Expectation of having consumed caffeine can improve performance and mood.
We explored whether caffeine, and expectation of having consumed caffeine, affects attention, reward responsivity and mood using double-blinded methodology. 88 participants were randomly allocated to 'drink-type' (caffeinated/decaffeinated coffee) and 'expectancy' (told caffeinated/told decaffeinated coffee) manipulations. Both caffeine and expectation of having consumed caffeine improved attention and psychomotor speed. Expectation enhanced self-reported vigour and reward responsivity. Self-reported depression increased at post-drink for all participants, but less in those receiving or expecting caffeine. These results suggest caffeine expectation can affect mood and performance but do not support a synergistic effect.


Efficacy of vaccines containing rhoptry-associated proteins RAP1 and RAP2 of Plasmodium falciparum in Saimiri boliviensis monkeys.
A vaccine trial was conducted with rhoptry-associated proteins 1 and 2 (RAP1 and RAP2) of Plasmodium falciparum in Saimiri boliviensis monkeys to compare the ability of parasite-derived (PfRAP1 and 2) and recombinant proteins (rRAP1 and 2) to induce protective immune responses and to find adjuvants suitable for use in humans. Eight groups of 6 monkeys each were immunized with parasite-derived or recombinant RAP1 and 2 with Freund's complete adjuvant (FCA) followed by Freund's incomplete adjuvant (FIA), Montanide ISA720 adjuvant, or CRL1005 adjuvant. Recombinant RAP1 and RAP2 were also administered separately, with Montanide ISA720. After 3 immunizations, monkeys were challenged by iv inoculation of 50,000 parasites of the Uganda Palo Alto strain of P. falciparum. Of the animals vaccinated using FCA/FIA, 1 of 6 control monkeys, 3 of 6 immunized with PfRAP1 and 2, and 2 of 6 with rRAP1 and 2 did not require drug treatment. Of the monkeys vaccinated with Montanide ISA720 adjuvant, 0 of the 6 control monkeys, 2 of 6 immunized with RAP1 and 2, 1 of 6 immunized with rRAP1, and 4 of 6 immunized with RAP2 did not require drug treatment. Two of 6 monkeys immunized with PfRAP1 and 2 with CRL1005 did not require treatment. All groups receiving RAP1, RAP2, or both had a significant decrease in initial parasite multiplication rates and there was a significant negative correlation between anti-RAP2 antibody and multiplication rates. Animals were rechallenged with the homologous parasite 126 days after the first challenge. Of the monkeys that did not require drug treatment after the first challenge, none developed detectable parasitemia following rechallenge.


Safety and efficacy of a self-expanding versus a balloon-expandable bioprosthesis for transcatheter aortic valve replacement in patients with symptomatic severe aortic stenosis: a randomised non-inferiority trial.
Transcatheter aortic valve replacement (TAVR) is the preferred treatment option for older patients with symptomatic severe aortic stenosis. Differences in the properties of available TAVR systems can affect clinical outcomes. Among patients undergoing TAVR, we compared the self-expanding ACURATE neo TAVR system with the balloon-expandable SAPIEN 3 TAVR system with regard to early safety and efficacy. In this randomised non-inferiority trial, patients (aged ≥75 years) undergoing transfemoral TAVR for treatment of symptomatic severe aortic stenosis, and who were deemed to be at increased surgical risk, were recruited at 20 tertiary heart valve centres in Germany, the Netherlands, Switzerland, and the UK. Participants were randomly assigned (1:1) to receive treatment with the ACURATE neo or the SAPIEN 3 with a computer-based randomly permuted block scheme, stratified by study centre and Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) category. The primary composite safety and efficacy endpoint comprised all-cause death, any stroke, life-threatening or disabling bleeding, major vascular complications, coronary artery obstruction requiring intervention, acute kidney injury (stage 2 or 3), rehospitalisation for valve-related symptoms or congestive heart failure, valve-related dysfunction requiring repeat procedure, moderate or severe prosthetic valve regurgitation, or prosthetic valve stenosis within 30 days of the procedure. Endpoint assessors were masked to treatment allocation. Non-inferiority of ACURATE neo compared with SAPIEN 3 was assessed in the intention-to-treat population on the basis of a risk-difference margin of 7·7% for the primary composite endpoint, with a one-sided α of 0·05. This trial is registered with ClinicalTrials.gov (number NCT03011346) and is ongoing but not recruiting. Between Feb 8, 2017, and Feb 2, 2019, up to 5132 patients were screened and 739 (mean age 82·8 years [SD 4·1]; median STS-PROM score 3·5% [IQR 2·6-5·0]) were enrolled. 30-day follow-up was available for 367 (99%) of 372 patients allocated to the ACURATE neo group, and 364 (99%) of 367 allocated to the SAPIEN 3 group. Within 30 days, the primary endpoint occurred in 87 (24%) patients in the ACURATE neo and in 60 (16%) in the SAPIEN 3 group; thus, non-inferiority of the ACURATE neo was not met (absolute risk difference 7·1% [upper 95% confidence limit 12·0%], p=0·42). Secondary analysis of the primary endpoint suggested superiority of the SAPIEN 3 device over the ACURATE neo device (95% CI for risk difference -1·3 to -12·9, p=0·0156). The ACURATE neo and SAPIEN 3 groups did not differ in incidence of all-cause death (nine patients [2%] vs three [1%]) and stroke (seven [2%] vs 11 [3%]); whereas acute kidney injury (11 [3%] vs three [1%]) and moderate or severe prosthetic aortic regurgitation (34 [9%] vs ten [3%]) were more common in the ACURATE neo group. TAVR with the self-expanding ACURATE neo did not meet non-inferiority compared to the balloon-expandable SAPIEN 3 device in terms of early safety and clinical efficacy outcomes. An early composite safety and efficacy endpoint was useful in discriminating the performance of different TAVR systems. Boston Scientific (USA).


Hyperreflective Foci Enhancement in a Combined Spatial-Transform Domain for SD-OCT Images.
Spectral-domain optical coherent tomography (SD-OCT) is a useful tool for visualizing, treating, and monitoring retinal abnormality in patients with different retinal diseases. However, the assessment of SD-OCT images is thwarted by the lack of image quality necessary for ophthalmologists to analyze and quantify the diseases. This has hindered the potential role of hyperreflective foci (HRF) as a prognostic indicator of visual outcome in patients with retinal diseases. We present a new multi-vendor algorithm that is robust to noise while enhancing the HRF in SD-OCT images. The proposed algorithm processes the SD-OCT images in two parallel processes simultaneously. The two parallel processes are combined by histogram matching. An inverse of both logarithmic and orthogonal transforms is applied to the mapped data to produce the enhanced image. We evaluated our algorithm on a dataset composed of 40 SD-OCT volumes. The proposed method obtained high values for the measure of enhancement, peak signal-to-noise ratio, structure similarity, and correlation (ρ) and a low value for mean square error of 36.72, 38.87, 0.87, 0.98, and 25.12 for Cirrus; 40.77, 41.84, 0.89, 0.98, and 22.15 for Spectralis; and 30.81, 32.10, 0.81, 0.96, and 28.55 for Topcon SD-OCT devices, respectively. The proposed algorithm can be used in the medical field to assist ophthalmologists and in the preprocessing of medical images. The proposed enhancement algorithm facilitates the visualization and detection of HRF, which is a step forward in assisting clinicians with decision making about patient treatment planning and disease monitoring.


Spatiotemporal character of the Bobylev-Pikin flexoelectric instability in a twisted nematic bent-core liquid crystal exposed to very low frequency fields.
The Bobylev-Pikin striped-pattern state induced by a homogeneous electric field is a volume flexoelectric instability, originating in the midregion of a planarly aligned nematic liquid crystal layer. We find that the instability acquires a spatiotemporal character upon excitation by a low frequency (0.5 Hz) square wave field. This is demonstrated using a bent-core liquid crystal, initially in the 90°-twisted planar configuration. The flexoelectric modulation appears close to the cathode at each polarity reversal and, at low voltage amplitudes, decays completely as the field becomes steady. Correspondingly, at successive polarity changes, the stripe direction switches between the alignment directions at the two substrates. For large voltages, the stripes formed nearly along the alignment direction at the cathode gradually reorient toward the midplane director. These observations are generally attributed to inhomogeneous and time-dependent field conditions that come to exist after each polarity reversal. Polarity dependence of the instability is attributed to the formation of intrinsic double layers that bring about an asymmetry in surface fields. Momentary field elevation near the cathode following a voltage sign reversal and concomitant gradient flexoelectric polarization are considered the key factors in accounting for the surfacelike modulation observed at low voltages.


Staphylococcus aureus persisters tolerant to bactericidal antibiotics.
Bacterial persister cells are non- or slow-growing reversible phenotypic variants of the wild type, tolerant to bactericidal antibiotics. We analyzed here Staphylococcus aureus persister levels by monitoring colony-forming unit counts of planktonically grown cells treated with six different antimicrobials over time. The model laboratory strains HG001-HG003, SA113 and the small colony variant (SCV) strains hemB and menD were challenged by the compounds at different logs of minimal inhibitory concentration (MIC) in exponential or stationary growth phase. Antibiotic tolerance was usually elevated in SCV strains compared to normally growing cells and in stationary versus exponential phase cultures. Biphasic killing kinetics, typical for persister cell enrichment, were observed in both growth phases under different selective conditions. Treatment of exponential phase cultures of HG001-HG003 with 10-fold MIC of tobramycin resulted in the isolation of persisters which upon cultivation on plates formed either normal or phenotypically stable small colonies. Trajectories of different killing curves indicated physiological heterogeneity within persister subpopulations. Daptomycin added at 100-fold MIC to stationary phase SA113 cells rapidly isolated very robust persisters. Fractions of antibiotic-tolerant cells were observed with all S. aureus strains and mutants tested. Our results refute the hypothesis that S. aureus stationary phase cells are equivalent to persisters, as not all of these cells showed antibiotic tolerance. Isolation of S. aureus persisters of different robustness seems to depend on the kind and concentration of the antibiotic, as well as on the strain used.


Safety and nutritional assessment of GM plants and derived food and feed: the role of animal feeding trials.
In this report the various elements of the safety and nutritional assessment procedure for genetically modified (GM) plant derived food and feed are discussed, in particular the potential and limitations of animal feeding trials for the safety and nutritional testing of whole GM food and feed. The general principles for the risk assessment of GM plants and derived food and feed are followed, as described in the EFSA guidance document of the EFSA Scientific Panel on Genetically Modified Organisms. In Section 1 the mandate, scope and general principles for risk assessment of GM plant derived food and feed are discussed. Products under consideration are food and feed derived from GM plants, such as maize, soybeans, oilseed rape and cotton, modified through the introduction of one or more genes coding for agronomic input traits like herbicide tolerance and/or insect resistance. Furthermore GM plant derived food and feed, which have been obtained through extensive genetic modifications targeted at specific alterations of metabolic pathways leading to improved nutritional and/or health characteristics, such as rice containing beta-carotene, soybeans with enhanced oleic acid content, or tomato with increased concentration of flavonoids, are considered. The safety assessment of GM plants and derived food and feed follows a comparative approach, i.e. the food and feed are compared with their non-GM counterparts in order to identify intended and unintended (unexpected) differences which subsequently are assessed with respect to their potential impact on the environment, safety for humans and animals, and nutritional quality. Key elements of the assessment procedure are the molecular, compositional, phenotypic and agronomic analysis in order to identify similarities and differences between the GM plant and its near isogenic counterpart. The safety assessment is focussed on (i) the presence and characteristics of newly expressed proteins and other new constituents and possible changes in the level of natural constituents beyond normal variation, and on the characteristics of the GM food and feed, and (ii) the possible occurrence of unintended (unexpected) effects in GM plants due to genetic modification. In order to identify these effects a comparative phenotypic and molecular analysis of the GM plant and its near isogenic counterpart is carried out, in parallel with a targeted analysis of single specific compounds, which represent important metabolic pathways in the plant like macro and micro nutrients, known anti-nutrients and toxins. Significant differences may be indicative of the occurrence of unintended effects, which require further investigation. Section 2 provides an overview of studies performed for the safety and nutritional assessment of whole food and feed. Extensive experience has been built up in recent decades from the safety and nutritional testing in animals of irradiated foods, novel foods and fruit and vegetables. These approaches are also relevant for the safety and nutritional testing of whole GM food and feed. Many feeding trials have been reported in which GM foods like maize, potatoes, rice, soybeans and tomatoes have been fed to rats or mice for prolonged periods, and parameters such as body weight, feed consumption, blood chemistry, organ weights, histopathology etc have been measured. The food and feed under investigation were derived from GM plants with improved agronomic characteristics like herbicide tolerance and/or insect resistance. The majority of these experiments did not indicate clinical effects or histopathological abnormalities in organs or tissues of exposed animals. In some cases adverse effects were noted, which were difficult to interpret due to shortcomings in the studies. Many studies have also been carried out with feed derived from GM plants with agronomic input traits in target animal species to assess the nutritive value of the feed and their performance potential. Studies in sheep, pigs, broilers, lactating dairy cows, and fish, comparing the in vivo bioavailability of nutrients from a range of GM plants with their near isogenic counterpart and commercial varieties, showed that they were comparable with those for near isogenic non-GM lines and commercial varieties. In Section 3 toxicological in vivo, in silico, and in vitro test methods are discussed which may be applied for the safety and nutritional assessment of specific compounds present in food and feed or of whole food and feed derived from GM plants. Moreover the purpose, potential and limitations of the 90-day rodent feeding trial for the safety and nutritional testing of whole food and feed have been examined. Methods for single and repeated dose toxicity testing, reproductive and developmental toxicity testing and immunotoxicity testing, as described in OECD guideline tests for single well-defined chemicals are discussed and considered to be adequate for the safety testing of single substances including new products in GM food and feed. Various in silico and in vitro methods may contribute to the safety assessment of GM plant derived food and feed and components thereof, like (i) in silico searches for sequence homology and/or structural similarity of novel proteins or their degradation products to known toxic or allergenic proteins, (ii) simulated gastric and intestinal fluids in order to study the digestive stability of newly expressed proteins and in vitro systems for analysis of the stability of the novel protein under heat or other processing conditions, and (iii) in vitro genotoxicity test methods that screen for point mutations, chromosomal aberrations and DNA damage/repair. The current performance of the safety assessment of whole foods is mainly based on the protocols for low-molecular-weight chemicals such as pharmaceuticals, industrial chemicals, pesticides, food additives and contaminants. However without adaptation, these protocols have limitations for testing of whole food and feed. This primarily results from the fact that defined single substances can be dosed to laboratory animals at very large multiples of the expected human exposure, thus giving a large margin of safety. In contrast foodstuffs are bulky, lead to satiation and can only be included in the diet at much lower multiples of expected human intakes. When testing whole foods, the possible highest concentration of the GM food and feed in the laboratory animal diet may be limited because of nutritional imbalance of the diet, or by the presence of compounds with a known toxicological profile. The aim of the 90-days rodent feeding study with the whole GM food and feed is to assess potential unintended effects of toxicological and/or nutritional relevance and to establish whether the GM food and feed is as safe and nutritious as its traditional comparator rather than determining qualitative and quantitative intrinsic toxicity of defined food constituents. The design of the study should be adapted from the OECD 90-day rodent toxicity study. The precise study design has to take into account the nature of the food and feed and the characteristics of the new trait(s) and their intended role in the GM food and feed. A 90-day animal feeding trial has a large capacity (sensitivity and specificity) to detect potential toxicological effects of single well defined compounds. This can be concluded from data reported on the toxicology of a wide range of industrial chemicals, pharmaceuticals, food substances, environmental, and agricultural chemicals. It is possible to model the sensitivity of the rat subchronic feeding study for the detection of hypothetically increased amount of compounds such as anti-nutrients, toxicants or secondary metabolites. With respect to the detection of potential unintended effects in whole GM food and feed, it is unlikely that substances present in small amounts and with a low toxic potential will result in any observable (unintended) effects in a 90-day rodent feeding study, as they would be below the no-observed-effect-level and thus of unlikely impact to human health at normal intake levels. Laboratory animal feeding studies of 90-days duration appear to be sufficient to pick up adverse effects of diverse compounds that would also give adverse effects after chronic exposure. This conclusion is based on literature data from studies investigating whether toxicological effects are adequately identified in 3-month subchronic studies in rodents, by comparing findings at 3 and 24 months for a range of different chemicals. The 90-day rodent feeding study is not designed to detect effects on reproduction or development other than effects on adult reproductive organ weights and histopathology. Analyses of available data indicate that, for a wide range of substances, reproductive and developmental effects are not potentially more sensitive endpoints than those examined in subchronic toxicity tests. Should there be structural alerts for reproductive/developmental effects or other indications from data available on a GM food and feed, then these tests should be considered. By relating the estimated daily intake, or theoretical maximum daily intake per capita for a given whole food (or the sum of its individual commercial constituents) to that consumed on average per rat per day in the subchronic 90-day feeding study, it is possible to establish the margin of exposure (safety margin) for consumers. Results obtained from testing GM food and feed in rodents indicate that large (at least 100-fold) 'safety' margins exist between animal exposure levels without observed adverse effects and estimated human daily intake. Results of feeding studies with feed derived from GM plants with improved agronomic properties, carried out in a wide range of livestock species, are discussed. The studies did not show any biologically relevant differences in the parameters tested between control and test animals. (ABSTRACT TRUNCATED)


Duration of Triple Antithrombotic Therapy and Outcomes Among Patients Undergoing Percutaneous Coronary Intervention.
The aim of this study was to compare clinical outcomes in relation to the duration of triple antithrombotic therapy (TAT) among patients with indications for oral anticoagulation undergoing percutaneous coronary intervention (PCI). TAT is recommended for patients undergoing PCI with a firm indication for oral anticoagulation. Duration of TAT may influence outcomes, but the optimal period of TAT remains uncertain. Between 2009 and 2013, 8,772 consecutive patients undergoing PCI for stable coronary artery disease or acute coronary syndrome were prospectively included in the Bern PCI Registry (NCT02241291). Of 568 patients with indications for oral anticoagulation, 245 (43%) were discharged on a regimen of 1-month TAT and 323 (57%) on a regimen >1-month TAT (mean 5.1 ± 3.3 months, median 3 months). The primary endpoint was a composite of cardiac death, myocardial infarction, stroke, definite stent thrombosis, or TIMI (Thrombolysis in Myocardial Infarction) major bleeding within 1 year. Patients on 1-month compared with >1-month TAT were more commonly women, with stable coronary artery disease, had higher HAS-BLED scores, and less frequently received drug-eluting stents. In multivariate analyses, the primary endpoint did not differ between groups (adjusted hazard ratio: 1.07; 95% confidence interval: 0.56 to 2.06; p = 0.84). Results were consistent in stratified analyses in relation to clinical presentation with acute coronary syndrome (38%) and PCI with drug-eluting stents (79%) (p for interaction = 0.18 and 0.95, respectively). There were no differences in the secondary bleeding endpoint, Bleeding Academic Research Consortium ≥3 bleeding (adjusted hazard ratio: 0.62; 95% confidence interval: 0.21 to 1.80; p = 0.37) and the secondary composite ischemic endpoint (cardiac death, myocardial infarction, stroke, or definite stent thrombosis) (adjusted hazard ratio: 1.12; 95% confidence interval: 0.55 to 2.29; p = 0.76). One-month TAT, used preferentially in patients with higher estimated bleeding risk in this observational study, was associated with similar net clinical outcomes compared with longer TAT durations throughout 1 year following PCI.


Modification of granular activated carbon using low molecular weight polymer for enhanced removal of Cu(2+) from aqueous solution.
Palm shell activated carbon was modified via surface impregnation with polyethyleneimine (PEI) to enhance removal of Cu(2+) from aqueous solution in this study. The effect of PEI modification on batch adsorption of Cu(2+) as well as the equilibrium behavior of adsorption of metal ions on activated carbon were investigated. PEI modification clearly increased the Cu(2+) adsorption capacities by 68% and 75.86% for initial solution pH of 3 and 5 respectively. The adsorption data of Cu(2+) on both virgin and PEI-modified AC for both initial solution pH of 3 and 5 fitted the Langmuir and Redlich-Peterson isotherms considerably better than the Freundlich isotherm.


Seroepidemiology of Foot and Mouth Disease using passive surveillance techniques in selected provinces of Lao PDR.
Foot and Mouth Disease (FMD) is a high-impact, contagious transboundary animal disease that is endemic in Southeast Asia. Abattoir samples were routinely collected in six selected provinces between March and December 2019. A total of 1280 samples of abattoir animals were tested for FMD Non-Structural Protein (NSP) antibodies to indicate natural infections. Overall, 22.8% were seropositive for FMD NSP antibodies while seroprevalence of cattle (n = 469), buffalo (n = 214), and pigs (n = 597) were 44.6%, 35.0%, and 1.3%, respectively. The highest seroprevalence destination province was Xiengkhouang (35.3% of 272 samples), followed by Savannakhet (27.0% of 244 samples). Risk factors for evidence of natural infection identified by a multivariate logistic regression model included age groups (p-value = 0.02) and origin provinces (p-value = 2.8 × 10-5) of the animals. There were significant differences of FMD NSP seroprevalence between age groups and origin provinces of the animals. The odds ratio of a seropositive result in the less than 1 year old group was 2.5 (95% CI; 1.4, 4.4) when compared to the 3-4 years old group, while the odds ratios for animals that originated from Khammouane and Xiengkhouang provinces were 4.5 (95% CI; 1.1, 18.7) and 2.4 (95% CI; 1.4, 4.1), respectively, when compared to Champasak province. Serotype-specific antibody ELISA for 44 NSP antibody-positive samples revealed evidence of FMD serotypes O and A virus circulation in some provinces. Despite the passive abattoir survey providing useful information on FMD virus previous exposure and geographic locations of the animals, timely information on FMD virus circulation and distribution is also crucial to an effective control program. Alternative approaches to increase the cost-effectiveness of the surveillance network are also discussed.


The Incidence of Oral and Oropharyngeal Cancers in Betel Quid-Chewing Populations in South Myanmar Rural Areas.
Oral cancer is a very common disease in South and Southeast Asia. Betel quid (BQ)- chewing and tobaccosmoking habits are etiological factors for oral cancer patients in these regions. We conducted an oral cancer screening in BQ-chewing endemic rural areas in South Myanmar for the early detection of oral cancer in BQ-chewing and smoking individuals. We examined 105 subjects who were at high risk of oral cancer due to their oral habits (BQ users and/or smokers). Three carcinoma cases were detected, and there were 8 dysplasia cases. The carcinoma detection rate was 2.9%, and the carcinoma and precancerous lesion detection rate was 10.5%. In Myanmar, oral cancer screening has been conducted sporadically on a voluntary basis, and nationwide surveys have never been performed. There are also few reports of oral cancer screening for high-risk groups among the general population in Myanmar. Our present findings highlight the need for further screening and surveys. Education on betel quid chewing- and tobacco- related oral diseases and screening for the early detection of oral cancer are of the utmost importance in the control and prevention of oral cancer.


The relationship between quantitative human epidermal growth factor receptor 2 gene expression by the 21-gene reverse transcriptase polymerase chain reaction assay and adjuvant trastuzumab benefit in Alliance N9831.
The N9831 trial demonstrated the efficacy of adjuvant trastuzumab for patients with human epidermal growth factor receptor 2 (HER2) locally positive tumors by protein or gene analysis. We used the 21-gene assay to examine the association of quantitative HER2 messenger RNA (mRNA) gene expression and benefit from trastuzumab. N9831 tested the addition of trastuzumab to chemotherapy in stage I-III HER2-positive breast cancer. For two of the arms of the trial, doxorubicin and cyclophosphamide followed by paclitaxel (AC-T) and doxorubicin and cyclophosphamide followed by paclitaxel and trastuzumab concurrent chemotherapy-trastuzumab (AC-TH), recurrence score (RS) and HER2 mRNA expression were determined by the 21-gene assay (Oncotype DX®) (negative <10.7, equivocal 10.7 to <11.5, and positive ≥11.5 log2 expression units). Cox regression was used to assess the association of HER2 expression with trastuzumab benefit in preventing distant recurrence. Median follow-up was 7.4 years. Of 1,940 total patients, 901 had consent and sufficient tissue. HER2 by reverse transcriptase polymerase chain reaction (RT-PCR) was negative in 130 (14 %), equivocal in 85 (9 %), and positive in 686 (76 %) patients. Concordance between HER2 assessments was 95 % for RT-PCR versus central immunohistochemistry (IHC) (>10 % positive cells = positive), 91 % for RT-PCR versus central fluorescence in situ hybridization (FISH) (≥2.0 = positive) and 94 % for central IHC versus central FISH. In the primary analysis, the association of HER2 expression by 21-gene assay with trastuzumab benefit was marginally nonsignificant (nonlinear p = 0.057). In hormone receptor-positive patients (local IHC) the association was significant (p = 0.002). The association was nonlinear with the greatest estimated benefit at lower and higher HER2 expression levels. Concordance among HER2 assessments by central IHC, FISH, and RT-PCR were similar and high. Association of HER2 mRNA expression with trastuzumab benefit as measured by time to distant recurrence was nonsignificant. A consistent benefit of trastuzumab irrespective of mHER2 levels was observed in patients with either IHC-positive or FISH-positive tumors. Trend for benefit was observed also for the small groups of patients with negative results by any or all of the central assays. Clinicaltrials.gov NCT00005970 . Registered 5 July 2000.


Acclimation effects on thermal tolerances of springtails from sub-Antarctic Marion Island: indigenous and invasive species.
Collembola are abundant and functionally significant arthropods in sub-Antarctic terrestrial ecosystems, and their importance has increased as a consequence of the many invasive alien species that have been introduced to the region. It has also been predicted that current and future climate change will favour alien over indigenous species as a consequence of more favourable responses to warming in the former. It is therefore surprising that little is known about the environmental physiology of sub-Antarctic springtails and that few studies have explicitly tested the hypothesis that invasive species will outperform indigenous ones under warmer conditions. Here we present thermal tolerance data on three invasive (Pogonognathellus flavescens, Isotomurus cf. palustris, Ceratophysella denticulata) and two indigenous (Cryptopygus antarcticus, Tullbergia bisetosa) species of springtails from Marion Island, explicitly testing the idea that consistent differences exist between the indigenous and invasive species both in their absolute limits and the ways in which they respond to acclimation (at temperatures from 0 to 20 degrees C). Phenotypic plasticity is the first in a series of ways in which organisms might respond to altered environments. Using a poorly explored, but highly appropriate technique, we demonstrate that in these species the crystallization temperature (Tc) is equal to the lower lethal temperature. We also show that cooling rate (1 degree C min(-1); 0.1 degrees C min(-1); 0.5 degrees C h(-1) from 5 to -1 degrees C followed by 0.1 degrees C min(-1)) has little effect on Tc. The indigenous species typically have low Tcs (c. -20 to -13 degrees C depending on the acclimation temperature), whilst those of the invasive species tend to be higher (c. -12 to -6 degrees C) at the lower acclimation temperatures. However, Ceratophysella denticulata is an exception with a low Tc (c. -20 to -18 degrees C), and in P. flavescens acclimation to 20 degrees C results in a pronounced decline in Tc. In general, the invasive and alien species do not differ substantially in acclimation effects on Tc (with the exception of the strong response in P. flavescens). Upper lethal temperatures (ULT50) are typically higher in the invasive (33-37 degrees C) than in the indigenous (30-33 degrees C) species and the response to acclimation differs among the two groups. The indigenous species show either a weak response to acclimation or ULT50 declines with increasing acclimation temperature, whereas in the invasive species ULT50 increases with acclimation temperature. These findings support the hypothesis that many invasive species will be favoured by climate change (warming and drying) at Marion Island. Moreover, manipulative field experiments have shown abundance changes in the indigenous and invasive springtail species in the direction predicted by the physiological data.


[Assessment of the risk of introduction to Tunisia of the Rift Valley fever virus by the mosquito Culex pipiens].
The mosquito Culex pipiens has been involved as vector of the West Nile virus in Tunisia. Its bio-ecological characteristics in combination with some environmental factors have favoured the emergence of this virus in a West-Nile free zone. This leads to question about the potential risk of introducing another arbovirus, the Rift Valley fever (RVF) virus, in Tunisia from neighbouring countries where RVF circulates. In this study, we have evaluated the vector competence of different populations of Cx. pipiens towards two strains of RVF virus, the virulent ZH548 and the avirulent Clone 13 by experimental infections and the genetic differentiation of these populations of Cx. pipiens using four microsatellite loci. We found disseminated infection rates ranging from 0% to 14.7% and a high genetic differentiation among populations without any geographical pattern (no isolation by distance). Thus, although Cx. pipiens is able to sustain an amplification of RVF virus, viral dissemination through mosquito dispersal would be unlikely. However, as RVF is an emerging disease transmitted by several other potential mosquito species (e.g. Ochlerotatus caspius), attention should be maintained to survey livestock and mosquitoes in Tunisia.


The non-specific nature of mental health and structural brain outcomes following childhood trauma.
Childhood trauma (CT) is associated with an increased risk of mental health disorders; however, it is unknown whether this represents a diagnosis-specific risk factor for specific psychopathology mediated by structural brain changes. Our aim was to explore whether (i) a predictive CT pattern for transdiagnostic psychopathology exists, and whether (ii) CT can differentiate between distinct diagnosis-dependent psychopathology. Furthermore, we aimed to identify the association between CT, psychopathology and brain structure. We used multivariate pattern analysis in data from 643 participants of the Personalised Prognostic Tools for Early Psychosis Management study (PRONIA), including healthy controls (HC), recent onset psychosis (ROP), recent onset depression (ROD), and patients clinically at high-risk for psychosis (CHR). Participants completed structured interviews and self-report measures including the Childhood Trauma Questionnaire, SCID diagnostic interview, BDI-II, PANSS, Schizophrenia Proneness Instrument, Structured Interview for Prodromal Symptoms and structural MRI, analyzed by voxel-based morphometry. (i) Patients and HC could be distinguished by their CT pattern with a reasonable precision [balanced accuracy of 71.2% (sensitivity = 72.1%, specificity = 70.4%, p ≤ 0.001]. (ii) Subdomains 'emotional neglect' and 'emotional abuse' were most predictive for CHR and ROP, while in ROD 'physical abuse' and 'sexual abuse' were most important. The CT pattern was significantly associated with the severity of depressive symptoms in ROD, ROP, and CHR, as well as with the PANSS total and negative domain scores in the CHR patients. No associations between group-separating CT patterns and brain structure were found. These results indicate that CT poses a transdiagnostic risk factor for mental health disorders, possibly related to depressive symptoms. While differences in the quality of CT exposure exist, diagnostic differentiation was not possible suggesting a multi-factorial pathogenesis.


Partial Recovery of Audiological, Vestibular, and Radiological Findings following Spontaneous Intralabyrinthine Haemorrhage.
The diagnosis, work-up, and treatment of sudden sensorineural hearing loss and sudden vestibular loss vary widely between units. With the increasing access to both magnetic resonance imaging and objective vestibular testing, our understanding of the various aetiologies at hand is increasing. Despite this, the therapeutic options are limited and without a particularly strong evidence base. We present a rare, yet increasingly diagnosed, case of intralabyrinthine haemorrhage (ILH) together with radiological, audiological, and vestibular test results. Of note, this occurred spontaneously and has shown partial recovery in all the mentioned modalities.


Sequence analysis of insecticidal genes from Xenorhabdus nematophilus PMFI296.
Three strains of Xenorhabdus nematophilus showed insecticidal activity when fed to Pieris brassicae (cabbage white butterfly) larvae. From one of these strains (X. nematophilus PMFI296) a cosmid genome library was prepared in Escherichia coli and screened for oral insecticidal activity. Two overlapping cosmid clones were shown to encode insecticidal proteins, which had activity when expressed in E. coli (50% lethal concentration [LC(50)] of 2 to 6 microg of total protein/g of diet). The complete sequence of one cosmid (cHRIM1) was obtained. On cHRIM1, five genes (xptA1, -A2, -B1, -C1, and -D1) showed homology with up to 49% identity to insecticidal toxins identified in Photorhabdus luminescens, and also a smaller gene (chi) showed homology to a putative chitinase gene (38% identity). Transposon mutagenesis of the cosmid insert indicated that the genes xptA2, xptD1, and chi were not important for the expression of insecticidal activity toward P. brassicae. One gene (xptA1) was found to be central for the expression of activity, and the genes xptB1 and xptC1 were needed for full activity. The location of these genes together on the chromosome and therefore present on a single cosmid insert probably accounted for the detection of insecticidal activity in this E. coli clone. Although multiple genes may be needed for full activity, E. coli cells expressing the xptA1 gene from the bacteriophage lambda P(L) promoter were shown to have insecticidal activity (LC(50) of 112 microg of total protein/g of diet). This is contrary to the toxin genes identified in P. luminescens, which were not insecticidal when expressed individually in E. coli. High-level gene expression and the use of a sensitive insect may have aided in the detection of insecticidal activity in the E. coli clone expressing xptA1. The location of these toxin genes and the chitinase gene and the presence of mobile elements (insertion sequence) and tRNA genes on cHRIM1 indicates that this region of DNA represents a pathogenicity island on the genome of X. nematophilus PMFI296.


CXCL12 expression by invasive trophoblasts induces the specific migration of CD16- human natural killer cells.
In the maternal decidua, natural killer (NK) cells, characterized by lack of CD16, are found in direct contact with the fetal extravillous trophoblasts (EVTs). It is yet unknown which factors contribute to the specific homing of this unique NK subset to the decidua. In this study we analyze the chemokine receptor repertoire on various NK populations derived from the peripheral blood and decidua. We show that CXCR4 and CXCR3 receptors are preferentially expressed on CD16- NK subsets derived either from the peripheral blood or the decidua and that these receptors are involved in migration of all NK subsets to their ligands. We further demonstrate in vivo that invading EVTs that eventually perform endovascular invasion express CXCL12, the ligand for CXCR4, but not ligands for CXCR3. Indeed, specific accumulation of the CD16- NK cells at the expense of CD16+ cells was observed only when in vitro migration was performed with ligands for CXCR4. Finally, incubation of the peripheral blood CD16- NK cells with cytokines present in the decidua, especially interleukin 15 (IL-15), resulted in the expression of chemokine receptor repertoire similar to that observed on decidual NK cells, suggesting an additional important regulatory effect of local decidual cytokines.


Metastatic phenotype is regulated by estrogen in thyroid cells.
Over 200 million people worldwide are affected by thyroid proliferative diseases, including cancer, adenoma, and goiter, annually. The incidences of thyroid malignancies are three to four times higher in women, suggesting the possible involvement of estrogen. Based on this observed sex bias, we hypothesize that estrogen modulates the growth and metastatic propensity of thyroid cancer cells. In this study, two thyroid cell lines (Nthy-ori 3-1 and BCPAP) were evaluated for the presence of estrogen receptor (ER) by Western blot analysis and estrogen responsiveness by using a cell proliferation assay. In addition, the effect of estradiol (E(2)) on modulation of metastatic phenotype was determined by using in vitro adhesion, migration, and invasion assays. Thyroid cells expressed a functionally active ER-alpha and ER-beta as evidenced by 50-150% enhancement of proliferation in the presence of E(2). E(2) also enhanced adhesion, migration, and invasion of thyroid cells in an in vitro experimental model system that, based on our results, is modulated by beta-catenin. Our data provide evidence that the higher incidence of thyroid cancer in women is potentially attributed to the presence of a functional ER that participates in cellular processes contributing to enhanced mitogenic, migratory, and invasive properties of thyroid cells. These findings will enable and foster the possible development of antiestrogenic therapy targeting invasion and migration, thus affecting metastatic propensity.


Tetradecylthiopropionic acid induces hepatic mitochondrial dysfunction and steatosis, accompanied by increased plasma homocysteine in mice.
Hepatic mitochondrial dysfunction plays an important role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Methyl donor supplementation has been shown to alleviate NAFLD, connecting the condition to the one-carbon metabolism. Thus, the objective was to investigate regulation of homocysteine (Hcy) and metabolites along the choline oxidation pathway during induction of hepatic steatosis by the fatty acid analogue tetradecylthiopropionic acid (TTP), an inhibitor of mitochondrial fatty acid oxidation. Mice were fed a control diet, or diets containing 0.3 %, 0.6 %, or 0.9 % (w/w) TTP for 14 days. Blood and liver samples were collected, enzyme activities and gene expression were analyzed in liver, lipid and fatty acid composition in liver and plasma, one-carbon metabolites, B-vitamin status, carnitine and acylcarnitines were analyzed in plasma. Liver mitochondrial fatty acid oxidation decreased by 40 % and steatosis was induced in a dose dependent manner; total lipids increased 1.6-fold in animals treated with 0.3 % TTP, 2-fold with 0.6 % TTP and 2.1 fold with 0.9 % TTP compared to control. The higher hepatic concentration of fatty acids was associated with shortening of carbon-length. Furthermore, the inhibited fatty acid oxidation led to a 30-fold decrease in plasma carnitine and 9.3-fold decrease in acetylcarnitine at the highest dose of TTP, whereas an accumulation of palmitoylcarnitine resulted. Compared to the control diet, TTP administration was associated with elevated plasma total Hcy (control: 7.2 ± 0.3 umol/L, 0.9 % TTP: 30.5 ± 5.9 umol/L) and 1.4-1.6 fold increase in the one-carbon metabolites betaine, dimethylglycine, sarcosine and glycine, accompanied by changes in gene expression of the different B-vitamin dependent pathways of Hcy and choline metabolism. A positive correlation between total Hcy and hepatic triacylglycerol resulted. The TTP-induced inhibition of mitochondrial fatty acid oxidation was not associated with increased hepatic oxidative stress or inflammation. Our data suggest a link between mitochondrial dysfunction and the methylation processes within the one-carbon metabolism in mice.


Financial Toxicity in Adults With Cancer: Adverse Outcomes and Noncompliance.
Because of the escalating cost of cancer care coupled with high insurance deductibles, premiums, and uninsured populations, patients with cancer are affected by treatment-related financial harm, known as financial toxicity. The purpose of this study was to describe individuals reporting financial toxicity and to identify rates of and reasons for affordability-related treatment noncompliance. From May 2010 to November 2015, adult patients (age ≥ 18 years) with cancer were identified from a Health Registry/Cancer Survivorship Cohort. Financial toxicity was defined as agreement with the phrase "You have to pay for more medical care than you can afford" from the Patient Satisfaction Questionnaire-18. Logistic regression and Fisher exact tests were used to compare groups. Of 1,988 participants, 524 (26%) reported financial toxicity. Patients reporting financial toxicity were more likely age 65 years or younger, female, nonwhite, non-English speaking, not married, less educated, and to have received a diagnosis more recently (all P < .001). Participants with financial toxicity were more likely to report noncompliance with medication, owing to inability to afford prescription drugs (relative risk [RR], 3.55; 95% CI, 2.53 to 4.98), and reported forgoing mental health care (RR, 3.89; 95% CI, 2.04 to 7.45), doctor's visits (RR, 2.98; 95% CI, 1.97 to 4.51), and medical tests (RR, 2.54; 95% CI, 1.49 to 4.34). The most endorsed reasons for delayed care were not having insurance coverage and being unable to afford household expenses. More than 25% of adults with cancer reported financial toxicity that was associated with an increased risk for medical noncompliance. Financial toxicity remains a major issue in cancer care, and efforts are needed to ensure patients experiencing high levels of financial toxicity are able to access recommended care.


A blinded clinical study using a subepidermal moisture biocapacitance measurement device for early detection of pressure injuries.
This study aimed to evaluate the sensitivity and specificity of subepidermal moisture (SEM), a biomarker employed for early detection of pressure injuries (PI), compared to the "Gold Standard" of clinical skin and tissue assessment (STA), and to characterize the timing of SEM changes relative to the diagnosis of a PI. This blinded, longitudinal, prospective clinical study enrolled 189 patients (n = 182 in intent-to-treat [ITT]) at acute and post-acute sites (9 USA, 3 UK). Data were collected from patients' heels and sacrums using a biocapacitance measurement device beginning at admission and continuing for a minimum of 6 days to: (a) the patient developing a PI, (b) discharge from care, or (c) a maximum of 21 days. Standard of care clinical interventions prevailed, uninterrupted. Principal investigators oversaw the study at each site. Blinded Generalists gathered SEM data, and blinded Specialists diagnosed the presence or absence of PIs. Of the ITT population, 26.4% developed a PI during the study; 66.7% classified as Stage 1 injuries, 23% deep tissue injuries, the remaining being Stage 2 or Unstageable. Sensitivity was 87.5% (95% CI: 74.8%-95.3%) and specificity was 32.9% (95% CI: 28.3%-37.8%). Area under the receiver operating characteristic curve (AUC) was 0.6713 (95% CI 0.5969-0.7457, P < .001). SEM changes were observed 4.7 (± 2.4 days) earlier than diagnosis of a PI via STA alone. Latency between the SEM biomarker and later onset of a PI, in combination with standard of care interventions administered to at-risk patients, may have confounded specificity. Aggregate SEM sensitivity and specificity and 67.13% AUC exceeded that of clinical judgment alone. While acknowledging specificity limitations, these data suggest that SEM biocapacitance measures can complement STAs, facilitate earlier identification of the risk of specific anatomies developing PIs, and inform earlier anatomy-specific intervention decisions than STAs alone. Future work should include cost-consequence analyses of SEM informed interventions.


[The fructose induced "glycogenosis". I. Ultrastructural and morphometric analysis of rat hepatocytes 7 days after fructose overload (author's transl)].
Infusion of fructose has been shown to stimulate the SER and to reduce the RER in rat liver cells. After feeding fructose of 7 days a glycogenosis of unknown pathogenesis occurs, which was analysed morphometrically. 60% fructose in water, was given as drinking water to animals deprived of other food. Controls had free access to Altromin-R-standard diet and drinking water. Liver tissue was analysed morphometrically according to the methods described by Weibel. Rat hepatocytes accumulate a material with histochemical properties of glycogen. The enlargement of hepatic nuclei is probably due to a pathological edema. The SER is decreased suggesting a drop of glycogen catabolizing enzymes. The drastic reduction of the RER and the non-membrane bound ribosomes are signs of inpeeded protein synthesis. According to this, the peroxisomes, which arise from the RER, are decreased in volume and number. The hepatocellular chondrioma is transformed morphometrically in a smaller number of larger, pleomorphic and cup-shaped mitochondria. The ATP level drops while, on the other hand, the cristeal membranes increase. This might be caused by a negative feed back mechanism. The hepatocellular cytoarchitecture described is similar to the one found in glycogenosis type I and in the cerebrohepato-renal syndrom.


Cancer incidence among pesticide applicators exposed to chlorpyrifos in the Agricultural Health Study.
Chlorpyrifos is one of the most widely used insecticides in the United States. We evaluated the incidence of cancer among pesticide applicators exposed to chlorpyrifos in the Agricultural Health Study, a prospective cohort study of licensed pesticide applicators in Iowa and North Carolina. A total of 54,383 pesticide applicators were included in this analysis. Detailed information on pesticide exposure and lifestyle factors was obtained from self-administered questionnaires completed at the time of enrollment (December 1993-December 1997). Poisson regression analysis was used to evaluate the association between chlorpyrifos exposure and cancer incidence after adjustment for potential confounders. All statistical tests were two-sided. A total of 2070 incident malignant neoplasms were diagnosed through 2001. The rate ratio for all cancers combined among chlorpyrifos-exposed applicators compared with nonexposed applicators was 0.97 (95% confidence interval = 0.87 to 1.08). For most cancers analyzed, there was no evidence of an exposure-response relationship. However, the incidence of lung cancer was statistically significantly associated with both chlorpyrifos lifetime exposure-days (P(trend) = .002) and chlorpyrifos intensity-weighted exposure-days (P(trend) = .036). After adjustment for other pesticide exposures and demographic factors, individuals in the highest quartile of chlorpyrifos lifetime exposure-days (>56 days) had a relative risk of lung cancer 2.18 (95% confidence interval = 1.31 to 3.64) times that of those with no chlorpyrifos exposure. Our findings suggest an association between chlorpyrifos use and incidence of lung cancer that deserves further evaluation.


The pelvifemoral rhythm in cam-type femoroacetabular impingement.
There is growing evidence that femoroacetabular impingement is a potentially important risk factor for the development of early idiopathic osteoarthritis in the nondysplastic hip. Understanding of affected joint kinematics is a basic prerequisite in the evaluation of mechanical disorders in a clinical and research oriented setting. The aim of the present study was to compare pelvifemoral kinematics between subjects diagnosed with femoroacetabular impingement and healthy controls. The authors collected motion data of the femur and pelvis on a total of 43 hips - 19 cam impingement hips and 24 healthy controls - using a validated electromagnetic tracking device. The pelvifemoral rhythm in supine position was defined during both active and passive hip flexion and statistically compared between both groups. A significant increase in posterior pelvic rotation was observed during active hip flexion in the femoroacetabular impingement group compared with the control group (P<0.001). During passive hip flexion, however, posterior pelvic rotation between the impingement group and the controls did not differ significantly (P=0.628). Posterior pelvic rotation during active high-end hip flexion is increased in femoroacetabular impingement, indicating the presence of an active compensational mechanism that decreases the extent of harmful joint conflict during high-flexion activities.


Burrowing Owls, Pulex irritans, and Plague.
Western Burrowing Owls (Athene cunicularia hypugaea) are small, ground-dwelling owls of western North America that frequent prairie dog (Cynomys spp.) towns and other grasslands. Because they rely on rodent prey and occupy burrows once or concurrently inhabited by fossorial mammals, the owls often harbor fleas. We examined the potential role of fleas found on burrowing owls in plague dynamics by evaluating prevalence of Yersinia pestis in fleas collected from burrowing owls and in owl blood. During 2012-2013, fleas and blood were collected from burrowing owls in portions of five states with endemic plague-Idaho, Oregon, Washington, Colorado, and South Dakota. Fleas were enumerated, taxonomically identified, pooled by nest, and assayed for Y. pestis using culturing and molecular (PCR) approaches. Owl blood underwent serological analysis for plague antibodies and nested PCR for detection of Y. pestis. Of more than 4750 fleas collected from owls, Pulex irritans, a known plague vector in portions of its range, comprised more than 99.4%. However, diagnostic tests for Y. pestis of flea pools (culturing and PCR) and owl blood (PCR and serology) were negative. Thus, even though fleas were prevalent on burrowing owls and the potential for a relationship with burrowing owls as a phoretic host of infected fleas exists, we found no evidence of Y. pestis in sampled fleas or in owls that harbored them. We suggest that studies similar to those reported here during plague epizootics will be especially useful for confirming these results.


TAP- and tapasin-dependent HLA-E surface expression correlates with the binding of an MHC class I leader peptide.
The human major histocompatibility complex (MHC) class lb molecule HLA-E is transcribed in most tissues but little is known about its localisation within the cell. We have recently shown that HLA-E binds signal-sequence-derived peptides from human MHC class I molecules in vitro. Using a newly characterised antibody recognising HLA-E, we show that HLA-E is expressed at the cell surface. We demonstrate that HLA-E surface expression is correlated with the presence of MHC class I molecules which provide suitable leader sequence peptides capable of binding to HLA-E. Further studies on the interaction of HLA-E with molecules in the endoplasmic reticulum revealed that HLA-E associates with the transporter associated with antigen processing (TAP) and calreticulin, and that HLA-E expression is TAP-dependent and tapasin-dependent. In addition, HLA-E dissociates from TAP upon binding of MHC class I leader sequence peptides. These experiments establish that surface expression of HLA-E is regulated by the binding of a restricted pool of peptides from the leader sequence of MHC class I molecules. The correlation between HLA-E and MHC class I surface expression might be relevant to the function of HLA-E. Our results also show that, although these HLA-E binding peptides are derived from signal sequences, they may be released back into the cytosol and subsequently translocated by the TAP complex and loaded onto HLA-E molecules.


Feasibility, acceptability and potential effectiveness of dignity therapy for family carers of people with motor neurone disease.
Dignity therapy is a brief psychotherapy that has been shown to enhance the end of life experience. Dignity therapy often involves family carers to support patients weakened by illness and family carers are also the usual recipients of the legacy documents created. No research to date has examined the impact of dignity therapy on family carers at the time of the intervention. This study examined the effects of dignity therapy on family carers of people with motor neurone disease (MND). This is a cross-sectional study utilizing a one-group pre-test post-test design with 18 family carers of people diagnosed with MND. Outcomes measured caregiver burden, anxiety, depression, and hopefulness. Acceptability was measured with a questionnaire. Feasibility was assessed by examining family carers' involvement in the therapy sessions, time taken to conduct sessions, and any special accommodations or deviations from the dignity therapy protocol. There were no significant pre-test post-test changes on the group level, but there were decreases in anxiety and depression on the individual level. Baseline measures indicate that 50% of family carers had moderate to severe scores for anxiety prior to dignity therapy. MND family carers saw benefits to the person with MND and to themselves after bereavement, but acceptability of dignity therapy at the time of the intervention was mixed with some family carers indicating it was helpful, some indicating it was harmful, and many expressing ambivalence. Dignity therapy involving MND family carers is feasible and the involvement of family carers has minimal impact on the therapy. Dignity therapy is not likely to alleviate caregiver burden in MND family carers, but it may have the ability to decrease or moderate anxiety and depression in distressed MND family carers. Dignity therapy is feasible and generally acceptable to MND family carers. Dignity therapists may provide a better experience for family carers when they are aware of acceptance levels and the quality of partner relationships. ANZCTR Trial Number: ACTRN12611000410954.


Diagnostic and clinical considerations in concomitant bone marrow involvement by plasma cell myeloma and chronic lymphocytic leukemia/monoclonal B-cell lymphocytosis: a series of 15 cases and review of literature.
Plasma cell myeloma and chronic lymphocytic leukemia are both common hematologic malignancies, sharing many epidemiologic features. Concomitant detection of the 2 conditions poses special diagnostic challenges for the pathologist. To describe the pathologic findings in cases of concomitant bone marrow involvement by myeloma and CD5(+) monoclonal B cells and to outline the differential diagnostic possibilities, suggest a workup for correct diagnosis, and examine clinical outcome. Fifteen cases that met the diagnostic criteria were identified from pathology databases at 4 participating institutions. Morphologic findings were reviewed, additional immunohistochemical stains performed, and flow cytometric, cytogenetic, and relevant laboratory and clinical information was summarized. Previously published cases were searched from electronic databases and cross-references. Most patients (13 of 15) were older males. Often (11 of 15) they presented clinically with myeloma, yet had both monotypic plasma cells and B cells in the diagnostic marrow. In 4 patients, myeloma developed 24 months or later after chronic lymphocytic leukemia. In 7 patients, myeloma and CD5(+) B cells showed identical immunoglobulin light-chain restriction. Primary differential diagnoses include lymphoplasmacytic lymphoma, marginal zone lymphoma, and chronic lymphocytic leukemia with plasmacytoid differentiation. CD56 and/or cyclin D1 expression by plasma cells was helpful for correct diagnosis. Most patients in our cohort and published reports were treated for plasma cell myeloma. Concomitant detection of myeloma and chronic lymphocytic leukemia in the bone marrow is a rare event, which must be carefully differentiated from lymphomas with lymphoplasmacytic differentiation for correct treatment.


A survey study on some neurological symptoms and sensations experienced by long term users of mobile phones.
A survey study was conducted to investigate the possible effects of mobile phone on headache, dizziness, extreme irritation, shaking in the hands, speaking falteringly, forgetfulness, neuro-psychological discomfort, increase in the carelessness, decrease of the reflex and clicking sound in the ears. There is no effect on dizziness, shaking in hands, speaking falteringly and neuro-psychological discomfort, but some statistical evidences are found that mobile phone may cause headache, extreme irritation, increase in the carelessness, forgetfulness, decrease of the reflex and clicking sound in the ears.


Plasma-free fatty acids, fatty acid-binding protein 4, and mortality in older adults (from the Cardiovascular Health Study).
Plasma-free fatty acids (FFAs) are largely derived from adipose tissue. Elevated levels of FFA and fatty acid-binding protein 4 (FABP4), a key cytoplasmic chaperone of fatty acids, have been associated with adverse cardiovascular outcomes, but limited data are available on the relation of these biomarkers with cardiovascular and total mortality. We studied 4,707 participants with a mean age of 75 years who had plasma FFA and FABP4 measured in 1992 to 1993 as part of the Cardiovascular Health Study, an observational cohort of community-dwelling older adults. Over a median follow-up of 11.8 years, 3,555 participants died. Cox proportional hazard regression was used to determine the association between FFA, FABP4, and mortality. In fully adjusted models, FFA were associated with dose-dependent significantly higher total mortality (hazard ratio [HR] per SD: 1.14, 95% confidence interval [CI] 1.09 to 1.18), but FABP4 levels were not (HR 1.04, 95% CI 0.98 to 1.09). In a cause-specific mortality analysis, higher concentrations of FFA were associated with significantly higher risk of death because of cardiovascular disease, dementia, infection, and respiratory causes but not cancer or trauma. We did not find evidence of an interaction between FFA and FABP4 (p = 0.45), but FABP4 appeared to be associated with total mortality differentially in men and women (HR 1.17, 95% CI 1.08 to 1.26 for men; HR 1.02, 95% CI 0.96 to 1.07 for women, interaction p value <0.001). In conclusion, in a cohort of community-dwelling older subjects, elevated plasma concentrations of FFA, but not FABP4, were associated with cardiovascular and noncardiovascular mortality.


Prioritizing performance measurement for emergency department care: consensus on evidence-based quality of care indicators.
The evaluation of emergency department (ED) quality of care is hampered by the absence of consensus on appropriate measures. We sought to develop a consensus on a prioritized and parsimonious set of evidence-based quality of care indicators for EDs. The process was led by a nationally representative steering committee and expert panel (representatives from hospital administration, emergency medicine, health information, government, and provincial quality councils). A comprehensive review of the scientific literature was conducted to identify candidate indicators. The expert panel reviewed candidate indicators in a modified Delphi panel process using electronic surveys; final decisions on inclusion of indicators were made by the steering committee in a guided nominal group process with facilitated discussion. Indicators in the final set were ranked based on their priority for measurement. A gap analysis identified areas where future indicator development is needed. A feasibility study of measuring the final set of indicators using current Canadian administrative databases was conducted. A total of 170 candidate indicators were generated from the literature; these were assessed based on scientific soundness and their relevance or importance. Using predefined scoring criteria in two rounds of surveys, indicators were coded as "retained" (53), "discarded" (78), or "borderline" (39). A final set of 48 retained indicators was selected and grouped in nine categories (patient satisfaction, ED operations, patient safety, pain management, pediatrics, cardiac conditions, respiratory conditions, stroke, and sepsis or infection). Gap analysis suggested the need for new indicators in patient satisfaction, a healthy workplace, mental health and addiction, elder care, and community-hospital integration. Feasibility analysis found that 13 of 48 indicators (27%) can be measured using existing national administrative databases. A broadly representative modified Delphi panel process resulted in a consensus on a set of 48 evidence-based quality of care indicators for EDs. Future work is required to generate technical definitions to enable the uptake of these indicators to support benchmarking, quality improvement, and accountability efforts.


Undifferentiated effects of calcium antagonists on pressor responses to selective alpha-1 and alpha-2 adrenoceptor agonists in anesthetized, spinal dogs.
Whether pressor responses mediated by alpha-2 adrenoceptors are more susceptible to calcium antagonists than those mediated by alpha-1 adrenoceptors was investigated in anesthetized, spinal dogs. All drugs were administered i.v. Methoxamine (3-100 mu/kg) or xylazine (3-300 micrograms/kg) produced a sustained increase in mean arterial pressure but almost no effect on heart rate. Both the initial and the sustained phase of the pressor response to methoxamine were selectively antagonized by prazosin, whereas those to xylazine were selectively antagonized by yohimbine. These results indicate that the peripheral arterial bed of the dog comprises alpha-1 and alpha-2 adrenoceptors and that both the initial and sustained phases of the pressor response to methoxamine are predominantly mediated by alpha-1 adrenoceptors, whereas those to xylazine are mediated by alpha-2 adrenoceptors. The calcium antagonists, i.e., nifedipine (0.3-3 micrograms/kg), diltiazem (10-100 micrograms/kg) and KB-944 (10-100 micrograms/kg), administered during the sustained phase of the pressor responses to equieffective doses of methoxamine (100 micrograms/kg) and xylazine (1000 micrograms/kg), lowered mean arterial pressure. The three calcium antagonists in these doses also lowered the baseline mean arterial pressure but to a lesser extent than the elevated one. These results altogether indicate that the calcium antagonists were more effective in lowering mean arterial pressure elevated by either an alpha-1 or alpha-2 adrenoceptor agonist than the base-line mean arterial pressure and that the sustained phase of the pressor response mediated by alpha-1 adrenoceptors would involve Ca++ influx as much as or more than those mediated by alpha-2 adrenoceptors.


Novel pyrrolidine ureas as C-C chemokine receptor 1 (CCR1) antagonists.
Monocyte infiltration is implicated in a variety of diseases including multiple myeloma, rheumatoid arthritis, and multiple sclerosis. C-C chemokine receptor 1 (CCR1) is a chemokine receptor that upon stimulation, particularly by macrophage inflammatory protein 1alpha (MIP-1alpha) and regulated on normal T-cell expressed and secreted (RANTES), mediates monocyte trafficking to sites of inflammation. High throughput screening of our combinatorial collection identified a novel, moderately potent CCR1 antagonist 3. The library hit 3 was optimized to the advanced lead compound 4. Compound 4 inhibited CCR1 mediated chemotaxis of monocytes with an IC(50) of 20 nM. In addition, the compound was highly selective over other chemokine receptors. It had good microsomal stability when incubated with rat and human liver microsomes and showed no significant cytochrome P450 (CYP) inhibition. Pharmacokinetic evaluation of the compound in the rat showed good oral bioavailability.


Contribution of IKBKE and IFIH1 gene variants to SLE susceptibility.
The type I interferon system genes IKBKE and IFIH1 are associated with the risk of systemic lupus erythematosus (SLE). To identify the sequence variants that are able to account for the disease association, we resequenced the genes IKBKE and IFIH1. Eighty-six single-nucleotide variants (SNVs) with potentially functional effect or differences in allele frequencies between patients and controls determined by sequencing were further genotyped in 1140 SLE patients and 2060 controls. In addition, 108 imputed sequence variants in IKBKE and IFIH1 were included in the association analysis. Ten IKBKE SNVs and three IFIH1 SNVs were associated with SLE. The SNVs rs1539241 and rs12142086 tagged two independent association signals in IKBKE, and the haplotype carrying their risk alleles showed an odds ratio of 1.68 (P-value=1.0 × 10(-5)). The risk allele of rs12142086 affects the binding of splicing factor 1 in vitro and could thus influence its transcriptional regulatory function. Two independent association signals were also detected in IFIH1, which were tagged by a low-frequency SNV rs78456138 and a missense SNV rs3747517. Their joint effect is protective against SLE (odds ratio=0.56; P-value=6.6 × 10(-3)). In conclusion, we have identified new SLE-associated sequence variants in IKBKE and IFIH1, and proposed functional hypotheses for the association signals.


Solubility and strength of zirconia-based dental materials after artificial aging.
Advanced high-strength dental ceramics based on zirconium oxide are widely used for dental restorations. However, their durability in liquids has been questioned. The purpose of this study was to compare the flexure strength of zirconium dioxide materials designed for different sintering techniques before and after surface exposure to an acidic solution and to correlate the dissolution of the materials with strength data. An accelerated aging test, immersion in hot (80°C) 4 vol% acetic acid was used to study the solubility of elements from the surface and the effect on the strength of 3 dental zirconia products: DY: Y-TZP material, milled in HIPed state (Denzir); DM: Mg-PSZ material, milled in dense-sintered state (Denzir M); and CY: Y-TZP material, milled from presintered block and then dense-sintered (Cercon base). Disks were prepared with a surface conditioning as for copings provided for dental restorations. After immersion for 1 week, the liquid was analyzed for a range of elements with ICP-MS. Biaxial flexure strength was measured for 3 samples (n=15) of each material: ground on a 20 µm diamond disk without immersion; after 1 week's immersion in acetic acid; and after 1 week's immersion, grinding, and 1 more week in acid. Fracture probability was analyzed by maximum likelihood attribution of individual measurements to 1 or 2 Weibull distributions, each with 2 free parameters. Dissolution was found to be limited. The total mass loss was less than 0.7 µg/cm(2) for Y-TZP and 3.5 µg/cm(2) for Mg-PSZ. The mean strength was reduced for all materials after immersion in the fluid. Weibull statistics revealed 2 fracture mechanisms in Y-TZP milled in fully sintered condition. For DY only, 2 distributions significantly (P>.99) improved the description of individual treatment data. Y-TZP materials showed the highest biaxial flexure strength. Immersion for 1 week in hot 4 vol% acetic acid weakened all 3 zirconia materials by 100 to 200 MPa. Milling in the presintered state resulted in less variability than milling in the HIPed state. Mg-PSZ exhibited the least variability.


White matter deficits correlate with visual motion perception impairments in dyslexic carriers of the DCDC2 genetic risk variant.
Motion perception deficits in dyslexia show a large intersubjective variability, partly reflecting genetic factors influencing brain architecture development. In previous work, we have demonstrated that dyslexic carriers of a mutation of the DCDC2 gene have a very strong impairment in motion perception. In the present study, we investigated structural white matter alterations associated with the poor motion perception in a cohort of twenty dyslexics with a subgroup carrying the DCDC2 gene deletion (DCDC2d+) and a subgroup without the risk variant (DCDC2d-). We observed significant deficits in motion contrast sensitivity and in motion direction discrimination accuracy at high contrast, stronger in the DCDC2d+ group. Both motion perception impairments correlated significantly with the fractional anisotropy in posterior ventral and dorsal tracts, including early visual pathways both along the optic radiation and in proximity of occipital cortex, MT and VWFA. However, the DCDC2d+ group showed stronger correlations between FA and motion perception impairments than the DCDC2d- group in early visual white matter bundles, including the optic radiations, and in ventral pathways located in the left inferior temporal cortex. Our results suggest that the DCDC2d+ group experiences higher vulnerability in visual motion processing even at early stages of visual analysis, which might represent a specific feature associated with the genotype and provide further neurobiological support to the visual-motion deficit account of dyslexia in a specific subpopulation.


Polo-like kinase 1 creates the tension-sensing 3F3/2 phosphoepitope and modulates the association of spindle-checkpoint proteins at kinetochores.
In mitosis, a mechanochemical system recognizes tension that is generated by bipolar microtubule attachment to sister kinetochores. This is translated into multiple outputs including the stabilization of microtubule attachments, changes in kinetochore protein dynamics, and the silencing of the spindle checkpoint. How kinetochores sense tension and translate this into various signals represent critical unanswered questions. The kinetochores of chromosomes not under tension are specifically phosphorylated at an epitope recognized by the 3F3/2 monoclonal antibody. Determining the kinase that generates the 3F3/2 phosphoepitope at kinetochores should reveal an important component of this system that regulates mitotic progression. We demonstrate that Polo-like kinase 1 (Plk1) creates the 3F3/2 phosphoepitope on mitotic kinetochores. In a permeabilized in vitro cell system, the depletion of Xenopus Plk1 from M phase extract leads to the loss of 3F3/2 kinase activity. Purified recombinant Plk1 is sufficient to generate the 3F3/2 phosphoepitope in this system. Using siRNA, we show that the reduction of Plk1 protein levels significantly diminishes 3F3/2 phosphoepitope expression at kinetochores. The consensus phosphorylation sites of Plk1 show strong similarity to the 3F3/2 phosphoepitope sequence determined by phosphopeptide mapping. The inhibition of Plk1 by siRNA alters the normal kinetochore association of Mad2, Cenp-E, Hec1/Ndc80, Spc24, and Cdc20 and induces a spindle-checkpoint-mediated mitotic arrest. Plk1 generates the 3F3/2 phosphoepitope at kinetochores that are not under tension and contributes to the normal kinetochore association of several key proteins important in checkpoint signaling. Mechanical tension regulates Plk1 accumulation at kinetochores and possibly its kinase activity.


Cutaneous lymphoid hyperplasia. Immunologic characteristics and assessment of criteria recently proposed as diagnostic of malignant lymphoma.
Fifteen cases of cutaneous lymphoid hyperplasia were studied immunohistologically with a large panel of monoclonal antibodies to determine their immunoarchitectural composition and to determine whether immunologic criteria recently proposed to identify lymphoma ever occur in benign skin lesions. All lesions were composed of T cells, polytypic B cells, macrophages, and Langerhans cells. Although only six cases containing lymphoid follicles were recognized in routinely stained sections, an additional five were identified in immunoperoxidase-stained sections. These follicles were of both the primary and secondary types and contained dendritic reticulum cell networks. The immunophenotypic features of these follicles were similar to those of reactive follicles in lymphoid organs and contrasted sharply with those reported previously for follicular lymphomas. Helper T cells were predominant in 11 cases. With regard to proposed criteria for T cell lymphoma, we did not detect loss of pan T cell antigens CD2, CD3, CD5, or BF-1, nor did we find populations of T cells with abnormal co-expression or loss of subset antigens such as CD4-8- or CD4+8+. Two cases in which relatively sparse infiltrates were present, however, were moderately CD7-deficient. This finding suggests that the CD7 criterion for cutaneous T cell neoplasia be modified in this situation. As observed previously, Leu-8 antigen deficiency was a common, nonspecific finding. With regard to proposed criteria for B cell lymphoma, we did not detect populations of B cells that were immunoglobulin-negative, nor did we observe preferential loss of one or more B-lineage antigens, histocompatibility complex-associated antigens, or lymphocyte function-associated antigens. We also did not identify any CD5+ B cells. On the basis of a comparison of our current data with prior studies of cutaneous lymphomas, we conclude that the immunologic findings recently proposed as general criteria for the differentiation of lymphoma from lymphoid hyperplasia are, in fact, applicable to cutaneous lymphoid lesions.


Effect of deficits in laryngeal sensation on laryngeal muscle biochemistry.
Swallowing deficits in elderly people are significant clinical problems and may be associated with impaired pharyngolaryngeal sensation. However, the extent to which sensory innervation affects the motor system is unclear. Our purpose was to examine differences in biochemical properties of laryngeal muscles following sensory nerve ablation. We used sodium dodecyl sulfate-polyacrylamide gel electrophoresis to evaluate laryngeal muscles of young and old Fischer 344/Brown Norway rats, and rats that underwent sensory ablation via bilateral section of the superior laryngeal nerve, internal branch (SLNi), or mixed sensory-motor nerve ablation via left-sided recurrent laryngeal nerve (RLN) section. In lateral thyroarytenoid muscle, a reduction was found in the proportion of the most rapidly contracting myosin heavy chain isoform (type 2B) with SLNi section, RLN section, and aging. Section of the SLNi did not alter the proportion of any myosin heavy chain isoform within the lateral cricoarytenoid or posterior cricoarytenoid muscles, but RLN section resulted in a reduction in the proportion of type 2B. Accordingly, alteration in biochemical properties of the lateral thyroarytenoid muscle alone was demonstrated following sensory ablation. We conclude that sensory changes may affect properties of laryngeal muscles, and may thus have an impact on motor control during critical functions, such as airway protection during swallowing.


[Colposcopy and cervical biopsy in patients with routine Papanicolaou smear].
The objective of this report was to assess the sensitivity and specificity of Pap smear and to evaluate if routine colposcopy can improve cervical screening. One hundred and fifty patients undergoing routine cervical cytologic screening in our outpatient clinic were randomly selected. All patients were evaluated by colposcopy and cervical punch biopsy. Pap smears and biopsies specimens were interpreted independently. Colposcopy was performed and interpreted without knowledge of cytologic or histologic findings. The statistical analysis was carried out with a chi square (chi 2) test. A P value of less than 0.05 was considered significant. Twenty three patients (15.3%) who had biopsy proved to have cervical pathology. Pap smear identified only 4/23 (17%) of these patients. Colposcopy noted atypical transformation zones in 20/23 (97%), P < 0.001). Fifteen of 27 patients (55.5%) with negative Pap smears had colposcopic anormalities and histologically proved cervical intraepithelial neoplasia (CIN). We concluded that it is necessary to improve sensitivity and that colposcopy may enhance cervical screening particularly in women with otherwise negative Papapnicolaou smears.


Protective Effects of Dietary Intake of Antioxidants and Treatment-Related Toxicity in Childhood Leukemia: A Report From the DALLT Cohort.
The benefits and risks of supplementation with antioxidants during cancer therapy have been a controversial area. Few studies have systematically evaluated dietary intake of antioxidants with toxicity and survival in childhood cancer. We sought to determine the role of dietary intake of antioxidants on rates of infections, mucositis, relapse, and disease-free survival during induction and postinduction phases of therapy among children and adolescents with acute lymphoblastic leukemia (ALL). We enrolled 794 children in a prospective clinical trial for treatment of ALL. Dietary intake was prospectively evaluated by a food frequency questionnaire. The association between dietary intake of antioxidants and treatment-related toxicities and survival were evaluated with the Benjamini-Hochberg false discovery rate (q) and logistic regression and the Kaplan-Meier method, respectively. Dietary surveys were available for analysis from 614 (77%), and 561 (71%) participants at diagnosis and at end of induction, respectively. Of 513 participants who completed the dietary surveys at both time points, 120 (23%) and 87 (16%) experienced a bacterial infection and 22 (4%) and 55 (10%) experienced mucositis during the induction or postinduction phases of treatment, respectively. Increased intake of dietary antioxidants was associated with significantly lower rates of infection and mucositis. No association with relapse or disease-free survival was observed. Supplementation was not associated with toxicity, relapse, or survival. Consumption of antioxidants through dietary intake was associated with reduced rates of infection or mucositis, with no increased risk of relapse or reduced survival. Dietary counseling on a well-balanced diet that includes an array of antioxidants from food sources alone may confer a benefit from infections and mucositis during treatment of childhood ALL.


Evolution of the feline-subgroup parvoviruses and the control of canine host range in vivo.
A related group of parvoviruses infects members of many different carnivore families. Some of those viruses differ in host range or antigenic properties, but the true relationships are poorly understood. We examined 24 VP1/VP2 and 8 NS1 gene sequences from various parvovirus isolates to determine the phylogenetic relationships between viruses isolated from cats, dogs, Asiatic raccoon dogs, mink, raccoons, and foxes. There were about 1.3% pairwise sequence differences between the VP1/VP2 genes of viruses collected up to four decades apart. Viruses from cats, mink, foxes, and raccoons were not distinguished from each other phylogenetically, but the canine or Asiatic raccoon dog isolates formed a distinct clade. Characteristic antigenic, tissue culture host range, and other properties of the canine isolates have previously been shown to be determined by differences in the VP1/VP2 gene, and we show here that there are at least 10 nucleotide sequence differences which distinguish all canine isolates from any other virus. The VP1/VP2 gene sequences grouped roughly according to the time of virus isolation, and there were similar rates of sequence divergence among the canine isolates and those from the other species. A smaller number of differences were present in the NS1 gene sequences, but a similar phylogeny was revealed. Inoculation of mutants of a feline virus isolate into dogs showed that three or four CPV-specific differences in the VP1/VP2 gene controlled the in vivo canine host range.


Changes in phenolic content of commercial potato varieties through industrial processing and fresh preparation.
Reported content and process stability of phenolics in potato products is inconsistent. Changes in phenolic content of select varieties through fresh and industrial preparation/reconstitution were assessed. Total chlorogenic acids (CQAs) ranged from 43 to 953mg/100g dw and were more concentrated in pigmented compared to white/yellow-fleshed potatoes. Anthocyanin (ANC) content ranged from 18.6 to 22.9mg/100g dw and were mainly present in the flesh of pigmented potatoes. Retention of phenolics through commercial processing ranged from 49 to 85% for pigmented varieties and 32-55% for white/yellow. CQA levels were reduced through processing but to a greater extent in white relative to pigmented potatoes. ANCs were well retained through industrial processing of pigmented potatoes (79-129%). Levels of CQA were significantly (p<0.05) lower in some industrially versus freshly processed products but not for all products. While some differences exist, overall, industrially processed potato products compare favorably to fresh preparation in levels and recovery of phenolics.


The patient at the centre: evidence from 17 European integrated care programmes for persons with complex needs.
As the prevalence of multi-morbidity increases in ageing societies, health and social care systems face the challenge of providing adequate care to persons with complex needs. Approaches that integrate care across sectors and disciplines have been increasingly developed and implemented in European countries in order to tackle this challenge. The aim of the article is to identify success factors and crucial elements in the process of integrated care delivery for persons with complex needs as seen from the practical perspective of the involved stakeholders (patients, professionals, informal caregivers, managers, initiators, payers). Seventeen integrated care programmes for persons with complex needs in 8 European countries were investigated using a qualitative approach, namely thick description, based on semi-structured interviews and document analysis. In total, 233 face-to-face interviews were conducted with stakeholders of the programmes between March and September 2016. Meta-analysis of the individual thick description reports was performed with a focus on the process of care delivery. Four categories that emerged from the overarching analysis are discussed in the article: (1) a holistic view of the patient, considering both mental health and the social situation in addition to physical health, (2) continuity of care in the form of single contact points, alignment of services and good relationships between patients and professionals, (3) relationships between professionals built on trust and facilitated by continuous communication, and (4) patient involvement in goal-setting and decision-making, allowing patients to adapt to reorganised service delivery. We were able to identify several key aspects for a well-functioning integrated care process for complex patients and how these are put into actual practice. The article sets itself apart from the existing literature by specifically focussing on the growing share of the population with complex care needs and by providing an analysis of actual processes and interpersonal relationships that shape integrated care in practice, incorporating evidence from a variety of programmes in several countries.


Expression of matrix metalloproteinases in the muscle of patients with inflammatory myopathies.
To investigate the role of matrix metalloproteinases (MMPs) in the pathogenesis of inflammatory myopathies and the amyloid formation in sporadic inclusion body myositis (s-IBM). MMPs comprise a family of calcium-dependent zinc endoproteinases induced by cytokines and secreted by inflammatory cells. They enhance T-cell migration or adhesion and degrade components of the extracellular matrix proteins. Some MMPs also have been implicated in the formation of beta-amyloid. We examined the expression of MMPs with single and double immunocytochemistry using antibodies against MMP-2, MMP-3, MMP-7, MMP-9, major histocompatibility complex (MHC) class I, CD8+ cells, macrophage, and beta-amyloid precursor protein (beta-APP) on serial muscle biopsy sections from patients with s-IBM, polymyositis (PM), dermatomyositis (DM), and disease control specimens. The enzyme activity of MMPs was measured by gelatin substrate zymography. Only the gelatinases, MMP-9 and MMP-2, were expressed in the muscle. In s-IBM and PM, but not the control specimens, MMP-9 and MMP-2 immunostained the non-necrotic and MHC class-I-expressing muscle fibers, and MMP-9, but not MMP-2, immunostained the autoinvasive CD8+ cytotoxic T cells. Zymography in muscle homogenates confirmed the increased MMP-2 and MMP-9 enzymatic activity. MMP-2, but not MMP-9, immunostained the rimmed vacuoles in s-IBM and colocalized with beta-APP, suggesting a possible involvement with the amyloid deposits. Because collagen IV is prominent on the muscle membrane, the overexpression of matrix metalloproteinases (MMPs) 2 and 9 on the non-necrotic muscle fibers in polymyositis (PM) and sporadic inclusion body myositis (s-IBM) may facilitate lymphocyte adhesion and enhance T-cell-mediated cytotoxicity by degrading extracellular matrix proteins. The findings may have practical implications in considering therapeutic trials with MMP inhibitors in patients with PM and s-IBM.


Molecular basis for heme-dependent induction of heme oxygenase in primary cultures of chick embryo hepatocytes. Demonstration of acquired refractoriness to heme.
The effects of heme on the induction of mRNA and protein synthesis for heme oxygenase-1 have been studied in primary cultures of chick embryo liver cells. Heme increased the amount of mRNA and the rate of heme oxygenase-1-gene transcription in a dose-dependent fashion, with a maximal 20-fold increase occurring at 20 microM heme. The largest increase in the rate of transcription, measured by nuclear run-on assays, occurred at 5 h, 2 h earlier than the maximum increase in the amount of mRNA, measured by densitometry of Northern blots. 7-15 h after heme addition, the half-life of heme-oxygenase-1 mRNA was 3.5 h in the presence or absence of actinomycin D. In contrast, addition of cycloheximide markedly increased the stability of the message (half-life = 18 h), suggesting that a short-lived protein plays a key role in modulating heme oxygenase-1 mRNA levels. The half-life of heme-induced heme-oxygenase-1 protein, measured by [35S]methionine labelling and immunoprecipitation, was 15 h. This long half-life of the protein can largely account for the additional finding that, following addition of heme, the amount of enzyme protein in the cells increased for 10 h, after which it remained essentially constant for 15 h. A striking finding was that, after an initial burst of heme-stimulated gene transcription, the cells became refractory to further heme-mediated induction. This acquired resistance could not be attributed to the following: a longer duration of culture time; cellular toxicity caused by heme; a lack of heme in the medium or the cells; secretion of heme-binding proteins into the medium, preventing further heme uptake; the induction of cellular heme catabolism sufficient to deplete cellular heme. Instead, the results suggest a down-regulation of the intracellular machinery required for heme-dependent induction of heme oxygenase-1.


Diagnostic Value of Semiquantitative Analysis of 99mTechnetium-Methoxyisobutylisonitrile (99mTc-MIBI) Imaging in Predicting Early-Stage Cervical Lymph Node Metastasis of Thyroid Carcinoma.
BACKGROUND The aim of this study was to evaluate the value of semiquantitative analysis (SQA) of 99mTc-MIBI imaging in predicting early-stage cervical lymph node metastasis (CLNM) in thyroid carcinoma (TC). MATERIAL AND METHODS TC patients (n =106) undergoing surgical resection and histopathological examination were enrolled. All patients received 99mTc-MIBI imaging prior to surgery. P-glycoprotein (P-gp) expression was detected by PT-PCR and immunohistochemistry. With pathological results as the criterion standard, the diagnostic efficiency of 99mTc-MIBI imaging in predicting early-stage CLNM was evaluated. The correlation of P-gp with 99mTc-MIBI imaging was investigated. Logistic regression analysis was applied for analyzing the factors affecting early-stage CLNM. RESULTS The detection rate and misdiagnosis rate of 99mTc-MIBI imaging for early-stage CLNM diagnosis were 87.3% and 12.7%, respectively. Receiver operating characteristic (ROC) curve analysis showed an accuracy of 99mTc-MIBI imaging of 85.85%. Preoperative 99mTc-MIBI scan showed statistical differences between metastasis and non-metastasis groups in early and delayed T/NT and washout rate (all P<0.05). The percentage of P-gp-expressing cells and the expression rate of P-gp gene both exhibited statistical differences between metastasis and no-metastasis groups (both P<0.05). Tumor diameter, lesion distribution, the percentage of P-gp-expressing cells, and the expression rate of P-gp gene were risk factors for CLNM (all P<0.05). CONCLUSIONS 99mTc-MIBI imaging has value in qualitative diagnosis of early-stage CLNM in TC. Tumor diameter, lesion distribution, the percentage of P-gp-expressing cells, and the expression rate of P-gp gene were risk factors for CLNM.


More than Action: The Dorsal Pathway Contributes to the Perception of 3-D Structure.
An evolving view in cognitive neuroscience is that the dorsal visual pathway not only plays a key role in visuomotor behavior but that it also contributes functionally to the recognition of objects. To characterize the nature of the object representations derived by the dorsal pathway, we assessed perceptual performance in the context of the continuous flash suppression paradigm, which suppresses object processing in the ventral pathway while sparing computation in the dorsal pathway. In a series of experiments, prime stimuli, which were rendered imperceptible by the continuous flash suppression, still contributed to perceptual decisions related to the subsequent perceptible target stimuli. However, the contribution of the prime to perception was contingent on the prime's structural coherence, in that a perceptual advantage was observed only for targets primed by objects with legitimate 3-D structure. Finally, we obtained additional evidence to demonstrate that the processing of the suppressed objects was contingent on the magnocellular, rather than the parvocellular, system, further linking the processing of the suppressed stimuli to the dorsal pathway. Together, these results provide novel evidence that the dorsal pathway does not only support visuomotor control but, rather, that it also derives the structural description of 3-D objects and contributes to shape perception.


Telemedicine in cardiovascular surgery during COVID-19 pandemic: A systematic review and our experience.
The SAR-COV-2 pandemic has had an unprecedented effect on the UK's healthcare systems. To reduce spread of the virus, elective treatments and surgeries have been postponed or canceled. There has been a rise in the use of telemedicine (TM) as an alternative way to carry outpatient consultations. This systematic review aims to evaluate the extent to which TM may be able to support cardiac and vascular surgery patients in the COVID-19 era. We looked into how TM can support the management of patients via triaging, preoperative, and postoperative care. Evaluations targeted the clinical effectiveness of common TM methods and the feasibility of applying those methods in the UK during this pandemic. Several studies have published their evidence on the benefit of TM and its benefit during COVID-19, the data related to cardiovascular surgery and how this will impact future practice of this speciality is emerging and yet larger studies with appropriate timing of outcomes to be published. Overall, the use of virtual consultations and remote monitoring is feasible and best placed to support these patients via triaging and postoperative monitoring. However, TM can be limited by the need of sophisticated technological requirement and patients' educational and know-how computer literacy level.


Organic nonvolatile memory transistors for flexible sensor arrays.
Using organic transistors with a floating gate embedded in hybrid dielectrics that comprise a 2-nanometer-thick molecular self-assembled monolayer and a 4-nanometer-thick plasma-grown metal oxide, we have realized nonvolatile memory arrays on flexible plastic substrates. The small thickness of the dielectrics allows very small program and erase voltages (< or = 6 volts) to produce a large, nonvolatile, reversible threshold-voltage shift. The transistors endure more than 1000 program and erase cycles, which is within two orders of magnitude of silicon-based floating-gate transistors widely employed in flash memory. By integrating a flexible array of organic floating-gate transistors with a pressure-sensitive rubber sheet, we have realized a sensor matrix that detects the spatial distribution of applied mechanical pressure and stores the analog sensor input as a two-dimensional image over long periods of time.


Personal projects, happiness, and meaning: on doing well and being yourself.
Personal Projects Analysis (B. R. Little, 1983) was adapted to examine relations between participants' appraisals of their goal characteristics and orthogonal happiness and meaning factors that emerged from factor analyses of diverse well-being measures. In two studies with 146 and 179 university students, goal efficacy was associated with happiness and goal integrity was associated with meaning. A new technique for classifying participants according to emergent identity themes is introduced. In both studies, identity-compensatory predictors of happiness were apparent. Agentic participants were happiest if their goals were supported by others, communal participants were happiest if their goals were fun, and hedonistic participants were happiest if their goals were being accomplished. The distinction between happiness and meaning is emphasized, and the tension between efficacy and integrity is discussed. Developmental implications are discussed with reference to results from archival data from a sample of senior managers.