Results of a Phase One study on robotically assisted myocardial revascularization on the beating heart.
The objective of this study was to evaluate the feasibility of computer assisted myocardial revascularization on the beating heart. Ten patients underwent at least one robotically assisted internal mammary artery (IMA) anastomosis utilizing the da Vinci surgical system (Intuitive Surgical, Inc, Mountain View, CA) performed through an open incision as part of standard multivessel off pump revascularization. Following chest closure a selective IMA angiogram was performed to assess patency. Three month follow-up included a stress echocardiogram. There were 12 anastomoses performed in 10 patients. The average age was 61 years with a mean ejection fraction of 56%. No patient required inotropic support. Eight of 10 patients were found to have fully patent IMA anastomoses by angiogram. One patient was noted to have an occluded left anterior descending coronary artery distal to the anastomosis and one had occlusion at the anastomosis. Both patients had immediate manual revision of the anastomosis. One patient who required anastomotic revision experienced postoperative myocardial infarction and sternal wound infection requiring pectoralis flaps. Because robotic instrumentation is meant for closed chest procedures, there were major issues with positioning of the robotic arms in this study since the chest was open. Although two patients required anastomotic revision, there were no complications or technical failures related to the robotic system. Thus, based upon this study robotically assisted beating heart revascularization appears to be feasible, safe, and effective. Further evaluation will be necessary to determine the role of robotically assisted totally endoscopic coronary artery bypass on the beating heart in the United States.


Amyloidogenesis. One serum amyloid A isotype is selectively removed from the circulation.
The deposits of fibrils found in amyloidosis of the A type are derived from only one of the three serum amyloid A (SAA) gene products, namely SAA2. In order to explore the mechanism of SAA isotype-specific amyloid protein AA deposition, the molecular kinetics of the serum amyloid proteins were examined in CBA mice during casein induction of amyloidosis. The presence of SAA mRNA in spleen was searched for; hepatic SAA1 and SAA2 mRNA levels, rates of specific protein synthesis and secretion by hepatocytes, and serum levels were measured during a 20-d period of amyloid induction. We observed the following: small amounts of amyloid substance appeared in the spleen by day 5 and increased steadily over the ensuing 15 d to occupy nearly 30% of splenic volume by day 20. No SAA mRNA was detected in spleen at any time during induction of amyloid formation. Total serum SAA levels peaked 1 d after we began casein treatment, and thereafter declined. This decline was accounted for entirely by a dramatic fall in SAA2, while SAA1 levels remained nearly constant throughout. The ratios of hepatic SAA2:SAA1 mRNA, as determined by in vitro translation, remained constant during the 20-d period, as did amounts of SAA1 and SAA2 synthesized and secreted by freshly isolated hepatocytes. These data indicate that the deposition of amyloid A protein derived from SAA2 is not due to local SAA production in spleen, nor excessive SAA2 production compared with SAA1, but involves the selective and accelerated removal of SAA2 from the circulating pool of both SAA1 and SAA2.


Profile and pattern of Stevens-Johnson syndrome and toxic epidermal necrolysis in a general hospital in Singapore: treatment outcomes.
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, but potentially life-threatening, reactions to medications. Both conditions have significant morbidity and mortality. The aim of this study was to document the epidemiological features, aetiologies, treatment and clinical outcomes of retrospectively reviewed data of all patients with SJS or TEN treated from January 2004 to November 2010 in a general hospital. There were 18 cases of SJS, seven cases of SJS/TEN overlap and three cases of TEN. Mean age was 50.6 years, with a range of 13-85 years. The male/female ratio was 1. Drugs accounted for 26 cases; one case was caused by Neisseria gonorrhoea infection. Anti-convulsants (35.7%) were the most common implicated drugs followed by antibiotics (28.5%), non-steroidal anti-inflammatory drugs (NSAIDS) (14.3%), allopurinol (7.1%) and traditional Chinese medication (7.1%). In seven cases, multiple drugs were implicated. Most SJS cases (88%) were treated with corticosteroids, of which 61% were given high-dose systemic corticosteroids. No infective complications were observed. Six out of the seven SJS/TEN overlap syndrome and all three TEN cases were given intravenous immunoglobulins. One patient with TEN died. In conclusion, anti-convulsants, especially carbamazepine, were the most frequently implicated drugs, followed by antibiotics and NSAIDS. High-dose corticosteroids were effective in SJS, whereas intra-venous immunoglobulin were useful in TEN and SJS/TEN overlap syndrome.


The evolutionary imprint of domestication on genome variation and function of the filamentous fungus Aspergillus oryzae.
The domestication of animals, plants, and microbes fundamentally transformed the lifestyle and demography of the human species [1]. Although the genetic and functional underpinnings of animal and plant domestication are well understood, little is known about microbe domestication [2-6]. Here, we systematically examined genome-wide sequence and functional variation between the domesticated fungus Aspergillus oryzae, whose saccharification abilities humans have harnessed for thousands of years to produce sake, soy sauce, and miso from starch-rich grains, and its wild relative A. flavus, a potentially toxigenic plant and animal pathogen [7]. We discovered dramatic changes in the sequence variation and abundance profiles of genes and wholesale primary and secondary metabolic pathways between domesticated and wild relative isolates during growth on rice. Our data suggest that, through selection by humans, an atoxigenic lineage of A. flavus gradually evolved into a "cell factory" for enzymes and metabolites involved in the saccharification process. These results suggest that whereas animal and plant domestication was largely driven by Neolithic "genetic tinkering" of developmental pathways, microbe domestication was driven by extensive remodeling of metabolism.


Dual roles of Nrf2 in cancer.
In response to oxidative stress, the transcription factor NF-E2-related factor 2 (Nrf2) controls the fate of cells through transcriptional upregulation of antioxidant response element (ARE)-bearing genes, including those encoding endogenous antioxidants, phase II detoxifying enzymes, and transporters. Expression of the Nrf2-dependent proteins is critical for ameliorating or eliminating toxicants/carcinogens to maintain cellular redox homeostasis. As a result, activation of the Nrf2 pathway, by naturally-occurring compounds or synthetic chemicals at sub-toxic doses, confers protection against subsequent toxic/carcinogenic exposure. Thus, the use of dietary compounds or synthetic chemicals to boost the Nrf2-dependent adaptive response to counteract environmental insults has emerged to be a promising strategy for cancer prevention. Interestingly, recent emerging data has revealed the "dark" side of Nrf2. Nrf2 and its downstream genes are overexpressed in many cancer cell lines and human cancer tissues, giving cancer cells an advantage for survival and growth. Furthermore, Nrf2 is upregulated in resistant cancer cells and is thought to be responsible for acquired chemoresistance. Therefore, it may be necessary to inhibit the Nrf2 pathway during chemotherapy. This review is primarily focused on the role of Nrf2 in cancer, with emphasis on the recent findings indicating the cancer promoting function of Nrf2 and its role in acquired chemoresistance.


Haptoglobin, alpha-thalassaemia and glucose-6-phosphate dehydrogenase polymorphisms and risk of abnormal transcranial Doppler among patients with sickle cell anaemia in Tanzania.
Transcranial Doppler ultrasonography measures cerebral blood flow velocity (CBFv) of basal intracranial vessels and is used clinically to detect stroke risk in children with sickle cell anaemia (SCA). Co-inheritance in SCA of alpha-thalassaemia and glucose-6-phosphate dehydrogenase (G6PD) polymorphisms is reported to associate with high CBFv and/or risk of stroke. The effect of a common functional polymorphism of haptoglobin (HP) is unknown. We investigated the effect of co-inheritance of these polymorphisms on CBFv in 601 stroke-free Tanzanian SCA patients aged <24 years. Homozygosity for alpha-thalassaemia 3·7 deletion was significantly associated with reduced mean CBFv compared to wild-type (β-coefficient -16·1 cm/s, P = 0·002) adjusted for age and survey year. Inheritance of 1 or 2 alpha-thalassaemia deletions was associated with decreased risk of abnormally high CBFv, compared to published data from Kenyan healthy control children (Relative risk ratio [RRR] = 0·53 [95% confidence interval (CI):0·35-0·8] & RRR = 0·43 [95% CI:0·23-0·78]), and reduced risk of abnormally low CBFv for 1 deletion only (RRR = 0·38 [95% CI:0·17-0·83]). No effects were observed for G6PD or HP polymorphisms. This is the first report of the effects of co-inheritance of common polymorphisms, including the HP polymorphism, on CBFv in SCA patients resident in Africa and confirms the importance of alpha-thalassaemia in reducing risk of abnormal CBFv.


Nerve conduction velocity in hypertensive patients.
Due to conflicting reports in the literature regarding nerve conduction velocities (NCVs) in hypertensives, peroneal and sural NCVs and facial nerve conduction latencies were studied in 30 hypertensives and in 30 controls. An improved technique of NCV measurement was used. Twenty-one of the hypertensives were retested after five weeks, and five of them were tested for motor and sensory NCVs of the median nerve during a short period of partial occlusion of blood flow in the arm. No changes were found that could be related to blood pressure, duration of hypertension, eyeground changes, or partial restriction of blood flow.


Solution structure of the ubiquitin-associated (UBA) domain of human autophagy receptor NBR1 and its interaction with ubiquitin and polyubiquitin.
NBR1 (neighbor of BRCA1 gene 1) is a protein commonly found in ubiquitin-positive inclusions in neurodegenerative diseases. Due to its high architectural similarity to the well studied autophagy receptor protein p62/SQSTM1, NBR1 has been thought to analogously bind to ubiquitin-marked autophagic substrates via its C-terminal ubiquitin-associated (UBA) domain and deliver them to autophagosomes for degradation. Unexpectedly, we find that NBR1 differs from p62 in its UBA structure and accordingly in its interaction with ubiquitin. Structural differences are observed on helix α-3, which is tilted farther from helix α-2 and extended by approximately one turn in NBR1. This results not only in inhibition of a p62-type self-dimerization of NBR1 UBA but also in a significantly higher affinity for monoubiquitin as compared with p62 UBA. Importantly, the NBR1 UBA-ubiquitin complex structure shows that the negative charge of the side chain in front of the conserved MGF motif in the UBA plays an integral role in the recognition of ubiquitin. In addition, NMR and isothermal titration calorimetry experiments show that NBR1 UBA binds to each monomeric unit of polyubiquitin with similar affinity and by the same surface used for binding to monoubiquitin. This indicates that NBR1 lacks polyubiquitin linkage-type specificity, in good agreement with the nonspecific linkages observed in intracellular ubiquitin-positive inclusions. Consequently, our results demonstrate that the structural differences between NBR1 UBA and p62 UBA result in a much higher affinity of NBR1 for ubiquitin, which in turn suggests that NBR1 may form intracellular inclusions with ubiquitylated autophagic substrates more efficiently than p62.


Management of a facial partial thickness chemical burn in a dog caused by bleach.
To describe the management and successful outcome of a late-recognition partial thickness bleach burn to the face and corneas of a dog. A 1-year-old male neutered Fox Terrier mix breed dog was evaluated for sloughing facial epithelium 5 days after coming into contact with an 8.25% household bleach cleaning solution. Severe erythema, edema, and crusting were noted around the muzzle and margins of both eyes, with moderate to severe alopecia in these areas. A partially detached, partial thickness eschar was present on the muzzle, while a firmly attached eschar was present in the region of both frontal sinuses. These injuries were consistent with a focal, superficial, and partial thickness chemical burn. Multiple ocular abnormalities, the most concerning of which was corneal ulceration, were also present. The patient's wounds were managed conservatively with limited surgical debridement of the affected epithelium 11 and 22 days after the initial exposure. Topical ocular medications, corneal debridement, and a superficial keratectomy were also used. All lesions resolved completely by 84 days postexposure, with no residual effects on the patient's quality of life. Chemical burns caused by contact with alkaline agents such as bleach (sodium hypochlorite) result in extensive necrosis of the skin and underlying structures. This is the first report of management alkaline facial burns in a dog. If inadequate or delayed hydrotherapy following exposure has resulted in superficial partial thickness burns, conservative management can be successful when traditional treatments, especially bandaging, are not feasible.


Patient-reported outcomes and final overall survival results from the randomized phase 3 PENELOPE trial evaluating pertuzumab in low tumor human epidermal growth factor receptor 3 (HER3) mRNA-expressing platinum-resistant ovarian cancer.
The PENELOPE trial evaluated pertuzumab added to chemotherapy for biomarker-selected platinum-resistant ovarian cancer. As previously reported, pertuzumab did not statistically significantly improve progression-free survival (primary end point: HR 0.74, 95% CI 0.50 to 1.11), although results in the paclitaxel and gemcitabine cohorts suggested activity. Here, we report final overall survival and patient-reported outcomes. Eligible patients had ovarian carcinoma that progressed during/within 6 months of completing ≥4 platinum cycles, low tumor human epidermal growth factor receptor 3 (HER3) mRNA expression, and ≤2 prior chemotherapy lines. Investigators selected single-agent topotecan, gemcitabine or weekly paclitaxel before patients were randomized to either placebo or pertuzumab (840→420 mg every 3 weeks), stratified by selected chemotherapy, prior anti-angiogenic therapy, and platinum-free interval. Final overall survival analysis (key secondary end point) was pre-specified after 129 deaths. Patient-reported outcomes (secondary end point) were assessed at baseline and every 9 weeks until disease progression. At database lock (June 9, 2016), 130 (83%) of 156 randomized patients had died. Median follow-up was 27 months in the pertuzumab arm versus 26 months in the control arm. In the intent-to-treat population there was no overall survival difference between treatment arms (stratified HR 0.90, 95% CI 0.61 to 1.32; p=0.60). Results in subgroups defined by stratification factors indicated heterogeneity similar to previous progression-free survival results. Updated safety was similar to previously published results. Compliance with patient-reported outcomes questionnaire completion was >75% for all validated patient-reported outcomes measures. Pertuzumab demonstrated neither beneficial nor detrimental effects on patient-reported outcomes compared with placebo, except for increased diarrhea symptoms. Consistent with the primary results, adding pertuzumab to chemotherapy for low tumor HER3 mRNA-expressing platinum-resistant ovarian cancer did not improve overall survival, but showed trends in some cohorts. Except for increased diarrhea symptoms, pertuzumab had no impact on patient-reported outcomes. ClinicalTrials.gov: ClinicalTrials.gov: NCT01684878.


Transcriptomic profiles of Wnt3a and insulin in primary cultured rat cortical neurones.
Glycogen synthase kinase 3 (GSK3) is a widely expressed, constitutively active, serine/threonine kinase that is negatively regulated by both Wnt and insulin via two independent signalling pathways. GSK3 is an important mediator in many physiological processes including glycogen metabolism, apoptosis and gene transcription. In addition, GSK3 is implicated in diseases such as Alzheimer's, schizophrenia and cancer, where it exhibits deregulated activity. In this study, we sought to determine the neuronal genes regulated by both Wnt and insulin in an in vitro cell culture model to further elucidate the signalling roles GSK3 plays in the CNS. Affymetrix Rat Genome 230 2.0 whole genome microarrays were used to explore the expression profiles of rat primary cortical neurones treated with recombinant Wnt3a (10 nM) or insulin (50 nM) for 2 h. Following a conservative correction (Bonferroni) for multiple testing, seven genes were identified to be differentially expressed from controls; four of these genes were regulated by insulin and three genes were regulated by both insulin and Wnt3a. The data were also analysed using a false discovery rate cut off, which is a less stringent correction for multiple testing. This approach yielded 105 genes that were differentially regulated from controls; 72 of the gene changes were attributable to insulin treatment, 11 were because of Wnt3a treatment and 22 genes were altered by both insulin and Wnt3a. These data demonstrate that the Wnt and insulin pathways exhibit both divergent and overlapping signalling activities in neuronal cells. The overlapping transcriptional response was not attributable to Wnt3a activating Akt. These findings have ramifications for neurodevelopment and neurological diseases, in which the Wnt and insulin signalling pathways are implicated.


Inhibition by antidepressant drugs of cyclic AMP response element-binding protein/cyclic AMP response element-directed gene transcription.
Clinical observations agree that antidepressant drugs are effective only after a lag phase of 1-3 weeks. This delay could be explained at the molecular level by an action on gene transcription. Transcription of many genes is directed by the cAMP/Ca(2+)-responsive element (CRE) and its cognate transcription factor CRE-binding protein (CREB). Membrane depolarization and cAMP induce the phosphorylation of CREB at Ser-119 and thereby stimulate the transcriptional activity of CREB. The effect of antidepressant drugs on CREB/CRE-directed gene transcription was investigated using transient transfections of reporter fusion genes in HIT and PC-12 cells. Clomipramine, imipramine, fluoxetine, doxepin, desipramine, amitriptyline, maprotiline, mianserin, and trazodone inhibited CRE-directed gene transcription that was stimulated by membrane depolarization, with IC50 values between 70 nM and 1.73 microM. Desipramine had no effect on transcription after stimulation by cAMP but blocked the synergistic effect of cAMP and membrane depolarization to the level of stimulation by cAMP alone. Upon membrane depolarization, desipramine reduced the phosphorylation of CREB at Ser-119 and also blocked the depolarization-induced increase in the intracellular free Ca2+ concentration in HIT cells. Thus, by interfering with the depolarization-induced activation of the transcription factor CREB, antidepressant drugs can inhibit CRE-directed gene transcription, which could underlie the pharmacological effects of these clinically important drugs.


Synthesis of a secondary N-desmethyl and a tertiary N-cyclopropylmethyl bridged hexahydroaporphine as precursors to bicyclic opioid ligands.
In an attempt to generate a bicyclic 5,8-ethano derivative of N-methylmorphinan, an isomeric bicyclic hexahydroaporphine 2 was synthesized. The phenolic analogue of 2 has demonstrated affinity for mu opioid receptors in vitro and, along with 2, provided weak, primarily nonopioid analgesic action when injected intracerebroventricularly in mice. It was of interest to assess the potential opioid antagonist action of bicyclic hexahydroaporphine analogues containing cyclopropylmethyl and allyl nitrogen substituents. As the first steps in the generation of these potential opioid antagonists, the secondary bicyclic hexahydroaporphine 3 and its N-cyclopropylmethyl congener 4 were synthesized. N-Demethylation of 2 was initially attempted via the von Braun reaction, but acid-catalyzed hydrolysis of the crude N-cyano intermediate resulted in product decomposition. A successful approach to 3 involved the hydrolysis of the N-formyl precursor 1 in ethanolic potassium hydroxide. Direct alkylation of the secondary amine 3 utilizing cyclopropylmethyl bromide and sodium bicarbonate successfully generated the alkylated derivative 4. Both products were purified in hydrochloride salt form and characterized by standard analytical and spectroscopic methods. The free base form of 3 was highly sensitive to photooxidation. Opioids are known to oxidize to 10-keto structures, and secondary amines can oxidize to hydroxylamines. Infrared analysis of the decomposition product indicated the presence of both hydroxy and carbonyl groups which were absent in the spectrum of the salt. Structures of potential oxidation products are proposed.


Transvenous extraction of a 26-year-old Accufix atrial lead using TightRail rotating dilator sheath.
With the increasing number of implanted pacemakers and implantable cardioverter defibrillators, removal is required more frequently. Presently described is the transvenous extraction of a 26-year-old Accufix atrial lead using a mechanical dilator sheath. A 50-year-old male patient was admitted to the clinic with a pacemaker pocket infection. The atrial lead was an Accufix Bipolar J-Atrial active fixation lead, a model that was recalled in 1994, after reports of 2 deaths and 2 nonfatal injuries related to protrusion of the J retention wire. Both the atrial and ventricular leads were extracted using a mechanical dilator sheath. The Pacemaker Lead Extraction with the Excimer Sheath (PLEXES) Trial reported that of the 57 Accufix leads randomized to a non-laser approach, only 47% were removed successfully, compared with 96% of laser-randomized cases. Since laser sheaths are not available in Turkey, use of a mechanical dilator sheath was required. To our knowledge, this is the oldest Accufix lead extracted with a non-laser sheath. During the extraction of the ventricular lead, the tip of the lead broke off inside the right ventricle and the residual part was left inside the heart. During 3 months of follow-up, no signs of infection or any other undesirable events were encountered.


Determining the control circuitry of redox metabolism at the genome-scale.
Determining how facultative anaerobic organisms sense and direct cellular responses to electron acceptor availability has been a subject of intense study. However, even in the model organism Escherichia coli, established mechanisms only explain a small fraction of the hundreds of genes that are regulated during electron acceptor shifts. Here we propose a qualitative model that accounts for the full breadth of regulated genes by detailing how two global transcription factors (TFs), ArcA and Fnr of E. coli, sense key metabolic redox ratios and act on a genome-wide basis to regulate anabolic, catabolic, and energy generation pathways. We first fill gaps in our knowledge of this transcriptional regulatory network by carrying out ChIP-chip and gene expression experiments to identify 463 regulatory events. We then interfaced this reconstructed regulatory network with a highly curated genome-scale metabolic model to show that ArcA and Fnr regulate >80% of total metabolic flux and 96% of differential gene expression across fermentative and nitrate respiratory conditions. Based on the data, we propose a feedforward with feedback trim regulatory scheme, given the extensive repression of catabolic genes by ArcA and extensive activation of chemiosmotic genes by Fnr. We further corroborated this regulatory scheme by showing a 0.71 r(2) (p<1e-6) correlation between changes in metabolic flux and changes in regulatory activity across fermentative and nitrate respiratory conditions. Finally, we are able to relate the proposed model to a wealth of previously generated data by contextualizing the existing transcriptional regulatory network.


Scale-dependent interaction of fire and grazing on community heterogeneity in tallgrass prairie.
Natural disturbances affect spatial and temporal heterogeneity in plant communities, but effects vary depending on type of disturbance and scale of analysis. In this study, we examined the effects of fire frequency (1-, 4-, and 20-yr intervals) and grazing by bison on spatial and temporal heterogeneity in species composition in tallgrass prairie plant communities. Compositional heterogeneity was estimated at 10-, 50-, and 200-m2 scales. For each measurement scale, we used the average Euclidean Distance (ED) between samples within a year (2000) to measure spatial heterogeneity and between all time steps (1993-2000) for each sample to measure temporal heterogeneity. The main effects of fire and grazing were scale independent. Spatial and temporal heterogeneity were lowest on annually burned sites and highest on infrequently burned (20-yr) sites at all scales. Grazing reduced spatial heterogeneity and increased temporal heterogeneity at all scales. The rate of community change over time decreased as fire frequency increased at all scales, whereas grazing had no effect on rate of community change over time at any spatial scale. The interactive effects of fire and grazing on spatial and temporal heterogeneity differed with scale. At the 10-m2 scale, grazing increased spatial heterogeneity in annually burned grassland but decreased heterogeneity in less frequently burned areas. At the 50-m2 scale, grazing decreased spatial heterogeneity on 4-yr burns but had no effect at other fire frequencies. At the 10-m scale, grazing increased temporal heterogeneity only on 1- and 20-yr burn sites. Our results show that the individual effects of fire and grazing on spatial and temporal heterogeneity in mesic prairie are scale independent, but the interactive effects of these disturbances on community heterogeneity change with scale of measurement. These patterns reflect the homogenizing impact of fire at all spatial scales, and the different frequency, intensity, and scale of patch grazing by bison in frequently burned vs. infrequently burned areas.


Functional consequences of necdin nucleocytoplasmic localization.
Necdin, a MAGE family protein expressed primarily in the nervous system, has been shown to interact with both nuclear and cytoplasmic proteins, but the mechanism of its nucleocytoplasmic transport are unknown. We carried out a large-scale interaction screen using necdin as a bait in the yeast RRS system, and found a wide range of potential interactors with different subcellular localizations, including over 60 new candidates for direct binding to necdin. Integration of these interactions into a comprehensive network revealed a number of coherent interaction modules, including a cytoplasmic module connecting to necdin through huntingtin-associated protein 1 (Hap1), dynactin and hip-1 protein interactor (Hippi); a nuclear P53 and Creb-binding-protein (Crebbp) module, connecting through Crebbp and WW domain-containing transcription regulator protein 1 (Wwtr1); and a nucleocytoplasmic transport module, connecting through transportins 1 and 2. We validated the necdin-transportin1 interaction and characterized a sequence motif in necdin that modulates karyopherin interaction. Surprisingly, a D234P necdin mutant showed enhanced binding to both transportin1 and importin β1. Finally, exclusion of necdin from the nucleus triggered extensive cell death. These data suggest that necdin has multiple roles within protein complexes in different subcellular compartments, and indicate that it can utilize multiple karyopherin-dependent pathways to modulate its localization.


Angle-resolved photoelectron spectroscopy and scanning tunnelling spectroscopy studies of the endohedral fullerene Li@C60.
Gas phase photoelectron spectroscopy (Rydberg Fingerprint Spectroscopy), TDDFT calculations and low temperature STM studies are combined to provide detailed information on the properties of the diffuse, low-lying Rydberg-like SAMO states of isolated Li@C60 endohedral fullerenes. The presence of the encapsulated Li is shown by the calculations to produce a significant distortion of the lowest-lying S- and P-SAMOs that is dependent on the position of the Li inside the fullerene cage. Under the high temperature conditions of the gas phase experiments, the Li is mobile and able to access different positions within the cage. This is accounted for in the comparison with theory that shows a very good agreement of the photoelectron angular distributions, allowing the symmetry of the observed SAMO states to be identified. When adsorbed on a metal substrate at low temperature, a strong interaction between the low-lying SAMOs and the metal substrate moves these states to energies much closer to the Fermi energy compared to the situation for empty C60 while the Li remains frozen in an off-centre position.


Selective membrane toxicity of the polyene antibiotics: studies on natural membranes.
The effect of polyene antibiotics on Candida albicans, human erythrocytes, and Acholeplasma laidlawii was studied. The results sustain the observations made with lecithin-sterol liposomes. The distribution of double bonds in the membrane sterol nucleus appears to be of major importance in conferring polyene susceptibility; those sterols with the ergosterol nucleus are far more effective than those with a nucleus similar to cholesterol. Different polyenes vary in their membrane selectivity. The clinical implications of these observations are discussed.


Policy resistance undermines superspreader vaccination strategies for influenza.
Theoretical models of infection spread on networks predict that targeting vaccination at individuals with a very large number of contacts (superspreaders) can reduce infection incidence by a significant margin. These models generally assume that superspreaders will always agree to be vaccinated. Hence, they cannot capture unintended consequences such as policy resistance, where the behavioral response induced by a new vaccine policy tends to reduce the expected benefits of the policy. Here, we couple a model of influenza transmission on an empirically-based contact network with a psychologically structured model of influenza vaccinating behavior, where individual vaccinating decisions depend on social learning and past experiences of perceived infections, vaccine complications and vaccine failures. We find that policy resistance almost completely undermines the effectiveness of superspreader strategies: the most commonly explored approaches that target a randomly chosen neighbor of an individual, or that preferentially choose neighbors with many contacts, provide at best a 2% relative improvement over their non-targeted counterpart as compared to 12% when behavioral feedbacks are ignored. Increased vaccine coverage in super spreaders is offset by decreased coverage in non-superspreaders, and superspreaders also have a higher rate of perceived vaccine failures on account of being infected more often. Including incentives for vaccination provides modest improvements in outcomes. We conclude that the design of influenza vaccine strategies involving widespread incentive use and/or targeting of superspreaders should account for policy resistance, and mitigate it whenever possible.


A Large-Scale RNAi Screen Identifies SGK1 as a Key Survival Kinase for GBM Stem Cells.
Glioblastoma multiforme (GBM) is the most common type of primary malignant brain cancer and has a very poor prognosis. A subpopulation of cells known as GBM stem-like cells (GBM-SC) have the capacity to initiate and sustain tumor growth and possess molecular characteristics similar to the parental tumor. GBM-SCs are known to be enriched in hypoxic niches and may contribute to therapeutic resistance. Therefore, to identify genetic determinants important for the proliferation and survival of GBM stem cells, an unbiased pooled shRNA screen of 10,000 genes was conducted under normoxic as well as hypoxic conditions. A number of essential genes were identified that are required for GBM-SC growth, under either or both oxygen conditions, in two different GBM-SC lines. Interestingly, only about a third of the essential genes were common to both cell lines. The oxygen environment significantly impacts the cellular genetic dependencies as 30% of the genes required under hypoxia were not required under normoxic conditions. In addition to identifying essential genes already implicated in GBM such as CDK4, KIF11, and RAN, the screen also identified new genes that have not been previously implicated in GBM stem cell biology. The importance of the serum and glucocorticoid-regulated kinase 1 (SGK1) for cellular survival was validated in multiple patient-derived GBM stem cell lines using shRNA, CRISPR, and pharmacologic inhibitors. However, SGK1 depletion and inhibition has little effect on traditional serum grown glioma lines and on differentiated GBM-SCs indicating its specific importance in GBM stem cell survival.Implications: This study identifies genes required for the growth and survival of GBM stem cells under both normoxic and hypoxic conditions and finds SGK1 as a novel potential drug target for GBM. Mol Cancer Res; 16(1); 103-14. ©2017 AACR.


Efficient and monolithic polarization conversion system based on a polarization grating.
We introduce a new polarization conversion system (PCS) based on a liquid-crystal polarization grating (PG) and louvered wave plate. A simple arrangement of these elements laminated between two microlens arrays results in a compact and monolithic element, with the ability to nearly completely convert unpolarized input into linearly polarized output across most of the visible bandwidth. In our first prototypes, this PG-PCS approach manifests nearly 90% conversion efficiency of unpolarized to polarized for ±11° input light divergence, leading to an energy efficient picoprojector that presents high efficacy (12 lm/W) with good color uniformity.


An assessment of the construct distinctiveness of stress arousal and burnout.
This study examined the construct and discriminant validity of stress arousal and burnout as measured on the Stress Arousal Scale and the multidimensional role-specific version of the Maslach Burnout Inventory, respectively. The analyses utilized data from 148 individuals randomly selected from a database of 563 respondents to a larger study. The sample responded to a survey sent to members of the American Institute of Certified Public Accountants (AICPA). Sample size used in this study fell within Loehlin's 1992 prescription that for confirmatory factor analysis with two to four factors, a minimum of 100 to 200 cases should be collected. Forty-six respondents indicated that they were partners, principals, or sole practitioners in accounting firms, and 103 indicated that they were staff members (juniors, seniors, or managers). Latent variables were first constructed for the stress arousal and burnout factors. Confirmatory factor analysis was then conducted on the scale data to assess whether the factors would load on their respective underlying theoretical constructs. Finally, a nested model constraining stress arousal and burnout to load on one underlying construct was tested against the hypothesized two-factor model. The results indicated good model fit for the two-factor model and a significant loss of fit for the one-factor model, thus providing strong support for the conceptualization of stress arousal and burnout as distinct constructs.


Transformation From Adenocarcinoma to Pleomorphic Carcinoma as an Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors.
Pulmonary pleomorphic carcinoma is a very rare histological type of primary lung cancer, and usually provides aggressive clinical courses. A 65-year-old Japanese woman was diagnosed by transbronchial biopsy of the primary tumor as c-stage IV (cT4N3M1b) of adenocarcinoma harboring L858R point mutation in the exon 21 of epidermal growth factor receptor (EGFR). She received EGFR tyrosine kinase inhibitors (TKIs) (gefitinib and erlotinib) and subsequently cytotoxic chemotherapies. Gefitinib achieved partial response, but was switched to erlotinib due to elevated serum aspartate transaminase. After resistance to EGFR-TKIs, the second transbronchial re-biopsy revealed pulmonary pleomorphic carcinoma. Both carcinomatous and sarcomatous components retained the L858R mutation, but did not acquire T790M mutation. This case suggested that the histological transformation to pulmonary pleomorphic carcinoma may be one of mechanisms of drug resistance to EGFR-TKIs.


cis-(+)-8-OH-1-CH3-DPAT, (+)ALK-3, a novel stereoselective pharmacological probe for characterizing 5-HT release-controlling 5-HT1A autoreceptors. An in vivo brain microdialysis study.
The somatodendritic 5-HT1A autoreceptor regulating 5-HT neuronal activity is currently poorly defined pharmacologically because there are no specific antagonists, but also because potent and stereoselective agonists are scarce. Moreover, there have been few, if any, attempts to specifically investigate structure-activity relationships for agonists acting at this site. Employing brain microdialysis techniques, we have examined the effects of the enantiomers of cis-8-hydroxy-1-methyl-2-(di-n-propylamino)tetralin (ALK-3; 0.01-0.3 mg/kg s.c.), its trans-1-methyl analogue (ALK-4; 0.3 mg/kg s.c.) and the pure enantiomers of the parent compound--8-OH-DPAT (0.3 mg/kg s.c.)--in an attempt to address stereochemical agonist structure-activity requirements of 5-HT release-controlling 5-HT1A autoreceptors in brain. The cis-1-methylated 8-OH-DPAT analogue (+)ALK-3 was comparable to the parent compound in reducing the 5-HT output from rat ventral hippocampus. In comparison, both (-)ALK-3 and the racemic trans-diastereomer to ALK-3, ALK-4, were inactive, while the two stereoisomers of 8-OH-DPAT strongly reduced 5-HT release. Pretreatment with (-)pindolol (8 mg/kg s.c.), which has high affinity for 5-HT1A radioligand binding sites, blocked the reduction of hippocampal 5-HT release induced by a submaximally effective dose of (+)ALK-3. The direct intrahippocampal administration of (+)ALK-3 (10 microM) via the perfusion medium did not affect 5-HT output. In summary, the data indicate that (+)ALK-3, like 8-OH-DPAT, is a very potent 5-HT receptor agonist which inhibits terminal 5-HT release in rat hippocampus, probably via activation of somatodendritic 5-HT1A autoreceptors.(ABSTRACT TRUNCATED AT 250 WORDS)


Biorenewable hydrogen production through biomass gasification: A review and future prospects.
Hydrogen is recognized as one of the cleanest energy carriers, which can be produced from renewable biomass as a promising feedstock to achieve sustainable bioeconomy. Thermochemical technologies (e.g., gasification and pyrolysis) are the main routes for hydrogen production from biomass. Although biomass gasification, including steam gasification and supercritical water gasification, shows a high potential in field-scale applications, the selectivity and efficiency of hydrogen production need improvement to secure cost-effective industrial applications with high atom economy. This article reviews the two main-stream biomass-to-hydrogen technologies and discusses the significance of operating conditions and considerations in the catalytic system design. Challenges and prospects of hydrogen production via biomass gasification are explored to advise on the critical information gaps that require future investigations.


Mechanisms of physiological gustatory sweating and flushing in the face.
Mechanisms of physiological gustatory sweating and flushing were investigated in 21 patients with a facial nerve lesion compromising parasympathetic outflow to the lacrimal gland, and in 13 patients undergoing diagnostic blockade of the stellate ganglion. Vascular responses and electrodermal activity (which reflects sweating) were monitored on each side of the forehead before and during gustatory stimulation with chillies or Tabasco sauce (derived from chillies). Vascular responses in the cheeks were also monitored in 14 patients with a facial nerve lesion. Sympathetic blockade increased gustatory vasodilatation but prevented gustatory sweating on the blocked side of the forehead. A facial nerve lesion did not affect gustatory sweating in the forehead or vasodilatation in the cheeks. However, a facial nerve lesion impaired vasodilatation in the forehead in all six patients who ate chillies, and also in four of five patients whose blood vessels dilated extensively on the normally-innervated side of the forehead when the patients tasted Tabasco sauce. These findings suggest that sympathetic sudomotor activity mediates physiological gustatory sweating in the forehead, whereas sympathetic vasoconstrictor tone inhibits gustatory vasodilatation in the forehead. A parasympathetic vasodilator reflex in the facial nerve contributes actively to gustatory flushing in the forehead, but some other unidentified mechanism influences vascular responses in the cheeks.


Load Carriage: An Integrated Risk Management Approach.
Military load carriage (LC) gives rise to substantial risks to soldier health, tactical performance, and mission success. The aim of this article was to extract and synthesize the key findings of a series of LC research reports previously published by the authors. Five reviews and 6 studies were included, with key findings extracted and synthesized in tabulated and critical narrative form. The weight of a soldier's load is a source of risk for soldier's injuries and tactical task performance. The resulting level of risk is influenced by risk modifiers (like speed of march, terrain grade, and task type and duration) and risk controls (like administrative controls and physical conditioning). In the Australian context, these risk controls were limited, with soldiers carrying heavier loads than those mandated by doctrine and policy, and LC conditioning not meeting best practice. The diversity of LC contexts, combined with the influence of risk modifiers and risk controls, means that levels of risk associated with LC are not consistent and must be assessed on a case-by-case basis. Load weight and marching routes (terrains, gradients), distances, speed, and duration are all potentially treatable sources of LC-related risk. Potential risk treatments include not only commanders directly addressing these specific sources of risk to the extent feasible, on a case-by-case basis, when planning or conducting LC tasks but also improving administration controls (i.e., doctrine and policies) and personal protection (i.e., the physical conditioning of the soldier) as part of the hierarchy of controls. Practical application would involve commanders developing and implementing dedicated LC doctrine and policies and implementing and enforcing LC conditioning programs that meets best practice.


Simulating Stable Isotope Ratios in Plumes of Groundwater Pollutants with BIOSCREEN-AT-ISO.
BIOSCREEN is a well-known simple tool for evaluating the transport of dissolved contaminants in groundwater, ideal for rapid screening and teaching. This work extends the BIOSCREEN model for the calculation of stable isotope ratios in contaminants. A three-dimensional exact solution of the reactive transport from a patch source, accounting for fractionation by first-order decay and/or sorption, is used. The results match those from a previously published isotope model but are much simpler to obtain. Two different isotopes may be computed, and dual isotope plots can be viewed. The dual isotope assessment is a rapidly emerging new approach for identifying process mechanisms in aquifers. Furthermore, deviations of isotope ratios at specific reactive positions with respect to "bulk" ratios in the whole compound can be simulated. This model is named BIOSCREEN-AT-ISO and will be downloadable from the journal homepage.


Biological changes associated with healthy versus pathological aging: a symposium review.
The Douglas Mental Health University Institute, in collaboration with the McGill Centre for Studies in Aging, organized a 2-day symposium entitled "Biological Changes Associated with Healthy Versus Pathological Aging" that was held in 13 and 14 December 2007 on the Douglas campus. The symposium involved presentations on current trends in aging and dementia research across several sub-disciplines: genetics, neurochemistry, structural and functional neuroimaging and clinical treatment and rehabilitation. The goal of this symposium was to provide a forum for knowledge-transfer between scientists and clinicians with different specializations in order to promote cross-fertilization of research ideas that would lead to future collaborative neuroscience research in aging and dementia. In this review article, we summarize the presentations made by the 13 international scientists at the symposium and highlight: (i) past research, and future research trends in neuroscience of aging and dementia and (ii) links across levels of analysis that can lead to fruitful transdisciplinary research programs that will advance knowledge about the neurobiological changes associated with healthy aging and dementia.


Peripheral axonal ensheathment is regulated by RalA GTPase and the exocyst complex.
Axon ensheathment is fundamental for fast impulse conduction and the normal physiological functioning of the nervous system. Defects in axonal insulation lead to debilitating conditions, but, despite its importance, the molecular players responsible are poorly defined. Here, we identify RalA GTPase as a key player in axon ensheathment in Drosophila larval peripheral nerves. We demonstrate through genetic analysis that RalA action through the exocyst complex is required in wrapping glial cells to regulate their growth and development. We suggest that the RalA-exocyst pathway controls the targeting of secretory vesicles for membrane growth or for the secretion of a wrapping glia-derived factor that itself regulates growth. In summary, our findings provide a new molecular understanding of the process by which axons are ensheathed in vivo, a process that is crucial for normal neuronal function.


The Clock Gene TOC1 in Shoots, Not Roots, Determines Fitness of Nicotiana attenuata under Drought.
The highly conserved core circadian clock component TIMING OF CAB EXPRESSION1 (TOC1) contextualizes environmental stress responses in plants, for example by gating abscisic acid signaling and suppressing thermoresponsive growth. Selective interaction of TOC1 with PHYTOCHROME B under far-red-enriched light suggests a connection between circadian gating of light responses and sensitivity to ABA, an important regulator of growth and stress responses, including under drought. However, the fitness consequences of TOC1 function, particularly in the root, are poorly understood. Here, we used the desert annual, Nicotiana attenuata, to investigate the function of TOC1 in shoots and roots for maintaining fitness under drought, in both field and glasshouse experiments. Despite marked decreases in leaf water loss, TOC1-deficient lines failed to maintain fitness in response to drought stress as measured by total seed capsule production. Restoring TOC1 transcript levels in shoots via micrografting was sufficient to restore wild-type drought responses under field conditions. Microarrays identified a coexpression module in leaves strongly linking red and far-red light signaling to drought responses in a TOC1-dependent manner, but experiments with phytochrome-deficient lines revealed that the effects of TOC1 deficiency under drought cannot be attributed to changes in red/far-red light perception alone. Taken together, these results elucidate the sophisticated, tissue-dependent role of the circadian clock in maintaining fitness in the face of long-term abiotic stresses such as drought.


Notoamide-type alkaloid induced apoptosis and autophagy via a P38/JNK signaling pathway in hepatocellular carcinoma cells.
Bioassay-guided fractionation of a coral-associated fungus Aspergillus ochraceus LZDX-32-15 resulted in the isolation of eleven notoamide-type alkaloids, including four new congeners, namely notoamides W-Z (1-4). The structures of the new alkaloids were determined by extensive analyses of spectroscopic data (1D and 2D NMR, HRESIMS), while ECD data were used for the configurational assignment. Three alkaloids (6, 10, 11) exerted potent inhibition against a panel of hepatocellular carcinoma (HCC) cell lines with IC50 values ranging from 0.42 to 3.39 μM, that are comparable to the data for paclitaxel. Notoamide G (6) inhibited the viability of HepG2 and Huh-7 cells via both apoptosis and autophagy pathways. Notoamide G activated the expression of caspase-3, caspase-8, and caspase-9, in association with the degradation of the downstream gene PARP in a dose-dependent manner, suggesting that notoamide G induced apoptosis via a mitochondrial pathway and a dead receptor-mediated pathway. In addition, notoamide G increased the autophagic vacuole in both HepG2 and Huh-7 cells in a dose-dependent manner after 24 h through the significant upregulation of the key proteins Beclin1 and LC3B. Further investigation revealed that notoamide G promoted P38 and JNK phosphorylation, whereas the total protein of P-38 and JNK was slightly influenced. Accordingly, the antitumor proliferation of notoamide G in HCC cells was mechanistically mediated by apoptosis and autophagy through a P38/JNK signaling pathway, while notoamide G was considered as a potent lead for further development as an antitumor agent.


Overosaurus paradasorum gen. et sp. nov., a new sauropod dinosaur (Titanosauria: Lithostrotia) from the late Cretaceous of Neuquén, Patagonia, Argentina.
A new lithostrotian sauropod, the small-sized Overosaurus paradasorum n. gen et sp. from the Anacleto Formation (Campanian, Late Cretaceous, Neuquén Group, Patagonia, Argentina) is here described. The specimen (MAU-Pv-CO-439) consists of a fully articulated vertebral series from the 10th cervical to the 20th caudal vertebra, the last cervical ribs, several dorsal ribs in articulation with their respective vertebrae, the complete right ilium and fragments of the left ilium. Overosaurus paradasorum is diagnosed by a unique combination of characters that includes (1) posterior cervical vertebrae with long pre- and postzygapophyses that project beyond the anterior and posterior borders of the centrum, respectively, (2) postspinal lamina absent in all dorsal neural spines, (3) wide and massive 9th and 10th caudal centra that are slightly excavated laterally and have relatively flat ventral surfaces, (4) laminar projection on the posterior border of the second and third dorsal rib, (5) ilium proportionally shorter anteroposteriorly and taller dorsoventrally than in other lithostrotians, and (6) the preacetabular process of the ilium strongly deflected laterally and with a ventrolaterally tapering end. Analysis of the phylogenetic relationships of Overosaurus places it within the Aeolosaurini, as the sister taxon of a monophyletic group formed by Aeolosaurus rionegrinus, A. maximus, Gondwanatitan faustoi and Pitekunsaurus macayai. Overosaurus is a new representative of a highly diversified assemblage of Campanian lithostrotians from Patagonia that includes both Aeolosaurini and saltasaurids (e.g. Saltasaurus, Neuquensaurus)--this small new taxon falls within the low end of the size spectrum represented by these Late Cretaceous sauropods.


Quantitative sensation and autonomic test abnormalities in transthyretin amyloidosis polyneuropathy.
This study assesses the value of standard quantitative autonomic (QAT) and sensation (QST) tests in detecting, characterizing, and quantitating the severity of transthyretin amyloid polyneuropathy (TTR-A-PN). This information is needed for prospective therapeutic trials, epidemiologic surveys, and medical practice. We reviewed 36 patients with TTR-A-PN who were evaluated between 1997 and 2007. They had neurologic, genetic, electrodiagnostic, and autonomic reflex screen evaluations and allowed their medical records and test results to be evaluated for research purposes. Of these, 22 patients had also been tested by quantitative sensation tests (QSTs). The median symptom duration was 4 years (range 1-30 years). Among quantitative nerve tests evaluated, composite scores of nerve conduction (Sigma5 NC nds), a composite score of QSTs (Sigma3 QST nds), and quantitative autonomic tests (QSART, HR(db), and CASS) gave high frequencies of abnormality. The results show that peripheral autonomic and small-fiber sensory dysfunction was prominent and characteristic of most of the patients we studied. However, this involvement was not selective for small-diameter sensory and autonomic nerve fibers; large motor and sensory fibers were also shown to be dysfunctional. Dysfunction of large fibers was approximately as frequent as that of small fibers. This study provides a rationale for the use of QAT, QST, and Sigma5 NC nds as standard, objective, and quantitative measures for assessing the severity of TTR-A-PN in epidemiologic surveys, therapeutic trials, and medical practice.


A report on the large measles outbreak in Lyon, France, 2010 to 2011.
In 2010 and 2011, the city of Lyon, located in the Rhône-Alpes region (France), has experienced one of the highest incidences of measles in Europe. We describe a measles outbreak in the Lyon area, where cases were diagnosed at Lyon University hospitals (LUH) between 2010 and mid-2011. Data were collected from the mandatory notification system of the regional public health agency, and from the virology department of the LUH. All patients and healthcare workers who had contracted measles were included. Overall, 407 cases were diagnosed, with children of less than one year of age accounting for the highest proportion (n=129, 32%), followed by individuals between 17 and 29 years-old (n=126, 31%). Of the total cases, 72 (18%) had complications. The proportions of patients and healthcare workers who were not immune to measles were higher among those aged up to 30 years. Consequently, women of childbearing age constituted a specific population at high risk to contract measles and during this outbreak, 13 cases of measles, seven under 30 years-old, were identified among pregnant women. This study highlights the importance of being vaccinated with two doses of measles vaccine, the only measure which could prevent and allow elimination of the disease.


Microcapsule of type III strains of group B Streptococcus: production and morphology.
The yield of purified type III polysaccharide of group B Streptococcus was significantly improved by modification of the growth medium. Culture of organisms in standard Todd-Hewitt broth resulted in acid accumulation during the exponential phase of growth and poor yield of type III polysaccharide when extracted from cells by washing with neutral buffer solution. By increasing the buffering capacity of the broth medium, acid accumulation was prevented, and the number of viable cells was increased at the stationary phase of growth. Further, by increasing the concentration of glucose in the buffered medium, the yield of type III polysaccharide was increased two to three times. Electron microscopic investigations of cells grown in the modified broth medium demonstrated a thicker microcapsule than was found in organisms grown in standard broth.


Autophagy in stem cells.
Autophagy is a highly conserved cellular process by which cytoplasmic components are sequestered in autophagosomes and delivered to lysosomes for degradation. As a major intracellular degradation and recycling pathway, autophagy is crucial for maintaining cellular homeostasis as well as remodeling during normal development, and dysfunctions in autophagy have been associated with a variety of pathologies including cancer, inflammatory bowel disease and neurodegenerative disease. Stem cells are unique in their ability to self-renew and differentiate into various cells in the body, which are important in development, tissue renewal and a range of disease processes. Therefore, it is predicted that autophagy would be crucial for the quality control mechanisms and maintenance of cellular homeostasis in various stem cells given their relatively long life in the organisms. In contrast to the extensive body of knowledge available for somatic cells, the role of autophagy in the maintenance and function of stem cells is only beginning to be revealed as a result of recent studies. Here we provide a comprehensive review of the current understanding of the mechanisms and regulation of autophagy in embryonic stem cells, several tissue stem cells (particularly hematopoietic stem cells), as well as a number of cancer stem cells. We discuss how recent studies of different knockout mice models have defined the roles of various autophagy genes and related pathways in the regulation of the maintenance, expansion and differentiation of various stem cells. We also highlight the many unanswered questions that will help to drive further research at the intersection of autophagy and stem cell biology in the near future.


Perceived unfairness and socioeconomic inequalities in functional decline: the Dutch SMILE prospective cohort study.
People in lower socioeconomic positions report worse health-related functioning. Only few examined whether perceptions of unfairness are particularly common in these people and whether this perceived unfairness relates to their subsequent poor health outcomes. We thus set out to examine the contribution of perceived unfairness to the higher risks of physical and mental dysfunction in men and women with a lower socioeconomic position. Seven-year prospective cohort data from the Dutch SMILE study among 1,282 persons, 55 years old and older, were used. Physical and mental health-related functioning was measured with the SF-36, socioeconomic status with income and education, and the perception of unfairness with an extended new measure asking for such perceptions in both work and non-work domains. Perceived unfairness was more common in lower socioeconomic positions. Such perpection was related to both physical (odds ratio = 1.57 (95% confidence interval: 1.17-2.11)) and mental (1.47 (1.07-2.03)) decline, while low socioeconomic position was only related to mental decline (1.33 (1.06-1.67)). When socioeconomic position and perceived unfairness were simultaneously controlled, odds ratios for both determinants decreased only very little. Socioeconomic position and perceived unfairness were for the largest part independently related to longitudinal health-related decline. The general perception of unfairness, at work and beyond work, might have implications for functional decline in middle and older age. We recommend that - rather than addressing and changing individual perceptions of unfairness--more research is needed to find out whether specific environments can be defined as unfair and whether such environments can be effectively tackled in an attempt to truly improve public health.


Active Learning Based on Locally Linear Reconstruction.
We consider the active learning problem, which aims to select the most representative points. Out of many existing active learning techniques, optimum experimental design (OED) has received considerable attention recently. The typical OED criteria minimize the variance of the parameter estimates or predicted value. However, these methods see only global euclidean structure, while the local manifold structure is ignored. For example, I-optimal design selects those data points such that other data points can be best approximated by linear combinations of all the selected points. In this paper, we propose a novel active learning algorithm which takes into account the local structure of the data space. That is, each data point should be approximated by the linear combination of only its neighbors. Given the local reconstruction coefficients for every data point and the coordinates of the selected points, a transductive learning algorithm called Locally Linear Reconstruction (LLR) is proposed to reconstruct every other point. The most representative points are thus defined as those whose coordinates can be used to best reconstruct the whole data set. The sequential and convex optimization schemes are also introduced to solve the optimization problem. The experimental results have demonstrated the effectiveness of our proposed method.


Biological assessment of triazine dendrimer: toxicological profiles, solution behavior, biodistribution, drug release and efficacy in a PEGylated, paclitaxel construct.
The physicochemical characteristics, in vitro properties, and in vivo toxicity and efficacy of a third generation triazine dendrimer bearing approximately nine 2 kDa polyethylene glycol chains and twelve ester linked paclitaxel groups are reported. The hydrodynamic diameter of the neutral construct varies slightly with aqueous solvent ranging from 15.6 to 19.4 nm. Mass spectrometry and light scattering suggest radically different molecular weights with the former approximately 40 kDa mass consistent with expectation, and the latter 400 kDa mass consistent with a decameric structure and the observed hydrodynamic radii. HPLC can be used to assess purity as well as paclitaxel release, which is insignificant in organic solvents or aqueous solutions at neutral and low pH. Paclitaxel release occurs in vitro in human, rat, and mouse plasma and is nonlinear, ranging from 7 to 20% cumulative release over a 48 h incubation period. The construct is 2-3 orders of magnitude less toxic than Taxol by weight in human hepatocarcinoma (Hep G2), porcine renal proximal tubule (LLC-PK1), and human colon carcinoma (LS174T) cells, but shows similar cytotoxicity to Abraxane in LS174T cells. Both Taxol and the construct appear to induce caspase 3-dependent apoptosis. The construct shows a low level of endotoxin, is not hemolytic and does not induce platelet aggregation in vitro, but does appear to reduce collagen-induced platelet aggregation in vitro. Furthermore, the dendrimer formulation slightly activates the complement system in vitro due most likely to the presence of trace amounts (<1%) of free paclitaxel. An animal study provided insight into the maximum tolerated dose (MTD) wherein 10, 25, 50, and 100 mg of paclitaxel/kg of construct or Abraxane were administered once per week for three consecutive weeks to non tumor bearing athymic nude mice. The construct showed in vivo toxicity comparable to that of Abraxane. Both formulations were found to be nontoxic at the administered doses, and the dendrimer had an acute MTD greater than the highest dose administered. In a prostate tumor model (PC-3-h-luc), efficacy was observed over 70 days with an arrest of tumor growth and lack of luciferase activity observed in the twice treated cohort.


Translational Functional Neuroimaging in the Explanation of Depression.
Translation as a notion and procedure is deeply embodied in medical science and education. Translation includes the possibility to translate data across disciplines to improve diagnosis and treatment procedures. The evidence accumulated using translation serves as a vehicle for reification of medical diagnoses. There are promising, established post hoc correlations between the different types of clinical tools (interviews and inventories) and neuroscience. The various measures represent statistical correlations that must now be integrated into diagnostic standards and procedures but this, as a whole, is a step forward towards a better understanding of the mechanisms underlying psychopathology in general and depression in particular. Here, we focus on functional magnetic resonance imaging studies using a trans-disciplinary approach and attempt to establish bridges between the different fields. We will selectively highlight research areas such as imaging genetics, imaging immunology and multimodal imaging, as related to the diagnosis and management of depression.


Statistics of spatially integrated speckle intensity difference.
We consider the statistics of the spatially integrated speckle intensity difference obtained from two separated finite collecting apertures. For fully developed speckle, closed-form analytic solutions for both the probability density function and the cumulative distribution function are derived here for both arbitrary values of the mean number of speckles contained within an aperture and the degree of coherence of the optical field. Additionally, closed-form expressions are obtained for the corresponding nth statistical moments.


Efficacy and Safety of Direct-Acting Oral Anticoagulants Use in Acute Portal Vein Thrombosis Unrelated to Cirrhosis.
In acute portal vein thrombosis (APVT) unrelated to cirrhosis, anticoagulant therapy is classically started with low molecular weight heparin or vitamin K antagonists. New direct-acting oral anticoagulants (DOACs) are used in the treatment of venous thrombosis outside the splanchnic vascular bed, but not in the latter. We report a young female with APVT occurring in a non-cirrhotic liver linked to heterozygosity of factor V-Leiden and prothrombin G20210A gene mutations. Rivaroxaban was started, with total recanalization of the left and partial recanalization of the right portal vein branches, without complications. New DOACs do not need daily subcutaneous injections nor routinely blood coagulation control tests, making its use attractive, eventually increasing patient's compliance. If proved to be safe and effective in the future studies, its use may be extended to PVT treatment. This case shows that rivaroxaban was safe, not only prevented the extension of thrombosis in the portal tract, but also resolved PVT, at least partially.


Incidence of sudden cardiac death in athletes: a state-of-the-art review.
Sudden cardiac death (SCD) is the leading medical cause of death in athletes; however, the precise incidence is unknown. The objectives of this review were to examine studies on the rate of SCD in athletes, assess the methodological strengths and weaknesses used to arrive at estimates, compare studies in athletes with estimates in similar populations and arrive at an approximation of the incidence of SCD based on the best available evidence. A comprehensive literature search was performed in PubMed using key terms related to SCD in athletes. Articles were reviewed for relevance and included if they contained information on the incidence of SCD in athletes or young persons up to the age of 40. The reference list from each manuscript was reviewed for additional relevant articles. The methods for case identification were examined, as well as the inclusion and exclusion criteria and the precision of the population denominator studied. Thirteen studies were found investigating the rate of SCD in athletes who ranged in age from 9 to 40. An additional 15 incidence studies were located examining the rate of SCD in other populations under the age of 40. Rates of SCD varied from 1:917,000 to 1:3000. Studies with higher methodological quality consistently yielded incidence rates in the range of 1:40,000 to 1:80,000. Some athlete subgroups, specifically men, African-American/black athletes and basketball players, appear to be at higher risk. The incidence of SCD in athletes is likely higher than traditional estimates which may impact the development of more effective prevention strategies.


Fluoxetine and Vortioxetine Reverse Depressive-Like Phenotype and Memory Deficits Induced by Aβ1-42 Oligomers in Mice: A Key Role of Transforming Growth Factor-β1.
Depression is a risk factor for the development of Alzheimer's disease (AD), and the presence of depressive symptoms significantly increases the conversion of mild cognitive impairment (MCI) into AD. A long-term treatment with antidepressants reduces the risk to develop AD, and different second-generation antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are currently being studied for their neuroprotective properties in AD. In the present work, the SSRI fluoxetine and the new multimodal antidepressant vortioxetine were tested for their ability to prevent memory deficits and depressive-like phenotype induced by intracerebroventricular injection of amyloid-β (1-42) (Aβ1-42) oligomers in 2-month-old C57BL/6 mice. Starting from 7 days before Aβ injection, fluoxetine (10 mg/kg) and vortioxetine (5 and 10 mg/kg) were intraperitoneally injected daily for 24 days. Chronic treatment with fluoxetine and vortioxetine (both at the dose of 10 mg/kg) was able to rescue the loss of memory assessed 14 days after Aβ injection by the passive avoidance task and the object recognition test. Both antidepressants reversed the increase in immobility time detected 19 days after Aβ injection by forced swim test. Vortioxetine exerted significant antidepressant effects also at the dose of 5 mg/kg. A significant deficit of transforming growth factor-β1 (TGF-β1), paralleling memory deficits and depressive-like phenotype, was found in the hippocampus of Aβ-injected mice in combination with a significant reduction of the synaptic proteins synaptophysin and PSD-95. Fluoxetine and vortioxetine completely rescued hippocampal TGF-β1 levels in Aβ-injected mice as well as synaptophysin and PSD-95 levels. This is the first evidence that a chronic treatment with fluoxetine or vortioxetine can prevent both cognitive deficits and depressive-like phenotype in a non-transgenic animal model of AD with a key contribution of TGF-β1.


Improving the Quality of Handoffs in Patient Care Between Critical Care Providers in the Intensive Care Unit.
With the ever-increasing adoption of shift models for intensive care unit (ICU) staffing, improving shift-to-shift handoffs represents an important step in reducing medical errors. The authors developed an electronic handoff tool integrated within the existing electronic medical record to improve handoffs in an adult ICU. First, stakeholder (staff intensivists, fellows, and nurse practitioners/physician assistants) input was sought to define what elements they perceived as being essential to a quality handoff. The principal outcome measure of handoff accuracy was the concordance between data transmitted by the outgoing team and data received by the incoming team (termed as agreement). Based on stakeholder input, the authors developed the handoff tool and provided regular education on its use. Handoffs were observed before and after implementation of the tool. There was an increase in the level of agreement for tasks and other important data points handed off without an increase in the time required to complete the handoff.


Effects of sweet bee venom pharmacopuncture treatment for chemotherapy-induced peripheral neuropathy: a case series.
This is a case series reporting safety and degree of response to 1 dose level of sweet bee venom pharmacopuncture (SBVP) or melittin as a symptom-control therapy for chemotherapy-induced peripheral neuropathy (CIPN). All treatments were conducted at the East West Cancer Center (EWCC), Dunsan Oriental Hospital, Daejeon University, Republic of Korea, an institution that uses complementary therapies for cancer patients. Five consecutive patients with CIPN were referred to the EWCC from March 20, 2010, to April 10, 2010. Patients with World Health Organization Chemotherapy-Induced Peripheral Neuropathy (WHO CIPN) grade 2 or more were treated with SBVP for 3 treatment sessions over a 1-week period. Measures of efficacy and safety. Validated Visual Analog System (VAS) pain scale, WHO CIPN grade, and Functional Assessment of Cancer Therapy-General (FACT-G) were compared before and after the 1-week course of treatment. To ensure the safety of SBVP, pretreatment skin response tests were given to patients to avoid any potential anaphylactic adverse effects. All patients were closely examined for any allergenic responses following each treatment session. One patient discontinued treatment after the first session, and 4 patients completed all treatment sessions. Using each patient as their own comparator, marked improvements of VAS, WHO CIPN grade, and physical section scores of FACT-G were seen in 3 patients. Most important, there were no related adverse side effects found. This safety results of the SBVP therapy merits further investigations in a larger size trial for it to develop into a potential intervention for managing CIPN symptoms. This study will be extended to a dose-response evaluation to further establish safety and response, prior to a randomized trial.


Circular RNA COL1A2 Mediates High Glucose-Induced Oxidative Stress and Pyroptosis by Regulating MiR-424-5p/SGK1 in Diabetic Nephropathy.
Diabetic nephropathy (DN) represents a major diabetes-related complication, which could undermine renal function. CircCOL1A2 has been previously reported to show abnormal expression during DN. However, its functional role in the progression of DN, as well as the potential molecular mechanisms, remains unclear. The present work examined the expression of circCOL1A2 in the plasma of DN patients, and employed high glucose (HG)-challenged HK-2 cells as the in vitro cell model of hyperglycemia (HG)-induced DN. CircCOL1A2 was silenced using siRNA in HK-2 cells to clarify the functional engagement of circCOL1A2 in HG-induced DN. We examined the roles of circCOL1A2 in regulating oxidative stress by measuring reactive oxygen species (ROS), lipid peroxidation, and superoxide dismutase (SOD) levels. Besides, the effects of circCOL1A2 silencing on pyroptosis were investigated by RT-qPCR, western blot (WB), and ELISA assays. StarBase (version 2.0) was used to identify the downstream effector of circCOL1A2, and their interactions were further verified through dual-luciferase reporter analysis, RNA pull-down assays, and RNA immunoprecipitation (RIP) assay. CircCOL1A2 was highly expressed in DN patients and HG-induced HK-2 cells. Knocking down circCOL1A2 alleviated oxidative stress and pyroptosis upon HG treatment. In addition, we demonstrated that circCOL1A2 knockdown could promote miR-424-5p expression while inhibiting Serum/Glucocorticoid Regulated Kinase 1 (SGK1) level. Furthermore, miR-424-5p inhibitor or SGK1 overexpression impaired the effects of circCOL1A2 knockdown on HG-induced oxidative stress and pyroptosis. Hence, our results demonstrated that the circCOL1A2 mediates HG-exposed pyroptosis and oxidative stress through modulating miR-424-5p/SGK1 axis in diabetic nephropathy, indicating that silencing circCOL1A2 is a potential intervention strategy for DN management.


Identification of Arthropods By Polymerase Chain Reaction As Probes For Infectious Disease Studies In Experimental Coprolites.
The study of arthropods is still scarce in paleoparasitology, especially their molecular identification. In this experimental study, we amplify DNA using a polymerase chain reaction from 2 ectoparasite species, Rhipicephalus sanguineus and Pediculus humanus capitis, in experimentally desiccated feces. This study shows perspectives for the study of the identification of arthropods in coprolites when taxonomic identification is not possible.


Implementing microbicides in low-income countries.
The magnitude of the global human immunodeficiency virus (HIV) epidemic is determined by women from lower income countries, specifically sub-Saharan Africa. Microbicides offer women who are unable to negotiate safe sex practices a self-initiated HIV prevention method. Of note, is its potential to yield significant public health benefits even with relatively conservative efficacy, coverage and user adherence estimates, making microbicides an effective intervention to invest scarce healthcare resources. Existing healthcare delivery systems provide an excellent opportunity to identify women at highest risk for infection and to also provide an access point to initiate microbicide use. Innovative quality improvement approaches, which strengthen existing sexual reproductive health services and include HIV testing, and linkages to care and treatment services, provide an opportunity to lay the foundations for wide-scale provision of microbicides. The potential to enhance health outcomes in women and infants and potentially affect rates of new HIV infection may soon be realised.


Absence of HinfI Restriction Abnormalities in Renal Oncocytoma Mitochondrial DNA.
Renal oncocytomas are characterized by bland-appearing eosinophilic cells with a profusion of mitochondria. Previous work has suggested that these tumors possess a mutation in the 16.5-kbp circular mitochondrial DNA (mtDNA) manifested by an abnormal restriction fragment pattern after digestion with HinfI (Welter et al, Genes Chromosomes Cancer 1989;1:7-82). To better characterize this mtDNA abnormality in renal oncocytomas, we amplified the entire mitochondrial genome from five paired normal and oncocytoma specimens and subjected the amplified fragments to digestion with the restriction enzyme HinfI. No somatically acquired alterations were detected in the mtDNA from any of the five renal oncocytomas. One specimen displayed a known HinfI polymorphism in the mtDNA from both the normal and oncocytoma tissues. Our data do not support the existence of somatically acquired mitochondrial genome abnormalities in renal oncocytomas.


New biomarkers with relevance to leprosy diagnosis applicable in areas hyperendemic for leprosy.
Leprosy is not eradicable with currently available diagnostics or interventions, as evidenced by its stable incidence. Early diagnosis of Mycobacterium leprae infection should therefore be emphasized in leprosy research. It remains challenging to develop tests based on immunological biomarkers that distinguish individuals controlling bacterial replication from those developing disease. To identify biomarkers for field-applicable diagnostics, we determined cytokines/chemokines induced by M. leprae proteins in blood of leprosy patients and endemic controls (EC) from high leprosy-prevalence areas (Bangladesh, Brazil, Ethiopia) and from South Korea, where leprosy is not endemic anymore. M. leprae-sonicate-induced IFN-γ was similar for all groups, excluding M. leprae/IFN-γ as a diagnostic readout. By contrast, ML2478 and ML0840 induced high IFN-γ concentrations in Bangladeshi EC, which were completely absent for South Korean controls. Importantly, ML2478/IFN-γ could indicate distinct degrees of M. leprae exposure, and thereby the risk of infection and transmission, in different parts of Brazilian and Ethiopian cities. Notwithstanding these discriminatory responses, M. leprae proteins did not distinguish patients from EC in one leprosy-endemic area based on IFN-γ. Analyses of additional cytokines/chemokines showed that M. leprae and ML2478 induced significantly higher concentrations of MCP-1, MIP-1β, and IL-1β in patients compared with EC, whereas IFN-inducible protein-10, like IFN-γ, differed between EC from areas with dissimilar leprosy prevalence. This study identifies M. leprae-unique Ags, particularly ML2478, as biomarker tools to measure M. leprae exposure using IFN-γ or IFN-inducible protein-10, and also shows that MCP-1, MIP-1β, and IL-1β can potentially distinguish pathogenic immune responses from those induced during asymptomatic exposure to M. leprae.


The founder's dilemma.
Why do people start businesses? For the money and the chance to control their own companies, certainly. But new research from Harvard Business School professor Wasserman shows that those goals are largely incompatible. The author's studies indicate that a founder who gives up more equity to attract cofounders, new hires, and investors builds a more valuable company than one who parts with less equity. More often than not, however, those superior returns come from replacing the founder with a professional CEO more experienced with the needs of a growing company. This fundamental tension requires founders to make "rich" versus "king" trade-offs to maximize either their wealth or their control over the company. Founders seeking to remain in control (as John Gabbert of the furniture retailer Room & Board has done) would do well to restrict themselves to businesses where large amounts of capital aren't required and where they already have the skills and contacts they need. They may also want to wait until late in their careers, after they have developed broader management skills, before setting up shop. Entrepreneurs who focus on wealth, such as Jim Triandiflou, who founded Ockham Technologies, can make the leap sooner because they won't mind taking money from investors or depending on executives to manage their ventures. Such founders will often bring in new CEOs themselves and be more likely to work with their boards to develop new, post-succession roles for themselves. Choosing between money and power allows entrepreneurs to come to grips with what success means to them. Founders who want to manage empires will not believe they are successes if they lose control, even if they end up rich. Conversely, founders who understand that their goal is to amass wealth will not view themselves as failures when they step down from the top job.


Remote control of lipophilic nucleic acids domain partitioning by DNA hybridization and enzymatic cleavage.
Lateral partitioning of lipid-modified molecules between liquid-disordered (ld) and liquid-ordered (lo) domains depends on the type of lipid modification, presence of a spacer, membrane composition, and temperature. Here, we show that the lo domain partitioning of the palmitoylated peptide nucleic acid (PNA) can be influenced by formation of a four-component complex with the ld domain partitioning tocopherol-modified DNA: the PNA-DNA complex partitioned into the ld domains. Enzymatic cleavage of the DNA linker led to the disruption of the complex and restored the initial distribution of the lipophilic nucleic acids into the respective domains. This modular system offers strategies for dynamic functionalization of biomimetic surfaces, for example, in nanostructuring and regulation of enzyme catalysis, and it provides a tool to study the molecular basis of controlled reorganization of lipid-modified proteins in membranes, for example, during signal transduction.


Antibody-mediated autoimmune myocarditis depends on genetically determined target organ sensitivity.
Injury to cardiac myocytes often leads to the production of anti-myosin antibodies. While these antibodies are a marker of myocardial injury, their contribution to pathogenesis in diseases such as autoimmune myocarditis or rheumatic fever is much less clear. We demonstrate in this report that monoclonal anti-myosin antibodies can mediate myocarditis in a susceptible mouse strain. Additionally, we show disease susceptibility depends on the presence of myosin or a myosin-like molecule in cardiac extracellular matrix. This study demonstrates that susceptibility to autoimmune heart disease depends not only on the activation of self-reactive lymphocytes but also on genetically determined target organ sensitivity to autoantibodies.


Gene number determination and genetic polymorphism of the gamma delta T cell co-receptor WC1 genes.
WC1 co-receptors belong to the scavenger receptor cysteine-rich (SRCR) superfamily and are encoded by a multi-gene family. Expression of particular WC1 genes defines functional subpopulations of WC1(+) γδ T cells. We have previously identified partial or complete genomic sequences for thirteen different WC1 genes through annotation of the bovine genome Btau_3.1 build. We also identified two WC1 cDNA sequences from other cattle that did not correspond to sequences in the Btau_3.1 build. Their absence in the Btau_3.1 build may have reflected gaps in the genome assembly or polymorphisms among animals. Since the response of γδ T cells to bacterial challenge is determined by WC1 gene expression, it was critical to understand whether individual cattle or breeds differ in the number of WC1 genes or display polymorphisms. Real-time quantitative PCR using DNA from the animal whose genome was sequenced ("Dominette") and sixteen other animals representing ten breeds of cattle, showed that the number of genes coding for WC1 co-receptors is thirteen. The complete coding sequences of those thirteen WC1 genes is presented, including the correction of an error in the WC1-2 gene due to mis-assembly in the Btau_3.1 build. All other cDNA sequences were found to agree with the previous annotation of complete or partial WC1 genes. PCR amplification and sequencing of the most variable N-terminal SRCR domain (domain 1 which has the SRCR "a" pattern) of each of the thirteen WC1 genes showed that the sequences are highly conserved among individuals and breeds. Of 160 sequences of domain 1 from three breeds of cattle, no additional sequences beyond the thirteen described WC1 genes were found. Analysis of the complete WC1 cDNA sequences indicated that the thirteen WC1 genes code for three distinct WC1 molecular forms. The bovine WC1 multi-gene family is composed of thirteen genes coding for three structural forms whose sequences are highly conserved among individual cattle and breeds. The sequence diversity necessary for WC1 genes to function as a multi-genic pattern recognition receptor array is encoded in the genome, rather than generated by recombinatorial diversity or hypermutation.


Cardiac output and stroke volume variation measured by the pulse wave transit time method: a comparison with an arterial pressure-based cardiac output system.
Hemodynamic monitoring is mandatory for perioperative management of cardiac surgery. Recently, the estimated continuous cardiac output (esCCO) system, which can monitor cardiac output (CO) non-invasively based on pulse wave transit time, has been developed. Patients who underwent cardiovascular surgeries with hemodynamics monitoring using arterial pressure-based CO (APCO) were eligible for this study. Hemodynamic monitoring using esCCO and APCO was initiated immediately after intensive care unit admission. CO values measured using esCCO and APCO were collected every 6 h, and stroke volume variation (SVV) data were obtained every hour while patients were mechanically ventilated. Correlation and Bland-Altman analyses were used to compare APCO and esCCO. Welch's analysis of variance, and four-quadrant plot and polar plot analyses were performed to evaluate the effect of time course, and the trending ability. A p-value < 0.05 was considered statistically significant. Twenty-one patients were included in this study, and 143 and 146 datasets for CO and SVV measurement were analyzed. Regarding CO, the correlation analysis showed that APCO and esCCO were significantly correlated (r = 0.62), and the bias ± precision and percentage error were 0.14 ± 1.94 (L/min) and 69%, respectively. The correlation coefficient, bias ± precision, and percentage error for SVV evaluation were 0.4, - 3.79 ± 5.08, and 99%, respectively. The time course had no effects on the biases between CO and SVV. Concordance rates were 80.3 and 75.7% respectively. While CO measurement with esCCO can be a reliable monitor after cardiovascular surgeries, SVV measurement with esCCO may require further improvement.


Assessing Stride Variables and Vertical Stiffness with GPS-Embedded Accelerometers: Preliminary Insights for the Monitoring of Neuromuscular Fatigue on the Field.
The aim of the present study was to examine the ability of a GPS-imbedded accelerometer to assess stride variables and vertical stiffness (K), which are directly related to neuromuscular fatigue during field-based high-intensity runs. The ability to detect stride imbalances was also examined. A team sport player performed a series of 30-s runs on an instrumented treadmill (6 runs at 10, 17 and 24 km·h(-1)) with or without his right ankle taped (aimed at creating a stride imbalance), while wearing on his back a commercially-available GPS unit with an embedded 100-Hz tri-axial accelerometer. Contact (CT) and flying (FT) time, and K were computed from both treadmill and accelerometers (Athletic Data Innovations) data. The agreement between treadmill (criterion measure) and accelerometer-derived data was examined. We also compared the ability of the different systems to detect the stride imbalance. Biases were small (CT and K) and moderate (FT). The typical error of the estimate was trivial (CT), small (K) and moderate (FT), with nearly perfect (CT and K) and large (FT) correlations for treadmill vs. accelerometer. The tape induced very large increase in the right - left foot ∆ in CT, FT and K measured by the treadmill. The tape effect on CT and K ∆ measured with the accelerometers were also very large, but of lower magnitude than with the treadmill. The tape effect on accelerometer-derived ∆ FT was unclear. Present data highlight the potential of a GPS-embedded accelerometer to assess CT and K during ground running. Key pointsGPS-embedded tri-axial accelerometers may be used to assess contact time and vertical stiffness during ground running.These preliminary results open new perspective for the field monitoring of neuromuscular fatigue and performance in run-based sports.


Neuregulin-1 attenuates mortality associated with experimental cerebral malaria.
Cerebral Malaria (CM) is a diffuse encephalopathy caused by Plasmodium falciparum infection. Despite availability of antimalarial drugs, CM-associated mortality remains high at approximately 30% and a subset of survivors develop neurological and cognitive disabilities. While antimalarials are effective at clearing Plasmodium parasites they do little to protect against CM pathophysiology and parasite-induced brain inflammation that leads to seizures, coma and long-term neurological sequelae in CM patients. Thus, there is urgent need to explore therapeutics that can reduce or prevent CM pathogenesis and associated brain inflammation to improve survival. Neuregulin-1 (NRG-1) is a neurotrophic growth factor shown to protect against brain injury associated with acute ischemic stroke (AIS) and neurotoxin exposure. However, this drug has not been tested against CM-associated brain injury. Since CM-associated brain injuries and AIS share similar pathophysiological features, we hypothesized that NRG-1 will reduce or prevent neuroinflammation and brain damage as well as improve survival in mice with late-stage experimental cerebral malaria (ECM). We tested the effects of NRG-1 on ECM-associated brain inflammation and mortality in P. berghei ANKA (PbA)-infected mice and compared to artemether (ARM) treatment; an antimalarial currently used in various combination therapies against malaria. Treatment with ARM (25 mg/kg/day) effectively cleared parasites and reduced mortality in PbA-infected mice by 82%. Remarkably, NRG-1 therapy (1.25 ng/kg/day) significantly improved survival against ECM by 73% despite increase in parasite burden within NRG-1-treated mice. Additionally, NRG-1 therapy reduced systemic and brain pro-inflammatory factors TNFalpha, IL-6, IL-1alpha and CXCL10 and enhanced anti-inflammatory factors, IL-5 and IL-13 while decreasing leukocyte accumulation in brain microvessels. This study suggests that NRG-1 attenuates ECM-associated brain inflammation and injuries and may represent a novel supportive therapy for the management of CM.


Far Forward Gaps in Hemorrhagic Shock and Prolonged Field Care: An Update of ALM Fluid Therapy for Field Use.
Future expeditionary missions are expected to occur in more remote austere environments where combat medics and casualties may have to wait up to 7 days before resupply or safe evacuation. Currently, there is no effective fluid therapy for hemorrhagic shock (HS) at the point-of-injury and continuum-of-care over this extended period. We have been developing a small-volume IV or IO ALM therapy for noncompressible HS and have shown in preclinical models that it extends survival to 3 days, reduces abdominal bleeding by 60%, blunts inflammation, corrects coagulopathy, preserves platelet function, and prevents immunodeficiency. The ALM-survival phenotype is associated with an upregulation of the master genes of metabolism and mitochrondrial biogenesis in heart and brain and a downregulation in the periphery. Future translational studies will investigate the timing and nature of the "switch" and extend survival to 7 days. We will also discuss some of the controversies of ALM resuscitation in pigs, present our Systems Hypothesis of Trauma (SHOT), and discuss future clinical safety trials before field use.


Arabidopsis transcription factors: genome-wide comparative analysis among eukaryotes.
The completion of the Arabidopsis thaliana genome sequence allows a comparative analysis of transcriptional regulators across the three eukaryotic kingdoms. Arabidopsis dedicates over 5% of its genome to code for more than 1500 transcription factors, about 45% of which are from families specific to plants. Arabidopsis transcription factors that belong to families common to all eukaryotes do not share significant similarity with those of the other kingdoms beyond the conserved DNA binding domains, many of which have been arranged in combinations specific to each lineage. The genome-wide comparison reveals the evolutionary generation of diversity in the regulation of transcription.


Lactic acid bacteria isolated from poultry protect the intestinal epithelial cells of chickens from in vitro wheat germ agglutinin-induced cytotoxicity.
Poultry fed on wheat-based diets regularly ingest wheat germ agglutinin (WGA) that has toxic effects in vitro on intestinal epithelial cells (IEC) obtained from 14-d-old broilers. Cytotoxicity and the potential role of 14 intestinal bacterial strains in the removal of bound lectins in epithelial cell cultures were investigated. Cytotoxicity was dependent on time and lectin concentration; the lethal dose (LD50) was 8.36 µg/ml for IEC exposed for 2 h to WGA. Complementary sugars to WGA were detected on the surface of one Enterococcus and 9 Lactobacillus strains isolated from poultry. These strains were evaluated as a lectin removal tool for cytotoxicity prevention. Incubation of lactic acid bacteria with WGA before IEC-lectin interaction caused a substantial reduction in the percentage of cell deaths. The protection was attributed to the amount of lectin bound to the bacterial surfaces and was strain-dependent. L. salivarius LET 201 and L. reuteri LET 210 were more efficient than the other lactic acid bacteria assayed. These results provide a basis for the development of probiotic supplements or cell-wall preparations of selected lactic acid bacteria intended to avoid harmful effects of a natural constituent of the grain in wheat-based diets.


Does chemotherapy prevent HBV-related hepatocellular carcinoma? Cons.
The retrospective scrutiny of studies that were originally designed to assess the antiviral activity of interferon (IFN) and nucleos(t)ide analogues (NUC) suggested reduced incidence of hepatocellular carcinoma (HCC) in responders. The interpretation of these studies, however, is questioned by the heterogeneity of patient referral, adoption of surrogate end-points, lack of control arms and, overall, by the lack of power to capture enough hard end-points of the natural history of hepatitis B, including HCC. Another point of criticism is that above all, IFN studies could have been affected by study enrolment skewed towards patients with less advanced liver disease, who had a better predicted compliance to therapy but a lower risk of developing HCC in the short-term. In my opinion, these constraints coupled with the lack of patient stratification by HCC predictors, make the evaluation of the prophylactic activity of IFN and NUC even more difficult. Overall, while single studies provide some evidence for a reduced HCC incidence in virological responders, particularly in those with moderate liver fibrosis, we still lack confirmation that anti-HBV therapy prevents HCC in patients with an established cirrhosis, too. Finally, tertiary prevention with anti-HBV treatments is controversial, due to the existence of a few, methodologically flawed studies.


IL-12-Dependent Cytomegalovirus-Specific CD4+ T Cell Proliferation, T-bet Induction, and Effector Multifunction during Primary Infection Are Key Determinants for Early Immune Control.
CMV remains an important opportunistic pathogen in solid organ and hematopoietic cell transplantation, particularly in lung transplant recipients (LTRs). LTRs mismatched for CMV (donor(+)/recipient(-); D(+)R(-)) are at high risk for active CMV infection and increased mortality; however, the immune correlates of viral control remain incompletely understood. We prospectively studied 27 D(+)R(-) LTRs during primary CMV infection to determine whether acute CD4(+) T cell parameters differentiated the capacity for viral control during early chronic infection. Unexpectedly, the T-box transcription factor, T-bet, was expressed at low levels in CD4(+) compared with CD8(+) T cells during acute primary infection. However, the capacity for in vitro CMV phosphoprotein 65-specific proliferation and CD4(+)T-bet(+) induction differentiated LTR controllers from early viremic relapsers, correlating with granzyme B loading and effector multifunction. Furthermore, impaired CMV-specific proliferative responses from relapsers, along with T-bet, and effector function could be significantly rescued, most effectively with phosphoprotein 65 Ag and combined exogenous IL-2 and IL-12. Acute CD4(+) T cell CMV-specific proliferative and effector responses were highly IL-12-dependent in blocking studies. In addition, we generated monocyte-derived dendritic cells using PBMC obtained during primary infection from relapsers and observed impaired monocyte-derived dendritic cell differentiation, a reduced capacity for IL-12 production, but increased IL-10 production compared with controls, suggesting an APC defect during acute CMV viremia. Taken together, these data show an important role for CMV-specific CD4(+) effector responses in differentiating the capacity of high-risk LTRs to establish durable immune control during early chronic infection and provide evidence for IL-12 as a key factor driving these responses.