standing. Six articles met the inclusion criteria. The articles reviewed used multiple functional means for assessment and training, with a wobble board or similar device being the most common. Despite effect sizes being inconsistent for measures of dynamic postural control, all interventions resulted in improvements. Significant improvements and strong effect sizes were demonstrated for self-reported outcomes. The reviewed studies using functional rehabilitation interventions and functional assessment tools were associated with improved ankle stability for both postural control and self-reported function, but more studies may be needed with more consistent effect sizes and confidence intervals to make a definitive conclusion.


Restoring teeth that are endodontically treated through existing crowns. Part I: Survey of pulpal status on access.
The purpose of this study was to identify the pulpal findings encountered by practitioners when accessing complete-coverage crowns that require nonsurgical root canal treatment and the relevance of coronal leakage to the success of the RTC. The survey package consisted of a cover letter stating the instructions, rationale, and purpose for the questionnaire, a questionnaire with 8 short-answer questions, and a stamped, self-addressed envelope. A randomized sample of active dentists (300 general practitioners, 300 prosthodontists, and 300 endodontists) was selected. Collected data were analyzed with the chi-square test. A 60% response rate was obtained. Statistically significant differences were found among the practitioner groups, depending on the question. General practitioners and endodontists obtain access through crowns and maintain these crowns as final restoration significantly more often than do prosthodontists. Practitioners responded that teeth with complete crowns require nonsurgical root canal treatment after 5 to 10 years. Respondents believe that leakage must be addressed when endodontic access cavities in artificial crowns are restored after nonsurgical root canal treatment. General practitioners perform nonsurgical root canal treatment more frequently than do prosthodontists. Practitioners indicated that when teeth with complete crowns require nonsurgical root canal treatment, treatment is most often performed 5 to 10 years after placement of the crown.


Reverse shoulder arthroplasty for the treatment of rotator cuff deficiency.
Early designs of reverse shoulder arthroplasty components for the treatment of glenohumeral arthritis associated with severe rotator cuff deficiency in some cases have been associated with mechanical failure. The purpose of this study was to perform a prospective outcomes study of reverse shoulder arthroplasty performed with use of 5.0-mm peripheral locking screws for baseplate fixation and a lateralized center of rotation for the treatment of a rotator cuff deficiency. From February 2004 to March 2005, 112 patients (114 shoulders) were treated with a reverse shoulder arthroplasty as part of a United States Food and Drug Administration Investigational Device Exemption study. Ninety-four patients (ninety-six shoulders) were available for a minimum follow-up of two years. Of the ninety-six shoulders, thirty-seven had a primary rotator cuff deficiency, thirty-three had a previous rotator cuff operation, twenty-three had a previous arthroplasty, and three had a proximal humeral nonunion. The patients were prospectively followed clinically (the American Shoulder and Elbow Surgeons [ASES] score, the Simple Shoulder Test [SST], and self-reported satisfaction) and radiographically (mechanical failure, loosening, and notching). Patients were videotaped while performing a standard active range-of-motion protocol before and after treatment. These videos were then analyzed in a blinded fashion by three independent observers using a digital goniometer. At two years, the average total ASES scores had improved from 30 preoperatively to 77.6; the average ASES pain scores, from 15 to 41.6; and the average SST scores, from 1.8 to 6.8 (p < 0.0001 for all). Blinded analysis of range of motion showed that average abduction improved from 61 degrees preoperatively to 109.5 degrees (p < 0.0001); average flexion, from 63.5 degrees to 118 degrees (p < 0.0001); and average external rotation, from 13.4 degrees to 28.2 degrees (p < 0.0001). The patients rated the outcome as excellent in fifty-three shoulders (55%), good in twenty-six (27%), satisfactory in eleven (12%), and unsatisfactory in six (6%). There was no evidence of mechanical failure of the baseplate or scapular notching in any of the patients. Six of the ninety-four patients in this study had a complication. Recent advances in reverse shoulder arthroplasty have allowed for improvement in patient outcomes while minimizing early mechanical failure and scapular notching and decreasing the overall complication rate at short-term follow-up.


Hepatic glutathione depletion and impaired bromosulphthalein clearance early after paracetamol overdose in man and the rat.
1. Plasma clearance of bromosulphthalein was impaired in patients within 8 h, and in rats within 2 h , of paracetamol overdose, before biochemical signs of liver damage had appeared. 2. Paracetamol and bromosulphthalein competed for uptake into the liver and excretion into the bile. Impaired hepatic uptake of bromosulphthalein could also be demonstrated in man at doses of the drug within the therapeutic range. 3. In patients studied a smaller proportion of bromosulphthalein was retained in the plasma as the glutathione conjugate after an overdose than after therapeutic doses. This effect could be reproduced in the rat and shown to be due to depletion of hepatic glutathione and to impairment in the activity of the enzyme glutathione-S-aryl transferase. 4. These studies provide further evidence that depletion of hepatic glutathione occurs after paracetamol overdose in man, as in the experimental animal, allowing the subsequent accumulation and binding of a toxic metabolite of the drug within liver cells. Impaired enzymic conjugation of the toxic metabolite with hepatic reduced glutathione may also be important in this situation.


Aerosolized Ebola vaccine protects primates and elicits lung-resident T cell responses.
Direct delivery of aerosolized vaccines to the respiratory mucosa elicits both systemic and mucosal responses. This vaccine strategy has not been tested for Ebola virus (EBOV) or other hemorrhagic fever viruses. Here, we examined the immunogenicity and protective efficacy of an aerosolized human parainfluenza virus type 3-vectored vaccine that expresses the glycoprotein (GP) of EBOV (HPIV3/EboGP) delivered to the respiratory tract. Rhesus macaques were vaccinated with aerosolized HPIV3/EboGP, liquid HPIV3/EboGP, or an unrelated, intramuscular, Venezuelan equine encephalitis replicon vaccine expressing EBOV GP. Serum and mucosal samples from aerosolized HPIV3/EboGP recipients exhibited high EBOV-specific IgG, IgA, and neutralizing antibody titers, which exceeded or equaled titers observed in liquid recipients. The HPIV3/EboGP vaccine induced an EBOV-specific cellular response that was greatest in the lungs and yielded polyfunctional CD8+ T cells, including a subset that expressed CD103 (αE integrin), and CD4+ T helper cells that were predominately type 1. The magnitude of the CD4+ T cell response was greater in aerosol vaccinees. The HPIV3/EboGP vaccine produced a more robust cell-mediated and humoral immune response than the systemic replicon vaccine. Moreover, 1 aerosol HPIV3/EboGP dose conferred 100% protection to macaques exposed to EBOV. Aerosol vaccination represents a useful and feasible vaccination mode that can be implemented with ease in a filovirus disease outbreak situation.


Outpatient management of heart valve disease following the COVID-19 pandemic: implications for present and future care.
The established processes for ensuring safe outpatient surveillance of patients with known heart valve disease (HVD), echocardiography for patients referred with new murmurs and timely delivery of surgical or transcatheter treatment for patients with severe disease have all been significantly impacted by the novel coronavirus pandemic. This has created a large backlog of work and upstaging of disease with consequent increases in risk and cost of treatment and potential for worse long-term outcomes. As countries emerge from lockdown but with COVID-19 endemic in society, precautions remain that restrict 'normal' practice. In this article, we propose a methodology for restructuring services for patients with HVD and provide recommendations pertaining to frequency of follow-up and use of echocardiography at present. It will be almost impossible to practice exactly as we did prior to the pandemic; thus, it is essential to prioritise patients with the greatest clinical need, such as those with symptomatic severe HVD. Local procedural waiting times will need to be considered, in addition to usual clinical characteristics in determining whether patients requiring intervention would be better suited having surgical or transcatheter treatment. We present guidance on the identification of stable patients with HVD that could have follow-up deferred safely and suggest certain patients that could be discharged from follow-up if waiting lists are triaged with appropriate clinical input. Finally, we propose that novel models of working enforced by the pandemic-such as increased use of virtual clinics-should be further developed and evaluated.


Non-invasive MRI and spectroscopy of mdx mice reveal temporal changes in dystrophic muscle imaging and in energy deficits.
In Duchenne muscular dystrophy (DMD), a genetic disruption of dystrophin protein expression results in repeated muscle injury and chronic inflammation. Magnetic resonance imaging shows promise as a surrogate outcome measure in both DMD and rehabilitation medicine that is capable of predicting clinical benefit years in advance of functional outcome measures. The mdx mouse reproduces the dystrophin deficiency that causes DMD and is routinely used for preclinical drug testing. There is a need to develop sensitive, non-invasive outcome measures in the mdx model that can be readily translatable to human clinical trials. Here we report the use of magnetic resonance imaging and spectroscopy techniques for the non-invasive monitoring of muscle damage in mdx mice. Using these techniques, we studied dystrophic mdx muscle in mice from 6 to 12 weeks of age, examining both the peak disease phase and natural recovery phase of the mdx disease course. T2 and fat-suppressed imaging revealed significant levels of tissue with elevated signal intensity in mdx hindlimb muscles at all ages; spectroscopy revealed a significant deficiency of energy metabolites in 6-week-old mdx mice. As the mdx mice progressed from the peak disease stage to the recovery stage of disease, each of these phenotypes was either eliminated or reduced, and the cross-sectional area of the mdx muscle was significantly increased when compared to that of wild-type mice. Histology indicates that hyper-intense MRI foci correspond to areas of dystrophic lesions containing inflammation as well as regenerating, degenerating and hypertrophied myofibers. Statistical sample size calculations provide several robust measures with the ability to detect intervention effects using small numbers of animals. These data establish a framework for further imaging or preclinical studies, and they support the development of MRI as a sensitive, non-invasive outcome measure for muscular dystrophy.


Location of the phrenic nucleus in the human spinal cord.
Eight normal human spinal cords were studied. Spinal segments were identified and embedded in paraffin wax. Serial cross sections were cut at 25 microm and stained by cresyl violet. Motor columns were reconstructed adapting Elliott's (1942) methods. Motor columns were classified into the medial and lateral divisions and were numbered sequentially from medial to lateral at the level of C1. In the cervical cord, 8 motor columns were traced. Column 1, corresponding to the medial column, presented 3 subdivisions designated as 1a, 1b and 1c with ventral, dorsal and lateral positions respectively. Columns 1a and 1b extended throughout the cervical region while 1c was confined to 3rd, 4th and 5th cervical segments. At the level of C3, 1c was a discrete column situated lateral to 1a and 1b but at C4 and C5 it became displaced medially close to the medial margin of the ventral horn. In cross section, it presented smaller medial and large lateral part. With the help of clinical and developmental evidence an attempt was made to correlate column 1c with the phrenic nucleus.


The culprit insect but not severity of allergic reactions to bee and wasp venom can be determined by molecular diagnosis.
Allergy to bee and wasp venom can lead to life-threatening systemic reactions. The identification of the culprit species is important for allergen-specific immunotherapy. To determine a panel of recombinant bee and wasp allergens which is suitable for the identification of bee or wasp as culprit allergen sources and to search for molecular surrogates of clinical severity of sting reactions. Sera from eighty-seven patients with a detailed documentation of their severity of sting reaction (Mueller grade) and who had been subjected to titrated skin testing with bee and wasp venom were analyzed for bee and wasp-specific IgE levels by ImmunoCAPTM. IgE-reactivity testing was performed using a comprehensive panel of recombinant bee and wasp venom allergens (rApi m 1, 2, 3, 4, 5 and 10; rVes v 1 and 5) by ISAC chip technology, ImmunoCAP and ELISA. IgG4 antibodies to rApi m 1 and rVes v 5 were determined by ELISA and IgE/IgG4 ratios were calculated. Results from skin testing, IgE serology and IgE/IgG4 ratios were compared with severity of sting reactions. The panel of rApi m 1, rApi m 10, rVes v 1 and rVes v 5 allowed identification of the culprit venom in all but two of the 87 patients with good agreement to skin testing. Severities of sting reactions were not associated with results obtained by skin testing, venom-specific IgE levels or molecular diagnosis. Severe sting reactions were observed in patients showing < 1 ISU and < 2kUA/L of IgE to Api m 1 and/or Ves v 5. We identified a minimal panel of recombinant bee and wasp allergens for molecular diagnosis which may permit identification of bee and/or wasp as culprit insect in venom-sensitized subjects. The severity of sting reactions was not associated with parameters obtained by molecular diagnosis.


New tools for investigating the comparative biology of Caenorhabditis briggsae and C. elegans.
Comparative studies of Caenorhabditis briggsae and C. elegans have provided insights into gene function and developmental control in both organisms. C. elegans is a well developed model organism with a variety of molecular and genetic tools to study gene functions. In contrast, there are only very limited tools available for its closest relative, C. briggsae. To take advantage of the full potential of this comparative approach, we have developed several genetic and molecular tools to facilitate functional analysis in C. briggsae. First, we designed and implemented an SNP-based oligonucleotide microarray for rapid mapping of genetic mutants in C. briggsae. Second, we generated a mutagenized frozen library to permit the isolation of targeted deletions and used the library to recover a deletion mutant of cbr-unc-119 for use as a transgenic marker. Third, we used the cbr-unc-119 mutant in ballistic transformation and generated fluorescently labeled strains that allow automated lineaging and cellular resolution expression analysis. Finally, we demonstrated the potential of automated lineaging by profiling expression of egl-5, hlh-1, and pha-4 at cellular resolution and by detailed phenotyping of the perturbations on the Wnt signaling pathway. These additions to the experimental toolkit for C. briggsae should greatly increase its utility in comparative studies with C. elegans. With the emerging sequence of nematode species more closely related to C. briggsae, these tools may open novel avenues of experimentation in C. briggsae itself.


A century of ecosystem change: human and seabird impacts on plant species extirpation and invasion on islands.
We used 116 years of floral and faunal records from Mandarte Island, British Columbia, Canada, to estimate the indirect effects of humans on plant communities via their effects on the population size of a surface-nesting, colonial seabird, the Glaucous-winged gull (Larus glaucescens). Comparing current to historical records revealed 18 extirpations of native plant species (32% of species historically present), 31 exotic species introductions, and one case of exotic introduction followed by extirpation. Contemporary surveys indicated that native species cover declined dramatically from 1986 to 2006, coincident with the extirpation of 'old-growth' conifers. Because vegetation change co-occurred with an increasing gull population locally and regionally, we tested several predictions from the hypothesis that the presence and activities of seabirds help to explain those changes. Specifically, we predicted that on Mandarte and nearby islands with gull colonies, we should observe higher nutrient loading and exotic plant species richness and cover than on nearby islands without gull colonies, as a consequence of competitive dominance in species adapted to high soil nitrogen and trampling. As predicted, we found that native plant species cover and richness were lower, and exotic species cover and richness higher, on islands with versus without gull colonies. In addition, we found that soil carbon and nitrogen on islands with nesting gulls were positively related to soil depth and exotic species richness and cover across plots and islands. Our results support earlier suggestions that nesting seabirds can drive rapid change in insular plant communities by increasing nutrients and disturbing vegetation, and that human activities that affect seabird abundance may therefore indirectly affect plant community composition on islands with seabird colonies.


Changes in diastolic time with various pharmacologic agents: implication for myocardial perfusion.
Diastolic time (DT) is calculated as the cycle length (RR) minus electromechanical systole (QS2). The ratio of DT (RR-QS2) to RR interval times 100, or the percent diastole (%D), varies nonlinearly with heart rate (HR), increasing rapidly with decreasing HR. The effect of commonly used cardioactive agents on %D was studied in five groups of normal subjects. In group 1 (n = 12), propranolol (160 mg daily) increased %D from 55.9 +/- 1.7 to 64.7 +/- 1.3 (p less than 0.001) by slowing HR. In group 2 (n = 12), dobutamine (2.5 micrograms/kg/min) increased %D from 56.4 +/- 1.4 to 61.8 +/- 1.3 (p less than 0.005) by shortening the QS2. In group 3 (n = 10), Cedilanid-D (1.6 mg i.v.) increased %D from 55.5 +/- 1 to 63.2 +/- 0.7 (p less than 0.001), both by slowing the HR and shortening the QS2. In group 4 (n = 12), isoproterenol (2 micrograms/min) increased HR and shortened the QS2 significantly. The net result was a significant reduction of %D from 56.1 +/- 1.4 to 53.5 +/- 1.1, (p less than 0.05). In group 5 (n = 15), a 100-mg bolus of i.v. lidocaine did not have a significant effect on %D. This study indicates that cardiovascular drugs may have significant effects on the relative duration of diastole either by affecting HR or the duration of systole. This may have clinical implications for patients with coronary artery disease and patients with left ventricular hypertrophy, since in both cases coronary flow in mostly diastolic.


Traumatic mechanisms of head injury in child abuse.
Child abuse is a complex sociophysical phenomenon in which a child may suffer physical and mental assault ranging from death to emotional deprivation. In this report, an effort is made to identify the pathogenetic mechanisms of head injury in child abuse and to describe the site of injury, incidence of head injury, and difficulties encountered in establishing a doctor-family relationship. During the years 1970 through 1979, 621 children were confirmed victims of child abuse and treated by the medical staff at the Children's Memorial Hospital in Chicago. Of these, there were 77 children (12%) who suffered associated head injuries ranging from cerebral concussion to irreversible brain damage and/or death. 85% of these head-injured children were under the age of 2 years. 62% were male and 38% female. In analyzing the type of injury which resulted in an associated head injury, we learned that 54% of all injuries were caused by direct blows to the head, face and other parts of the body, 35% were due to dropping, throwing or falling; only 8% were caused by 'shaking'. 55 injuries (48%) out of 115 trauma cases were thought to be caused by injury to head or face. 53 patients showed 113 external skin wounds such as ecchymoses of eyes, excoriations, bruises, contusion, hematoma, burns, etc. 46% of all external wounds were found over the head and face. This may probably indicate to us that a traumatic force causing injury to the brain is directed to the head and face. The traumatic mechanisms are analyzed and discussed to assess the behavioral derangement of the assault.


Using TRIPS flexibilities to facilitate access to medicines.
The problem of how to mitigate the impact of pharmaceutical patents on the delivery of essential medicines to the world's poor is as far from being resolved as it has ever been. Extensive academic commentary and policy debate have achieved little in terms of practical outcomes. Although international instruments are now in place allowing countries to enact legislation that permits the generic manufacture of patented pharmaceuticals, many countries have not yet enacted appropriate legislation and most of those that have yet to make use of it. One major problem is that the requirements of international instruments and implementing legislation are seen as being so stringent as to be unworkable. This paper calls for fresh attempts to enact workable legislation that fits within the prescribed requirements of international law without going beyond them. It argues that high-income nations should refocus on their moral obligation to enact appropriate legislative mechanisms and provide appropriate incentives for their use. Draft legislation currently being considered in Australia is used to illustrate how workable legislative frameworks can be developed.


Residual Efficacy of Fungicides for Controlling Brown Patch on Creeping Bentgrass Fairways.
Residual efficacy of five fungicides (azoxystrobin, flutolanil, metconazole, polyoxin D, and pyraclostrobin) applied to creeping bentgrass (Agrostis stolonifera) maintained under golf course fairway conditions was determined using a bioassay method. During 2010 and 2011, six different field experiments were conducted. Each consisted of a single fungicide application followed by periodic (0, 3, 7, 10, 14, 17, and 21 days after application) turf sampling, inoculation of samples with an isolate of Rhizoctonia solani, and incubation in a controlled environment chamber for 48 h. For each sample date, fungicide efficacy was determined by measuring the extent of symptom expansion on fungicide treated and nontreated samples. Efficacy half-life values based on a two-parameter Weibull function were 3.1 to 14.0 days for the fungicides used in this study. Residual efficacy was further examined in 2011 by analyzing residues from creeping bentgrass verdure using liquid chromatography/time-of-flight mass spectrometry (LC/TOF-MS). Quantitative analysis from LC/TOF-MS revealed that fungicide residues were depleted rapidly following application to turfgrass and reinforced the precipitous decline in fungicide efficacy demonstrated by the bioassays. Regardless of fungicide, more than 90% of active ingredient applied was depleted from the verdure between 3 and 8 days after application, and more than 99% of fungicide was depleted at 17 days after application. This research provides a quantitative description of the temporal nature of loss of fungicide and fungicide protection from turf.


Compressed biodegradable matrices of spray-dried PLGA microspheres for the modified release of ketoprofen.
A spray-drying technique was used to prepare poly(lactide-co-glycolide) (PLGA) drug loaded microspheres. Ketoprofen was chosen as a model NSAID drug. The microspheres were characterized in terms of morphology, drug content and release behaviour. The spray-dried particles were subject to a direct compression process for the preparation of biodegradable matrix tablets. The spray-dried powders were found to have good compaction properties. Tablets were also prepared from a mixture of microspheres and microcrystalline cellulose, mannitol and hydroxypropylmethylcellulose or sodium alginate. The release of ketoprofen in phosphate buffer (pH 7.4) was significantly sustained, indicating the suitability of using tabletted spray-dried PLGA microspheres for controlled drug delivery. The results show that spray-dried PLGA particles have promising properties as direct compression and release controlling excipients in matrix tablets for oral administration.


Complementation of SOD-deficient Escherichia coli by manganese porphyrin mimics of superoxide dismutase activity.
Cationic Mn(III) porphyrins substituted on the methine bridge carbons (meso positions) with N-alkylpyridinium or N,N'-diethylimidazolium groups have been prepared and characterized, both chemically and as SOD mimics. The ortho tetrakis N-methylpyridinium compound was substantially more active than the corresponding para isomer. This ortho compound also exhibited a more positive redox potential and greater ability to facilitate the aerobic growth of a SOD-deficient Escherichia coli. Analogs with longer alkyl side chains and with methoxyethyl side chains, as well as with N,N'-diethylimidazolium and N,N'-dimethoxyethylimidazolium groups on the meso positions, have been prepared in anticipation of greater penetration of the cells due to greater lipophilicity. We now report that the more lipophilic compounds were effective at complementing the SOD-deficient E. coli at lower concentrations than were needed with the less lipophilic compounds. The greater efficacy of the more lipophilic compounds was achieved at the cost of greater toxicity that became apparent when these compounds were applied at higher concentrations.


Dural arteriovenous fistulas without cortical venous drainage: presentation, treatment, and outcomes.
Current evidence suggests that intracranial dural arteriovenous fistulas (dAVFs) without cortical venous drainage (CVD) have a benign clinical course. However, no large study has evaluated the safety and efficacy of current treatments and their impact over the natural history of dAVFs without CVD. The authors conducted an analysis of the retrospectively collected multicenter Consortium for Dural Arteriovenous Fistula Outcomes Research (CONDOR) database. Patient demographics and presenting symptoms, angiographic features of the dAVFs, and treatment outcomes of patients with Borden type I dAVFs were reviewed. Clinical and radiological follow-up information was assessed to determine rates of new intracranial hemorrhage (ICH) or nonhemorrhagic neurological deficit (NHND), worsening of venous hyperdynamic symptoms (VHSs), angiographic recurrence, and progression or spontaneous regression of dAVFs over time. A total of 342 patients/Borden type I dAVFs were identified. The mean patient age was 58.1 ± 15.6 years, and 62% were women. The mean follow-up time was 37.7 ± 54.3 months. Of 230 (67.3%) treated dAVFs, 178 (77%) underwent mainly endovascular embolization, 11 (4.7%) radiosurgery alone, and 4 (1.7%) open surgery as the primary modality. After the first embolization, most dAVFs (47.2%) achieved only partial reduction in early venous filling. Multiple complementary interventions increased complete obliteration rates from 37.9% after first embolization to 46.7% after two or more embolizations, and 55.2% after combined radiosurgery and open surgery. Immediate postprocedural complications occurred in 35 dAVFs (15.2%) and 6 (2.6%) with permanent sequelae. Of 127 completely obliterated dAVFs by any therapeutic modality, 2 (1.6%) showed angiographic recurrence/recanalization at a mean of 34.2 months after treatment. Progression to Borden-Shucart type II or III was documented in 2.2% of patients and subsequent development of a new dAVF in 1.6%. Partial spontaneous regression was found in 22 (21.4%) of 103 nontreated dAVFs. Multivariate Cox regression analysis demonstrated that older age, NHND, or severe venous-hyperdynamic symptoms at presentation and infratentorial location were associated with worse prognosis. Kaplan-Meier curves showed no significant difference for stable/improved symptoms survival probability in treated versus nontreated dAVFs. However, estimated survival times showed better trends for treated dAVFs compared with nontreated dAVFs (288.1 months vs 151.1 months, log-rank p = 0.28). This difference was statistically significant for treated dAVFs with 100% occlusion (394 months, log-rank p < 0.001). Current therapeutic modalities for management of dAVFs without CVD may provide better symptom control when complete angiographic occlusion is achieved.


Automated Bone Scan Index as an Imaging Biomarker to Predict Overall Survival in the Zometa European Study/SPCG11.
Owing to the large variation in treatment response among patients with high-risk prostate cancer, it would be of value to use objective tools to monitor the status of bone metastases during clinical trials. Automated Bone Scan Index (aBSI) based on artificial intelligence has been proposed as an imaging biomarker for the quantification of skeletal metastases from bone scintigraphy. To investigate how an increase in aBSI during treatment may predict clinical outcome in a randomised controlled clinical trial including patients with high-risk prostate cancer. We retrospectively selected all patients from the Zometa European Study (ZEUS)/SPCG11 study with image data of sufficient quality to allow for aBSI assessment at baseline and at 48-mo follow-up. Data on aBSI were obtained using EXINIboneBSI software, blinded for clinical data and randomisation of zoledronic acid treatment. Data on age, overall survival (OS), and prostate-specific antigen (PSA) at baseline and upon follow-up were available from the study database. Association between clinical parameters and aBSI increase during treatment was evaluated using Cox proportional-hazards regression models, Kaplan-Meier estimates, and log-rank test. Discrimination between prognostic variables was assessed using the concordance index (C-index). In this cohort, 176 patients with bone metastases and a change in aBSI from baseline to follow-up of ≤0.3 had a significantly longer median survival time than patients with an aBSI change of >0.3 (p<0.0001). The increase in aBSI was significantly associated with OS (p<0.01 and C-index=0.65), while age and PSA change were not. The aBSI used as an objective imaging biomarker predicted outcome in prostate cancer patients in the ZEUS/SPCG11 study. An analysis of the change in aBSI from baseline to 48-mo follow-up represents a valuable tool for prognostication and monitoring of prostate cancer patients with bone metastases. The increase in the burden of skeletal metastases, as measured by the automated Bone Scan Index (aBSI), during treatment was associated with overall survival in patients from the Zometa European Study/SPCG11 study. The aBSI may be a useful tool also in monitoring prostate cancer patients with newly developed bone metastases.


Machine behaviour.
Machines powered by artificial intelligence increasingly mediate our social, cultural, economic and political interactions. Understanding the behaviour of artificial intelligence systems is essential to our ability to control their actions, reap their benefits and minimize their harms. Here we argue that this necessitates a broad scientific research agenda to study machine behaviour that incorporates and expands upon the discipline of computer science and includes insights from across the sciences. We first outline a set of questions that are fundamental to this emerging field and then explore the technical, legal and institutional constraints on the study of machine behaviour.


Rats selectively bred for differences in aerobic capacity have similar hypertensive responses to chronic intermittent hypoxia.
Exposure to chronic intermittent hypoxia (CIH) is an animal model that mimics the repetitive bouts of hypoxemia experienced by humans with sleep apnea. Rats exposed to CIH develop hypertension that depends on the activation of sympathetic nerve activity (SNA). Since obesity and metabolic syndrome have been linked to neurogenic hypertension and sleep apnea, and because sleep apnea can adversely affect aerobic exercise capacity, we tested the hypothesis that rats bred for selection of low aerobic capacity running (LCR) would have a greater hypertensive response to CIH than rats bred for high aerobic capacity running (HCR). Blockade of ganglionic transmission was performed to compare the contribution of SNA to the maintenance of resting mean arterial pressure (MAP). Next, hypertensive responses to 7 days of CIH were compared across LCR and HCR rats (14-16 mo old). Finally, the contribution of the hypothalamic paraventricular nucleus (PVN) to the maintenance of SNA and hypertension after CIH was determined and compared across groups. Although LCR rats were less active and had greater body weights than HCR rats, resting MAP, the contribution of ongoing SNA to the maintenance of MAP, and hypertensive responses to CIH were similar between groups. Contrary to our hypothesis, chemical inhibition of the PVN with muscimol (1 mmol/100 nl) caused a larger fall of MAP in HCR rats than in LCR rats. We conclude that LCR rats do not have resting hypertension or an exaggerated hypertensive response to CIH. Interestingly, the maintenance of CIH hypertension in LCR rats compared with HCR rats appears less reliant on ongoing PVN neuronal activity.


Association of butyrylcholinesterase K variant with cholinesterase-positive neuritic plaques in the temporal cortex in late-onset Alzheimer's disease.
In confirmed late-onset (>65 years) Alzheimer's disease, we found a greater load, both of overall neuritic plaques and of cholinesterase-positive neuritic plaques, in the temporal cortex of carriers of the butyrylcholinesterase K variant (BCHE-K) aged <80 years than of all other patients. The differences were most striking in the case of cholinesterase-positive neuritic plaques. Among BCHE-K carriers, densities of such plaques were over six times higher in patients <80 years at death than in those >80 years (P=0.01). Furthermore, in subjects <80 years, BCHE-K carriers had nearly six-fold greater densities of these plaques than non-carriers (P=0.009). We consider three potential explanations for these findings: that the K variant binds more readily to plaque constituents, that it promotes fibril formation or that it induces aberrant neurite growth.


Quality of life and hernia development 5 years after open abdomen treatment with vacuum-assisted wound closure and mesh-mediated fascial traction.
To report incisional hernia (IH) incidence, abdominal wall (AW) discomfort and quality of life (QoL) 5 years after open abdomen treatment with vacuum-assisted wound closure and mesh-mediated fascial traction (VAWCM). Five-year follow-up of patients included in a prospective study 2006-2009. The protocol included physical examination, patient interview, chart review, questionnaires on abdominal wall and stoma complaints and the SF-36 questionnaire. Fifty-five (12 women, 43 men; median age 70 years) of 111 included patients were alive. Follow-up rate was 91 %. Cumulative IH incidence during the whole study was 62 %. One-third of the IHs was repaired. At 5-year follow-up 59 % of IHs were clinically detectable. AW symptoms were equivalent in patients with (15/23) and without (11/21) IH (p = 0.541). SF-36 scores were lower than population mean for component scores and all subscales except bodily pain. Patients with major co-morbidity had lower physical component score [31.6 (95 %, CI 25.6-37.4)] compared to those without [48.9 (95 %, CI 46.2-51.4)]. Major co-morbidity was not associated with IH (p = 0.56), AW symptoms (p = 0.54) or stoma (p = 0.10). Patients with IH or other AW symptoms had similar SF-36 results compared to those without, whereas patients with a stoma had >5 point lower mean scores for general health, social function and physical component score compared to those without. VAWCM treatment results in high incidence of IH. However, at five years, there was no detectable difference in abdominal wall complaints and QoL in patients with IH compared to those without. Lower QoL appeared mainly to be associated with the presence of major co-morbidity.


HIV-1-associated thrombocytopenia. The role of splenectomy.
Thrombocytopenic purpura is a common hematologic abnormality occurring in individuals infected with the human immunodeficiency virus, HIV-1. Of the nearly two million people infected with HIV-1, approximately 11% have platelet counts of less than 100,000/mm3. If no etiology other than HIV-1 infection can be found for the thrombocytopenia, the syndrome is referred to as HIV-1-associated thrombocytopenia (HAT). Steroids lead to an improvement in the platelet count in 60% to 80% of effected individuals but the majority of those who respond cannot maintain a normal platelet count when steroids are withdrawn. Furthermore concern over chronic steroid therapy in HIV-1-infected individuals has led to the investigation of other forms of treatment for this syndrome. This report describes the experience at Duke University Medical Center with eight patients who developed HAT and subsequently underwent splenectomy. In this group there was 1 complete response, 5 partial responses, and 2 patients who did not respond. There were no perioperative deaths and minimal perioperative morbidity. No evidence for the progression of HIV-1 infection in asymptomatic patients after splenectomy to AIDS related complex (ARC) or to the acquired immune deficiency syndrome (AIDS) was seen. In addition no increase in the susceptibility to infections by encapsulated organisms as a result of splenectomy was observed after a mean follow-up of 13.25 months. A review of 79 other cases reported in the literature suggests a higher response rate than that observed in our patients. Reasons for this discrepancy are discussed and an algorithm defining the role of splenectomy in the management of HAT is presented.


Operant conditioning of heart rate in curarized rats: hemodynamic changes.
Three groups of curarized rats were subjected to operant heart rate conditioning with use of a shock-avoidance procedure while cardiac output, mean arterial pressure, and total peripheral resistance were measured. Heart rate changes in the control group remained constant during the entire 90-min experimental period, while cardiac output decreased significantly. Those rats that were reinforced for increasing their heart rate had a small but statistically significant increase in heart rate, but cardiac output decreased to approximately the same extent as in the control group. The group reinforced for decreasing their heart rate demonstrated a large, significant decrease in heart rate and an even larger drop in cardiac output, which was significantly greater than that of either of the other two groups. Operant conditioning of a single facet of the cardiovascular system resulted in significantly larger changes in other cardiovascular parameters, which may have been partly masked by the physiological effects of d-tubocurarine. Therefore, only when these other measures of cardiovascular function are taken into consideration can interpretation of operant heart rate conditioning become meaningful.


Analysis of gene expression regulated by the ETV5 transcription factor in OV90 ovarian cancer cells identifies FOXM1 overexpression in ovarian cancer.
Epithelial ovarian cancer is the most lethal gynecologic malignancy and the fifth leading cause of cancer death in women in the Western world. ETS transcription factors have been implicated in the regulation of gene expression during a variety of biologic processes including cell growth and differentiation. We recently examined the role of the ETS transcription factor ETV5 in epithelial ovarian cancer and described ETV5 as being upregulated in ovarian tumor samples as compared with ovarian tissue controls. In ovarian cancer cells, we showed that ETV5 regulated the expression of cell adhesion molecules, enhancing ovarian cancer cell survival in anchorage-independent conditions and suggesting that it plays a role in ovarian cancer cell dissemination and metastasis into the peritoneal cavity. To understand the role of ETV5 transcription factor during ovarian cancer cell dissemination, we analyzed by gene expression microarray technology those genes whose expression was altered in an ovarian cancer cell line with a stable downregulation of ETV5. The analysis of the genes and signaling pathways under the control of ETV5 in OV90 cells has unraveled new signaling pathways that interact with ETV5, among them the cell-cycle progression and the TGFβ signaling pathway. In addition, we found that the downregulation of ETV5 reduced the expression of the oncogenic transcription factor FOXM1. Consistently, FOXM1 was overexpressed in ovarian tumor samples, and its transcriptional levels increased with ETV5 transcription in ovarian tumor samples. Moreover, FOXM1 expression levels increased with tumor grade, suggesting a role in the progression of ovarian cancer.


Products from the oxidation of linear isomers of hexene.
The experimental study of the oxidation of the three linear isomers of hexene was performed in a quartz isothermal jet-stirred reactor (JSR) at temperatures ranging from 500 to 1100 K including the negative temperature coefficient (NTC) zone, at quasi-atmospheric pressure (1.07 bar), at a residence time of 2 s and with dilute stoichiometric mixtures. The fuel and reaction product mole fractions were measured using online gas chromatography. In the case of 1-hexene, the JSR has also been coupled through a molecular-beam sampling system to a reflectron time-of-flight mass spectrometer combined with tunable synchrotron vacuum ultraviolet photoionization. A difference of reactivity between the three fuels, which varies with the temperature range has been observed and is discussed according to the changes in the possible reaction pathways when the double bond is displaced. An enhanced importance of the reactions via the Waddington mechanism and of those of allylic radicals with HO2 radicals can be noted for 2- and 3-hexenes compared to 1-hexene.


Combining an in silico proarrhythmic risk assay with a tPKPD model to predict QTc interval prolongation in the anesthetized guinea pig assay.
Human-based in silico models are emerging as important tools to study the effects of integrating inward and outward ion channel currents to predict clinical proarrhythmic risk. The aims of this study were 2-fold: 1) Evaluate the capacity of an in silico model to predict QTc interval prolongation in the in vivo anesthetized cardiovascular guinea pig (CVGP) assay for new chemical entities (NCEs) and; 2) Determine if a translational pharmacokinetic/pharmacodynamic (tPKPD) model can improve the predictive capacity. In silico simulations for NCEs were performed using a population of human ventricular action potential (AP) models. PatchXpress® (PX) or high throughput screening (HTS) ion channel data from respectively n = 73 and n = 51 NCEs were used as inputs for the in silico population. These NCEs were also tested in the CVGP (n = 73). An M5 pruned decision tree-based regression tPKPD model was used to evaluate the concentration at which an NCE is liable to prolong the QTc interval in the CVGP. In silico results successfully predicted the QTc interval prolongation outcome observed in the CVGP with an accuracy/specificity of 85%/73% and 75%/77%, when using PX and HTS ion channel data, respectively. Considering the tPKPD predicted concentration resulting in QTc prolongation (EC5%) increased accuracy/specificity to 97%/95% using PX and 88%/97% when using HTS. Our results support that human-based in silico simulations in combination with tPKPD modeling can provide correlative results with a commonly used early in vivo safety assay, suggesting a path toward more rapid NCE assessment with reduced resources, cycle time, and animal use.


In vitro cytotoxicity, cellular pharmacology, and DNA lesions induced by annamycin, an anthracycline derivative with high affinity for lipid membranes.
Annamycin (AN) is an anthracycline antibiotic with high affinity for lipid membranes which is being developed for clinical studies formulated in liposomes. We studied the in vitro cytotoxicity, cellular pharmacology, and DNA damage induced by AN in P388 cells sensitive and resistant to doxorubicin (DOX). AN was as cytotoxic as DOX against P388-sensitive cells and about 50 times more cytotoxic than DOX against P388-resistant cells (resistance index 5 for AN versus 250 for DOX). Cellular uptake of AN by sensitive cells was 2-3-fold higher than that of DOX. In resistant cells, cellular uptake of AN and DOX was approximately 65% and 30%, respectively, of the cellular uptake in sensitive cells. As a result, cellular uptake of AN by resistant cells was higher than uptake of DOX by sensitive cells. DOX was fully retained in sensitive cells while it was effluxed rapidly from resistant cells. In contrast, efflux of AN was similar in sensitive and resistant cells, thus suggesting that it is not mediated by P-glycoprotein. AN was more effective than DOX in inducing single DNA breaks, double DNA breaks, and DNA-protein cross-links, both in sensitive and resistant cells, although DNA damage was lower in resistant cells than in sensitive cells. DNA lesions induced by AN in resistant cells were similar to or greater than those induced by DOX in sensitive cells. These studies indicate that the lack of cross-resistance between DOX and AN appears to be related, at least in part, to the relatively higher cellular uptake of AN compared with DOX and is associated with the ability of AN to induce significant DNA damage in resistant cells.


Peripheral demyelination and neuropathic pain behavior in periaxin-deficient mice.
The Prx gene in Schwann cells encodes L- and S-periaxin, two abundant PDZ domain proteins thought to have a role in the stabilization of myelin in the peripheral nervous system (PNS). Mice lacking a functional Prx gene assemble compact PNS myelin. However, the sheath is unstable, leading to demyelination and reflex behaviors that are associated with the painful conditions caused by peripheral nerve damage. Older Prx-/- animals display extensive peripheral demyelination and a severe clinical phenotype with mechanical allodynia and thermal hyperalgesia, which can be reversed by intrathecal administration of a selective NMDA receptor antagonist We conclude that the periaxins play an essential role in stabilizing the Schwann cell-axon unit and that the periaxin-deficient mouse will be an important model for studying neuropathic pain in late onset demyelinating disease.


Development of cell surface linkage complexes in cultured fibroblasts.
The possible role of a 140K membrane-associated protein complex (140K) in fibronectin-cytoskeleton associations has been examined. The 140K was identified by the monoclonal antibody JG22E. Monoclonal and polyclonal antibodies to the 140K showed identical patterns of binding to the cell membranes of fixed and permeabilized chicken embryonic fibroblasts; localization was diffuse, but with marked concentration in cell-to-extracellular matrix contact sites. Correlative localization with interference reflection microscopy and double-label or triple-label immunofluorescence showed that 140K co-distributed with extracellular fibronectin fibrils and intracellular alpha-actinin in microfilament bundles at extracellular matrix contact sites but tended not to co-localize with tropomyosin present in bundles at sites farther from adhesion sites. In addition, binding of antibodies to 140K, alpha-actinin, and fibronectin was excluded from vinculin-rich focal adhesion sites at the cellular periphery. A progressive development of cell surface alpha-actinin-140K-fibronectin associations was observed in early spreading cells. The anti-140K monoclonal antibody JG22E inhibited the attachment and spreading of both normal and Rous sarcoma virus-transformed chicken embryonic fibroblasts to a fibronectin substratum. However, the anti-140K monoclonal antibody became a positive mediator of cell attachment and spreading if it was adsorbed or cross-linked to the substratum. Our results provide the first description of a membrane-associated protein complex that co-localizes with fibronectin and microfilament bundles, and they suggest that the 140K complex may be part of a cell surface linkage between fibronectin and the cytoskeleton.


MicroRNA-134 as a potential plasma biomarker for the diagnosis of acute pulmonary embolism.
Acute pulmonary embolism (APE) remains a diagnostic challenge due to a variable clinical presentation and the lack of a reliable screening tool. MicroRNAs (miRNAs) regulate gene expression in a wide range of pathophysiologic processes. Circulating miRNAs are emerging biomarkers in heart failure, type 2 diabetes and other disease states; however, using plasma miRNAs as biomarkers for the diagnosis of APE is still unknown. Thirty-two APE patients, 32 healthy controls, and 22 non-APE patients (reported dyspnea, chest pain, or cough) were enrolled in this study. The TaqMan miRNA microarray was used to identify dysregulated miRNAs in the plasma of APE patients. The TaqMan-based miRNA quantitative real-time reverse transcription polymerase chain reactions were used to validate the dysregulated miRNAs. The receiver-operator characteristic (ROC) curve analysis was conducted to evaluate the diagnostic accuracy of the miRNA identified as the candidate biomarker. Plasma miRNA-134 (miR-134) level was significantly higher in the APE patients than in the healthy controls or non-APE patients. The ROC curve showed that plasma miR-134 was a specific diagnostic predictor of APE with an area under the curve of 0.833 (95% confidence interval, 0.737 to 0.929; P < 0.001). Our findings indicated that plasma miR-134 could be an important biomarker for the diagnosis of APE. Because of this finding, large-scale investigations are urgently needed to pave the way from basic research to clinical utilization.


Absorption mechanisms of lead in aqueous solutions with hydrous manganese dioxide.
Hydrous manganese dioxide (HMO) has been synthesized through a facile method. It is found that HMO has an excellent Pb(II) adsorption performance, and an equilibrium adsorption capacity of 127 mg g-1 is expected under room conditions. The sorption capacity is strongly dependent on pH when pH < 7.0, but is not affected by ionic strength, suggesting a mechanism of inner-sphere surface complexation confirmed by X-ray photoelectron analyses (XPS) and Fourier transform infrared spectroscopy (FTIR). The adsorption capacity of Pb(II) in the presence of coexisting negative ions is higher than positive ions. The best fitting of adsorption kinetics and isotherm data are simulated by pseudo-second order equation and Langmuir model, respectively. An endothermic and spontaneous nature in the adsorption process of Pb(II) can be deduced from the obtained thermodynamic data (ΔG < 0, ΔH > 0, ΔS > 0).


Design of nanocarriers for nanoscale drug delivery to enhance cancer treatment using hybrid polymer and lipid building blocks.
Polymer-lipid hybrid nanoparticles (PLN) are an emerging nanocarrier platform made from building blocks of polymers and lipids. PLN integrate the advantages of biomimetic lipid-based nanoparticles (i.e. solid lipid nanoparticles and liposomes) and biocompatible polymeric nanoparticles. PLN are constructed from diverse polymers and lipids and their numerous combinations, which imparts PLN with great versatility for delivering drugs of various properties to their nanoscale targets. PLN can be classified into two types based on their hybrid nanoscopic structure and assembly methods: Type-I monolithic matrix and Type-II core-shell systems. This article reviews the history of PLN development, types of PLN, lipid and polymer candidates, fabrication methods, and unique properties of PLN. The applications of PLN in delivery of therapeutic or imaging agents alone or in combination for cancer treatment are summarized and illustrated with examples. Important considerations for the rational design of PLN for advanced nanoscale drug delivery are discussed, including selection of excipients, synthesis processes governing formulation parameters, optimization of nanoparticle properties, improvement of particle surface functionality to overcome macroscopic, microscopic and cellular biological barriers. Future directions and potential clinical translation of PLN are also suggested.


Inhibition of HIV-1 replication by an aqueous extract of Spirulina platensis (Arthrospira platensis).
An aqueous extract of the blue-green filamentous algae Arthrospira platensis (previously called Spirulina platensis) inhibited HIV-1 replication in human T-cell lines, peripheral blood mononuclear cells (PBMC), and Langerhans cells (LC). Extract concentrations ranging between 0.3 and 1.2 microg/ml reduced viral production by approximately 50% (50% effective concentration [EC50]) in PBMCs. The 50% inhibitory concentration (IC50) of extract for PBMC growth ranged between 0.8 and 3.1 mg/ml. Depending on the cell type used, therapeutic indices ranged between 200 and 6000. The extract inactivated HIV-1 infectivity directly when preincubated with virus before addition to human T-cell lines. Fractionation of the extract revealed antiviral activity in the polysaccharide fraction and also in a fraction depleted of polysaccharides and tannins. We conclude that aqueous A platensis extracts contain antiretroviral activity that may be of potential clinical interest.


On the mechanism of photochromism of 4'-N,N-dimethylamino-7-hydroxyflavylium in pluronic F127.
The photochromism of the compound 4'-N,N-dimethylamino-7-hydroxyflavylium incorporated in Pluronic F127 micelles and gels was studied in great detail. The red flavylium ion (AH(+)) or the quinoidal base (A), depending on pH, are the irradiation products of the colorless trans-chalcone (Ct). Absorption and fluorescence (steady-state, time-resolved, and anisotropy), pH jumps, and flash photolysis were used to characterize the system. At moderately acidic to neutral pH values, the Ct species is distributed between the core and corona of the Pluronic micelle, as well as in the aqueous phase. At acidic pH values, AH(+) remains most probably in the water phase. The Ct maximum absorption wavelength constitutes a good sensor for the critical micelle concentration (CMC) or critical micelle temperature (CMT). The apparent acidity constant pK'(a) was found to be a relatively good sensor for CMC and also for detection of the sol-gel critical temperature. The Ct photochromic mechanism was analyzed by comparing the photophysics in pure solvents and the pluronic media. Solvatochromic effects show a lack of solvent polarity dependence of the Stokes shift, indicating a low dipolar moment change between the ground and the locally excited state. An internal charge transfer nonradiative process (ICT) competes with Ct photoisomerization and is the dominant process in highly polar solvents, preventing the appearance of photochromism, in contrast with lower polar environments, such as micelles and ethanol. In high viscous environments as those found in the core of the Pluronic F127 micelles or glycerol, both ICT and photoisomerization are reduced, enhancing the Ct fluorescence quantum yield. According to the data from fluorescence measurements and pH jumps, evidence for the Ct distribution among different sites within the pluronic aggregate was found, (i) a hydrophilic/fluid region where Ct has poor fluorescence and isomerization yields, bulk region; (ii) the corona of the micelle where photoisomerization is maximized; and (iii) the hydrophobic/viscous region where the fluorescence quantum yield is higher (and photoisomerization lower). This effect leads to a selective Ct photochemistry.


Doping through supplement use: a review of the available empirical data.
The potential for supplement use to result in doping infringements is likely to be of concern for anyone involved in sports nutrition. The available data indicates that between 40-70% of athletes use supplements, and that between 10-15% of supplements may contain prohibited substances. Such data indicates that there is a considerable risk of accidental or inadvertent doping through using supplements. Accordingly, this paper sets out to provide an overview of the currently available empirical evidence of accidental doping by supplement use. In carrying out this task, the authors refer to press releases and proxy measures associated with nutritional supplement use, as well as statistical data on supplement contamination rates and doping infractions. A number of different indications as to the percentage of doping cases that might be attributed to supplement use are presented, ranging from 6.4% to 8.8%. Such percentages are not comparable; instead they are provided as indications as to how difficult it is to ascertain or estimate the scale of this problem. Although some forms of estimation can be made, it is suggested that it is currently not possible to quantify the scale of the problem. By way of conclusion, it is argued that antidoping regulators may wish to review current data gathering and information provision systems so that the problem of inadvertent doping can be more directly assessed as a factor in sports doping overall.


AC-YVAD-CMK Inhibits Pyroptosis and Improves Functional Outcome after Intracerebral Hemorrhage.
Intracerebral hemorrhage (ICH) refers to bleeding in the brain and is associated with the release of large amount of inflammasomes, and the activation of different cell death pathways. These cell death pathways lead to removal of inactivated and damaged cells and also result in neuronal cell damage. Pyroptosis is a newly discovered cell death pathway that has gained attention in recent years. This pathway mainly depends on activation of caspase-1-mediated cascades to cause cell death. We tested a well-known selective inhibitor of caspase-1, AC-YVAD-CMK, which has previously been found to have neuroprotective effects in ICH mice model, to ascertain its effects on the activation of inflammasomes mediated pyroptosis. Our results showed that AC-YVAD-CMK could reduce caspase-1 activation and inhibit IL-1β production and maturation, but has no effect on NLRP3 expression, an upstream inflammatory complex. AC-YVAD-CMK administration also resulted in reduction in M1-type microglia polarization around the hematoma, while increasing the number of M2-type cells. Furthermore, AC-YVAD-CMK treated mice showed some recovery of neurological function after hemorrhage especially at the hyperacute and subacute stage resulting in some degree of limb movement. In conclusion, we are of the view that AC-YVAD-CMK could inhibit pyroptosis, decrease the secretion or activation of inflammatory factors, and affect the polarization of microglia resulting in improvement of neurological function after ICH.


Stress echocardiography with contrast for the diagnosis of coronary artery disease: an evidence-based analysis.
In July 2009, the Medical Advisory Secretariat (MAS) began work on Non-Invasive Cardiac Imaging Technologies for the Diagnosis of Coronary Artery Disease (CAD), an evidence-based review of the literature surrounding different cardiac imaging modalities to ensure that appropriate technologies are accessed by patients suspected of having CAD. This project came about when the Health Services Branch at the Ministry of Health and Long-Term Care asked MAS to provide an evidentiary platform on effectiveness and cost-effectiveness of non-invasive cardiac imaging modalities.After an initial review of the strategy and consultation with experts, MAS identified five key non-invasive cardiac imaging technologies for the diagnosis of CAD. Evidence-based analyses have been prepared for each of these five imaging modalities: cardiac magnetic resonance imaging, single photon emission computed tomography, 64-slice computed tomographic angiography, stress echocardiography, and stress echocardiography with contrast. For each technology, an economic analysis was also completed (where appropriate). A summary decision analytic model was then developed to encapsulate the data from each of these reports (available on the OHTAC and MAS website).The Non-Invasive Cardiac Imaging Technologies for the Diagnosis of Coronary Artery Disease series is made up of the following reports, which can be publicly accessed at the MAS website at: www.health.gov.on.ca/mas or at www.health.gov.on.ca/english/providers/program/mas/mas_about.htmlSINGLE PHOTON EMISSION COMPUTED TOMOGRAPHY FOR THE DIAGNOSIS OF CORONARY ARTERY DISEASE: An Evidence-Based AnalysisSTRESS ECHOCARDIOGRAPHY FOR THE DIAGNOSIS OF CORONARY ARTERY DISEASE: An Evidence-Based AnalysisSTRESS ECHOCARDIOGRAPHY WITH CONTRAST FOR THE DIAGNOSIS OF CORONARY ARTERY DISEASE: An Evidence-Based Analysis64-Slice Computed Tomographic Angiography for the Diagnosis of Coronary Artery Disease: An Evidence-Based AnalysisCARDIAC MAGNETIC RESONANCE IMAGING FOR THE DIAGNOSIS OF CORONARY ARTERY DISEASE: An Evidence-Based AnalysisPease note that two related evidence-based analyses of non-invasive cardiac imaging technologies for the assessment of myocardial viability are also available on the MAS website:POSITRON EMISSION TOMOGRAPHY FOR THE ASSESSMENT OF MYOCARDIAL VIABILITY: An Evidence-Based AnalysisMAGNETIC RESONANCE IMAGING FOR THE ASSESSMENT OF MYOCARDIAL VIABILITY: an Evidence-Based AnalysisThe Toronto Health Economics and Technology Assessment Collaborative has also produced an associated economic report entitled:The Relative Cost-effectiveness of Five Non-invasive Cardiac Imaging Technologies for Diagnosing Coronary Artery Disease in Ontario [Internet]. Available from: http://theta.utoronto.ca/reports/?id=7 OBJECTIVE: The objective of this report is to compare echocardiography (ECHO) performed with microsphere contrast agents (contrast echocardiography) to ECHO performed without contrast and to single photon emission computed tomography (SPECT). CONTRAST ECHO: Contrast agents for ECHO have been available since the technology was first introduced in the 1990s. Composed of tiny 'microbubbles' of an inert gas encapsulated within a lipid, protein, or polymer coat, these agents act to scatter incident ultrasound waves at the gas/liquid interface to increase the strength of a returning ECHO signal. When injected into a patient's arm, they are transported throughout even the smallest capillaries to greatly enhance the blood pool signal, which would otherwise appear black on conventional two dimensional ECHO. The enhanced signal then helps cardiologists to determine what parts of the patient's heart muscle are poorly perfused. The first commercially available microsphere contrast agent was Albunex, which received approval by the Food and Drug Administration in the United States in 1994. This original microsphere agent was limited by its rapid gas volume loss which caused a decline in the ultrasound signal. It worked well in the right chambers of the heart, but dissolved when passing through the pulmonary capillaries and so was unable to provide contrast in the left side. Second generation agents employed different gases that prolonged the life of the microbubbles within the circulation and increased the reproducibility of results. Today, the most common use for contrast ECHO is to enhance the definition of the left ventricular (LV) endocardial border for cases of LV opacification. The aim of contrast ECHO is to provide better quantification of LV volume and assessment of LV wall motion than ECHO alone. The newest area of development in the research of contrast ECHO is myocardial perfusion assessment, also known as myocardial contrast ECHO. Theoretically, since myocardial ischemia and infarction affect both perfusion and contractility (wall motion), contrast ECHO could be an ideal non-invasive imaging test as it could assess both perfusion and contractility, simultaneously and in real time. Notably, critically ill patients on ventilators and those with lung problems are more likely to generate poor or 'suboptimal' echocardiograms than other patients, as are obese patients and those who've undergone recent chest operations. Contrast agents can potentially be used in 10% to 15% of all studies and in approximately 33% of stress tests due to from such suboptimal echocardiograms. Stress can be induced either pharmaceutically (e.g., through dobutamine, dipyrimidamole, adenosine) or with exercise. Generally, contrast agents are used more in pharmaceutical stress echocardiograms than in exercise stress echocardiograms. EVIDENCE-BASED ANALYSIS: This MAS analysis sought to address the following research questions: Is contrast ECHO more effective than 99-technetium SPECT in terms its ability to detect CAD?What is the effectiveness of contrast ECHO in assessing patients with suboptimal echocardiograms?Is contrast ECHO safe compared to other cardiac imaging modalities?Is contrast ECHO cost-effective compared to other cardiac imaging modalities? Literature searches were performed on June 22, 2009 and July 27, 2009 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 2004 until June 30, 2009. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria; full-text articles were obtained. Reference lists were also examined for any relevant studies not identified through the search. Systematic reviews, meta-analyses, randomized controlled trials, prospective observational studies, retrospective analysesMinimum sample size of 20 enrolled patients (human only)The contrast agent used in the study must be licensed by Health CanadaComparison to reference standard (coronary angiography for the diagnosis of coronary artery disease)Reporting accuracy data on individual patients (rather than accuracy data stratified by segments of the heart)English language Non-systematic reviews, case reportsGrey literature (e.g. conference abstracts) Accuracy outcomes (sensitivity, specificity, positive predictive value, negative predictive value)Adverse eventsCosts Twenty-three observational studies were identified that assessed the diagnostic accuracy of contrast ECHO for the diagnosis of CAD. All of these studies used stress ECHO with contrast. In addition, nine retrospective chart reviews were identified, which assessed the safety of contrast ECHO at rest or stress. Based on the results of these studies the following conclusions were made: Stress ECHO with contrast has a higher diagnostic accuracy in the diagnosis of CAD than stress ECHO (without contrast).Stress ECHO with contrast seems to have a similar diagnostic accuracy to 99 technetium SPECT.The addition of contrast to ECHO in patients with suboptimal ECHO results significantly improves interpretability of the results.There is not a statistically significantly higher mortality rate in patients who receive contrast compared to those who do not.


Latent S alleles are widespread in cultivated self-compatible Brassica napus.
The genetic control of self-incompatibility in Brassica napus was investigated using crosses between resynthesized lines of B. napus and cultivars of oilseed rape. These crosses introduced eight C-genome S alleles from Brassica oleracea (S16, S22, S23, S25, S29, S35, S60, and S63) and one A-genome S allele from Brassica rapa (SRM29) into winter oilseed rape. The inheritance of S alleles was monitored using genetic markers and S phenotypes were determined in the F1, F2, first backcross (B1), and testcross (T1) generations. Two different F1 hybrids were used to develop populations of doubled haploid lines that were subjected to genetic mapping and scored for S phenotype. These investigations identified a latent S allele in at least two oilseed rape cultivars and indicated that the S phenotype of these latent alleles was masked by a suppressor system common to oilseed rape. These latent S alleles may be widespread in oilseed rape varieties and are possibly associated with the highly conserved C-genome S locus of these crop types. Segregation for S phenotype in subpopulations uniform for S genotype suggests the existence of suppressor loci that influenced the expression of the S phenotype. These suppressor loci were not linked to the S loci and possessed suppressing alleles in oilseed rape and non-suppressing alleles in the diploid parents of resynthesized B. napus lines.


Awareness of the National Standards for Culturally and Linguistically Appropriate Services at an academic health center.
The study's objectives were to (a) determine the level of familiarity of faculty and students at an academic health center with the National Standards for Culturally and Linguistically Appropriate Services (CLAS), (b) identify faculty's and students' interest and preferred method of learning Medical Spanish, and (c) determine their aptitude for working with medical interpreters. A survey was developed, piloted, and sent via e-mail to all faculty members (n = 1,025) and students (n = 1,956) currently affiliated with or enrolled at the Medical College of Georgia. Reminder e-mails were sent after 2 weeks, and responses were accepted for 1 month. The total response rate for faculty members was 29% (300/1,025), and that for students was 44% (871/1,956). Nearly 22% of the responding faculty and 23% of the responding students reported that they were less than familiar with the National Standards for CLAS. Both faculty (46%) and students (70%) were willing to spend time learning Medical Spanish. Web-based instruction was the preferred educational delivery mode for those who completed the survey; however, 18% of faculty and 5% of students strongly disagreed with this point. When questioned about how often interpreters services are used, the rates for faculty and students ranged from 34% to 39%. These results suggest that a void exists in understanding the National Standards for CLAS and that there are varying levels of willingness to learn medical Spanish.


Acute effects of whole-body vibration on trunk and neck muscle activity in consideration of different vibration loads.
The intention of this study was to systematically analyze the impact of biomechanical parameters in terms of different peak-to-peak displacements and knee angles on trunk and neck muscle activity during whole-body vibration (WBV). 28 healthy men and women (age 23 ± 3 years) performed four static squat positions (2 peak-to-peak displacements x 2 knee angles) on a side alternating vibration platform with and without vibration stimulus. Surface electromyography (EMG) was used to record the neuromuscular activity of the erector spinae muscle, the rectus abdominis muscle, and of the splenius muscle. EMG levels normalized to maximal voluntary contractions ranged between 3.2 - 27.2 % MVC during WBV. The increase in muscle activity caused by WBV was significant, particularly for the back muscles, which was up to 19.0 % MVC. The impact of the factor 'condition' (F-values ranged from 13.4 to 132.0, p ≤ 0.001) and of the factor 'peak-to-peak displacement' (F-values ranged from 6.4 to 69.0 and p-values from < 0.001 to 0.01) were statistically significant for each muscle tested. However, the factor 'knee angle' only affected the back muscles (F-value 10.3 and 7.3, p ≤ 0.01). The results of this study should give more information for developing effective and safe training protocols for WBV treatment of the upper body. Key pointsThe maximum levels of muscle activity were significantly reached at high amplitudes at a vibration frequency of 30 Hz.WBV leads to a higher muscle activation of the lower back muscles than of the abdominal muscles.Both knee angles of 30° and 45° have similar effects on the vibration load and represent safe positions to prevent any actual harm.Certain combinations of the biomechanical variables have similar effects on the level of muscle activity.


Regional pulmonary distribution of iodine-125-labeled oleic acid. Its relationship to the pattern of oleic acid edema and pulmonary blood flow.
Oleic acid infusion in dogs produces a patchy, predominantly peripheral lesion on CT scans. This study correlates the pattern of oleic acid injury with the distribution of infused oleic acid and pulmonary blood flow. Radiolabeled oleic acid (I-125, 0.05 ml/kg) and radiolabeled 15-micron microspheres (Co-57) were infused into the right atria of 11 dogs. Oleic acid was given after the microspheres in six dogs and before microspheres in five dogs. Ten minutes after infusion, the lungs were removed. Four transverse slices (0.5 cm thick) of the lower lobes were taken from each dog and cubed. Samples were grouped into three regions of the transverse slice: outer, middle, and inner concentric rings. In both groups, I-125 (oleic acid) activity was greater in the outer than the middle and inner concentric layers (P less than 0.001). When Cobalt-57 microspheres were given before oleic acid, Cobalt-57 activity was marginally lower in the outer layer compared with the middle and inner layers. However, when oleic acid was given first, microsphere activity in the outer layer was significantly lower (P less than 0.001) than the middle layer. Thus, oleic acid was preferentially distributed to the peripheral regions of the lung, similar to the regions of injury on CT. This distribution did not correspond to the pattern of pulmonary blood flow as indicated by the microspheres. Immediately after oleic acid infusion, pulmonary blood flow to the periphery was reduced, reflecting a response to the predominantly peripheral injury by oleic acid.


Increase in tomato locule number is controlled by two single-nucleotide polymorphisms located near WUSCHEL.
In tomato (Solanum lycopersicum) fruit, the number of locules (cavities containing seeds that are derived from carpels) varies from two to up to 10 or more. Locule number affects fruit shape and size and is controlled by several quantitative trait loci (QTLs). The large majority of the phenotypic variation is explained by two of these QTLs, fasciated (fas) and locule number (lc), that interact epistatically with one another. FAS has been cloned, and mutations in the gene are described as key factors leading to the increase in fruit size in modern varieties. Here, we report the map-based cloning of lc. The lc QTL includes a 1,600-bp region that is located 1,080 bp from the 3' end of WUSCHEL, which encodes a homeodomain protein that regulates stem cell fate in plants. The molecular evolution of lc showed a reduction of diversity in cultivated accessions with the exception of two single-nucleotide polymorphisms. These two single-nucleotide polymorphisms were shown to be responsible for the increase in locule number. An evolutionary model of locule number is proposed herein, suggesting that the fas mutation appeared after the mutation in the lc locus to confer the extreme high-locule-number phenotype.


"Ping-pong" interactions between mitochondrial tRNA import receptors within a multiprotein complex.
The mitochondrial genomes of a wide variety of species contain an insufficient number of functional tRNA genes, and translation of mitochondrial mRNAs is sustained by import of nucleus-encoded tRNAs. In Leishmania, transfer of tRNAs across the inner membrane can be regulated by positive and negative interactions between them. To define the factors involved in such interactions, a large multisubunit complex (molecular mass, approximately 640 kDa) from the inner mitochondrial membrane of the kinetoplastid protozoon Leishmania, consisting of approximately 130-A particles, was isolated. The complex, when incorporated into phospholipid vesicles, induced specific, ATP- and proton motive force-dependent transfer of Leishmania tRNA(Tyr) as well as of oligoribonucleotides containing the import signal YGGYAGAGC. Moreover, allosteric interactions between tRNA(Tyr) and tRNA(Ile) were observed in the RNA import complex-reconstituted system, indicating the presence of primary and secondary tRNA binding sites within the complex. By a combination of antibody inhibition, photochemical cross-linking, and immunoprecipitation, it was shown that binding of tRNA(Ile) to a 21-kDa component of the complex is dependent upon tRNA(Tyr), while binding of tRNA(Tyr) to a 45-kDa component is inhibited by tRNA(Ile). This "ping-pong" mechanism may be an effective means to maintain a balanced tRNA pool for mitochondrial translation.


Rapid global form binding with loss of associated colors.
Distributed neural processing creates a binding problem: the representations of the various features of an object are distributed across brain areas but must be associated with, or bound to, the same object. Here we determine the limits that binding imposes on the perception of global form in static flow fields defined by oriented dot pairs. The binding of local orientation signals into global form is shown to operate at rapid 20-Hz rates, implying that visual signals at the point of global form extraction retain precise temporal registration. Binding global form with color is limited to rates of 3-5Hz, showing that binding across attributes can impose a severe temporal limit on perception. Judgment of the temporal sequence of the global structures is also limited to slow rates. These results point to a substantial loss of temporal resolution in the visual system following the extraction of global form but preceding visual awareness.


Hepatitis B vaccination for patients with chronic renal failure.
Chronic renal failure patients are at particular risk of hepatitis B virus infection. Early studies have demonstrated that renal failure patients benefit from vaccination; however, not all studies have consistently shown benefit. To determine the beneficial and harmful effects of hepatitis B vaccine and of a reinforced vaccination series in chronic renal failure patients. We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Renal Group Controlled Trials Register, The Cochrane Controlled Trials Register on The Cochrane Library (Issue 1, 2002),PubMed/MEDLINE (1966 to July 2003), EMBASE (1985 to November 2003), Current Clinical Practice Guidelines (Canadian Immunization Guide and Vaccine Preventable Diseases Surveillance Manual), and Science Citation Index as well as journals, published abstracts, and reference lists of articles. Randomised clinical trials comparing plasma vaccine with placebo, recombinant vaccine with placebo, recombinant vaccine with plasma vaccine, and a reinforced vaccination series (ie, more than three inoculations) with three inoculations of vaccine in chronic renal failure patients. Primary outcome measures included incidence of patients developing hepatitis B virus antibodies and infections while secondary outcomes included adverse events, liver-related morbidity, and mortality. Random effects models were used and reported relative risks and 95% confidence intervals (RR and 95% CI). We included seven randomised clinical trials. None of them had high quality. Plasma vaccine was significantly more effective than placebo in achieving hepatitis B antibodies (RR 23.0, 95% CI 14.39 to 36.76, 3 trials). We found no statistically significant difference between plasma vaccine or placebo regarding hepatitis B virus infections (RR 0.50, 95% CI 0.20 to 1.24). We found no statistically significant differences between recombinant vaccine and plasma vaccine in achieving hepatitis B antibodies (RR 0.65, 95% CI 0.28 to 1.53, 2 trials). Heterogeneity was significant and appeared to be attributable to the dose of vaccine. Two trials examined a reinforced recombinant vaccine strategy, which was not statistically more effective than three inoculations of recombinant vaccine regarding development of hepatitis B antibodies (RR 1.36, 95% CI 0.85 to 2.16). Plasma derived vaccines are more effective than placebo in achieving hepatitis B antibodies, while no statistically significant difference was found between recombinant and plasma vaccines. No statistically significant difference of effectiveness was observed between a reinforced vaccination series versus routine vaccinations of three inoculations of recombinant vaccine.


Effects of kaolin particle film on oviposition, larval mining, and infestation of cotton by pink bollworm (Lepidoptera: Gelechiidae).
We tested effects of kaolin particle film on oviposition, larval mining, and infestation of cotton by pink bollworm, Pectinophora gossypiella (Saunders) (Lepidoptera: Gelechiidae), in the laboratory, greenhouse, and field. In laboratory choice tests, females laid seven times more eggs on untreated bolls than on bolls treated with kaolin. When neonates were put on bolls in the laboratory, each boll with a treated and untreated half, larvae and mines were found 24 h later on the untreated half but not on the treated half. In oviposition choice tests with whole plants in the greenhouse, females laid four times more eggs on untreated plants than on treated plants and the number of eggs on bolls was five times higher for untreated plants than for treated plants. Kaolin treatments altered the distribution of eggs among plant parts, with untreated bolls receiving a higher percentage than treated bolls, whereas the opposite occurred for petioles. In field tests, treatment with kaolin alone reduced the proportion of bolls infested with pink bollworm, but a mixture of kaolin and the pyrethroid lambda-cyhalothrin was most effective. The results suggest that kaolin particle film may be useful against pink bollworm, particularly in conjunction with other control tactics.


Maternal exposure to triclosan impairs thyroid homeostasis and female pubertal development in Wistar rat offspring.
Although the effects of triclosan have been examined in male reproductive functions, it is unknown whether this potent antibacterial agent affects pregnancy and female pubertal development. Effects of maternal exposure to triclosan on thyroid homeostasis (TH) and reproductive-tract development in female Wistar rats were thus studied. Dams were exposed daily to triclosan (0, 1, 10, or 50 mg/kg/d) from 8 d before mating to lactation day 21. Offspring were also exposed after weaning. In vivo triclosan estrogenic activity was screened by uterotrophic assay and vaginal opening (VO), with first estrus and uterus and ovarian weight determined in offspring. Dam blood samples were taken during pregnancy and lactation to examine the effect of triclosan on TH. No apparent external signs of toxicity or differences in mean numbers of implantation sites were observed in treated rats. Triclosan treatment decreased total serum T(4) and T(3) in pregnant rats and also lowered sex ratio, lowered pup body weights on postnatal day (PND) 20, and delayed VO in offspring. In addition, the highest dose of triclosan significantly reduced the live birth index (percentage) and 6-d survival index. Data indicate that triclosan impairs thyroid homeostasis and reproductive toxicity in adult rats and produces fetal toxicity in offspring exposed in utero, during lactation, and after weaning.


Intercomparison of passive radon-detectors under field conditions in epidemiological studies.
The Ardennes and Eifel region is a geologically distinct area covering parts of Germany, Belgium, France, and Luxembourg where enhanced concentrations of radon occur in some houses and other buildings. An international case-control study is being conducted to examine the role of radon in the etiology of lung cancer in this area. The radon detectors used are issued by different laboratories involving a variety of detector types and processes. A series of intercomparisons in houses was therefore conducted under similar conditions of exposure in the field. In most situations the different detectors gave similar results. Nevertheless, in some situations open and closed detectors yielded different results. Therefore, estimates of radon exposure have to be adjusted if results are to be pooled.


Sizing up Australia: toward a national sizing survey.
This paper reports on the outcomes of research on the use of anthropometric data by designers of Australian workplaces and products used in Australian workplaces. Australian designers were asked how they used anthropometric data, and about the adequacy of data that were available to them for their needs as designers. In addition to a review of published and grey literature, designers were surveyed and asked for detailed information about their use of anthropometric data and about their needs. Thirty-two completed questionnaires were received. Two focus groups of designers were conducted; 13 people attended in Adelaide and 16 in Melbourne. The data indicated that designers either did not use anthropometric data at all or had difficulty finding data that were reliable and relevant to their specific needs. In response to the findings the Human Factors and Ergonomics Society of Australia developed a Special Interest Group for anthropometry that currently has over 150 members. The Group is actively lobbying government for an Australian Sizing Survey, so this research is an important stimulus to a major policy investment for Australia.


Cisplatin down-regulates topoisomerase I activity in lung cancer cell lines.
Many clinical studies have reported that irinotecan has reproducible antitumor activity against lung cancer. Both cisplatin and SN-38 are key drugs in the treatment of lung cancer, and their combination is one of the most promising regimens available. Using lung cancer cell lines, ABC-1 and SBC-3, we examined the cytotoxic effect of the schedule, as well as the effect of cisplatin on topoisomerase I activity. Cytotoxicity was determined by MTT assay. ABC-1 or SBC-3 cells were incubated with or without various concentrations of both drugs in 96-well microplates for 72 or 96 hours in a humidified 5% CO2 atmosphere at 37 degrees C. Synergism was evaluated by median-effect plot analysis and a combination index isobologram method by Chou and Talalay. After ABC-1 or SBC-3 cells had been exposed to 10/microM cisplatin for one hour, topoisomerase I activities were determined by supercoiled-DNA relaxation assay. Synergism was observed in ABC-1 and SBC-3 cells when cisplatin was given first, followed by SN-38 (7-ethyl-10-hydroxycamptothecin) and cisplatin. Topoisomerase I activity decreased at 1-2 hours after exposure to cisplatin and recovered gradually after 4-5 hours of cisplatin exposure in both ABC-1 and SBC-3 cells. Accordingly, pretreatment with cisplatin will have an impact on the sensitivity to SN-38.


Trends and determinants of survival for over 200 000 patients on antiretroviral treatment in the Botswana National Program: 2002-2013.
To determine the incidence and risk factors of mortality for all HIV-infected patients receiving antiretroviral treatment at public and private healthcare facilities in the Botswana National HIV/AIDS Treatment Programme. We studied routinely collected data from 226 030 patients enrolled in the Botswana National HIV/AIDS Treatment Programme from 2002 to 2013. A person-years (P-Y) approach was used to analyse all-cause mortality and follow-up rates for all HIV-infected individuals with documented antiretroviral therapy initiation dates. Marginal structural modelling was utilized to determine the effect of treatment on survival for those with documented drug regimens. Sensitivity analyses were performed to assess the robustness of our results. Median follow-up time was 37 months (interquartile range 11-75). Mortality was highest during the first 3 months after treatment initiation at 11.79 (95% confidence interval 11.49-12.11) deaths per 100 P-Y, but dropped to 1.01 (95% confidence interval 0.98-1.04) deaths per 100 P-Y after the first year of treatment. Twelve-month mortality declined from 7 to 2% of initiates during 2002-2012. Tenofovir was associated with lower mortality than stavudine and zidovudine. The observed mortality rates have been declining over time; however, mortality in the first year, particularly first 3 months of antiretroviral treatment, remains a distinct problem. This analysis showed lower mortality with regimens containing tenofovir compared with zidovudine and stavudine. CD4 cell count less than 100 cells/μl, older age and being male were associated with higher odds of mortality.


Working towards a Co-Ordinated Approach to Invasive Mosquito Detection, Response and Control in the UK.
The United Kingdom (UK) has reported a single detection of the eggs of the invasive mosquito vector Aedes albopictus in each of the three years from 2016 to 2018, all in southeast England. Here, we report the detection of mosquito eggs on three occasions at two sites in London and southeast England in September 2019. Mosquito traps were deployed at 56 sites, in England, Scotland, Wales, and Northern Ireland, as part of a coordinated surveillance programme with local authorities, Edge Hill University, and government departments. Response to each detection was coordinated by Public Health England's (PHE) local health protection teams, with technical support from PHE's Medical Entomology group, and control conducted by the respective local authority. Control, including source reduction and larviciding, was conducted within a 300 metre radius of the positive site. The response followed a National Contingency Plan for Invasive Mosquitoes: Detection of Incursions. Although the response to these incidents was rapid and well co-ordinated, recommendations are made to further develop mosquito surveillance and control capability for the UK.


Dopaminergic Modulation of Synaptic Plasticity, Its Role in Neuropsychiatric Disorders, and Its Computational Modeling.
Neuromodulators modify intrinsic characteristics of the nervous system in order to reconfigure the functional properties of neural circuits. This reconfiguration is crucial for the flexibility of the nervous system to respond on an input-modulated basis. Such a functional rearrangement is realized by modification of intrinsic properties of the neural circuits including synaptic interactions. Dopamine is an important neuromodulator involved in motivation and stimulus-reward learning process, and adjusts synaptic dynamics in multiple time scales through different pathways. The modification of synaptic plasticity by dopamine underlies the change in synaptic transmission and integration mechanisms, which affects intrinsic properties of the neural system including membrane excitability, probability of neurotransmitters release, receptors' response to neurotransmitters, protein trafficking, and gene transcription. Dopamine also plays a central role in behavioral control, whereas its malfunction can cause cognitive disorders. Impaired dopamine signaling is implicated in several neuropsychiatric disorders such as Parkinson's disease, drug addiction, schizophrenia, attention-deficit/hyperactivity disorder, obsessive-compulsive disorder and Tourette's syndrome. Therefore, dopamine plays a crucial role in the nervous system, where its proper modulation of neural circuits may enhance plasticity-related procedures, but disturbances in dopamine signaling might be involved in numerous neuropsychiatric disorders. In recent years, several computational models are proposed to formulate the involvement of dopamine in synaptic plasticity or neuropsychiatric disorders and address their connection based on the experimental findings.


Oxytocin Receptor Activation Rescues Opioid-Induced Respiratory Depression by Systemic Fentanyl in the Rat.
Opioid overdose intervention by naloxone, a high affinity receptor antagonist, reverses opioid-induced respiratory depression (OIRD) and analgesia by displacing opioids. Systemic naloxone stimulates release of the hypothalamic neuropeptide oxytocin, which has analgesic properties and participates in cardiorespiratory homeostasis. To test the hypothesis that oxytocin can reverse OIRD, we assessed the rescue potential of graded doses (0, 0.1, 2, 5, 10, 50 nmol/kg, i.v.) of oxytocin to counter fentanyl (60 nmol/kg, i.v.)-induced depression of neural inspiration indexed by recording phrenic nerve activity (PNA) in anesthetized (urethane/α-chloralose), vagotomized, and artificially ventilated rats. Oxytocin dose-dependently rescued fentanyl OIRD by almost immediately reversing PNA burst arrest (P = 0.0057) and restoring baseline burst frequency (P = 0.0016) and amplitude (P = 0.0025) at low but not high doses, resulting in inverted bell-shaped dose-response curves. Oxytocin receptor antagonism (40 nmol/kg, i.v.) prevented oxytocin reversal of OIRD (arrest: P = 0.0066, frequency: P = 0.0207, amplitude: P = 0.0022). Vasopressin 1A receptor (V1aR) antagonism restored high-dose oxytocin efficacy to rescue OIRD (P = 0.0170 to P < 0.0001), resulting in classic sigmoidal dose-response curves, and prevented (P = 0.0135) transient hypertension from V1aR cross-activation (P = 0.0275). Alone, vasopressin (5 nmol/kg, i.v.) failed to reverse fentanyl respiratory arrest (P = 0.6184). The nonpeptide oxytocin receptor agonist WAY-267464 (75 nmol/kg, i.v.), which has V1aR antagonist properties, quickly reversed fentanyl OIRD (P < 0.0001), with rapid recovery of PNA frequency (P = 0.0011) and amplitude (P = 0.0044) without adverse hemodynamic consequences (P = 0.9991). Findings indicate that peptide and nonpeptide agonist activation of oxytocin receptors without V1aR cross-activation rescues fentanyl OIRD. Oxytocin receptor agonists could be lifesaving resuscitation agents that enhance rather than interrupt opioid analgesia. SIGNIFICANCE STATEMENT: Oxytocin receptor activation produces analgesia. Here, we demonstrate that activation by the US Food and Drug Administration-approved agonist oxytocin and the nonpeptide partial agonist WAY-267464 can each reverse fentanyl cardiorespiratory depression. Selective targeting of oxytocin receptors for resuscitation from opioid overdose, alone or in combination with an opioid antagonist, could eliminate or attenuate negative side effects associated with traditional opioid receptor antagonism.


Fitting the child's mind to the world: adaptive norm-based coding of facial identity in 8-year-olds.
In adults, facial identity is coded by opponent processes relative to an average face or norm, as evidenced by the face identity aftereffect: adapting to a face biases perception towards the opposite identity, so that a previously neutral face (e.g. the average) resembles the identity of the computationally opposite face. We investigated whether children as young as 8 use adaptive norm-based coding to represent faces, a question of interest because 8-year-olds are less accurate than adults at recognizing faces and do not show the adult neural markers of face expertise. We found comparable face identity aftereffects in 8-year-olds and adults: perception of identity in both groups shifted in the direction predicted by norm-based coding. This finding suggests that, by 8 years of age, the adaptive computational mechanisms used to code facial identity are like those of adults and hence that children's immaturities in face processing arise from another source.