Dynamic impacts of the inhibition of the molecular chaperone Hsp90 on the T-cell proteome have implications for anti-cancer therapy.
The molecular chaperone Hsp90-dependent proteome represents a complex protein network of critical biological and medical relevance. Known to associate with proteins with a broad variety of functions termed clients, Hsp90 maintains key essential and oncogenic signalling pathways. Consequently, Hsp90 inhibitors are being tested as anti-cancer drugs. Using an integrated systematic approach to analyse the effects of Hsp90 inhibition in T-cells, we quantified differential changes in the Hsp90-dependent proteome, Hsp90 interactome, and a selection of the transcriptome. Kinetic behaviours in the Hsp90-dependent proteome were assessed using a novel pulse-chase strategy (Fierro-Monti et al., accompanying article), detecting effects on both protein stability and synthesis. Global and specific dynamic impacts, including proteostatic responses, are due to direct inhibition of Hsp90 as well as indirect effects. As a result, a decrease was detected in most proteins that changed their levels, including known Hsp90 clients. Most likely, consequences of the role of Hsp90 in gene expression determined a global reduction in net de novo protein synthesis. This decrease appeared to be greater in magnitude than a concomitantly observed global increase in protein decay rates. Several novel putative Hsp90 clients were validated, and interestingly, protein families with critical functions, particularly the Hsp90 family and cofactors themselves as well as protein kinases, displayed strongly increased decay rates due to Hsp90 inhibitor treatment. Remarkably, an upsurge in survival pathways, involving molecular chaperones and several oncoproteins, and decreased levels of some tumour suppressors, have implications for anti-cancer therapy with Hsp90 inhibitors. The diversity of global effects may represent a paradigm of mechanisms that are operating to shield cells from proteotoxic stress, by promoting pro-survival and anti-proliferative functions. Data are available via ProteomeXchange with identifier PXD000537.


Activity of topotecan 21-day infusion in patients with previously treated large cell lymphoma: long-term follow-up of an Eastern Cooperative Oncology Group study (E5493).
The purpose of this study was to determine the activity of topotecan given by 21-day continuous infusion in patients previously treated with one prior therapy for a diffuse large-cell lymphoma or immunoblastic lymphoma. Patients with appropriate histology and measurable disease who had been treated with one prior chemotherapy regimen were eligible for study. Slides of tumor biopsies were submitted for central review of pathology. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 and adequate bone marrow function. Patients were treated with continuous infusion topotecan, 0.4 mg/m(2)/day × 21 days. Therapy could be escalated to 0.5 and then 0.6 mg/m(2)/day in subsequent cycles if there was no dose-limiting toxicity at the initial dose level. Patients were treated with two cycles after achieving a complete response or until disease progression or unacceptable toxicity occurred. Thirty-seven patients were enrolled. However, only 26 cases were eligible due to a performance status of > 2 (n = 2), more than one prior chemotherapy (n = 1) and wrong histology on review (n = 8). Due to the unexpectedly high ineligibility rate, two sets of analysis were done for all 37 patients enrolled and for the 26 eligible patients, respectively. Of the 37 patients (15 males and 22 females), the International Prognostic Index included 11% low risk, 30% low intermediate risk, 46% high intermediate risk and 8% high risk. The median follow-up was 77 months. A total of 136 cycles of therapy were given with a median of 3 cycles per patient. Grade 4 toxicities included: 14% grade 4 thrombocytopenia; 14% grade 4 granulocytopenia, 8% leukopenia, 3% each anemia, hemorrhage, infection, vomiting, thrombosis, liver toxicity and neuromotor toxicity. The response analysis including all 37 patients showed five complete responses (CRs) and four partial responses (PRs) for a total response rate of 24% (90% two-stage confidence interval 13-39%). Median progression-free survival (PFS) was 3.7 months, with 1- and 2-year PFS of 21% and 6%, respectively (90% confidence interval 11-34% and 2-15%). Median overall survival (OS) was 10.5 months, with 1- and 2-year OS of 41% and 27%, respectively (90% confidence interval 27-53% and 16-39%). Analysis including only eligible patients showed similar response rates and survival outcomes. Single agent topotecan has moderate activity for previously treated high-grade lymphoma equivalent to that of several newer agents, and should be considered for incorporation into multi-drug salvage chemotherapy programs.


High-valent intermediates of heme proteins and model compounds.
Recent computational and experimental probes of high-valent intermediates in heme proteins and model compounds reveal a rich spectrum of chemical behavior that is dependent on the nature of the proximal ligand, metal center, distal- and proximal-binding site environment, porphyrin macrocycle architecture, and consequent electronic structure. The results of such studies reveal an underlying complexity, which is simply understood once one is cognizant of the 'chameleon'-like behavior of such intermediates is determined by the high-valent intermediate environment.


Mercury bioaccumulation in aquatic biota along a salinity gradient in the Saint John River estuary.
Although estuaries are critical habitats for many aquatic species, the spatial trends of toxic methylmercury (MeHg) in biota from fresh to marine waters are poorly understood. Our objective was to determine if MeHg concentrations in biota changed along a salinity gradient in an estuary. Fourspine Stickleback (Apeltes quadracus), invertebrates (snails, amphipods, and chironomids), sediments, and water were collected from ten sites along the Saint John River estuary, New Brunswick, Canada in 2015 and 2016, with salinities ranging from 0.06 to 6.96. Total mercury (proxy for MeHg) was measured in whole fish and MeHg was measured in a subset of fish, pooled invertebrates, sediments, and water. Stable sulfur (δ34S), carbon (δ13C), and nitrogen (δ15N) isotope values were measured to assess energy sources (S, C) and relative trophic level (N). There were increases in biotic δ13C and δ34S from fresh to more saline sites and these measures were correlated with salinity. Though aqueous MeHg was higher at the freshwater than more saline sites, only chironomid MeHg increased significantly with salinity. In the Saint John River estuary, there was little evidence that MeHg and its associated risks increased along a salinity gradient.


Fractionation by liquid chromatography combined with comprehensive two-dimensional gas chromatography-mass spectrometry for analysis of cyclics in oligomerisation products of Fischer-Tropsch derived light alkenes.
In oligomerisation products of High Temperature Fischer-Tropsch (HTFT) derived light alkenes using a solid phosphoric acid (SPA) catalyst, the presence of cyclics was presumed although their occurrence could not be explained by the generally accepted oligomerisation mechanism. Notwithstanding the use of GC×GC-TOFMS, the cyclic alkanes could not be differentiated from the alkenes. On the one hand, compounds co-eluted in GC×GC and, on the other hand, MS cannot distinguish between these classes because of identical molecular masses and very similar mass fragmentation patterns. An LC pre-fractionation procedure utilising a silver-modified column was developed to separate the saturates from the unsaturates. Using this approach we were able, for the first time, to confirm the presence of cyclics, probably resulting from secondary reactions, in HTFT oligomerisation products. The occurrence of cyclics can be an indication of the beginning of carbonaceous deposit formation that could eventually lead to catalyst deactivation.


How gender-expectancy affects the processing of "them".
How sensitive is pronoun processing to expectancies based on real-world knowledge and language usage? The current study links research on the integration of gender stereotypes and number-mismatch to explore this question. It focuses on the use of them to refer to antecedents of different levels of gender-expectancy (low-cyclist, high-mechanic, known-spokeswoman). In a rating task, them is considered increasingly unnatural with greater gender-expectancy. However, participants might not be able to differentiate high-expectancy and gender-known antecedents online because they initially search for plural antecedents (e.g., Sanford & Filik), and they make all-or-nothing gender inferences. An eye-tracking study reveals early differences in the processing of them with antecedents of high gender-expectancy compared with gender-known antecedents. This suggests that participants have rapid access to the expected gender of the antecedent and the level of that expectancy.


Inherited variation at MC1R and histological characteristics of primary melanoma.
Variation in the melanocortin-1receptor (MC1R) gene is associated with pigmentary phenotypes and risk of malignant melanoma. Few studies have reported on MC1R variation with respect to tumor characteristics, especially clinically important prognostic features. We examined associations between MC1R variants and histopathological melanoma characteristics. Study participants were enrolled from nine geographic regions in Australia, Canada, Italy and the United States and were genotyped for MC1R variants classified as high-risk [R] (D84E, R142H, R151C, R160W, and D294H, all nonsense and insertion/deletion) or low-risk [r] (all other nonsynonymous) variants. Tissue was available for 2,160 white participants of the Genes, Environment and Melanoma (GEM) Study with a first incident primary melanoma diagnosis, and underwent centralized pathologic review. No statistically significant associations were observed between MC1R variants and AJCC established prognostic tumor characteristics: Breslow thickness, presence of mitoses or presence of ulceration. However, MC1R was significantly associated with anatomic site of melanoma (p = 0.002) and a positive association was observed between carriage of more than one [R] variant and melanomas arising on the arms (OR = 2.39; 95% CI: 1.40, 4.09). We also observed statistically significant differences between sun-sensitive and sun-resistant individuals with respect to associations between MC1R genotype and AJCC prognostic tumor characteristics. Our results suggest inherited variation in MC1R may play an influential role in anatomic site presentation of melanomas and may differ with respect to skin pigmentation phenotype.


C9orf72 Hexanucleotide Expansions Are Associated with Altered Endoplasmic Reticulum Calcium Homeostasis and Stress Granule Formation in Induced Pluripotent Stem Cell-Derived Neurons from Patients with Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.
An expanded hexanucleotide repeat in a noncoding region of the C9orf72 gene is a major cause of amyotrophic lateral sclerosis (ALS), accounting for up to 40% of familial cases and 7% of sporadic ALS in European populations. We have generated induced pluripotent stem cells (iPSCs) from fibroblasts of patients carrying C9orf72 hexanucleotide expansions, differentiated these to functional motor and cortical neurons, and performed an extensive phenotypic characterization. In C9orf72 iPSC-derived motor neurons, decreased cell survival is correlated with dysfunction in Ca(2+) homeostasis, reduced levels of the antiapoptotic protein Bcl-2, increased endoplasmic reticulum (ER) stress, and reduced mitochondrial membrane potential. Furthermore, C9orf72 motor neurons, and also cortical neurons, show evidence of abnormal protein aggregation and stress granule formation. This study is an extensive characterization of iPSC-derived motor neurons as cellular models of ALS carrying C9orf72 hexanucleotide repeats, which describes a novel pathogenic link between C9orf72 mutations, dysregulation of calcium signaling, and altered proteostasis and provides a potential pharmacological target for the treatment of ALS and the related neurodegenerative disease frontotemporal dementia. Stem Cells 2016;34:2063-2078.


Matrix-Encoding Gene Diversity of 624 Influenza A/H3N2 Genomes Does Not Show Association with Impaired Viral Detection by Commercialized qPCR Assays.
As for the case of SARS-CoV-2, genome sequencing of influenza viruses is of potential interest to raise and address virological issues. Recently, false-negativity of real-time reverse transcription-PCR (qPCR) assays that detect influenza A/H3N2 virus RNA were reported and associated with two mutations (A37T and C161T) in the Matrix-encoding (M1) gene located on viral segment 7. This triggered a national alert in France. The present study sought to assess the association between the presence of these mutations and potential false negative results of influenza A/H3N2 virus RNA detection by commercialized qPCR assays at the clinical virology laboratory of our university hospitals in southern France. This study focused on the genetic diversity in the M1 gene and segment 7 of 624 influenza A/H3N2 virus genomes obtained from respiratory samples having tested qPCR-positive with M1 gene-targeting assays in our clinical virology laboratory. A total of 585 among the 624 influenza A/H3N2 virus genomes (93.7%) were of clade 3C.2a1b.2a.2, and 39 (6.3%) were of clade 3C.2a1b.1a. M1 gene substitutions A37T and C161T were both present in 582 (93.3%) genomes, only of clade 3C.2a1b.2a.2. Substitution A37T was present in 621 (99.5%) genomes. Substitution C161T was present in 585 genomes (93.8%), all of clade 3C.2a1b.2a.2. Moreover, 21 other nucleotide positions were mutated in ≥90% of the genomes. The present study shows that A37T/C and C161T mutations, and other mutations in the M1 gene and segment 7, were widely present in influenza A/H3N2 virus genomes recovered from respiratory samples diagnosed qPCR-positive with commercialized assays.


Impact of telemedicine on acute management of stroke patients undergoing endovascular procedures.
Telemedicine is improving acute stroke care in remote areas. Delay in hospital-to-hospital transfer is a common reason why acute ischemic stroke patients are excluded from interventional therapy. The progressive implementation of these procedures, requiring highly specialized professionals in comprehensive stroke centers, will certainly challenge even more the geographic equity in the access to the best acute stroke treatments. We aimed to assess the benefits of telemedicine in selecting stroke patients for endovascular treatments. In our Reference Comprehensive Stroke Center (RCSC), we perform urgent intra-arterial procedures in acute stroke patients. Patients may be primarily admitted (PA) or referred from community hospitals with (TMHs; 2 centers) or without telemedicine (nonTMHs; 7 centers). We prospectively studied all consecutive stroke patients undergoing urgent endovascular recanalization procedures in the RCSC. We studied different outcome measures according to the patients' initial admission: PA patients, TMH patients or nonTMH patients. For all patients, demographic and outcome data including serial National Institute of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) scores at 3 months were recorded. Clinical improvement was defined as a decrease ≥4 points on the NIHSS at 7 days or discharge and favorable outcome as mRS ≤2 at 3 months. Whether an endovascular procedure was indicated was decided according to clinical, radiological and transcranial Doppler (TCD) data, independently of the patient's initial admission center. During a 2-year period, 119 patients received endovascular treatment: PA patients 74 (63.1%), TMH patients 25 (20.5%), nonTM patients 20 (16.4%). The mean distance to the RCSC was 52 ± 15 km for TMHs and 34.5 ± 12 km for nonTMHs (p = 0.4). There were no differences in baseline characteristics including age (71, 71.6 and 66.5 years; p = 0.25), baseline NIHSS (18.5, 19 and 18; p = 0.57) and previous use of intravenous tissue plasminogen activator (56.5, 56.5 and 57.9%; p = 0.95). The rate of recanalization (modified Thrombolysis in Cerebral Infarction Score ≥2a) was similar in all groups (75, 66.6 and 68.4%; p = 0.682). TMH and PA patients had similar clinical improvement (61 vs. 63.8%; p = 0.51) and good functional outcome (36.8 vs. 35.3%; p = 0.722). Conversely, nonTMH patients presented a lesser degree of clinical improvement (31.3%) and poorer functional outcome (15.8%) than TMH (p = 0.019 and p = 0.046) and PA patients (p = 0.05 and p = 0.013). TMH patients had significantly shorter door-to-groin puncture times (47 vs. 69 min; p = 0.047). Telemedicine assessment to select patients for endovascular procedures improves the efficiency in stroke management and possibly the early and long-term outcome in patients receiving intra-arterial reperfusion treatment.


Telaprevir for previously treated chronic HCV infection.
Patients with genotype 1 hepatitis C virus (HCV) who do not have a sustained response to therapy with peginterferon alfa and ribavirin have a low likelihood of success with retreatment. We randomly assigned patients with HCV genotype 1 who had not had a sustained virologic response after peginterferon alfa-ribavirin therapy to one of four treatment groups: 115 patients to the T12PR24 group, receiving telaprevir (1125-mg loading dose, then 750 mg every 8 hours) for 12 weeks and peginterferon alfa-2a (180 microg per week) and ribavirin (1000 or 1200 mg per day, according to body weight) for 24 weeks; 113 patients to the T24PR48 group, receiving telaprevir for 24 weeks and peginterferon alfa-2a and ribavirin for 48 weeks (at the same doses as in the T12PR24 group); 111 patients to the T24P24 group, receiving telaprevir and peginterferon alfa-2a for 24 weeks (at the same doses as in the T12PR24 group); and 114 patients to the PR48 (or control) group, receiving peginterferon alfa-2a and ribavirin for 48 weeks (at the same doses as in the T12PR24 group). The primary end point was sustained virologic response (undetectable HCV RNA levels 24 weeks after the last dose of study drugs). The rates of sustained virologic response in the three telaprevir groups--51% in the T12PR24 group, 53% in the T24PR48 group, and 24% in the T24P24 group--were significantly higher than the rate in the control group (14%; P<0.001, P<0.001, and P=0.02, respectively). Response rates were higher among patients who had previously had relapses than among nonresponders. One of the most common adverse events in the telaprevir groups was rash (overall, occurring in 51% of patients, with severe rash in 5%). Discontinuation of study drugs because of adverse events was more frequent in the telaprevir groups than in the control group (15% vs. 4%). In HCV-infected patients in whom initial peginterferon alfa and ribavirin treatment failed, retreatment with telaprevir in combination with peginterferon alfa-2a and ribavirin was more effective than retreatment with peginterferon alfa-2a and ribavirin alone. (ClinicalTrials.gov number, NCT00420784.)


The glycinergic control of spinal pain processing.
Alterations in synaptic transmission within the spinal cord dorsal horn play a key role in the development of pathological pain. While N-methyl-D-aspartate (NMDA) receptors and activity-dependent synaptic plasticity have been the focus of research for many years, recent evidence attributes very specific functions to inhibitory glycinergic and gamma-aminobutyric acid (GABA)-ergic neurotransmission in the generation of inflammatory and neuropathic pain. The central component of inflammatory pain originates from a disinhibition of dorsal horn neurons, which are relieved from glycinergic neurotransmission by the inflammatory mediator prostaglandin E2 (PGE2). PGE2 activates prostaglandin E receptors of the EP2 subtype and leads to a protein kinase A-dependent phosphorylation and inhibition of glycine receptors containing the alpha3 subunit (GlyRalpha3). This GlyRalpha3 is distinctly expressed in the superficial dorsal horn, where nociceptive afferents terminate. Other but probably very similar disinhibitory mechanisms may well contribute to abnormal pain occurring after peripheral nerve injury.


Ancient geodynamics and global-scale hydrology on Mars.
Loading of the lithosphere of Mars by the Tharsis rise explains much of the global shape and long-wavelength gravity field of the planet, including a ring of negative gravity anomalies and a topographic trough around Tharsis, as well as gravity anomaly and topographic highs centered in Arabia Terra and extending northward toward Utopia. The Tharsis-induced trough and antipodal high were largely in place by the end of the Noachian Epoch and exerted control on the location and orientation of valley networks. The release of carbon dioxide and water accompanying the emplacement of approximately 3 x 10(8) cubic kilometers of Tharsis magmas may have sustained a warmer climate than at present, enabling the formation of ancient valley networks and fluvial landscape denudation in and adjacent to the large-scale trough.


Underestimation of perceived number at the time of saccades.
Saccadic eye movements produce transient distortions in both space and time. Mounting evidence suggests that space and time perception are linked, and associated with the perception of another important perceptual attribute, numerosity. Here we investigate the effect of saccades on the perceived numerosity of briefly presented arrays of visual elements. We report a systematic underestimation of numerosity for stimuli flashed just before or during saccades, of about 35% of the reference numerosity. The bias is observed only for relatively large arrays of visual elements, in line with the notion that a distinct perceptual mechanism is involved with enumeration of small numerosities in the 'subitizing' range. This study provides further evidence for the notion that space, time and number share common neural representations, all affected by saccades.


Cost-effectiveness of capecitabine and bevacizumab maintenance treatment after first-line induction treatment in metastatic colorectal cancer.
Capecitabine and bevacizumab (CAP-B) maintenance therapy has shown to be more effective compared with observation in metastatic colorectal cancer patients achieving stable disease or better after six cycles of first-line capecitabine, oxaliplatin, bevacizumab treatment in terms of progression-free survival. We evaluated the cost-effectiveness of CAP-B maintenance treatment. Decision analysis with Markov modelling to evaluate the cost-effectiveness of CAP-B maintenance compared with observation was performed based on CAIRO3 study results (n = 558). An additional analysis was performed in patients with complete or partial response. The primary outcomes were the incremental cost-effectiveness ratio (ICER) defined as the additional cost per life year (LY) and quality-adjusted life years (QALY) gained, calculated from EQ-5D questionnaires and literature and LYs gained. Univariable sensitivity analysis was performed to assess the influence of input parameters on the ICER, and a probabilistic sensitivity analysis represents uncertainty in model parameters. CAP-B maintenance compared with observation resulted in 0.21 QALYs (0.18LYs) gained at a mean cost increase of €36,845, yielding an ICER of €175,452 per QALY (€204,694 per LY). Varying the difference in health-related quality of life between CAP-B maintenance and observation influenced the ICER most. For patients achieving complete or partial response on capecitabine, oxaliplatin, bevacizumab induction treatment, an ICER of €149,300 per QALY was calculated. CAP-B maintenance results in improved health outcomes measured in QALYs and LYs compared with observation, but also in a relevant increase in costs. Despite the fact that there is no consensus on cost-effectiveness thresholds in cancer treatment, CAP-B maintenance may not be considered cost-effective.


Cell-cycle dysregulation in breast cancer: breast cancer therapies targeting the cell cycle.
Breast cancer is the most commonly diagnosed cancer in American women. The underlying mechanisms that cause aberrant cell proliferation and tumor growth involve conserved pathways, which include components of the cell cycle machinery. Proto-oncogenes, growth factors, and steroids have been implicated in the pathogenesis of breast cancer. Surgery, local irradiation, and chemotherapy have been the mainstay of treatment for early and advanced stage disease. Potential targets for selective breast cancer therapy are herein reviewed. Improved understanding of the biology of breast cancer has led to more specific "targeted therapies" directed at biological processes that are selectively deregulated in the cancerous cells. Examples include tamoxifen for estrogen receptor positive tumors and imunoneutralizing antibodies such as trastuzumab for Her2/neu overexpressing tumors. Other novel anticancer agents such as paclitaxel, a microtubule binding molecule, and flavopiridol, a cyclin dependent kinase inhibitor, exert their anticancer effects by inhibiting cell cycle progression.


Guillain-Barré syndrome in northern China. Relationship to Campylobacter jejuni infection and anti-glycolipid antibodies.
Guillain-Barré syndrome has been considered to be primarily an acute inflammatory demyelinating polyneuropathy (AIDP). Our experience with Guillain-Barré syndrome in northern China differs from the traditional concept. Electrophysiologically and pathologically, most of our patients have motor axonal degeneration with minimal cellular inflammation, which we have termed 'acute motor axonal neuropathy' (AMAN). The current studies were undertaken to characterize prospectively the clinical, electrophysiological, and serological features of Guillain-Barré syndrome, defined clinically, in northern China. In 1991 and 1992, we characterized by electrodiagnostic criteria 129 Chinese patients with Guillain-Barré syndrome. The AMAN form was present in 65% of patients, the AIDP form in 24% and 11% were unclassifiable. For the 38 patients who presented from January to October, 1992, we performed serological assays for antibodies to Campylobacter jejuni and to glycolipids. Of these 38 patients, 55% had AMAN, 32% had AIDP and 13% were unclassifiable. Sixty-six percent of the 38 had serological evidence of recent C. jejuni infection as compared with 16% of village controls (P = 0.001). Seventy-six percent of AMAN patients and 42% of AIDP patients were seropositive. IgG anti-GM1 antibodies were more frequent in Guillain-Barré syndrome patients compared with village controls (42% versus 6%; P < 0.01). However, no statistically significant correlations were found between the pattern of disease, AMAN or AIDP, anti-glycolipid antibodies, or C. jejuni antibodies. Based on electrophysiological criteria, Guillain-Barré syndrome in northern China can be divided into two predominant forms: AIDP and AMAN. The AMAN form is more common and predominates in the yearly summer outbreaks of Guillain-Barré syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)


Present and future status of flexible spectral imaging color enhancement and blue laser imaging technology.
The usefulness of flexible spectral imaging color enhancement (FICE) has been reported for evaluating the esophagus, stomach, and small and large intestine. Higher contrast is shown between cancer and the surrounding mucosa in the esophagus and stomach and may facilitate the detection of gastric cancers missed by white light imaging alone. The surface patterns of gastric mucosa are clearly visualized in non-malignant areas but are irregular and blurred in malignant areas, leading to clear demarcation. Capsule endoscopy with FICE detects angiodysplasia and erosions of the small intestine. The surface and vascular pattern with FICE is useful for the differential diagnosis of colorectal polyps. However, FICE remains somewhat poor at visualizing mucosal microvasculature on a tumor surface. Narrow-band imaging (NBI) is dark in observing whole gastric mucosa and poor at visualizing mucosal microstructure. Blue laser imaging (BLI) has the potential to resolve these limitations. Narrow-band laser light combined with white light shows irregular microvessels on both differentiated and undifferentiated gastric cancer similar to those using NBI. In addition, irregular surface patterns including minute white zones are clearly seen on the uneven surface of differentiated lesions, resulting in exclusion of undifferentiated lesions. Using both distant and close-up views, a high contrast between green intestinal metaplasia and brown gastric cancer may lead to early detection of gastric cancers and determination of a demarcation line. BLI produces high-contrast images in esophageal cancer with clear vision of intrapapillary capillary loops and also predicts the histopathological diagnosis and depth of invasion in colorectal neoplasms.


The dynamic ligand field of a molecular qubit: decoherence through spin-phonon coupling.
Quantum coherence of S = 1/2 transition metal-based quantum bits (qubits) is strongly influenced by the magnitude of spin-phonon coupling. While this coupling is recognized as deriving from dynamic distortions about the first coordination sphere of the metal, a general model for understanding and quantifying ligand field contributions has not been established. Here we derive a general ligand field theory model to describe and quantify the nature of spin-phonon coupling terms in S = 1/2 transition metal complexes. We show that the coupling term for a given vibrational mode is governed by: (1) the magnitude of the metal-based spin-orbit coupling constant, (2) the magnitude and gradient in the ligand field excited state energy, which determines the magnitude of ground state orbital angular momentum, and (3) dynamic relativistic nephelauxetic contributions reflecting the magnitude and gradient in the covalency of the ligand-metal bonds. From an extensive series of density functional theory (DFT) and time-dependent DFT (TDDFT) calculations calibrated to a range of experimental data, spin-phonon coupling terms describing minimalistic D4h/D2d [CuCl4]2- and C4v [VOCl4]2- complexes translate to and correlate with experimental quantum coherence properties observed for Cu(ii)- and V(iv)-based molecular qubits with different ligand sets, geometries, and coordination numbers. While providing a fundamental framework and means to benchmark current qubits, the model and methodology described herein can be used to screen any S = 1/2 molecular qubit candidate and guide the discovery of room temperature coherent materials for quantum information processing.


Towards the just and sustainable use of antibiotics.
The emergence and spread of antibiotic resistant pathogens poses a big challenge to policy-makers, who need to oversee the transformation of health systems that evolved to provide easy access to these drugs into ones that encourage appropriate use of antimicrobials, whilst reducing the risk of resistance. This is a particular challenge for low and middle-income countries with pluralistic health systems where antibiotics are available in a number of different markets. This review paper considers access and use of antibiotics in these countries from a complex adaptive system perspective. It highlights the main areas of intervention that could provide the key to addressing the sustainable long term use and availability of antibiotics. A focus on the synergies between interventions addressing access strategies, antibiotic quality, diagnostics for low-resource settings, measures to encourage just and sustainable decision making and help seeking optimal therapeutic and dosing strategies are key levers for the sustainable future of antibiotic use. Successful integration of such strategies will be dependent on effective governance mechanisms, effective partnerships and coalition building and accurate evaluation systems at national, regional and global levels.


Lupus autoantibodies target ribosomal P proteins.
All nine SLE (systemic lupus erythematosus) sera with antiribosomal antibody activity targeted the same three ribosomal protein antigens, of molecular masses 38 and 17/19 kD when analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blotting. One serum reacted with an additional protein of approximately kD. Ribosomal subunit fractionation by composite gel electrophoresis and sucrose density ultracentrifugation showed that these proteins were part of the large subunit. Isoelectric focusing in agarose, and two-dimensional polyacrylamide gel electrophoresis revealed that the antigens had pI between 4.5 and 6.5, but that the 17/19 kD antigens were more acidic than the 38 kD antigen. Similarities in the molecular masses, charges, as well as the presence of highly conserved crossreactive epitopes, failure to bind to carboxymethylcellulose at pH 4.2, and extractability of the 17/19 kD proteins by 400 mM NH4Cl-ethanol at 0 degrees C indicated that these antigens were analogous to the proteins P0 (38 kD) and P1/P2 (17/19 kD) described previously (25, 36). Co-identity was confirmed using reference antibodies and antigen. Although antibodies to these proteins were only found in 5-10% of more than 50 sera screened by radioimmunoassay or Western blotting, the selective production of antibodies to epitopes on three (out of a total of more than 80) ribosomal proteins may provide further clues to autoantibody induction of SLE.


Teaching law in medical schools: first, reflect.
Law is now routinely included in the medical school curriculum, often incorporated into bioethics and/or practice of medicine coursework. There seems to lack, however, a systematic understanding of what works in terms of getting across an effective depth and breadth of legal knowledge for medical students - or what such would even look like. Moreover, and more critically, while some literature addresses these what, when, how, and who questions, a more fundamental question is left unanswered: why teach law in medical school? This article suggests a process to reveal a more consensual understanding of this latter question. The author highlights findings and recommendations of some of the leading literature to date related to teaching law in medical schools, and also recent U.K. projects addressing legal teaching in medical schools. Reflecting on these materials and activities, the author suggests that we take a "pause" before we argue for more or different legal topics within the medical curriculum. Before we alter the curricula for more and/or different "law," first, it is critical to have a meaningful, stakeholder-driven, consensus-seeking discussion of the goals of legal education: why do we think it matters that medical students learn about "the law"?


PIM serine/threonine kinases in the pathogenesis and therapy of hematologic malignancies and solid cancers.
The identification as cooperating targets of Proviral Integrations of Moloney virus in murine lymphomas suggested early on that PIM serine/threonine kinases play an important role in cancer biology. Whereas elevated levels of PIM1 and PIM2 were mostly found in hematologic malignancies and prostate cancer, increased PIM3 expression was observed in different solid tumors. PIM kinases are constitutively active and their activity supports in vitro and in vivo tumor cell growth and survival through modification of an increasing number of common as well as isoform-specific substrates including several cell cycle regulators and apoptosis mediators. PIM1 but not PIM2 seems also to mediate homing and migration of normal and malignant hematopoietic cells by regulating chemokine receptor surface expression. Knockdown experiments by RNA interference or dominant-negative acting mutants suggested that PIM kinases are important for maintenance of a transformed phenotype and therefore potential therapeutic targets. Determination of the protein structure facilitated identification of an increasing number of potent small molecule PIM kinase inhibitors with in vitro and in vivo anticancer activity. Ongoing efforts aim to identify isoform-specific PIM inhibitors that would not only help to dissect the kinase function but hopefully also provide targeted therapeutics. Here, we summarize the current knowledge about the role of PIM serine/threonine kinases for the pathogenesis and therapy of hematologic malignancies and solid cancers, and we highlight structural principles and recent progress on small molecule PIM kinase inhibitors that are on their way into first clinical trials.


Are Individuals Who Engage in More Frequent Self-Regulation Less Susceptible to Mental Fatigue?
The aim of this study was to investigate whether individuals who engage in more frequent self-regulation are less susceptible to mental fatigue. Occupational cognitive demand and participation in sports or exercise were quantified as activities requiring self-regulation. Cardiorespiratory fitness was also assessed. On separate occasions, participants either completed 90 min of an incongruent Stroop task (mental exertion condition) or watched a 90-min documentary (control condition). Participants then completed a cycling time-to-exhaustion (physical endurance) test. There was no difference in the mean time to exhaustion between conditions, although individual responses varied. Occupational cognitive demand, participation in sports or exercise, and cardiorespiratory fitness predicted the change in endurance performance (p = .026, adjusted R2 = .279). Only cognitive demand added significantly to the prediction (p = .024). Participants who reported higher levels of occupational cognitive demand better maintained endurance performance following mental exertion.


Renal Tubular Cell Mitochondrial Dysfunction Occurs Despite Preserved Renal Oxygen Delivery in Experimental Septic Acute Kidney Injury.
To explain the paradigm of significant renal functional impairment despite preserved hemodynamics and histology in sepsis-induced acute kidney injury. Prospective observational animal study. University research laboratory. Male Wistar rats. Using a fluid-resuscitated sublethal rat model of fecal peritonitis, changes in renal function were characterized in relation to global and renal hemodynamics, and histology at 6 and 24 hours (n = 6-10). Sham-operated animals were used as comparison (n = 8). Tubular cell mitochondrial function was assessed using multiphoton confocal imaging of live kidney slices incubated in septic serum. By 24 hours, serum creatinine was significantly elevated with a concurrent decrease in renal lactate clearance in septic animals compared with sham-operated and 6-hour septic animals. Renal uncoupling protein-2 was elevated in septic animals at 24 hours although tubular cell injury was minimal and mitochondrial ultrastructure in renal proximal tubular cells preserved. There was no significant change in global or renal hemodynamics and oxygen delivery/consumption between sham-operated and septic animals at both 6- and 24-hour timepoints. In the live kidney slice model, mitochondrial dysfunction was seen in proximal tubular epithelial cells incubated with septic serum with increased production of reactive oxygen species, and decreases in nicotinamide adenine dinucleotide and mitochondrial membrane potential. These effects were prevented by coincubation with the reactive oxygen species scavenger, 4-hydroxy-2,2,6,6-tetramethyl-piperidin-1-oxyl. Renal dysfunction in sepsis occurs independently of hemodynamic instability or structural damage. Mitochondrial dysfunction mediated by circulating mediators that induce local oxidative stress may represent an important pathophysiologic mechanism.


Deguelin exerts potent nematocidal activity via the mitochondrial respiratory chain.
As a result of limited classes of anthelmintics and an over-reliance on chemical control, there is a great need to discover new compounds to combat drug resistance in parasitic nematodes. Here, we show that deguelin, a plant-derived rotenoid, selectively and potently inhibits the motility and development of nematodes, which supports its potential as a lead candidate for drug development. Furthermore, we demonstrate that deguelin treatment significantly increases gene transcription that is associated with energy metabolism, particularly oxidative phosphorylation and mitoribosomal protein production before inhibiting motility. Mitochondrial tracking confirmed enhanced oxidative phosphorylation. In accordance, real-time measurements of oxidative phosphorylation in response to deguelin treatment demonstrated an immediate decrease in oxygen consumption in both parasitic (Haemonchus contortus) and free-living (Caenorhabditis elegans) nematodes. Consequently, we hypothesize that deguelin is exerting its toxic effect on nematodes as a modulator of oxidative phosphorylation. This study highlights the dynamic biologic response of multicellular organisms to deguelin perturbation.-Preston, S., Korhonen, P. K., Mouchiroud, L., Cornaglia, M., McGee, S. L., Young, N. D., Davis, R. A., Crawford, S., Nowell, C., Ansell, B. R. E., Fisher, G. M., Andrews, K. T., Chang, B. C. H., Gijs, M. A. M., Sternberg, P. W., Auwerx, J., Baell, J., Hofmann, A., Jabbar, A., Gasser, R. B. Deguelin exerts potent nematocidal activity via the mitochondrial respiratory chain.


Presentation of Autoantigen in Peripheral Lymph Nodes Is Sufficient for Priming Autoreactive CD8+ T Cells.
Peripheral tolerance is an important mechanism by which the immune system can guarantee a second line of defense against autoreactive T and B cells. One autoimmune disease that is related to a break of peripheral tolerance is diabetes mellitus type 1. Using the RIP-GP mouse model, we analyzed the role of the spleen and lymph nodes (LNs) in priming CD8+ T cells and breaking peripheral tolerance. We found that diabetes developed in splenectomized mice infected with the lymphocytic choriomeningitis virus (LCMV), a finding showing that the spleen was not necessary in generating autoimmunity. By contrast, the absence of LNs prevented the priming of LCMV-specific CD8+ T cells, and diabetes did not develop in these mice. Additionally, we found that dendritic cells are responsible for the distribution of virus in secondary lymphoid organs, when LCMV was administered intravenously. Preventing this distribution with the sphingosine-1-phosphate receptor antagonist FTY720 inhibits the transport of antigen to peripheral LNs and consequently prevented the onset of diabetes. However, in case of subcutaneous infection, administration of FTY720 could not inhibit the onset of diabetes because the viral antigen is already presented in the peripheral LNs. These findings demonstrate the importance of preventing the presence of antigen in LNs for maintaining tolerance.


Migration distance-based platelet function analysis in a microfluidic system.
Aggregation and adhesion of platelets to the vascular wall are shear-dependent processes that play critical roles in hemostasis and thrombosis at vascular injury sites. In this study, we designed a simple and rapid assay of platelet aggregation and adhesion in a microfluidic system. A shearing mechanism using a rotating stirrer provided adjustable shear rate and shearing time and induced platelet activation. When sheared blood was driven through the microchannel under vacuum pressure, shear-activated platelets adhered to a collagen-coated surface, causing blood flow to significantly slow and eventually stop. To measure platelet adhesion and aggregation, the migration distance (MD) of blood through the microchannel was monitored. As the microstirrer speed increased, MD initially decreased exponentially but then increased beyond a critical rpm. For platelet-excluded blood samples, there were no changes in MD with increasing stirrer speed. These findings imply that the stirrer provided sufficiently high shear to activate platelets and that blood MD is a potentially valuable index for measuring the shear-dependence of platelet activation. Our microfluidic system is quick and simple, while providing a precise assay to measure the effects of shear on platelet aggregation and adhesion.


Comparison of ultrashort echo time sequences for MRI of an ancient mummified human hand.
To compare the three different short-echo time (TE) pulse sequences ultrashort echo time (UTE), point-wise encoding time reduction with radial acquisition (PETRA), and single point imaging (SPI) for MRI of ancient remains. MRI of mummies is challenging due to the extremely low water content and the very short transverse relaxation times T2 *. To overcome the signal loss associated with the short T2 *, three pulse sequences with very short TEs were compared. MR images of an ancient mummified human hand were acquired at field strengths of 1.5 Tesla (T) and 3T using home-made solenoid Tx/Rx radiofrequency (RF) coils. In all MR images, tissues could be differentiated and anatomical structures such as bones and tendons were clearly identified. Skin with embalming resin was hyperintense in MRI, whereas it appeared iso-intense in computed tomography. PETRA has the highest signal to noise ratio. With UTE, short scan times and a homogeneous RF excitation can be achieved, and blurring is less pronounced than with PETRA. SPI shows no blurring artifacts; however, it requires long scan times. This work provided an initial analysis for the optimization of imaging protocols for paleoradiology studies with MRI, and, ultimately, for MRI of tissue with extremely short T2 *.


Eleven years of experience with extracorporeal cardiopulmonary resuscitation for paediatric patients with in-hospital cardiac arrest.
The study aims to describe 11 years of experience with extracorporeal cardiopulmonary resuscitation (ECPR) for in-hospital paediatric cardiac arrest in a university affiliated tertiary care hospital. Paediatric patients who received extracorporeal membrane oxygenation (ECMO) during active extracorporeal cardiopulmonary resuscitation (ECPR) at our centre from 1999 to 2009 were included in this retrospective study. The results from three different cohorts (1999-2001, 2002-2005 and 2006-2009) were compared. Survival rates and neurological outcomes were analysed. Favourable neurological outcome was defined as paediatric cerebral performance categories (PCPC) 1, 2 and 3. We identified 54 ECPR events. The survival rate to hospital discharge was 46% (25/54), and 21 (84%) of the survivors had favourable neurological outcomes. The duration of CPR was 39±17 min in the survivors and 52±45 min in the non-survivors (p=NS). The patients with pure cardiac causes of cardiac arrest had a survival rate similar to patients with non-cardiac causes (47% (18/38) vs. 44% (7/16), p=NS). The non-survivors had higher serum lactate levels prior to ECPR (13.4±6.4 vs. 8.8±5.1 mmol/L, p<0.01) and more renal failure after ECPR (66% (19/29) vs. 20% (5/25), p<0.01). The patients resuscitated between 2006 and 2009 had shorter durations of CPR (34±13 vs. 78±76 min, p=0.032) and higher rates of survival (55% (16/29) vs. 0% (0/8), p=0.017) than those resuscitated between 1999 and 2002. In our single-centre experience with ECPR for paediatric in-hospital cardiac arrest, the duration of CPR has become shorter and outcomes have improved in recent years. Higher pre-ECPR lactate levels and the presence of post-ECPR renal failure were associated with increased mortality. The presence of non-cardiac causes of cardiac arrest did not preclude successful ECPR outcomes. The duration of CPR was not significantly associated with poor outcomes in this study.


Granulomatous variants of cutaneous T-cell lymphoma. The histopathology of granulomatous mycosis fungoides and granulomatous slack skin.
Granulomatous mycosis fungoides is an unusual histologic variant of mycosis fungoides, a condition that is ordinarily indolent. Granulomatous slack skin, like granulomatous mycosis fungoides, shows epidermotropism, granulomatous inflammation, a clonal T-helper cell population, and progression to systemic lymphoma in some cases. Unlike granulomatous mycosis fungoides, it is characterized clinically by bulky, pendulous skin folds. The similarities between the two conditions prompted us to compare the histologic features. We reviewed 24 biopsies from 10 patients with granulomatous mycosis fungoides. These showed several distinct histologic patterns, including three cases that mimicked granuloma annulare. We also reviewed biopsy specimens from four patients with granulomatous slack skin. These specimens had a more stereotypic appearance, with permeation of the entire dermis and subcutis by lymphocytes, marked epidermotropism, and a more even distribution of granulomas and giant cells within the infiltrate. Biopsies of fully developed lesions of granulomatous slack skin showed elastolysis involving the full thickness of the dermis--a feature not seen in any of our granulomatous mycosis fungoides cases. Biopsy specimens from granulomatous mycosis fungoides and granulomatous slack skin may be mistaken for nonneoplastic granulomatous dermatitides, but they can usually be distinguished from these by the presence of epidermotropism or atypical lymphocytes. Because several of our patients with granulomatous mycosis fungoides died after courses of unremarkable length, it seems unlikely that the presence of granulomas is invariably correlated with a more benign course than nongranulomatous mycosis fungoides.


Estimating the additive benefit of surgical excision to stereotactic radiosurgery in the management of metastatic brain disease.
There are limited data on the benefits of surgical tumor resection plus stereotactic radiosurgery (SRS) in comparison with SRS alone for patients with oligometastatic brain disease. To determine the benefit of adding resection to SRS. We reviewed 162 consecutive patients with oligometastatic brain disease, who underwent surgical tumor resection and SRS boost (n = 49) or SRS alone (n = 113). Patients receiving prior whole brain radiation therapy were excluded. Factors related to patient survival and time-to-local recurrence (TTLR) were determined by Cox regression. The effect of complete resection + SRS boost on survival was further explored by propensity score matching. The average age of the cohort was 65.3 years, it was 49.4% female, and included 260 brain tumors, of which 119 tumors were single. Seventy-three brain tumors recurred (28%). TTLR was related to radiation-sensitive pathology (hazards ratio [HR] = 0.34, P = .001), treatment volume (HR = 1.078/mL, P = .002), and complete tumor resection (HR = 0.37, P = .015). Factors related to survival were age (HR = 1.21/decade, P = .037), Eastern Cooperative Oncology Group performance score (HR = 1.9, P = .001), and complete surgical resection (HR = 0.55, P = .01). Propensity score matched analysis of complete surgical resection + SRS boost (n = 40) vs SRS alone (n = 80) yielded nearly identical survival results (HR = 0.52, P = .030) compared with the initial unmatched sample. Incomplete tumor resection had both median survival and TTLR equivalent to SRS alone. Complete surgical resection + SRS boost is associated with improved survival and reduced likelihood of local tumor recurrence in comparison with SRS alone. Incomplete resection did not improve survival or TTLR compared with SRS alone.


Use of conditioned taste aversion as a conflict model: effects of anxiolytic drugs.
Moderate taste aversions were induced by pairing the initial consumption of 0.25% sodium saccharin (SACC) with either 25 mg/kg i.p. l-5-hydroxytryptophan or 30 mg/kg i.p. LiCl. The expression of these moderate conditioned SACC aversions was antagonized by pretreatments (i.p. or p.o.) with benzodiazepine and non-benzodiazepine anxiolytic drugs (lorazepam, diazepam, chlordiazepoxide, oxazepam, phenobarbital, meprobamate, and chlormezanone). Chlordiazepoxide produced less or no antagonism of the expression of stronger SACC aversions induced by 50 or 75 mg/kg l-5-hydroxytryptophan or by 60 or 90 mg/kg LiCl. Nonanxiolytic drugs, including dipsogenic compounds that increased the water intake of hydrated rats (2 M NaCl i.p.; isoproterenol HCl s.c.; and histamine diphosphate s.c.), and even additional 24 hr of fluid deprivation did not antagonize the expression of moderate conditioned taste aversions, indicating that anxiolytic drugs have a very selective effect and that they do not appear to act through homeostatic drinking mechanisms. An essential feature of the taste aversion conflict model is that thirsty rats encounter only SACC. When water was conspicuously available in addition to SACC in two-bottle tests, neither chlordiazepoxide nor phenobarbital antagonized the expression of conditioned taste aversion. Thus, anxiolytic drugs do not produce amnesia for the conditioned aversion, but attenuate the ability of conditioned SACC aversion to suppress SACC consumption in one-bottle tests. The antagonism of the expression of conditioned taste aversion measured with a one-bottle testing method offers a simple, sensitive, and selective screen for anxiolytic drugs. A possible mechanism by which anxiolytics increase both suppressed as well as unsuppressed fluid consumption is discussed.


The Flawed Reliance on Randomized Controlled Trials in Studies of HIV Behavioral Prevention Interventions for People Who Inject Drugs and Other Populations.
This article discusses ways in which randomized controlled trials do not accurately measure the impact of HIV behavioral interventions. This is because: 1. Such trials measure the wrong outcomes. Behavior change may have little to do with changes in HIV incidence since behavior change in events between HIV-concordant people have no impact on incidence. Even more important, the comparison of HIV incidence rates between study arms of individual-level RCTs does not measure the true outcome of interest-whether or not the intervention reduces HIV transmission at the community level. This is because this comparison cannot measure the extent to which the intervention stops transmission by HIV-infected people in the study to those outside it. (And this is made even worse if HIV-infected are excluded from the evaluation of the intervention.) 2. There are potential harms implicit in most cognitively oriented behavioral interventions that are not measured in current practice and may not be measurable using RCTs. Intervention trials often reinforce norms and values of individual self-protection. They rarely if ever measure whether doing this reduces community trust, solidarity, cohesion, organization, or activism in ways that might facilitate HIV transmission. 3. Many interventions are not best conceived of as interventions with individuals but rather with networks, cultures of risks, or communities. As such, randomizing individuals leads to effective interventions that diffuse protection through a community; but these are evaluated as ineffective because the changes diffuse to the control arm, which leads to systematic and erroneous reductions in the evaluated effectiveness as RCTs measure it. The paper ends by discussing research designs that are superior to individual-level RCTs at measuring whether an intervention reduces or increases new HIV transmission.


SEP spectral analysis of cholesterol rich rats.
In this study, twenty four albino rats, weighing between 180 and 200 g were tested. One half was fed with a diet containing 1% cholesterol for 12 weeks and the other half was fed with a normal lab diet for the same period. After the experimental period, the plasma cholesterol level in the diet group was 134.04 +/- 21.11 mg/dl compared with the control group 72.72 +/- 10.5 mg/dl. In the two groups, SEPs were recorded from central (Cz) referenced to frontal (Fz) following left posterior tibial nerve (PTN) stimulation. Amplitude spectra of SEPs were computed by Fast Fourier Transform (FFT) algorithm. Their amplitude maxima were found to occupy the frequency bands of 1-3.5, 4-5, 6-7, 8-10, 11-12, 13-20, 20.5-36 and 36 Hz and above. The decibel (dB) values of the maxima were statistically lower for hypercholesterolemia than for the normals in the all the frequency bands.


Gender differences in the field of sexology: new contexts and old definitions.
To analyze concepts of gender and sexuality present in the field of sex therapeutic interventions. An ethnographic observation was conducted, and it was completed with the analysis of printed material originated from the X Congresso Brasileiro de Sexualidade Humana (10th Brazilian Congress on Human Sexuality), promoted by the Sociedade Brasileira de Estudos em Sexualidade Humana (Brazilian Society of Human Sexuality Studies), and the VIII Congresso Brasileiro sobre Inadequações Sexuais (8th Brazilian Congress on Sexual Inadequacies), promoted by the Associação Brasileira para o Estudo das Inadequações Sexuais (Brazilian Association of Sexual Inadequacy Studies), both held in 2005. The analysis emphasized the interaction between the quantitative perspective in the processing of the variables (participants' gender and profession and lecture topics) and the qualitative perspective in the analysis and interpretation of the more general set of data. The topics of sessions and focus of presentations suggest that the field is divided by the contrast between two medical specialties: gynecology and urology, the former is aimed at female and couple dysfunctions, while the latter is aimed at male dysfunctions. Male sexuality is approached from the predominantly biomedical perspective, centered on the physiology of erection and drug prescription, whereas female sexuality is considered to be conditioned by relationship problems, when psychological intervention is more adequate.


The role of endovascular therapy in the treatment of acute ischemic stroke.
Of the approximately 795,000 strokes in the United States annually, 87% are ischemic and result in significant morbidity and mortality. Improvements in acute ischemic stroke (AIS) outcomes have been achieved with intravenous thrombolytics (IVT) and intra-arterial thrombolytics vs supportive medical therapy. Given its ease of administration, noninvasiveness, and most validated efficacy, IVT is the standard of care in AIS patients without contraindications to systemic fibrinolysis. However, patients with large-vessel occlusions respond poorly to IVT. Recent trials designed to select this population for randomization to IVT vs IVT with adjunctive endovascular therapy have not shown improvement in clinical outcomes with endovascular therapy. This could be due to the lack of utilization of modern thrombectomy devices such as Penumbra aspiration devices, Solitaire stent-trievers, or Trevo stent-trievers, which have shown the best recanalization results. Continued improvement in the techniques with using these devices as well as randomized controlled trials using them is warranted. This article defines the goals of AIS revascularization, presents the evolution of treatment from the initial use of IVT to modern thrombectomy devices, and discusses current treatment and ongoing AIS trials.


MicroRNAs as outcome predictors in patients with metastatic colorectal cancer treated with bevacizumab in combination with FOLFOX.
Bevacizumab is a humanized anti-vascular endothelial growth factor monoclonal antibody, used in combination with a oxaliplatin-based chemotherapy in the treatment of metastatic colorectal cancer (mCRC). The aim of the present study was to identify microRNA (miRNA)-based predictive biomarkers of therapy response in order to avoid unnecessary and costly therapy to non-responding patients. High-throughput miRNA microarray profiling (Affymetrix miRNA array) was performed on a discovery cohort of patients with mCRC. The discovery cohort was (n=20) divided into either responding (n=10) or non-responding (n=10) groups of bevacizumab/5-flourouracil, leucovorin, oxaliplatin (FOLFOX) treatment according to Response Evaluation Criteria in Solid Tumors criteria. Validation of candidate miRNAs was performed on an independent cohort of 41 patients with mCRC using quantitative reverse transcription polymerase chain reaction. Normalized data were subjected to receiver operating characteristic and Kaplan-Meier analyses. In total, 67 miRNAs were identified to be differentially expressed when miRNA expression was compared between responding and non-responding patients to bevacizumab/FOLFOX treatment (P<0.05). A total of 7 miRNAs were chosen for independent validation, which confirmed significantly higher expression of miR-92b-3p, miR-3156-5p, miR-10a-5p and miR-125a-5p (P<0.005) in tumor tissue of responding patients compared with non-reponding patients. Using the combination of miRNAs, the present study identified responders to the therapy with sensitivity 82% and specificity 64% (area under the curve = 0.8015). In conclusion, 4 predictive miRNAs associated with progression-free survival (PFS) were identified in patients with mCRC treated with bevacizumab/FOLFOX. Following further independent validations, detection of these miRNA may enable identification of patients with mCRC who may potentially benefit from the therapy.


Biomaterial evolution parallels behavioral innovation in the origin of orb-like spider webs.
Correlated evolution of traits can act synergistically to facilitate organism function. But, what happens when constraints exist on the evolvability of some traits, but not others? The orb web was a key innovation in the origin of >12,000 species of spiders. Orb evolution hinged upon the origin of novel spinning behaviors and innovations in silk material properties. In particular, a new major ampullate spidroin protein (MaSp2) increased silk extensibility and toughness, playing a critical role in how orb webs stop flying insects. Here, we show convergence between pseudo-orb-weaving Fecenia and true orb spiders. As in the origin of true orbs, Fecenia dragline silk improved significantly compared to relatives. But, Fecenia silk lacks the high compliance and extensibility found in true orb spiders, likely due in part to the absence of MaSp2. Our results suggest how constraints limit convergent evolution and provide insight into the evolution of nature's toughest fibers.


Phylogeography of a subterranean amphipod reveals cryptic diversity and dynamic evolution in extreme environments.
Extreme conditions in subsurface are suspected to be responsible for morphological convergences, and so to bias biodiversity assessment. Subterranean organisms are also considered as having poor dispersal abilities that in turn generate a large number of endemic species when habitat is fragmented. Here we test these general hypotheses using the subterranean amphipod Niphargus virei. All our phylogenetic analyses (Bayesian, maximum likelihood and distance), based on two independent genes (28S and COI), revealed the same tripartite structure. N. virei populations from Benelux, Jura region and the rest of France appeared as independent evolutionary units. Molecular rates estimated via global or Bayesian relaxed clock suggest that this split is at least 13 million years old and accredit the cryptic diversity hypothesis. Moreover, the geographical distribution of these lineages showed some evidence of recent dispersal through apparent vicariant barrier. In consequence, we argue that future analyses of evolution and biogeography in subsurface, or more generally in extreme environments, should consider dispersal ability as an evolving trait and morphology as a potentially biased marker.


Is Embryo Cryopreservation Causing Macrosomia-and What Else?
The number of embryos transferred during an IVF cycle is directly related to the high incidence of multiple births, which is the culprit of perinatal morbidity. Therefore, single fresh embryo transfer (ET) strategy, or freeze-all, followed by a single frozen-thawed embryo transfer (FET) cycle, may dramatically reduce the rate of multiple births, without compromising the cumulative live birth rates (LBRs). A literature review was conducted for all available evidences assessing obstetrics and perinatal outcomes associated with FET compared to fresh ET and natural conception. While studies comparing fresh and FET cycles in normal responders have yielded conflicting results for pregnancy rate, FET was associated with lower risk of prematurity and low birth weight and increased risk of large for gestational age (LGA) and/or macrosomic in singletons, when compared with fresh ET. Macrosomic/LGA births have a higher risk of fetal hypoxia, stillbirth, shoulder dystocia, perineal lacerations, cesarean section, postpartum hemorrhage and neonatal metabolic disturbances at birth. Nonetheless, it seems that other than higher risk of fetal macrosomia, there are additional obstetric complications associated with FET. The relative risk of hypertensive disorders in pregnancy, as well as perinatal mortality were also demonstrated to be increased in FET compared with singletons from fresh ET and natural conception. Therefore, when considering elective freeze-all policy, in addition to LBR and the risk of ovarian hyperstimulation syndrome, physicians should consider the aforementioned increased FET cycles' pregnancy complications, including LGA/ macrosomia, hypertensive disorders of pregnancy, as well as perinatal mortality.


Ventricular intramural and epicardial potential distributions during ventricular activation and repolarization in the intact dog.
Ventricular intramural and epicardial potential distributions were measured during normal excitation and repolarization in intact dogs. Potential distributions were chosen because they can be unambiguously measured, are useful in understanding the shapes of wave forms at many specific sites, and provide a direct measure of repolarization. Unipolar wave forms were recorded from intramural and epicardial electrodes and converted into potential distributions. Well-known shapes of wave forms recorded at the inner and outer layers of the ventricles as well as peak-to-peak voltages were shown by the potential distributions to be determined primarily by superposition effects of distant excitation waves. These effects were most prominent before epicardial breakthrough and then receded during the last half of the QRS complex. However, the potential distributions became more complex as excitation waves merged, collided, and terminated. During terminal depolarization, there were scattered positive repolarization potentials intramurally. Normal repolarization was characterized by positive potentials over the ventricular epicardium while there were changes intramurally and on the atrium. Throughout the T wave, there was a predominant transmural unidirectional gradient with the inner wall being more negative than the outer wall. This finding confirms that the sequence of repolarization is from the epicardium to the endocardium with the middle layers having an intermediate time.


Omega-3 fatty acids and cardiovascular disease: epidemiology and effects on cardiometabolic risk factors.
Clinical and epidemiological studies provide support that the polyunsaturated omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid from fish and fish oils are cardioprotective, particularly in the setting of secondary prevention. Omega-3 fatty acids benefit multiple cardiometabolic risk factors including lipids, blood pressure, vascular reactivity and cardiac function, as well as having antithrombotic, anti-inflammatory and anti-oxidative actions. Omega-3 fatty acids do not associate with any adverse effects and do not adversely interact with prescriptive drugs such as lipid-lowering, antihypertensive or hypoglycaemic medications. Clinical studies suggest that doses up to 4 g daily when prescribed with anticoagulant or antiplatelet drugs do not associate with increased risk of major bleeding episodes. Omega-3 fatty acids have gained widespread usage by general practitioners and clinicians in clinical settings such as pregnancy and infant development, secondary prevention in coronary heart disease patients and treatment of dyslipidaemias. Health authorities currently recommend an intake of at least two oily fish meals per week for the general population which equates to approximately 500 mg per day of eicosapentaenoic acid and docosahexaenoic acid. In patients with coronary heart disease the guidelines recommend 1 g daily supplements and in hypertriglyceridaemic patients up to 4 g per day. These doses are now achievable with readily available purified encapsulated preparations of omega-3 fatty acids. However, a more practical recommendation for increasing omega-3 fatty acid intake in the general population is to incorporate fish as part of a healthy diet that includes increased consumption of fruits and vegetables, and moderation of salt intake.


Response and relapse in patients with schizophrenia treated with olanzapine, risperidone, quetiapine, or haloperidol: 12-month follow-up of the Intercontinental Schizophrenia Outpatient Health Outcomes (IC-SOHO) study.
The primary aim of this study was to compare the effectiveness of 12 months' treatment with olanzapine, risperidone, quetiapine, or haloperidol in preventing relapse of schizophrenia. The study also examined other measures of clinical effectiveness and tolerability. Outpatients with schizophrenia (ICD-10 or DSM-IV), who initiated or changed antipsychotic treatment, entered this 3-year, naturalistic, prospective, observational study between November 2000 and December 2001. At baseline, subsets of patients were prescribed monotherapy with olanzapine (N = 3222), risperidone (N = 1116), quetiapine (N = 189), or haloperidol (N = 256). Patients remaining on monotherapy were assessed using the Clinical Global Impression-Schizophrenia scale. Relapse rate was determined from the responder subset. Treatment patterns, patient perception of treatment compliance, substance and alcohol intake patterns, and treatment tolerability were recorded. Results are based on 12-month treatment data. Compared to haloperidol-treated patients, olanzapine- and risperidone-treated patients had approximately 3 to 4 times higher odds of response at 12 months (p <or= .001) and 6 times lower odds of relapse (p <or= .001 for olanzapine-treated patients). Among patients treated with atypical antipsychotics, olanzapine- and risperidone-treated patients had lower odds of relapse (although the difference was not significant at p <or= .001) and significantly higher odds of response (p <or= .001) compared to quetiapine-treated patients. The tolerability profile generally favored the atypical antipsychotics over haloperidol. These interim results support the findings of randomized controlled trials and verify that in this naturalistic study, patients treated with olanzapine or risperidone monotherapy were less likely to experience relapse than patients who received haloperidol. The clinical effectiveness and tolerability profile varied significantly between the atypical antipsychotics.


The epidemiology of trauma-related mortality in the United States from 2002 to 2010.
Epidemiologic trends in trauma-related mortality in the United States require updating and characterization. We hypothesized that during the past decade, there have been changing trends in mortality that are associated with multiple public health and health care-related factors. Multiple sources were queried for the period of 2002 to 2010: the National Trauma Data Bank, the National Centers for Disease Control, the National Highway Traffic Safety Administration, the Nationwide Emergency Department Sample, and the US Census Bureau. The incidence of injury and mortality for motor vehicle traffic (MVT) collisions, firearms, and falls were determined using National Centers for Disease Control data. National Highway Traffic Safety Administration data were used to determine motor vehicle collision information. Injury severity data were derived from the Nationwide Emergency Department Sample and National Trauma Data Bank. Analysis of mortality trends by year was performed using the Cochran-Armitage test for trend. Time-trend multivariable Poisson regression was used to determine risk-adjusted mortality over time. From 2002 to 2010, the total trauma-related mortality decreased by 6% (p < 0.01). However, mortality trends differed by mechanism. There was a 27% decrease in the MVT death rate associated with a 20% decrease in motor vehicle collisions, 19% decrease in the number of occupant injuries per collision, lower injury severity, and improved outcomes at trauma centers. While firearm-related mortality remained relatively unchanged, mortality caused by firearm suicides increased, whereas homicide-associated mortality decreased (p < 0.001 for both). In contrast, fall-related mortality increased by 46% (5.95-8.70, p < 0.01). MVT mortality rates have decreased during the last decade, owing in part to decreases in the number and severity of injuries. Conversely, fall-related mortality is increasing and is projected to exceed both MVT and firearm mortality rates should current trends continue. Trauma systems and injury prevention programs will need to take into account these changing trends to best accommodate the needs of the injured population. Epidemiologic study, level III.


Effects of a classroom-based yoga intervention on cortisol and behavior in second- and third-grade students: a pilot study.
This uncontrolled pilot study examined the effects of a classroom-based yoga intervention on cortisol concentrations and perceived behavior in children. A 10-week Yoga 4 Classrooms intervention was implemented in one second-grade and one third-grade classroom. Students' salivary cortisol responses were assessed at 3 time points. Classroom teachers also documented their perceptions of the effects of the intervention on students' cognitive, social, and emotional skills. Second, but not third, graders showed a significant decrease in baseline cortisol from before to after the intervention. Second and third graders both showed significant decreases in cortisol from before to after a cognitive task, but neither grade showed additional decreases from before to after a single yoga class. The second-grade teacher perceived significant improvements in several aspects his/her students' behavior. The third-grade teacher perceived some, but fewer, improvements in his/her students' behavior. Results suggest that school-based yoga may be advantageous for stress management and behavior.


Solar energy utilization in the direct photocarboxylation of 2,3-dihydrofuran using CO2.
The conversion of CO2 into high energy products (fuels) and the direct carboxylation of C-H bonds require a high energy input. Energy cannot be derived from fossil carbon, in this case. Solar energy can be used instead, with a low environmental impact and good profit. We have studied the use of white light or solar energy in the photoreduction of CO2 and in photocarboxylation reactions, using different semiconductors modified at their surface. Two examples of reduction of CO2 to methanol and CO will be shortly discussed, and two cases of carboxylation of organic substrates. The case of carboxylation of 2,3-dihydrofuran will be discussed in detail.


Controlling deposition and release of polyol-stabilized latex on boronic acid-derivatized cellulose.
Poly(glycerol monomethacrylate)-stabilized polystyrene (PGMA-PS) latex particles undergo specific, pH-dependent adsorption onto regenerated cellulose film bearing surface phenylboronic acid groups (cellulose-PBA). Deposition occurs at pH 10 and is driven by the boronate ester formation with the polyol latex surface coating. In contrast, no deposition occurs at pH 4, and previously deposited particles can be readily desorbed at this lower pH. In control experiments, conventional anionic sulfate-stabilized polystyrene latex did not deposit onto the hydrophilic cellulose surface. The distribution of boronate groups in the cellulose was determined by exposure to Alizarin Red S dye, which forms a fluorescent complex with phenylboronic acid; confocal microscopy was used to determine a surface density of 3 nm(2) per boronic acid group on the cellulose surface. Although the boronic acid binding constant with PGMA is relatively low (5.4 L/mol), the cooperative interactions between multiple PBA surface sites and the many PGMA chains per latex particle are sufficient to induce specific latex adsorption, providing a convenient new tool for controlling nanoparticle deposition on surfaces.


Molecular responses to high-intensity interval exercise.
From a cell-signaling perspective, short-duration intense muscular work is typically associated with resistance training and linked to pathways that stimulate growth. However, brief repeated sessions of high-intensity interval exercise training (HIT) induce rapid phenotypic changes that resemble traditional endurance training. Given the oxidative phenotype that is rapidly upregulated by HIT, it is plausible that metabolic adaptations to this type of exercise could be mediated in part through signaling pathways normally associated with endurance training. A key controller of oxidative enzyme expression in skeletal muscle is peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha), a transcriptional coactivator that serves to coordinate mitochondrial biogenesis. Most studies of acute PGC-1alpha regulation in humans have used very prolonged exercise interventions; however, it was recently shown that a surprisingly small dose of very intense interval exercise, equivalent to only 2 min of all-out cycling, was sufficient to increase PGC-1alpha mRNA during recovery. Intense interval exercise has also been shown to acutely increase the activity of signaling pathways linked to PGC-1alpha and mitochondrial biogenesis, including AMP-activated protein kinase (alpha1 and alpha2 subunits) and the p38 mitogen-activated protein kinase. In contrast, signaling pathways linked to muscle growth, including protein kinase B/Akt and downstream targets p70 ribosomal S6 kinase and 4E binding protein 1, are generally unchanged after acute interval exercise. Signaling through AMP-activated protein kinase and p38 mitogen-activated protein kinase to PGC-1alpha may therefore explain, in part, the metabolic remodeling induced by HIT, including mitochondrial biogenesis and an increased capacity for glucose and fatty acid oxidation.


Du-Zhong (Eucommia ulmoides Oliv.) cortex extract prevent OVX-induced osteoporosis in rats.
Du-Zhong, rich in polyphenolic compounds such as lignans, phenolic acid, and flavonoids, is a kidney-tonifying herbal medicine with a long history of safe use for treatment of bone fractures and joint diseases in China. In the present study, we examined whether Du-Zhong cortex extract (DZCE) with graded doses exerted its preventive effects on estrogen deficiency-induced osteoporosis. Eighty 3-month-old female Sprague-Dawley rats were used and randomly assigned into sham-operated group (Sham) and five ovariectomy (OVX) subgroups, i.e. OVX with vehicle (OVX); OVX with 17alpha-ethinylestradiol (E(2), 25 microg/kg/day); OVX with DZCE of graded doses (100, 300, or 500 mg/kg/day). Daily oral administration of DZCE or E(2) started on week 4 after OVX for 16 weeks. Treatment with DZCE at higher doses (300 or 500 mg/kg/day) was found to be able to significantly prevent OVX-induced decrease in biomechanical quality of femur such as maximum stress and Young's modulus. The mechanical changes were associated with the prevention of a further bone mineral density (BMD) decrease or even with some improvements in microarchitecture. DZCE dose-dependently inhibited total BMD decrease in the femur caused by OVX, which was accompanied by a significant decrease in skeletal remodeling, as was evidenced by the decreased levels of the bone turnover markers osteocalcin (OC), alkaline phosphatese (ALP), deoxypyridinoline (DPD), and urinary Ca and P excretions. muCT analysis of the femoral metaphysis showed that DZCE at the highest doses (500 mg/kg/day) significantly prevents decrease in bone volume/tissue volume (BV/TV), connect density (Conn.D), trabecula number (Tb.N) and trabecula thickness (Tb.Th), and increase in trabecula separation (Tb.Sp) and structure model index (SMI) in OVX rats. We conclude that 16 weeks of DZCE treatment improves bone biomechanical quality through modifications of BMD, and trabecular microarchitecture without hyperplastic effect on uterus, and it might be a potential alternative medicine for treatment of postmenopausal osteoporosis.


Evaluation of an in-shoe pressure measurement system in horses.
To develop an objective, accurate method for quantifying forelimb ground reaction forces in horses by adapting a human in-shoe pressure measurement system and determine the reliability of the system for shod and unshod horses. 6 adult Thoroughbreds. Horses were instrumented with a human in-shoe pressure measurement system and evaluated at a trot (3 m/s) on a motorized treadmill. Maximum force, stance time, and peak contact area were evaluated for shod and unshod horses. Three trials were performed for shod and unshod horses, and differences in the measured values were examined with a mixed model ANOVA for repeated measures. Sensor accuracy was evaluated by correlating measured variables to clinically observed lameness and by a variance component analysis. 4 of 6 horses were determined to be lame in a forelimb on the basis of clinical examination and measured values from the system. No significant differences were observed between shod and unshod horses for maximum force and stance time. A significant decrease in peak contact area was observed for shod and unshod horses at each successive trial. Maximum force measurements provided the highest correlation for detecting lameness (r = 0.91, shod horses; r = 1.0, unshod horses). A variance component analysis revealed that 3 trials provided a variance of 35.35 kg for maximum force (+/- 5.78% accuracy), 0.007 seconds for stance time (+/- 2.5% accuracy), and 8.58 cm2 for peak contact area (+/- 11.95% accuracy). The in-shoe pressure measurement system provides an accurate, objective, and effective method to evaluate lameness in horses.


Design, synthesis, and evaluation of hydroxamic acid-based molecular probes for in vivo imaging of histone deacetylase (HDAC) in brain.
Hydroxamic acid-based histone deacetylase inhibitors (HDACis) are a class of molecules with therapeutic potential currently reflected in the use of suberoylanilide hydroxamic acid (SAHA; Vorinostat) to treat cutaneous T-cell lymphomas (CTCL). HDACis may have utility beyond cancer therapy, as preclinical studies have ascribed HDAC inhibition as beneficial in areas such as heart disease, diabetes, depression, neurodegeneration, and other disorders of the central nervous system (CNS). However, little is known about the pharmacokinetics (PK) of hydroxamates, particularly with respect to CNS-penetration, distribution, and retention. To explore the rodent and non-human primate (NHP) brain permeability of hydroxamic acid-based HDAC inhibitors using positron emission tomography (PET), we modified the structures of belinostat (PXD101) and panobinostat (LBH-589) to incorporate carbon-11. We also labeled PCI 34051 through carbon isotope substitution. After characterizing the in vitro affinity and efficacy of these compounds across nine recombinant HDAC isoforms spanning Class I and Class II family members, we determined the brain uptake of each inhibitor. Each labeled compound has low uptake in brain tissue when administered intravenously to rodents and NHPs. In rodent studies, we observed that brain accumulation of the radiotracers were unaffected by the pre-administration of unlabeled inhibitors. Knowing that CNS-penetration may be desirable for both imaging applications and therapy, we explored whether a liquid chromatography, tandem mass spectrometry (LC-MS-MS) method to predict brain penetrance would be an appropriate method to pre-screen compounds (hydroxamic acid-based HDACi) prior to PET radiolabeling. LC-MS-MS data were indeed useful in identifying additional lead molecules to explore as PET imaging agents to visualize HDAC enzymes in vivo. However, HDACi brain penetrance predicted by LC-MS-MS did not strongly correlate with PET imaging results. This underscores the importance of in vivo PET imaging tools in characterizing putative CNS drug lead compounds and the continued need to discover effect PET tracers for neuroepigenetic imaging.


Postactivation potentiation, fiber type, and twitch contraction time in human knee extensor muscles.
In small mammals, muscles with shorter twitch contraction times and a predominance of fast-twitch, type II fibers exhibit greater posttetanic twitch force potentiation than muscles with longer twitch contraction times and a predominance of slow-twitch, type I fibers. In humans, the correlation between potentiation and fiber-type distribution has not been found consistently. In the present study, postactivation potentiation (PAP) was induced in the knee extensors of 20 young men by a 10-s maximum voluntary isometric contraction (MVC). Maximal twitch contractions of the knee extensors were evoked before and after the MVC. A negative correlation (r = -0. 73, P < 0.001) was found between PAP and pre-MVC twitch time to peak torque (TPT). The four men with the highest (HPAP, 104 +/- 11%) and lowest (LPAP, 43 +/- 7%) PAP values (P < 0.0001) underwent needle biopsies of vastus lateralis. HPAP had a greater percentage of type II fibers (72 +/- 9 vs. 39 +/- 7%, P < 0.001) and shorter pre-MVC twitch TPT (61 +/- 12 vs. 86 +/- 7 ms, P < 0.05) than LPAP. These data indicate that, similar to the muscles of small mammals, human muscles with shorter twitch contraction times and a higher percentage of type II fibers exhibit greater PAP.


Primed innate immunity leads to autoinflammatory disease in PSTPIP2-deficient cmo mice.
The mouse Lupo (I282N) mutation in proline-serine-threonine phosphatase-interacting protein 2 (PSTPIP2) leads to reduced expression of PSTPIP2 that is associated with a macrophage-mediated autoinflammatory disease. Another mutation in PSTPIP2, L98P, termed chronic multifocal osteomyelits (cmo), leads to a disease in mice that resembles chronic recurrent multifocal osteomyelits in humans. The cellular basis of cmo disease was investigated. cmo disease develops independently of lymphocytes and is cured by bone marrow transplantation. Macrophages, mast cells, and osteoclasts from cmo mice fail to express detectable PSTPIP2 protein. Asymptomatic Pstpip2(cmo/cmo) mice have increased circulating levels of macrophage inflammatory protein 1-alpha and interleukin-6, and their macrophages exhibit increased production of these inflammatory mediators, which is normalized by retroviral expression of wild-type PSTPIP2. Spleens of asymptomatic cmo mice contain increased numbers of macrophage precursors, and cmo mice mobilize more macrophage precursors in response to a sterile inflammatory stimulus. Signal transducer and activator of transcription 1 is elevated in cmo splenic macrophages, which also exhibit increased colony-stimulating factor-1-stimulated proliferation and increased extracellular signal-regulated kinase 1/2 phosphorylation. PSTPIP2 overexpression in macrophages leads to the opposite phenotype. Thus, PSTPIP2 deficiency causes both an expansion of macrophage progenitors and increased responsiveness of mature macrophages to activating stimuli, which together prime the organism for exaggerated and sustained responses leading to autoinflammatory disease.


Comparison of two flow cytometric methods for detection of human invariant natural killer T cells (iNKT).
Invariant natural killer cells (iNKT) are an important immunoregulatory T cell subset. Currently several flow cytometry-based approaches exist for the identification of iNKT cells, which rely on using the 6B11 monoclonal antibody or a combination of anti-Valpha24 and anti-Vbeta11 antibodies. The aim of this study was to compare the ability of two flow cytometry-based methods for detecting the frequency of circulating iNKT cells. The frequency of iNKT cells was detected in the peripheral blood of 37 healthy adult donors by flow cytometry using the 6B11 antibody or a combination of anti-Valpha24 and anti-Vbeta11 antibodies. The frequency of iNKT cells detected by 6B11 antibody or by combination of anti-Valpha24 and anti-Vbeta11 antibodies was significantly different (0.54% vs. 0.31%, respectively, p<0.001) but the values were highly correlated (Spearman r = 0.742, p<0.0001). The results of this study indicate that different combinations of mAbs detect different frequencies of peripheral blood iNKT cells and a consensus in the field needs to be established to allow better assessment of iNKT-related studies and suggest using different methods for accurate identification of iNKT cells.


Inverse molecular design in a tight-binding framework.
The number of chemical species of modest molecular weight that can be accessed with known synthetic methods is astronomical. An open challenge is to explore this space in a manner that will enable the discovery of molecular species and materials with optimized properties. Recently, an inverse molecular design strategy, the linear combination of atomic potentials (LCAP) approach [J. Am. Chem. Soc. 128, 3228 (2006)] was developed to optimize electronic polarizabilities and first hyperpolarizabilities. Here, using a simple tight-binding (TB) approach, we show that continuous optimization can be carried out on the LCAP surface successfully to explore vast chemical libraries of 10(2) to 10(16) extended aromatic compounds. We show that the TB-LCAP optimization is not only effective in locating globally optimal structures based on their electronic polarizabilities and first hyperpolarizabilities, but also is straightforwardly extended to optimize transition dipole moments and HOMO-LUMO energy gaps. This approach finds optimal structures among 10(4) candidates with about 40 individual molecular property calculations. As such, for structurally similar molecular candidates, the TB-LCAP approach may provide an effective means to identify structures with optimal properties.


Health Insurance for "Humans": Information Frictions, Plan Choice, and Consumer Welfare.
Traditional models of insurance choice are predicated on fully informed and rational consumers protecting themselves from exposure to financial risk. In practice, choosing an insurance plan is a complicated decision often made without full information. In this paper we combine new administrative data on health plan choices and claims with unique survey data on consumer information to identify risk preferences, information frictions, and hassle costs. Our additional friction measures are important predictors of choices and meaningfully impact risk preference estimates. We study the implications of counterfactual insurance allocations to illustrate the importance of distinguishing between these micro-foundations for welfare analysis.


A two-stage storage routing model for green roof runoff detention.
Green roofs have been adopted in urban drainage systems to control the total quantity and volumetric flow rate of runoff. Modern green roof designs are multi-layered, their main components being vegetation, substrate and, in almost all cases, a separate drainage layer. Most current hydrological models of green roofs combine the modelling of the separate layers into a single process; these models have limited predictive capability for roofs not sharing the same design. An adaptable, generic, two-stage model for a system consisting of a granular substrate over a hard plastic 'egg box'-style drainage layer and fibrous protection mat is presented. The substrate and drainage layer/protection mat are modelled separately by previously verified sub-models. Controlled storm events are applied to a green roof system in a rainfall simulator. The time-series modelled runoff is compared to the monitored runoff for each storm event. The modelled runoff profiles are accurate (mean Rt(2) = 0.971), but further characterization of the substrate component is required for the model to be generically applicable to other roof configurations with different substrate.


Axonal degeneration, regeneration and ganglion cell death in a rodent model of anterior ischemic optic neuropathy (rAION).
Using laser-induced photoactivation of intravenously administered rose Bengal in rats, we generated an ischemic infarction of the intrascleral portion of the optic nerve (ON) comparable to that which occurs in humans to investigate optic nerve axon degenerative events following optic nerve infarct and the potential for axon re-growth. Animals were euthanized at different times post infarct. Axon degeneration was evaluated with SMI312 immunolabeling, and GAP-43 immunostaining was used to identify axon regeneration. Terminal dUTP nick end labeling (TUNEL) was used to evaluate retinal ganglion cell (RGC) death. There was significant axon structural disruptinot ion at the anterior intrascleral portion of the ON by 3d post-infarct, extending to the posterior ON by 7d post-stroke. Destruction of normal axon structure and massive loss of axon fibers occurred by 2 weeks. GAP-43 immunoreactivity occurred in the anterior ON by 7d post-infarct, lasting 3-4 weeks, without extension past the primary ischemic lesion. TUNEL-positive cells in the RGC layer appeared by 7d post-insult. These results indicate that following induction of ischemic optic neuropathy, significant axon damage occurs by 3d post-infarct, with later neuronal death. Post-stroke adult rat retinal ganglion cells attempt to regenerate their axons, but this effort is restricted to the unmyelinated region of the anterior ON. These responses are important in understanding pathologic process that underlies human non-arteritic anterior ischemic optic neuropathy (NAION) and may guide both the appropriate treatment of NAION and the window of opportunity for such treatment.


Factors associated with successful revascularization using the aspiration component of ADAPT in the treatment of acute ischemic stroke.
ADAPT (a direct aspiration first pass technique) has been shown to be fast, cost-effective, and associated with excellent angiographic and clinical outcomes in the treatment of acute ischemic stroke (AIS). To identify any and all preoperative factors that are associated with successful revascularization using aspiration alone. A retrospective review of 76 patients with AIS treated with thrombectomy was carried out. Cohort 1 included cases in which aspiration alone was successful (Thrombolysis in Cerebral Infarction 2b or 3). Cohort 2 included cases in which aspiration was unsuccessful or could not be performed despite an attempt. There was no difference between cohorts in gender, race, medications, National Institute of Health Stroke Scale score, IV tissue plasminogen activator, site or side of the occlusion, dense vessel sign, aortic arch type, severe stenosis, clot length, operator years of experience, and guide/aspiration catheters used. Patients in cohort 1 were on average younger (66.5 vs 74.1 years, p=0.025). There was a trend for more patients in cohort 2 to have atrial fibrillation/arrhythmias (62.5% vs 45.5%, p=0.168) and have a cardiogenic stroke etiology (78.1% vs 56.8%, p=0.086). There was also a trend for more reverse curves (2.3 vs 1.7, p=0.107), larger vessel diameter (3.26 mm vs 2.88 mm, p=0.184), larger vessel-to-catheter ratio (2.09 vs 1.87, p=0.192), and worse clot burden score (5.38 vs 6.68, p=0.104) in cohort 2. Aspiration success was associated with younger age. Our findings suggest that ADAPT can be used for the vast majority of patients but it may be beneficial to use a different method first in the elderly.


Phase II study of perifosine and sorafenib dual-targeted therapy in patients with relapsed or refractory lymphoproliferative diseases.
To evaluate safety and activity of perifosine and sorafenib combination therapy in patients with lymphoproliferative diseases. Patients with relapsed and refractory lymphoproliferative diseases received perifosine (50 mg twice daily) for 1 month. Patients achieving less than partial response (PR) after perifosine alone were administered the combination therapy [perifosine plus sorafenib (400 mg twice daily)] until progressive disease (PD) or unacceptable toxicity occurred. The pERK and pAKT in peripheral blood lymphocytes as well as serum cytokine levels were investigated as predictive biomarkers of response. Forty patients enrolled in this study. After 1 month of perifosine alone, 36 who achieved less than PR went on to combination therapy, whereas four patients with chronic lymphocytic leukemia (CLL) who achieved PR continued with perifosine alone for a median of 10 months (range, 4-21). The most common drug-related toxicities were grade 1-2 anemia (17%), thrombocytopenia (9%), diarrhea (25%), joint pain (22%), and hand-foot skin reaction (25%). Three patients experienced grade 3 pneumonitis. Eight patients (22%) achieved PR, 15 (42%) achieved stable disease, and 13 (36%) experienced PD. A 28% PR rate was recorded for 25 patients with Hodgkin lymphoma. Among all patients, median overall survival and progression-free survival were 16 and 5 months, respectively. Early reductions in pERK and pAKT significantly correlated with the probability of clinical response. Perifosine and sorafenib combination therapy is feasible with manageable toxicity and demonstrates promising activity in patients with Hodgkin lymphoma. The predictive value of pERK and pAKT should be confirmed in a larger patient cohort.


A Simon-like effect in Go/No-Go tasks performed in isolation.
The present study was conducted to decipher whether a spatial correspondence effect can emerge in Go/No-Go tasks (cSE, in reference to Donders' type c task) performed in isolation (participant alone in the cubicle). To this aim, a single participant was centrally positioned in front of a device and was required to respond by a hand key-press to the color of the stimulus. Half the participants were seated in front of a table equipped with only one response key and the other half in front of a table equipped with two response keys (one active and the other one useless). Using a substantial number of subjects (48) and trials (960), the present study revealed a numerically small but statistically reliable cSE. This result contrasts with referential coding predictions and suggests that the representation of a concurrently active response is not a prerequisite for the cSE to emerge. Moreover, the presence of a second response button in the participant's peripersonal space exerted no measurable influence on the cSE. The lack of statistical power of numerous previous studies may explain why the cSE has often been considered to be nil.