Cognitive remediation therapy (CRT) benefits more to patients with schizophrenia with low initial memory performances.
Cognitive deficits in schizophrenia mainly affect memory, attention and executive functions. Cognitive remediation is a technique derived from neuropsychology, which aims to improve or compensate for these deficits. Working memory, verbal learning, and executive functions are crucial factors for functional outcome. Our purpose was to assess the impact of the cognitive remediation therapy (CRT) program on cognitive difficulties in patients with schizophrenia, especially on working memory, verbal memory, and cognitive flexibility. We collected data from clinical and neuropsychological assessments in 24 patients suffering from schizophrenia (Diagnostic and Statistical Manual of mental Disorders-Fourth Edition, DSM-IV) who followed a 3-month (CRT) program. Verbal and visuo-spatial working memory, verbal memory, and cognitive flexibility were assessed before and after CRT. The Wilcoxon test showed significant improvements on the backward digit span, on the visual working memory span, on verbal memory and on flexibility. Cognitive improvement was substantial when baseline performance was low, independently from clinical benefit. CRT is effective on crucial cognitive domains and provides a huge benefit for patients having low baseline performance. Such cognitive amelioration appears highly promising for improving the outcome in cognitively impaired patients.


Prehospital factors associated with an acute life-threatening condition in non-traumatic chest pain patients - A systematic review.
Chest pain is a common symptom among patients contacting the emergency medical services (EMS). Risk stratification of these patients is warranted before arrival in hospital, regarding likelihood of an acute life-threatening condition (LTC). To identify factors associated with an increased risk of acute LTC among patients who call the EMS due to non-traumatic chest pain. Several databases were searched for relevant articles. Identified articles were quality-assessed using the Scottish Intercollegiate Guidelines Network checklists. Extracted data was analysed using a semi-quantitative synthesis evaluating the level of evidence of each identified factor. In total, 10 of 1245 identified studies were included. These studies provided strong evidence for an increased risk of an acute LTC with increasing age, male gender, elevated heart rate, low systolic blood pressure and ST elevation or ST depression on a 12-lead ECG. The level of evidence regarding the history of myocardial infarction, angina pectoris or presence of a Q wave or a Left Bundle Branch Block on the ECG was moderate. The evidence was inconclusive regarding dyspnoea, cold sweat/paleness, nausea/vomiting, history of chronic heart failure, smoking, Right Bundle Branch Block or T-inversions on the ECG. Factors reflecting age, gender, myocardial ischemia and a compromised cardiovascular system predicted an increased risk of an acute life-threatening condition in the prehospital setting in cases of acute chest pain. These factors may form the basis for prehospital risk stratification in acute chest pain.


Single-agent cisplatin treatment of children with high-risk hepatoblastoma.
The use of neoadjuvant chemotherapy has improved the survival of patients with hepatoblastoma (HB). However, an increased number of treatment complications and toxic deaths, particularly from heart failure, have been observed with doxorubicin treatment. We have applied cisplatin as a single agent to treat children with high-risk HB to improve event-free survival (EFS). Between 2007 and 2009, 14 patients with untreated high-risk HB were enrolled in this study. All the patients received a single-agent treatment of cisplatin. The initial cisplatin cycle was administered in a continuous intravenous 24-hour infusion of 80 mg/m/24 h. The primary outcome was the rate of complete resection. Secondary outcomes were EFS and overall survival (OS). Eleven patients (78.6%) had an overall partial response. Two patients (14.3%) had stable disease. One patient experienced (7.1%) progression. Of the 4 patients who presented with lung metastases initially, 1 patient achieved complete response, 2 patients achieved partial response, and 1 patient experienced progression during preoperative chemotherapy. The complete resection rate was 78.6% (95% CI, 49%-95%). The Kaplan-Meier estimates of 2-year EFS and OS for the whole group were 64.3% (95% CI, 35%-87%) and 85.7% (95% CI, 57%-98%), respectively. The 2-year EFS and OS rates of patients who achieved complete resection were 81.8% (95% CI, 48%-98%) and 100% (95% CI, 62%-100%), respectively. The single-agent cisplatin had less toxicity than cisplatin plus doxorubicin and achieved an equal rate of complete resection in high-risk HB compared with conventional multiagent chemotherapy.


Anti-pseudomonad Activity of Manuka Honey and Antibiotics in a Specialized ex vivo Model Simulating Cystic Fibrosis Lung Infection.
Pseudomonas aeruginosa causes problematic chronic lung infections in those suffering from cystic fibrosis. This is due to its antimicrobial resistance mechanisms and its ability to form robust biofilm communities with increased antimicrobial tolerances. Using novel antimicrobials or repurposing current ones is required in order to overcome these problems. Manuka honey is a natural antimicrobial agent that has been used for many decades in the treatment of chronic surface wounds with great success, particularly those infected with P. aeruginosa. Here we aim to determine whether the antimicrobial activity of manuka honey could potentially be repurposed to inhibit pulmonary P. aeruginosa infections using two ex vivo models. P. aeruginosa isolates (n = 28) from an international panel were tested for their susceptibility to manuka honey and clinically relevant antibiotics (ciprofloxacin, ceftazidime, and tobramycin), alone and in combination, using conventional antimicrobial susceptibility testing (AST). To increase clinical applicability, two ex vivo porcine lung (EVPL) models (using alveolar and bronchiolar tissue) were used to determine the anti-biofilm effects of manuka honey alone and in combination with antibiotics. All P. aeruginosa isolates were susceptible to manuka honey, however, varying incidences of resistance were seen against antibiotics. The combination of sub-inhibitory manuka honey and antibiotics using conventional AST had no effect on activity against the majority of isolates tested. Using the two ex vivo models, 64% (w/v) manuka honey inhibited many of the isolates where abnormally high concentrations of antibiotics could not. Typically, combinations of both manuka honey and antibiotics had increased antimicrobial activity. These results highlight the potential of manuka honey as a future antimicrobial for the treatment of pulmonary P. aeruginosa isolates, clearing potential infection reservoirs within the upper airway.


Differential effects of gut hormones on pancreatic and intestinal growth during administration of an elemental diet.
Liquid elemental diets (ED) will, in time, cause atrophy of the gut. Pentagastrin (PG), neurotensin (NT), and bombesin (BBS) are peptides that have trophic effects on the gut of normal rats. This study examined the effect of these three agents on gut atrophy produced by ED. Four groups of rats were given an ED and injected with either saline (control), PG (250 micrograms/kg), NT (300 micrograms/kg), or BBS (10 micrograms/kg) subcutaneously every 8 hours for 5 or 10 days. A fifth group was fed rat chow ad libidum. The rats were killed on day 6 or 11; the pancreas and segments of small intestine were removed. Atrophy of ileal mucosa was apparent on days 6 and 11, and atrophy of jejunal mucosa was manifest by day 11. Bombesin prevented jejunal mucosal atrophy and significantly increased ileal mucosal growth (compared with control). Neurotensin prevented the jejunal, but not the ileal, mucosal atrophy produced by ED. Pentagastrin had no effect on gut mucosa. Bombesin and PG, but not NT, stimulated pancreatic growth. Neurotensin stimulates pancreaticobiliary secretions (PBS), which are known to stimulate gut growth. Jejunoileal bypass was performed to determine whether trophic effects of NT on gut mucosa were mediated through stimulation of PBS. After 1 week treatment, animals were killed and segments of intestine removed. As expected NT was trophic for gut mucosa in continuity with the luminal stream; furthermore NT produced significant stimulation of growth of gut mucosa in the bypassed segment. We conclude that both BBS and NT are trophic for intestinal mucosa of rats given ED; both agents have a more pronounced effect on jejunum. The trophic effect of NT is mediated, in part, by a mechanism unrelated to stimulation of PBS. Bombesin and NT may have important regulatory functions in the adaptive growth of small bowel mucosa and in the maintenance of gut mucosal integrity.


The TRP superfamily of cation channels.
The transient receptor potential (TRP) protein superfamily consists of a diverse group of cation channels that bear structural similarities to Drosophila TRP. TRP channels play important roles in nonexcitable cells; however, an emerging theme is that many TRP-related proteins are expressed predominantly in the nervous system and function in sensory physiology. The TRP superfamily is divided into seven subfamilies, the first of which is composed of the "classical" TRPs" (TRPC subfamily). Some TRPCs may be store-operated channels, whereas others appear to be activated by production of diacylglycerol or regulated through an exocytotic mechanism. Many members of a second subfamily (TRPV) function in sensory physiology and respond to heat, changes in osmolarity, odorants, and mechanical stimuli. Two members of the TRPM family function in sensory perception and three TRPM proteins are chanzymes, which contain C-terminal enzyme domains. The fourth and fifth subfamilies, TRPN and TRPA, include proteins with many ankyrin repeats. TRPN proteins function in mechanotransduction, whereas TRPA1 is activated by noxious cold and is also required for the auditory response. In addition to these five closely related TRP subfamilies, which comprise the Group 1 TRPs, members of the two Group 2 TRP subfamilies, TRPP and TRPML, are distantly related to the group 1 TRPs. Mutations in the founding members of these latter subfamilies are responsible for human diseases. Each of the TRP subfamilies are represented by members in worms and flies, providing the potential for using genetic approaches to characterize the normal functions and activation mechanisms of these channels.


Evaluating partnership working: lessons for palliative care.
Partnership working in palliative care is being increasingly promoted as the solution to poorly coordinated health and social care services. A key example is the UK National Institute for Clinical Excellence (NICE) guidance on supportive and palliative care. However, partnerships have costs in negotiating, developing and maintaining working relationships and translating these into successful outcomes, so may not always be the best or most effective method of service improvement. This article explores structural, procedural, financial, professional and legitimacy barriers to partnership working. We conclude that these five barriers could be sufficient to destroy emerging partnerships. Nowhere in the NICE guidance on supportive and palliative care are such barriers acknowledged. We suggest that current and projected palliative care partnerships should be critically evaluated against both process and outcome success criteria. Such evaluations must be integral to partnerships, to learn about what makes an effective palliative care partnership, and what affects partnerships have on patient care and outcomes. Partnerships may not be the panacea for issues of fragmentation, and should not be the only solution considered. Lessons should be learnt from the UK's promulgation of partnerships to ensure that these are used appropriately and only where patient benefit can be anticipated.


Light-responsive polymer nanoreactors: a source of reactive oxygen species on demand.
Various domains present the challenges of responding to stimuli in a specific manner, with the desired sensitivity or functionality, and only when required. Stimuli-responsive systems that are appropriately designed can effectively meet these challenges. Here, we introduce nanoreactors that encapsulate photosensitizer-protein conjugates in polymer vesicles as a source of "on demand" reactive oxygen species. Vesicles made of poly(2-methyloxazoline)-poly(dimethylsiloxane)-poly(2-methyloxazoline) successfully encapsulated the photosensitizer Rose Bengal-bovine serum albumin conjugate (RB-BSA) during a self-assembly process, as demonstrated by UV-Vis spectroscopy. A combination of light scattering and transmission electron microscopy indicated that the nanoreactors are stable over time. They serve a dual role: protecting the photosensitizer in the inner cavity and producing in situ reactive oxygen species (ROS) upon irradiation with appropriate electromagnetic radiation. Illumination with appropriate wavelength light allows us to switch on/off and to control the production of ROS. Because of the oxygen-permeable nature of the polymer membrane of vesicles, ROS escape into the environment around vesicles, as established by electron paramagnetic resonance. The light-sensitive nanoreactor is taken up by HeLa cells in a Trojan horse fashion: it is nontoxic and, when irradiated with the appropriate laser light, produces ROS that induce cell death in a precise area corresponding to the irradiation zone. These nanoreactors can be used in theranostic approaches because they can be detected via the fluorescent photosensitizer signal and simultaneously produce ROS efficiently "on demand".


Increased mortality and AIDS-like immunopathology in wild chimpanzees infected with SIVcpz.
African primates are naturally infected with over 40 different simian immunodeficiency viruses (SIVs), two of which have crossed the species barrier and generated human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2). Unlike the human viruses, however, SIVs do not generally cause acquired immunodeficiency syndrome (AIDS) in their natural hosts. Here we show that SIVcpz, the immediate precursor of HIV-1, is pathogenic in free-ranging chimpanzees. By following 94 members of two habituated chimpanzee communities in Gombe National Park, Tanzania, for over 9 years, we found a 10- to 16-fold higher age-corrected death hazard for SIVcpz-infected (n = 17) compared to uninfected (n = 77) chimpanzees. We also found that SIVcpz-infected females were less likely to give birth and had a higher infant mortality rate than uninfected females. Immunohistochemistry and in situ hybridization of post-mortem spleen and lymph node samples from three infected and two uninfected chimpanzees revealed significant CD4(+) T-cell depletion in all infected individuals, with evidence of high viral replication and extensive follicular dendritic cell virus trapping in one of them. One female, who died within 3 years of acquiring SIVcpz, had histopathological findings consistent with end-stage AIDS. These results indicate that SIVcpz, like HIV-1, is associated with progressive CD4(+) T-cell loss, lymphatic tissue destruction and premature death. These findings challenge the prevailing view that all natural SIV infections are non-pathogenic and suggest that SIVcpz has a substantial negative impact on the health, reproduction and lifespan of chimpanzees in the wild.


Induction of calpain-mediated spectrin fragments by pathogenic treatments in long-term hippocampal slices.
The use of cultured hippocampal slices for studies of calpain-mediated pathogenesis was investigated. Breakdown products (BDPs), which result from proteolysis of spectrin by calpain I, were assayed with BDP-specific antibodies developed against peptide sequences on either side of the calpain cleavage site. The antibodies recognized either amino- or carboxy-terminal BDPs (147-kD BDPN and 152-kD BDPC, respectively). Various pathogenic manipulations, including trimethyltin, certain snake venoms and agonists for excitatory amino acid receptors, were found to cause rapid and pronounced increases in the proteolytic fragments. These effects were selective, i.e., chemicals or toxins directed at nonglutamatergic neurons had little effect on BDP concentrations. Transient accumulations of spectrin fragments were obtained with brief applications of N-methyl-D-aspartate; longer infusions resulted in lasting increases. Results similar to these have been observed in vivo with ischemic episodes of varying duration. Agonists of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subclass of glutamate receptors produced significant increases in spectrin proteolysis; however, prolonged exposure of the slices to centrally active drugs that enhance the currents passed by the receptors did not. The sensitivity, selectivity and temporal properties of the proteolytic response support the idea that cultured slices can be used to analyze the events leading to and following from calpain activation in the adult brain.


Acceptability and Feasibility of Using a Novel Geospatial Method to Measure Neighborhood Contexts and Mobility Among Transgender Women in New York City.
Purpose: To date, no studies utilizing global positioning system (GPS) technologies to measure mobility and environmental exposures have been conducted among a sample of transgender women despite the potential salient role neighborhood contexts may play in the health of this population. As such, the purpose of this study was to assess the acceptability and feasibility of a weeklong GPS protocol among a sample of transgender women in New York City. Methods: A sample of 14 transgender women residing in the New York City metropolitan area were recruited through community based methods to wear and charge a GPS device for 7 days to measure daily mobility. The acceptability of these methods was assessed using a pre- and postprotocol survey and their feasibility was measured using objective data derived from the GPS device. Pre- and postprotocol survey measures were compared using McNemar's test. Results: Participants reported high ratings of preprotocol acceptability, as well as few concerns regarding safety, appearance, and losing the device, all of which were maintained after completing the protocol. All 14 devices that were distributed were returned. In addition, all 14 participants had GPS data for at least 1 h on 1 day, and nine participants (64.3%) had at least 8 h of GPS data on all days. Conclusion: The findings of this pilot study demonstrate that the GPS methods are both acceptable and feasible among this sample of transgender women. GPS devices may be used in research among transgender women to understand neighborhood determinants of HIV and other STIs.


Effect of Dexrazoxane on Left Ventricular Systolic Function and Treatment Outcomes in Patients With Acute Myeloid Leukemia: A Report From the Children's Oncology Group.
To determine whether dexrazoxane provides effective cardioprotection during frontline treatment of pediatric acute myeloid leukemia (AML) without increasing relapse risk or noncardiac toxicities of the chemotherapy regimens. This was a multicenter study of all pediatric patients with AML without high allelic ratio FLT3/ITD treated in the Children's Oncology Group trial AAML1031 between 2011 and 2016. Median follow-up was 3.5 years. Dexrazoxane was administered at the discretion of treating physicians and documented at each course. Ejection fraction (EF) and shortening fraction (SF) were recorded after each course and at regular intervals in follow-up. Per protocol, anthracyclines were to be withheld if there was evidence of left ventricular systolic dysfunction (LVSD) defined as SF < 28% or EF < 55%. Occurrence of LVSD, trends in EF and SF, 5-year event-free survival (EFS) and overall survival (OS), and treatment-related mortality (TRM) were compared by dexrazoxane exposure. A total of 1,014 patients were included in the analyses; 96 were exposed to dexrazoxane at every anthracycline course, and 918 were never exposed. Distributions of sex, age, race, presenting WBC count, risk group, treatment arm, and compliance with cardiac monitoring were similar for dexrazoxane-exposed and -unexposed patients. Dexrazoxane-exposed patients had significantly smaller EF and SF declines than unexposed patients across courses and a lower risk for LVSD (26.5% v 42.2%; hazard ratio, 0.55; 95% CI, 0.36 to 0.86; P = .009). Dexrazoxane-exposed patients had similar 5-year EFS (49.0% v 45.1%; P = .534) and OS (65.0% v 61.9%; P = .613) to those unexposed; however, there was a suggestion of lower TRM with dexrazoxane (5.7% v 12.7%; P = .068). Dexrazoxane preserved cardiac function without compromising EFS and OS or increasing noncardiac toxicities. Dexrazoxane should be considered for cardioprotection during frontline treatment of pediatric AML.


Probing soluble guanylate cyclase activation by CO and YC-1 using resonance Raman spectroscopy.
Soluble guanylate cyclase (sGC) is weakly activated by carbon monoxide (CO) but is significantly activated by the binding of YC-1 to the sGC-CO complex. In this report, resonance Raman (RR) spectroscopy was used to study selected sGC variants. Addition of YC-1 to the sGC-CO complex alters the intensity pattern of RR bands assigned to the vinyl and propionate heme substituents, suggesting changes in the tilting of the pyrrole rings to which they are attached. YC-1 also shifts the RR intensity of the nu(FeC) and nu(CO) bands from 473 and 1985 cm(-1) to 487 and 1969 cm(-1), respectively, and induces an additional nu(FeC) band, at 521 cm(-1), assigned to five-coordinate heme-CO. Site-directed variants in the proximal heme pocket (P118A) or in the distal heme pocket (V5Y and I149Y) reduce the extent of YC-1 activation, along with the 473 cm(-1) band intensity. These lower-activity sGC variants display another nu(FeC) band at 493 cm(-1) which is insensitive to YC-1 addition and is attributed to protein that cannot be activated by the allosteric activator. The results are consistent with a model in which YC-1 binding to the sGC-CO complex results in a conformational change that activates the protein. Specifically, YC-1 binding alters the heme geometry via peripheral nonbonded contacts and also relieves an intrinsic electronic effect that weakens FeCO backbonding in the native, YC-1 responsive protein. This electronic effect might involve neutralization of the heme propionates via H-bond contacts or negative polarization by a distal cysteine residue. YC-1 binding also strains the Fe-histidine bond, leading to a population of the five-coordinate sGC-CO complex in addition to a conformationally distinct population of the six-coordinate sGC-CO complex. The loss of YC-1 activation in the sGC variants might involve a weakening of the heme-protein contacts that are thought to be critical to a YC-1-induced conformational change.


Topography of social touching depends on emotional bonds between humans.
Nonhuman primates use social touch for maintenance and reinforcement of social structures, yet the role of social touch in human bonding in different reproductive, affiliative, and kinship-based relationships remains unresolved. Here we reveal quantified, relationship-specific maps of bodily regions where social touch is allowed in a large cross-cultural dataset (N = 1,368 from Finland, France, Italy, Russia, and the United Kingdom). Participants were shown front and back silhouettes of human bodies with a word denoting one member of their social network. They were asked to color, on separate trials, the bodily regions where each individual in their social network would be allowed to touch them. Across all tested cultures, the total bodily area where touching was allowed was linearly dependent (mean r(2) = 0.54) on the emotional bond with the toucher, but independent of when that person was last encountered. Close acquaintances and family members were touched for more reasons than less familiar individuals. The bodily area others are allowed to touch thus represented, in a parametric fashion, the strength of the relationship-specific emotional bond. We propose that the spatial patterns of human social touch reflect an important mechanism supporting the maintenance of social bonds.


Reemployment crafting: Proactively shaping one's job search.
This article introduces the concept of reemployment crafting: the proactive, self-initiated behaviors undertaken by the unemployed to shape the environmental conditions of their job search in a way that enhances the person-environment (P-E) fit during the job search process. Using 2 longitudinal studies (Study 1: 3-wave study over a 3-month period, N = 153; Study 2: 4-day diary study, N = 189, days = 627), we investigated whether the manner in which the unemployed craft their job search is similar to the way employees craft their job. We examined whether reemployment crafting was positively related to job search performance (i.e., environmental exploration and networking behavior) and reemployment chances. Moreover, we examined whether contingency factors (i.e., social support and subjective goal attainment) affected the effectiveness of reemployment crafting. Results from both samples confirmed that the way the unemployed craft their job searches is similar to the way that employees craft their jobs. Reemployment crafting was positively related to job search performance, both within a 3-month period and within days. Moreover, reemployment crafting was especially beneficial for environmental exploration on days when social support and goal attainment were low. Last, environmental exploration was related to networking behavior, which in turn was predictive of reemployment chances. Specifically, in the diary study networking quality was related to reemployment status, while within the 3-month period, networking intensity seemed more effective. We conclude that reemployment crafting seems a promising way to enhance job search performance and ultimately the chances of finding reemployment. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Chains of transmission and control of Ebola virus disease in Conakry, Guinea, in 2014: an observational study.
An epidemic of Ebola virus disease of unprecedented size continues in parts of west Africa. For the first time, large urban centres such as Conakry, the capital of Guinea, are affected. We did an observational study of patients with Ebola virus disease in three regions of Guinea, including Conakry, aiming to map the routes of transmission and assess the effect of interventions. Between Feb 10, 2014, and Aug 25, 2014, we obtained data from the linelist of all confirmed and probable cases in Guinea (as of Sept 16, 2014), a laboratory database of information about patients, and interviews with patients and their families and neighbours. With this information, we mapped chains of transmission, identified which setting infections most probably originated from (community, hospitals, or funerals), and computed the context-specific and overall reproduction numbers. Of 193 confirmed and probable cases of Ebola virus disease reported in Conakry, Boffa, and Télimélé, 152 (79%) were positioned in chains of transmission. Health-care workers contributed little to transmission. In March, 2014, individuals with Ebola virus disease who were not health-care workers infected a mean of 2·3 people (95% CI 1·6-3·2): 1·4 (0·9-2·2) in the community, 0·4 (0·1-0·9) in hospitals, and 0·5 (0·2-1·0) at funerals. After the implementation of infection control in April, the reproduction number in hospitals and at funerals reduced to lower than 0·1. In the community, the reproduction number dropped by 50% for patients that were admitted to hospital, but remained unchanged for those that were not. In March, hospital transmissions constituted 35% (seven of 20) of all transmissions and funeral transmissions constituted 15% (three); but from April to the end of the study period, they constituted only 9% (11 of 128) and 4% (five), respectively. 82% (119 of 145) of transmission occurred in the community and 72% (105) between family members. Our simulations show that a 10% increase in hospital admissions could have reduced the length of chains by 26% (95% CI 4-45). In Conakry, interventions had the potential to stop the epidemic, but reintroductions of the disease and poor cooperation of a few families led to prolonged low-level spread, showing the challenges of Ebola virus disease control in large urban centres. Monitoring of chains of transmission is crucial to assess and optimise local control strategies for Ebola virus disease. Labex IBEID, Reacting, PREDEMICS, NIGMS MIDAS initiative, Institut Pasteur de Dakar.


FMRI of past tense processing: the effects of phonological complexity and task difficulty.
The generation of regular and irregular past tense verbs has been an important issue in cognitive science and has been used to advance different models of the organization of language in the brain. The dual-system view holds that the regular past tense forms are generated by a rule while irregular forms are retrieved from memory. The single-system view, on the other hand, holds that both forms are generated by a single integrated system and differ only in their reliance on factors such as phonology and semantics. We conducted an event-related fMRI study to examine the activation patterns associated with the generation and reading of regular and irregular past tense forms, in addition to the reading of their stems. Regular and irregular past tense generation activated similar brain regions compared to the reading of their respective stems. The areas activated more for irregular generation compared to regular generation included inferior frontal, precentral, and parietal regions bilaterally. This activation can be interpreted as reflecting the greater attentional and response selection demands of irregular generation. Compared to irregular generation, regular generation activated a small region in the left superior temporal gyrus when the regular and irregular past tense forms were mismatched on phonological complexity. No areas were more activated for regulars than irregulars when the past tense forms were matched on this variable. This suggests that the activation specific to regulars was related to the higher phonological complexity of their past tense forms rather than to their generation. A contrast of the reading of regular and irregular past tense forms was consistent with this hypothesis. These results support a single-system account of past tense generation.


Targeting the monocytic ubiquitin system with extracellular ubiquitin.
Recent findings suggest that extracellular ubiquitin has pleiotropic effects on host defence mechanisms, but its cellular mechanism of action is not yet understood. Using fluorescence and in vivo confocal microscopy, we observed uptake of N-terminal fluorescein-labelled ubiquitin into human PBMC and MonoMac 6 cells. Immunoblotting experiments indicated that extracellular ubiquitin is then rapidly conjugated to a multitude of intracellular proteins. LPS and lipoteichoic acid significantly increased uptake and subsequent conjugation to intracellular proteins dose dependently. This mechanism showed saturation kinetics with a K(d) value for ubiquitin in the low nanomolar range (<10 nmol/L) and a B(max) value of 0.14-0.27 micromol ubiquitin/mg protein. These results suggest that the monocytic ubiquitin system can be targeted with physiologically relevant concentrations of extracellular ubiquitin during inflammation. This concept could provide a simple explanation for a multitude of extracellular ubiquitin's actions and open up new strategies to influence ubiquitin-dependent intracellular processes.


Phenothiazines induce PP2A-mediated apoptosis in T cell acute lymphoblastic leukemia.
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer that is frequently associated with activating mutations in NOTCH1 and dysregulation of MYC. Here, we performed 2 complementary screens to identify FDA-approved drugs and drug-like small molecules with activity against T-ALL. We developed a zebrafish system to screen small molecules for toxic activity toward MYC-overexpressing thymocytes and used a human T-ALL cell line to screen for small molecules that synergize with Notch inhibitors. We identified the antipsychotic drug perphenazine in both screens due to its ability to induce apoptosis in fish, mouse, and human T-ALL cells. Using ligand-affinity chromatography coupled with mass spectrometry, we identified protein phosphatase 2A (PP2A) as a perphenazine target. T-ALL cell lines treated with perphenazine exhibited rapid dephosphorylation of multiple PP2A substrates and subsequent apoptosis. Moreover, shRNA knockdown of specific PP2A subunits attenuated perphenazine activity, indicating that PP2A mediates the drug's antileukemic activity. Finally, human T-ALLs treated with perphenazine exhibited suppressed cell growth and dephosphorylation of PP2A targets in vitro and in vivo. Our findings provide a mechanistic explanation for the recurring identification of phenothiazines as a class of drugs with anticancer effects. Furthermore, these data suggest that pharmacologic PP2A activation in T-ALL and other cancers driven by hyperphosphorylated PP2A substrates has therapeutic potential.


Patient-specific motion artifacts in 4DCT.
Four-dimensional computed tomography (4DCT) has enhanced images of the thorax and upper abdomen during respiration, but intraphase residual motion artifacts will persist in cine-mode scanning. In this study, the source and magnitude of projection artifacts due to intraphase target motion is investigated. A theoretical model of geometric uncertainty due to partial projection artifacts in cine-mode 4DCT was derived based on ideal periodic motion. Predicted artifacts were compared to measured errors with a rigid lung phantom attached to a programmable motion platform. Ideal periodic motion and actual patient breathing patterns were used as input for phantom motion. Reconstructed target dimensions were measured along the direction of motion and compared to the actual, known dimensions. Artifacts due to intraphase residual motion in cine-mode 4DCT range from a few mm up to a few cm on a given scanner, and can be predicted based on target motion and CT gantry rotation time. Errors in ITV and GTV dimensions were accurately characterized by the theoretical uncertainty at all phases when sinusoidal motion was considered, and in 96% of 300 measurements when patient breathing patterns were used as motion input. When peak-to-peak motion of 1.5 cm is combined with a breathing period of 4 s and gantry rotation time of 1 s, errors due to partial projection artifacts can be greater than 1 cm near midventilation and are a few mm in the inhale and exhale phases. Incorporation of such uncertainty into margin design should be considered in addition to other uncertainties. Artifacts due to intraphase residual motion exist in 4DCT, even for ideal breathing motions (e.g., sine waves). It was determined that these motion artifacts depend on patient-specific tumor motion and CT gantry rotation speed. Thus, if the patient-specific motion parameters are known (i.e., amplitude and period), a patient-specific margin can and should be designed to compensate for this uncertainty.


Beneficial Effect of Mildly Pasteurized Whey Protein on Intestinal Integrity and Innate Defense in Preterm and Near-Term Piglets.
The human digestive tract is structurally mature at birth, yet maturation of gut functions such as digestion and mucosal barrier continues for the next 1-2 years. Human milk and infant milk formulas (IMF) seem to impact maturation of these gut functions differently, which is at least partially related to high temperature processing of IMF causing loss of bioactive proteins and formation of advanced glycation end products (AGEs). Both loss of protein bioactivity and formation of AGEs depend on heating temperature and time. The aim of this study was to investigate the impact of mildly pasteurized whey protein concentrate (MP-WPC) compared to extensively heated WPC (EH-WPC) on gut maturation in a piglet model hypersensitive to enteral nutrition. WPC was obtained by cold filtration and mildly pasteurized (73 °C, 30 s) or extensively heat treated (73 °C, 30 s + 80 °C, 6 min). Preterm (~90% gestation) and near-term piglets (~96% gestation) received enteral nutrition based on MP-WPC or EH-WPC for five days. Macroscopic and histologic lesions in the gastro-intestinal tract were evaluated and intestinal responses were further assessed by RT-qPCR, immunohistochemistry and enzyme activity analysis. A diet based on MP-WPC limited epithelial intestinal damage and improved colonic integrity compared to EH-WPC. MP-WPC dampened colonic IL1-β, IL-8 and TNF-α expression and lowered T-cell influx in both preterm and near-term piglets. Anti-microbial defense as measured by neutrophil influx in the colon was only observed in near-term piglets, correlated with histological damage and was reduced by MP-WPC. Moreover, MP-WPC stimulated iALP activity in the colonic epithelium and increased differentiation into enteroendocrine cells compared to EH-WPC. Compared to extensively heated WPC, a formula based on mildly pasteurized WPC limits gut inflammation and stimulates gut maturation in preterm and near-term piglets and might therefore also be beneficial for preterm and (near) term infants.


Optical forces and torques on realistic plasmonic nanostructures: a surface integral approach.
We develop a novel formalism to calculate the optical forces and torques on complex and realistic nanostructures by combining the surface integral equation (SIE) technique with Maxwell's stress tensor. The optical force is calculated directly on the scatterer surface from the currents obtained from the SIE, which does not require an additional surface to evaluate Maxwell's stress tensor; this is especially useful for intricate geometries such as plasmonic antennas. SIE enables direct evaluation of forces from the surface currents very efficiently and accurately for complex systems. As a proof of concept, we establish the accuracy of the model by comparing the results with the calculations from the Mie theory. The flexibility of the method is demonstrated by simulating a realistic plasmonic system with intricate geometry.


The Underlying Social Dynamics of Paradigm Shifts.
We develop here a multi-agent model of the creation of knowledge (scientific progress or technological evolution) within a community of researchers devoted to such endeavors. In the proposed model, agents learn in a physical-technological landscape, and weight is attached to both individual search and social influence. We find that the combination of these two forces together with random experimentation can account for both i) marginal change, that is, periods of normal science or refinements on the performance of a given technology (and in which the community stays in the neighborhood of the current paradigm); and ii) radical change, which takes the form of scientific paradigm shifts (or discontinuities in the structure of performance of a technology) that is observed as a swift migration of the knowledge community towards the new and superior paradigm. The efficiency of the search process is heavily dependent on the weight that agents posit on social influence. The occurrence of a paradigm shift becomes more likely when each member of the community attaches a small but positive weight to the experience of his/her peers. For this parameter region, nevertheless, a conservative force is exerted by the representatives of the current paradigm. However, social influence is not strong enough to seriously hamper individual discovery, and can act so as to empower successful individual pioneers who have conquered the new and superior paradigm.


Social class culture cycles: how three gateway contexts shape selves and fuel inequality.
America's unprecedented levels of inequality have far-reaching negative consequences for society as a whole. Although differential access to resources contributes to inequality, the current review illuminates how ongoing participation in different social class contexts also gives rise to culture-specific selves and patterns of thinking, feeling, and acting. We integrate a growing body of interdisciplinary research to reveal how social class culture cycles operate over the course of the lifespan and through critical gateway contexts, including homes, schools, and workplaces. We first document how each of these contexts socializes social class cultural differences. Then, we demonstrate how these gateway institutions, which could provide access to upward social mobility, are structured according to middle-class ways of being a self and thus can fuel and perpetuate inequality. We conclude with a discussion of intervention opportunities that can reduce inequality by taking into account the contextual responsiveness of the self.


Detection of interleukin 8 and tumor necrosis factor in normal humans after intravenous endotoxin: the effect of antiinflammatory agents.
Interleukin 8 (IL-8), a potent activator of neutrophils, may be important in the early host response to serious Gram-negative infections. IL-8 was measured with other acute phase cytokines (tumor necrosis factor alpha [TNF-alpha], IL-6 and IL-1 beta) in 25 normal humans randomized to receive either intravenous endotoxin alone or endotoxin after oral administration of ibuprofen or pentoxifylline, agents that alter some of the inflammatory responses induced by endotoxin in vitro. TNF immunoreactivity was maximum at 1.5 h, and total TNF (area under the curve) was 4.2- and 4.5-fold greater in subjects given endotoxin/ibuprofen compared to subjects given endotoxin alone (p = 0.026) or endotoxin/pentoxifylline (p = 0.004), respectively. IL-6 levels were maximum at 2-3 h and did not differ among the three groups. No IL-1 beta was detected in any subject. IL-8 levels peaked at 2 h in subjects given either endotoxin alone or endotoxin/pentoxifylline, falling towards baseline by 5 h. Subjects given endotoxin/ibuprofen had a more sustained rise in IL-8 with peak levels 2.8- and 2.5-fold higher at 3 h compared to endotoxin alone (p = 0.048) or endotoxin/pentoxifylline (p = 0.023), respectively. Differences in total IL-8 release among groups approached statistical significance (ANOVA, p = 0.07). This trend reflected the increased release of IL-8 by the subjects receiving ibuprofen compared to pentoxifylline (1.9-fold higher; p = 0.024). This suggests that cyclooxygenase products may provide important negative feedback loops for cytokine production in vivo. Increases in circulating IL-8 are part of the acute inflammatory response of humans to endotoxin. Altered cytokine responses caused by antiinflammatory therapy may have important implications for both host defense and injury during septicemia.


Gene in the major cotransduction gap of the Escherichia coli K-12 linkage map required for the expression of chromosomal resistance to tetracycline and other antibiotics.
In Escherichia coli K-12, amplifiable resistance to tetracycline, chloramphenicol, and other unrelated antibiotics was mediated by at least four spatially separated loci. Tetracycline-sensitive mutants were isolated by Tn5 insertional inactivation of an amplified multiply resistant strain. One of these, studied in detail, showed coordinate loss of expression of all other resistance phenotypes. The Tn5 element in this mutant mapped to 34 min on the E. coli K-12 linkage map. We have designated the locus marA (multiple antibiotic resistance). Tetracycline-sensitive mutants containing marA::Tn5 regained all resistance phenotypes at frequencies of 10(-8) to 10(-7) upon precise excision of Tn5. Moreover, a newly described tetracycline efflux system (A. M. George and S. B. Levy, J. Bacteriol. 155:531-540, 1983) was inactivated in tetracycline-sensitive mutants, but recovered in tetracycline-resistant revertants. In merodiploids, F-prime marA+ expressed partial or complete dominance over corresponding mutant chromosomal alleles. Dominance tests also established that a previously amplified host and a mutant marA allele were preconditions for the expression of phenotypic resistances.


Clinical outcomes after the introduction of dolutegravir for second-line antiretroviral therapy in South Africa: a retrospective cohort study.
Dolutegravir is now recommended for second-line anti-retroviral therapy (ART) in low- and middle-income countries. We compared outcomes with dolutegravir (DTG) versus the previous lopinavir/ritonavir (LPV/r) regimen in South Africa. We used routinely collected, de-identified data from 59 South African clinics. We included people living with HIV aged ≥ 15 years with virologic failure (two consecutive viral loads ≥1000 copies/mL) on first-line tenofovir disoproxil fumarate (TDF)-based ART and switched to second-line ART. We used modified Poisson regression models to compare outcomes of 12-month retention-in-care and viral suppression (<50 copies/ml) after switching to second-line regimens of zidovudine (AZT), emtricitabine/lamivudine (XTC), DTG and TDF/XTC/DTG and AZT/XTC/LPV/r. Of 1214 participants, 729 (60.0%) were female, median age was 36 years (interquartile range 30 to 42), 689 (56.8%) were switched to AZT/XTC/LPV/r, 217 (17.9%) to AZT/XTC/DTG and 308 (25.4%) to TDF/XTC/DTG. Retention-in-care was higher with AZT/XTC/DTG (85.7%, adjusted risk ratio (aRR) 1.14, 95% confidence interval (CI) 1.03 to 1.27; adjusted risk difference (aRD) 10.89%, 95%CI 2.01 to 19.78) but not different with TDF/XTC/DTG (76.9%, aRR 1.01, 95%CI 0.94 to 1.10; aRD 1.04%, 95%CI -5.03 to 7.12) compared to AZT/XTC/LPV/r (75.2%). Retention-in-care with TDF/XTC/DTG was not statistically significantly different from AZT/XTC/DTG (aRR 0.89, 95%CI 0.78 to 1.01; aRD -9.85%, 95%CI -20.33 to 0.63). Of 799 participants who were retained-in-care with a 12-month viral load, viral suppression was higher with AZT/XTC/DTG (59.3%, aRR 1.25, 95%CI 1.06 to 1.47; aRD 11.57%, 95%CI 2.37 to 20.76) and TDF/XTC/DTG (60.7%, aRR 1.30, 95%CI 1.14 to 1.48; aRD 14.16%, 95%CI 7.14 to 21.18) than with the AZT/XTC/LPV/r regimen (46.7%). DTG-based second-line regimens were associated with similar or better retention-in-care and better viral suppression than the LPV/r-based regimen. TDF/XTC/DTG had similar viral suppression compared to AZT/XTC/DTG. Bill & Melinda Gates Foundation, Africa Oxford Initiative.


Learning styles and the prospective ophthalmologist.
Understanding the learning styles of individual trainees may enable trainers to tailor an educational program and optimise learning. Surgical trainees have previously been shown to demonstrate a tendency towards particular learning styles. We seek to clarify the relationship between learning style and learned surgical performance using a simulator, prior to surgical training. The Kolb Learning Style Inventory was administered to a group of thirty junior doctors. Participants were then asked to perform a series of tasks using the EyeSi virtual reality cataract surgery simulator (VR Magic, Mannheim, Germany). All completed a standard introductory programme to eliminate learning curve. They then undertook four attempts of level 4 forceps module binocularly. Total score, odometer movement (mm), corneal area injured (mm(2)), lens area injured (mm(2)) and total time taken (seconds) recorded. Mean age was 31.6 years. No significant correlation was found between any learning style and any variable on the EyeSi cataract surgery simulator. There is a predominant learning style amongst surgical residents. There is however no demonstrable learning style that results in a better (or worse) performance on the EyeSi surgery simulator and hence in learning and performing cataract surgery.


Self-assembly and gelation behavior of tris(phenylisoxazolyl)benzenes.
Low-molecular-mass organic gelators (LMOG), tris(phenylisoxazolyl)benzenes, were synthesized, and their self-assembling behavior was examined using (1)H NMR and UV-vis absorption spectroscopies. They turned into a gel in both nonpolar and highly polar solvents such as methylcyclohexane, ether, acetone, dimethylsulfoxide, etc. Field emission scanning electron microscopy (FESEM) observation of the xerogels of 1 and 3 possessing the saturated alkyl chains revealed that well-developed straight fibers were formed, whereas the unsaturated termini of the alkyl chains of 2 promoted the formation of both the right- and left-handed helical fibers. The self-association behavior of 1, 2, and 5 in solution were investigated using (1)H NMR and UV-vis spectroscopies. The flat aromatic compound 1 stacked in a columnar fashion along its C(3) axis via π-π stacking interactions. The assemblies were regulated by the peripheral alkyl substituents; the saturated alkyl groups facilitated the assemblies while terminal double bonds impeded the intermolecular association, and the branched substituents obviously interfered in the formation of the stacks, probably due to steric requirements. Theoretical calculations suggest that the three dipoles of the isoxazole groups adopt the circular array. The conformational search of the hexameric stacks of 4 using MacroModel V9.1 gave rise to two major conformers: one is nonhelical and the other is helical. Further detailed structural analysis of the assemblies of chiral 5 using circular dichroism (CD) measurements indicated that their assemblies adopt helical structures in solution. CD spectra and DFT calculations revealed that R-5 forms a left-handed supramolecular helicate. The coassembly of R- and S-5 displayed chiral amplification, since the chiral information from 5 was transferred to the supramolecular chirality of the helical assemblies of 1. A small amount of optically active 5 provided enough chiral stimulus to produce a remarkable chiral response and supramolecular helical structures of 1.


Further Evidence for Bats as the Evolutionary Source of Middle East Respiratory Syndrome Coronavirus.
The evolutionary origins of Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV) are unknown. Current evidence suggests that insectivorous bats are likely to be the original source, as several 2c CoVs have been described from various species in the family Vespertilionidae Here, we describe a MERS-like CoV identified from a Pipistrellus cf. hesperidus bat sampled in Uganda (strain PREDICT/PDF-2180), further supporting the hypothesis that bats are the evolutionary source of MERS-CoV. Phylogenetic analysis showed that PREDICT/PDF-2180 is closely related to MERS-CoV across much of its genome, consistent with a common ancestry; however, the spike protein was highly divergent (46% amino acid identity), suggesting that the two viruses may have different receptor binding properties. Indeed, several amino acid substitutions were identified in key binding residues that were predicted to block PREDICT/PDF-2180 from attaching to the MERS-CoV DPP4 receptor. To experimentally test this hypothesis, an infectious MERS-CoV clone expressing the PREDICT/PDF-2180 spike protein was generated. Recombinant viruses derived from the clone were replication competent but unable to spread and establish new infections in Vero cells or primary human airway epithelial cells. Our findings suggest that PREDICT/PDF-2180 is unlikely to pose a zoonotic threat. Recombination in the S1 subunit of the spike gene was identified as the primary mechanism driving variation in the spike phenotype and was likely one of the critical steps in the evolution and emergence of MERS-CoV in humans.IMPORTANCE Global surveillance efforts for undiscovered viruses are an important component of pandemic prevention initiatives. These surveys can be useful for finding novel viruses and for gaining insights into the ecological and evolutionary factors driving viral diversity; however, finding a viral sequence is not sufficient to determine whether it can infect people (i.e., poses a zoonotic threat). Here, we investigated the specific zoonotic risk of a MERS-like coronavirus (PREDICT/PDF-2180) identified in a bat from Uganda and showed that, despite being closely related to MERS-CoV, it is unlikely to pose a threat to humans. We suggest that this approach constitutes an appropriate strategy for beginning to determine the zoonotic potential of wildlife viruses. By showing that PREDICT/PDF-2180 does not infect cells that express the functional receptor for MERS-CoV, we further show that recombination was likely to be the critical step that allowed MERS to emerge in humans.


The microbiota metabolite indole inhibits Salmonella virulence: Involvement of the PhoPQ two-component system.
The microbial community present in the gastrointestinal tract is an important component of the host defense against pathogen infections. We previously demonstrated that indole, a microbial metabolite of tryptophan, reduces enterohemorrhagic Escherichia coli O157:H7 attachment to intestinal epithelial cells and biofilm formation, suggesting that indole may be an effector/attenuator of colonization for a number of enteric pathogens. Here, we report that indole attenuates Salmonella Typhimurium (Salmonella) virulence and invasion as well as increases resistance to colonization in host cells. Indole-exposed Salmonella colonized mice less effectively compared to solvent-treated controls, as evident by competitive index values less than 1 in multiple organs. Indole-exposed Salmonella demonstrated 160-fold less invasion of HeLa epithelial cells and 2-fold less invasion of J774A.1 macrophages compared to solvent-treated controls. However, indole did not affect Salmonella intracellular survival in J774A.1 macrophages suggesting that indole primarily affects Salmonella invasion. The decrease in invasion was corroborated by a decrease in expression of multiple Salmonella Pathogenicity Island-1 (SPI-1) genes. We also identified that the effect of indole was mediated by both PhoPQ-dependent and independent mechanisms. Indole also synergistically enhanced the inhibitory effect of a short chain fatty acid cocktail on SPI-1 gene expression. Lastly, indole-treated HeLa cells were 70% more resistant to Salmonella invasion suggesting that indole also increases resistance of epithelial cells to colonization. Our results demonstrate that indole is an important microbiota metabolite that has direct anti-infective effects on Salmonella and host cells, revealing novel mechanisms of pathogen colonization resistance.


Mannose-binding lectin deficiency is associated with early onset of polyarticular juvenile rheumatoid arthritis: a cohort study.
Mannose-binding lectin (MBL) is an innate immune protein. The aim of our study was to determine whether genetically determined MBL deficiency is associated with susceptibility to juvenile rheumatoid arthritis (JRA) and whether MBL2 genotypes are associated with JRA severity. In a retrospective cohort study of 218 patients with polyarthritis (n = 67) and oligoarthritis (n = 151), clinical and laboratory disease variables were obtained by clinical examination and chart reviews. Healthy Caucasian adults (n = 194) served as control individuals. MBL2 gene mutations were determined by Taqman analysis to identify genotypes with high, medium and low expression of MBL. Functional MBL plasma concentrations were measured using enzyme-linked immunosorbent assay. Associations between clinical and laboratory variables and MBL2 genotypes were determined by Kruskal-Wallis and chi2 tests. MBL2 genotype frequencies were similar in polyarthritis and oligoarthritis patients as compared with control individuals. MBL plasma concentrations were associated with the high, medium and low MBL genotype expression groups (P < 0.01). In polyarthritis patients, the presence of low-expressing (deficient) MBL2 genotypes was associated with early age at onset of disease (P = 0.03). In oligoarthritis patients, patients with low-expressing MBL2 genotypes were more often in remission (81%) than patients in the medium (54%) and high (56%) genotype groups (P = 0.02). The remaining clinical and laboratory variables, such as arthritis severity index, presence of radiographic erosions and antinuclear antibody positivity, were not associated with MBL2 genotypes. Genetically determined MBL deficiency does not increase susceptibility to JRA, but MBL deficiency is associated with a younger age at onset of juvenile polyarthritis. On the other hand, MBL-deficient children with juvenile oligoarthritis are more often in remission. Therefore, MBL appears to play a dual role in JRA.


Antifatigue effect of fresh royal jelly in mice.
We investigated the antifatigue effect of royal jelly (RJ), which had been stored at -20 degrees C from immediately after collection, in male Std ddY mice. The mice were accustomed to swimming in an adjustable-current swimming pool, then subjected to forced swimming five times during 2 wk, and the total swimming period until exhaustion was measured. They were separated into three groups with equal swimming capacity, which were administered RJ, RJ stored at 40 degrees C for 7 d (40-7d RJ), or the control solution including casein, cornstarch, and soybean oil before swimming. All mice were forced to swim for 15 min once; then the maximum swimming time to fatigue was measured after a rest period. The swimming endurance of the RJ group significantly increased compared with those of the other groups. The mice in the RJ group showed significantly decreased accumulation of serum lactate and serum ammonia and decreased depletion of muscle glycogen after swimming compared with the other groups, whereas there was no significant difference between the 40-7d RJ group and the control group in these parameters after swimming. A quantitative analysis of constituents in RJ showed that 5 7-kDa protein, which we previously identified as a possible freshness marker of RJ, was specifically degraded in RJ stored at 40 degrees C for 7 d, whereas the contents of various vitamins, 10-hydroxy-2-decenoic acid, and other fatty acids in RJ were unchanged. These findings suggest that RJ can ameliorate the physical fatigue after exercise, and this antifatigue effect of RJ in mice seems to be associated with the freshness of RJ, possibly with the content of 5 7-kDa protein.


Albumin administration prevents the onset of pressure ulcers in intensive care unit patients.
Pressure ulcers (PUs) are a common problem in critically ill patients admitted to the intensive care units (ICUs) and they account for more than 70% of patients with low serum albumin at admission. The aim of this study was to test the efficacy of intravenous administration of albumin in patients with low serum albumin < 3·3 g/dl. In a 1-year period, a total of 73 patients were admitted to the ICU (males 45, 61·64% and females 28, 38·36%); of these, 21 patients were admitted with hypoalbuminaemia (serum albumin < 3·3 g/dl) and randomised into two groups: 11 patients were treated with 25 g intravenous albumin for the first 3 days within the first week of ICU stay (group A) and 10 patients did not receive albumin (group B). Three patients (27·27%) showed the onset of PUs in group A, whereas seven patients (70%) showed the onset of PUs within the first 7 days of stay in group B. Moreover, ulcers of group B were more severe than those of group A. This study shows that intravenous administration of albumin reduces the onset of PUs in patients admitted to the ICU and in some cases it also reduces the risk of progression to advanced stages of PUs.


Elliptical metallic hollow fiber inner-coated with non-uniform dielectric layer.
We report on the fabrication and characterization of an elliptical hollow fiber inner coated with a silver layer and a dielectric layer for polarization maintaining and low loss transmission of terahertz (THz) radiation. The primary purpose of adding the dielectric layer is to prevent the silver layer from oxidation. The thickness of the dielectric layer is non-uniform owing to the surface tension of the coating, which was initially applied as a liquid. Transmission loss and polarization maintenance are experimentally characterized. Effects of the dielectric layer on transmission properties are analyzed by comparing the fiber to Ag-only fiber. Results show that a dielectric layer with thickness less than λ/10 can effectively decreases the power distributed on the metal surface and thus can practically reduce loss resulting from roughness of the silver layer. Bending effects on transmission loss and polarization maintenance are also investigated.


Purine nucleoside phosphorylase deficiency: altered kinetic properties of a mutant enzyme.
Erythrocyte purine nucleoside phosphorylase from two brothers had 0.5% of normal activity. It differed from the normal enzyme by a tenfold increase in the Michaelis constant for inosine, an inability of inosine to protect against thermal lability, and a more positive net charge. The altered kinetic properties may account for the milder disease in the patients compared to the previously described cases. The data provide evidence for a structural gene mutation and genetic heterogeneity in the new disease of purine nucleoside phosphorylase deficiency and T cell dysfunction.


Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.


Regulation of adipose tissue stromal cells behaviors by endogenic Oct4 expression control.
To clarify the role of the POU domain transcription factor Oct4 in Adipose Tissue Stromal Cells (ATSCs), we investigated the regulation of Oct4 expression and other embryonic genes in fully differentiated cells, in addition to identifying expression at the gene and protein levels. The ATSCs and several immature cells were routinely expressing Oct4 protein before and after differentiating into specific lineages. Here, we demonstrated the role of Oct4 in ATSCs on cell proliferation and differentiation. Exogenous Oct4 improves adult ATSCs cell proliferation and differentiation potencies through epigenetic reprogramming of stemness genes such as Oct4, Nanog, Sox2, and Rex1. Oct4 directly or indirectly induces ATSCs reprogramming along with the activation of JAK/STAT3 and ERK1/2. Exogenic Oct4 introduced a transdifferentiation priority into the neural lineage than mesodermal lineage. Global gene expression analysis results showed that Oct4 regulated target genes which could be characterized as differentially regulated genes such as pluripotency markers NANOG, SOX2, and KLF4 and markers of undifferentiated stem cells FOXD1, CDC2, and EPHB1. The negatively regulated genes included FAS, TNFR, COL6A1, JAM2, FOXQ1, FOXO1, NESTIN, SMAD3, SLIT3, DKK1, WNT5A, BMP1, and GLIS3 which are implicated in differentiation processes as well as a number of novel genes. Finally we have demonstrated the therapeutic utility of Oct4/ATSCs were introduced into the mouse traumatic brain, engrafted cells was more effectively induces regeneration activity with high therapeutic modality than that of control ATSCs. Engrafted Oct4/ATSCs efficiently migrated and transdifferentiated into action potential carrying, functionally neurons in the hippocampus and promoting the amelioration of lesion cavities.


An Atoh1 CRE Knock-In Mouse Labels Motor Neurons Involved in Fine Motor Control.
Motor neurons (MNs) innervating the digit muscles of the intrinsic hand (IH) and intrinsic foot (IF) control fine motor movements. The ability to reproducibly label specifically IH and IF MNs in mice would be a beneficial tool for studies focused on fine motor control. To this end, we find that a CRE knock-in mouse line of Atoh1, a developmentally expressed basic helix-loop-helix (bHLH) transcription factor, reliably expresses CRE-dependent reporter genes in ∼60% of the IH and IF MNs. We determine that CRE-dependent expression in IH and IF MNs is ectopic because an Atoh1 mouse line driving FLPo recombinase does not label these MNs although other Atoh1-lineage neurons in the intermediate spinal cord are reliably identified. Furthermore, the CRE-dependent reporter expression is enriched in the IH and IF MN pools with much sparser labeling of other limb-innervating MN pools such as the tibialis anterior (TA), gastrocnemius (GS), quadricep (Q), and adductor (Ad). Lastly, we find that ectopic reporter expression begins postnatally and labels a mixture of α and γ-MNs. Altogether, the Atoh1 CRE knock-in mouse strain might be a useful tool to explore the function and connectivity of MNs involved in fine motor control when combined with other genetic or viral strategies that can restrict labeling specifically to the IH and IF MNs. Accordingly, we provide an example of sparse labeling of IH and IF MNs using an intersectional genetic approach.


Can we defeat meningococcal disease in low and middle income countries?
The development of multivalent conjugate and protein-based meningococcal vaccines may make global control of meningococcal disease possible. However, achieving control of meningococcal disease in low and middle income countries will be challenging. In low income countries whose vaccination programmes receive financial support from the Global Alliance for Vaccination and Immunisation, the main challenge is lack of sufficient epidemiological information to allow rational decisions on vaccine introduction to be made and, in these countries, enhanced surveillance is needed. In middle income countries, financial challenges predominate. These could be met by demonstration of the cost effectiveness of new meningococcal vaccines and through the introduction of a tiered-pricing system.


Adapted Three-step Restorative Technique: Recovering Dental Substrate Compromised by Complex Erosive Wear in a Young Patient.
This article presents the dental restoration of a young female patient complaining of erosive dental wear using a three-step restorative technique, an alternative approach with some novel adjustments. For successful tooth wear treatment, determining the etiological systemic and local factors is the main priority before deciding on effective and long-term preventive and/or therapeutic restorative approaches. In addition to professional intervention, achieving optimal outcomes requires patients to control their diet and/or gastric issues, thus minimizing the wear process. However, continuous wear constitutes the most challenging scenario, mainly when it affects young patients' dentitions. This article describes the dental restoration of posterior teeth with reestablishment of occlusal vertical dimension before treating the anterior teeth, while educating the patient and providing medical monitoring. The three-step restorative technique seems to be properly applicable in cases of significant dental compromise due mainly to erosive wear and is based on direct procedures, which can assure a reliable and feasible approach.


Apoptosis inhibition by the human DEK oncoprotein involves interference with p53 functions.
The DEK proto-oncogene has been associated with human carcinogenesis-either as a fusion with the CAN nucleoporin protein or when transcriptionally upregulated. Mechanisms of intracellular DEK functions, however, have remained relatively unexplored. We have recently demonstrated that DEK expression is induced by the high-risk human papillomavirus (HPV) E7 protein in a manner which is dependent upon retinoblastoma protein function and have implicated DEK in the inhibition of cellular senescence. Additionally, overexpression of DEK resulted in significant life span extension of primary human keratinocytes. In order to determine whether DEK expression is required for cellular proliferation and/or survival, we monitored cellular responses to the knockdown of DEK in cancer and primary cells. The results indicate that DEK expression protects both HPV-positive cancer and primary human cells from apoptotic cell death. Cell death in response to DEK depletion was accompanied by increased protein stability and transcriptional activity of the p53 tumor suppressor and consequent upregulation of known p53 target genes such as p21CIP and Bax. Consistent with a possible role for p53 in DEK-mediated cell death inhibition, the p53-negative human osteosarcoma cell line SAOS-2 was resistant to the knockdown of DEK. Finally, expression of a dominant negative p53 miniprotein inhibited DEK RNA interference-induced p53 transcriptional induction, as well as cell death, thus directly implicating p53 activation in the observed apoptotic phenotype. These findings suggest a novel role for DEK in cellular survival, involving the destabilization of p53 in a manner which is likely to contribute to human carcinogenesis.


The ban on smokeless tobacco products is systematically violated in Chennai, India.
India is the world's third largest consumer of tobacco. There are twice as many users of smokeless tobacco products (STPs) as cigarette smokers. The Government of Tamil Nadu has banned the sale of gutkha and pan masala in 2013. Our aim was to identify the varieties of illegal STP available in Chennai, India. In systematically chosen zones and regions of Chennai city, we randomly identified three kinds of kiosks (n = 18) and asked for "gutkha" and "pan masala," one of each product available. Details of each product were reviewed based on the information printed on the sachets. Totally 65 STPs were collected; 26 distinct products and 23 brands. All products were claimed to be "tobacco" by the shop keepers. Sixty-five percent of the products informed to contain tobacco and 15.4% to contain pan masala. Five sachets did not inform about the content; 30.8% did not have a pictorial warning; a text warning was printed on 80.8%, but only two products had the messages in Tamil; 70% had promotional messages printed, and 57% had their registration numbers printed. The ban on STP is being systematically violated in Chennai. STP are cheap and easily available and due to promotional laudatory messages and lacking information about the content and warning of health damage, the consumers are left with the perception that they buy more or less harmless product. The Indian Government must introduce policies to control production, import, and sale of illicit STP but we also call for a coordinated international solution.


Research progress of perovskite materials in photocatalysis- and photovoltaics-related energy conversion and environmental treatment.
Meeting the growing global energy demand is one of the important challenges of the 21st century. Currently over 80% of the world's energy requirements are supplied by the combustion of fossil fuels, which promotes global warming and has deleterious effects on our environment. Moreover, fossil fuels are non-renewable energy and will eventually be exhausted due to the high consumption rate. A new type of alternative energy that is clean, renewable and inexpensive is urgently needed. Several candidates are currently available such as hydraulic power, wind force and nuclear power. Solar energy is particularly attractive because it is essentially clean and inexhaustible. A year's worth of sunlight would provide more than 100 times the energy of the world's entire known fossil fuel reserves. Photocatalysis and photovoltaics are two of the most important routes for the utilization of solar energy. However, environmental protection is also critical to realize a sustainable future, and water pollution is a serious problem of current society. Photocatalysis is also an essential route for the degradation of organic dyes in wastewater. A type of compound with the defined structure of perovskite (ABX3) was observed to play important roles in photocatalysis and photovoltaics. These materials can be used as photocatalysts for water splitting reaction for hydrogen production and photo-degradation of organic dyes in wastewater as well as for photoanodes in dye-sensitized solar cells and light absorbers in perovskite-based solar cells for electricity generation. In this review paper, the recent progress of perovskites for applications in these fields is comprehensively summarized. A description of the basic principles of the water splitting reaction, photo-degradation of organic dyes and solar cells as well as the requirements for efficient photocatalysts is first provided. Then, emphasis is placed on the designation and strategies for perovskite catalysts to improve their photocatalytic activity and/or light adsorption capability. Comments on current and future challenges are also provided. The main purpose of this review paper is to provide a current summary of recent progress in perovskite materials for use in these important areas and to provide some useful guidelines for future development in these hot research areas.


The impact of HIV infection on primary headache. Unexpected findings from retrospective, cross-sectional, and prospective analyses.
Headache is one of the most important factors influencing the quality of life in patients infected with the human immunodeficiency virus type 1 (HIV). However, only symptomatic headache but not changes or primary headache types during HIV infection have been studied to date. Therefore, we aimed to determine the impact of an HIV infection on frequency and semiology of different primary headache types. Patients with confirmed HIV type 1 infection underwent a neurological examination, neuroimaging or EEG, and a standardized interview. Time pattern and symptoms of headaches (cross-sectional analysis), changes of headaches preexisting to their infection (longitudinal retrospective analysis), and changes of primary headaches during a 2-year follow-up (longitudinal prospective analysis) were evaluated as were the correlations between these headache patterns and different markers of HIV infection. One hundred thirty-one consecutive HIV-infected patients without evidence of a cerebral manifestation except mild encephalopathy were enrolled. The point prevalence of migraine was 16.0% (confidence interval (CI) 10.1-25.4%), of headache with a semiology of tension-type headache 45.8% (CI 33.7-62.2%), and of other headache types 6.1% (CI 3.0-12.5%). During the natural course of infection, the migraine frequency significantly decreased in the retrospective and in the prospective analyses, whereas the frequency of the headache with a semiology of tension-type headache significantly increased in all three analyses. In 20% of all patients, the tension-type headache could be considered as symptomatic due to the infection but not due to focal or general cerebral lesions. Changes of primary headache were significantly associated with different stages of the infection and with the presence of mild encephalopathy but not with antiretroviral treatment or CD4 cell count. HIV infection seems to be associated with a progressive decrease in migraine frequency and intensity which probably is related to the immunological state of the patients. Tension-type headache becomes more frequent during HIV infection. However, this can in part be related to secondary headache caused by the HIV in less than 50% of patients with tension-type headache. The progressing immunological deficiency of HIV-infected patients seems to influence pain processing of primary headache types in different ways.


Cloning and characterization of a Xenopus poly(A) polymerase.
During oocyte maturation and early embryogenesis in Xenopus laevis, the translation of several mRNAs is regulated by cytoplasmic poly(A) elongation, a reaction catalyzed by poly(A) polymerase (PAP). We have cloned, sequenced, and examined several biochemical properties of a Xenopus PAP. This protein is 87% identical to the amino-terminal portion of bovine PAP, which catalyzes the nuclear polyadenylation reaction, but lacks a large region of the corresponding carboxy terminus, which contains the nuclear localization signal. When injected into oocytes, the Xenopus PAP remains concentrated in the cytoplasm, suggesting that it is a specifically cytoplasmic enzyme. Oocytes contain several PAP mRNA-related transcripts, and the levels of at least the one encoding the putative cytoplasmic enzyme are relatively constant in oocytes and early embryos but decline after blastulation. When expressed in bacteria and purified by affinity and MonoQ-Sepharose chromatography, the protein has enzymatic activity and adds poly(A) to a model substrate. Importantly, affinity-purified antibodies directed against Xenopus PAP inhibit cytoplasmic polyadenylation in egg extracts. These data suggest that the PAP described here could participate in cytoplasmic polyadenylation during Xenopus oocyte maturation.


Diet-induced pseudohypoparathyroidism: A hypocalcemia and milk fever risk factor.
Subclinical hypocalcemia may affect half of all multiparous cows, and clinical hypocalcemia or milk fever affects approximately 5% of dairy cows each year. This disorder of calcium homeostasis can be induced by several dietary factors. Recent studies implicate high dietary potassium and high dietary cation-anion difference (DCAD) with increased risk of milk fever. The hypothesis tested in this study was that high-DCAD diets fed to prepartum cows reduce tissue sensitivity to parathyroid hormone (PTH), inducing a pseudohypoparathyroid state that diminishes calcium homeostatic responses. Multiparous Jersey cows were fed low- or high-DCAD diets in late gestation, creating a compensated metabolic alkalosis in the high-DCAD cows and a compensated metabolic acidosis in the low-DCAD cows. They then received synthetic PTH injections at 3-h intervals for 48 h. Parathyroid hormone is expected to cause an increase in plasma calcium by increasing renal production of 1,25-dihydroxyvitamin D and increasing bone calcium resorption. Plasma calcium concentration increased at a significantly lower rate in cows fed the high-DCAD diet. Cows fed the high-DCAD diet also produced significantly less 1,25-dihydroxyvitamin D in response to the PTH injections than cows fed the low-DCAD diet. Serum concentrations of the bone resorption marker carboxyterminal telopeptide of type I collagen were numerically lower in cows fed the high-DCAD diet but this difference was not statistically significant. These data provide direct evidence that high-DCAD diets reduce tissue sensitivity to PTH. The metabolic alkalosis associated with high-DCAD diets likely induces a state of pseudohypoparathyroidism in some dairy cows at the onset of lactation, resulting in hypocalcemia and milk fever.


Calibration of sulfate levels in the archean ocean.
The size of the marine sulfate reservoir has grown through Earth's history, reflecting the accumulation of oxygen into the atmosphere. Sulfur isotope fractionation experiments on marine and freshwater sulfate reducers, together with the isotope record, imply that oceanic Archean sulfate concentrations were <200 microM, which is less than one-hundredth of present marine sulfate levels and one-fifth of what was previously thought. Such low sulfate concentrations were maintained by volcanic outgassing of SO2 gas, and severely suppressed sulfate reduction rates allowed for a carbon cycle dominated by methanogenesis.


Informing the dosing of interventions in randomized trials.
Dosing is potentially the most important decision that must be made when building or refining behavioral interventions. In this paper, we propose standardized terminology and reporting of dosing information, which would inform intervention development, refinement for dissemination, and systematic reviews of dose-response relationships. Dosing of interventions may be characterized by duration, frequency, and amount. To illustrate the value of operationalizing these three parameters to evaluate dose-response relationships, 31 published reports of behavioral interventions to increase adherence to antiretroviral therapy (ART) were reviewed. The ART literature was characterized by under-reporting of dosing parameters, heterogeneity in dosing schedules, and heterogeneity in type of control group, which complicate analysis of dose-response relationships in systematic review and determination of the optimal dose for intervention dissemination. Improved reporting of the three dosing parameters and comparison of intended to actual delivery can inform the identification of the most effective intervention doses and the efficient implementation of efficacious interventions in clinical practice.


Asthma and asthma-related health care utilization among people without disabilities and people with physical disabilities.
Previous research has shown that people with disabilities have higher rates of some chronic diseases and receive poorer disease-specific care than their counterparts without disabilities. Yet, little is known about the relationship between asthma and disability. This study examines whether differences in the prevalence of asthma, asthma flare, and asthma-related measures of health care quality, utilization and cost exist among people with physical limitations (PL) and without any limitations. Data from the 2004-2010 Medical Expenditure Panel Survey were pooled to compare outcomes for working-age adults (18-64) with PL to those with no limitations. People with PL had higher rates of asthma (13.8% vs. 5.9%, p < 0.001) and recent asthma flare (52.6% vs. 39.6%, p < 0.001) than people without limitations. There were no differences in health care quality, utilization or cost between people with PL and people without limitations in multivariate analyses. Although there are no differences in asthma-related quality or utilization of health care, people with PL have poorer asthma control than people without limitations. Research is needed to determine what factors (e.g., focus on other acute ailments, perceptions that asthma control cannot improve) are related to this outcome. Future research must also examine differences in asthma severity, and its impact on asthma control and health care-related outcomes, among people with and without disabilities.


Peritoneal inflammation - A microenvironment for Epithelial Ovarian Cancer (EOC).
Epithelial ovarian cancer (EOC) is a significant cause of cancer related morbidity and mortality in women. Preferential involvement of peritoneal structures contributes to the overall poor outcome in EOC patients. Advances in biotechnology, such as cDNA microarray, are a product of the Human Genome Project and are beginning to provide fresh opportunities to understand the biology of EOC. In particular, it is now possible to examine in depth, at the molecular level, the complex relationship between the tumor itself and its surrounding microenvironment.This review focuses on the anatomy, physiology, and current immunobiologic research of peritoneal structures, and addresses certain potentially useful animal models. Changes in both the inflammatory and non-inflammatory cell compartments, as well as alterations to the extracellular matrix, appear to be signal events that contribute to the remodeling effects of the peritoneal stroma and surface epithelial cells on tumor growth and spread. These alterations may involve a number of proteins, including cytokines, chemokines, growth factors, either membrane or non-membrane bound, and integrins. Interactions between these molecules and molecular structures within the extracellular matrix, such as collagens and the proteoglycans, may contribute to a peritoneal mesothelial surface and stromal environment that is conducive to tumor cell proliferation and invasion. These alterations need to be examined and defined as possible prosnosticators and as therapeutic or diagnostic targets.


Principles of RNA and nucleotide discrimination by the RNA processing enzyme RppH.
All enzymes face a challenge of discriminating cognate substrates from similar cellular compounds. Finding a correct substrate is especially difficult for the Escherichia coli Nudix hydrolase RppH, which triggers 5'-end-dependent RNA degradation by removing orthophosphate from the 5'-diphosphorylated transcripts. Here we show that RppH binds and slowly hydrolyzes NTPs, NDPs and (p)ppGpp, which each resemble the 5'-end of RNA. A series of X-ray crystal structures of RppH-nucleotide complexes, trapped in conformations either compatible or incompatible with hydrolysis, explain the low reaction rates of mononucleotides and suggest two distinct mechanisms for their hydrolysis. While RppH adopts the same catalytic arrangement with 5'-diphosphorylated nucleotides as with RNA, the enzyme hydrolyzes 5'-triphosphorylated nucleotides by extending the active site with an additional Mg2+ cation, which coordinates another reactive nucleophile. Although the average intracellular pH minimizes the hydrolysis of nucleotides by slowing their reaction with RppH, they nevertheless compete with RNA for binding and differentially inhibit the reactivity of RppH with triphosphorylated and diphosphorylated RNAs. Thus, E. coli RppH integrates various signals, such as competing non-cognate substrates and a stimulatory protein factor DapF, to achieve the differential degradation of transcripts involved in cellular processes important for the adaptation of bacteria to different growth conditions.


Objective neuropsychological deficits in post-traumatic stress disorder and mild traumatic brain injury: what remains beyond symptom similarity?
This exploratory study intends to characterize the neuropsychological profile in persons with post-traumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI) using objective measures of cognitive performance. A neuropsychological battery of tests for attention, memory and executive functions was administered to four groups: PTSD (n = 25), mTBI (n = 19), subjects with two formal diagnoses: Post-traumatic Stress Disorder and Mild Traumatic Brain Injury (mTBI/PTSD) (n = 6) and controls (n = 25). Confounding variables, such as medical, developmental or neurological antecedents, were controlled and measures of co-morbid conditions, such as depression and anxiety, were considered. The PTSD and mTBI/PTSD groups reported more anxiety and depressive symptoms. They also presented more cognitive deficits than the mTBI group. Since the two PTSD groups differ in severity of PTSD symptoms but not in severity of depression and anxiety symptoms, the PTSD condition could not be considered as the unique factor affecting the results. The findings underline the importance of controlling for confounding medical and psychological co-morbidities in the evaluation and treatment of PTSD populations, especially when a concomitant mTBI is also suspected.


Psychiatric correlates of behavioral inhibition in young children of parents with and without psychiatric disorders.
Behavioral inhibition is a laboratory-based temperamental category by the tendency to constrict behavior in unfamiliar situations and assumed to reflect low thresholds of limbic arousal. We previously found behavioral inhibition prevalent in the offspring of parents with panic disorder and agoraphobia. In this report, we examined the psychiatric correlates of behavioral inhibition by evaluating the sample of offspring of parents with panic disorder and agoraphobia, previously dichotomized as inhibited and not inhibited, and an existing epidemiologically derived sample of children, followed by Kagan and colleagues and originally identified at 21 months of age as inhibited or uninhibited. A third group of healthy children was added for comparison. Our findings indicate that inhibited children had increased risk for multiple anxiety, overanxious, and phobic disorders. It is suggested that behavioral inhibition may be associated with risk for anxiety disorders in children.


The Effects of Muscle Mass on Homocyst(e)ine Levels in Plasma and Urine.
The present study was designed to examine the relationship between homocyst(e)ine (H[e]) levels and muscle mass. Two experimental groups each of 24 Caucasian males, one consisting of higher-muscle mass subjects (HMM) and the other of lower-muscle mass subjects (LMM) participated in this study. Muscle mass was estimated from 24-hour urine collections of creatinine (Crt). Muscle mass was 40.3 ± 15.9 kg in HMM and 37.2 ± 11.4 kg in LMM (P= 0.002). Mean plasma H(e) levels in HMM were 10.29 ± 2.9 nmol/mL, and in LMM were 10.02 ± 2.4 nmol/L (Not significant, [NS]). Urinary H(e) levels (UH[e]) were 9.95 ± 4.3 nmol/mL and 9.22 ± 2.9 nmol/mL for HMM and LMM, respectively (NS). Plasma H(e) levels correlated well with UH(e) (HMM: r= 0.58, P= 0.009; LMM: r= 0.66, P= 0.004). Muscle mass and was not correlated to either plasma H(e) or UH(e). However, in HMM trends were identified for body mass to be correlated with UH(e) (r= 0.39, P= 0.10) and UCrt (r= 0.41, P= 0.08). Surprisingly, in HMM plasma and UCrt were only weakly correlated (r= 0.44, P= 0.06). Our results do not support a causal relationship between the amount of muscle mass and H(e) levels in plasma or urine.


Personality traits in dumpling squid (Euprymna tasmanica): context-specific traits and their correlation with biological characteristics.
Personality traits are a major class of behavioral variation often observed within populations of animals. However, little is known of the integration between personality and an individual's underlying biology. To address this, the authors measured personality traits in squid (Euprymna tasmanica) in 2 contexts while also describing trait correlates with biological parameters. Four traits (shy avoidance- bold aggression, activity, bury persistence, and reactivity) were reliably measured; however, trait expression between contexts was not correlated and thus was context-specific. Trait variation was not a function of gender or of somatic or reproductive condition but was explained partially by a squid's sexual maturity and its size. Results are discussed in terms of the interplay between personality variation and resulting life history strategies in animals.


Natural compounds against doxorubicin-induced cardiotoxicity: A review on the involvement of Nrf2/ARE signaling pathway.
Cardiotoxicity is the main concern for long-term use of the doxorubicin (DOX). Reactive oxygen species (ROS) generation leads to oxidative stress that significantly contributes to the cardiac damage induced by DOX. The nuclear factor erythroid 2-related factor (Nrf2) acts as a protective player against DOX-induced myocardial oxidative stress. Several natural compounds (NCs) with anti-oxidative effects, were examined to suppress DOX cardiotoxicity such as asiatic acid, α-linolenic acid, apigenin, baicalein, β-lapachone, curdione, dioscin, ferulic acid, Ganoderma lucidum polysaccharides, genistein, ginsenoside Rg3, indole-3-carbinol, naringenin-7-O-glucoside, neferine, p-coumaric acid, pristimerin, punicalagin, quercetin, sulforaphane, and tanshinone IIA. The present article, reviews NCs that showed protective effects against DOX-induced cardiac injury through induction of Nrf2 signaling pathway.


Multiphoton-excited luminescent lanthanide bioprobes: two- and three-photon cross sections of dipicolinate derivatives and binuclear helicates.
Multiphoton excited luminescent properties of water-soluble Eu(III) and Tb(III) complexes with derivatives of dipicolinic acid functionalized with a polyoxyethylene pendant arm and terminal groups, [Eu(L(OMe))(3)](3-), [Eu(L(NH2))(3)](3-), and [Tb(L(OH))(3)](3-), as well as of binuclear helicates with overall composition [Ln(2)(L(CX))(3)] (X = 2, 5) are investigated. Characteristic emission from the (5)D(0) and (5)D(4) excited levels of Eu(III) and Tb(III), respectively, upon approximately 800 nm excitation results from three-photon absorption (3PA) for [Eu(L(OMe))(3)](3-), [Eu(L(NH2))(3)](3-), [Tb(L(OH))(3)](3-), and [Ln(2)(L(C2))(3)], while luminescence from [Eu(2)(L(C5))(3)] is induced by two-photon absorption (2PA) owing to its 1PA spectrum extending further into the visible. The 3PA cross sections have been determined and are the first ones reported for lanthanide complexes: (i) those of Eu(III) and Tb(III) bimetallic helicates [Ln(2)(L(C2))(3)] are 20 times larger compared to the corresponding values for tris(dipicolinates); (ii) derivatization of dipicolinic acid for Tb(III) complexes has almost no influence on the 3PA cross section; however, for Eu(III) complexes a approximately 2 times decrease is observed. The feasibility of [Eu(2)(L(C5))(3)] as multiphoton luminescence bioprobe is demonstrated by two-photon scanning microscopy imaging experiments on HeLa cells incubated with this bimetallic helicate.


Multifunctional structural energy storage composite supercapacitors.
This paper addresses the challenge of producing multifunctional composites that can simultaneously carry mechanical loads whilst storing (and delivering) electrical energy. The embodiment is a structural supercapacitor built around laminated structural carbon fibre (CF) fabrics. Each cell consists of two modified structural CF fabric electrodes, separated by a structural glass fibre fabric or polymer membrane, infused with a multifunctional polymeric electrolyte. Rather than using conventional activated carbon fibres, structural carbon fibres were treated to produce a mechanically robust, high surface area material, using a variety of methods, including direct etching, carbon nanotube sizing, and carbon nanotube in situ growth. One of the most promising approaches is to integrate a porous bicontinuous monolithic carbon aerogel (CAG) throughout the matrix. This nanostructured matrix both provides a dramatic increase in active surface area of the electrodes, and has the potential to address mechanical issues associated with matrix-dominated failures. The effect of the initial reaction mixture composition is assessed for both the CAG modified carbon fibre electrodes and resulting devices. A low temperature CAG modification of carbon fibres was evaluated using poly(3,4-ethylenedioxythiophene) (PEDOT) to enhance the electrochemical performance. For the multifunctional structural electrolyte, simple crosslinked gels have been replaced with bicontinuous structural epoxy-ionic liquid hybrids that offer a much better balance between the conflicting demands of rigidity and molecular motion. The formation of both aerogel precursors and the multifunctional electrolyte are described, including the influence of key components, and the defining characteristics of the products. Working structural supercapacitor composite prototypes have been produced and characterised electrochemically. The effect of introducing the necessary multifunctional resin on the mechanical properties has also been assessed. Larger scale demonstrators have been produced including a full size car boot/trunk lid.


Functional constraints on tooth morphology in carnivorous mammals.
The range of potential morphologies resulting from evolution is limited by complex interacting processes, ranging from development to function. Quantifying these interactions is important for understanding adaptation and convergent evolution. Using three-dimensional reconstructions of carnivoran and dasyuromorph tooth rows, we compared statistical models of the relationship between tooth row shape and the opposing tooth row, a static feature, as well as measures of mandibular motion during chewing (occlusion), which are kinetic features. This is a new approach to quantifying functional integration because we use measures of movement and displacement, such as the amount the mandible translates laterally during occlusion, as opposed to conventional morphological measures, such as mandible length and geometric landmarks. By sampling two distantly related groups of ecologically similar mammals, we study carnivorous mammals in general rather than a specific group of mammals. Statistical model comparisons demonstrate that the best performing models always include some measure of mandibular motion, indicating that functional and statistical models of tooth shape as purely a function of the opposing tooth row are too simple and that increased model complexity provides a better understanding of tooth form. The predictors of the best performing models always included the opposing tooth row shape and a relative linear measure of mandibular motion. Our results provide quantitative support of long-standing hypotheses of tooth row shape as being influenced by mandibular motion in addition to the opposing tooth row. Additionally, this study illustrates the utility and necessity of including kinetic features in analyses of morphological integration.