Increased prevalence of antibiotic-resistant E. coli in gulls sampled in Southcentral Alaska is associated with urban environments.
Antibiotic-resistant bacteria pose challenges to healthcare delivery systems globally; however, limited information is available regarding the prevalence and spread of such bacteria in the environment. The aim of this study was to compare the prevalence of antibiotic-resistant bacteria in large-bodied gulls (Larus spp.) at urban and remote locations in Southcentral Alaska to gain inference into the association between antibiotic resistance in wildlife and anthropogenically influenced habitats. Escherichia coli was cultured (n=115 isolates) from fecal samples of gulls (n=160) collected from a remote location, Middleton Island, and a more urban setting on the Kenai Peninsula. Screening of E. coli from fecal samples collected from glaucous-winged gulls (Larus glaucescens) at Middleton Island revealed 8% of isolates were resistant to one or more antibiotics and 2% of the isolates were resistant to three or more antibiotics. In contrast, 55% of E. coli isolates derived from fecal samples collected from large-bodied gulls (i.e. glaucous, herring [Larus argentatus], and potentially hybrid gulls) on the Kenai Peninsula were resistant to one or more antibiotics and 22% were resistant to three or more antibiotics. In addition, total of 16% of the gull samples from locations on the Kenai Peninsula harbored extended-spectrum cephalosporin-resistant E. coli isolates (extended-spectrum beta-lactamases [ESBL] and plasmid-encoded AmpC [pAmpC]), in contrast to Middleton Island where no ESBL- or pAmpC-producing isolates were detected. Our findings indicate that increased prevalence of antibiotic resistance is associated with urban environments in Southcentral Alaska and presumably influenced by anthropogenic impacts. Further investigation is warranted to assess how migratory birds may maintain and spread antimicrobial-resistant bacteria of relevance to human and animal health.


Whole-body vibration induced adaptation in knee extensors; consequences of initial strength, vibration frequency, and joint angle.
It was hypothesized that both vibration frequency and muscle length modulate the strengthening of muscles that is assumed to result from whole-body vibration (WBV). Length of knee extensor muscles during vibration is affected by the knee joint angle; the lengths of the knee extensors increase with more flexed knee joint angles. In an intervention study 28 volunteers were randomly assigned to 1 of 4 groups. Each group received 4 weeks of WBV at 1 of 3 different frequencies (20, 27, or 34 Hz) or 1 of 2 different lengths of knee extensors. Voluntary, isometric knee extension moment-angle relationship was determined. Initially, stronger subjects reacted differently to WBV than weaker participants. In stronger subjects knee extension moment did not improve; in the weaker subjects considerable improvements were observed ranging from 10 to 50%. Neither vibration frequency nor muscle length during the intervention affected the improvements. In addition to strength, the knee joint angle at which the maximal joint moment was generated (optimal joint angle) was affected. When trained at short muscle lengths, optimal angle shifted to more extend joint position. WBV training at long muscle lengths tended to induce an opposite shift. The amount of this shift tended to be influenced by vibration frequency; the lower the vibration frequency the larger the shift. Shifts of optimal lengths occurred in both weaker and stronger subjects. This study shows that muscle length during training affects the angle of knee joint at which the maximal extension moment was generated. Moreover, in weaker subjects WBV resulted in higher maximal knee joint extension moments. Vibration frequency and muscle length during vibration did not affect this joint moment gain.


Cloacibacillus evryensis gen. nov., sp. nov., a novel asaccharolytic, mesophilic, amino-acid-degrading bacterium within the phylum 'Synergistetes', isolated from an anaerobic sludge digester.
A novel anaerobic, mesophilic, amino-acid-utilizing bacterium, strain 158T, was isolated from an anaerobic digester of a wastewater treatment plant. Cells of strain 158T were non-motile, rod-shaped (2.0-3.0 x 0.8-1.0 microm) and stained Gram-negative. Optimal growth occurred at 37 degrees C and pH 7.0 in an anaerobic basal medium containing 1 % Casamino acids. Strain 158T fermented arginine, histidine, lysine and serine and showed growth on yeast extract, brain-heart infusion (BHI) medium and tryptone, but not on carbohydrates, organic acids or alcohols. The end products of degradation were: acetate, butyrate, H2 and CO2 from arginine; acetate, propionate, butyrate, H2 and CO2 from lysine; and acetate, propionate, butyrate, valerate, H2 and CO2 from histidine, serine, BHI medium, Casamino acids and tryptone. The DNA G+C content was 55.8 mol%. The 16S rRNA gene sequence of strain 158T showed only 92.6 % sequence similarity with that of Synergistes jonesii, the only described species of the 'Synergistes' group. The major cellular fatty acids were iso-C(15:0) (16.63 %), iso-C(15:0) 3-OH (12.41 %) and C(17:1)omega6c (9.46 %) and the polar fatty acids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and phosphatidylmonomethylamine; these fatty acid profiles did not resemble those of any recognized bacterial species. Due to the considerable differences in genotypic, phenotypic and phylogenetic characteristics between strain 158T and those of its nearest relative, it is proposed that strain 158T represents a novel species in a new genus, Cloacibacillus evryensis gen. nov., sp. nov., in the phylum 'Synergistetes'. The type strain is 158T (=DSM 19522T=JCM 14828T).


EPA Prevents the Development of Abdominal Aortic Aneurysms through Gpr-120/Ffar-4.
Abdominal aortic aneurysms (AAAs), which commonly occur among elderly individuals, are accompanied by a risk of rupture with a high mortality rate. Although eicosapentaenoic acid (EPA) has been reported to prevent AAA formation, the mechanism by which EPA works on vascular smooth muscle cells is unknown. This study aimed to investigate the mechanism by which orally-administered EPA prevents the formation of severe AAAs that develop in Osteoprotegerin (Opg) knockout (KO) mice. In the CaCl2-induced AAA model, EPA attenuated the enhanced progression of AAAs in Opg-KO mice, including the increase in aortic diameter with destruction of elastic fibers in the media. Immunohistochemical analyses showed that EPA reduced the phosphorylation of transforming growth factor beta-activated kinase-1/Map3k7 (Tak-1) and c-Jun NH2-terminal kinase (JNK), as well as the expression of Matrix metalloproteinase-9 (Mmp-9) in the media of the aorta. In smooth muscle cell cultures, rh-TRAIL-induced activation of the Tak-1-JNK pathway and increase in Mmp-9 expression were inhibited by EPA. Moreover, GW9508, a specific ligand for G-protein coupled receptor (Gpr)-120/Free fatty acid receptor (Ffar)-4, mimicked the effects of EPA. The effects of EPA were abrogated by knockdown of the Gpr-120/Ffar-4 receptor gene. Our data demonstrate that the Trail-Tak-1-JNK-Mmp-9 pathway is responsible for the enhancement of AAAs in Opg-KO mice, and that EPA inhibits the Tak-1-JNK pathway by activating Gpr-120/Ffar-4, which results in the attenuation of AAA development.


Immunohistochemistry compared to cytosol assays for determination of estrogen receptor and prediction of the long-term effect of adjuvant tamoxifen.
The purpose of this study is to compare immunohistochemistry (IHC) and cytosol-based assays for determination of estrogen receptor (ER) and prediction of response to adjuvant tamoxifen treatment in postmenopausal women with early-stage invasive breast cancer. The Stockholm Breast Cancer Study Group conducted a randomized trial during 1976 through 1990 comparing adjuvant tamoxifen versus control. The patients were stratified according to tumor size and lymph node status in high-risk and low-risk groups. In this study we evaluated 683 patients with "low risk" breast cancer (size ≤30 mm, lymph node-negative) for whom ER status had been determined by both the cytosol assays and IHC at one pathology laboratory. The median follow-up was 17 years. Six hundred eighty-three patients had tumors with ER determined by both methods, 536 (78.5%) were ER-positive by cytosol assays using the cutoff level at ≥0.05 fmol/μg DNA and 539 patients were ER-positive (79%) by IHC using the cutoff level at ≥10% cell stained. Thirty-nine tumors (5.7%) were ER-positive by cytosol but not by IHC, whereas the opposite pattern was found for 42 cases (6.1%). Only seven tumors had stained cells between 0 and 9% by IHC. The concordance between IHC and cytosol assays was high (88%). The kappa statistic was 0.65, 95% CI 0.58-0.72. Among patients classified as ER-negative no therapeutic benefit from tamoxifen was observed. Among patients with ER-expressing tumors, tamoxifen resulted in significantly better recurrence-free survival irrespective of the method (IHC: HR, 0.53, P < 0.001; cytosol: HR, 0.53, P < 0.001). The effect on overall survival was not statistically significant probably due to the limited sample size. Both IHC and cytosol assay accurately predict long-term response to adjuvant tamoxifen.


Attitudes of Professional Caregivers and Family Members Regarding the Use of Monitoring Devices to Improve Assessments of Pain and Discomfort During Continuous Sedation Until Death.
Assessing consciousness and pain during continuous sedation until death (CSD) by behavior-based observational scales alone has recently been put into question. Instead, the use of monitoring technology has been suggested to make more objective and reliable assessments. Insights into which factors influence attitudes toward using these monitoring devices in a context of CSD is a first step in formulating recommendations to inform future practice. The aim of this study was to find out what influences professional caregivers' and family members' (FMs) attitudes regarding the use of monitors during CSD. We conducted semistructured face-to-face interviews with 20 professional caregivers and 15 FMs, who cared for a patient or had an FM, respectively, who took part in a study using monitoring devices. Recruitment took place in an academic hospital, a locoregional hospital, and two nursing homes, all located in Belgium. Two researchers independently analyzed the data, using grounded theory to inductively develop a model that represents the emerging attitude toward use of monitors during CSD. Our model shows that the emerging attitudes toward using monitors during CSD is determined by view on CSD, desire for peace of mind, emotional valence attached to using monitors, and the realization that the sole use of behavior-based observational measures could be unreliable in a CSD context. We identified several facilitators and barriers to inform future implementation strategies. Most participants had no objections, and all participants found the use of monitoring devices during CSD feasible and acceptable. We identified a number of facilitators and barriers and suggested that being aware that care can be improved, good communication, shared decision making, and continuing professional education can overcome the identified barriers. We suggest future research would focus on developing implementation strategies and guidelines for introducing objective monitoring devices in diverse palliative care settings.


Trans fatty acids content and fatty acid profiles in the selected food products from Korea between 2005 and 2008.
Since a high intake of trans fatty acids (TFA) has been associated with the increased risk of developing cardiovascular disease, food regulation worldwide has been amended with respect to nutrition labeling and health claims on TFA. In the present study, the TFA levels of Korean food products were investigated to assess the regulation effect of TFA labeling. Same Korean food products within 7 different categories were purchased in years 2005 and 2008, and the contents of TFA and lipid and fatty acid composition were investigated. Lipid and TFA contents decreased in all food products manufactured in 2008. TFA levels were 0.01 to 6.88 g/100 g food in 2005, but the levels remarkably decreased to nondetectable level or up to 0.5 g TFA/100 g food in 2008. The foods from 2005 contained a various level of TFA ranging 0.6% to 44.6% of total fatty acids; however, the TFA level significantly decreased in most foods up to 3.8% from year 2008. For TFAs, trans C18:1 levels were greater than trans isomers of C18:2, and the levels in 2005 were significantly reduced in 2008 (P < 0.05). TFA levels at the sn-2 position were up to 48.3% of total fatty acids in 2005, but the level considerably decreased up to 5.4% in 2008. The considerably decreased content of TFA in 2008 suggested that food manufacturers recognized the adverse effect of TFA on human health and followed the compulsory trans fat labeling rule by Korean Food and Drug Administration (KFDA), which started December 2007.


Historical change of suicide seasonality in the canton of zurich, Switzerland.
Current research is yielding an increasingly heterogeneous picture of suicide seasonalities: They seem to depend on methods and, moreover, they seem to have smoothed in recent decades. This work examines the latter issue by comparing suicide seasonalities in the canton of Zurich, Switzerland, in the 16 th -18 th centuries, 1901-1920 and 1969-94. The results indicate shifts of peaks and lows on suicide seasonalities over the centuries, with a smoothing of seasonalities toward the 21 th century. The recent period does not show any suicide seasonality at all. The canton of Zurich seems to be ahead of the general trend found in other regions of Switzerland.


Antipsychotic-like activity of noni (Morinda citrifolia Linn.) in mice.
Noni fruit is widely consumed in tropical regions of Indonesia to the Hawaiian Islands. The noni plant has a long history of use as a medicinal plant to treat a wide variety of ailments including CNS disorders. The present investigation was designed to evaluate the antipsychotic effect of noni fruits (Morinda citrifolia Linn.) using mouse models of apomorphine-induced climbing behaviour and methamphetamine-induced stereotypy (licking, biting, gnawing and sniffing). In acute study, the methanolic extract of Morinda citrifolia (MMC) at different doses 1, 3, 5, 10 g/kg was administered orally one hour prior to apomorphine (5 mg/kg, i.p) and methamphetamine (5 mg/kg, i.p) injection respectively in Swiss albino mice. In chronic studies, (TAHITIAN NONI® Juice, TNJ) was made available freely in daily drinking water at 30, 50 and 100% v/v for 7 days; 30 and 50% v/v for 21 days respectively. On the test day, an equivalent average daily divided dose of TNJ was administered by oral gavage one hour prior to apomorphine treatment. Immediately after apomorphine/ methamphetamine administration, the animals were placed in the cylindrical metal cages and observed for climbing behaviour/ stereotypy and climbing time. The acute treatment of MMC (1, 3, 5, 10 g/kg, p.o) significantly decreased the apomorphine-induced cage climbing behaviour and climbing time in mice in a dose dependent manner. The MMC also significantly inhibited methamphetamine-induced stereotypy behaviour and climbing time in mice dose-dependently. The 7 and 21 days treatment of TNJ in drinking water at 50 and 100%v/v significantly alleviated the apomorphine-induced climbing behaviour and climbing time in mice. The present study results demonstrated the antidopaminergic effect of Morinda citrifolia Linn. in mice, suggesting that noni has antipsychotic-like activity which can be utilized in the treatment of psychiatric disorders. However further studies are warranted to identify the active principles responsible for the antipsychotic activity of noni.


ACOG Committee Opinion Number 540: Risk of venous thromboembolism among users of drospirenone-containing oral contraceptive pills.
Although the risk of venous thromboembolism is increased among oral contraceptive users compared with nonusers who are not pregnant and not taking hormones, and some data have suggested that use of drospirenone-containing pills has a higher risk of venous thromboembolism, this risk is still very low and is much lower than the risk of venous thromboembolism during pregnancy and the immediate postpartum period. When prescribing any oral contraceptive, clinicians should consider a woman's risk factors for venous thromboembolism and refer to the U.S. Medical Eligibility Criteria for Contraceptive Use issued by the Centers for Disease Control and Prevention. Patient education materials, including product labeling, should place information regarding oral contraceptive use and venous thromboembolism risks in context by also providing information about overall venous thromboembolism risks and venous thromboembolism risks during pregnancy and the postpartum period. Decisions regarding choice of oral contraceptive should be left to clinicians and their patients, taking into account the possible minimally increased risk of venous thromboembolism, patient preference, and available alternatives.


Sequence-specific targeting of dosage compensation in Drosophila favors an active chromatin context.
The Drosophila MSL complex mediates dosage compensation by increasing transcription of the single X chromosome in males approximately two-fold. This is accomplished through recognition of the X chromosome and subsequent acetylation of histone H4K16 on X-linked genes. Initial binding to the X is thought to occur at "entry sites" that contain a consensus sequence motif ("MSL recognition element" or MRE). However, this motif is only ∼2 fold enriched on X, and only a fraction of the motifs on X are initially targeted. Here we ask whether chromatin context could distinguish between utilized and non-utilized copies of the motif, by comparing their relative enrichment for histone modifications and chromosomal proteins mapped in the modENCODE project. Through a comparative analysis of the chromatin features in male S2 cells (which contain MSL complex) and female Kc cells (which lack the complex), we find that the presence of active chromatin modifications, together with an elevated local GC content in the surrounding sequences, has strong predictive value for functional MSL entry sites, independent of MSL binding. We tested these sites for function in Kc cells by RNAi knockdown of Sxl, resulting in induction of MSL complex. We show that ectopic MSL expression in Kc cells leads to H4K16 acetylation around these sites and a relative increase in X chromosome transcription. Collectively, our results support a model in which a pre-existing active chromatin environment, coincident with H3K36me3, contributes to MSL entry site selection. The consequences of MSL targeting of the male X chromosome include increase in nucleosome lability, enrichment for H4K16 acetylation and JIL-1 kinase, and depletion of linker histone H1 on active X-linked genes. Our analysis can serve as a model for identifying chromatin and local sequence features that may contribute to selection of functional protein binding sites in the genome.


An antibiotic-resistance conferring mutation in a neisserial porin: Structure, ion flux, and ampicillin binding.
Gram-negative bacteria cause the majority of highly drug-resistant bacterial infections. To cross the outer membrane of the complex Gram-negative cell envelope, antibiotics permeate through porins, trimeric channel proteins that enable the exchange of small polar molecules. Mutations in porins contribute to the development of drug-resistant phenotypes. In this work, we show that a single point mutation in the porin PorB from Neisseria meningitidis, the causative agent of bacterial meningitis, can strongly affect the binding and permeation of beta-lactam antibiotics. Using X-ray crystallography, high-resolution electrophysiology, atomistic biomolecular simulation, and liposome swelling experiments, we demonstrate differences in drug binding affinity, ion selectivity and drug permeability of PorB. Our work further reveals distinct interactions between the transversal electric field in the porin eyelet and the zwitterionic drugs, which manifest themselves under applied electric fields in electrophysiology and are altered by the mutation. These observations may apply more broadly to drug-porin interactions in other channels. Our results improve the molecular understanding of porin-based drug-resistance in Gram-negative bacteria.


AIDS retrovirus (ARV-2) clone replicates in transfected human and animal fibroblasts.
A molecular clone of the AIDS-associated retrovirus (ARV-2) was transfected into human T lymphocyte and monocyte cell lines as well as mouse, mink, monkey, and human fibroblast lines. A replicating virus with cytopathic and biologic properties of ARV-2 was recovered from all the cell lines. The animal and human fibroblast cells are resistant to direct infection by ARV, and in these experiments virus production in the fibroblast lines, especially mouse, was reduced compared to human lymphocytes. However, human fibroblasts were more permissive to virus expression than mouse cells. These results show that, whereas the primary block to ARV infection in certain cells may occur at the cell surface, intracellular mechanisms can also participate in controlling virus replication. The results have relevance to vaccine development and encourage further work with modified molecular clones to examine regions of the ARV genome necessary for cytopathology and replication.


1,2-Dichlorobenzene-induced lipid peroxidation in male Fischer 344 rats is Kupffer cell dependent.
1,2-Dichlorobenzene (1,2-DCB) is a potent hepatotoxicant in male Fischer 344 (F344) rats and previous studies have suggested that reactive oxygen species may play a role in the development of hepatotoxicity. Since reactive oxygen species can damage lipid membranes, this study was conducted to determine the extent of lipid peroxidation after administration of 1,2-DCB by immuno-histochemical analysis of 4-hydroxynonenal (4-HNE) protein adduct formation in liver and conjugated diene formation in liver and serum. The contribution of Kupffer cells to the lipid peroxidation was also investigated. Male F344 rats were administered 1,2-DCB (3.6 mmol/kg i.p. in corn oil) and killed at selected times between 3 and 48 h. Time course studies revealed the greatest abundance of 4-HNE protein adducts in the centrilobular regions of the liver 24 h after 1,2-DCB administration, with much lower levels at 16 h. Adducts were present in necrotic and vacuolized centrilobular hepatocytes of 1,2-DCB treated rats but not in livers of controls. Further, conjugated dienes were significantly increased in liver and serum 16 and 24 h after 1,2-DCB administration, peaking at 24 h. These data correlated with hepatocellular injury, determined by serum alanine aminotransferase activity and histopathological evaluation, which was markedly elevated within 16 h and peaked at 24 h. When rats were pretreated with gadolinium chloride (GdCl3; 10 mg/kg i.v. 24 h prior to 1,2-DCB), an inhibitor of Kupffer cells, hepatotoxicity was decreased by 89 and 86%, at 16 and 24 h, respectively. Conjugated diene concentrations were decreased to control values at these times after 1,2-DCB administration. Moreover, no 4-HNE protein adducts were detected in livers of 1,2-DCB-treated rats pretreated with GdCl3. Finally, Kupffer cells isolated from 1,2-DCB-treated rats produced significantly more superoxide anion than Kupffer cells isolated from vehicle controls. These data, along with previous findings, suggest that lipid peroxidation associated with 1,2-DCB is mediated in part by Kupffer cell-derived reactive oxygen species.


Improvement in coronary anastomosis with cardiac surgery simulation.
Cardiac surgery trainees might benefit from simulation training in coronary anastomosis and more advanced procedures. We evaluated distributed practice using a portable task station and experience on a beating-heart model in training coronary anastomosis. Eight cardiothoracic surgery residents performed 2 end-to-side anastomoses with the task station, followed by 2 end-to-side anastomoses to the left anterior descending artery by using the beating-heart model at 70 beats/min. Residents took home the task station, recording practice times. At 1 week, residents performed 2 anastomoses on the task station and 2 anastomoses on the beating-heart model. Performances of the anastomosis were timed and reviewed. Times to completion for anastomosis on the task station decreased 20% after 1 week of practice (351 +/- 111 to 281 +/- 53 seconds, P = .07), with 2 residents showing no improvement. Times to completion for beating-heart anastomosis decreased 15% at 1 week (426 +/- 115 to 362 +/- 94 seconds, P = .03), with 2 residents demonstrating no improvement. Home practice time (90-540 minutes) did not correlate with the degree of improvement. Performance rating scores showed an improvement in all components. Eighty-eight percent of residents agreed that the task station is a good method of training, and 100% agreed that the beating-heart model is a good method of training. In general, distributed practice with the task station resulted in improvement in the ability to perform an anastomosis, as assessed by times to completion and performance ratings, not only with the task station but also with the beating-heart model. Not all residents improved, which is consistent with a "ceiling effect" with the simulator and a "plateau effect" with the trainee. Simulation can be useful in preparing residents for coronary anastomosis and can provide an opportunity to identify the need and methods for remediation.


GFP-based evaluation system of recombinant expression through the secretory pathway in insect cells and its application to the extracellular domains of class C GPCRs.
Applications of the GFP-fusion technique have greatly facilitated evaluations of the amounts and qualities of sample proteins used for structural analyses. In this study, we applied the GFP-based sample evaluation to secreted protein expression by insect cells. We verified that a GFP variant, GFPuv, retains proper folding and monodispersity within all expression spaces in Sf9 cells, such as the cytosol, organelles, and even the extracellular space after secretion, and thus can serve as a proper folding reporter for recombinant proteins. We then applied the GFPuv-based system to the extracellular domains of class C G-protein coupled receptors (GPCRs) and examined their localization, folding, and oligomerization upon insect cell expression. The extracellular domain of metabotropic glutamate receptor 1 (mGluR1) exhibited good secreted expression by Sf9 cells, and the secreted proteins formed dimer with a monodisperse hydrodynamic state favorable for crystallization, consistent with the results from previous successful structural analyses. In contrast, the extracellular domains of sweet/umami taste receptors (T1R) almost completely remained in the cell. Notably, the T1R and mGluR1 subfractions that remained in the cellular space showed polydisperse hydrodynamic states with large aggregated fractions, without forming dimers. These results indicated that the proper folding and oligomerization of the extracellular domains of the class C GPCR are achieved through the secretory pathway.


Curiosity at Gale crater, Mars: characterization and analysis of the Rocknest sand shadow.
The Rocknest aeolian deposit is similar to aeolian features analyzed by the Mars Exploration Rovers (MERs) Spirit and Opportunity. The fraction of sand <150 micrometers in size contains ~55% crystalline material consistent with a basaltic heritage and ~45% x-ray amorphous material. The amorphous component of Rocknest is iron-rich and silicon-poor and is the host of the volatiles (water, oxygen, sulfur dioxide, carbon dioxide, and chlorine) detected by the Sample Analysis at Mars instrument and of the fine-grained nanophase oxide component first described from basaltic soils analyzed by MERs. The similarity between soils and aeolian materials analyzed at Gusev Crater, Meridiani Planum, and Gale Crater implies locally sourced, globally similar basaltic materials or globally and regionally sourced basaltic components deposited locally at all three locations.


On the implications of aerosol liquid water and phase separation for organic aerosol mass.
Organic compounds and liquid water are major aerosol constituents in the southeast United States (SE US). Water associated with inorganic constituents (inorganic water) can contribute to the partitioning medium for organic aerosol when relative humidities or organic matter to organic carbon (OM/OC) ratios are high such that separation relative humidities (SRH) are below the ambient relative humidity (RH). As OM/OC ratios in the SE US are often between 1.8 and 2.2, organic aerosol experiences both mixing with inorganic water and separation from it. Regional chemical transport model simulations including inorganic water (but excluding water uptake by organic compounds) in the partitioning medium for secondary organic aerosol (SOA) when RH > SRH led to increased SOA concentrations,· particularly at night. Water uptake to the organic phase resulted in even greater SOA concentrations as a result of a positive feedback in which water uptake increased SOA, which further increased aerosol water and organic aerosol. Aerosol properties· such as the OM/OC and hygroscopicity parameter (κorg), were captured well by the model compared with measurements during the Southern Oxidant and Aerosol Study (SOAS) 2013. Organic nitrates from monoterpene oxidation were predicted to be the least water-soluble semivolatile species in the model, but most biogenically derived semivolatile species in the Community Multiscale Air Quality (CMAQ) model were highly water soluble and expected to contribute to water-soluble organic carbon (WSOC). Organic aerosol and SOA precursors were abundant at night, but additional improvements in daytime organic aerosol are needed to close the model-measurement gap. When taking into account deviations from ideality, including both inorganic (when RH > SRH) and organic water in the organic partitioning medium reduced the mean bias in SOA for routine monitoring networks and improved model performance compared to observations from SOAS. Property updates from this work will be released in CMAQ v5.2.


Human social motor solutions for human-machine interaction in dynamical task contexts.
Multiagent activity is commonplace in everyday life and can improve the behavioral efficiency of task performance and learning. Thus, augmenting social contexts with the use of interactive virtual and robotic agents is of great interest across health, sport, and industry domains. However, the effectiveness of human-machine interaction (HMI) to effectively train humans for future social encounters depends on the ability of artificial agents to respond to human coactors in a natural, human-like manner. One way to achieve effective HMI is by developing dynamical models utilizing dynamical motor primitives (DMPs) of human multiagent coordination that not only capture the behavioral dynamics of successful human performance but also, provide a tractable control architecture for computerized agents. Previous research has demonstrated how DMPs can successfully capture human-like dynamics of simple nonsocial, single-actor movements. However, it is unclear whether DMPs can be used to model more complex multiagent task scenarios. This study tested this human-centered approach to HMI using a complex dyadic shepherding task, in which pairs of coacting agents had to work together to corral and contain small herds of virtual sheep. Human-human and human-artificial agent dyads were tested across two different task contexts. The results revealed (i) that the performance of human-human dyads was equivalent to those composed of a human and the artificial agent and (ii) that, using a "Turing-like" methodology, most participants in the HMI condition were unaware that they were working alongside an artificial agent, further validating the isomorphism of human and artificial agent behavior.


Mass Media Use to Learn About COVID-19 and the Non-intention to Be Vaccinated Against COVID-19 in Latin America and Caribbean Countries.
The Latin American and Caribbean (LAC) region has been one of the regions most affected by the COVID-19 pandemic, with countries presenting some of the highest numbers of cases and deaths from this disease in the world. Despite this, vaccination intention is not homogeneous in the region, and no study has evaluated the influence of the mass media on vaccination intention. The objective of this study was to evaluate the association between the use of mass media to learn about COVID-19 and the non-intention of vaccination against COVID-19 in LAC countries. An analysis of secondary data from a Massachusetts Institute of Technology (MIT) survey was conducted in collaboration with Facebook on people's beliefs, behaviors, and norms regarding COVID-19. Crude and adjusted prevalence ratios (aPR) with their respective 95% confidence intervals (95%CI) were calculated to evaluate the association between the use of mass media and non-vaccination intention using generalized linear models of the Poisson family with logarithmic link. A total of 350,322 Facebook users over the age of 18 from LAC countries were included. 50.0% were men, 28.4% were between 18 and 30 years old, 41.4% had a high school education level, 86.1% lived in the city and 34.4% reported good health condition. The prevalence of using the mass media to learn about COVID-19 was mostly through mixed media (65.8%). The non-intention of vaccination was 10.8%. A higher prevalence of not intending to be vaccinated against COVID-19 was found in those who used traditional media (aPR = 1.36; 95%CI: 1.29-1.44; p < 0.001) and digital media (aPR = 1.70; 95%CI: 1.24-2.33; p = 0.003) compared to those using mixed media. We found an association between the type of mass media used to learn about COVID-19 and the non-intention of vaccination. The use of only traditional or digital information sources were associated with a higher probability of non-intention to vaccinate compared to the use of both sources.


Perinatal prevention of bronchopulmonary dysplasia.
Bronchopulmonary dysplasia (BPD), defined as oxygen dependency for at least 28 days after birth, is a common adverse outcome of very premature birth. Affected children require frequent readmissions to hospital in the fi rst 2 years, and although lung growth and remodelling results in progressive improvement in lung function, airflow abnormalities may remain. Indeed, the most severely affected experience troublesome respiratory symptoms as adolescents and young adults. As a consequence, many potential preventative strategies have been investigated, and some have resulted in a reduction in BPD but with a negative risk/benefit ratio, for example, postnatal corticosteroids. Others therapies, namely antenatal corticosteroids and postnatal surfactant, have resulted in significant benefits to infants, including reductions in respiratory distress syndrome, necrotising enterocolitis, intraventricular haemorrhage and neonatal death, but have not impacted favourably on the incidence of BPD, perhaps due to the increased survival of very immature infants. In one major trial, it has been shown that BPD can be reduced without adverse effects by caffeine administration. Avoidance of high oxygen concentrations at resuscitation is also a promising approach to reduce BPD.


Active living in rural Appalachia: Using the rural active living assessment (RALA) tools to explore environmental barriers.
People residing in rural communities are more likely to be physically inactive and subsequently have elevated risks for chronic disease. Recent evidence has shown this could stem from environmental barriers, inadequate programming and policies directed at the promotion of physical activity (PA) in rural settings. The objective of this research was to assess active living features in rural towns and townships (n = 16) across seven counties in northwestern North Carolina (NC). The study utilized the Town-Wide and Street Segment components of the Rural Active Living Assessment (RALA) as well as the 2014 American Community Survey results. The assessments were conducted in the summer of 2016 in the rural Appalachia region of NC. Using the RALA town-wide assessment scoring system (0 - 100), the range of scores was 18-84, with the mean being 50.06. Three towns had no sidewalks, nine towns had sidewalks on only one side of the main streets, and four had sidewalks on both sides of the main streets. One town was rated as highly walkable, seven towns as moderately walkable, five towns as moderately unwalkable, and three towns as highly unwalkable. The rural Appalachia region of NC offers unique topographic, geographic and environmental barriers to PA. However, our findings indicate many rural towns offer common PA amenities. Future research should utilize qualitative methods and a community-based participatory research approach to more fully understand the challenges with increasing PA in the rural and often isolated Appalachia communities.


On-chip quasi-digital optical switch using silicon microring resonator-coupled Mach-Zehnder interferometer.
In this work, we demonstrate thermo-optical quasi-digital optical switch (q-DOS) using silicon microring resonator-coupled Mach-Zehnder interferometer. The optical transmission spectra show box-like response with 1-dB and 3-dB bandwidths of ~1.3 nm and ~1.6 nm, respectively. Such broadband flat-top optical response improves the tolerance to the light source wavelength fluctuation of ± 6 Å and temperature variation of ± 6 °C. Dynamic characterizations show the device with switching power of ~37 mW, switching time of ~7 μs, and on/off ratio of > 30 dB. For performance comparison, we also demonstrate a carrier injection-based electro-optical q-DOS by integrating lateral P-i-N junction with the microring resonator, which significantly reduces power consumption to ~12 mW and switching time to ~0.7 ns only.


Water soluble poly(1-vinyl-1,2,4-triazole) as novel dielectric layer for organic field effect transistors.
Water soluble poly(1-vinyl-1,2,4-triazole) (PVT) as a novel dielectric layer for organic field effect transistor is studied. Dielectric spectroscopy characterization reveals it has low leakage current and rather high breakdown voltage. Both n-channel and p-channel organic field effect transistors are fabricated using pentacene and fullerene as active layers. Both devices show device performances with lack of hysteresis, very low threshold voltages and high on/off ratios. Excellent film formation property is utilized to make AlO x and thin PVT bilayer in order to decrease the operating voltage of the devices. All solution processed ambipolar device is fabricated with simple spin coating steps using poly(2-methoxy-5-(2-ethyl-hexyloxy)-1,4-phenylenevinylene) (MEH-PPV) end capped with polyhedral oligomeric silsesquioxanes (POSS) as active layer. Our investigations show that PVT can be a very promising dielectric for organic field effect transistors.


Characterization of three RXR genes that mediate the action of 9-cis retinoic acid.
An understanding of the differences and similarities of the retinoid X receptor (RXR) and retinoic acid receptor (RAR) systems requires knowledge of the diversity of their family members, their patterns of expression, and their pharmacological response to ligands. In this paper we report the isolation of a family of mouse RXR genes encoding three distinct receptors (RXR alpha, beta, and gamma). They are closely related to each other in their DNA- and ligand-binding domains but are quite divergent from the RAR subfamily in both structure and ligand specificity. Recently, we demonstrated that all-trans retinoic acid (RA) serves as a "pro-hormone" to the isomer 9-cis RA, which is a high-affinity ligand for the human RXR alpha. We extend those findings to show that 9-cis RA is also "retinoid X" for mouse RXR alpha, beta, and gamma. Trans-activation analyses show that although all three RXRs respond to a variety of endogenous retinoids, 9-cis RA is their most potent ligand and is up to 40-fold more active than all-trans RA. Northern blot and in situ hybridization analyses define a broad spectrum of expression for the RXRs, which display unique patterns and only partially overlap themselves and the RARs. This study suggests that the RXR family plays critical roles in diverse aspects of development, from embryo implantation to organogenesis and central nervous system differentiation, as well as in adult physiology.


Hypotension in severe dimethoate self-poisoning.
Acute self-poisoning with the organophosphorus (OP) pesticide dimethoate has a human case fatality three-fold higher than poisoning with chlorpyrifos despite similar animal toxicity. The typical clinical presentation of severe dimethoate poisoning is quite distinct from that of chlorpyrifos and other OP pesticides: many patients present with hypotension that progresses to shock and death within 12-48 h post-ingestion. The pathophysiology of this syndrome is not clear. We present here three patients with proven severe dimethoate poisoning. Clinically, all had inappropriate peripheral vasodilatation and profound hypotension on presentation, which progressed despite treatment with atropine, i.v. fluids, pralidoxime chloride, and inotropes. All died 2.5-32 h post-admission. Continuous cardiac monitoring and quantification of troponin T provided little evidence for a primary cardiotoxic effect of dimethoate. Severe dimethoate self-poisoning causes a syndrome characterized by marked hypotension with progression to distributive shock and death despite standard treatments. A lack of cardiotoxicity until just before death suggests that the mechanism is of OP-induced low systemic vascular resistance (SVR). Further invasive studies of cardiac function and SVR, and post-mortem histology, are required to better describe this syndrome and to establish the role of vasopressors and high-dose atropine in therapy.


Violent video games, externalizing behavior, and prosocial behavior: A five-year longitudinal study during adolescence.
Decades of research on the effects of media violence have examined associations between viewing aggressive material in the media and aggression and prosocial behavior. However, the existing longitudinal studies have tended to exclusively examine aggression and prosocial behavior as outcomes, with a limited range of potential mediators. The current study examines associations between playing violent video games and externalizing and prosocial behavior over a 5-year period across adolescence. Additionally, the study examines potential mediators of these associations, including empathic concern, benevolence, and self-regulation. Participants included 488 adolescents (Mage of child at Wave 1 = 13.83, SD = 0.98) and their parents, who completed self- and parental measures at three different time points, each 2 years apart. Results revealed that early exposure to video game violence was indirectly associated with lower levels of prosocial behavior as mediated by lower levels of benevolence. Additionally, early video game violence play was associated with higher levels of externalizing behavior at the cross-sectional level, but not 5 years later. Implications of results for adolescents and parents are discussed. (PsycINFO Database Record


Concurrent cisplatin and 5-fluorouracil chemotherapy and radiation therapy for advanced-stage squamous carcinoma of the vulva.
A phase II trial of concurrent cisplatin and 5-fluorouracil (5-FU) chemotherapy and radiation therapy (CT + RT) was conducted for the primary treatment of 12 patients with retrospective surgical FIGO stages III-IV squamous carcinoma of the vulva. Eight patients were stage III and four were stage IV. Chemotherapy was used as a radiation sensitizer and it was administered in two 5-day cycles 28 days apart. Cisplatin, 50 mg/m2/day iv on Days 1 and 2 or 100 mg/m2 on Day 1 or 2, plus continuous-infusion 5-FU, 1000 mg/m2/day for 4-5 days commencing on Days 1 and 28 of external-beam radiation therapy, are given. The pelvic radiation to a dose of 4400-5400 cGy is administered AP and PA to treat the primary tumor, the groin nodes, and the iliac vessels to the level below the common iliac nodes. Complete tumor responses were seen in 8 of 12 (67%) patients. Responses were observed in 6 of 8 (75%) stage III patients and 2 of 4 (50%) stage IV patients. Partial response were observed in 3 patients, and 1 patient had persistent disease. At the completion of concurrent chemoradiation therapy, radical vulvectomy or excision was used in 3 patients and posterior exenteration in 1. With a median follow-up of 37 months (range, 7-60 months), 10 patients are alive and free of disease, and 2 patients died at 12 and 15 months. There were no treatment-related deaths and no grade 4 toxicity. The morbidity included moist desquamation of the vulva in all patients, with grade 2 toxicity in 10 and grade 3 in 2. One patient had a deep venous thrombosis that responded to anticoagulation therapy. These data support the use of concurrent cisplatin and 5-FU chemotherapy and radiation therapy as an alternative to primary radical surgery to treat advanced-stage squamous carcinoma of the vulva.


Simultaneous Spinal and Intracranial Chronic Subdural Hematoma Cured by Craniotomy and Laminectomy: A Video Case Report.
Simultaneous spinal and intracranial chronic subdural hematoma (CSDH) is a rare entity. A 67-year-old man visited our hospital due to headache after diving into a river 2 weeks before. Non-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) revealed bilateral intracranial CSDH. The bilateral CSDH was evacuated and his symptoms improved. Three days after craniotomy, he complained of sensory disturbance on his buttocks. Lumbar MRI showed a space-occupying lesion behind the thecal sac at L5. CT with myelography showed a subdural mass lesion; there was no communication with the subarachnoid space. Fourteen days after craniotomy, L5 laminectomy was performed and the dura mater was incised carefully. The video shows that a liquid hematoma similar to the intracranial CSDH flowed out, followed by cerebrospinal fluid. His symptoms improved after the operation and the hematoma did not recur. This is a rare condition of spinal CSDH demonstrated by neuroimaging and intraoperative video.


Gastric Residual to Predict Necrotizing Enterocolitis in Preterm Piglets As Models for Infants.
Necrotizing enterocolitis (NEC) is a serious intestinal inflammatory disease in preterm infants. High volume of gastric residual (GR) after oral feedings is often used as a predictor of NEC, but evidence is limited. Using NEC-sensitive preterm piglets as models, we hypothesized that GR mass and related plasma biomarkers predict early onset of NEC. In total, 258 newborn preterm piglets were fed bovine milk-based formulas for 5 days. At euthanasia, the stomach, small intestine, and colon were evaluated for NEC lesions. Mass, acidity, gastrin, and bile acid levels were determined for GR content, together with gastrin, glucagon-like peptide 2 (GLP-2), and gastric inhibitory polypeptide (GIP) levels in plasma. In total, 48% of piglets had NEC lesions in the small intestine and/or colon. These piglets had higher GR mass (+32%, P < 0.001) and lower gastric bile acid concentrations (-22%, P < 0.05) than piglets without NEC lesions. The positive and negative predictive values for these markers were 34%-61%. Gastric acidity, gastrin, GLP-2, and GIP levels were similar for piglets with and without NEC lesions. Elevated GR mass correlates positively with NEC lesions but may be a poor predictor of NEC, even when combined with other biomarkers. More knowledge about gastric emptying and gut transit in preterm neonates is required to understand how GR volume and composition relate to morbidities, such as NEC, in preterm neonates.


Teens and indoor tanning: a cancer prevention opportunity for pediatricians.
In October 2011, California became the first US state to ban indoor tanning for minors under age 18 years. Vermont followed in May 2012. Increasingly, scientific evidence shows that artificial tanning raises the risk of skin cancer, including melanoma, a common cancer in adolescents and young adults and the type most likely to result in death. The World Health Organization, the American Academy of Pediatrics, the American Academy of Dermatology, the American Medical Association, and other organizations strongly recommend legislation to ban minors under age 18 from indoor tanning. Several nations have banned teen tanning. Yet, tanning in salons is still a prevalent practice in the United States, especially among teen girls, where rates for the oldest teens approach 40%. There is no federal legislation to restrict minors from salon tanning. More than 60% of states have some kind of legislation regarding minors' use of tanning salons, but only California and Vermont have passed complete bans of indoor tanning for minors. The Indoor Tanning Association, an industry advocacy group, has vigorously opposed legislative efforts. Pediatricians can play key roles in counseling families and with legislative efforts. In this update, we review the prevalence of salon tanning, association with skin cancer risk, tanning addiction, the roles of the federal and state governments in regulation and legislation, and responses to arguments created by industry to oppose legislation. Preventing exposure to artificial tanning may save lives, including young lives, and is a key cancer prevention opportunity for pediatricians.


Renoprotective effect of edaravone in acute limb ischemia/reperfusion injury.
In this experimental study, we aimed to investigate the efficacy of edaravone on renal injury due to acute lower limb ischemia/reperfusion in a rat model. Between June 2015 and August 2015, a total of 40 male Wistar rats were used in this study. The rats were randomly divided into the sham, ischemia/reperfusion, edaravone, and solvent groups (n=10 in each). The infrarenal abdominal aorta was clamped for 120 min and was, then, reperfused for 120 min after clamp removal. Edaravone was administered intravenously 30 min before the induction of ischemia. Serum and kidney tissue samples were subjected to biochemical and histopathological analyses. Edaravone decreased the serum and tissue malondialdehyde levels in the ischemia/reperfusion group. The serum superoxide dismutase activity in the edaravone group was significantly higher than the ischemia/reperfusion and solvent groups. The serum nitric oxide level in the ischemia/reperfusion group was numerically higher than the sham group. The serum nitric oxide level was decreased by edaravone. The serum nitric oxide level was lower in the edaravone group than the solvent group. The tissue nitric oxide level was significantly higher in the ischemia/reperfusion than the sham group. In the ischemia/ reperfusion group, the histopathological changes were improved by edaravone. Edaravone ameliorated renal injury caused by lower-limb ischemia/reperfusion. Therefore, it can be used to ameliorate acute ischemia/reperfusion injury during aortic and peripheral vascular surgery.


A plasminogen-activating protease specifically controls the development of primary pneumonic plague.
Primary pneumonic plague is transmitted easily, progresses rapidly, and causes high mortality, but the mechanisms by which Yersinia pestis overwhelms the lungs are largely unknown. We show that the plasminogen activator Pla is essential for Y. pestis to cause primary pneumonic plague but is less important for dissemination during pneumonic plague than during bubonic plague. Experiments manipulating its temporal expression showed that Pla allows Y. pestis to replicate rapidly in the airways, causing a lethal fulminant pneumonia; if unexpressed, inflammation is aborted, and lung repair is activated. Inhibition of Pla expression prolonged the survival of animals with the disease, offering a therapeutic option to extend the period during which antibiotics are effective.


Somatic, hematologic phenotype, long-term outcome, and effect of hematopoietic stem cell transplantation. An analysis of 97 Fanconi anemia patients from the Italian national database on behalf of the Marrow Failure Study Group of the AIEOP (Italian Association of Pediatric Hematology-Oncology).
We analyzed 97 Fanconi anemia patients from a clinic/biological database for genotype, somatic, and hematologic phenotype, adverse hematological events, solid tumors, and treatment. Seventy-two patients belonged to complementation group A. Eighty percent of patients presented with mild/moderate somatic phenotype and most with cytopenia. No correlation was seen between somatic/hematologic phenotype and number of missense mutations of FANCA alleles. Over follow-up, 33% of patients improved or maintained mild/moderate cytopenia or normal blood count, whereas remaining worsened cytopenia. Eleven patients developed a hematological adverse event (MDS, AML, pathological cytogenetics) and three developed solid tumors. 10 years cumulative risk of death of the whole cohort was 25.6% with median follow-up 5.8 years. In patients eligible to hematopoietic stem cell transplantation because of moderate cytopenia, mortality was significantly higher in subjects transplanted from matched unrelated donor over nontransplanted subjects, whereas there was no significant difference between matched sibling donor transplants and nontransplanted patients. In patients eligible to transplant because of severe cytopenia and clonal disease, mortality risk was not significantly different in transplanted from matched unrelated versus matched sibling donor versus nontransplanted subjects. The decision to transplant should rely on various elements including, type of donor, HLA matching, patient comorbidities, impairment, and clonal evolution of hematopoiesis. Am. J. Hematol. 91:666-671, 2016. © 2016 Wiley Periodicals, Inc.


CTA in acute stroke: short intensive training intervention is highly effective in improving radiologists' performance.
To determine whether focussed radiology training in reporting stroke computed tomography angiography (CTA) improved diagnostic performance of general radiology specialty trainees staffing regional on call rotas. A validated case archive (VCA) consisting of 50 hyperacute stroke CTA cases was developed for a full day course on CTA interpretation. Training days were organised ensuring all local trainees had a chance to attend. The rate of major and minor amendments by neuroradiology consultants were reviewed in 252 on-call radiology trainee reports. Before training, radiology trainees had a total discrepancy (reporting error) rate of 37%: 12% major, 25% minor. Following CTA training, the total discrepancy rate was not significantly reduced (34%) but there was a substantial reduction in major discrepancies to 4% (p=0.037; odds ratio=3.30, 95% confidence interval [CI]: 1.08 to 10.12). An intensive training course based on a hyperacute stroke VCA significantly reduced major discrepancies in stroke CTA interpretation for radiology trainees. The ability of radiology trainees to recognise large vessel occlusions and other significant findings improved.


Professionalization and its effect on health locus of control among Indian dental students.
The objectives of this study were to assess the effect of different stages of professionalization on the health locus of control of students in an Indian dental school and to describe possible factors that may influence the health locus of control among dental students. The multidimensional health locus of control (MHLC) scale was distributed to 372 undergraduate dental students at one school in India, and 325 students returned completed forms. Comparison of the mean scores for the three MHLC subscales (Internal, Chance, and Powerful Others) from first year to final year showed that the mean Internal score remained unchanged in the first and second year, but decreased in the third year and rose sharply in the final year. The mean score for the Internal subscale was consistently higher, followed by the mean scores for Powerful Others in all the years of study. No significant differences were observed between mean scores of the MHLC subscales when compared with gender, previous treatment histories, and missing appointments. Those with self-perceived oral problems were found to have a lower internal locus of control than those who did not report any. The findings of this study provided credible support for the MHLC model in assessing changing health attitudes and may provide a basis for dental educators to effect changes in the locus of control among students.


Hox gene expression in postmetamorphic juveniles of the brachiopod Terebratalia transversa.
Hox genes encode a family of homeodomain containing transcription factors that are clustered together on chromosomes of many Bilateria. Some bilaterian lineages express these genes during embryogenesis in spatial and/or temporal order according to their arrangement in the cluster, a phenomenon referred to as collinearity. Expression of Hox genes is well studied during embryonic and larval development of numerous species; however, relatively few studies focus on the comparison of pre- and postmetamorphic expression of Hox genes in animals with biphasic life cycle. Recently, the expression of Hox genes was described for embryos and larvae of Terebratalia transversa, a rhynchonelliformean brachiopod, which possesses distinct metamorphosis from planktonic larvae to sessile juveniles. During premetamorphic development, T. transversa does not exhibit spatial collinearity and several of its Hox genes are recruited for the morphogenesis of novel structures. In our study, we determined the expression of Hox genes in postmetamorphic juveniles of T. transversa in order to examine metamorphosis-related changes of expression patterns and to test whether Hox genes are expressed in the spatially collinear way in the postmetamorphic juveniles. Hox genes are expressed in a spatially non-collinear manner in juveniles, generally showing similar patterns as ones observed in competent larvae: genes labial and post1 are expressed in chaetae-related structures, sex combs reduced in the shell-forming epithelium, whereas lox5 and lox4 in dorso-posterior epidermis. After metamorphosis, expression of genes proboscipedia, hox3, deformed and antennapedia becomes restricted to, respectively, shell musculature, prospective hinge rudiments and pedicle musculature and epidermis. All developmental stages of T. transversa, including postmetamorphic juveniles, exhibit a spatial non-collinear Hox genes expression with only minor changes observed between pre- and postmetamorphic stages. Our results are concordant with morphological observation that metamorphosis in rhynchonelliformean brachiopods, despite being rapid, is rather gradual. The most drastic changes in Hox gene expression patterns observed during metamorphosis could be explained by the inversion of the mantle lobe, which relocates some of the more posterior larval structures into the anterior edge of the juveniles. Co-option of Hox genes for the morphogenesis of novel structures is even more pronounced in postmetamorphic brachiopods when compared to larvae.


Optic Nerve Hypoplasia: A Retrospective Analysis of Clinical Presentation and Disease Severity.
Through the establishment of relationships between optic nerve hypoplasia (ONH), optical coherence tomography (OCT) spectralis retinal nerve fiber layer (RNFL) thickness results and clinical sequelae, this study aims to identify long-term outcomes for individuals with ONH. A retrospective review of pediatric ophthalmology patients at Children's Hospital of Omaha from January 2000 to October 2018 was performed. All patients with ONH evaluated with Heidelberg Engineering's OCT Spectralis were identified. Patient records were investigated for visual acuity, presence of nystagmus, strabismus, and endocrinopathies. Statistical analysis with linear regression models, random intercepts models, and odds ratios were used to define relationships between RNFL thickness at the optic nerve head, nystagmus, strabismus, and endocrine dysfunction. There exists a strong trend of worsening visual acuity as RNFL thickness at the optic nerve head decreases in all scanned regions. This is strongest at the temporal-superior (p=0.009) and nasal-inferior (p=0.006) regions in patients with bilateral ONH. There is insufficient evidence of a difference in prevalence of nystagmus or strabismus between subjects with unilateral or bilateral ONH. Endocrinopathy is present in 21.6% of the subjects, with no statistical difference in the type of endocrinopathy or laterality of ONH. Trends established indicate that best-corrected visual acuity is related to RNFL thickness at the optic nerve head. Odds ratios for the prevalence of nystagmus also point to RNFL thickness as a contributing factor. These trends may have the potential to characterize ONH severity by objective measurement of clinical outcomes and RNFL thickness at the optic nerve head.


Trends in cardiovascular risk factor and disease prevalence in patients undergoing non-cardiac surgery.
Cardiovascular risk factors are prevalent in the population undergoing non-cardiac surgery. Changes in perioperative cardiovascular risk factor profiles over time are unknown. The objective of this study was to evaluate national trends in cardiovascular risk factors and atherosclerotic cardiovascular disease (ASCVD) among patients undergoing non-cardiac surgery. Adults aged ≥45 years old who underwent non-cardiac surgery were identified using the US National Inpatient Sample from 2004 to 2013. The prevalence of traditional cardiovascular risk factors (hypertension, dyslipidaemia, diabetes mellitus, obesity and chronic kidney disease) and ASCVD (coronary artery disease, peripheral artery disease and prior stroke] were evaluated over time. A total of 10 581 621 hospitalisations for major non-cardiac surgery were identified. Between 2008 and 2013, ≥2 cardiovascular risk factors and ASCVD were present in 44.5% and 24.3% of cases, respectively. Over time, the prevalence of multiple (≥2) cardiovascular risk factors increased from 40.5% in 2008-2009 to 48.2% in 2012-2013, P<0.001. The proportion of patients with coronary artery disease (17.2% in 2004-2005 vs 18.2% in 2012-2013, P<0.001), peripheral artery disease (6.3% in 2004-2005 vs 7.4% in 2012-2013, P<0.001) and prior stroke (3.5% in 2008-2009 vs 4.7% 2012-2013, P<0.001) also increased over time. The proportion of patients with a modified Revised Cardiac Risk Index score ≥3 increased from 6.6% in 2008-2009 to 7.7% in 2012-2013 (P<0.001). Among patients undergoing major non-cardiac surgery, the burden of cardiovascular risk factors and the prevalence of ASCVD increased over time. Adverse trends in risk profiles require continued attention to improve perioperative cardiovascular outcomes.


Enabling Routine MHC-II-Associated Peptide Proteomics for Risk Assessment of Drug-Induced Immunogenicity.
Major histocompatibility complex-II (MHC-II)-Associated Peptide Proteomics (MAPPs) is a mass spectrometry-based approach to identify and relatively quantitate naturally processed and presented MHC-II-associated peptides that can potentially activate T cells and contribute to the immunogenicity of a drug. Acceptance of the MAPPs technology as an appropriate preclinical (and potentially clinical) immunogenicity risk assessment tool depends not only on its technical stability and robustness but also on the ability to compare results across experiments and donors. To this end, we developed a specialized MAPPs data processing pipeline, dataMAPPs, which presents complex mass spectrometric data sets in the form of heat maps (heatMAPPs), enabling rapid and convenient comparison between conditions and donors. A customized normalization procedure based on identified endogenous peptides standardizes signal intensities within and between donors and enables cross-experimental comparison. We evaluated the technical reproducibility of the MAPPs platform using tool compounds with respect to the most prominent experimental factors and found that the systematic biological differences across donors by far outweighed any technical source of variation. We illustrate the capability of the MAPPs platform to generate data that may be used for preclinical risk assessment of drug-induced immunogenicity and discuss its applicability in the clinics.


A mineralogical record of ocean change: Decadal and centennial patterns in the California mussel.
Ocean acidification, a product of increasing atmospheric carbon dioxide, may already have affected calcified organisms in the coastal zone, such as bivalves and other shellfish. Understanding species' responses to climate change requires the context of long-term dynamics. This can be particularly difficult given the longevity of many important species in contrast with the relatively rapid onset of environmental changes. Here, we present a unique archival dataset of mussel shells from a locale with recent environmental monitoring and historical climate reconstructions. We compare shell structure and composition in modern mussels, mussels from the 1970s, and mussel shells dating back to 1000-2420 years BP. Shell mineralogy has changed dramatically over the past 15 years, despite evidence for consistent mineral structure in the California mussel, Mytilus californianus, over the prior 2500 years. We present evidence for increased disorder in the calcium carbonate shells of mussels and greater variability between individuals. These changes in the last decade contrast markedly from a background of consistent shell mineralogy for centuries. Our results use an archival record of natural specimens to provide centennial-scale context for altered minerology and variability in shell features as a response to acidification stress and illustrate the utility of long-term studies and archival records in global change ecology. Increased variability between individuals is an emerging pattern in climate change responses, which may equally expose the vulnerability of organisms and the potential of populations for resilience.


Alcohol abolishes the hypotensive effect of clonidine in spontaneously hypertensive rats.
This study tested the hypothesis that concurrent ethanol administration attenuates the hypotensive effect of clonidine. Four groups of spontaneously hypertensive rats matched for baseline systolic pressure and body weight were randomly assigned the following treatments: (1) water (control), (2) ethanol, (3) clonidine, and (4) ethanol plus clonidine for 13 weeks. Ethanol was provided in the drinking water as 5% for 1 week, 10% for the next 2 weeks, and 20% from week 4 to 13. Starting from similar baseline systolic blood pressures, the blood pressure of the control group increased 10 to 15 mm Hg over the 13-week treatment period. A similar rise in systolic blood pressure occurred in ethanol-treated rats despite a drastic (40% to 50%, P < .05) reduction in fluid intake. Clonidine (300 micrograms/kg per day) caused a smaller and shorter reduction in fluid intake. The fluid intake of the combined treatment group was similar to that of the ethanol group. Either treatment caused a significant and additive reduction in body weight gain. Treatment-related mortality (20%) occurred only in the combined treatment group by the 12th week. Clonidine elicited a slowly developing hypotensive response (P < .05) that started 2 to 3 weeks after treatment was initiated and lasted throughout the treatment period. Ethanol abolished the hypotensive effect of clonidine and resulted in blood pressure values that were not significantly different from those of the control or the ethanol group. Blood ethanol concentration was similar in the presence or absence of clonidine (5.5 +/- 1.9 versus 6.5 +/- 3 mmol/L).(ABSTRACT TRUNCATED AT 250 WORDS)


The economic impact of a nurse practitioner-directed lung cancer screening, incidental pulmonary nodule, and tobacco-cessation clinic.
Lung cancer screening programs have become increasingly prevalent within the United States after the National Lung Screening Trial results. We aimed to review the financial impact after programmatic implementation of Advanced Registered Nurse Practitioner-led programs of Lung Cancer Screening and Tobacco Related Diseases, Incidental Pulmonary Nodule Clinic, and Tobacco Cessation Services. We reviewed revenue from 2013 to 2016 by our nurse practitioner-led program. Encounters were queried for charges related to outpatient evaluation and management, professional procedures, and facility charges related to both outpatient and inpatient procedures. Revenue was normalized using 2016 data tables and the national Medicare conversion factor (35.8043). Our program evaluated 694 individuals, of whom 75% (518/694) are enrolled within the lung cancer-screening program. Overall revenue associated with the programs was $733,336. Outpatient evaluation and management generated revenue of $168,372. In addition, professional procedure revenue accounted for an additional $60,015 with facility revenue adding an additional $504,949. A nurse practitioner-led program of lung cancer screening, incidental pulmonary nodules, and tobacco-cessation services can provide additional revenue opportunities for a Thoracic Surgery and Interventional Pulmonology Division, as well as a health care system. The current national, median annual wage of a nurse practitioner is $98,190, and the cost associated directly to their salary (and benefits) may remain neutral or negative within certain programs. However, the larger economic benefit may be realized within the division and institution. This potential additional revenue appears related to evaluation of newly identified diseases and subsequent evaluations, procedures, and operations.


Prospective study of survival outcomes in Non-Hodgkin's lymphoma patients with rheumatoid arthritis.
Although preliminary studies suggest that non-Hodgkin's lymphoma (NHL) complicating rheumatoid arthritis (RA) may be a clinically distinct entity compared with that occurring in the general population, studies examining the impact of antecedent RA on survival are limited. In this prospective study, we examined the association of RA with survival in patients with NHL. Using two large lymphoma registries, we identified patients with evidence of RA preceding NHL. Survival in RA patients was compared with that of controls using proportional hazards regression, adjusting for the effects of age, sex, lymphoma diagnosis-to-treatment lag time, calendar year, International Prognostic Index score, and NHL grade. The frequency of NHL subtypes was similar in RA patients (n = 65) and controls (n = 1,530). Compared with controls, RA patients with NHL had similar overall survival (hazard ratio [HR] = 0.95; 95% CI, 0.70 to 1.30) but were at lower risk of lymphoma progression or relapse (HR = 0.41; 95% CI, 0.25 to 0.68) or death related to lymphoma or its treatment (HR = 0.60; 95% CI, 0.37 to 0.98), but were more than twice as likely to die from causes unrelated to lymphoma (HR = 2.16; 95% CI, 1.33 to 3.50). RA is associated with improved NHL-related outcomes, including a 40% reduced risk of death occurring as a result of lymphoma or its treatment and approximately a 60% lower risk of lymphoma relapse or progression compared with non-RA controls. However, the survival advantage gained in RA from the acquisition of lymphomas with favorable prognoses is negated through an increased mortality from other comorbid conditions.


Uniportal video-assisted thoracic surgery for pneumothorax and blebs/bullae.
The last British Society of Thoracic Surgeons guidelines of 2010 for the management of primary spontaneous pneumothorax (PSP) stated that, after the first recurrence, the treatment of PSP should be a surgical operation, like a bullectomy accompanying with a procedure for inducing pleural adhesions. Therefore, the surgical approach is considered the best treatment to minimise the risk of recurrence in patients who experienced a PSP. There is substantial evidence in the literature demonstrating that the minimally invasive approach should be preferred to the thoracotomic procedure since it can reduce the postoperative pain and it is associated with a faster recovery of the physical and working activity. The video-assisted thoracic surgery (VATS) approach has been shown to offer greater advantages about patient pain and respiratory function when compared to thoracotomic incisions. A single port or single incision or uniportal approach was developed as an alternative to the standard multi-port VATS. Uniportal technique has shown to be safe and efficient not only for pulmonary resections and biopsies but also for lobectomy. When used for PSP, the bullectomy/blebectomy and pleural abrasion/pleurectomy is performed through the single incision through which the chest drain is then inserted. In this perspective, evidence showed that the minimally invasive approach should be preferred, confirming the advantages in comparison with traditional techniques.


Diclofenac for acute postoperative pain in children.
Many children undergo various surgeries, which often lead to acute postoperative pain. This pain influences recovery and quality of life. Non-steroidal anti-inflammatory drugs (NSAIDs), specifically cyclo-oxygenase (COX) inhibitors such as diclofenac, can be used to treat pain and reduce inflammation. There is uncertainty regarding diclofenac's benefits and harms compared to placebo or other drugs for postoperative pain. To assess the efficacy and safety of diclofenac (any dose) for acute postoperative pain management in children compared with placebo, other active comparators, or diclofenac administered by different routes (e.g. oral, rectal, etc.) or strategies (e.g. 'as needed' versus 'as scheduled'). We used standard, extensive Cochrane search methods. We searched CENTRAL, MEDLINE, and trial registries on 11 April 2022. We included randomised controlled trials (RCTs) in children under 18 years of age undergoing surgery that compared diclofenac (delivered in any dose and route) to placebo or any active pharmacological intervention. We included RCTs comparing different administration routes of diclofenac and different strategies. We used standard methodological procedures expected by Cochrane. Our primary outcomes were: pain relief (PR) reported by the child, defined as the proportion of children reporting 50% or better postoperative pain relief; pain intensity (PI) reported by the child; adverse events (AEs); and serious adverse events (SAEs). We presented results using risk ratios (RR), mean differences (MD), and standardised mean differences (SMD), with the associated confidence intervals (CI). We included 32 RCTs with 2250 children. All surgeries were done using general anaesthesia. Most studies (27) included children above age three. Only two studies had an overall low risk of bias; 30 had an unclear or high risk of bias in one or several domains. Diclofenac versus placebo (three studies) None of the included studies reported on PR or PI. We are very uncertain about the benefits and harms of diclofenac versus placebo on nausea/vomiting (RR 0.83, 95% CI 0.38 to 1.80; 2 studies, 100 children) and any reported bleeding (RR 3.00, 95% CI 0.34 to 26.45; 2 studies, 100 children), both very low-certainty evidence. None of the included studies reported SAEs. Diclofenac versus opioids (seven studies) We are very uncertain if diclofenac reduces PI at 2 to 24 hours postoperatively compared to opioids (median pain intensity 0.3 (interquartile range (IQR) 0.0 to 2.5) for diclofenac versus median 0.7 (IQR 0.1 to 2.4) in the opioid group; 1 study, 50 children; very low-certainty evidence). None of the included studies reported on PR or PI for other time points. Diclofenac probably results in less nausea/vomiting compared to opioids (41.0% in opioids, 31.0% in diclofenac; RR 0.75, 95% CI 0.58 to 0.96; 7 studies, 463 participants), and probably increases any reported bleeding (5.4% in opioids, 16.5% in diclofenac; RR 3.06, 95% CI 1.31 to 7.13; 2 studies, 222 participants), both moderate-certainty evidence. None of the included studies reported SAEs. Diclofenac versus paracetamol (10 studies) None of the included studies assessed child-reported PR. Compared to paracetamol, we are very uncertain if diclofenac: reduces PI at 0 to 2 hours postoperatively (SMD -0.45, 95% CI -0.74 to -0.15; 2 studies, 180 children); reduces PI at 2 to 24 hours postoperatively (SMD -0.64, 95% CI -0.89 to -0.39; 3 studies, 300 children); reduces nausea/vomiting (RR 0.47, 95% CI 0.25 to 0.87; 5 studies, 348 children); reduces bleeding events (RR 0.57, 95% CI 0.12 to 2.62; 5 studies, 332 participants); or reduces SAEs (RR 0.50, 95% CI 0.05 to 5.22; 1 study, 60 children). The evidence certainty was very low for all outcomes. Diclofenac versus bupivacaine (five studies) None of the included studies reported on PR or PI. Compared to bupivacaine, we are very uncertain about the effect of diclofenac on nausea/vomiting (RR 1.28, 95% CI 0.58 to 2.78; 3 studies, 128 children) and SAEs (RR 4.52, 95% CI 0.23 to 88.38; 1 study, 38 children), both very low-certainty evidence. Diclofenac versus active pharmacological comparator (10 studies) We are very uncertain about the benefits and harms of diclofenac versus any other active pharmacological comparator (dexamethasone, pranoprofen, fluorometholone, oxybuprocaine, flurbiprofen, lignocaine), and for different routes and delivery of diclofenac, due to few and small studies, no reporting of key outcomes, and very low-certainty evidence for the reported outcomes. We are unable to draw any meaningful conclusions from the numerical results. We remain uncertain about the efficacy of diclofenac compared to placebo, active comparators, or by different routes of administration, for postoperative pain management in children. This is largely due to authors not reporting on clinically important outcomes; unclear reporting of the trials; or poor trial conduct reducing our confidence in the results. We remain uncertain about diclofenac's safety compared to placebo or active comparators, except for the comparison of diclofenac with opioids: diclofenac probably results in less nausea and vomiting compared with opioids, but more bleeding events. For healthcare providers managing postoperative pain, diclofenac is a COX inhibitor option, along with other pharmacological and non-pharmacological approaches. Healthcare providers should weigh the benefits and risks based on what is known of their respective pharmacological effects, rather than known efficacy. For surgical interventions in which bleeding or nausea and vomiting are a concern postoperatively, the risks of adverse events using opioids or diclofenac for managing pain should be considered.


Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas.
The poor survival of patients with human malignant gliomas relates partly to the inability to deliver therapeutic agents to the tumor. Because it has been suggested that circulating bone marrow-derived stem cells can be recruited into solid organs in response to tissue stresses, we hypothesized that human bone marrow-derived mesenchymal stem cells (hMSC) may have a tropism for brain tumors and thus could be used as delivery vehicles for glioma therapy. To test this, we isolated hMSCs from bone marrow of normal volunteers, fluorescently labeled the cells, and injected them into the carotid artery of mice bearing human glioma intracranial xenografts (U87, U251, and LN229). hMSCs were seen exclusively within the brain tumors regardless of whether the cells were injected into the ipsilateral or contralateral carotid artery. In contrast, intracarotid injections of fibroblasts or U87 glioma cells resulted in widespread distribution of delivered cells without tumor specificity. To assess the potential of hMSCs to track human gliomas, we injected hMSCs directly into the cerebral hemisphere opposite an established human glioma and showed that the hMSCs were capable of migrating into the xenograft in vivo. Likewise, in vitro Matrigel invasion assays showed that conditioned medium from gliomas, but not from fibroblasts or astrocytes, supported the migration of hMSCs and that platelet-derived growth factor, epidermal growth factor, or stromal cell-derived factor-1alpha, but not basic fibroblast growth factor or vascular endothelial growth factor, enhanced hMSC migration. To test the potential of hMSCs to deliver a therapeutic agent, hMSCs were engineered to release IFN-beta (hMSC-IFN-beta). In vitro coculture and Transwell experiments showed the efficacy of hMSC-IFN-beta against human gliomas. In vivo experiments showed that treatment of human U87 intracranial glioma xenografts with hMSC-IFN-beta significantly increase animal survival compared with controls (P < 0.05). We conclude that hMSCs can integrate into human gliomas after intravascular or local delivery, that this engraftment may be mediated by growth factors, and that this tropism of hMSCs for human gliomas can be exploited to therapeutic advantage.


Dictyostelium DdCP224 is a microtubule-associated protein and a permanent centrosomal resident involved in centrosome duplication.
A cDNA encoding a 224-kDa Dictyostelium discoideum centrosomal protein (DdCP224) was isolated by immunoscreening. DdCP224 was detected at the centrosome and, more weakly, along microtubules throughout the entire cell cycle. Centrosomal localization does not require microtubules, suggesting that DdCP224 is a genuine centrosomal component. DdCP224 exhibits sequence identity to a weakly conserved class of microtubule-associated proteins including human TOGp and yeast Stu2p. Stu2p has a size of only approximately 100 kDa and corresponds to the N-terminal half of DdCP224. The functions of the N- and C-terminal halves of DdCP224 were investigated in the corresponding GFP-fusion mutants. Surprisingly, the N-terminal construct showed only cytosolic localization, whereas the C-terminal construct localized exclusively to the centrosome. This is unexpected because Stu2p is localized at the spindle pole body. Full-length DdCP224-GFP was present both at centrosomes and along microtubules. Furthermore, it bound to microtubules in vitro, unlike the two truncated mutants. Thus centrosome binding is determined by the C-terminal half and microtubule binding may require the interaction of the N- and C-terminal halves. Interestingly, cells expressing full-length DdCP224-GFP exhibit supernumerary centrosomes and show a cytokinesis defect, suggesting that DdCP224 plays an important role in centrosome duplication. These features are unique among the known centrosomal proteins.


Angiotensin converting enzyme and endotoxin induced lung damage in the mouse.
Acute pulmonary oedema can be induced by intraperitoneal injection of Escherichia coli endotoxin in the mouse. A fall in serum angiotensin converting enzyme activity is found in mice given endotoxin and in patients with septic adult respiratory distress syndrome, and has been proposed as an indicator of lung microvascular injury. Protein concentration and angiotensin converting enzyme activity in serum, lung, and bronchoalveolar lavage fluid were determined in male mice up to eight hours after injection of endotoxin. By six hours the serum protein concentration had increased and the bronchoalveolar lavage fluid protein concentration had fallen, suggesting fluid shift into the lung. Angiotensin converting enzyme activity fell in serum and lung but increased in bronchoalveolar lavage fluid. As these changes in enzyme activity were not paralleled by changes in protein concentration they are unlikely to be a result of fluid shift or protein leak, and may indicate an active role of the enzyme in the response to sepsis.


Abnormal uterine bleeding in pre-menopausal women.
Abnormal uterine bleeding is the direct cause of a significant health care burden for women, their families, and society as a whole. Up to 30% of women will seek medical assistance for this problem during their reproductive years. This guideline replaces previous clinical guidelines on the topic and is aimed to enable health care providers with the tools to provide the latest evidence-based care in the diagnosis and the medical and surgical management of this common problem. To provide current evidence-based guidelines for the diagnosis and management of abnormal uterine bleeding (AUB) among women of reproductive age. Outcomes evaluated include the impact of AUB on quality of life and the results of interventions including medical and surgical management of AUB. Members of the guideline committee were selected on the basis of individual expertise to represent a range of practical and academic experience in terms of location in Canada, type of practice, subspecialty expertise, and general gynaecology background. The committee reviewed relevant evidence in the English medical literature including published guidelines. Recommendations were established as consensus statements. The final document was reviewed and approved by the Executive and Council of the SOGC. This document provides a summary of up-to-date evidence regarding diagnosis, investigations, and medical and surgical management of AUB. The resulting recommendations may be adapted by individual health care workers when serving women with this condition. Abnormal uterine bleeding is a common and sometimes debilitating condition in women of reproductive age. Standardization of related terminology, a systematic approach to diagnosis and investigation, and a step-wise approach to intervention is necessary. Treatment commencing with medical therapeutic modalities followed by the least invasive surgical modalities achieving results satisfactory to the patient is the ultimate goal of all therapeutic interventions. Published literature was retrieved through searches of MEDLINE and the Cochrane Library in March 2011 using appropriate controlled vocabulary (e.g. uterine hemorrhage, menorrhagia) and key words (e.g. menorrhagia, heavy menstrual bleeding, abnormal uterine bleeding). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies written in English and published from January 1999 to March 2011. Searches were updated on a regular basis and incorporated in the guideline to February 2013. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table). Implementation of the guideline recommendations will improve the health and well-being of women with abnormal uterine bleeding, their families, and society. The economic cost of implementing these guidelines in the Canadian health care system was not considered.


Promoting Motor Cortical Plasticity with Acute Aerobic Exercise: A Role for Cerebellar Circuits.
Acute aerobic exercise facilitated long-term potentiation-like plasticity in the human primary motor cortex (M1). Here, we investigated the effect of acute aerobic exercise on cerebellar circuits, and their potential contribution to altered M1 plasticity in healthy individuals (age: 24.8 ± 4.1 years). In Experiment 1, acute aerobic exercise reduced cerebellar inhibition (CBI) (n = 10, p = 0.01), elicited by dual-coil paired-pulse transcranial magnetic stimulation. In Experiment 2, we evaluated the facilitatory effects of aerobic exercise on responses to paired associative stimulation, delivered with a 25 ms (PAS25) or 21 ms (PAS21) interstimulus interval (n = 16 per group). Increased M1 excitability evoked by PAS25, but not PAS21, relies on trans-cerebellar sensory pathways. The magnitude of the aerobic exercise effect on PAS response was not significantly different between PAS protocols (interaction effect: p = 0.30); however, planned comparisons indicated that, relative to a period of rest, acute aerobic exercise enhanced the excitatory response to PAS25 (p = 0.02), but not PAS21 (p = 0.30). Thus, the results of these planned comparisons indirectly provide modest evidence that modulation of cerebellar circuits may contribute to exercise-induced increases in M1 plasticity. The findings have implications for developing aerobic exercise strategies to "prime" M1 plasticity for enhanced motor skill learning in applied settings.


Improving data reliability using a non-compliance detection method versus using pharmacokinetic criteria.
Data from clinical trials present numerous problems for the data analyst. These include non-compliance with the prescribed dosing regimen and inaccurate recollection of dosing history by patients as well as mistakes in recording data. Several methods have been proposed to address these issues. One such technique by Lu et al. (Selecting reliable pharmacokinetic data for explanatory analyses of clinical trials in the presence of possible noncompliance. J. Pharmacokinet. Pharmacodyn. 28:343-362 (2001)) identifies occasions in pharmacokinetic (PK) data where the preceding dosing history is likely to be unreliable. We used this method, implemented in the software program NONMEM (beta) VI, to clean a dataset containing indinavir (IDV) plasma concentrations from HIV-1 infected patients. The data was also cleaned by inspection in Microsoft Excel using clinical PK criteria. A one-compartment model with first order absorption and elimination was fit to both sets of cleaned data. IDV population PK parameters obtained from these analyses were similar to those reported previously. It is established that IDV nephrotoxicity is related to high IDV exposure. However, no relationships were found between any PK parameters and nephrotoxicity in the "compliance cleaned" dataset. In the "PK cleaned" dataset, the oral clearance and apparent volume were lower by 9.1% and 6.6%, respectively in patients with any type of nephrotoxicity and the maximum IDV concentration (C(max)) was 12.1% higher. In patients suffering from nephrolithiasis in particular, C(max) was 15.5% higher. Accordingly, the use of the non-compliance detection method did not improve the reliability of our dataset over the usual method of applying clinical criteria. In fact, analyses on the compliance-cleaned dataset missed some exposure-toxicity relationships. Thus, automated methods must be tested rigorously with 'real life' datasets, used with caution, and always in conjunction with clinical reasoning to avoid overlooking a signal in noisy data.


Involvement of mitogen-activated protein kinase activation in the signal-transduction pathways of the soya bean oxidative burst.
The oxidative burst constitutes one of the most rapid defence responses characterized in the Plant Kingdom. We have observed that four distinct elicitors of the soya bean oxidative burst activate kinases of masses approximately 44 kDa and approximately 47 kDa. Evidence that these kinases regulate production of reactive oxygen species include: (i) their rapid activation by oxidative burst elicitors, (ii) their tight temporal correlation between activation/deactivation of the kinases and activation/deactivation of the oxidative burst, (iii) the identical pharmacological profile of kinase activation and oxidant production for 13 commonly used inhibitors, and (iv) the autologous activation of both kinases and oxidant production by calyculin A and cantharidin, two phosphatase inhibitors. Immunological and biochemical studies reveal that the activated 44 kDa and 47 kDa kinases are mitogen-activated protein (MAP) kinase family members. The kinases prefer myelin basic protein as a substrate, and they phosphorylate primarily on threonine residues. The kinases are themselves phosphorylated on tyrosine residues, and this phosphorylation is required for activity. Finally, both kinases are recognized by an antibody against activated MAP kinase immediately after (but not before) cell stimulation by elicitors. Based on these and other observations, a preliminary sequence of signalling steps linking elicitor stimulation, kinase activation and Ca(2+) entry, to initiation of oxidant production, is proposed.


Recommendations for age-appropriate education of children and adolescents with diabetes and their parents in the European Union.
Education is the keystone of diabetes care, and structured self-management education is the key to a successful outcome. Existing guidelines provide comprehensive guidance on the various aspects of education and offer general and organizational principles of education, detailed curricula at different ages and stages of diabetes, and recommendations on models, methods, and tools to attain educative objectives. The International Society for Pediatric and Adolescent Diabetes guidelines give the most elaborate and detailed descriptions and recommendations on the practice of education, which other national guidelines address on specific aspects of education and care. The aim of the work package on education developed by Better Control in Paediatric and Adolescent Diabetes in the European Union: Working to Create Centers of Reference (SWEET) project was not to generate new guidelines but to evaluate how the existing guidelines were implemented in some pediatric diabetes reference centers. The SWEET members have completed a questionnaire that elaborates on the many aspects of delivery of education. This survey highlights a profound diversity of practices across centers in Europe, in terms of organization as well as the practices and the content of initial and continuing education. A toolbox is being developed within SWEET to facilitate exchanges on all aspects of education and to establish a process of validation of materials, tools, written structured age-adjusted programs, and evaluation procedures for the education of children and adolescents with diabetes.


Extracorporeal continuous portal diversion plus temporal plasmapheresis for "small-for-size" syndrome.
To investigate the effect of plasmapheresis via the portal vein for "small-for-size" syndrome (SFSS) aided by extracorporeal continuous portal diversion (ECPD). Extensive or total hepatectomy in the pig is usually adopted as a postoperative liver failure (PLF) or SFSS model. In this study, animals which underwent 85%-90% hepatectomy were randomized into either the Systemic group (n = 7) or the Portal group (n = 7). In the Systemic group, all pigs received temporal plasmapheresis (PP) via the extracorporeal catheter circuit (systemic to systemic circulation) from 24 to 30 h post-hepatectomy (PH); in the Portal group, all pigs received ECPD to divert partial portal vein flow (PVF) to the systemic circulation after hepatectomy, then converted to temporal PP from 24 to 30 h PH, and subsequently converted to ECPD again until 48 h PH. In the Portal group, the PVF was preserved at 3.0-3.3 times that of the baseline value, similar to that following 70% hepatectomy, which was regarded as the optimal PVF to the hypertrophic liver remnant. At 48 h PH, all pigs were re-opened and the portal vein pressure (PVP), PVF, and HAF (hepatic artery flow) were measured, and then diversion of the portal venous flow was terminated. After 1 h the PVP, PVF, and HAF were re-measured. The portal hemodynamic changes, liver injury, liver regeneration and bacterial/lipopolysaccharide (LPS) translocation were evaluated in the two groups. The PVP in the Portal group was significantly lower than that in the Systemic group during the time period from 2 to 49 h PH (P < 0.05). Serum alanine aminotransferase (ALT), total bilirubin (TB) and ammonia were significantly reduced in the Portal group compared with the Systemic group from 24 to 48 h PH (P < 0.05). The Portal group may have attenuated sinusoidal endothelial injury and decreased the level of HA compared with the Systemic group. In the Systemic group, there was significant sinusoidal dilation, hydropic changes in hepatocytes and hemorrhage into the hepatic parenchyma, and the sinusoidal endothelial lining was partially destroyed and detached into the sinusoidal space. CD₃₁ immunostaining revealed significant destruction of the endothelial lining. In the Portal group, there was no intraparenchymal hemorrhage and the sinusoidal endothelial cells and hepatocytes were well preserved. CD₃₁ immunostaining was mild which indicated less destruction of the endothelial lining. HA was significantly decreased in the Portal group compared with the Systemic group from 2 to 48 h PH. The rate of liver remnant regeneration was elevated, while apoptosis was attenuated in the Portal group compared with the Systemic group. Thymidine kinase activity was much higher in the Portal group than in the Systemic group at 48 h PH. The PCNA index was significantly increased and the apoptotic index was significantly decreased in the Portal group compared with the Systemic group. Bacterial translocation and endotoxin, as well as the inflammatory response, were significantly attenuated in the Portal group compared with the Systemic group. LPS, tumor necrosis factor-α and interleukin-6 levels were all significantly decreased in the Portal group compared with the Systemic group from 24 to 48 h PH, while bacterial DNA level was significantly decreased from 2 to 48 h PH. PP plus ECPD via the portal vein can attenuate toxic load and hyperperfusion injury, and should be undertaken instead of PP via the systemic circulation in SFSS or PLF.