Effects of overfeeding on the neuronal response to visual food cues.
The regulation of energy intake is a complex process involving the integration of homeostatic signals and both internal and external sensory inputs. Environmental visual cues are one of the first and primary inputs signaling the potential availability of food. We examined the effects of short-term overfeeding on the neuronal responses to food-related visual stimuli in thin individuals. Twenty-five thin individuals (13 women, 12 men) were studied. Functional magnetic resonance imaging (fMRI) was performed after 2 days of eucaloric energy intake and after 2 days of 30% overfeeding in a counterbalanced design. fMRI was performed while the subjects were presented with visual stimuli in 3 different categories: neutral control objects, foods of neutral hedonic value, and foods of high hedonic value. Measures of appetite were obtained by using visual analogue scales before and after meals. In the eucaloric state, pictures of foods of high hedonic value elicited greater activation of neuronal regions than did neutrally rated foods, which is consistent with visual processing and attention (inferior temporal visual cortex, posterior parietal cortex, premotor cortex, and hippocampus) and with activation of the hypothalamus. Two days of overfeeding led to significant attenuation of these responses. Overfeeding also resulted in reduced hunger ratings and increased satiety ratings. These findings emphasize the important role of external food-related visual cues and suggest that there are interactions between external visual sensory inputs, energy balance status, and brain regions important in the homeostatic regulation of energy intake.


Protein requirements of healthy pregnant women during early and late gestation are higher than current recommendations.
Adequate maternal dietary protein intake is necessary for healthy pregnancy. However, current protein intake recommendations for healthy pregnant women are based on factorial calculations of nitrogen balance data derived from nonpregnant adults. Thus, an estimate of protein requirements based on pregnancy-specific data is needed. The objective of this study was to determine protein requirements of healthy pregnant women at 11-20 (early) and 31-38 (late) wk of gestation through use of the indicator amino acid oxidation method. Twenty-nine healthy women (24-37 y) each randomly received a different test protein intake (range: 0.22-2.56 g · kg(-1) · d(-1)) during each study day in early (n = 35 observations in 17 women) and late (n = 43 observations in 19 women) gestation; 7 women participated in both early and late gestation studies. The diets were isocaloric and provided energy at 1.7 × resting energy expenditure. Protein was given as a crystalline amino acid mixture based on egg protein composition, except phenylalanine and tyrosine, which were maintained constant across intakes. Protein requirements were determined by measuring the oxidation rate of L-[1-(13)C]phenylalanine to (13)CO2 (F(13)CO2). Breath and urine samples were collected at baseline and isotopic steady state. Linear regression crossover analysis identified a breakpoint (requirement) at minimal F(13)CO2 in response to different protein intakes. The estimated average requirement (EAR) for protein in early and late gestation was determined to be 1.22 (R(2) = 0.60; 95% CI: 0.79, 1.66 g · kg(-1) · d(-1)) and 1.52 g · kg(-1) · d(-1) (R(2) = 0.63; 95% CI: 1.28, 1.77 g · kg(-1) · d(-1)), respectively. These estimates are considerably higher than the EAR of 0.88 g · kg(-1) · d(-1) currently recommended by the Dietary Reference Intakes. To our knowledge, this study is the first to directly estimate gestational stage-specific protein requirements in healthy pregnant women and suggests that current recommendations based on factorial calculations underestimate requirements. This trial was registered at clinicaltrials.gov as NCT01784198.


Catalytic Asymmetric Construction of the Tryptanthrin Skeleton via an Enantioselective Decarboxylative [4 + 2] Cyclization.
The first catalytic asymmetric construction of the tryptanthrin skeleton has been established, taking advantage of a palladium(0)/chiral ligand-catalyzed enantioselective decarboxylative [4 + 2] cyclization of vinyl benzoxazinanones with isatins. This reaction has not only provided a direct and efficient method for constructing chiral tryptanthrin skeleta in high yields and excellent enantioselectivities (up to 97% yield, >99% ee) but also represents the first catalytic asymmetric decarboxylative cyclization of vinyl benzoxazinanones with isatins.


Stimuli-Responsive Delivery of Antimicrobial Peptides Using Polyelectrolyte Complexes.
Antimicrobial peptides (AMPs) are antibiotics with the potential to address antimicrobial resistance. However, their translation to the clinic is hampered by issues such as off-target toxicity and low stability in biological media. Stimuli-responsive delivery from polyelectrolyte complexes offers a simple avenue to address these limitations, wherein delivery is triggered by changes occurring during microbial infection. The review first provides an overview of pH-responsive delivery, which exploits the intrinsic pH-responsive nature of polyelectrolytes as a mechanism to deliver these antimicrobials. The examples included illustrate the challenges faced when developing these systems, in particular balancing antimicrobial efficacy and stability, and the potential of this approach to prepare switchable surfaces or nanoparticles for intracellular delivery. The review subsequently highlights the use of other stimuli associated with microbial infection, such as the expression of degrading enzymes or changes in temperature. Polyelectrolyte complexes with dual stimuli-response based on pH and temperature are also discussed. Finally, the review presents a summary and an outlook of the challenges and opportunities faced by this field. This review is expected to encourage researchers to develop stimuli-responsive polyelectrolyte complexes that increase the stability of AMPs while providing targeted delivery, and thereby facilitate the translation of these antimicrobials.


Detecting low-quality markers using map expanders.
Genetic marker data play a crucial role in gene mapping, and genotyping errors may have substantial influence on the power to detect and the precision to locate disease loci. Statistical methods can identify individuals, markers, or pedigrees with a high likelihood of containing genotyping errors, and the putative erroneous genotypes can then be rechecked and either verified, removed, or corrected to reduce the loss of power introduced by errors. We present a method to identify genetic markers with a high genotyping error rate. Genotyping errors are likely to appear as double recombinations which expand the genetic map around the marker. Markers flagged as map expanders (i.e., having an excessive number of double recombinations) can then be reread or regenotyped, or a replacement marker of higher quality can be used instead. The proposed method can be applied to any type of pedigree. Simulation studies of nuclear pedigrees and sib-pairs show that the proposed method generally has high power to identify map expanders when the set of markers is reasonably dense (average intermarker distance of 5 cM), even when the nominal genotyping error rate is low (2%). Not surprisingly, the power to detect map expanders increases with marker heterozygosity and genotyping error rate, and is reduced with increasing intermarker distance. When the method was applied to a real dataset consisting of 56 nuclear pedigrees genotyped for 20 microsatellite markers on chromosome 4, the method diagnosed three markers as map expanders. Subsequent examination of these markers proved that they all had high genotyping error frequencies.


Clinical and microbiological effects of subgingival antimicrobial irrigation with citric acid as evaluated by an enzyme immunoassay and culture analysis.
The purpose of the present study was to compare an enzyme immunoassay with culture samples from untreated and non-surgically treated periodontal pockets and to assess the clinical and microbiological effects of citric acid irrigation as a supplement to scaling and root planing. The enzyme immunoassay used in this study is a chairside diagnostic tool aimed at identifying the presence of P. gingivalis, P. intermedia, and A. actinomycetemcomitans. Six sites with pocket depths > or = 6 mm in each of 16 patients were monitored for 24 weeks using clinical and microbiological parameters. In two out of the six sites, scaling and root planing was supplemented with subgingival citric acid irrigation of the pocket after completion of the mechanical treatment. The sensitivity of the immunoassay in relation to culture was calculated to 85.5% and the specificity to 90.2%. The immunoassay corresponded to a detection level of 10(4) as estimated by culture. Sites treated with a combination of scaling and irrigation with citric acid demonstrated a similar healing pattern as sites treated with scaling and root planing alone. The profile of the marker bacteria was almost parallel for the two groups. The results of this investigation thus indicated that the immunoassay can be used as a screening tool for selected periodontal pathogens and that adjunctive irrigation with citric acid has no measurable clinical or microbiological effects.


Contact conductivity detection in poly(methyl methacrylate)-based microfluidic devices for analysis of mono- and polyanionic molecules.
An on-column contact conductivity detector was developed for the analysis of various mono- and polyanionic compounds separated by electrophoresis chips fabricated in poly(methyl methacrylate) (PMMA) using hot embossing techniques from Ni electroforms. The detector consisted of a pair of Pt wires (127 microm diameter) with an end-to-end spacing of approximately 20 microm and situated within the fluidic channel. The waveform applied to the electrode pair was a bipolar pulse with a frequency of 5.0 kHz and was used to reduce the charging current from measurement so that the current recorded at the end of one pulse is more representative of the solution conductivity. Using the detector, separations of amino acids, peptides, proteins, and oligonucleotides were demonstrated. For the amino acids and peptides, free-solution zone electrophoresis was performed. A calibration plot for the amino acid alanine was found to be linear from approximately 10 to 100 nM in a carrier electrolyte consisting of 10 mM triethylamonium acetate. The concentration detection limit was found to be 8.0 nM, with the corresponding mass detection limit equal to 3.4 amol (injection volume = 425 pL). The protein separations with conductivity detection were performed using MEKC, in which the carrier electrolyte contained the anionic surfactant sodium dodecyl sulfate (SDS) above its cmc. Near baseline resolution was achieved in the PMMA microchip for a solution containing 8 different proteins. In the case of the DNA fragments, capillary electrochromatography was used with a C18-modified PMMA chip and a carrier electrolyte containing an ion-pairing agent.


A malarial cysteine proteinase is necessary for hemoglobin degradation by Plasmodium falciparum.
To obtain free amino acids for protein synthesis, trophozoite stage malaria parasites feed on the cytoplasm of host erythrocytes and degrade hemoglobin within an acid food vacuole. The food vacuole appears to be analogous to the secondary lysosomes of mammalian cells. To determine the enzymatic mechanism of hemoglobin degradation, we incubated trophozoite-infected erythrocytes with peptide inhibitors of different classes of proteinases. Leupeptin and L-transepoxy-succinyl-leucyl-amido-(4-guanidino)-butane (E-64), two peptide inhibitors of cysteine proteinases, inhibited the proteolysis of globin and caused the accumulation of undegraded erythrocyte cytoplasm in parasite food vacuoles, suggesting that a food vacuole cysteine proteinase is necessary for hemoglobin degradation. Proteinase assays of trophozoites demonstrated cysteine proteinase activity with a pH optimum similar to that of the food vacuole and the substrate specificity of lysosomal cathepsin L. We also identified an Mr 28,000 proteinase that was trophozoite stage-specific and was inhibited by leupeptin and E-64. We conclude that the Mr 28,000 cysteine proteinase has a critical, perhaps rate-limiting, role in hemoglobin degradation within the food vacuole of Plasmodium falciparum. Specific inhibitors of this enzyme might provide new means of antimalarial chemotherapy.


Detecting cervical cancer progression through extracted intrinsic fluorescence and principal component analysis.
Intrinsic fluorescence spectra of the human normal, cervical intraepithelial neoplasia 1 (CIN1), CIN2, and cervical cancer tissue have been extracted by effectively combining the measured polarized fluorescence and polarized elastic scattering spectra. The efficacy of principal component analysis (PCA) to disentangle the collective behavior from smaller correlated clusters in a dimensionally reduced space in conjunction with the intrinsic fluorescence is examined. This combination unambiguously reveals the biochemical changes occurring with the progression of the disease. The differing activities of the dominant fluorophores, collagen, nicotinamide adenine dinucleotide, flavins, and porphyrin of different grades of precancers are clearly identified through a careful examination of the sectorial behavior of the dominant eigenvectors of PCA. To further classify the different grades, the Mahalanobis distance has been calculated using the scores of selected principal components.


[Qualitative analysis of health preparedness policies in ChileUma análise qualitativa das políticas de preparação na área de saúde no Chile].
Analyze health preparedness policies in Chile and identify their strengths and weaknesses. No other studies to date provide an analysis of the country's preparedness policies. A desk review and semi-structured interviews with experts in emergency preparedness and response were conducted to identify the regulatory framework, key actors, and the strengths and weaknesses of health preparedness policies. The researchers identified 103 standards and interviewed seven preparedness experts. The reviewed standards and interviews show that Chile is in a transitional phase between the old National Civil Protection System and the new National Disaster Prevention and Response System. Only three standards were directly related to health, but the preparedness regulations provide for a multidisciplinary set of actors to address any threat. The experts gave a positive assessment of the Chilean system, although they agreed that certain weaknesses must be corrected. The country's main strength is its disaster response experience, along with its coordination mechanisms. The main shortcomings include risk communication, mitigation, preparedness and assessment, and human resources. Chile has a solid regulatory framework with an all-hazards approach and a set of multisectoral institutions. The new National Disaster Prevention and Response System must build on its strengths to correct the weaknesses that limit its emergency preparedness and response capacity.


Manipulation of plant tolerance to herbicides through co-ordinated metabolic engineering of a detoxifying glutathione transferase and thiol cosubstrate.
The diphenyl ether herbicide fomesafen can be used selectively in soybean (Glycine max) due to its rapid detoxification by tau class glutathione transferases (GmGSTUs) which preferentially utilize the endogenous thiol homoglutathione (hGSH) as cosubstrate. Soybean cDNAs encoding GmGSTU21, which is highly active in detoxifying fomesafen, and an hGSH synthetase (GmhGS) have been cloned and functionally identified in Escherichia coli. Tobacco plants, which have limited GST activities towards fomesafen and which accumulate glutathione (GSH), rather than hGSH, have been transformed with either GmhGS alone, or a dual construct of GmhGS-GmGSTU21, both under the control of constitutive promoters. Using either construct, the transgenic tobacco accumulated hGSH, with a concomitant increase in GSH content. Segregating T1 plants were analysed for thiol content and GST activity towards fomesafen with GSH and hGSH as cosubstrates, and then scored for photobleaching injury caused by applications of fomesafen. These studies showed that hGSH accumulation alone gave no significant protection against the herbicide and that tolerance was only seen in plants which contained appreciable concentrations of hGSH and GmGSTU21 activity. Tolerance in the dual transformants was associated with the metabolism of radiolabelled fomesafen to inactive hGSH-derived conjugates, while susceptible lines were unable to detoxify the herbicide. These studies confirm the combined importance of specific GSTs and their preferred thiol cosubstrates in conferring herbicide selectivity traits in planta.


Effects of the selective sigma receptor ligand, 6-[6-(4-hydroxypiperidinyl)hexyloxy]-3-methylflavone (NPC 16377), on behavioral and toxic effects of cocaine.
Certain sigma receptor ligands have been shown to block locomotor stimulation produced by cocaine at doses that do not have significant behavioral activity when given alone. Using a potent and selective ligand of sigma binding sites, 6-[6-(4-hydroxypiperidinyl)hexyloxy]-3-methylflavone (NPC 16377), we further investigated the influence of sigma ligands on additional behavioral and toxic effects of cocaine in mice. A behaviorally inactive dose of NPC 16377 shifted the dose-effect function for the locomotor stimulant effects of cocaine to the right by a factor of 2.5. A higher dose of NPC 16377 produced an insurmountable blockade of this stimulant effect of cocaine. Prior exposure to cocaine enhances the locomotor stimulant effects of cocaine (sensitization). NPC 16377 prevented the development of cocaine sensitization without producing behavioral effects of its own. However, NPC 16377 was unable to block the expression of sensitization in mice previously exposed to cocaine. NPC 16377 also did not consistently alter the discriminative stimulus effects of cocaine or methamphetamine in rats discriminating either 3 or 10 mg/kg of cocaine, or 1 mg/kg of methamphetamine from saline. The potential phencyclidine-like behavioral effects of NPC 16377 were also evaluated. Unlike the NMDA channel ligand, dizocilpine, NPC 16377 did not increase responding under a fixed-interval schedule of food presentation in rats nor did it substitute for the discriminative stimulus effects of either 1.5 mg/kg of phencyclidine or 0.2 mg/kg of dizocilpine in rats discriminating these drugs from saline. NPC 16377 displayed limited but significant anticonvulsant activity against diazepam-sensitive cocaine convulsions. The lethal effects of higher doses of cocaine were neither significantly blocked nor enhanced in rats or mice with NPC 16377. These findings extend earlier observations on the cocaine-blocking effects of sigma ligands to a novel structure with exceptional selectivity for sigma sites. These data indicate that some sigma ligands may be capable of altering certain behavioral and toxic actions of cocaine without notable behavioral side effects as evidenced in preclinical tests. As such, these compounds may ultimately be useful in the treatment of cocaine abuse.


Caregiver outcomes of partners in dementia care: effect of a care coordination program for veterans with dementia and their family members and friends.
The objective is to test the effectiveness of Partners in Dementia Care (PDC), a care-coordination program that integrates and improves access to medical and nonmedical services, while strengthening the informal care network and providing information, coaching, and emotional support. PDC was delivered via a partnership between Veterans Affairs (VA) Medical Centers (VAMCs) and Alzheimer's Association chapters, for caregivers of veterans with dementia living in the community and receiving primary care from the VA. The initial sample was 486 caregivers of 508 veterans with diagnosed dementia. Outcomes were evaluated for 394 and 324 caregivers who completed 6- and 12- month follow-up, respectively. PDC had a standardized protocol that included assessment and reassessment, action planning, and ongoing monitoring. It was delivered by telephone and e-mail for cost efficiency and the ability to handle caseloads of 100 to 125. Care coordinators from VAMCs and Alzheimer's Association chapters worked as a team using a shared computerized record. A variety of caregiver outcomes was measured after 6 and 12 months. Intervention group caregivers had significant improvements in outcomes representing unmet needs, three types of caregiver strains, depression, and two support resources. Most improvements were evident after 6 months, with more-limited improvements from Months 6 to 12. Some outcomes improved for all caregivers, whereas some improved for caregivers experiencing more initial difficulties or caring for veterans with more-severe impairments. PDC is a promising model that improves linkages between healthcare services and community services, which is a goal of several new national initiatives such as the National Plan to Address Alzheimer's Disease and a proposed amendment to the Older Americans Act.


Plasmapheresis in the treatment of ventilator-dependent myasthenia gravis patients. Report of four cases.
During a 42-month period, we used plasmapheresis to treat four cases of myasthenia gravis with refractory respiratory failure. All four patients were ventilator dependent for prolonged periods and were not responding to management with cholinesterase inhibitors and corticosteroids. All four patients rapidly responded to the plasmapheresis; respiratory muscle strength returned sufficiently to allow discontinuation of assisted mechanical ventilation and removal of the artificial airway. In our experience, plasmapheresis is indicated in the treatment of the myasthenia gravis patient with respiratory failure which is refractory to conventional drug therapy.


The AGNP-TDM Expert Group Consensus Guidelines: focus on therapeutic monitoring of antidepressants.
Therapeutic drug monitoring (TDM) of psychotropic drugs such as antidepressants has been widely introduced for optimization of pharmacotherapy in psychiatric patients. The interdisciplinary TDM group of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) has worked out consensus guidelines with the aim of providing psychiatrists and TDM laboratories with a tool to optimize the use of TDM. Five research-based levels of recommendation were defined with regard to routine monitoring of drug plasma concentrations: (i) strongly recommended; (ii) recommended; (iii) useful; (iv) probably useful; and (v) not recommended. In addition, a list of indications that justify the use of TDM is presented, eg, control of compliance, lack of clinical response or adverse effects at recommended doses, drug interactions, pharmacovigilance programs, presence of a genetic particularity concerning drug metabolism, and children, adolescents, and elderly patients. For some drugs, studies on therapeutic ranges are lacking, but target ranges for clinically relevant plasma concentrations are presented for most drugs, based on pharmacokinetic studies reported in the literature. For many antidepressants, a thorough analysis of the literature on studies dealing with the plasma concentration-clinical effectiveness relationship allowed inclusion of therapeutic ranges of plasma concentrations. In addition, recommendations are made with regard to the combination of pharmacogenetic (phenotyping or genotyping) tests with TDM. Finally, practical instructions are given for the laboratory practitioners and the treating physicians how to use TDM: preparation of TDM, drug analysis, reporting and interpretation of results, and adequate use of information for patient treatment TDM is a complex process that needs optimal interdisciplinary coordination of a procedure implicating patients, treating physicians, clinical pharmacologists, and clinical laboratory specialists. These consensus guidelines should be helpful for optimizing TDM of antidepressants.


What Drives Employees' Innovative Behaviors in Emerging-Market Multinationals? An Integrated Approach.
The coronavirus disease 2019 (COVID-19) pandemic has severely damaged the global industrial supply chain and accelerated the digital transformation of the global economy. In such rapidly changing environments, multinational corporations (MNCs) should encourage employees to be more innovative in various fields than ever before. With the onset of the COVID-19 pandemic, employees have become psychologically anxious, their working conditions have deteriorated, and they are in danger of losing their jobs. In this study, we aim to address the question of whether servant leadership facilitates the innovative behavior of employees working in emerging-market MNCs when servant leadership is adopted within the firms. In addition, we explore the mediating roles of work-life balance and psychological stability perceived by employees, and the moderating role of organizational climate in the relationship between servant leadership and MNC employees' innovative behavior. In doing so, we collected data from a sample of 307 Chinese employees who are employed by five different Chinese MNCs from the Internet, information technology, electronics, and e-commerce industries. Based on a sample of survey data collected from employees of Chinese MNCs, we empirically test these ideas by specifically examining how servant leadership may shape the innovation behavior of employees in these MNCs. The results suggest that servant leadership positively influences employees' innovative behavior, and that the contribution of servant leadership to employees' innovative behavior is mediated by work-life balance and psychological stability as well as moderated by the degree of organizational climate. Moreover, the different organizational climates of these MNC employees are also expected to significantly shape the relationship between servant leadership and employees' innovative behavior. This study enriches our understanding of the importance of servant leadership in driving the innovative behaviors of employees in emerging-market MNCs and provides new insights into the mechanisms through which emerging-market MNCs can motivate their employees to be more innovative in their jobs. Thus, this study contributes to the research on human resource management by offering important implications vis-à-vis how MNCs manage their employees more effectively in addressing and responding to the dramatically changing global landscape in the post COVID-19 era.


Selective reduction of 6-O-sulfation in heparan sulfate from transformed mammary epithelial cells.
Heparan sulfate at cell surfaces and in the extracellular matrix regulates cell proliferation and adhesion by binding to growth factors and matrix proteins via structurally specific oligosaccharide domains. We have used the hormonally regulated mouse mammary carcinoma cell line S115 as a model to elucidate the effect of malignant transformation on the structure of heparan sulfate. When cultured in the presence of testosterone, S115 cells form tumor cell colonies in soft agar and exhibit fibroblast-like morphology; withdrawal of testosterone results in a loss of the tumorigenic capacity and a switch towards epithelial morphology. Metabolically 35SO4-labeled heparan sulfate was isolated from testosterone-treated and non-treated S115 cells and subjected to structural analysis. We found that the testosterone-dependent malignant transformation was associated with reduced sulfation of heparan sulfate due to a approximately 40% decrease in the amount of GlcN6S units. By contrast, no significant differences were observed in the amounts of 2-O-sulfate or N-sulfate groups. The reduced 6-O-sulfation of GlcN units in heparan sulfate from transformed S115 cells led to a marked decrease in the amount of trisulfated IdoA2S-GlcNS6S units (IdoA, L-iduronic acid), implicated in many heparan sulfate-protein interactions.


Impact of microclimatic conditions and resource availability on spring and autumn phenology of temperate tree seedlings.
Microclimatic effects (light, temperature) are often neglected in phenological studies and little information is known about the impact of resource availability (nutrient and water) on tree's phenological cycles. Here we experimentally studied spring and autumn phenology in four temperate trees in response to changes in bud albedo (white-painted vs black-painted buds), light conditions (nonshaded vs c. 70% shaded), water availability (irrigated, control and reduced precipitation) and nutrients (low vs high availability). We found that higher bud albedo or shade delayed budburst (up to +12 d), indicating that temperature is sensed locally within each bud. Leaf senescence was delayed by high nutrient availability (up to +7 d) and shade conditions (up to +39 d) in all species, except oak. Autumn phenological responses to summer droughts depended on species, with a delay for cherry (+7 d) and an advance for beech (-7 d). The strong phenological effects of bud albedo and light exposure reveal an important role of microclimatic variation on phenology. In addition to the temperature and photoperiod effects, our results suggest a tight interplay between source and sink processes in regulating the end of the seasonal vegetation cycle, which can be largely influenced by resource availability (light, water and nutrients).


Evaluation of 7 serum biomarkers and uterine artery Doppler ultrasound for first-trimester prediction of preeclampsia: a systematic review.
Preeclampsia (PE) affects 1% to 2% of pregnant women and is a leading cause of maternal and perinatal morbidity and mortality worldwide. The clinical syndrome of PE arises in the second half of pregnancy. However, many underlying factors including defective placentation may already be apparent in the first and early second trimester in many patients. In clinical practice, there is currently no reliable screening method in the first trimester of pregnancy with sufficient accuracy to identify women at high risk to develop PE. Early identification of high-risk pregnancy may facilitate the development of new strategies for antenatal surveillance or prevention and thus improve maternal and perinatal outcome. The aim of this systematic review was to study the literature on the predictive potential of first-trimester serum markers and of uterine artery Doppler velocity waveform assessment (Ut-A Doppler). Literature on the 7 most studied serum markers (ADAM12, fβ-hCG, Inhibin A, Activin A, PP13, PlGF, and PAPP-A) and Ut-A Doppler was primarily selected. In the selected literature, a combination of these markers was analyzed, and where relevant, the value of maternal characteristics was added. Measurements of serum markers and Ut-A Doppler were performed between week 8 + 0 and 14 + 0 GA. Low levels of PP13, PlGF, and PAPP-A and elevated level of Inhibin A have been found to be significantly associated with the development of PE later in pregnancy. The detection rates of single markers, fixed at 10% false-positive rate, in the prediction of early-onset PE were relatively low, and ranged from 22% to 83%. Detection rates for combinations of multiple markers varied between 38% and 100%. Therefore, a combination of multiple markers yields high detection rates and is promising to identify patients at high risk of developing PE. However, large scale prospective studies are required to evaluate the power of this integrated approach in clinical practice. Obstetricians and Gynecologists, Family physicians Learning Objectives: After completion of this article, the reader should be better able to appraise the recent literature on the development of preeclampsia in the first-trimester, evaluate the predictive value of first-trimester markers and use first-trimester markers, either individually or in combination, to assess the risk of preeclampsia.


A high level of mutation tolerance in the multifunctional sequence encoding the RNA encapsidation signal of an avian hepatitis B virus and slow evolution rate revealed by in vivo infection.
In all hepadnaviruses, protein-primed reverse transcription of the pregenomic RNA (pgRNA) is initiated by binding of the viral polymerase, P protein, to the ε RNA element. Universally, ε consists of a lower stem and an upper stem, separated by a bulge, and an apical loop. Complex formation triggers pgRNA encapsidation and the ε-templated synthesis of a DNA oligonucleotide (priming) that serves to generate minus-strand DNA. In vitro systems for duck hepatitis B virus (DHBV) yielded important insights into the priming mechanism, yet their relevance in infection is largely unexplored. Moreover, additional functions encoded in the DHBV ε (Dε) sequence could affect in vivo fitness. We therefore assessed the in vivo performances of five recombinant DHBVs bearing multiple mutations in the upper Dε stem. Three variants with only modestly reduced in vitro replication competence established chronic infection in ducks. From one variant but not another, three adapted new variants emerged upon passaging, as demonstrated by increased relative fitness in coinfections with wild-type DHBV. All three showed enhanced priming and replication competence in vitro, and in one, DHBV e antigen (DHBeAg) production was restored. Pronounced impacts on other Dε functions were not detected; however, gradual, synergistic contributions to overall performance are suggested by the fact of none of the variants reaching the in vivo fitness of wild-type virus. These data shed more light on the P-Dε interaction, define important criteria for the design of future in vivo evolution experiments, and suggest that the upper Dε stem sequences provided an evolutionary playground for DHBV to optimize in vivo fitness.


Reporting of pain by people with chronic obstructive pulmonary disease (COPD): comparative results from the HUNT3 population-based survey.
Chronic obstructive pulmonary disease (COPD) is often associated with chronic pain, but pain in COPD remains poorly understood, particularly in comparison to pain in other groups. We compared the pain reported by people with COPD with that reported by arthritis, heart disease, diabetes, and those not reporting any disease, while adjusting for the effects of selected sociodemographic and lifestyle factors, comorbidities, anxiety, and depression. Using cross-sectional data from a population-based health survey in Norway (HUNT3; n = 50,807), we included participants with COPD (n = 1199), participants without COPD, but with arthritis (n = 8582), heart disease (n = 4109), or diabetes (n = 1254), and participants without any disease (n = 18,811). Logistic and linear regression analyses were performed to estimate the probability of reporting chronic pain and the level of pain intensity in the different groups adjusting for other relevant factors. Approximately half (51.8%) of people with COPD reported chronic pain, which was a significantly higher rate than in the diabetes and non-disease groups, and similar to the heart disease group. People with arthritis had a chronic pain rate of 75.4%, which was higher than all other groups, including COPD. Analyses of pain intensity yielded similar findings, with the COPD group having higher pain intensity than the diabetes and non-disease groups, similar pain intensity as the heart disease group, and less pain intensity than the arthritis group. The likelihood of chronic pain and the intensity of pain were generally higher among women, people employed in occupations with low educational requirements, smokers, and those with comorbidity. Chronic pain rates and pain intensity increased with age and higher anxiety and depression scores, and were inversely related to physical activity. People with COPD are at increased risk for chronic pain and higher pain intensity, second only to those with arthritis among the disease groups included in this study. The findings indicate a close relationship between pain and anxiety and depression. The relationships between pain and socioeconomic and lifestyle factors (e.g., smoking and exercise) suggest the need for efforts at the societal level to reduce inequality in health.


Effects of linolenic acid on the canine heart.
Disturbances in lipid metabolism have been observed during the early phase of acute myocardial ischemia. Accumulation of fatty acids in and around the ischemic cardiac cells has been implicated to play a role in both contractile and electrophysiological abnormalities. Linolenic acid is an essential fatty acid and constitutes the phospholipid moiety of the cell membrane. The purpose of this work was to study the effects of linolenic acid on the heart using canine preparations. A direct left atrial injection was used as the route of administration because intravenous injections of linolenic acid inevitably cause pulmonary edema. A surface lead electrocardiogram (ECG), an epicardial electrogram, femoral arterial pressure, left ventricular pressure and its time derivative (dp/dt) were recorded before and after drug administration. Various dosages of linolenic acid (1 mg, 5 mg, 10 mg, 20 mg, 30 mg and 60 mg/kg) and a control buffer solution were tested. The results showed that linolenic acid has a potent dose-dependent bradycardic and myocardial depression effect starting from a dose of 5 mg/kg (delta HR = -20.1 +/- 4.0 bpm, delta dp/dt = 364.3 +/- 66.0 mmHg, sec-1, p less than 0.01 vs. control). At a high dose of 30 mg/kg, linolenic acid induced premature ventricular complexes. Furthermore, ventricular tachycardia was observed in 5 of the 8 dogs (62.5%) receiving the high dose of 60 mg/kg. We conclude that linolenic acid has profound effects on the canine heart; at a low dose, it causes bradycardia and myocardial depression, while at a high dose, it also produces ventricular irritability.


Improve the operational stability of the inverted organic solar cells using bilayer metal oxide structure.
Operational stability is a big obstacle for the application of inverted organic solar cells (OSCs), however, less talked about in the research reports. Due to photoinduced degradation of the metal oxide interlayer, which can cause shunts generation and degeneration in ZnO interlayer, a significant degradation of open circuit voltage (Voc) and fill factor (FF) has been observed by in situ periodic measurements of the device current density-voltage (J-V) curves with light illumination. By combining TiOx and ZnO to form bilayer structures on ITO, the photovoltaic performance is improved and the photoinduced degradation is reduced. It was found that the device based on ZnO/TiOx bilayer structure achieved better operational stability as compared to that with ZnO or TiOx interlayer.


Vitamin D status and immune function reconstitution in HIV-infected men initiating therapy.
Despite effective antiretroviral therapy (HAART) and durable viral suppression, many HIV-infected individuals still do not achieve CD4 cell count (CD4) normalization. Vitamin D has immunoregulatory functions, including inducing the development of T cells and higher levels may improve CD4 rebound. Longitudinal study of men from the Multicenter AIDS Cohort Study who virally suppressed following HAART initiation and had pre-HAART and post-HAART 25(OH)D and 1,25(OH)2D measurements and repeated measures of CD4. CD4 rebound was modeled using a nonlinear mixed effects model. We estimated the adjusted effect (adjusted for pre-HAART antiretroviral exposure, black race, age and CD4 at HAART initiation) of pre-HAART and post-HAART vitamin D metabolite levels on the rate of CD4 increase and final CD4 plateau. Among the 263 HIV-infected HAART initiators with pre-HAART vitamin D measurements, a 1-SD higher pre-HAART 25(OH)2D level was associated with a 9% faster rate of rise (P = 0.02) but no gain in final CD4 plateau. In contrast, a 1-SD higher 1,25(OH)2D level was associated with a 43-cell lower final CD4 (P = 0.04). Among 560 men with post-HAART measurements, findings were similar to those for pre-HAART 25(OH)2D with 1-SD higher level associated with faster rate of rise but no improvement in final CD4. We found no evidence that higher vitamin D metabolite levels pre-HAART or post-HAART are associated with better CD4 outcomes among HIV-infected HAART initiators. However, the value of pre-HAART 1,25(OH)2D levels as an indicator of immune response dysregulation could be further explored.


Zygosaccharomyces favi sp. nov., an obligate osmophilic yeast species from bee bread and honey.
Five yeast strains representing a hitherto undescribed yeast species were isolated from bee bread and honey in Hungary. They are obligate osmophilic, i.e. they are unable to grow in/on high water activity culture media. Following isogamous conjugation, they form 1-4 spheroid or subspheroid ascospores in persistent asci. The analysis of the sequences of their large subunit rRNA gene D1/D2 domain placed the new species in the Zygosaccharomyces clade. In terms of pairwise sequence similarity, Zygosaccharomyces gambellarensis is the most closely related species. Comparisons of D1/D2, internal transcribed spacer and translation elongation factor-1α (EF-1α) gene sequences of the five strains with that of the type strain of Z. gambellarensis revealed that they represent a new yeast species. The name Zygosaccharomyces favi sp. nov. (type strain: NCAIM Y.01994(T) = CBS 13653(T) = NRRL Y-63719(T) = ZIM 2551(T)) is proposed for this new yeast species, which based on phenotype can be distinguished from related Zygosaccharomyces species by its obligate osmophilic nature. Some intragenomic sequence variability, mainly indels, was detected among the ITS copies of the strains of the new species.


Immunosuppression with a combination of triptolide and cyclosporin A in rat vascularized groin flap allotransplantation.
Triptolide is an immunosuppressive fraction purified from a Chinese medicinal plant. In an effort to develop a new immunosuppressive strategy for vascularized composite allotransplantation, the authors investigated the effects of combined treatment with cyclosporin A and triptolide on the survival of rat groin flap allotransplants. Groin flap transplantation was performed from Brown Norway rats to Fischer 344 recipients, which were then treated with triptolide, cyclosporin A, or both. Flap biopsy specimens were harvested, stained, and submitted to histopathologic evaluation. Levels of CCR5, CCR7, CCL19, CCL21, and Foxp3 in spleen were examined by real-time polymerase chain reaction, and the percentage of CD4+CD25+ regulatory T cells was detected by flow cytometry. The mean survival time for allografts in recipients receiving triptolide and cyclosporin A was 57 ± 7.7 days compared with 20.5 ± 2.3 days for cyclosporin A alone, 23.3 ± 3.6 days for triptolide alone, and 7.8 ± 0.8 days for no treatment. Histologic examination also showed that inflammatory cell infiltration was reduced in grafts with combination treatment. Down-regulation of CCR5, CCR7, and CCL19 in the combination treatment was accompanied by increased expression of Foxp3. Flow cytometric analysis also revealed that the percentage of CD4+CD25+ regulatory T cells in the combination treatment was higher than in the monotherapy groups. Combination therapy with triptolide and cyclosporin A substantially prolonged allograft survival, which means calcineurin inhibitor-related drug-toxicity may be alleviated and treatment cost reduced. This immunosuppressive effect is mediated by inhibition of dendritic cells maturation and the expansion of regulatory T cells.


The Roles of Disliking, Deservingness, and Envy in Predicting Schadenfreude.
Schadenfreude (pleasure about another's misfortune) was studied using written scenarios that were manipulated to include elements that elicited disliking of the target, envy of the target, and/or deservingness of the misfortune. This was the first time all the three predictors were included in a single study, allowing for a test of their possible interactive effects. Study 1 created a large pool of scenarios based on a pilot study and had participants rate them regarding how much disliking, deservingness, or envy was felt. The eight scenarios that were most effective in eliciting the various combinations of predictors were then used in Study 2 to test for schadenfreude reactions. Results revealed strong main effects for disliking and deservingness. Interactions showed that disliking attenuated the effect of deservingness, especially for female participants. Finally, further evidence was found that malicious but not benign envy predicted schadenfreude.


[Freud, Meynert, and Mathilde: hypnosis in question].
During the Paris Congress of 1889, Freud showed little interest in the presentations on hypnosis. This surprising attitude may have been due to a certain ambivalence on his part, related not only to the controversy that put him in opposition to Meynert, but also to the case of Mathilde. Freud mentioned this patient, who died of sulfonal intoxication, in his Irma dream associations. Documents that, until now, have not been published, reveal that Freud had treated her for years by hypnosis for melancholia and that after a manic decompensation, he was forced to have her committed to a private clinic. The patient records, partially reproduced, reveal information about her, her sickness, and the attempted treatments, as well as information about her relationship with Freud, towards whom she had developed a massive sexualized transfer psychosis that, at the time, was untreatable. Her death, in 1890, must have weighed heavily on him, and the Irma dream attests to prolonged after-effects.


Galectin-9 controls CD40 signaling through a Tim-3 independent mechanism and redirects the cytokine profile of pathogenic T cells in autoimmunity.
While it has long been understood that CD40 plays a critical role in the etiology of autoimmunity, glycobiology is emerging as an important contributor. CD40 signaling is also gaining further interest in transplantation and cancer therapies. Work on CD40 signaling has focused on signaling outcomes and blocking of its ligand, CD154, while little is known about the actual receptor itself and its control. We demonstrated that CD40 is in fact several receptors occurring as constellations of differentially glycosylated forms of the protein that can sometimes form hybrid receptors with other proteins. An enticing area of autoimmunity is differential glycosylation of immune molecules leading to altered signaling. Galectins interact with carbohydrates on proteins to effect such signaling alterations. Studying autoimmune prone NOD and non-autoimmune BALB/c mice, here we reveal that in-vivo CD40 signals alter the glycosylation status of non-autoimmune derived CD4 T cells to resemble that of autoimmune derived CD4 T cells. Galectin-9 interacts with CD40 and, at higher concentrations, prevents CD40 induced proliferative responses of CD4(lo)CD40(+) effector T cells and induces cell death through a Tim-3 independent mechanism. Interestingly, galectin-9, at lower concentrations, alters the surface expression of CD3, CD4, and TCR, regulating access to those molecules and thereby redirects the inflammatory cytokine phenotype and CD3 induced proliferation of autoimmune CD4(lo)CD40(+) T cells. Understanding the dynamics of the CD40 receptor(s) and the impact of glycosylation status in immunity will gain insight into how to maintain useful CD40 signals while shutting down detrimental ones.


[The concept of temperament and its contribution to the understanding of the bipolar spectrum].
The present article attempts first to provide a historical overview of the concept of temperament,The present article attempts first to provide a historical overview of the concept of temperament,since its foundation by Polybos (4th century B.C.) and the school of Cos, its predominant role in theshaping of the anthropological and humanitarian sciences, until the modern theoretical formulations,such as those proposed by Robert Cloninger and Hagop Akiskal. Secondly, recent literature ispresented, which suggests a strong link of different temperament structures to mental health andpsychopathology. Hans Eysenck (1916-1997) was the first psychologist to establish approaches topersonality differences and to distinguish three dimensions of personality: Neuroticism, Extraversionand Psychotisism. Eysenck was followed by McCrae and Costa who proposed that there are five basicdimensions of personality ("Big Five"). In the mid-1980s, Robert Cloninger developed a distinctivedimensional model of temperament and character traits. Hagop Akiskal emphasized on the affectivecomponents of temperament and their possible connections to mood disorders and creativity.Specifically, temperament assessment seems to help in differentiating between the relationship ofvarious temperaments and the clinical manifestations of bipolar illness. Within the area of mood disorders,specific affective temperaments might constitute vulnerability factors, as well as clinical pictureand illness course modifiers. Viewing mood disorders under this prism gives birth to the concept ofthe bipolar spectrum with major implications for all aspects of mental health research and providingof care. The hyperthymic and the depressive temperaments are related to the more 'classic' bipolarpicture (that is euphoria, grandiose and paranoid thinking, antisocial behavior, psychomotor accelerationand reduced sleep and depressive episodes respectively). On the contrary cyclothymic, anxiousand irritable temperaments are related to more complex pictures and might predict poor responseto treatment, violent or suicidal behavior and high comorbidity. Unipolar disorder diagnosis is oftenchanged due to the fact that a manic or mixed episode can occur after several years of treatment failure.In these cases the evaluation of temperament can prove to be effective in distinguishing betweenunipolar and bipolar depression and thus favoring treatment planning. In addition, temperament assessmentchanges the definition of bipolarity by supporting the concept of "bipolar spectrum". This isa factor that can lead to a rise in prevalence of bipolar cases. Furthermore, the evaluation of temperamenthas shifted our understanding of bipolarity towards the concept of the 'bipolar spectrum'. It hasalso led to an increase in the prevalence of bipolar disorder cases, notably bipolar II, and a decrease in unipolar cases. Finally, incorporating the concept of temperament in our understanding of bipolardisorder constitutes a challenging issue, which can lead to better treatment and outcome of patients.


A new universal rat restrainer for ophthalmic research.
Immobilization of rats is required in many psychological and physiological experiments. The aim of the current paper was to invent a universal device allowing for adaptation of rats of a wide age range and to maximize convenience for in vivo exposure to optical radiation under not-anaesthetized conditions. Eighty-three 6-week-old and three 18-week-old Sprague-Dawley albino female rats were progressively familiarized daily with the restraining device 5 days prior to exposure to acquire a conditioned response and to reduce stress. After initial habituation, 10 min preceding the ultraviolet radiation (UVR) exposure, the animal was fixed in the rat restrainer. Each unanaesthetized animal was unilaterally exposed to a single dose of 8 kJ/m² UVR-300 nm for 15 min. Three of the 6-week-old and three of the 18-week-old rats were in vivo exposed to UVR once for 10 consecutive days. All rats acclimatized well to immobilization in the restrainer. Young rats adapted quicker than older rats. The device prevented head movement and body rotation, which allowed for uncomplicated single as well as repeated in vivo exposures to UVR. The restrainer effectively immobilizes unanaesthetized rats in the age range 6-18 weeks old, making it useful in future projects involving chronic repeated in vivo exposure of the eye to UVR.


Correlation of immunochemical detection of HPV L1 capsid protein in pap smears with regression of high-risk HPV positive mild/moderate dysplasia.
To immunostain Pap smears of high-risk (hr) HPV DNA-positive early squamous lesions for detecting HPV L1 protein. Routinely stained archival slides from 84 mild and moderate hrHPV DNA-positive dysplasias were immunostained using a panreactive HPV L1 antibody. Follow-up smears were taken from women with remission for a mean period of 22.8 months (range, 6-46). Conization was done in patients with persistence or progression (3 and 48 patients, respectively) after a mean time of 12 months (range, 9-48). Twenty-nine of 84 smears (34.5%) had positively stained squamous epithelial cell nuclei. In 9 of 29 (31%) women progressive disease occurred (2 cervical intraepithelial neoplasia [CIN] 2 and 7 CIN 3 lesions on conization) 20 (69%) had remission. Of the 55 L1-negative cases, 13 (23.6%) had remission, 42 (76.4%) progressed (3 CIN 2, 38 CIN 3, 1 microinvasive carcinoma). The difference in follow-up between L1 positive and negative cases was statistically significant (chi2 test, p< or =0.001). Low and moderate dysplastic squamous lesions without immunochemically detectable HPV L1 protein are significantly more likely to progress than are L1-positive cases. Immunochemical L1 capsid detection in routine Pap smears thus offers prognostic information about early dysplastic lesions.


Arthroscopic percutaneous inverted mattress suture fixation of isolated greater tuberosity fracture of humerus.
The purpose of the study was to evaluate the clinical and radiographic outcomes of treatment in patients with isolated greater tuberosity (GT) fractures of humerus using arthroscopic percutaneous inverted mattress suture fixation technique. We attempted to use the arthroscopic percutaneous inverted mattress suture fixation technique in 17 consecutive cases with isolated displaced GT fractures. Fourteen patients were successfully treated without switching to other methods and were available for follow-up at a mean of 22 months (range: 17-38 months) after surgery. For assessment of clinical outcomes, we evaluated the range of motion and the visual analog scale (VAS) score, the shoulder index of the American Shoulder and Elbow Surgeons (ASES), and the Korean Shoulder Scale (KSS). At the final follow-up, the VAS improved to 1.0 points (range: 0-3), the mean ASES score improved to 86.9 points (range: 78.3-100) and the KSS improved to 88.6 points (range: 82-100) postoperatively. Mean union time was 10 weeks. Mean forward flexion was 167.8° (range: 140-180°), mean external rotation in neutral position was 36° (range: 20-70°), and mean internal rotation was at the 12th thoracic level (range: T6-L3) at final follow-up. Three cases were switched to open surgery after attempted arthroscopic technique due to large fragment or osteoporosis. In select cases, the arthroscopic percutaneous inverted mattress suture fixation of GT fracture is a simple and reproducible technique with encouraging early results.


Instruction prioritization in task-based balance training for individuals with idiopathic Parkinson's disease.
The objective of the study was to evaluate the effect of prioritization of instruction in balance training for individuals with Parkinson's disease (PD). Thirty-six participants were evaluated before and after the training using the Berg Balance Scale, Dynamic Gait Index, and Geriatric Depression Scale. Results show that dual task training with variable priority instruction is as effective as single task training in improving the balance performance of individuals with idiopathic PD.


Improved Tandem Mass Spectrometry Detection and Resolution of Low Molecular Weight Perfluoroalkyl Ether Carboxylic Acid Isomers.
Per- and polyfluoroalkyl substances (PFAS) are emerging contaminants widely used in a variety of industrial and consumer applications. Due to phasing out legacy PFAS, some manufacturers developed short-chain alternatives like perfluoroalkyl ether carboxylic acids (PFECA). Published liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods cover a wide range of these replacement chemicals including PFMPA (perfluoro-3-methoxypropanoic acid) and PFMBA (perfluoro-4-methoxybutanoic acid). However, many methods do not monitor for their branched isomers, PMPA (perfluoro-2-methoxypropanoic acid) and PEPA (perfluoro-2-ethoxypropanoic acid), respectively. Although these isomers are chromatographically separable under certain conditions, using the common MS/MS transitions for PFMPA (m/z 229 → 85) and PFMBA (m/z 279 → 85) can yield low or no detection signals for PMPA and PEPA, thus leading to underestimated values or nondetects. We compared various MS/MS transitions for these isomers and determined the optimal transitions for PMPA (m/z 185 → 85) and PEPA (m/z 235 → 135). We applied the developed method to water sampled near two chemical manufacturing plants and observed these analytes, plus a suspected third isomer. Using these MS/MS transitions will ensure all isomers are detected and will lead to better monitoring and exposure estimates of PFECA in humans and the environment.


Level of inflammatory factors in chronic hemodialysis patients with and without cardiovascular disease.
Considering the existence of controversies about the predictive value of inflammatory markers for cardiovascular disease (CVD), we aimed to compare the level of high-sensitivity C-reactive protein (hs-CRP) and interlukin-6 (IL-6) level in chronic hemodialysis (HD) patients with and without CVD. In this historical cohort study, HD patients with and without CVD disease were enrolled. The presence of CVD risk factors, level of inflammatory factors including IL-6 and hs-CRP as well as lipid levels, fasting blood sugar, and other biochemical factors were compared in two studied groups. During the study, eighty HD patients with (n = 40) and without (n = 40) CVD were enrolled. Diabetes was more prevalent among HD patients with CVD than those without CVD (P < 0.05). The level of IL-6 and hs-CRP were not different in two studied groups (P > 0.05). Univariate analysis of variance test indicated that there was not any significant relationship between hs-CRP and CVD (P > 0.05). The findings indicated that the level of inflammatory factors including hs-CRP and IL-6 are not significantly different in HD patients with and without CVD. However, for obtaining more definite conclusion in this field and evaluation their predicting role in this field, it is recommended to study other novel inflammatory markers as well as the additive effect of the inflammatory factors with traditional ones in larger sample size and longer follow-up.


Disproportionately high levels of HGF induce the degradation of the c-met receptor through the proteasomal degradation pathway.
Hepatocyte growth factor (HGF) receptor is a member of the receptor tyrosine kinases (RTKs) and has been reported to perform diverse functions in various cell types during both the developmental and adult stages. Among different roles, HGF is best known for its angiogenic effects of inducing the migration of endothelial cells. Because angiogenesis is one of the prerequisite steps for tumor metastasis, HGF-dependent cell migration has to be tightly controlled. However, the underlying mechanisms regulating the optimum level of HGF/c-met signaling have been poorly understood. In this study, we tested whether the migration of endothelial cells is regulated by a negative feedback mechanism under disproportionately large amounts of HGF. Data from endothelial cell migration assays showed that HGF activity increased as its concentration increased, but declined beyond a certain point. Under limiting conditions, amounts of phosphorylated Erk and Akt surged, reaching a plateau in which the enhanced level was more or less maintained. The c-met receptor was degraded when unnecessarily large amounts of HGF were present. Under these conditions, HGF could no longer activate downstream signaling pathways even if cells were re-treated with optimal amounts of HGF. Excessive doses of HGF increased the phosphorylation of tyrosine residue 1003 involved in the ubiquitination of c-met, and phosphorylated c-met was diverted toward the proteasomal degradation pathway. Taken together, HGF/c-met signaling is tightly regulated by a negative feedback loop through an ubiquitin-proteasomal degradation pathway.


Automated prediction of emphysema visual score using homology-based quantification of low-attenuation lung region.
The purpose of this study was to investigate the relationship between visual score of emphysema and homology-based emphysema quantification (HEQ) and evaluate whether visual score was accurately predicted by machine learning and HEQ. A total of 115 anonymized computed tomography images from 39 patients were obtained from a public database. Emphysema quantification of these images was performed by measuring the percentage of low-attenuation lung area (LAA%). The following values related to HEQ were obtained: nb0 and nb1. LAA% and HEQ were calculated at various threshold levels ranging from -1000 HU to -700 HU. Spearman's correlation coefficients between emphysema quantification and visual score were calculated at the various threshold levels. Visual score was predicted by machine learning and emphysema quantification (LAA% or HEQ). Random Forest was used as a machine learning algorithm, and accuracy of prediction was evaluated by leave-one-patient-out cross validation. The difference in the accuracy was assessed using McNemar's test. The correlation coefficients between emphysema quantification and visual score were as follows: LAA% (-950 HU), 0.567; LAA% (-910 HU), 0.654; LAA% (-875 HU), 0.704; nb0 (-950 HU), 0.552; nb0 (-910 HU), 0.629; nb0 (-875 HU), 0.473; nb1 (-950 HU), 0.149; nb1 (-910 HU), 0.519; and nb1 (-875 HU), 0.716. The accuracy of prediction was as follows: LAA%, 55.7% and HEQ, 66.1%. The difference in accuracy was statistically significant (p = 0.0290). LAA% and HEQ at -875 HU showed a stronger correlation with visual score than those at -910 or -950 HU. HEQ was more useful than LAA% for predicting visual score.


Effectiveness of physiotherapy and minimal invasive technics on functional status and quality of life in geriatric patients with low back pain.
The aim of the study was to determine the effect of physiotherapy and minimal invasive technics (MIT) on pain, quality of life and functional disability in geriatric patients with chronic low back pain. According to previous files, 61 geriatric patients who received MIT and physiotherapy allocated to group 1, the patient who received physiotherapy alone allocated to group 2. All patients received soft tissue mobilizations, muscle-energy technics and spinal stabilization exercises. Pain severity, functional disability, life quality, and fear avoidance were assessed with visual analogue scale, Oswestry Disability Index (ODI), Nottingham Health Profile (NHP) and Fear Avoidance Beliefs Questionnaire, respectively. Improvements in ODI and NHP were seen in favor of group 2 after treatment as to baseline (P<0.05). Although both treatments showed pain relief, functional restoration, and improvement in quality of life; there was no additional improvement in patients received MIT different from the patients received physiotherapy alone.


Airborne grass and ragweed pollen in the southern Panonnian Valley--consideration of rural and urban environment.
The aims of this study were to describe and compare the characteristics of grass and ragweed airborne pollen in rural and urban areas in the southern Panonnian Valley. Airborne pollen data were collected by using Hirst type volumetric samplers simultaneously in rural and urban localities. If rural and urban environment are considered, both grass and ragweed daily pollen concentrations showed a significant degree of association. Observed parameters (pollen index, maximum daily concentration, number of days during which the pollen is recorded in the air and start day of main pollen season), showed year-to-year variations for both grass and ragweed aeropollen. Average values of these parameters were higher in the rural environment, but the difference was statistically significant only for grass pollen index. Such a low difference indicates the possibility for conducting dose response clinical trials based on data obtained from one sampling station. The least year-to-year variations as well as the least difference between rural and urban environment, have been observed in the case of start date of the MPS. Such a situation suggests the possibility for using data obtained in one type of environment for the development of long-term forecast models for an entire region.


Activation of the receptor EphB4 by its specific ligand ephrin B2 in human osteoarthritic subchondral bone osteoblasts.
Abnormal subchondral bone metabolism is involved in osteoarthritis (OA). It has been suggested that ephrin B2 and its specific receptor EphB4 participate in bone homeostasis. We previously reported that human OA subchondral bone osteoblasts could be classified into 2 subpopulations: low (L), having proresorption properties, and high (H), having proformation properties. The purpose of this study was to investigate the importance of the ephrin system in OA subchondral bone osteoblasts. The presence of the EphB4 receptor was determined by immunohistochemistry, and its expression level, modulation upon treatment, and consequences of activation by ephrin B2 were determined by quantitative polymerase chain reaction. The effects of ephrin B2 activation of the EphB4 receptor on bone resorption activity were also determined. EphB4 receptor activation signaling pathways were investigated by specific enzyme-linked immunosorbent assay. EphB4 receptors were present in subchondral bone osteoblasts and osteocytes. Compared with normal and H-OA osteoblasts, EphB4 receptor expression levels were significantly increased in L-OA osteoblasts, with no difference between normal and H-OA osteoblasts. EphB4 receptor levels in L-OA osteoblasts were significantly up-regulated by prostaglandin E2 (PGE2) and interleukin-17 (IL-17). Ephrin B2, PGE2, and IL-17 significantly inhibited bone resorption activity in these cells. EphB4 activation by ephrin B2 significantly inhibited the expression of IL-1beta, IL-6, matrix metalloproteinase 1 (MMP-1), MMP-9, MMP-13, and RANKL, but not MMP-2 and osteoprotegerin. EphB4 receptor activation significantly inhibited the phosphatidylinositol 3-kinase/Akt pathway. This study is the first to provide evidence that EphB4 receptor activation by ephrin B2 in OA subchondral bone could affect abnormal metabolism in this tissue by inhibiting resorption factors and their activities. Ephrin B2 could be targeted as a specific therapeutic approach in the development of a disease-modifying OA drug.


New insights in the mechanisms of weight-loss maintenance: Summary from a Pennington symposium.
Obesity is a chronic disease that affects more than 650 million adults worldwide. Obesity not only is a significant health concern on its own, but predisposes to cardiometabolic comorbidities, including coronary heart disease, dyslipidemia, hypertension, type 2 diabetes, and some cancers. Lifestyle interventions effectively promote weight loss of 5% to 10%, and pharmacological and surgical interventions even more, with some novel approved drugs inducing up to an average of 25% weight loss. Yet, maintaining weight loss over the long-term remains extremely challenging, and subsequent weight gain is typical. The mechanisms underlying weight regain remain to be fully elucidated. The purpose of this Pennington Biomedical Scientific Symposium was to review and highlight the complex interplay between the physiological, behavioral, and environmental systems controlling energy intake and expenditure. Each of these contributions were further discussed in the context of weight-loss maintenance, and systems-level viewpoints were highlighted to interpret gaps in current approaches. The invited speakers built upon the science of obesity and weight loss to collectively propose future research directions that will aid in revealing the complicated mechanisms involved in the weight-reduced state.


Recovery constructs and the continued debate that limits consumer recovery.
It is generally agreed that the concept of recovery is the result of two primary influences: longitudinal studies and the work, writing, perspectives, and advocacy of the consumer-survivor movement. To clarify what is actually meant by recovery, investigators have compared and contrasted the constructs being conveyed through each primary influence. This process has resulted in the proposal of two main taxonomies-"recovery from" as opposed to "recovery in" and "recovery as an outcome" as opposed to "recovery as a process." The author draws on her experience as a consumer to examine the efficacy of distinguishing the recovery constructs in each of these ways, concluding that both taxonomies limit the consumer recovery paradigm in a way that is neither valid nor helpful. It is essential to the progress of recovery-based services that the mental health field avoid the trap of a dualistic, either-or approach to recovery that was once so prevalent.


A cryptic peptide from the preprothyrotropin-releasing hormone precursor stimulates thyrotropin gene expression.
The precursor peptide of TRH (prepro-TRH) contains five copes of pro-TRH linked by other peptide sequences. These peptides are coprocessed with TRH in the median eminence of the hypothalamus and released into the portal circulation, rendering this family of peptides available to act at the level of the anterior pituitary. Therefore, we tested the potential bioactivity of one cryptic peptide, prepro-TRH amino acids 160-169 [prepro-TRH-(160-169)], in a TRH-responsive pituitary cell line (GH3). In a heterologous TSH expression assay, we found that prepro-TRH-(160-169) stimulated TSH beta gene promoter activity in a time- and dose-dependent manner; moreover, the effect of prepro-TRH-(160-169) was more rapid and of greater magnitude than that of TRH on TSH beta-directed chloramphenicol acetyltransferase synthesis. In the same cells, we found that prepro-TRH-(160-169) stimulated PRL synthesis and secretion, but the effect was similar in magnitude and duration to that of TRH. The effect of prepro-TRH-(160-169) appears to be additive to that of TRH, suggesting that prepro-TRH-(160-169) may act through a mechanism separate from that of TRH. Thus, prepro-TRH-(160-169) has potent endocrinological effects at the level of the genome.


The impact of ultrasonography on the prognosis of pancreatic cancer.
The authors review 207 consecutive patients admitted for pancreatic cancer from 1960 to 1989 to the 1st Department of Surgery of the University of Rome "La Sapienza", in order to ascertain whether ultrasonography contributes to achieving the ideal goal of early diagnoses. The results achieved show a higher number of early diagnoses (< 1 month from first symptoms) performed by means of US, and a concurrent increase of cases amenable to radical surgery during the period 1975-1989, and basically from 1985 to 1989. Diagnostic imaging, namely US, is therefore deemed to provide earlier diagnoses and higher rates of pancreatic resectability.


Searching of Clinical Trials Made Easier in cBioPortal Using Patients' Genetic and Clinical Profiles.
Molecular tumor boards (MTBs) cope with the complexity of an increased usage of genome sequencing data in cancer treatment. As for most of these patients, guideline-based therapy options are exhausted, finding matching clinical trials is crucial. This search process is often performed manually and therefore time consuming and complex due to the heterogeneous and challenging dataset. In this study, a prototype for a search tool was developed to demonstrate how cBioPortal as a clinical and genomic patient data source can be integrated with ClinicalTrials.gov, a database of clinical studies to simplify the search for trials based on genetic and clinical data of a patient. The design of this tool should rest on the specific needs of MTB participants and the architecture of the integration should be as lightweight as possible and should not require manual curation of trial data in advance with the goal of quickly and easily finding a matching study. Based on a requirements analysis, interviewing MTB experts, a prototype was developed. It was further refined using a user-centered development process with multiple feedback loops. Finally, the usability of the application was evaluated with user interviews including the thinking-aloud protocol and the system usability scale (SUS) questionnaire. The integration of ClinicalTrials.gov in cBioPortal is achieved by a new tab in the patient view where the genomic profile for the search is prefilled and additional parameters can be adjusted. These parameters are then used to query the application programming interface (API) of ClinicalTrials.gov. The returned search results subsequently are ranked and presented to the user. The evaluation of the application resulted in an SUS score of 83.5. This work demonstrates the integration of cBioPortal with ClinicalTrials.gov to use clinical and genomic patient data to search for appropriate trials within an MTB.


Individual differences in trajectories of emotion regulation processes: the effects of maternal depressive symptomatology and children's physiological regulation.
Trajectories of emotion regulation processes were examined in a community sample of 269 children across the ages of 4 to 7 using hierarchical linear modeling. Maternal depressive symptomatology (Symptom Checklist-90) and children's physiological reactivity (respiratory sinus arrhythmia [RSA]) and vagal regulation (Delta RSA) were explored as predictors of individual differences in trajectories of emotion regulation and negativity (mother-reported Emotion Regulation Checklist; A. M. Shields & D. Cicchetti, 1997). In addition, the authors explored whether children's physiological regulation would moderate the effect of maternal depressive symptomatology on children's emotion regulation trajectories. Results indicated that over time, emotion regulation increased whereas negativity decreased, though considerable individual variability in the pattern of change was observed. Greater maternal depressive symptomatology was associated with less steep emotion regulation trajectories. There was a significant Maternal Depressive Symptomatology x Baseline RSA x Age interaction predicting emotion regulation trajectories. Overall, it appears that the development of emotion regulation over time is compromised when mothers report greater depressive symptomatology. There is also evidence that children's capacity for physiological regulation can buffer some of the adverse consequences associated with maternal depressive symptomatology.


European Medicinal Leeches-New Roles in Modern Medicine.
Before the advent of modern medicine, natural resources were widely used by indigenous populations for the prevention and treatment of diseases. The associated knowledge, collectively described as folk medicine or traditional medicine, was largely based on trial-and-error testing of plant extracts (herbal remedies) and the use of invertebrates, particularly medicinal maggots of the blowfly Lucilia sericata and blood-sucking leeches. The widespread use of traditional medicine in the West declined as scientific advances allowed reproducible testing under controlled conditions and gave rise to the modern fields of biomedical research and pharmacology. However, many drugs are still derived from natural resources, and interest in traditional medicine has been renewed by the ability of researchers to investigate the medical potential of diverse species by high-throughput screening. Likewise, researchers are starting to look again at the benefits of maggot and leech therapy, based on the hypothesis that the use of such animals in traditional medicine is likely to reflect the presence of specific bioactive molecules that can be developed as drug leads. In this review, we consider the modern medical benefits of European medicinal leeches based on the systematic screening of their salivary proteins.


Recent Progress in Technologies for Tactile Sensors.
Over the last two decades, considerable scientific and technological efforts have been devoted to developing tactile sensing based on a variety of transducing mechanisms, with prospective applications in many fields such as human-machine interaction, intelligent robot tactile control and feedback, and tactile sensorized minimally invasive surgery. This paper starts with an introduction of human tactile systems, followed by a presentation of the basic demands of tactile sensors. State-of-the-art tactile sensors are reviewed in terms of their diverse sensing mechanisms, design consideration, and material selection. Subsequently, typical performances of the sensors, along with their advantages and disadvantages, are compared and analyzed. Two major potential applications of tactile sensing systems are discussed in detail. Lastly, we propose prospective research directions and market trends of tactile sensing systems.


[Twenty years in the 21st century: research hotspots and frontier analysis on Chinese medicine processing mechanism].
The research on the processing mechanism of Chinese medicine is the key and core foundation to improve processing technologies of Chinese medicine, formulate the quality standards of Chinese medicinal pieces, enhance the clinical efficacy of Chinese medicine, enrich Chinese medicine processing theories, and promote the development of Chinese medicine processing. Many researc-hers have conducted in-depth exploration on the processing mechanism of Chinese medicine in the 20 years in the 21 st century. Significant progress has been made in the transformation of chemical components during the processing, the change of active components in the body, the law of toxicity attenuation in the processing of toxic Chinese medicine, the mechanism of efficacy enhancement and toxicity attenuation of processing with auxiliary materials, and the application of new biomedical technologies. At present, the processing mechanism of multiple Chinese medicines has been preliminarily clarified, which has greatly promoted the development of Chinese me-dicine processing. The development of the processing mechanism of Chinese medicine reveals that the in vitro transformation of chemical components is combined with the in vivo absorption, transport, and metabolism, and the macroscopic biological effects of the organism are combined with the cells, molecules, targets, and pathways in the study of the processing mechanism of Chinese medicine. More attention has been paid to exploring the processing mechanism from the overall level, and a modern systematic research system on the processing mechanism of Chinese medicine has been initially formed. To further promote the scientific development of Chinese me-dicine processing, the present study proposed that the research on the processing mechanism of Chinese medicine should take Chinese medicine properties into account, focus on the influence of disease condition on the mode of action and effect strength of the drugs, comply with the characteristics of clinical compound compatibility of Chinese medicine, use the holistic view research strategies of systems bio-logy, and deeply explore the processing mechanism of Chinese medicine from traditional Chinese medicine theories and the characteristics of clinical medication of Chinese medicine.


Numerical Evaluation of the Influence of Skull Heterogeneity on Transcranial Ultrasonic Focusing.
In transcranial penetration, ultrasound undergoes refraction, diffraction, multi-reflection, and mode conversion. These factors lead to phase aberration and waveform distortion, which impede the realization of transcranial ultrasonic imaging and therapy. Ray tracing has been used to correct the phase aberration and is computationally more efficient than traditional full-wave simulation. However, when ray tracing has been used for transcranial investigation, it has generally been on the premise that the skull medium is homogeneous. To find suitable homogeneity that balances computational speed and accuracy, the present work investigates how the focus deviates after phase-aberration compensation with ray tracing using time-reversal theory. The waveforms are synthetized with ray tracing for phase aberration, by which the properties of the skull bone are simplified for refraction calculation as those of either (i) the cortical bone or (ii) the mean of the entire skull bone, and the focusing accuracy is evaluated for each hypothesis. The propagation of ultrasound for transcranial focusing is simulated with the elastic model using the k-space pseudospectral method. Unlike the fluid model, the elastic model does not omit shear waves in the skull bones, and the influence of that omission is investigated, with the fluid model resulting in a focal deflection of 0.5 mm. The focusing deviations are huge when the properties of the skull bone are idealized with ray tracing as those of the mean of the entire skull bone. The focusing accuracy improves when the properties of the skull bone are idealized as those of the cortical bone. The results reveal minimal deviation (8.6, 3.9, and 3.2% in the three Cartesian coordinates) in the focal region and suggest that transcranial focusing deflections are caused mostly by ultrasonic refraction on the surface of the skull bone. A heterogeneous skull bone causes wave bending but minimal focusing deflection. The proposed simplification of a homogeneous skull bone is more accurate for transcranial ultrasonic path estimation and offers promising applications in transcranial ultrasonic focusing and imaging.


Fast-Switching Vis-IR Electrochromic Covalent Organic Frameworks.
Electrochromic coatings are promising for applications in smart windows or energy-efficient optical displays. However, classical inorganic electrochromic materials such as WO3 suffer from low coloration efficiency and slow switching speed. We have developed highly efficient and fast-switching electrochromic thin films based on fully organic, porous covalent organic frameworks (COFs). The low band gap COFs have strong vis-NIR absorption bands in the neutral state, which shift significantly upon electrochemical oxidation. Fully reversible absorption changes by close to 3 OD can be triggered at low operating voltages and low charge per unit area. Our champion material reaches an electrochromic coloration efficiency of 858 cm2 C-1 at 880 nm and retains >95% of its electrochromic response over 100 oxidation/reduction cycles. Furthermore, the electrochromic switching is extremely fast with response times below 0.4 s for the oxidation and around 0.2 s for the reduction, outperforming previous COFs by at least an order of magnitude and rendering these materials some of the fastest-switching frameworks to date. This combination of high coloration efficiency and very fast switching reveals intriguing opportunities for applications of porous organic electrochromic materials.


Training, Deployment Preparation, and Behavioral Health of New York National Guard Personnel Deployed to Assist with COVID-19 Decedent Work.
A small body of research conducted mostly among civilians has shown that adequate training and preparation can prevent or reduce the development of behavioral health problems in first responders. Several civilian studies have shown that social support is protective against behavioral health problems. However, very few studies have examined the impact of these factors on the behavioral health of military first responders. Military first responders, who serve in the aftermath of natural disasters and disease outbreaks such as the coronavirus disease 2019 (COVID-19) pandemic, are often members of the National Guard (NG). The purpose of this study was to examine the impact of mortuary affairs training/handling human remains, role preparation, equipment preparation, and unit social support provided to families on the behavioral health of New York (NY) NG personnel deployed to assist the NY Office of Chief Medical Examiner with handling the remains of COVID-19 decedents. We invited 410 NYNG personnel who deployed for the Office of Chief Medical Examiner mission to complete an anonymous online questionnaire 3 to 6 months post-mission. Of the 158 participants, we used the data of the 141 participants who provided consent. Standard behavioral health measures (depression, anxiety, post-traumatic stress disorder, alcohol misuse, and insomnia) as well as study-specific items designed to understand the unique dynamics of this deployment were included. Hierarchical logistic regression analysis was used to examine the relationships between mortuary training, role preparation, equipment preparation, and unit support with behavioral health. Close to two-thirds of the sample reported that they had not been trained in mortuary affairs/handling human remains before the mission. We also found that that lower levels of role preparation and unit support provided to the service members' families increased the odds of meeting criteria for one or more behavioral health problems, but that training in mortuary affairs and equipment preparation was unrelated to behavioral health. Our research points to the importance of emotionally and cognitively preparing service members for the specific dynamics of a deployment and the roles that that they are expected to play. Furthermore, it suggests that supporting the families of NG personnel during domestic missions can benefit the behavioral health of the NG personnel. Additional research is needed to corroborate these findings, particularly the impact of unit support provided to family members on service members' behavioral health.


Studies on porcine pancreatic elastase activity. II. Immunoreactive elastase level during acute hemorrhagic pancreatitis in pigs.
Acute hemorrhagic pancreatitis was produced in pig to study serum concentration of elastase and its physiological role. Pancreatitis was induced in two groups of young pigs by the injection of autologous bile. One group was injected with autologous bile (0.5 ml/kg) at high pressure, and the second group was injected as low pressure (100 cm H2O). Then femoral blood, portal blood and thoracic lymph were sampled at scheduled time intervals. The control level of immunoreactive elastase was around 90 ng/ml in each site, which significantly increased beginning 15 min after bile injection; the level of immunoreactive elastase was higher in the thoracic lymph duct than in the femoral and portal vein. The total and free elastase of both groups in pancreatic tissue were significantly decreased in pancreatitis, and an abundance of immunoreactive elastase was found in the ascites. The increasing pattern of immunoreactive elastase and amylase after bile injection was very similar. Therefore, the level of immunoreactive elastase was considered to be inadequate to determine the grade of severity of pancreatitis as well as the level of amylase which is already known.


Influence of Psychological Separation on Master Graduates' Career Maturity: Mediating Role of Occupational Self-Efficacy.
This research adopts the career maturity as an indicator of one's intention and ability in career development, and explores whether and how psychological separation from parents and occupational self-efficacy influence one's career maturity. A structural equation model is constructed and tested with data from a survey of 584 master graduates in top universities across China. According to the study, it is founded that: (1) The psychological separation and occupational self-efficacy of master graduates are significantly and positively correlated with occupational self-efficacy, and career maturity, respectively. (2) Occupational self-efficacy plays a part of the mediating role between psychological separation and career maturity. (3) Master graduates with a high degree of psychological separation are more confident in achieving their career goals, more involved in the career selection process and have a higher level of career development. These findings will arouse the attention of the society to the master graduates' career maturity to some extent.


The value of AFP and HCG half lives in predicting the efficacy of combination chemotherapy in patients with non-seminomatous germ cell tumors of the testis.
The decline of serum levels of AFP or HCG in 26 patients with disseminated non-seminomatous germ cell tumors during chemotherapy showed two different patterns: a linear decline or an increasing apparent half life (AHL). The initial AFP half life in 13 patients with a linear decline was 7.2 +/- 1.8 days, and did not differ from the initial half life in 5 patients with a curvi-linear pattern. HCG half life was 3.0 +/- 0.5 days in 10 patients with a linear AHL, and was not different from the initial half life in 6 patients with delayed marker disappearance. Based on the half life pattern of AFP or HCG the result of chemotherapy was predicted. When AFP or HCG showed a linear decline, all viable tumor appeared to be eliminated in 38 and 40% respectively of the patients. An increasing AHL indicated the presence of active tumor, mostly mature teratoma, in 60% of the patients with AFP and in 83% of the patients with HCG. Thus, the pattern of AFP or HCG half life does not predict the eventual outcome of chemotherapy with certainty.


Moderate alcohol disrupts a mechanism for detection of rare events in human visual cortex.
Moderate doses of alcohol (blood alcohol concentration [BAC] of about 0.05%) may result in acute impairments at various levels of information processing. A number of reports have documented detrimental effects of moderate alcohol on the mismatch negativity (MMN), the electrocortical manifestation of a rapid (100 ms poststimulus) mechanism dedicated to the detection of unexpected auditory change (e.g., Jääskeläinen, et al., 1995). Recently, we and others identified a partial visual counterpart of the MMN, sometimes called the rareness-related negativity (RRN). Analogous to the MMN, the RRN evolves at about 100 ms after the unexpected change and was localized in visual cortex (Kenemans, et al., 2003). Rapid detection of unexpected events is important for everyday-life conditions like driving, prompting the question whether the visual RRN shows sensitivity to moderate alcohol similar to the MMN. In all, 16 subjects were tested either under moderate alcohol or under placebo. Unexpected visual change was implemented by presenting 2.4 versus 0.6 c/d gratings in pseudorandom sequences according to a deviant (10%)/standard (90%) schedule. The alcohol effects on MMN reported before were replicated. Furthermore, the RRN, defined as the difference between deviant and standard event-related potentials between 120 and 170 ms at Oz, was present under placebo but not under alcohol. It is concluded that moderate alcohol does indeed impair the rapid detection in visual cortex of unexpected changes. In contrast, electrocortical correlates of lower level sensory processing were still significantly present under alcohol.


Overexpression of toll-like receptors 3 and 4 in synovial tissue from patients with early rheumatoid arthritis: toll-like receptor expression in early and longstanding arthritis.
To analyze the expression, regulation, and biologic relevance of Toll-like receptors (TLRs) 1-10 in synovial and skin fibroblasts and to determine the expression levels of TLRs 2, 3, and 4 in synovial tissues from patients with early rheumatoid arthritis (RA), longstanding RA, and osteoarthritis (OA). Expression of TLRs 1-10 in RA synovial fibroblasts (RASFs), OASFs, and skin fibroblasts was analyzed by real-time polymerase chain reaction (PCR). Fibroblasts were stimulated with tumor necrosis factor alpha, interleukin-1beta (IL-1beta), bacterial lipopeptide, poly(I-C), lipopolysaccharide, and flagellin. Production of IL-6 was determined by enzyme-linked immunosorbent assay and induction of TLRs 2-5, matrix metalloproteinases (MMPs) 3 and 13 messenger RNA by real-time PCR. Expression of TLRs 2-4 in synovial tissues was analyzed by immunohistochemistry. Synovial fibroblasts expressed TLRs 1-6, but not TLRs 7-10. Among the expressed TLRs, TLR-3 and TLR-4 were the most abundant in synovial fibroblasts, and stimulation of synovial fibroblasts with the TLR-3 ligand poly(I-C) led to the most pronounced increase in IL-6, MMP-3, and MMP-13. In contrast, skin fibroblasts did not up-regulate MMP-3 or MMP-13 after stimulation with any of the tested stimuli. In synovial tissues from patients with early RA, TLR-3 and TLR-4 were highly expressed and were comparable to the levels of patients with longstanding RA. These expression levels were elevated as compared with those in OA. Our findings of high expression of TLRs, particularly TLRs 3 and 4, at an early stage of RA and the reactivity of synovial fibroblasts in vitro to TLR ligands suggest that TLR signaling pathways resulting in persistent inflammation and joint destruction are activated early in the disease process.


Immunohistochemical evidence for the selective involvement of dorsal root fibres in Friedreich's ataxia.
An immunohistochemical study was carried out in order to elucidate the selective involvement of the dorsal root fibres from two patients with Friedreich's ataxia in comparison with those of 10 neurologically normal control individuals. For this purpose, antibodies to substance P and to synaptophysin were used. Substance P-immunoreactive unmyelinated fibres forming a dense network in the normal substantia gelatinosa of the spinal dorsal horn predominantly originate from a subpopulation of small cells of the dorsal root ganglia, while synaptophysin is present in virtually all nerve cell axon terminals and is useful for visualizing axon terminals in the nervous system. Strong substance P-like immunoreactivity was seen in the substantia gelatinosa of patients with Friedreich's ataxia. By contrast, there was marked depletion of synaptophysin immunoreactivity in the posterior column nuclei, with the gracile nucleus showing greater loss of positive puncta than the cuneate nucleus.


Cortical Responses to Input From Distant Areas are Modulated by Local Spontaneous Alpha/Beta Oscillations.
Any given area in human cortex may receive input from multiple, functionally heterogeneous areas, potentially representing different processing threads. Alpha (8-13 Hz) and beta oscillations (13-20 Hz) have been hypothesized by other investigators to gate local cortical processing, but their influence on cortical responses to input from other cortical areas is unknown. To study this, we measured the effect of local oscillatory power and phase on cortical responses elicited by single-pulse electrical stimulation (SPES) at distant cortical sites, in awake human subjects implanted with intracranial electrodes for epilepsy surgery. In 4 out of 5 subjects, the amplitudes of corticocortical evoked potentials (CCEPs) elicited by distant SPES were reproducibly modulated by the power, but not the phase, of local oscillations in alpha and beta frequencies. Specifically, CCEP amplitudes were higher when average oscillatory power just before distant SPES (-110 to -10 ms) was high. This effect was observed in only a subset (0-33%) of sites with CCEPs and, like the CCEPs themselves, varied with stimulation at different distant sites. Our results suggest that although alpha and beta oscillations may gate local processing, they may also enhance the responsiveness of cortex to input from distant cortical sites.


Melatonin Alleviates Radiculopathy Against Apoptosis and NLRP3 Inflammasomes Via the Parkin-Mediated Mitophagy Pathway.
Animal experimental study with intervention. To investigate the effect of melatonin on rat radiculopathy model and dorsal root ganglion (DRG) cells, and to elucidate the underlying mechanism. Melatonin has a well-documented efficacy in intervertebral disc degeneration (IVDD) and low back pain. IVDD can also lead to other complications such as disc herniation which will cause radiculopathy. Herniated nucleus pulposus (NP) induced apoptosis and NLR pyrin domain containing 3 (NLRP3) activation in DRG. However, the effect and underlying mechanism of melatonin on radiculopathy and DRG cells are still unclear. Rat radiculopathy model was induced by implanting NP tissue from the tail disc of the same rat into the left L4/5 inter-laminar space near the left DRG. Melatonin was injected intraperitoneally in the treated group to test its function. Apoptosis was determined by Tunnel staining and flow cytometry. NLRP3 inflammasome activation was determined by levels of NLRP3, ASC, GSMDM-N, IL-1β, and Caspase-1. Mitophagy was determined by levels of Parkin, Beclin-1, p62, and LCB-II. Mitophagy was blocked by treatment with Parkin-si or cyclosporine A (CsA). NLRP3 was significantly upregulated in DRG of rat radiculopathy model; moreover, melatonin markedly decreased pain behavior in rat radiculopathy model. Furthermore, melatonin treatment decreases the incidence of apoptosis in DRG cells. Melatonin also promotes mitophagy and inhibits NLRP3 inflammasomes in DRG cells. In addition, mitophagy was blocked by treatment with Parkin-si and CsA. Both Parkin-si and CsA attenuated melatonin's inhibitory effect on apoptosis and the NLRP3 inflammasome, indicating that the beneficial effects of melatonin in DRG cells are mediated through the Parkin-mediated mitophagy. Melatonin alleviates radiculopathy against apoptosis and NLRP3 inflammasomes by promoting Parkin-mediated mitophagy, which may help us provide a potential target for the treatment of radiculopathy.Level of Evidence: N/A.