Using confirmatory factor analysis and Rasch analysis to examine the dimensionality of The Patient Assessment of Care for Chronic Illness Care (PACIC).
The PACIC assesses key components of the Chronic Care Model. The purpose of this study is to examine the dimensionality and psychometric properties of the PACIC. A convenience sample of 221 adults in Canada who self-identified as living with one or more physical and/or mental chronic diseases was invited to participate via an online survey link. Rasch analysis was performed, including item and person misfit, reliability, response format, targeting, unidimensionality of subscales, and differential item functioning (DIF). Also, Confirmatory Factor Analysis (CFA) was conducted and model fit of alternative factor structures proposed for the PACIC in the literature and those suggested by the Rasch analysis were explored. The patient activation, delivery system, and problem-solving subscales fit the Rasch model expectations; no modifications were required. The goal setting item 10 had a disordered threshold and was recoded. Four of the five follow-up subscale items had a disordered threshold and were recoded. All subscales were unidimensional and no local dependency was detected. DIF was only detected for some items in the follow-up subscale. The CFA revealed that none of the published factor structures fit the data; the fit statistics were appropriate when item 10 was removed and the follow-up subscale was removed. Improving chronic disease care relies upon having validated measures to evaluate the extent to which care goals are met. With some modifications, four of the five PACIC subscales were found to be psychometrically robust.


Efficacy of short duration versus conventional electroacupuncture in the treatment of obesity: a randomized crossover study.
To compare the efficacy of short duration electroacupuncture (EA) with conventional EA to reduce weight and other parameters in obese Thai women. A randomized crossover study was conducted in 76 simple obese women. Participants were randomized to undergo either eight weeks of 30-minute EA (EA30) followed by an eight-week washout period, then eight weeks of five-minute EA (EA5), or EA5 followed by a washout period, then EA30. Electro-acupuncture was performed at 14 acupoints for two sessions per week. Participants were randomized to undergo either eight weeks of EA30 followed by an eight-week washout period, then eight weeks of EA5, or EA5 followed by a washout period, then EA30. Electro-acupuncture was performed using a stainless silver needle at 14 acupoints for two sessions per week. The needle was connected to an electric stimulator that delivered a constant current, 40 Hz and 3 mA, for 30 or five minutes according to the assigned treatment period. The primary outcome was the difference in weight reduction between the short-duration and the conventional EA while differences in other anth-ropometric parameters and biochemical parameters were considered as secondary outcomes. After each treatment period, all anthro-pometric characteristics of both groups decreased from the baseline regardless of the treatment sequence, including body weight (1.4-1.8 kg; 0.01), body mass index (0.56-0.70 kg/m ; 0.01), waist and hip circumference, skinfold thickness and body fat percentage as well as the improvement in fasting blood glucose and lipid profiles. There were no significant differences of the treatment effects on anthropometric parameters and biomedical chemistries between conventional and short-duration EA. No adverse effects were reported. Short duration EA at 14 acupuncture points had comparable efficacy to conventional EA in reduction of weight and other anthropometric parameters as well as to improve biochemistry parameters in obese women.


The Drosophila Huntington's disease gene ortholog dhtt influences chromatin regulation during development.
Huntington's disease is an autosomal dominant neurodegenerative disorder caused by a CAG expansion mutation in HTT, the gene encoding huntingtin. Evidence from both human genotype-phenotype relationships and mouse model systems suggests that the mutation acts by dysregulating some normal activity of huntingtin. Recent work in the mouse has revealed a role for huntingtin in epigenetic regulation during development. Here, we examine the role of the Drosophila huntingtin ortholog (dhtt) in chromatin regulation in the development of the fly. Although null dhtt mutants display no overt phenotype, we found that dhtt acts as a suppressor of position-effect variegation (PEV), suggesting that it influences chromatin organization. We demonstrate that dhtt affects heterochromatin spreading in a PEV model by modulating histone H3K9 methylation levels at the heterochromatin-euchromatin boundary. To gain mechanistic insights into how dhtt influences chromatin function, we conducted a candidate genetic screen using RNAi lines targeting known PEV modifier genes. We found that dhtt modifies phenotypes caused by knockdown of a number of key epigenetic regulators, including chromatin-associated proteins, histone demethylases (HDMs) and methyltransferases. Notably, dhtt strongly modifies phenotypes resulting from loss of the HDM dLsd1, in both the ovary and wing, and we demonstrate that dhtt appears to act as a facilitator of dLsd1 function in regulating global histone H3K4 methylation levels. These findings suggest that a fundamental aspect of huntingtin function in heterochromatin/euchromatin organization is evolutionarily conserved across phyla.


The effect of drugs on the labeling of blood elements with technetium-99m.
The influence of drugs on the labeling of red blood cells and plasma proteins with 99mTc has been reported. Any drug, which alters the labeling of the tracer, could be expected to modify the disposition of the radiopharmaceuticals. Red blood cells (RBC) labeled with technetium-99m (99mTc) are used for several evaluations in nuclear medicine. We have evaluated the effect of Thuya occidentalis, Peumus boldus and Nicotiana tabacum (tobacco) extracts on the labeling of RBC and plasma and cellular proteins with 99mTc. Blood was incubated with the drugs. Stannous chloride (SnCl2) solutions and 99mTc were added. Plasma (P) and blood cells (BC) were separated. The percentage of radioactivity (%ATI) bound to P and BC was determined. The %ATI on the plasma and cellular proteins was also evaluated by precipitation of P and BC samples with trichloroacetic acid (TCA) and isolation of soluble (SF) and insoluble (IF) fractions. The analysis of the results shows that there is a decrease in %ATI (from 97.64 to 75.89 percent) in BC with Thuya occidentalis extract. The labeling of RBC and plasma proteins can be decreased in presence of tobacco. This can be due either a direct or indirect effect (reactive oxygen species) of tobacco. The analysis of radioactivity in samples of P and BC isolated from samples of whole blood treated with Peumus boldus showed a rapid uptake of the radioactivity by blood cells in the presence of the Peumus boldus, whereas there was a slight decrease in the amount of 99mTc radioactivity in the TCA-insoluble fraction of plasma. This study shows that extracts of some medicinal plants can affect the radiolabeling of red blood cells with 99mTc using an in vitro technique.


Atrial natriuretic peptide and oxytocin induce natriuresis by release of cGMP.
Our hypothesis is that oxytocin (OT) causes natriuresis by activation of renal NO synthase that releases NO followed by cGMP that mediates the natriuresis. To test this hypothesis, an inhibitor of NO synthase, L-nitroarginine methyl ester (NAME), was injected into male rats. Blockade of NO release by NAME had no effect on natriuresis induced by atrial natriuretic peptide (ANP). This natriuresis presumably is caused by cGMP because ANP also activates guanylyl cyclase, which synthesizes cGMP from GTP. The 18-fold increase in sodium (Na+) excretion induced by OT (1 microgram) was accompanied by an increase in urinary cGMP and preceded by 20 min a 20-fold increase in NO3- excretion. NAME almost completely inhibited OT-induced natriuresis and increased NO3- excretion; however, when the dose of OT was increased 10-fold, a dose that markedly increases plasma ANP concentrations, NAME only partly inhibited the natriuresis. We conclude that the natriuretic action of OT is caused by a dual action: generation of NO leading to increased cGMP and at higher doses release of ANP that also releases cGMP. OT-induced natriuresis is caused mainly by decreased tubular Na+ reabsorption mediated by cGMP. In contrast to ANP that releases cGMP in the renal vessels and the tubules, OT acts on its receptors on NOergic cells demonstrated in the macula densa and proximal tubules to release cGMP that closes Na+ channels. Both ANP- and OT-induced kaliuresis also appear to be mediated by cGMP. We conclude that cGMP mediates natriuresis and kaliuresis induced by both ANP and OT.


A Chinese Prescription Yu-Ping-Feng-San Administered in Remission Restores Bronchial Epithelial Barrier to Inhibit House Dust Mite-Induced Asthma Recurrence.
Clinically, the treatments against asthma like β2 agonist focus on controlling the symptoms rather than inhibiting recurrence radically. This study aims to evaluate the efficacy and mechanism of a potent Chinese prescription Yu-Ping-Feng-San (YPFS) against asthma recurrence. We here established an optimized house dust mite (HDM)-induced asthma recurrence mice model with typical asthmatic responses such as significantly augmented airway hyperresponsiveness (AHR), elevated serum IgE, pulmonary type 2 cytokines IL-5 and IL-13 levels, pathological changes including thickening bronchial wall, inflammatory infiltration of lung tissue, etc. Moreover, all typical asthmatic pathological features were prominently alleviated by YPFS applied during remission phase ahead of second elicitation, which was even more effective than three different types of medications dexamethasone, montelukast and salbutamol, which were commonly applied in clinical practice, administered during recurrence phase. Besides, we found that desmoglein 1 (DSG1) remained deficient when asthmatic responses regressed whereas tight junction (TJ) claudin 1 (CLDN1) or adherin junction (AJ) E-cadherin restored spontaneously. In vitro, DSG1 interference resulted in increased thymic stromal lymphopoietin (TSLP) secretion, and epithelial barrier compromise evidenced by significantly elevated transepithelial electrical resistance (TEER) and increased 4-kDa FITC-dextran influx. YPFS could downregulate TSLP production and restore HDM-induced DSG1 deficiency and barrier destruction, which was further reversed by shDSG1. Collectively, administration of YPFS in remission prominently alleviated HDM-induced asthma relapse by restoring DSG1 and decreasing TSLP overexpression, which might be the key factors contributing to chronic asthma relapse. Our data not only demonstrated the pivotal role of DSG1 in asthma pathogenesis, but also provided a novel and potent therapeutic strategy against chronic asthma.


Radar studies of the vertical distribution of insects migrating over southern Britain: the influence of temperature inversions on nocturnal layer concentrations.
Insects migrating over two sites in southern UK (Malvern in Worcestershire, and Harpenden in Hertfordshire) have been monitored continuously with nutating vertical-looking radars (VLRs) equipped with powerful control and analysis software. These observations make possible, for the first time, a systematic investigation of the vertical distribution of insect aerial density in the atmosphere, over temporal scales ranging from the short (instantaneous vertical profiles updated every 15 min) to the very long (profiles aggregated over whole seasons or even years). In the present paper, an outline is given of some general features of insect stratification as revealed by the radars, followed by a description of occasions during warm nights in the summer months when intense insect layers developed. Some of these nocturnal layers were due to the insects flying preferentially at the top of strong surface temperature inversions, and in other cases, layering was associated with higher-altitude temperature maxima, such as those due to subsidence inversions. The layers were formed from insects of a great variety of sizes, but peaks in the mass distributions pointed to a preponderance of medium-sized noctuid moths on certain occasions.


Evaluation of the "Early" Use of Albumin in Children with Extensive Burns: A Randomized Controlled Trial.
To compare early versus delayed albumin resuscitation in children with burns in terms of clinical outcome and response. Randomized controlled trial. Burn center at a tertiary care teaching hospital. Forty-six children aged 1-12 years with burns greater than 15-45% total body surface area admitted within 12 hours of burn injury. Fluid resuscitation was based on the Parkland formula (3 mL/kg/% total body surface area), adjusted according to urine output. Patients received 5% albumin solution between 8 and 12 hours post burn in the intervention group (n = 23) and 24 hours post burn in the control group (n = 23). Both groups were assessed for reduction in crystalloid fluid infusion during resuscitation, development of fluid creep, and length of hospital stay. There was no difference between groups regarding age, weight, sex, % total body surface area, cause of burn, or severity scores. The median crystalloid fluid volume required during the first 3 days post burn was lower in the intervention than in the control group (2.04 vs 3.05 mL/kg/% total body surface area; p = 0.025 on day 1; 1.2 vs 1.71 mL/kg/% total body surface area; p = 0.002 on day 2; and 0.82 vs 1.3 mL/kg/% total body surface area; p = 0.002 on day 3). The median urine output showed no difference between intervention and control groups (2.1 vs 2.0 mL/kg/hr; p = 0.152 on day 1; 2.58 vs 2.54 mL/kg/hr; p = 0.482 on day 2; and 2.9 vs 3.0 mL/kg/hr; p = 0.093 on day 3). Fluid creep was observed in 13 controls (56.5%) and in one patient (4.3%) in the intervention group. The median length of hospital stay was 18 days (range, 15-21 d) for controls and 14 days (range, 10-17 d) in the intervention group (p = 0.004). Early albumin infusion in children with burns greater than 15-45% total body surface area reduced the need for crystalloid fluid infusion during resuscitation. Significantly fewer cases of fluid creep and shorter hospital stay were also observed in this group of patients.


Definitive chemoradiation for the treatment of locally advanced non small-cell lung cancer.
A third of patients with newly diagnosed non-small-cell lung cancer (NSCLC) have locally advanced disease not amenable for curative resection. Addition of chemotherapy to thoracic radiation improves survival in patients with locally advanced NSCLC when compared with thoracic radiation alone. Over the past two decades, we have made slow but steady progress in improving the outcomes of therapy in this subset of patients. This review summarizes the past two decades of research and outlines the direction we need to pursue to significantly enhance the outcomes. The widespread use of positron emission tomography (identifying those with occult distant metastatic disease and sparing them combined-modality therapy), improved radiation techniques, and better supportive care resulting in improved chemotherapy delivery have resulted in improved outcomes. There is considerable interest in studying the role of higher doses of thoracic radiation (74 Gy) in this disease, and this is the subject of an ongoing intergroup study. Despite some recent setbacks, molecularly targeted therapies need to be studied carefully in combination with chemoradiotherapy. There is an urgent need to develop regimens that incorporate chemotherapy agents that can be administered at doses that are systemically active and yet tolerable.


Consumer expectations and experiences of quality in Australian home-based community services.
Australians want to live at home as they age and seek support from health and social care services to achieve this. The consumer driven market-based approach to community services in Australia has resulted in an increases in user's expectations of quality. What constitutes a quality service from the consumer's perspective is an important agenda to understand as the focus of care delivery moves to the domiciliary setting. This paper presents one aspect from a grounded theory PhD study, the aim of which was to understand the lived experience of receiving services in the home and its impact on the meaning of home. Participants were 11 people with dementia and 18 family supporters living in the state of Victoria, Australia. Data were collected between 2015 and 2017 through multiple interviews, photographic images, field notes and memos. NVIVO 10 qualitative analysis software program was used to support constant comparative analysis. Using a grounded theory approach, this study found that the decision to engage with community services was driven by the need to maintain autonomy, self-identity and home life. Participants sought quality services but discovered a dichotomy of positive and negative aspects in the way services were delivered. The most common reaction to the experience of poor-quality care was to reflect on their expectations for care quality; and manage the reality of what was delivered. Team work and service responsiveness were positive characteristics but were offset by service limitations and inefficiencies caused by poor communication and poor staff retention. The interpersonal relationships that participants developed with staff was highlighted; trust was an important factor whereas unreliable, task orientated and poorly trained staff would be rejected. The implications for policy and practice are described.


The intracellular enzymatic response of neutrophils and lymphocytes in patients with precancerous states and cancer of the uterine cervix.
In patients with precancerous states and cancer of the uterine cervix prior to and after radiotherapy exhibit the decreased activity of neutrophil beta-glucuronidase. Moreover, patients treated by radiotherapy before the age 6 to 9 years demonstrate deficiency of N-acetyl-beta-glucuronidase in the above cells. The main finding in lymphocytes of the patients studied was in the appearance by diffusion of the above enzymes and of acid phosphatase in the cytoplasm, reflecting their release from lysosomes and immunological mobilization of these cells. The authors discuss the possible role of neutrophil enzymatic deficiency in lowering the antitumor cytotoxic effect of these cells.


Description of a riboflavin biosynthetic gene variant prevalent in the phylum Proteobacteria.
Riboflavin (vitamin B2) is the precursor of flavin mononucleotide and flavin adenine dinucleotide, which are cofactors essential for a host of intracellular redox reactions. Microorganisms synthesize flavins de novo to fulfill nutritional requirements, but it is becoming increasingly clear that flavins play a wider role in cellular physiology than was previously appreciated. Flavins mediate diverse processes beyond the cytoplasmic membrane, including iron acquisition, extracellular respiration, and interspecies interactions. While investigating the regulation of flavin electron shuttle biosynthesis in the Gram-negative gammaproteobacterium Shewanella oneidensis, we discovered that a riboflavin biosynthetic gene (ribBA) annotated as encoding a bifunctional 3,4-dihydroxy-2-butanone 4-phosphate (DHBP) synthase/GTP cyclohydrolase II does not possess both functions. The novel gene, renamed ribBX here, encodes an amino-terminal DHBP synthase domain. The carboxy-terminal end of RibBX not only lacks GTP cyclohydrolase II activity but also has evolved a different function altogether in S. oneidensis, regulating the activity of the DHBP synthase domain. Phylogenetic analysis revealed that the misannotation of ribBX as ribBA is rampant throughout the phylum Proteobacteria (40% of 2,173 annotated ribBA genes) and that ribBX emerged early in the evolution of this group of microorganisms. We examined the functionality of representative ribBX genes from Beta-, Gamma-, and Epsilonproteobacteria and found that, consistent with sequence-based predictions, the encoded GTP cyclohydrolase II domains lack catalytic activity. The persistence of ribBX in the genomes of so many phylogenetically divergent bacterial species lends weight to the argument that ribBX has evolved a function which lends a selective advantage to the host.


Ophthalmic Features of Outpatient Children Diagnosed with Intracranial Space-Occupying Lesions by Ophthalmologists.
Brain tumors in children often involve the visual system, but most retrospective series are by neurologists or oncologists. In this study we highlight the ophthalmic findings of outpatient children with visual complaints and/or strabismus who, based on ophthalmic examination, were suspected to and confirmed to harbor intracranial space-occupying lesions by magnetic resonance imaging (MRI). Retrospective case series of children (less than 18 years) who for visual complaints and/or strabismus underwent cranial MRI at a referral eye hospital (2005-2012), which revealed intracranial space-occupying lesions. Exclusion criteria were known preexisting orbital or ocular trauma, ocular tumor, or neurological disease. For 26 patients (3 months-17 years; mean 7 years; median 9 years; and 14 boys), the most common clinical presentation was decreased vision with disc pallor (10) or swelling (three). Other presentations were strabismus with disc pallor or swelling (four; two of which were left sixth nerve palsies), acquired esotropia with diplopia (three; one bilateral and two left sixth nerve palsies), acquired exotropia (four; two of which were bilateral third nerve palsies, one of which was left partial third nerve palsy, and one of which was associated with headache), nystagmus (one), and disc swelling with headache (one). Most lesions were in the sellar/suprasellar space (10), posterior fossa (six), or optic nerve/chasm (four). The majority of outpatient children diagnosed by ophthalmologists with intracranial space-occupying lesions presented with disc swelling or pallor in the context of decreased vision or strabismus. Two strabismus profiles that did not include disc swelling or pallor were acquired sixth nerve palsy and acquired exotropia (with ptosis (third nerve palsy), nystagmus, or headache).


The cutaneous trunci reflex for localising and grading thoracolumbar spinal cord injuries in dogs.
To evaluate the accuracy of the cutaneous trunci reflex to localise thoracolumbar spinal cord injuries and to assess the correlation between focal loss (cut-off) of the reflex and clinical severity of thoracolumbar spinal cord injury. Prospective study of 41 dogs with thoracolumbar spinal cord injuries investigated by magnetic resonance imaging. Linear regression analysis was performed to determine the relationship between the vertebral level of the cutaneous trunci reflex cut-off and the maximal and cranial lesion extent. The association between cutaneous trunci reflex cut-off and spinal cord injury severity was tested using a Mann-Whitney U test. Cutaneous trunci reflex cut-off was evident in 33 (80%) of dogs. The cut-off level was 0 to 4 vertebrae caudal to the maximal spinal cord lesion in all dogs. In 16 (48.5%) dogs the cut-off was either 2 or 3 vertebrae caudal to the lesion. The presence of a cut-off significantly correlated with increasing severity (P=0.0001). Loss of the reflex occurred at less severe grades than loss of ambulation and in dogs with ambulatory paresis it was significantly (P=0.0084) associated with increasing severity. The cutaneous trunci reflex allows localisation of thoracolumbar spinal cord lesions within four vertebrae and facilitates clinical segregation of dogs with ambulatory paresis into mild and severe categories.


Cost-effectiveness of adding Endocuff® to standard colonoscopies for interval colorectal cancer screening.
Background and aims: Higher screening colonoscopy adenoma detection rates (ADRs) correlate with reduced risk of interval colorectal cancer (CRC). The Endocuff® device has been shown to improve ADRs compared to standard colonoscopy (SC). This cost-effectiveness analysis compared interval CRC screening using Endocuff®-assisted colonoscopy (EC) vs SC. Methods: A decision-analytic Markov model followed patients through screening, CRC diagnosis, progression, remission, and death. ADRs, CRC progression, and utilities were from literature. CRC incidence, stage distribution, and mortality were from the Surveillance, Epidemiology, and End Results (SEER) and SEER-Medicare linked databases. Screening and annual patient costs were from public databases and literature. Endocuff® device average sales price was applied. Lifetime device and medical costs were evaluated separately for device purchaser, health plan, and accountable care organization (ACO) perspectives. Results: Consistent use of EC instead of SC was expected to reduce lifetime risks of interval CRC and related death by 0.98% and 0.19%, respectively, preventing one case per 102 patients and one death per 526 patients. Survival and quality-of-life (QoL) improved by 0.025 life-years and 0.011 quality-adjusted life-years (QALYs) per patient on average. EC instead of SC led to incremental cost-effectiveness ratios to the device purchaser of $4,421 per life-year gained and $9,843 per QALY gained, and $199 or $87 average cost-savings per patient to the health plan or ACO, respectively. Conclusion: Endocuff® for screening colonoscopies was expected to reduce interval CRC incidence and death, improve QoL, and be cost-effective to the device purchaser and cost-saving to a health plan or ACO.


Partner notification uptake for sexually transmitted infections in China: a systematic literature review.
China's sexually transmitted infection (STI) epidemic requires comprehensive control programmes. Partner services are traditional pillars of STI control but have not been widely implemented in China. This study was a systematic literature review to examine STI partner notification (PN) uptake in China. Four English and four Chinese language databases were searched up to March 2011 to identify articles on PN of STIs including HIV in China. PN uptake was defined as the number of partners named, notified, evaluated or diagnosed per index patient. A total of 11 studies met inclusion criteria. For STI (excluding HIV) PN, a median 31.6% (IQR 27.4%-65.8%) of named partners were notified, 88.8% (IQR 88.4%-90.8%) of notified partners were evaluated and 37.9% (IQR 33.1%-43.6%) of evaluated partners were diagnosed. For HIV PN, a median 15.7% (IQR 13.2%-36.5%) of named partners were notified, 86.7% (IQR 72.9%-90.4%) of notified partners were evaluated and 27.6% (IQR 24.1%-27.7%) of evaluated partners were diagnosed. A mean of 80.6% (SD=12.6%) of patients attempted PN, and 72.4% (IQR 63.8%-81.1%) chose self-referral when offered more than one method of PN. Perceived patient barriers included social stigma, fear of relationship breakdown, uncertainty of how to notify and lack of partner contact information. Perceived infrastructure barriers included limited time and trained staff, mistrust of health workers and lack of PN guidelines. PN programmes are feasible in China. Further research on STI PN, particularly among men who have sex with men and other high-risk groups, is an important public health priority. PN policies and guidelines are urgently needed in China.


Feasibility of smaller arterial cannulas in venoarterial extracorporeal membrane oxygenation.
To facilitate venoarterial extracorporeal membrane oxygenation (ECMO) insertion for cardiogenic shock, we recently adopted a strategy of using a 15F arterial cannula in all patients, rather than 1 designed to maximize flow. We aimed to compare the clinical outcomes of these 2 strategies. In this retrospective study, 101 consecutive patients supported with ECMO via femoral cannulation between March 2007 and March 2013 were divided into 2 groups: Group L (17F-24F arterial cannula to accommodate full flow [ie, cardiac index of 2.5 L/m(2)/min]; n = 51) and Group S (15F arterial cannula; n = 50). The primary outcomes of interest were patients' overall status at 24 hours of support and cannulation-related adverse events. There were no significant differences in patient demographics, etiology of cardiogenic shock, or severity of illness before ECMO initiation between the 2 groups. Group L had significantly higher ECMO flow than Group S (flow index at 24 hours: 2.2 ± 0.7 vs 1.7 ± 0.3 L/m(2)/min; P < .001). However, there was no significant difference in use of vasoactive medication/hemodynamic parameters/laboratory parameters. Group L had higher incidence of cannulation-related adverse events (35% vs 22% in Group S [P = .14]), particularly in cannulation site bleeding (28% vs 10% [P = .03]). Thirty-day survival was 55% in Group L versus 52% in Group S (P = .77). Bleeding complication occurred in 53% in Group L versus 32% in Group S (P = .03). Compared with the use of larger cannulas, ECMO with a 15F arterial cannula appears to provide comparable clinical support with reduced bleeding complications.


Quantitative analysis of enzymatic fractionation of multiple substrate mixtures.
The enzymatic conversion of mixtures of multiple substrates was studied quantitatively, based on established methodology used for the enzymatic kinetic resolution of racemic mixtures, involving the use of competitive factors: ratios of specificity constants (k(cat)/K(M)) of substrate pairs. The competitive factors of the substrates were defined in relation to a reference substrate. These competitive factors were used to predict the composition of the reaction mixture as a function of the degree of conversion of the reaction. The methodology was evaluated using three different lipases to hydrolyze a model mixture of four fatty acid methyl esters and for the esterification of a mixture of the same fatty acids in free form with ethanol. In most cases, the competitive factors determined from the initial phase of the reactions predicted the product composition during the rest of the reaction very well. The slowest reacting fatty acid was erucic acid (both in free form and as methyl ester), which was thus enriched in the remaining substrate fraction, while the other fatty acids: lauric acid, palmitic acid and oleic acid were converted faster. Simulations of the compositions of reaction mixtures with different values of the competitive factors were carried out to provide an overview of what could be achieved using enzymatic enrichment. Possible applications include reactions involving homologous substrates and mixtures of multiple isomers. The analysis presented provides guidelines that can be useful in the screening and development of enzymes for enzymatic enrichment applications.


Louder sounds can produce less forward masking: effects of component phase in complex tones.
The influence of the degree of envelope modulation and periodicity on the loudness and effectiveness of sounds as forward maskers was investigated. In the first experiment, listeners matched the loudness of complex tones and noise. The tones had a fundamental frequency (F0) of 62.5 or 250 Hz and were filtered into a frequency range from the 10th harmonic to 5000 Hz. The Gaussian noise was filtered in the same way. The components of the complex tones were added either in cosine phase (CPH), giving a large crest factor, or in random phase (RPH), giving a smaller crest factor. For each F0, subjects matched the loudness between all possible stimulus pairs. Six different levels of the fixed stimulus were used, ranging from about 30 dB SPL to about 80 dB SPL in 10-dB steps. Results showed that, at a given overall level, the CPH and the RPH tones were louder than the noise, and that the CPH tone was louder than the RPH tone. The difference in loudness was larger at medium than at low levels and was only slightly reduced by the addition of a noise intended to mask combination tones. The differences in loudness were slightly smaller for the higher than for the lower F0. In the second experiment, the stimuli with the lower F0s were used as forward maskers of a 20-ms sinusoid, presented at various frequencies within the spectral range of the maskers. Results showed that the CPH tone was the least effective forward masker, even though it was the loudest. The differences in effectiveness as forward maskers depended on masker level and signal frequency; in order to produce equal masking, the level of the CPH tone had to be up to 35 dB above that of the RPH tone and the noise. The implications of these results for models of loudness are discussed and a model is presented based on neural activity patterns in the auditory nerve; this predicts the general pattern of loudness matches. It is suggested that the effects observed in the experiments may have been influenced by two factors: cochlear compression and suppression.


NXSensor web tool for evaluating DNA for nucleosome exclusion sequences and accessibility to binding factors.
Nucleosomes, a basic structural unit of eukaryotic chromatin, play a significant role in regulating gene expression. We have developed a web tool based on DNA sequences known from empirical and theoretical studies to influence DNA bending and flexibility, and to exclude nucleosomes. NXSensor (available at http://www.sfu.ca/~ibajic/NXSensor/) finds nucleosome exclusion sequences, evaluates their length and spacing, and computes an 'accessibility score' giving the proportion of base pairs likely to be nucleosome-free. Application of NXSensor to the promoter regions of housekeeping (HK) genes and those of tissue-specific (TS) genes revealed a significant difference between the two classes of gene, the former being significantly more open, on average, particularly near transcription start sites (TSSs). NXSensor should be a useful tool in assessing the likelihood of nucleosome formation in regions involved in gene regulation and other aspects of chromatin function.


[Influence of tobacco-Chuanminshen violaceum rotation on microbe community in soil].
Soil microbes are the important indicator of soil quality. For exploring Chuanminshen violaceum planting to microbial effects in tobacco soil, this paper adopted Illumina MiSeq high-throughput sequencing to research the change of bacteria and fungi at the phylum and genus in the soil. The results showed that the Ch. violaceum planting increased the biodiversity of bacteria and fungi. The influence on fungi was greater than that on bacteria. It greatly increased the sequence of fungi, it obtained 32 978 16S rDNA and 32 229 18S rDNA sequence number. There was no change of the top three phylums in bacteria, but the content changed, Proteobacteria and Acidobacteria reduced by 1.73% and 1.4% respectively, and Actinobacteria increased by 0.65%. The advantage phylum Ascomycete in tobacco reduced by 27.99% to be second advantage phylum after Ch. violaceum planting, and the second advantage phylum Basidiomycete increased by 23.69% to become the first dominant fungi. At the genus, Ch. violaceum planting changed the order of dominant genus and the abundance was also changed. Some changed largely such as uncultured Acidobacteriaceae Subgroup-1, Gemmatimonas, Subgroup-2,uncultured Nitrosomonadaceae for bacteria, norank Sordariales, norank Agaricomycetes, Phialophora for fungi. Especially the rotation increased antagonistic microbes and physiological microbes and decreased pathogenic microbes. So the Ch. violaceum planting can improve the microbe community in tobacco soil.


Persistent binding of MgADP to the E187A mutant of Escherichia coli phosphofructokinase in the absence of allosteric effects.
MgADP binding to the allosteric site enhances the affinity of Escherichia coli phosphofructokinase (PFK) for fructose 6-phosphate (Fru-6-P). X-ray crystallographic data indicate that MgADP interacts with the conserved glutamate at position 187 within the allosteric site through an octahedrally coordinated Mg(2+) ion [Shirakihara, Y., and Evans, P. R. (1988) J. Mol. Biol. 204, 973-994]. Lau and Fersht reported that substituting an alanine for this glutamate within the allosteric site of PFK (i.e., mutant E187A) causes MgADP to lose its allosteric effect upon Fru-6-P binding [Lau, F. T.-K., and Fersht, A. R. (1987) Nature 326, 811-812]. However, these authors later reported that MgADP inhibits Fru-6-P binding in the E187A mutant. The inhibition presumably occurs by preferential binding to the inactive (T) state complex of the Monod-Wyman-Changeux two-state model [Lau, F. T.-K., and Fersht, A. R. (1989) Biochemistry 28, 6841-6847]. The present study provides an alternative explanation of the role of MgADP in the E187A mutant. Using enzyme kinetics, steady-state fluorescence emission, and anisotropy, we performed a systematic linkage analysis of the three-ligand interaction between MgADP, Fru-6-P, and MgATP. We found that MgADP at low concentrations did not enhance or inhibit substrate binding. Anisotropy shows that MgADP binding at the allosteric site occurred even when MgADP produced no allosteric effect. However, as in the wild-type enzyme, the binding of MgADP to the active site in the mutant competitively inhibited MgATP binding and noncompetitively inhibited Fru-6-P binding. These results clarified the mechanism of a three-ligand interaction and offered a nontraditional perspective on allosteric mechanism.


Stress signaler p38 mitogen-activated kinase activation: a cause for concern?
Oxidative stress (OS) induced activation of p38 mitogen-activated kinase (MAPK) and cell fate from p38 signaling was tested using the human fetal membrane's amnion epithelial cells (AEC). We created p38 KO AEC using the CRISPR/Cas9 approach and tested cell fate in response to OS on an AEC-free fetal membrane extracellular matrix (ECM). Screening using image CyTOF indicated OS causing epithelial-mesenchymal transition (EMT). Further testing revealed p38 deficiency prevented AEC senescence, EMT, cell migration, and inflammation. To functionally validate in vitro findings, fetal membrane-specific conditional KO (cKO) mice were developed by injecting Cre-recombinase encoded exosomes intra-amniotically into p38αloxP/loxP mice. Amnion membranes from p38 cKO mice had reduced senescence, EMT, and increased anti-inflammatory IL-10 compared with WT animals. Our study suggested that overwhelming activation of p38 in response to OS inducing risk exposures can have an adverse impact on cells, cause cell invasion, inflammation, and ECM degradation detrimental to tissue homeostasis.


Effect of Storage Conditions on Growth of Heat-Stressed Yersinia Enterocolitica in Ground Pork.
Ground pork was inoculated with either heat-shocked or non-heat-shocked (control) Yersinia enterocolitica . After thorough mixing, the meat was divided into 25-g portions in plastic pouches and sealed under air, vacuum, or modified atmosphere (50% CO2 and 50% N2). All the samples were heat-treated at 55°C for 15 min and then stored at either 25 or 4°C. Samples were plated at regular intervals after storage and the growth of Y. enterocolitica was determined. Survivors were also examined for pathogenicity by performing certain biochemical assays. The growth of Y. enterocolitica , both heat-shocked and control, was observed under all atmospheres and both temperatures. There was no significant difference in growth rates between the heat-shocked and control samples under all the storage atmospheres and temperatures. Also, in both heat-shocked and control samples, Y. enterocolitica grew rapidly under all atmospheres, and the survivors remained pathogenic. The results indicated that storage of meat at 4°C, whether under vacuum or modified atmosphere, was insufficient to inhibit growth of Y. enterocolitica and that prior heat shock had no effect on growth rate or pathogenicity of survivors.


Transglutaminase 2 is needed for the formation of an efficient phagocyte portal in macrophages engulfing apoptotic cells.
Transglutaminase 2 (TG2), a protein cross-linking enzyme with many additional biological functions, acts as coreceptor for integrin beta(3). We have previously shown that TG2(-/-) mice develop an age-dependent autoimmunity due to defective in vivo clearance of apoptotic cells. Here we report that TG2 on the cell surface and in guanine nucleotide-bound form promotes phagocytosis. Besides being a binding partner for integrin beta(3), a receptor known to mediate the uptake of apoptotic cells via activating Rac1, we also show that TG2 binds MFG-E8 (milk fat globulin EGF factor 8), a protein known to bridge integrin beta(3) to apoptotic cells. Finally, we report that in wild-type macrophages one or two engulfing portals are formed during phagocytosis of apoptotic cells that are characterized by accumulation of integrin beta(3) and Rac1. In the absence of TG2, integrin beta(3) cannot properly recognize the apoptotic cells, is not accumulated in the phagocytic cup, and its signaling is impaired. As a result, the formation of the engulfing portals, as well as the portals formed, is much less efficient. We propose that TG2 has a novel function to stabilize efficient phagocytic portals.


Transdermal delivery of insulin in mice by using lecithin vesicles as a carrier.
The present study was undertaken to characterize the preparation of flexible lecithin vesicles containing insulin and to assess the enhancing effect of these flexible vesicles on the transdermal delivery of a hydrophilic protein. Both conventional and flexible vesicles were prepared by reverse-phase evaporation and treated further by sonication. The free drug was separated from vesicles by column chromatography and analyzed by HPLC. Both conventional and flexible vesicles were transparent colloidal dispersions. The particle size of the conventional and flexible vesicles was 73.5 nm and 87.1 nm with a polydispersity index of 44.5% and 15.6%, respectively. The entrapment efficiencies of conventional and flexible vesicles were 35% and 81%, respectively. When vesicles were nonocclusively applied onto the abdominal mice skin at a dose of 0.90 IU/cm2, in vivo hypoglycemic study showed the drop percentage of blood glucose by flexible vesicles was 21.42 +/- 10.19% at 1 hr, reached 61.48 +/- 8.97% at 5 hr, and was larger than 50% within 18 hr. Conventional vesicles, insulin solution, and saline had no hypoglycemic effect. Probably due to the incorporation or adsorption of a certain amount of insulin into the flexible vesicles during the mixing process, blank flexible vesicles mixed with insulin solution had a certain degree of hypoglycemic effect, though much less than the effect of flexible vesicles containing insulin (p < 0.05). Flexible vesicle may become a promising carrier for the transdermal delivery of hydrophilic polypeptides.


Induction of local immunosuppression in allogeneic cell transplantation by cell-type-specific expression of PD-L1 and CTLA4Ig.
Immune rejection has long hindered allogeneic cell transplantation therapy. Current genetic modification approaches, including direct targeting of major histocompatibility complex or constitutive expression of immune inhibitory molecules, exhibit drawbacks such as severe adverse effects or elevated tumorigenesis risks. To overcome these limitations, we introduce an innovative approach to induce cell-type-specific immune tolerance in differentiated cells. By engineering human embryonic stem cells, we ensure the exclusive production of the immune inhibitory molecules PD-L1/CTLA4Ig in differentiated cells. Using this strategy, we generated hepatocyte-like cells expressing PD-L1 and CTLA4Ig, which effectively induced local immunotolerance. This approach was evaluated in a humanized mouse model that mimics the human immune system dynamics. We thus demonstrate a robust and selective induction of immunotolerance specific to hepatocytes, improving graft survival without observed tumorigenesis. This precise immune tolerance strategy holds great promise for advancing the development of stem cell-based therapeutics in regenerative medicine.


DietCam: Multiview Food Recognition Using a Multikernel SVM.
Food recognition is a key component in evaluation of everyday food intakes, and its challenge is due to intraclass variation. In this paper, we present an automatic food classification method, DietCam, which specifically addresses the variation of food appearances. DietCam consists of two major components, ingredient detection and food classification. Food ingredients are detected through a combination of a deformable part-based model and a texture verification model. From the detected ingredients, food categories are classified using a multiview multikernel SVM. In the experiment, DietCam presents reliability and outperformance in recognition of food with complex ingredients on a database including 15,262 food images of 55 food types.


An Economic Analysis of Aneuploidy Screening of Oocytes in Assisted Reproduction in Germany.
Background The randomized ESTEEM trial reported that preimplantation genetic aneuploidy testing of oocytes by polar body biopsy (PGT-A) with array comparative genomic hybridization (aCGH) in women aged 36 - 40 years undergoing assisted reproduction treatment reduces the number of embryo transfers and the risk of miscarriage while not impacting the live birth rate. Method A decision tree model based on data from the ESTEEM trial was created and analyzed, using three cost scenarios for assisted reproduction treatment in Germany (statutory health insurance [GKV] = the deductible is 50% of the standard medical costs; private medical insurance [PKV] = invoicing is based on the German medical fee schedule [GOÄ]; private medical insurance with a simple GOÄ factor [simple GOÄ factor] = invoicing is based on the standard medical fees multiplied by a linear GOÄ factor). The scenarios were compared for cost-effectiveness (cost per live birth), cost per prevented miscarriage and the threshold values for cost and effectiveness. Results PGT-A increased the costs per live birth in all scenarios (GKV: + 208%; PKV: + 49%; simple GOÄ factor: + 89%). A threshold analysis showed a substantial cost discrepancy between the actual cost of the intervention based on GOÄ (€ 5801) vs. the theoretically tolerable PGT-A cost (GKV: € 561, PKV: € 1037, single GOÄ-factor: € 743). The incremental cost per one prevented miscarriage was approximately € 70 000 - 75 000 for all cost scenarios. Conclusion The use of PGT-A with aCGH in assisted reproduction cannot be recommended from a cost-effectiveness perspective.


An Alternative Route for Entrapped Inferior Orbital Nerve in Orbital Floor Fracture.
Orbital floor fractures pose a grave threat for injury to the infraorbital nerve, resulting in the patient suffering from a disturbing paraesthesia. It is challenging for the operating surgeon to release and secure the entrapped nerve with reconstruction of the orbital floor. We present an interesting case of orbital floor fracture with entrapped infraorbital nerve, wherein we have decompressed the nerve and provided it, a new course.


Enhancement of carboplatin-mediated lung cancer cell killing by simultaneous disruption of glutathione and thioredoxin metabolism.
Cancer cells (relative to normal cells) show increased steady-state levels of hydroperoxides that are compensated by increased glucose and hydroperoxide metabolism. The current study determined whether inhibitors of glucose and hydroperoxide metabolism could induce chemoradiosensitization by enhancing oxidative stress in lung cancer cells. A549 and NCI-H292 human lung carcinoma cells were treated with 2-deoxy-d-glucose (2DG) combined with carboplatin + ionizing radiation (IR). Lung cancer cells were further sensitized with inhibitors of glutathione (GSH)- and thioredoxin (Trx)-dependent metabolism [buthionine sulfoximine (BSO) and auranofin, respectively] in vitro and in vivo. When 2DG was combined with carboplatin + IR, clonogenic cell killing was enhanced in A549 and NCI-H292 cells, and this combination was more effective than paclitaxel + carboplatin + IR. The thiol antioxidant (N-acetylcysteine, NAC) was capable of protecting cancer cells from 2DG + carboplatin -induced cell killing. Simultaneous treatment of cancer cells with BSO and auranofin, at doses that were not toxic as single agents, also enhanced lung cancer cell killing and sensitivity to 2DG + carboplatin. This treatment combination also increased oxidation of both GSH and Trx, which were inhibited by NAC. Mice treated with auranofin + BSO showed no alterations in circulating leukocytes or red blood cells. Xenograft lung tumor growth in mice was more effectively inhibited by treatment with auranofin + BSO + carboplatin than animals treated with carboplatin or auranofin + BSO alone. These results show in vitro and in vivo that simultaneous inhibition of GSH and Trx metabolism can effectively inhibit lung cancer cell growth and induce chemosensitization by a mechanism that involves thiol-mediated oxidative stress.


Chinese Herbal Medicine Hepatotoxicity: The Evaluation and Recognization Based on Large-scale Evidence Database.
Due to the special nature of Chinese Herbal medicine and the complexity of its clinical use, it is difficult to identify and evaluate its toxicity and resulting herb induced liver injury (HILI). First, the database would provide full profile of HILI from the basic ingredients to clinical outcomes by the most advanced algorithms of artificial intelligence, and it is also possible that we can predict possibilities of HILI after patients taking Chinese herbs by individual patient evaluation and prediction. Second, the database would solve the chaos and lack of the relevant data faced by the current basic research and clinical practice of Chinese Herbal Medicine. Third, we can also screen the susceptible patients from the database and thus prevent the accidents of HILI from the very beginning. The Roussel Uclaf Causality Assessment Method (RUCAM) is the most accepted method to evaluate DILI, but at present before using the RUCAM evaluation method, data resource collection and analysis are yet to be perfected. Based on existing research on drug-metabolizing enzymes mediating reactive metabolites (RMs), the aim of this study is to explore the possibilities and methods of building multidimensional hierarchical database composing of RMs evidence library, Chinese herbal evidence library, and individualized reports evidence library of herb induced liver injury HILI. The potential benefits lie in its ability to organize, use vast amounts of evidence and use big data mining techniques at the center for Chinese herbal medicine liver toxicity research, which is the most difficult key point of scientific research to be investigated in the next few years.


Perceiving blocks of emotional pictures and sounds: effects on physiological variables.
Most studies on physiological effects of emotion-inducing images and sounds examine stimulus locked variables reflecting a state of at most a few seconds. We here aimed to induce longer lasting emotional states using blocks of repetitive visual, auditory, and bimodal stimuli corresponding to specific valence and arousal levels. The duration of these blocks enabled us to reliably measure heart rate variability as a possible indicator of arousal. In addition, heart rate and skin conductance were determined without taking stimulus timing into account. Heart rate was higher for pleasant and low arousal stimuli compared to unpleasant and high arousal stimuli. Heart rate variability and skin conductance increased with arousal. Effects of valence and arousal on cardiovascular measures habituated or remained the same over 2-min intervals whereas the arousal effect on skin conductance increased. We did not find any effect of stimulus modality. Our results indicate that blocks of images and sounds of specific valence and arousal levels consistently influence different physiological parameters. These parameters need not be stimulus locked. We found no evidence for differences in emotion induction between visual and auditory stimuli, nor did we find bimodal stimuli to be more potent than unimodal stimuli. The latter could be (partly) due to the fact that our bimodal stimuli were not optimally congruent.


Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis.
Clopidogrel and prasugrel are subject to efflux via P-glycoprotein (encoded by ABCB1, also known as MDR1). ABCB1 polymorphisms, particularly 3435C→T, may affect drug transport and efficacy. We aimed to assess the effect of this polymorphism by itself and alongside variants in CYP2C19 on cardiovascular outcomes in patients treated with clopidogrel or prasugrel in TRITON-TIMI 38. We also assessed the effect of genotype on the pharmacodynamic and pharmacokinetic properties of these drugs in healthy individuals. We genotyped ABCB1 in 2932 patients with acute coronary syndromes undergoing percutaneous intervention who were treated with clopidogrel (n=1471) or prasugrel (n=1461) in the TRITON-TIMI 38 trial. We evaluated the association between ABCB1 3435C→T and rates of the primary efficacy endpoint (cardiovascular death, myocardial infarction, or stroke) until 15 months. We then assessed the combined effect of ABCB1 3435C→T genotype and reduced-function alleles of CYP2C19. 321 healthy individuals were also genotyped, and we tested the association of genetic variants with reduction in maximum platelet aggregation and plasma concentrations of active drug metabolites. In patients treated with clopidogrel, ABCB1 3435C→T genotype was significantly associated with the risk of cardiovascular death, myocardial infarction, or stroke (p=0·0064). TT homozygotes had a 72% increased risk of the primary endpoint compared with CT/CC individuals (Kaplan-Meier event rates 12·9% [52 of 414] vs 7·8% [80 of 1057 participants]; HR 1·72, 95% CI 1·22-2·44, p=0·002). ABCB1 3435C→T and CYP2C19 genotypes were significant, independent predictors of the primary endpoint, and 681 (47%) of the 1454 genotyped patients taking clopidogrel who were either CYP2C19 reduced-function allele carriers, ABCB1 3435 TT homozygotes, or both were at increased risk of the primary endpoint (HR 1·97, 95% CI 1·38-2·82, p=0·0002). In healthy participants, 3435 TT homozygotes had an absolute reduction in maximum platelet aggregation with clopidogrel that was 7·3 percentage points less than for CT/CC individuals (p=0·0127). ABCB1 genotypes were not significantly associated with clinical or pharmacological outcomes in patients with an acute coronary syndrome or healthy individuals treated with prasugrel, respectively. Individuals with the ABCB1 3435 TT genotype have reduced platelet inhibition and are at increased risk of recurrent ischaemic events during clopidogrel treatment. In patients with acute coronary syndromes who have undergone percutaneous intervention, when both ABCB1 and CYP2C19 are taken into account, nearly half of the population carries a genotype associated with increased risk of major adverse cardiovascular events while on standard doses of clopidogrel. Daiichi Sankyo Company Ltd and Eli Lilly and Company.


Clinical utility of bile acid sequestrants in the treatment of dyslipidemia: a scientific review.
Bile acid sequestrants (BAS) continue to command a position in the treatment of dyslipidemias 25 years after their introduction. Partial diversion of the enterohepatic circulation using BAS depletes the endogenous bile acid pool by approximately 40%, thus stimulating an increase in bile acid synthesis from cholesterol, which lowers low-density lipoprotein cholesterol (LDL-C) by 15 to 26%. Three BAS are currently used for treating hypercholesterolemia in the United States: the conventional sequestrants, cholestyramine and colestipol, and the specifically engineered BAS, colesevelam hydrochloride (HCl). Compared with conventional BAS, colesevelam HCl has enhanced specificity, greater affinity, and higher capacity for binding bile acids, due to its polymer structure engineered for bile acid sequestration. BAS are not absorbed by the intestine and thus have no systemic drug-drug interactions, but may interfere with the absorption of some drugs. Although BAS monotherapy effectively lowers LDL-C, combination therapy, especially with BAS and statins, is becoming increasingly common due to complementary mechanisms of action. Low-dose statin plus BAS combinations lead to greater or similar LDL-C reductions compared with high-dose statin monotherapy and may have a better safety profile. Combinations of BAS with nonstatin lipid-lowering agents, including niacin, fibrates, and cholesterol absorption inhibitors, may be useful in those patients who require intensive lipid-lowering, but are statin intolerant. BAS treatment can significantly reduce coronary artery disease (CAD) progression and the risk of CAD-associated outcomes. It is also becoming clear that BAS and other therapies that manipulate the bile acid synthetic pathway may have clinically useful therapeutic effects on other metabolic disorders including type 2 diabetes.


Naïve individuals promote collective exploration in homing pigeons.
Group-living animals that rely on stable foraging or migratory routes can develop behavioural traditions to pass route information down to inexperienced individuals. Striking a balance between exploitation of social information and exploration for better alternatives is essential to prevent the spread of maladaptive traditions. We investigated this balance during cumulative route development in the homing pigeon Columba livia. We quantified information transfer within pairs of birds in a transmission-chain experiment and determined how birds with different levels of experience contributed to the exploration-exploitation trade-off. Newly introduced naïve individuals were initially more likely to initiate exploration than experienced birds, but the pair soon settled into a pattern of alternating leadership with both birds contributing equally. Experimental pairs showed an oscillating pattern of exploration over generations that might facilitate the discovery of more efficient routes. Our results introduce a new perspective on the roles of leadership and information pooling in the context of collective learning.


["I would like to so much--but then also; but, but--!!!"--torment of a private lecturer at the beginning of the 19th century].
The biography of Carl Friedrich August Theodor Kastner (1797-after 1841), the brother of the famous chemist and teacher of Justus von Liebig (1803-1873) Karl Wilhelm Gottlob Kastner (1783-1857), is an interesting example of the difficult situation of outside lecturers at the universities in the first half of the 19th century; a big group of scientists, which are absolutely underrepresented in the source material and in the historiography too. This paper tries to show the facts and the backgrounds for the problems in the career of outside lecturers.


Affective computing and autism.
This article highlights the overlapping and converging goals and challenges of autism research and affective computing. We propose that a collaboration between autism research and affective computing could lead to several mutually beneficial outcomes--from developing new tools to assist people with autism in understanding and operating in the socioemotional world around them, to developing new computational models and theories that will enable technology to be modified to provide an overall better socioemotional experience to all people who use it. This article describes work toward this convergence at the MIT Media Lab, and anticipates new research that might arise from the interaction between research into autism, technology, and human socioemotional intelligence.


Subacute care as a new source of revenue.
Subacute rehabilitation is a segment of subacute care that offers potential financial rewards for providers while offering needed care to rehabilitation patients who would qualify for subacute care. It is also a logical level of care for acute care providers and/or rehabilitation providers to implement. While a subacute rehabilitation unit definitely can be a more financially attractive opportunity than a traditional skilled nursing unit, success in such a venture requires an in-depth understanding of the structure of such units and of reimbursement for skilled nursing care.


Beyond the 5-HT2A Receptor: Classic and Nonclassic Targets in Psychedelic Drug Action.
Serotonergic psychedelics, such as psilocybin and LSD, have garnered significant attention in recent years for their potential therapeutic effects and unique mechanisms of action. These compounds exert their primary effects through activating serotonin 5-HT2A receptors, found predominantly in cortical regions. By interacting with these receptors, serotonergic psychedelics induce alterations in perception, cognition, and emotions, leading to the characteristic psychedelic experience. One of the most crucial aspects of serotonergic psychedelics is their ability to promote neuroplasticity, the formation of new neural connections, and rewire neuronal networks. This neuroplasticity is believed to underlie their therapeutic potential for various mental health conditions, including depression, anxiety, and substance use disorders. In this mini-review, we will discuss how the 5-HT2A receptor activation is just one facet of the complex mechanisms of action of serotonergic psychedelics. They also interact with other serotonin receptor subtypes, such as 5-HT1A and 5-HT2C receptors, and with neurotrophin receptors (e.g., tropomyosin receptor kinase B). These interactions contribute to the complexity of their effects on perception, mood, and cognition. Moreover, as psychedelic research advances, there is an increasing interest in developing nonhallucinogenic derivatives of these drugs to create safer and more targeted medications for psychiatric disorders by removing the hallucinogenic properties while retaining the potential therapeutic benefits. These nonhallucinogenic derivatives would offer patients therapeutic advantages without the intense psychedelic experience, potentially reducing the risks of adverse reactions. Finally, we discuss the potential of psychedelics as substrates for post-translational modification of proteins as part of their mechanism of action.


Croatian anthropological terminology--challenges and dilemmas.
This paper describes the project ANTRONA aimed at constructing basic anthropological terminology that covers the entire range of anthropology as a science. It is a part of national language planning oriented terminology management for the Croatian language, and as such it is focused solely at the production of a terminographic database. The major difficulties encountered during the procedural stages of the project are outlined, such as the wide range of the interdisciplinary field of anthropology, including concepts and terms from natural and social sciences and humanities, as well as polysemy and fuzzy boundaries between the lexicon of the general language and specialized language. On the basis of several examples, we argue that terminography should be dealt with primarily by keeping in mind the range of its subsequent applications the aim of which is not only ontological, but also communicative in nature, and that functional pragmatic approach offers a more flexible framework for dealing with the demands of terminology in such an interdisciplinary field.


Analysis and evaluation of the moral distress theory.
Moral distress is a pervasive problem in nursing resulting in a detriment to patient care, providers, and organizations. Over a decade ago, the moral distress theory (MDT) was proposed and utilized in multiple research studies. This middle range theory explains and predicts the distress that occurs in a nurse because of moral conflict. The research findings born from this theory have been substantial. Since inception of this theory, moral distress has been extensively examined which has further elaborated its understanding. This paper provides an analysis and evaluation of the MDT according to applicable guidelines. Current understanding of the phenomenon indicates that a new theory may be warranted to better predict, treat, and manage moral distress.


Visitor presence and a changing soundscape, alongside environmental parameters, can predict enclosure usage in captive flamingos.
The sound environment of a zoo animal is a complex milieu of animal and human-generated sounds; coming from the species itself, other species, visitors, keepers and other zoo-users. Research determining how different components of the sound environment affect animal behaviour is surprisingly lacking but could have real-world impacts for animal welfare and zoo enclosure design. The current study investigated the effects of the sound environment on two flocks of flamingos housed in open-air enclosures at British zoos. Measures of how each flock used its enclosure (as a response variable) and environmental variables (Inband Power and Peak Frequency were recorded as characteristics of the sound environment, as well as temperature, humidity and cloud cover, and finally visitor presence-all as potential predictor variables) were made over a 2-month period. Assessment of space use by zoo animals is often used as a measure of the appropriateness of an exhibit and to understand welfare. Given that flamingo activity is influenced by weather and that the sound environment of the zoo is likely to be influenced by the number and the presence of visitors, it was assumed that these predictor variables would influence where the flamingos were located at different times of the day. As expected, there was a complicated relationship between enclosure use and Inband Power (average spectral density, a measure of sound energy) in both flocks; visitors generated salient sound but other visitor characteristics such as their physical presence may have impacted the movement of the birds around their enclosures. Results show a complex picture where environmental conditions influence flamingo enclosure usage as well as visitor presence and sounds around/in the enclosure. Findings are not consistent between the two flocks, with one flock demonstrating distinct temporal change to enclosure zone occupancy and the other responsive to humidity and cloud cover variation. We believe enclosure use can provide a valuable indication of how birds react to their soundscape; however, our findings suggest more work is needed to unpick the components of captive sound environments, and their relative effects on how animals use their space.


Mechanical evidence that flamingos can support their body on one leg with little active muscular force.
Flamingos (Phoenicopteridae) often stand and sleep on one leg for long periods, but it is unknown how much active muscle contractile force they use for the mechanical demands of standing on one leg: body weight support and maintaining balance. First, we demonstrated that flamingo cadavers could passively support body weight on one leg without any muscle activity while adopting a stable, unchanging, joint posture resembling that seen in live flamingos. By contrast, the cadaveric flamingo could not be stably held in a two-legged pose, suggesting a greater necessity for active muscle force to stabilize two-legged versus one-legged postures. Our results suggest that flamingos engage a passively engaged gravitational stay apparatus (proximally located) for weight support during one-legged standing. Second, we discovered that live flamingos standing on one leg have markedly reduced body sway during quiescent versus alert behaviours, with the point of force application directly under the distal joint, reducing the need for muscular joint torque. Taken together, our results highlight the possibility that flamingos stand for long durations on one leg without exacting high muscular forces and, thus, with little energetic expenditure.


Paraneoplastic refractory hypercalcemia due to advanced metastatic esthesioneuroblastoma.
Esthesioneuroblastoma (ENB) is a rare malignant neoplasm arising from the olfactory neuroepithelium. ENB has no distinctive clinical picture, but often presents as chronic unilateral nasal obstruction or epistaxis. It has a long natural history; the 5-year survival rates have been estimated at 82%. A number of paraneoplastic syndromes have been described in the setting of ENB. Humoral hypercalcemia of malignancy (HHM) has never been described with ENB before. We describe a case of Kadish Stage C ENB with recurrent Hypercalcemia. The hypercalcemia became refractory to therapy and was the cause of death.


Ureidoglycolate hydrolase, amidohydrolase, lyase: how errors in biological databases are incorporated in scientific papers and vice versa.
An opaque biochemical definition, an insufficient functional characterization, an interpolated database description, and a beautiful 3D structure with a wrong reaction. All these are elements of an exemplar case of misannotation in biological databases and confusion in the scientific literature concerning genes and enzymes acting on ureidoglycolate, an intermediate of purine catabolism. Here we show biochemical evidence for the relocation of genes assigned to EC 188.8.131.52 (ureidoglycolate hydrolase, releasing ammonia), such as allA of Escherichia coli or DAL3 of Saccharomyces cerevisiae, to EC 18.104.22.168 (ureidoglycolate lyase, releasing urea). The EC 188.8.131.52 should be more appropriately named ureidoglycolate amidohydrolase and include genes equivalent to UAH of Arabidopsis thaliana. The distinction between ammonia- or urea-releasing activities from ureidoglycolate is relevant for the understanding of nitrogen metabolism in various organisms and of virulence factors in certain pathogens rather than a nomenclature problem. We trace the original fault in database annotation and provide a rationale for its incorporation and persistence in the scientific literature. Notwithstanding the technological distance, yet not surprising for the constancy of human nature, error categories and mechanisms established in the study of the work of amanuensis monks still apply to the modern curation of biological databases.


[Spatial variation of soil properties and quality evaluation for arable Ustic Cambosols in central Henan Province].
A GIS-based 500 m x 500 m soil sampling point arrangement was set on 248 points at Wenshu Town of Yuzhou County in central Henan Province, where the typical Ustic Cambosols locates. By using soil digital data, the spatial database was established, from which, all the needed latitude and longitude data of the sampling points were produced for the field GPS guide. Soil samples (0-20 cm) were collected from 202 points, of which, bulk density measurement were conducted for randomly selected 34 points, and the ten soil property items used as the factors for soil quality assessment, including organic matter, available K, available P, pH, total N, total P, soil texture, cation exchange capacity (CEC), slowly available K, and bulk density, were analyzed for the other points. The soil property items were checked by statistic tools, and then, classified with standard criteria at home and abroad. The factor weight was given by analytic hierarchy process (AHP) method, and the spatial variation of the major 10 soil properties as well as the soil quality classes and their occupied areas were worked out by Kriging interpolation maps. The results showed that the arable Ustic Cambosols in study area was of good quality soil, over 95% of which ranked in good and medium classes and only less than 5% were in poor class.


Structure and function of the glandular vas deferens in Ascaris suum (Nematoda).
The glandular vas deferens in the linearly arranged male reproductive tract in Ascaris suum produces substances which cause marked morphological and physiological changes in the spermatozoa. The glandular secretions, presumably formed by the rough endoplasmic reticulum and Golgi saccules, are extruded from the cells and coalesce to form homogeneous masses in the gland lumen. In sexually inactive worms the secretory material is separated from the spermatozoa by a sphincter comprised of neuro-muscular-like cells. During copulation the sphincter lumen enlarges and the spermatozoa and sperm-activating glandular material are mixed and simultaneously transferred to the female worm.


Approaches to transplantation tolerance in humans.
Although transplantation tolerance to organ allografts has been achieved using a wide variety of immunologic interventions in laboratory animals, few tolerance induction protocols with complete immunosuppressive drug withdrawal have been tested in humans. Preclinical and clinical studies of the use of total lymphoid irradiation for the induction of chimeric and nonchimeric tolerance are summarized here.


Anion-conductive membranes with ultralow vanadium permeability and excellent performance in vanadium flow batteries.
Anion exchange membranes prepared from quaternized poly(tetramethyl diphenyl ether sulfone) (QAPES) were first investigated in the context of vanadium flow battery (VFB) applications. The membranes showed an impressive suppression effect on vanadium ions. The recorded vanadium permeability was 0.02×10(-7)-0.09×10(-7) cm(2) min(-1), which was two orders of magnitude lower than that of Nafion 115. The self-discharge duration of a VFB single cell with a QAPES membrane is four times longer than that of Nafion 115. The morphological difference in hydrophilic domains between QAPES and Nafion was confirmed by TEM. After soaking the membranes in VO(2)(+) solution, adsorbed vanadium ions can barely be found in QAPES, whereas the hydrophilic domains of Nafion were stained. In the ex situ chemical stability test, QAPES showed a high tolerance to VO(2)(+) and remained intact after immersion in VO(2)(+) solution for over 250 h. The performance of a VFB single cell assembled with QAPES membranes is equal to or even better than that of Nafion 115 and remains stable in a long-term cycle test. These results indicate that QAPES membranes can be an ideal option in the fabrication of high-performance VFBs with low electric capacity loss.


Three novel clade B serine protease inhibitors from disk abalone, Haliotis discus discus: Molecular perspectives and responses to immune challenges and tissue injury.
Serine protease inhibitors (SERPINs) control cellular protease activity in order to maintain cellular homeostasis. The immune and inflammatory responses of invertebrate clade B SERPINs have not been widely reported. In the present study, three proteins with high similarity to clade B SERPINs, referred to as AbSERPIN-1, AbSERPIN-2 and AbSERPIN-3, were identified from disk abalone (Haliotis discus discus). While AbSERPIN-1 (399 aa) was of a typical size for this protein class, AbSERPIN-2 (506 aa) and AbSERPIN-3 (532 aa) were relatively larger. Bioinformatic analysis revealed the characteristic SERPIN domain in each AbSERPIN. In addition, the N-terminal region of both AbSERPIN-2 and AbSERPIN-3 contained a predicted low complexity region (LCR) and a signal peptide, suggesting that these proteins are secretory proteins and are, thus, novel peptides. Tertiary structural models of the AbSERPINs highlighted their structural and functional conservation. Ubiquitous expression of AbSERPIN transcripts was evaluated by quantitative real time PCR (qPCR) analysis in seven tissue types. AbSERPIN-1, AbSERPIN-2, and AbSERPIN-3 transcript levels were highest in mantle, hemocytes, and muscles, respectively. Temporal expression analysis revealed that AbSERPINs were significantly (P < 0.05) elevated in hemocytes during the early/middle stages following the injection of a bacterial pathogen (Vibrio parahaemolyticus or Listeria monocytogenes) or an immuno-stimulant (lipopolysaccharide). Moreover, mantle tissue injury led to significant changes in the temporal expression of AbSERPIN mRNA. Specifically, transcription of AbSERPIN-1 and AbSERPIN-3 was considerably up-regulated, while expression of AbSERPIN-2 was suppressed. These results suggest a potential role of AbSERPINs in response to pathogen invasion and tissue injury in disk abalone.


Home videos of cystic fibrosis patients using tobramycin inhalation powder: Relation of flow and cough.
Many cystic fibrosis (CF) patients chronically infected with Pseudomonas aeruginosa are on maintenance tobramycin inhalation therapy. Cough is reported as a side effect of tobramycin inhalation powder (TIP) in 48% of the patients. Objectives of this study were to investigate the association between the inspiratory flow of TIP and cough and to study the inhalation technique. We hypothesized that cough is related to a fast inhalation. In this prospective observational study, CF patients ≥ 6 years old on TIP maintenance therapy from four Dutch CF centers were visited twice at home. Video recordings were obtained and peak inspiratory flow (PIF) was recorded while patients inhaled TIP. Between the two home visits, the patients made three additional videos. CF questionnaire-revised, spirometry data, and computed tomography scan were collected. Two observers scored the videos for PIF, cough, and mistakes in inhalation technique. The associations between PIF and cough were analyzed using a logistic mixed-effects model accounting for FEV1 % predicted and capsule number. Twenty patients were included, median age 22 (18-28) years. No significant associations were found between PIF and cough. The risk of cough was highest after inhalation of the first capsule when compared to the second, third, and fourth capsule (P ≤ .015). Fourteen patients (70%) coughed at least once during TIP inhalation. A breath-hold of less than 5 seconds after inhalation and no deep expiration before inhalation were the most commonly observed mistakes. PIF is not related to cough in CF patients using TIP.


[Image methods in the development of optometry].
The review analyzes the authors' own paper aimed at assessing the functional status of human spatial vision. New technologies are shown to provide optometrists with the means of textual image synthesis, which effectively measure contrast sensitivity in relation to the spatial frequency of textual images. The review also outlines new effective methods for measuring human contrast sensitivity and its spatial working range. It is suggested that this line will determine the development of practical optometry.


[Autoimmune mechanisms of modulation of the activity of glutamate receptors in children with epilepsy and craniocerebral injury].
The role of glutamate receptors and their hyperstimulation in the development of autoimmune processes is discussed with reference to brain pathology associated with hypoxia and ischemia. Epilepsy, paroxismal condition, and craniocerebral injury (CCI) in children are shown to be accompanied by a rise in the levels of antibodies against AMPA and NMDA receptors of glutamate and nitric oxide markers (cGMP, nitrates + nitrites). Also enhanced in epilepsy and paroxismal condition are the levels of cGMP and antibodies against AMPA(GluR1) receptors of glutamate. Acute CCI period is characterized by a marked change in the levels of NO metabolites and antibodies to two subtypes of glutamate receptor, AMPA and NMDA. The levels of antibodies to NMDA(NR2A) receptors are significantly different within 1 day after CCI depending on its outcome. Unfavourable outcome of CCI is associated with the lowest level of antibodies and high NO metabolite content. Relationship between the levels of NO and antibodies against glutamate receptors is discussed with the use of experimental data. It is concluded that antibodies to glutamate receptors and receptor hyperstimulation play an important role in pathogenesis of hypoxia.


Elite Junior Australian Football Players Experience Significantly Different Loads Across Levels of Competition and Training Modes.
Lathlean, TJH, Gastin, PB, Newstead, S, and Finch, CF. Elite junior Australian football players experience significantly different loads across levels of competition and training modes. J Strength Cond Res 32(7): 2031-2038, 2018-Well-developed physical qualities such as high jumping ability, running endurance, acceleration, and speed can help aspiring junior elite Australian football (AF) players transition to the Australian Football League competition. To do so, players need to experience sufficient load to enhance their physical resilience without increasing their risk of negative outcomes in terms of impaired wellness or injury. The aim of this study was to investigate the differences in load for different levels of competition and training modes across one competitive season. Elite junior AF players (n = 562, aged 17.7 ± 0.3, range: 16-18 years) were recruited from 9 teams across the under-18 state league competition in Victoria. All players recorded their training and match intensities according to the session rating of perceived exertion method. Training sessions were categorized according to skills, strength, conditioning, and other activities, whereas matches were identified according to level of competition. The loads in U18 state league matches (656.7 ± 210.9 au) were significantly higher (p = 0.027) than those in school matches (643.3 ± 260.9 au) and those in U18 representative matches (617.2 ± 175.4). Players, who undertook more than one match per week, experienced significantly less load in subsequent matches (p < 0.001). Furthermore, U18 state league training sessions carried the most load when compared with other training modes. This article highlights that different combinations of training and match involvement affect overall player load, which may predispose players to negative outcomes such as impaired wellness or increased injury risk.


Comparison of nickel adsorption on biochars produced from mixed softwood and Miscanthus straw.
In order to understand the influence of feedstock type on biochar adsorption of heavy metals, the adsorption characteristics of nickel (Ni2+), copper (Cu2+) and lead (Pb2+) onto biochars derived from mixed softwood and Miscanthus straw were compared. The biochars were produced from mixed softwood pellets (SWP) and Miscanthus straw pellets (MSP), at both 550 and 700 °C for each material, using a standardised production procedure recommended by the UK Biochar Research Centre. Kinetics analyses show that the adsorption of Ni2+ to all four biochars reached equilibrium within 5 min. The degree of Ni2+ removal for all four biochars remained nearly constant within initial pH values of 3-8, because the equilibrium pH values within this range were similar due to the buffering effect of the biochars. A sharp increase of Ni2+ removal percentage for all biochars at initial solution pH 8-10 was observed as the equilibrium pH also increased. MSP derived biochars generally had higher maximum adsorption capacities (Qmax) for the three tested metals as compared with those from SWP, which was likely due to their higher degree of carbonisation during production. This study shows that feedstock type is a primary factor affecting the adsorption capacities of the tested biochars for heavy metals.


Metabolic changes preceding functional and morphologic indices of rejection in heterotopic cardiac allografts. A 31P nuclear magnetic resonance study.
Eight beagles receiving heterotopic (cervical) cardiac allografts from outbred donors were evaluated by serial 31P NMR, septal endocardial biopsy, and left ventricular pressure measurements for signs of rejection. Early postoperative myocardial energy levels, as assessed by ratios of phosphocreatine to inorganic phosphate (PCr/Pi) and phosphocreatine to beta-ATP (PCr/B-ATP), were acceptable in all recipients. In these nonimmunosuppressed animals, the mean ratios of PCr/Pi and PCr/B-ATP progressively decreased, with a greater than 25% reduction noted by postoperative day two and greater than 50% reduction by day three. In sharp contrast, left ventricular end-diastolic pressures remained stable and at baseline levels for the first three postoperative days, and only then markedly increased. Likewise, histologic evidence of rejection did not become prominent until postoperative day four. These results suggest that metabolic abnormalities significantly precede either functional or histologic changes in rejecting allografts. The early detection of these metabolic changes by 31P NMR appears to have important potential for the noninvasive diagnosis of cardiac allograft rejection.


Seizure-associated pulmonary edema and cerebral oxygenation in the rat.
Cerebral partial pressure of O2 (PO2), relative changes in the ratio of reduced/oxidized cytochrome aa3, blood flow, and the arteriovenous difference in O2 content were measured during seizures with and without pulmonary edema. Seizures were induced with bicuculline (0.2-1.2 mg/kg iv) in rats anesthetized with 70% N2O and paralyzed with curare. Briefer seizures were accompanied by increased cerebral PO2 and increased oxidation of cytochrome aa3. Lung water content and arterial O2 partial pressure (PaO2) remained normal. Longer duration seizures were also accompanied initially by increases in cerebral oxygenation. Within minutes, however, PaO2 fell from a mean of 118 to 51 mmHg, and lung water content increased from 76.2 to 83.6%. Cerebral PO2 fell but most often rose back to or above control levels, while cytochrome aa3 became markedly reduced. Simultaneously, cerebral blood flow increased more than 300% above preseizure values and O2 delivery increased more than O2 consumption. The reductive shift of cytochrome aa3 was greater than that produced by lowering PaO2 to equivalent values in seizure-free rats. The reductive shift of cytochrome aa3, despite increased O2 delivery, may be indicative of derangements in cerebral O2 diffusion or energy metabolism.


Relations between entropies produced in nondeterministic thermodynamic processes.
Landauer's erasure principle is generalized to nondeterministic processes on systems having an arbitrary number of nonsymmetrical logical states. The condition that the process is applied in the same way, irrespective of the initial logical state, imposes some restrictions on the individual heat exchanges associated with each possible transition. The complete set of such restrictions are derived by a statistical analysis of the phase-space flow induced by the process. Landauer's erasure principle can be derived from and is a special case of these.


Modelling the transmission dynamics of dengue in the presence of Wolbachia.
Use of the bacterium Wolbachia is an innovative new strategy designed to break the cycle of dengue transmission. There are two main mechanisms by which Wolbachia could achieve this: by reducing the level of dengue virus in the mosquito and/or by shortening the host mosquito's lifespan. However, although Wolbachia shortens the lifespan, it also gives a breeding advantage which results in complex population dynamics. This study focuses on the development of a mathematical model to quantify the effect on human dengue cases of introducing Wolbachia into the mosquito population. The model consists of a compartment-based system of first-order differential equations; seasonal forcing in the mosquito population is introduced through the adult mosquito death rate. The analysis focuses on a single dengue outbreak typical of a region with a strong seasonally-varying mosquito population. We found that a significant reduction in human dengue cases can be obtained provided that Wolbachia-carrying mosquitoes persist when competing with mosquitoes without Wolbachia. Furthermore, using the Wolbachia strain WMel reduces the mosquito lifespan by at most 10% and allows them to persist in competition with non-Wolbachia-carrying mosquitoes. Mosquitoes carrying the WMelPop strain, however, are not likely to persist as it reduces the mosquito lifespan by up to 50%. When all other effects of Wolbachia on the mosquito physiology are ignored, cytoplasmic incompatibility alone results in a reduction in the number of human dengue cases. A sensitivity analysis of the parameters in the model shows that the transmission probability, the biting rate and the average adult mosquito death rate are the most important parameters for the outcome of the cumulative proportion of human individuals infected with dengue.


Cytochrome c as a Peroxidase: Activation of the Precatalytic Native State by H2O2-Induced Covalent Modifications.
In addition to serving as respiratory electron shuttle, ferri-cytochrome c (cyt c) acts as a peroxidase; i.e., it catalyzes the oxidation of organic substrates by H2O2. This peroxidase function plays a key role during apoptosis. Typical peroxidases have a five-coordinate heme with a vacant distal coordination site that permits the iron center to interact with H2O2. In contrast, native cyt c is six-coordinate, as the distal coordination site is occupied by Met80. It thus seems counterintuitive that native cyt c would exhibit peroxidase activity. The current work scrutinizes the origin of this structure-function mismatch. Cyt c-catalyzed peroxidase reactions show an initial lag phase that is consistent with the in situ conversion of a precatalyst to an active peroxidase. Using mass spectrometry, we demonstrate the occurrence of cyt c self-oxidation in the presence of H2O2. The newly generated oxidized proteoforms are shown to possess significantly enhanced peroxidase activity. H2O2-induced modifications commence with oxidation of Tyr67, followed by permanent displacement of Met80 from the heme iron. The actual peroxidase activation step corresponds to subsequent side chain carbonylation, likely at Lys72/73. The Tyr67-oxidized/carbonylated protein has a vacant distal ligation site, and it represents the true peroxidase-active structure of cyt c. Subsequent self-oxidation eventually causes deactivation. It appears that this is the first report that identifies H2O2-induced covalent modifications as an essential component for the peroxidase activity of "native" cyt c.


Lineage switch under blinatumomab treatment of relapsed common acute lymphoblastic leukemia without MLL rearrangement.
Blinatumomab is a bispecific T-cell engaging αCD19 antibody used in refractory or relapsed B-cell precursor acute lymphoblastic leukemia (ALL). Recently, lineage switch to a myeloid phenotype has been described following CD19 targeting treatment in three pediatric patients with mixed lineage leukemia (MLL) rearranged ALL. We report the case of a female who received blinatumomab for a first relapse of ALL without MLL alterations. She suffered from a second relapse early after hematopoietic stem cell transplantation and was treated with blinatumomab again. During this treatment, the leukemia lost CD19 expression as well as nearly all other B-cell markers, while still harboring the initial minimal residual disease marker, and switched to a myeloid phenotype.


Visuo-perceptive priming in Alzheimer's disease: evidence for a multi-componential implicit memory system.
In the past two decades research has highlighted how implicit memory processes are spared in degenerative disorders, such as Alzheimer's disease (AD), which are characterized by the early onset of explicit memory deficits. However, according to recent studies, there may be dissociations among different types of implicit memory. Although several studies have shown selective sparing of lexical priming in AD, it is not completely clear what happens to other types of implicit memory processes, such as visuo-perceptual priming. The present study examines the possibility that the visuo-perceptual priming effect is spared in AD. We tested two groups of participants, i.e., a group of AD patients and a group of healthy age-matched controls, using a visuo-perceptual priming task. The task required the identification of fragmented pictures. Results showed a deficient priming effect in AD patients when it was measured by an Identification of Fragmented Pictures task. We discuss our results in light of the current hypothesis of a functional segregation in priming processes.


Isolation of a stable subpopulation of mobilized dental pulp stem cells (MDPSCs) with high proliferation, migration, and regeneration potential is independent of age.
Insights into the understanding of the influence of the age of MSCs on their cellular responses and regenerative potential are critical for stem cell therapy in the clinic. We have isolated dental pulp stem cells (DPSCs) subsets based on their migratory response to granulocyte-colony stimulating factor (G-CSF) (MDPSCs) from young and aged donors. The aged MDPSCs were efficiently enriched in stem cells, expressing high levels of trophic factors with high proliferation, migration and anti-apoptotic effects compared to young MDPSCs. In contrast, significant differences in those properties were detected between aged and young colony-derived DPSCs. Unlike DPSCs, MDPSCs showed a small age-dependent increase in senescence-associated β-galactosidase (SA-β-gal) production and senescence markers including p16, p21, Interleukin (IL)-1β, -6, -8, and Groα in long-term culture. There was no difference between aged and young MDPSCs in telomerase activity. The regenerative potential of aged MDPSCs was similar to that of young MDPSCs in an ischemic hindlimb model and an ectopic tooth root model. These results demonstrated that the stem cell properties and the high regenerative potential of MDPSCs are independent of age, demonstrating an immense utility for clinical applications by autologous cell transplantation in dental pulp regeneration and ischemic diseases.


The effect of Eleutheroside E on behavioral alterations in murine sleep deprivation stress model.
Eleutheroside E (EE), a principal component of Eleutherococcus senticosus, has been reported to have anti-inflammatory and protective effects in ischemia heart etc. However, whether it can mitigate behavioral alterations induced by sleep deprivation, has not yet been elucidated. Numerous studies have demonstrated that memory deficits induced by sleep deprivation in experimental animals can be used as a model of behavioral alterations. The present study investigated the effect of EE, on cognitive performances and biochemical parameters of sleep-deprived mice. Animals were repeatedly treated with saline, 10 or 50mg/kg EE and sleep-deprived for 72 h by the multiple platform method. Briefly, groups of 5-6 mice were placed in water tanks (45 × 34 × 17 cm), containing 12 platforms (3 cm in diameter) each, surrounded by water up to 1cm beneath the surface or kept in their home cage. After sleep deprivation, mice showed significant behavioral impairment as evident by reduced latency entering into a dark chamber, locomotion and correctly rate in Y maze, and increased monoamines in hippocampus. However, repeated treatment with EE restored these behavioral and biochemical alterations in mice. In conclusion, the beneficial effect of EE may provide an effective and powerful strategy to alleviate behavioral alterations induced by sleep deprivation.


Accuracy and reproducibility of the IDS rapID STR system for species identification of streptococci.
The RapID STR system (Innovative Diagnostic Systems, Inc., Atlanta, Ga.) was evaluated in the identification of 266 streptococci. Organisms included 60 beta-hemolytic streptococci, 71 group D strains (48 enterococci and 23 nonenterococci), 26 Streptococcus pneumoniae, and 109 viridans group strains. With concomitant optochin testing, as is currently recommended by the manufacturer for all alpha-hemolytic strains, the RapID STR system correctly identified 100% of beta-hemolytic strains, 87.3% of group D strains (93.7% of enterococci, 73.9% of nonenterococci), 88.5% of S. pneumoniae, and 72.5% of viridans strains. Without the use of optochin, the correct identification of S. pneumoniae and the viridans group was 26.9 and 52.3%, respectively. The RapID STR system incorrectly identified 3.0% of strains, including four group D streptococci, three pneumococci, and one viridans isolate. Reproducibility was excellent, with 95% of strains tested in triplicate yielding identical results on each of the three occasions. The RapID STR system represents a worthwhile advance in streptococcal species identification, especially for group D and viridans strains.


Prevalence of herbal and traditional medicine in Ethiopia: a systematic review and meta-analysis of 20-year studies.
The widely accepted prevalence of traditional medicine (TM) in Ethiopia was about 80 %, of which 95 % were sourced from plants. The purpose of this study was to update knowledge of the prevalence of herbal medicine or TM in Ethiopia and describe the characteristics of the population mostly relying on herbal medicine or TM to inform health policy-makers. PubMed, Google Scholar, Hinari, Scopus, and the Directory of Open Access Journals (DOAJ) were searched. The methodological quality of each included study was assessed using the quality assessment checklist for prevalence studies. Meta-analysis was conducted using STATA version 17, and the heterogeneity between studies was assessed using I2 test statistics based on the random effect model. Forest and funnel plots were used to present the data. Subgroup analysis was done by the study population, region, and setting. Thirty-six studies with a total of 16,288 participants met the inclusion criteria. Meta-analysis of the study revealed that the prevalence of herbal medicine use in Ethiopia is 46 % (95 % CI, 37-54 %), with significant heterogeneity among the studies (I2 = 99.19 %). Egger's test for publication bias of herbal medicine use revealed significant results (Egger, P = 0.002) which indicates possible missing of small sample size studies. The prevalence of TM use in Ethiopia is 65 % (95 % CI, 52-77 %) with significant heterogeneity among the studies (I2 = 99.18 %). Egger's test for publication bias of TM use revealed non-significant results (Egger, P = 0.275). The subgroup analysis by the study setting and the region revealed variability amongst the studies. Community-based studies and Oromia National Regional State showed higher prevalence. By population type, a higher prevalence of TM use was observed amongst children and lowest amongst malaria suspects. The current study revealed that TM/herbal medicine utilization remained an important source of primary healthcare in Ethiopia. In comparison to the commonly reported prevalence of TM/herbal medicine, there is a considerable decline in TM/herbal medicine prevalence. High TM/herbal medicine use tendency during pregnancy necessitates safety studies to optimize the utilization.